Epidemiology of Ocular Tumors 2013

Epidemiology of
Ocular Tumors in
Children and Adults
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Epidemiology of
Ocular Tumors in
Children and Adults
Tamara T Mouratova
Doctor of Medical Sciences
Professor
Ex-head of Uzbekistan’s Onco-ophthalmologic Centre and Ophthalmologic
Department of the Research
Institute of Oncology and Radiology of Uzbekistan’s Academy of Sciences
Emeritus Member of the Belgian Societies of Ophthalmology
Foreword
Veniamin V Volkov
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Epidemiology of Ocular Tumors in Children and Adults
First Edition: 2013
ISBN 978-93-5025-948-1
Printed at
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Dedicated to
My Mother
Valentina Efimovna Mouratova
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Foreword
Every expert ophthalmologist who treats patients with ocular tumors

would like to know how the disease develops, how much chance of
survival do patients with malignant ocular tumors have, which gender
suffers more frequently from various neoplasms, which countries have the
highest incidence of some ocular malignancies, what mortality rate is the
lowest with regard to one or other tumors, etc. An epidemiological study
can give answer to these and many other questions. However, the existing
information on incidence, mortality and survival rates of patients with
benign and malignant ocular tumors, especially in children, ranges widely;
and in some cases, one report contradicts the other.
The main purpose of this book is to show the wide spectrum of the
existing scientific views on age, gender, percentage, incidences, mortality and
survival rates of ocular tumors and the impacts of the environment on these
rates. The book collects the results of many international researchers and
compares international reports looking for epidemiological studies of benign
and malignant ocular tumors in children and adults with the results of own
epidemiological studies of these tumors in Uzbekistan. Moreover, very few
studies deal with such important problems as environmental impacts (e.g.
water and soil pollution, air emissions) on incidence and mortality of patients
with malignant ocular tumors. Until today, there have not been published
other studies on the subject. Author has also included chapter “Classification
of Ocular Tumors”, because a universal classification unifying both histological
and clinical signs of all ocular tumors still have not been established, therefore,
she has described the majority of ocular tumor classifications to give as more
information about ocular tumor classifications as possible. On the other hand,
to compare results of research work between each other, it is necessary to use
similar terms to be described in a classification and application of the similar
terms for medical experts internationally. Until today, there have not been any
published studies on the subject. The book is useful for clinical and scientific
Ophthalmologists, Oncologists, Pediatricians, Epidemiologists, Social Workers,
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viii Epidemiology of Ocular Tumors in Children and Adults
Specialists of environmental areas, Journalists who are interested in relationship

between incidence and mortality from malignant tumors and environment.
The book is also suitable for graduate and postgraduate students and for those
interested in epidemiology of ocular tumors.
Veniamin V Volkov
Doctor of Medical Sciences, Professor and Academician
Laser Academy of Sciences of the Russian Federation
Academy of Medico-Technical Sciences of the Russian Federation
Honoured Academician of Russian Academy of Natural Sciences
Honoured Scientist of Russian Federation
Honoured Doctor of Russian Military Academy
Hero of Socialist Labour
whose name is included into the Oxford IB Center Hall of Fame
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Preface
The idea of this book came to me many years ago but only now I have managed
to put it into life. Ocular tumors are not infectious diseases being the usual
topic of epidemiological studies. Nevertheless, research into the noninfectious
diseases like malignant and benign tumors of the eye and ocular adnexa
using epidemiological methods can reveal some uncontemplated aspects of
tumor development process both in children and adults. Since such studies
are essentially interdisciplinary crossing boundaries between ophthalmology,
oncology and epidemiology, there are a few scientists worldwide involved
with this topic. This is precisely why many epidemiological aspects in
ophthalmo-oncology are not adequately studied, despite that numerous books
on ophthalmology, oncology and especially ophthalmo-oncology contain
information on patient’s age, sex, number of patients with tumors in either
right or left eye, and localization of the tumor according of anatomical sites.
Yet there are still few studies of incidence, mortality and survival rates of
patients according to the anatomical localization of an eye tumor per certain
number of population, usually per 100,000 people. Clinical work even in large
eye hospitals does not allow getting definitive numbers of incidence, mortality
and survival rates of eye cancer patients, if one does not compare the cases
among similar population group in terms of age and sex, because percentage
frequently used in the relevant literature gives very rough picture which is
quite hard to compare with the results of other studies. As a consequence,
many reports do not often agree, or differ considerably or simply contradict
each other.
The main objective of the book is to show the whole range of variations in
numbers and views with regard to the epidemiology of the most commonly
encountered benign and malignant ocular tumors in children and adults. Our
research is based on the results of over 20 years’ work at the ophthalmological
department—one of the 11 clinical departments within the Research Institute
of Oncology and Radiology under Uzbekistan’s Academy of Sciences. The
department has been the only one in Uzbekistan with all necessary conditions
to diagnose and treat children and adults with all types of benign and malignant
tumors of the eye and its adnexa. In addition, I used my own professional
experience of over 30 years’ treatment of eye cancer patients. The book
provides comprehensive information on various factors such eyes and skin
color, age, gender, influence of ultraviolet radiation, cellular phones radiation
and environmental impacts on the development, incidence, mortality and
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x Epidemiology of Ocular Tumors in Children and Adults
survival of ocular tumors in different geographical areas and countries across

the globe comparing with the original results from Uzbekistan—the site of
one of the largest environmental catastrophes in the world history known as
the Aral Sea disaster. The most of our results were published in journals in
English, in my Doctoral dissertation and publications in Russian, which based
on my colleagues experience in the Institute of Oncology and Radiology of the
Uzbekistan’s Academy of Sciences, on my own more than 30 years’ experience
in this institute as the founder and Head of Department of Ophthalmology
and Head of Republic Onco-ophthalmological Center.
Tamara T Mouratova
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Acknowledgments
I am highly indebted to Professor Nariman Muratkhodjaev, Academician

of the Uzbekistan’s Academy of Sciences; Professor Alevtina Brovkina,
Academician of the Russian Academy of Medical Sciences; Professor Elena
Kremkova, Ophthalmological Chair of Russian State Medical University;
Professor Raimund Hennekes, Vrije Universiteit Brussel; Valery Votrin,
Environmental Resources Management (ERM); Ikhtibor Yuldasheva,
Candidate of Geographical Sciences, Scientific Secretary of the Central Asian
Regional Research Hydrometeorological Institute; Dr Galina Kozlovskaya, Dr
Marfua Nigmanova, Dr Damira Khakimova, Candidate of Medical Sciences;
Dr Naphisa Ubaidullaeva, Candidate of Medical Sciences, Department of
Ophthalmology, Research Institute of Oncology and Radiology of Uzbekistan’s
Academy of Sciences; Natalya Griva, Mentral Regional Computing Center;
Mikhail Chuprinin, the Institute of Nuclear Physics; Boris Konyukhov,
Candidate of Geographical Sciences, the State Committee of Natural
Protection; Alexei Tolmachev and Vladimir Rukavitsin for computer support,
to all of my colleagues in the Department of Ophthalmology and in IOR, to
my husband Guenrikh Votrin, my brother Alexander, our daughter Elena,
our son Valery, our grand-daughter Ester, our grandson Matvei and all of our
friends whose contribution made this book possible.
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Contents
1. Classification of Ocular Tumors 1

• Criteria for Suitability for Treatment 3
• Pathologic Staging of Retinoblastoma 4
2. Epidemiology of Ocular Tumors in Children 19

• Epidemiology of Benign Eyelids, Conjunctival,
Intraocular and Orbital Tumors 20
• Malignant Eyelid and Conjunctival Tumors 34
• Malignant Intraocular Tumors 38
• Malignant Orbital Tumors 68
3. Epidemiology of Ocular Tumors in Adults 77

• Epidemiology of Benign Eyelid, Conjunctival,
Intraocular and Orbital Tumors 77
• Malignant Eyelid Tumors 100
• Malignant Conjunctival Tumors 123
• Malignant Intraocular Tumors 143
• Malignant Orbital Tumors 177
• Malignant Ocular Tumors in Adults 198
Index 213
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CHAPTER 1
Classifications of Ocular Tumors
“A broadly accepted tumor classification system is a powerful clinical tool. It

helps to generate a roadmap for initial therapy; it provides clinicians with an
assessment of the likely prognosis before treatment begins; it allows prediction
of treatment morbidity; and it created the environment for the generation of
successful multicenter clinical trials.”
— A Linn Murphree1
There is a need for an uniform classification of any disease since common
terms used by such classification form a basis for mutual understanding among
experts in this area and in related areas, particularly when discussing various
issues in different languages. Without a classification of tumors, biological
measurements on individual tumor samples cannot be generalized to other
tumors and constitutive properties common to a class of tumors cannot be
distinguished from informative data collected from a complex and chaotic
biological system. By classifying tumors by lineage, problems arising from
molecular and morphologic tumor classifications can be resolved or posed as
testable hypothesis.2 For the last 30 to 40 years, the development of a uniform
histological classification has been an issue of special attention. World Health
Organization (WHO) got first involved in this issue in 1956 when the Executive
Committee passed the resolution proposing the Director General to consider
the establishment of the WHO reference centers in a number of countries that
would be involved in the collection of tumor tissues and their histological
classification.3 In 1958, WHO, in accordance with the resolution approved by
the World Health Assembly4 set-up 23 Reference Research Centers for tumors
of various localizations, including ocular tumors. Apart from the publication of
books and microphotographs for them, a Cooperating Center also prepares up
to 100 sets of tissue specimens for the national pathologists’ societies. In 1972,
the WHO Reference Center for the histological classification of the ocular
tumors and its adnexa was organized within the Armed Forces Institute of
Pathology, Washington DC, US. In 1980 at first in English, and then in 1984 in
Russian by LE Zimmerman in collaboration with LH Sobin, pathologists of the
World Health Organization and with pathologists of 13 country International
Histologic Classification of tumors No 24 with Histological Typing of
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2 Epidemiology of Ocular Tumors in Children and Adults
Tumors of the eye and its adnexa was published.5 It emphasized the fact that
different terms are frequently used to name the same pathologic process and,
vice versa, one term is used to signify different lesions. The internationally
accepted classification of tumors, equally acceptable for physicians, surgeons,
radiologists, pathologists, and statisticians, provides a possibility for
oncologists from all countries to compare the data and facilitates collaboration
between them. The Histological Classification, which has been the result of
teamwork of the most prominent specialists from different countries is not
only the unification of terminology, but also presents microphotographs,
which help pathologists in the formulation of morphological diagnosis. It
considers if a tumor grows from epithelial, pigment, soft tissue or bone tissues,
which are subdivided into benign, precancerous and malignant. Furthermore,
tumor-like lesions such as pterygium, cheloid and inflammatory tumor-like
diseases (e.g. spring, lingnous and papillary conjunctivitis, dacryocystitis and
or canaliculitis) are also represented.
The WHO has embarked on a new project entitled World Organization
Classification of Tumors. This is a continuation of the International
Histological Classification of Tumors, which produced two series of WHO
series continues to standardize the classification of tumors and, in addition
to providing histologic criteria, will include information on molecular
genetics, which are increasingly important in the typing on human cancers
and as predictive factors for response to therapy and for clinical outcome.
In spite on that the first and the second volume have not include ocular
tumors, this project is to cover all tumor sites within next 5 years. Authors
are committed to making the new WHO “Blue Books” the standard reference
for tumor classification world and reliable basis for communication among
pathologists, clinicians, and the basic cancer research community.6
Ophthalmologists, oncologists and pathologists of Russia developed the
classification of ocular tumors,7 which divides all neoplasms into benign,
locally invasive and precancerous, and malignant tumors taking into account
their localization: A—eyelids, conjunctiva and cornea; B—inside the eyeball
and C—the orbit. The tissue from which a tumor arises (e.g. epithelial, pigment,
soft tissue, optic nerve or bone tissues) is also taken into account. The most
distinct section in this classification is Locally Invasive Tumors. Some tumors
described in this section (e.g. hemangiopericytoma) are classified as benign
tumors by Histological Typing, which does not classify tumors as locally
invasive. In clinical practice however, tumors are often classified depending on
their size. So, uveal melanoma is divided into:
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Classifications of Ocular Tumors 3
1. Small: range from 1.0 to 3.0 mm in apical height and 5.0 to 16 mm in
largest basal dimension.8,9
2. Medium: range from 2.0 to 3.0 mm up to 10 mm in apical height and have
a basal diameter of less than 16 mm.9,10
3. Large: greater than 10 mm in apical height or have a basal diameter of at
least 16 mm.11
4. Diffuse: horizontal, flat growth pattern, with thickness of the tumor
measuring approximately 20.0 percent or less than the greatest basal
dimension; this uncommon variant of uveal melanoma seems to have a
poorer prognosis.12
The tumor base may be estimated in average optic disk diameter (1 dd – 1.5
mm). The average elevation may be estimated in diopters (3 diopters = 1 mm).
Other techniques should be used to provide more accurate measurements.12
The Reese-Ellsworth (R-E) classification of retinoblastoma13,14 is a method
to predict prognosis of treated eyes to save or preserve the eye. The higher the
Group member in the system, the poorer the chance is for saving the eye.
CRITERIA FOR SUITABILITY FOR TREATMENT

Group I–Very favorable.
a. Solitary tumor, less than 4 disk diameter (dd) in size, at or behind the
equator.
b. Multiple tumors, none over 4 dd in size, all at or behind the equator.
Group II–Favorable.
a. Solitary tumor, 4 to 10 dd in size, at or behind the equator.
b. Multiple tumors, 4 to 10 dd in size, behind the equator.
Group III–Doubtful.
a. Any lesion anterior to the equator.
b. Solitary tumors larger than 10 dd in size benign the equator.
Group IV–Unfavorable.
a. Multiple tumors, some larger than 10 dd.
b. Any lesions extending anteriorly to the ora serrata.
Group V–Very unfavorable.
a. Massive tumors involving over half the retina.
b. Vitreous seeding.
But Reese-Ellsworth classification does not predict extraocular
retinoblastoma and in 1987, Grabowski and Abramson published staging
system for extraocular retinoblastoma:15
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PATHOLOGIC STAGING OF RETINOBLASTOMA

Stage Description
I Intraocular disease
a. Retinal tumor, single or multiple
b. Extension to lamina cribrosa
c. Uveal extension
II Orbital disease
a. Orbital tumor
1. Scattered episcleral cells
2. Tumor mass
b. Optic nerve
1. Distal nerve; line of section and meninges clear
2. Tumor at line of section or in meninges
III Intracranial metastasis
a. Positive cerebrospinal fluid alone
b. Mass lesion in central nervous system
IV Hematogenous metastasis
a. Positive bone marrow alone
b. Focal bone lesion with or without positive marrow
c. Other organ involvement
Grabowski-Abramson pathologic staging system of retinoblastoma also
published as Abramson Staging System for retinoblastoma16 and it is possible
to compare both systems.
Abramson Staging System for Retinoblastoma

1. Intraocular disease
a. Retinal tumors
b. Extension into choroids
c. Extension up to lamina cribrosa
d. Extension into sclera
2. Orbital disease
a. Orbital tumor
1. Suspicious (pathology of scattered episcleral cells)
2. Proven (biopsy-proven orbital tumor)
b. Local nodal involvement
3. Optic nerve disease
a. Tumor beyond lamina cribrosa but not up to cut section
b. Tumor at cut section of optic nerve
4. Intraocular metastasis
a. Positive CSF only
b. Mass CNS section
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5. Hematogenous metastasis
a. Positive bone marrow lesions
b. Other organ involvement
In 2005, this System was changed with participation of Grabowski,17
because to authors opinion patients are classified according to extent of disease
and the presence of overt extraocular extension. A proposal for substaging
considering histopathological features of enucleated specimens is presented to
further discriminate between Stage I and Stage II patients. The following is a
summary of the classification system developed:
Stage 0: Patients treated conservatively (subject to presurgical
ophthalmologic classification)
Stage I: Eye enucleated, completely resected histologically
Stage II: Eye enucleated, microscopic residual tumor
Stage III: Regional extension [(a) overt orbital disease, (b) preauricular or
cervical lymph node extension]
Stage IV: Metastatic disease
[(a) hematogenous metastasis: (1) single lesion, (2) multiple lesions;
(b) CNS extension: (1) prechiasmatic lesion, (2) CNS mass, (3)
leptomeningeal disease].
A proposal is also presented for substaging of enucleated Stages I and II
eyes.
Another staging system attempted to relate the extent of the tumor
within and outside the eye.1 There are four stages of tumor involvement in
this classification are recognized: retinal (I), intraocular (II), regional (III)
and metastatic (IV). Stage I and Stage IIA may be based on ophthalmologic
findings only, although any enucleated eye where tumor is confined to the
retina would also classified in three stages. Stage IIB and beyond are the result
of histologic examination of the globe and clinical evaluation of regional and
metastatic tumor involvement. For comparative purposes, Stages IM and IIA
on this system would be the equivalent of Reese-Ellsworth classification Group
IV and V. The treatment of patients modifying in the latter report depends on
staging groups.18,19 The St Jude Staging System for retinoblastoma has been
used for a number of years and in 1997 was updated.1
The 1997 modified St Jude Staging System for retinoblastoma:
Stage I–Tumor Confined to the Retina

A. <6 DD
B. Multiple lesions, all <6 DD
C. Solitary or multiple lesions involving <50 percent of the retina behind the
equator.
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Stage II–Tumor Confined to the Globe/ Extraretinal

A. Extends to optic nerve head
B. Extends to choroids
1. Extends to choroid
2. Extends to choroids with replacement
C. Anterior chamber involvement
D. Extending to choroids and optic nerve head
E. Extending to choroids (1 or 2) and optic nerve
Stage III–Extrachoroidal Extension

A. Extends to emissaries
B. Extends beyond out end of optic nerve (including subarachnoid)
C. Extends through sclera into orbit
D. Extends to choroids (1 or 2) and beyond out end of optic nerve (includes
subarachnoid)
E. Extends through sclera and out end of the optic nerve
Stage IV–Distant Disease

A. Extends through optic nerve into brain (includes cerebrospinal fluid)
B. Blood-borne metastases to soft tissues, nodes, or bone
C. Bone marrow metastases
This system incorporates the natural history of intraocular retinoblastoma
using histologic data gained from enucleated specimens and clinical
information about the extend of the disease from the medical record. The
current Reese-Ellsworth group classification has not been updated since it was
first published 35 years ago. In 2001, the newly organized Children’s Oncology
Group created a standing Retinoblastoma Disease Committee to develop
clinical trial protocols. Observation on the natural history of intraocular
retinoblastoma and outcome data analysis from patients treated at Children
Hospital, Los Angeles led to the generation on this classification as well as
several other retinoblastoma centers in the United States, Canada, France,
Switzerland, and Mexico—also have been evaluating the system clinically.
There is proposed new group classification for intraocular retinoblastoma:1
Group A–Very Low Risk

Eyes with small discrete tumors away from critical structures. All tumors are
3 mm or staller, confined to the retina, and located at least 3 mm from the
foveola and 1.5 mm from the optic nerve. No vitreous or subretinal seeding is
allowed.
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Group B–Low Risk
Eyes with no vitreous or subretinal seeding and discrete retinal tumor of any
size of location. Retinal tumors may be of any size of location not in Group A.
No vitreous or subretinal seeding allowed. A small cuff of subretinal fluid
extending no more tumor is allowed.
Group C–Moderate Risk

Eyes with only focal vitreous or subretinal seeding and discrete retinal tumors
of any size and location. Any seeding must be local, fine, and limited so as to
be theoretically treatable with a radioactive plaque. Retinal tumors are discrete
and of any size, and location. Up to one quadrant of subretinal fluid may be
present.
Group D–High Risk

Eyes with diffuse vitreous or subretinal seeding and/or massive, nondiscrete
endophytic or exophytic disease. Eyes with more extensive seeding than
Group C. Massive and/or diffuse intraocular disseminated disease may consist
of “fine” or “greasy” vitreous seeding or avascular masses. Subretinal seeding
may be plaque-like, includes exophytic disease and more than one quadrant of
retinal detachment.
Group E–Very High Risk Eyes with Any One or More of the Following
Eyes, that have been destroyed anatomically or functionally by the tumor. Eyes
with one or more of the following: irreversible neovascular glaucoma, massive
intraocular hemorrhage, aseptic orbital cellulitis, tumor anterior to anterior
vitreous face, tumor touching the lens, diffuse infiltrating retinoblastoma,
phthisis or pre-phthisis.
New group classification for intraocular retinoblastoma ranks tumor
groups for the risk of treatment failure and enucleation or external beam
radiation therapy by specific morphologic features and the extent of disease
in the eye at initial diagnosis. Its ordered groups from early disease (group
A) to late disease (group E), group A eyes have the lowest risk of treatment
failure, whereas group E eyes have the highest risk. The other groups have
intermediate risk between groups A and E. Like the Reese-Ellsworth group
classification, this group classification addresses only the risk for loss of the
eye. It is not a staging system for the disease in the child, and it does not address
the risk to the child from retinoblastoma. According to author’s experience,
undertreating an eye is a frequent cause of failure to salvage that eye.1
Yang et al.20 morphologically divided the choroidal invasion of
retinoblastoma into four stages:
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Stage I: Only retinal pigment epithelium involved, the Bruch’s membrane

was intact.
Stage 2: The Bruch’s membrane was destroyed and the choroidal capillaries
were not infiltrated.
Stage 3: Choroidal capillary and middle blood vessel layer in small limits
were infiltrated.
Stage 4: Invasion involved in choroids in great limits and involvement of
sclera existed simultaneously.
That classification (also called pigment epithelium-choroid stage, PEC
- stage) reflected both infiltrated procedure of tumor cells and preventive
mechanism in eye and morphological criterion half-quantitatively. Authors
find that it can be used as a united standard to compare the infiltration degree
of retinoblastoma among different individuals and different studies.
The practice of dividing cancer cases into groups according to so-called
“Stages” arose from the fact that survival rates were higher for cases, in which
the disease had extended beyond the organ of origin. These groups were often
referred to as “early cases” and “late cased” implying some regular progression
with time. Actually, the stage of disease at the time of diagnosis may be a
reflection not only of the rate of growth and extension of the neoplasm but also
of the type of tumor and of the tumor-host relationship.21 This system is TNM
system, which is here in a short variant and which describes the anatomical
extend disease basing on the assessment of three components:
T – The extend of the primary tumor
N – The condition of the regional lymph nodes and in certain regions of the
juxta-regional lymph nodes
M – The absence of presence of distant metastasis
The addition of numbers of these three components indicates the extending
of the malignant disease, thus: T0, T1, T2, T3, T4; N0, N1, N2, N3, N4; M0,
M1.
Other supplementary symbols are also used for specific purposes. Pre-
Treatment Clinical classification is designated as pTNM. Histopathological
Grading in pTNM has symbol G (G1–High degree of differentiation, G2–
Medium degree of differentiation, G3–Low degree of differentiation, GX–
Grade cannot be assessed). Scleral invasion has symbol S (S0–No exidence
of scleral invasion, S1–Evidence of intrascleral invasion, S2–Evidence of
extrascleral invasion, SX–Scleral invasion cannot be assessed). Venous
invasion has symbol V (V0–No evidence of venous invasion, V1–Veins
in melanoma contain tumor, V2–Vortex vein contain tumor, VX–Venous
invasion cannot be assessed). Symbol y is used in those cases, in which
definitive surgery is performed after treatment by other methods, the pTNM
categories may be identified by a “y” prefix, e.g. ypT2pnlpM0. These cases
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must be reported separately. Symbol r is used in cases of recurrent tumors
and placed before the appropriate TNM or pTNM category. Named the Level
of Certainly or C–Factor, it reflects the information available at a point in the
time and according to the diagnostic methods employed (C1–Evidence from
clinical examination only, C2–Evidence obtained by special diagnosis means,
C3–Evidence from surgical exploration only, C4–Evidence of the extent of
disease following definitive surgery and including the complete examination
of the therapeutically resected specimens, C5–Evidence from autopsy). For
example, the case might be described as T3C2, N2C1, M0C2. Classification
by the TNM system achieves reasonably precise description and recording of
the apparent anatomical extent of disease. The classification applies only to
carcinoma and malignant melanoma of eyelid, to carcinoma and malignant
melanoma of conjunctiva, to malignant melanoma of uvea (iris, ciliary body
and choroidea). According to TNM classification retinoblastoma occupying
more than 50 percent of the retina and/or with extension beyond the retina,
but remaining intraocular has symbol a, b and c:
T3a Tumor(s) occupying more than 50 percent of the retina and/or clumps
of tumor cells in the vitreous.
T3b Involvement of the optic disk.
T3c Involvement of anterior chamber and/or of uvea.
T4 Tumor with extraocular extension.
T4a Extension into the retrobulbar optic nerve.
T4b Extension other than into the optic nerve.
The following suffixes may be added to the appropriate T Categories:
(m) to indicate multiple tumors, e.g. T2(m).
(f) to indicate cases with a known family history.
(d) to indicate diffuse retinal involvement without the formation of discrete
masses.
There is no stage grouping for carcinoma of eyelid at present
recommendation. For malignant melanoma of eyelid stage grouping for
example is: stage la–pT1, pT2, pN0, pM0; stage lb–p3, pT4, pN0, pM0, etc.
For carcinoma and malignant melanoma of conjunctiva no stage grouping is
at present recommended. For malignant melanoma of iris and ciliary body
Stage I is T1N0M0; Stage II–T2N0M0; Stage III–T3N0M0, etc. The TNM
classification allows dimensions of tumors in pTNM postsurgical classification
(for example for malignant melanoma of conjunctiva pT1 corresponds to T2
when tumor is 2 mm or less in thickness; pT3 corresponds to T1 or T2 when
tumor is more than 2 mm in thickness, etc. The general rules applicable to
all sites are as follows: 1. All cases should be confirmed histologically. Any
cases not so proved must be reported separately, 2. The TNM categories, once
Ch-01.indd 9 31-08-2012 12:29:59

established, must remain unchanged, 3. After assigning T, N and M categories,

with degrees of extension these may be grouped into clinical stages, etc.
The TNM classification united results of clinical and histological
investigations. In some tumors, this system can recommend to use stage
grouping. According to TNM classification it is possible to compare results
with and without treatment.22,23 However, an universal classification unifying
both histological and clinical symptoms of all benign and malignant ocular
tumors still has not been established.
TNM revisions have been published in 1987, where ophthalmic tumors
except for changes in melanoma of the eyelid made to conform to melanoma
of the skin, the classification of the various sites in this group are unaltered24 in
1997 the T categories of soft tissue sarcomas have been divided into superficial
and deep tumors;25 and most recently the TNM classification in 2002 was
revisioned.26
Kujala and Kivela27 evaluated how the 6th edition (TNM6) improves on
the previous one (TNM5). Two hundred eighty-nine consecutive patients with
a ciliary body and choroidal melanoma in the period between 1962 and 1981
were revised. The authors found that TNM6 is an improvement over TNM5 in
some, but not all, respects. Areas for development include taking into account
ciliary body involvement and extraocular extension in more detail and
combining into each stage tumor categories with similar rather than different
prognosis. Some ophthalmologists28 use the Clark method assesses the level of
penetration into the various skin layers by melanoma:
Level I: Confined to the epidermis (in situ)
Level II: Invasion into the papillary dermis
Level III: Penetration to the papillary-reticular interface
Level IV: Invasion into the reticular dermis
Level V: Penetration into subcutaneous fat
Others29 used the Breslow microstaging method measures the thickness of
the cutaneous lesion in millimeters with ocular micrometer. The total vertical
height of the melanoma is measured from the superficial layers to the area of
deepest penetration. If the lesion is ulcered, measurements are made from the
surface of the ulcer to the deepest part of the lesion:
Thickness 0.75 mm or less
Thickness 0.76 mm to 1.50 mm
Thickness 1.51 mm to 4.0 mm
Thickness 4.0 mm or greater
The Clinical Staging System adopted by the American Joint Committee
on Cancer on the basis of the Clark’s classification can be used to malignant
melanomas of the eyelid and conjunctiva:
Ch-01.indd 10 31-08-2012 12:29:59

Stage Criteria
IA Localized melanoma <0.75 mm or Clark level II
IB Localized melanoma 0.76 to 1.5 mm or level III
IIA Localized melanoma 1.5 to 4.0 mm or level IV
IIB Localized melanoma >4.0 mm or level V
III Limited nodal metastasis involving only one regional lymph node basin, or fewer
than 5 in transit metastasis without nodal metastasis
IV Advanced regional metastasis or any patient with distant metastasis
In the literature, there is no classification for lacrimal sac melanoma,

therefore some authors use the NOSPECS classification scheme,30 which was
introduced by Werner in 1969 for signs and symptoms of Graves orbitopathy.31
This classification is common mnemonic and means N–no signs or symptoms;
O–only signs (lid retraction/lag/edema); S–soft tissue swelling; P–proptosis;
E–extraocular muscle involvement; M–corneal exposure; S–sign loss.32
The Developmental Lineage Classification and Taxonomy of Neoplasms
group found that tumors of a common developmental lineage will share
common metabolic pathways and common responses to drugs that target these
pathways and that grouping tumors according to their developmental lineage
can reconcile certain fundamental discrepancies resulting from morphologic
and molecular approaches to neoplasm classification. There is growing rift
between morphologic and molecular approaches to tumor classification:
1) the morphologic separation between epithelial and nonepithelial tumors;
2) the grouping of tumors based on shared cellular functions; 3) the distinction
between germ cell tumors and pluripotent tumors of non-germ origin; 4) the
distinction between tumors that have lost their differentiation and tumors
that arise from uncommitted stem cells; 5) the molecular properties shared by
morphologically disparate tumors that have a common developmental lineage
and 6) the problem of re-classifying morphologically identical but clinically
distinct subsets of tumor.2,33 For over 150 years, pathologists have relied on
histomorphology to classify and diagnose neoplasms. Their success has been
stunning, permitting the accurate diagnosis of thousands types of neoplasms
using only microscope and a trained eye.2,33 Cancer researchers need in a way
that others can find, build upon, and relate to the specific clinical conditions of
individual patients.34 Ever-improving diagnosis methods, based increasingly
on genetic studies and pathologic studies have prompted a third edition of
the ICD-0 (International Classification of Disease for Oncology), which
introduced numerous new morphology codes.35 Basing on the ICD-0-3, the
third edition of International Classification of Childhood Cancer (ICCC-3)
was proposed and for example, retinoblastoma has morphologically code
9510-9514, and rhabdomyosarcomas have code 8900-8905, 8910, 8912, 8920,
8991. Primary orbital rhabdomyosarcoma histologically can be embryonal,
Ch-01.indd 11 31-08-2012 12:29:59

alveolar and other types.5 However, Volpe and Jacobec36 believe that this
malignant tumor can be divided into three main types: embryonal, alveolar
and pleomorphic. Rhabdomyosarcoma can be also divided into four staging
groups according to Intergroup Rhabdomyosarcoma Study:37
Group 1 Localized disease, completely resected
Group 2 Regional disease, with or without lymph nodes, grossly resected
Group 3 Incomplete resection or biopsy with gross residual disease
Group 4 Distant metastases (lung, bone marrow and brain)
Classification schemes of lymphomas which is also used in ophthalmologic
practice have evolved with time from those based on morphology alone such
as the Working Formulation38 to the most recent proposed World Health
Organization (WHO) Classification39 and its precursor, Revised European
American Lymphoma Classification (REAL),40,43 which incorporate clinical
features and ancillary laboratory investigations such as immunophenotyping
and genotyping in addition to the histopathological findings.41
Cahill et al.42 have compared of selected subtypes in REAL classification,40
Working Formulation38 and Updated Kiel classification as follows:43
REAL classification40 Working Formulation38 Updated Kiel classification43

Extranodal marginal zone B Small lymphocytic*. No equivalent
cell lymphoma (low grade B Diffuse, small cleaved cell.
cell lymphoma of MALT type) Diffuse, mixed small and
large cell
Lymphoplasmacytoid Small lymphocytic Lymphoplasmacytic
lymphoma plasmocytoid immunocytoma
Diffuse, mixed small and
large cell
Follicular center lymphoma, Diffuse, small cleaved cell Centroblastic-centrocytic,
diffuse, small cell follicular Follicular, predominantly diffuse
center lymphoma, follicular small, large, or mixed cells Centroblastic-centrocytic,
follicular
Follicular, mixed small and
large cells
Follicular, predominantly
large cell
Diffuse large B cell lymphoma Diffuse, large cell Centroblastic or B
Large cell immunoblastic immunoblastic
large cell
Mantle cell lymphoma Diffuse, small cleaved cell Centrocytic, centroblastic,
Small lymphocytic centrocytoid subtype
...Contd.
Ch-01.indd 12 31-08-2012 12:29:59

...Contd.
Follicular, small cleaved cell
large cell
Diffuse, large cleaved cell
Peripheral T cell lymphoma, Diffuse, mixed small and Pleomorphic, medium sized
unspecified large cell and large T cell
*When REAL category is equivalent to more than one working formulation or updated Kiel
category, italicized category comprises the majority of cases
A prognosis related classification for radiation retinopathy is the Finger

classification:44
Stage Sign Symptom Location Best viewed Risk of vision
by loss
1 Cotton-wool spots None Extramacular Ophthalmoscopy Mild
Retinal hemorrhages None Extramacular Ophthalmoscopy Mild
Retinal microaneurysms None Extramacular Ophthalmoscopy Mild
Ghost vessels None Extramacular Ophthalmoscopy Mild
Exudate None Extramacular Ophthalmoscopy Mild
Uveal effusion None Extramacular Ophthalmoscopy Mild
Chorioretinal atrophy None Extramacular Ophthalmoscopy Mild
Choroidopathy None Extramacular Angiography Mild
Retinal ischemia (<5DA) None Extramacular Angiography Mild
2 Above findings None Macular Both Moderate
3 Any combination of the
above plus
Retinal neovascularization VL Extramacular Angiography Severe
Macular edema-new VL Macular Angiography Severe
onset
4 Any combination of the VL
above plus
Vitreous hemorrhage VL Vitreous Ophthalmoscopy Severe
Retinal ischemia > or Extramacular
= 5 DA VL and macular Angiography Severe
Abbreviations: DA: Disk areas; VL: Vision loss must be related to associated sign(s)
When located outside the macula, stage 1 findings are consistent with
excellent central vision and a good visual prognosis (mild risk). In contrast,
stage 2 radiation retinopathy requires that these pathological findings are
located in the macula and therefore, carry a more guarded prognosis for vision
(moderate risk). When the eye enters stage 3, some vision loss has probably
occurred and the prognosis for return to pretreatment vision is poor (severe
risk). Despite its location, the presence of retinal neovascularization is ominous.
It suggests a profound ischemic drive and carries a worse prognosis for long-
term visual acuity. Vitreous hemorrhage, large areas of retinal ischemia and
Ch-01.indd 13 31-08-2012 12:29:59

iris neovascularization are associated with a worse prognosis for vision and
globe salvage. Vitreous hemorrhage clouds out ability to use laser treatment
and to monitor the progression of radiation retinopathy. Patients who present
with vitreous hemorrhage often have occult neovascularization and are at risk
for ghost cell or neovascular glaucoma.44
Shields and Shields45 found that in the literature there is no comprehensive
classification of orbital cysts of childhood and proposed this one:
I. Cysts of the surface epithelium
A. Simple epithelial cyst
1. Cutaneous epithelial cyst (epidermoid cyst)
2. Conjunctival epithelial cyst
3. Respiratory epithelial cyst
4. Apocrine gland cyst
B. Dermoid cyst
1. Epidermal dermoid cyst
2. Conjunctival dermoid cyst
II. Teratomatous cyst (teratoma)
III. Neural cysts
A. Neural cysts associated with ocular maldevelopment
1. Congenital cystic eye
2. Colobomatous cyst (neuroectodermal cyst with microphthalmia)
B. Neural cysts associated with brain and meningeal tissue
1. Cephalocele and ectopic brain tissue
2. Orbital optic nerve meningocele
IV. Secondary cysts from adjacent structures
A. Mucocele
B. Dentigerous cyst
V. Inflammatory cysts (parasitic cyst)
A. Echinococcal cyst
B. Cysticercosis
C. Others
VI. Noncystic orbital lesions with cystic component
A. Adenoid cystic carcinoma
B. Rhabdomyosarcoma
C. Lymphangioma
D. Others
A considerable number of tumor classifications have been developed that
call for, first of all, the use of a unified terminology. “The terminology employed
during classification, grouping, and staging tumors generates confusion even
among professionals in oncology. The words “group” and “stage” are used
imprecisely by many authors. These two words have specific meanings in the
Ch-01.indd 14 31-08-2012 12:29:59

classification lexicon. “Grouping” focuses on the tumor, whereas “staging”
focuses on the patient. The term “group” is a more appropriate name for each
of the levels in a classification of intraocular retinoblastoma than is the term
“stage”.l Thus, there are a lot of classifications in the literature. For the same
tumor, for example, for retinoblastoma, some authors are using the Reese-
Ellsworth classification, others are using Grabowski-Abramson classification,
thirds are using TNM classification and there are a number reports giving
outcome data for eyes with and without tumor not using any classification
system.46-48 Moreover, in some reports is applied the terminology, which is not
used in any classifications, e.g. ‘low stage, “small tumor”, “advanced disease”
or “advanced stage”,49-51 or “type I, II, III, IV” for retinoblastoma.52 As result
of this confused terminology and absence of a unified classification system
for all ocular tumors but not for only choroidal melanoma or retinoblastoma
there appears the problem of the absense of the possibility to compare the
results of studies. At the same time, classifications, which existed for many
years are still applicable and apparently can be used as a basis for developing
the unified classification for all ocular tumors and its adnexa, taking into
consideration the clinical symptoms and the histological structure. This seems
to be extremely complex task for future studies. Some classifications were
published 50 to 60 years ago, but they are still actually today. For example,
Callender classification54 of six prognostic subtypes of malignant melanotic
eye tumors (spindle A, spindle B, fascicular, mixed, epithelioid and necrotic)
was published in 1931. After 74 years, in 2004, this classification has been used
by Singh et al.53 We agree with Linn Murphree,l in that “A broadly accepted
classification system is a powerful clinical tool. It becomes easy-to-learn and
easy-to-remember language used by professionals to communicate efficiently
with other and with the child’s family”.
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LE, WHO, Geneva 1980. p. 9.
4. WHO Official Records, No 79,1957, p 467 (Resolution WHAIO, 18).
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LE, WHO, Geneva 1980. pp. 10-11.
5. International Histological Classification of Tumors No 24. Histological Typing
of Tumors of the Eye and its Adnexa, Ed: Zimmerman LE. WHO, Jeneva, 1980.
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7. Paches AI, Brovkina AF, Ziangirova GG. Klinicheskaya onkologiya organa
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8. No authors listed. Factors predictive of growth and treatment of small choroidal
melanoma: COMS Report No 5. The Collaborative Ocular Melanoma Study
Group. Arch Ophthalmol. 1997;115:1537-44.
9. Van Ginderdeuren R, van Limbergen E, Spileers W. 18 years experience with
high dose rate strontium-90 brachytherapy of small to medium sized uveal
melanoma. Br J Ophthalmol. 2005;89:1306-10.
10. Diener-West M, Earle JD, Fine SL, et al. The COMS randomized trial of iodine
125 brachytherapy for choroidal melanoma,III: Initial mortality findings. COMS
Report No.18. Arch Ophthalmol. 2001;119:969-82.
11. No authors listed. The Collaborative Ocular Melanoma Study (COMS)
randomized trial of pre-enucleation radiation of large choroidal melanoma I:
Characteristics of patients enrolled and not enrolled. COMS Report No. 9. Am J
Ophthalmol 1998;125:767-78.
12. Classification and stage information. Tumor size. National Cancer Institute-
Intraocular (Eye) Melanoma Treatment: http://www.nci.nih.gov/cancertopics/
pdq/treatment/intraocularmelanoma/HelthProfe...
13. Reese AB, Ellsworth RM. The evaluation and current concept of retinoblastoma
therapy. Trans Am Acad Ophthalmol Otolaryngolog. 1963;67:164-72.
14. Ellsworth RM. The practical management of retinoblastoma. Trans Am
Ophthalmol Soc. 1969;67:463-534.
15. Grabowski EF, Abramson DH. Intraocular and extraocular retinoblastoma.
Hematol Oncol Clin North Am 1987;1:721-35.
16. Parent’s Guide: Classification. Abramson Staging System for Retinoblastoma:
http://www.retinoblastoma.com/guide9.htm.
17. Chantada G, Doz F, Antoneli CB. A proposal for an international retinoblastoma
staging system. Pediatr Blood Cancer 2005. p. 15.
18. Pratt CB. Management of malignant solid tumors in children. Pediatr Clin
North 1972;19:1141-55.
19. Howarth C, Meyer D, Hustu HO, et al. Stage-related combined modality treat-
ment of retinoblastoma. Results of a prospective study. Cancer 1980;45:851-8.
20. Yang H, Schilling H, Effert R, et al. Morphologic classification of choroidal
invasion of retinoblastoma. J Tongji Med Univ 1999;19:149-54.
21. THM classification of ophthalmic tumors. International Union Against Cancer.
Harmer MH, Oosterhuis JA (Eds). Geneva 1985. p. 41.
22. Kaneko A. TNM classification of ophthalmic malignant tumors. Gan To Kagaku
Ryoho 1998;25:1231-40.
23. Cinek P, Stibor V. THM classification of malignant ocular tumors. Cesk Slov
Oftalmol 2004;60:408-15.
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24. Sobin LH, Hermanek P, Hutter RVP. THM Classification of malignant tumors.
Cancer 1988;61:2310-4.
25. Sobin LH, Fleming ID. TNM Classification of malignant tumors (5th edn).
Cancer 1997;80:1803-4.
26. Piemonte M. TNM classification of malignant tumors (VI edition
2002): Innovation in the classification of head and neck neoplasm. Acta
Otorhinolaryngol. Ital 2003;23:132-5.
27. Kujala E, Kivela T. Tumor, node, metastasis classification of malignant ciliary
body and choroidal melanoma evaluation of the 6th edition and future direction.
Ophthalmology 2005;112:1135-44.
28. Silberman AW. Malignant melanoma. Staging system: http://www.cancernews.
com/articles/melanomas.htm.
29. Skin cancer. Clark’s classification (level of invasion): http://www.cancerpage.
com/articles/default.asp?id=2&subarea=Your_Illness
30. Gleizal A, Nimeskem N, Kodjikian L, et al. Lacrimal sac melanoma. Rev Stomatol
Chir Maxillofac 2005;106:103-5.
31. Ophthalmic Hyperguide. Section: Oculoplastics. Kazim M: Werner’s
NOSPECS classification scheme. http;//www.ophthalmic.hypergides.com./
tutorials/oculoplastics/graves_orbit/tutorial.a…
32. Dickson AI, Vaidya B, Miller M, et al. Doubleblind, placebo-controlled trial of
octreotide long-acting repeatable (LAR) in thyroid-associated ophthalmopathy.
J Clin Endocrinol Metab 2004;89:5908-9.
33. Berman JJ. Tumor taxonomy for the developmental lineage classification of
neoplasms. BMC Cancer 2004;4:88.
34. De Coronado S, Haber MW, Sioutos N, et al. NCI Theasaurus: Using science-
based terminology to integrate cancer research results. Medinfo 2004;11:33-7.
35. Steliarova-Foucher E, Stiller C, Lacour P, et al. International Classification of
Childhood Cancer (3rd edn). Cancer 2005;103:1457-67.
36. Volpe NJ, Jacobec FA. Pediatric orbital tumors. Int Ophthalmol Clin 1992;32:201-
21.
37. The intergroup rhabdomyosarcoma study: A preliminary report. Cancer
1977;40:2015-26.
38. No authors listed. National Cancer Institute sponsored study of classifications of
non-Hodgkin’s lymphomas: Summary and description of a working formulation
for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classification
Project. Cancer 1982;49:2112-35.
39. Jaffe ES, Harris NL, Diebold J, et al. World Health Organization classification
of neoplastic diseases of the hematopoietic and lymphoid tissues. A progress
report. Am J Clin Pathol 1999;111(1 Suppl 1):S8-12.
40. Harris NL, Jaffe ES, Stein H, Banks PM, et al. A Revised European-American
Classification of Lymphoid Neoplasms: A proposal from the International
Lymphoma Study Group Blood 1994;84:1361-92.
41. McKelvie PA, McNab A, Francis IC, et al. Ocular adnexa lymphoproliferative
disease: A series of 73 cases. Clin Experiment Ophthalmol 2001;28:387-93.
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42. Cahill M, Barness C, Moriarty P, et al. Ocular adnexal lymphoma—comparison

of MALT lymphoma with other histological types. Br J Ophthalmol 1999;83:
742-7.
43. Wright DH. Updated Kiel classification for lymphomas. J Pathol 1989;157:238-
84.
44. Finger PT, Kurli M. Laser photocoagulation for radiation retinopathy after
ophthalmic plaque radiation therapy. Br J Ophthalmol 2005;89:730-8.
45. Shields JA, Shields CL. Orbital cysts of childhood—classification, clinical
features, and management. Surv Ophthalmol 2004;49:281-99.
46. Biswas J, Mani B, Shanmugam MP, et al. Retinoblastoma in adults: Report of the
literature. Surv Ophthalmol 2000;44:409-14.
47. Ulla Ek, Seregard S, Jacobson L, et al. A prospective study of children treated for
retinoblastoma: Cognitive and visual outcomes in relation to treatment. Acta
Ophthalmol. Scand 2002;80:294-9.
48. Desjardins L, Charif Chefehaouni M, Lumbroso L, et al. Functional results of
retinoblastoma treatment with local treatment used in isolation or associated
with chemotherapy. J Fr Ophthalmol 2005;28:725-31.
49. Wirix M, Parys-Vanginderdeuren R, Casteels I, et al. Delayed diagnosis of
retinoblastoma. Bull Soc belge Ophthalmol 2000;278:37-41.
50. Beck MN, Balmer A, Dessing C, et al. First-line chemotherapy with local
treatment can prevent external-beam irradiation and enucleation in low-stage
intraocular retinoblastoma. J Clin Oncol 2000;18:2881-7.
51. Sahu S, Banavali SD, Pai SK, et al. Retinoblastoma: Problems and perspectives
from India. Pediatr Hematol Oncol 1998;15:501-8.
52. Schueler AO, Jurklies C, Heimann H, et al. Thermochemotherapy in hereditary
retinoblastoma. Br J Ophthalmol 2003;87:90-95.
53. Singh AD, Rennie IG, Kivela T, et al. The Zimmerman-McLean-Foster
hypothesis: 25 years later. Br J Ophthalmol 2004;88:962-7.
54. Callender GR. Malignant melanotic tumors of the eye: A study of histologic
types in 111 cases. Trans Am Acad Ophthalmol Otolaryngol 1931;36:131-42.
Ch-01.indd 18 31-08-2012 12:29:59

CHAPTER 2
Epidemiology of Ocular Tumors in Children
Epidemiological study of the ocular tumors is very important in identifying

the relationship between various external and internal factors and incidence in
order to determine methods of prevention and effective treatment. Advanced
research in epidemiological aspects of benign and malignant ocular tumors
can establish a theoretical and practical knowledge base to ensure steady
progress in the treatment of the eye tumors, which pose a serious health risk
for the patients, especially children. The basis for each epidemiological study
is research into the characteristics of incidence, mortality and survival rates.
Incidence is defined as “a number of new cancers or specific site/type
occurring in a specified population during a year, usually expressed as a
number of cancers per 100,000 population. Age-adjusted incidence is a
weighted average of the age-specific rates, where the weights are the proportion
of persons in the corresponding age groups of a standard population”.1 The
standardized incidence is calculated first by estimating the age-specific
rates and then applying these rates to the reference population, which is the
Standard World Population.2 To calculate incidence rate, age-adjusted and
standardized incidence, a similar number of population divided by the same
age subgroups. In the literature, besides these incidences the authors’ writing
on the subject use different other incidences so as age-standardized incidence,3
mean age-adjusted incidence,4 average annual age-adjusted incidence,5
average annual incidence,6 average annual age-standardized incidence,7
incidence,8 age-specific incidence,9 specific incidence,10 and standardized
incidence.11,12 Most authors calculate incidence rate per 100000 populations,
some calculate incidence per million inhabitans,12,13 1 per 15789 live births,14
but there are a lot of reports using percentage to study an epidemiology of the
ocular tumors and named percentage as incidence.15-18 In addition, types and
locations of malignant ocular tumors differ greatly, e.g. “eye”,6,10 “eye, orbit,
related adnexa”,3 “intraocular”,8 “intraocular, conjunctival, orbital”,7 “ocular
malignant melanoma”,12 “endo-ocular tumors”,16 “orbito-ocular tumors”,19-21
“oculo-orbital tumors”,22 semimalignant tumors.23
Ch-2.indd 19 31-08-2012 12:30:44

The incidence of benign and malignant ocular tumors has a great

variation due to reviewed cases. Some reports analyzed incidence of cases
with histological studies. Other studies based on clinical information alone.
In these cases, the incidence of tumors may be too low or too high. Some
reports include primary, secondary, benign and malignant tumors, metastatic
tumors, pseudotumors, inflammationally and non-tumors diseases in adults
together with children. Moreover, there are reports from specific departments
or centers, or certain countries, or geographic regions, which form different
variation and therefore, it is difficult to compare a number of reports with
each other. Furthermore, in the literature population-based research on tumor
incidence are rare studies and information on the age and gender of patients
may be absent. We agree with Shikishima et al.24 “unfortunately, in most of
the published reports, there was no precise information on the age of the
subjects given. However, even though we could not comprehensively assess
the age distribution, there appeared to be no apparent differences among the
cases for each of these series”. In recent work, we have analyzed percentage
and incidences of benign and malignant ocular tumors in children separate
from adults because the most of children’s ocular tumors are not common in
adults. On the contrary, some benign and malignant tumors in adults are not
frequently disease for patients aged above 15 years.
EPIDEMIOLOGY OF BENIGN EYELIDS, CONJUNCTIVAL,

INTRAOCULAR AND ORBITAL TUMORS
The benign tumors of the eye in children occurred more frequent (64.3%) than
malignant tumors (35.7%) and the most often observed benign tumor was
nevus pigmentosus (23.7%) of all ocular tumors in childhood.25
Benign eyelid tumors: Benign eyelid tumors seen in children occurred in
17.8 percent (142 cases) of all benign and malignant eye tumors (800 cases).27
The four most common eyelid tumors of patients younger than 17 years old,
in order of frequency, were epidermal cysts (23.1%), dermoid cysts (17.9%),
squamous cell papillomas (11.5%) and compound nevi (9.0%) which were
histopathologically diagnosed during 1991 to 2000.26 However, Abdi et al.28
found that of 122 eyelid tumors and tumor like lesions the most common
were vascular tumors (23.3%), then neural tumors (18.0%), dermoid cysts
(16.4%), squamous cell papilloma (13.1%), and nevi (12.3%), diagnosed
histopathologically in 1951 to 1991.28 Castillo and Kaufman29 found chalazion
being the most common pediatric eyelids tumor.29
Benign eyelids tumors were usually seen in the first two decades of live.28
Figure 2.1 shows 1-year-old girl with hemangioma in the right eye of the low
lid and plica semilunaris treated in our Department.
Ch-2.indd 20 31-08-2012 12:30:44

Epidemiology of Ocular Tumors in Children 21
Fig. 2.1: Hemangioma in the right eye’s low lid and plica semilunaris of a 1-year-old girl
Benign tumors of the conjunctiva and cornea are studied in the same chapter
because epithelium of cornea topographically is continued to epithelium of
the conjunctiva. In children, benign conjunctival tumors occur in more than
(99.0%) cases.30
Of 41 benign tumors of conjunctiva in children aged from 1 to 17 years
the most common were pigmented nevi accounting for 83.0 percent (35
cases) of the histopathologically diagnosed lesions, then in decreasing order
of frequency were angioma (4.9%), dermolipoma (4.9%), dermoid (2.4%), and
papilloma (2.4%).31 The first place for nevi was also found by Cunha et al.32
but then other benign tumors were choristomas, epithelial inclusion cysts, and
papillomas. However, Elsas and Green33 in over a 49 years period found that in
302 children from birth through 15 years of age, the most common epibulbar
tumors were choristomas (33.0%). Nevi were the second most frequent lesion,
present in 29.0 percent, epithelial inclusion cysts in 11.0 percent, papillomas
in 7.0 percent, pyogenic granulomas in 6.0 percent, granulomas in 5.0 percent,
vascular hamartomas in 2.0 percent, and lipomas in 2.0 percent. In majority
cases tumors were localized at the corneoscleral limbus.31-33 The mean age of
children at the time of surgical excision was 10 years, 45 percent were males.31
Benign intraocular tumors are uncommon in children and there is very
little information on their incidence, most information about them has
come from single case reports or from the rare study of children, which was
undertaken in children together with adults.
Adenoma of the iris pigment epithelium or benign epithelioma is a rare
benign malignancy in children that may remain relatively stable for years.34
Ch-2.indd 21 31-08-2012 12:30:44

Age of patients ranged from 11 to 85 years, male/female ratio was 1:1. All
lesions were solitary and unilateral.35
Iris cysts are uncommon in children. Primary cysts of the iris pigment
epithelium as well as anterior chamber epithelial cysts may develop as a
complication of penetrating trauma of intraocular surgery, or they may
be congenital in origin.36 Of 57 iris cysts of children under age 20 years 53
(93.0%) were primary and only 4 cases 7.0 percent were secondary. Peripheral
or iridociliary type of iris cysts accounted for 59.0 percent of all childhood
iris cysts. It was most commonly diagnosed in the teenage years. Girls were
more frequently affected in 68.0 percent, than boys and was not recognized in
infancy.36
Iris melanocytoma is also rare benign type of iris nevus tumor in children.
The term “melanocytoma” was suggested by Zimmerman37 in 1965 to
describe this tumor and reported two adult patients with iris melanocytoma
after enucleation. Iris melanocytoma is generally diagnosed in adults and has
been uncommon tumor in children. So, of 13 well-documented cases of iris
melanocytoma in the literature only 2 patients (15.4%) were under the age
of 10 years. In the authors’ own series of 47 patients with iris melanocytoma
there were 4 patients (8.5%) under the age of 10 years.38 In rare instances
melanocytoma can arise in iris, ciliary body, choroids or conjunctiva.39
Melanocytoma of optic disk or magnocellular nevus is extremely rare in
children, which can be dark brown to black because of very pigmented
melanocytes.33,40 Bilateral melanocytoma of optic disk is also extremely rare
tumor in children. For example, of 115 patients with such a tumor there was
only one (0.9%) 10-month-old boy with bilateral involvement.40
Medulloepithelioma is another benign intraocular tumor, which is so rare
that “ a few clinicians have had experience with more than one case”.41 For
the first time medulloepithelioma was described by Badal and Lagrange in
1892 as carcinoma primitive. In 1904, Verhoeff pathohistologically in detail
described this tumor as teratoneuroma and Fuchs in 1908 termed it as dictioma
because of the net-like arrangement or ribbons of poorly differentiated cells.
In 1931, Grinkel provided that tumor developed from medullary epithelium
and termed it as medulloepithelioma. This historical aspect of the name of
medulloepithelioma was published elsewhere.43,45,46 Medulloepithelioma
arises from the primitive medullary epithelium and most often occurs in
the ciliary body41 being very rare tumor in the ophthalmic part of the retina
and is identic with medulloepithelioma of ciliary body.34 It may be benign or
malignant depending on whether poorly differentiated cells are present.29,42
Malignant medulloepithelioma is such a rare tumor that only 2 cases occurred
during 10 years.44 This malignancy accounts for almost all the tumors in the
congenital group, but they are much rare than retinoblastoma. For benign
Ch-2.indd 22 31-08-2012 12:30:44

medulloepithelioma the longest interval between onset of signs or symptoms
and diagnosis was 5 years,43 or age from 2 months to 10 years.41 It is generally
a tumor of childhood.43 Medulloepithelioma of iris occurs in children from 6
months to 6 years.45 In all cases whether benign or malignant this tumor was
unilateral and there was an equal distribution between the right and left eyes.
No racial predilection was observed and males and females were equally
affected.43 However, Canning et al.46 in small series of 15 children over 25 years
observed period found a predilection of girls 6 of 9 children, 66.7 percent, with
benign medulloepithelioma aged from 11 months to 14 years when benign
tumor occurred in 60.0 percent (9 of 15 children). These tumors rarely involve
the optic nerve and are classified as nonteratoid and teratoid types; the later
contains heterologous tissue. Benign nonteratoid medulloepithelioma of the
retina is also possible tumor.47 Although medulloepithelioma is unilateral tumor
and bilateral cases are uncommon presumed bilateral medulloepithelioma of
ciliary body in a 7-year-old boy was described in the literature.48
Leiomyoma is a rare benign smooth muscle intraocular tumor, which
can occur in younger patients but more common in adults with distinct
predilection for females.49,50 However, 3 females and 2 males aged 5, 8, 11, 12
and 16 years respectively were found by Richter et al.51 who analyzed 32 cases
of a ciliary body leiomyomas described in the literature from 1950 to 2000. If
include author’s case of a 13-year-old boy than it became equal number of boys
and girls with a ciliary body leiomyoma.
Intraocular leiomyoma may be more common than previously believed.
It is possible that some cases of leiomyoma have been misdiagnosed
histopathologically as a low-grade amelanotic melanomas. It is also possible
that some tumors, which are treated with irradiation as suspected melanomas
actually may be leiomyomas.50 It tends to affect the ciliary body and rarely
occurs purely in the choroids.49
Choroidal osteoma is a rare benign, ossifying tumor, described by Goss
and Williams in 1978, typically found in health young females,50,52 which can
be unilateral53 or bilateral.54 The youngest patient with osteoma reported in
the literature was a 8-month-old infant.55 This tumor may occur in siblings.
Three siblings (a sister and two identical-twin brothers) had bilateral choroidal
osteoma. The sister was seen at 11 years of age and the tumor showed
significant growth two years later. The twin brother’s tumor was diagnosed
at 9 years of age. The siblings’ mother had a yellow mottling situated nasal to
the disk in each eye that was similar in appearance to that in one eye of one
of the twins.56 A long-term follow-up of choroidal osteoma for a mean of 10
years (range, 2–22 years) found growth observed for (41.0%). The probability
of loss of visual acuity was (58.0%) by 10 years and (62.0%) by 20 years.53 There
is a case of familial choroidal osteoma in two brothers of 12 and 15 years old
Ch-2.indd 23 31-08-2012 12:30:45

with bilateral choroidal osteomas. To the author’s opinion, familial choroidal

osteoma might have separate etiologic or modified factors.57
Choroidal hemangioma is an uncommon benign vascular tumor especially
in children. It can be circumscribed or diffuse. The circumscribed choroidal
hemangiomas occur sporadically without any associated local or systemic
anomalies and usually diagnosed between the second to fourth decade of
life,58 or from 9 to 86 years,59 or from 10 to 60 years.45 More frequently, this
kind of vascular tumors occur in adults60,61 and in children they rare occurred.
The circumscribed type has an equal incidence in the right and left eyes.61
In contrast, diffuse choroidal hemangiomas are usually evident at birth and
generally occur as a part of neuro-oculocutaneous hemangiomas (Sturge-
Weber syndrome).33,50,61 Diffuse type of choroidal hemangiomas appears to
be slightly more common in Whites, than in Blacks, the left eye involved more
often than the right one, ipsilateral to an associated facial angioma occurred at
a median age of 8 years.61
Retinal benign tumors occur in children very rare and, as a rule, they
represented by tumors of vascular capillary, cavernous or racemouse lesions.45
Singh et al.62 found that retinal vascular tumors can be classified into four
distinct clinical entities: retinal capillary hemangioma, retinal arteriovenous
communication (Wyburn-Mason syndrome, about it below), and retinal
vasoproliferative tumors. According to the “Histological typing of the eye
tumors”34 there are angiomatosis of the retina (hemangioblastoma) and
capillary telangiectasia (milliary aneurism of Leber) except capillary and
cavernous retinal hemangioma. Capillary retinal hemangioma at first was
described by Eugen von Hippel, coined the term angiomatosis retinae in
1902 and Arvid Lindau described an association between cerebral and
retinal hemangioblastomas and the term von Hippel-Lindau disease (VHL)
was established in 1964.45,62 Capillary retinal hemangioma can occur in
association with VHL an autosomal dominant disease, or sporadically. The
risk of association VHL disease is higher in younger patients and is the most
common and earliest manifestation of VHL disease. The maximal probability
of VHL disease in patients with a retinal capillary hemangioma was estimated
to be 30.0 percent to 46.0 percent.62 In children with intraocular tumors
and simulating conditions retinal capillary hemangioma in 7.0 percent was
clinically diagnosed.63 and only 5.0 percent of patients with VHL present
retinal capillary hemangioma before the age of 10 years; it was already found
in children.64 The median age at diagnosis of retinal capillary hemangioma
in patients with VHL disease (range 2.8–46.7 years) was almost 18 years
less than those without VHL disease (range 7.0–74 years).65 Of all capillary
hemangiomas retinal capillary hemangiomas occur in 6.0 percent with
incidence 1:85000; about 25.0 percent of patients have familial history, 50.0
Ch-2.indd 24 31-08-2012 12:30:45

percent of patients have bilaterally lesions.45 Capillary telangiectasia or
milliary aneurysms of Leber can associate with exudative retinopathy and is
famous as syndrome or disease of Coats.33 Retinal cavernous hemangiomas
are believed to be congenital hamartomas that may not be detected in
childhood.66 However, Messmer et al.67 in small series of 9 patients found the
age of presentation ranged from 1 to 55 years. This tumor can be sporadic and
syndromic associating with cerebral cavernous malformation syndrome and
this tumor should be included with neuro-oculocutaneous (phakomatoses)
syndrome.62 On the other side, 5.0 percent of patients with familial cerebral
cavernomas have retinal cavernomas.68 Familial malformations have been
linked to three loci on chromosomes 3q, 7p and 7q.69-71
Wyburn-Mason syndrome is a rare sporadic order characterized by
congenital arteriovenous malformation principally of the retina and brain.72
In a small series of 14 patiens with Wyburn-Mason syndrome 10 patients
71.4 percent were children aged from 4 to 16 years, 5 girls and 5 boys. The
age of patients when they presented with symptoms was younger than the
age of patients with sporadic brain arteriovenous malformations.73 Cerebral
hemangiomas usually become symptomatic by the second or third decade of
live.62 Of 26 literature and 1 author’s cases of Wyburn-Mason syndrome 11
cases 40.7 percent were children aged from “birth” to 14 years, males were 3,
females were 8, of the lesion described 3 were right-sided, 6 were left-sided and
1 patient was bilateral. With regard to ethnicity 1 patient was Middle Eastern,
3 were Caucasian and 7 were of uncommon ethnicity.74
Retinal vasoprolipherative tumors is an uncommon lesions that have
only recently been recognized as a distinct clinical entity. Although retinal
vasoproliferative tumors usually present in the third or fourth decade of life
they may present in childhood62 and bilaterally in twins.75 The presence of
either retinal cavernous or choroidal hemangioma should alert the physician
to search for features suggestive of systemic and familial involvement71 and
strongly support the recommendation to undertake screening of the children
of VHL parents.76
Retinal astrocytoma in typically cases developes from the astrocytes of the
retina or of the optic nerve disk , more often they are growing towards corpus
vitreous not frequently on the cases of sclerosis tuberous. In 1921 at first this
type of tumor described by Van der Hoeva. However, later Schwab found that
retinal astrocytoma can occur in patients with sclerosis tuberoses only in 20.0
percent of cases. It can be asymptomatic in children and young adults.45 In the
literature, there is report about solitary astrocytoma in an infant of 5-month-
old.77 The median age of 4 children with retinal astrocytoma was 3 years.78 It is
possible to develop cysts in the retinal astrocytoma.33,45
Ch-2.indd 25 31-08-2012 12:30:45

In total, intraocular benign tumors occurred in children only in 10.6

percent (38 children) of all benign and malignant intraocular tumors (358
children) and in 4.8 percent of all ocular tumors (800 children).27
Benign orbital tumors occur with the frequency according to the type
of study (clinical, histopathological, or radiological) and whether the series
comes from a primary or tertiary facility. Orbital cellulitis, inflammatory
pseudotumor, capillary hemangioma, optic nerve glioma, and fibrous dysplasia
often do not require biopsy and can be diagnosed and treated based on clinical
information alone. Therefore, in these cases, the incidence of orbital tumors
may be erroneous.79 Perhaps therefore, the registration rate in Britain may be
about 10.0 percent less than the true incidence.80 The most common benign
orbital tumors in children from neonatals up to 16 years of age were represented
by epidermal cyst (18 patients), followed by orbital capillary hemangioma
(4 patients) of all 41 consecutive patients with orbital disease,81 or in 53.7
percent of all orbital tumors in children.82 Dermatomas and angiomas were
the most frequently encountered primary orbital tumors in children between
1981 and 1990 years.83 In children less than 10 years old, the most common
tumors were dermoid cyst (26.0%), capillary hemangioma 11.0 percent, and
hemorrhagic lymphangioma 11.0 percent.84 Benign cystic lesions (excluding
lacrimal gland cysts) accounted for 6.8 percent of all biopsed orbital lesions of
patients 18 years and younger,85 or in 6.0 percent of all intraorbital tumors.86
Another percentage of cysts and vascular lesions were found in the reviewed
cases of histopathologically verified orbital tumors from 340 patients aged 18
years and younger for the period 1932 to 1991. Cysts 23.2 percent and vascular
lesions 17.6 percent were the most common tumors and they are in as much
as 3.3 percent of all ophthalmic surgical procedures in children.87 Johansen
et al.88 found cystic tumors (dermoid, teratoma and epithelial) in (13.8%) in
children aged 0.0 to 18.8 years of all orbital space-occuping biopsed/surgically
removed lesions in the period 1974 to 1997. Of all dermoids in the body orbital
and periorbital dermoid account for 37.0 percent.89 Other authors also found
that cystic lesions mostly 64.1 percent occur in patients aged 18 years or less,90
or in the 0 to 20 age group and the number of cysts progressively decreased
from age group 0-20 to >30.91
Hemangiomas of the orbit occur in 3.3 percent of all orbital tumors in
children 0 to 18.8 years (cavernous was in 2.0 percent, capillary in 0.7 percent
and arteriovenous in 0.7 percent).88 Capillary hemangiomas mostly occurred
in children in the first year of life.85,92 However, in children less than 10 years
old with orbital tumors capillary hemangioma was in 11.0 percent.84 Figure
2.2 demonstrates 8-year-old girl with cavernous hemangioma in the left orbit
treated in our Department.
Ch-2.indd 26 31-08-2012 12:30:45

Fig. 2.2: Cavernous hemangioma in the left orbit of a 8-year-old girl
Lacrimal gland’s epithelial tumors such as pleomorphic adenoma (benign

mixed tumor) very seldom develop in prepubescent children and they are
never bilateral.33 For example, of 250 consecutive biopsies for orbital space-
occupying lesions in children aged 18 and younger there were no cases of
pleomorphic adenoma in the period 1962 to 1983,85 or during 24 years (1974–
1997) there was only 1 patient (0.7%) of all orbital lesions.88 However, in the
literature a rare case of 5-month-old child with primary pleomorphic adenoma
of lacrimal fossa lesion described.93 The cystic lesions of lacrimal gland had the
largest number for 10-year-old or younger. Lacrimal fossa lesions was in 0 age
group in 4.8 percent and in10 years age group in 3.9 percent. Yearly incidences
of lacrimal fossa lesions is 0.04 and 0.026 per 100000 people by decade in these
age groups respectively. Yearly incidences of primary pleomorphic adenoma
of lacrimal fossa lesion in these age groups were 0.008 and 0.009 per 100000
people by decade respectively.93 A malignant transformation of a formerly
benign pleomorphic adenoma of the lacrimal gland is possible and occurred
in a 11 years old patient nine years after the first operation.94
Optic nerve gliomas are slowly growing astrocytic neoplasms of the
anterior visual pathways, the majority of which occur within the first decade
of life in 65.0 percent and only 5.0 percent of orbital gliomas occur before two
years of life,45 or within the first two decades of life with equal sex incidence
in about 1 to 200000 patients with eye complaints. The incidence is greater
in neurofibromatosis. There is possible bilateral optic nerve involvement.95
Glioma of the optic nerve is the most frequent lesion seen in children and it
occurs in 26.3 percent of all orbital biopsed or surgically removed lesions or
in 57.4 percent,96 or in 81.6 percent88 of all optic nerve neoplasms. In children
less than 10 years old with orbital tumors optic nerve glioma occurred in 11.0
percent.84 More frequently this tumor occurs in females in 32.7 percent (33
females of 101 children with tumors of optic nerve.96
Ch-2.indd 27 31-08-2012 12:30:45

Optic nerve meningiomas arise from the nerve sheath and are to be
distinguished from orbital meningiomas arising from ectopic arachnoidal
cells or those secondarily involving the orbit by extension from adjacent sites.
Up to (80.0%) of orbital meningiomas occur in females, in two peaks, (25.0%)
in the first decade, and the rest in the 5th decade.95 As a rule, meningiomas are
unilateral, but it is possible bilateral cases.97 There were six cases of optic nerve
or meningial tumors, accounted for (2.4%),85 or (1.9%)88 of all childhood
orbital tumors. Five of six cases of optic nerve tumors were juvenile pilocytic
astrocytomas (optic nerve gliomas), and one was a primary optic nerve
meningioma.85 However, Lindegaard et al.96 found meningioma of optic nerve
in (23.3%) of all optic nerve tumors with significantly prevalence of boys in
(80.6%) (25 boys and 6 girls). Totally, benign orbital tumors seen in children
occurred in 50.9 percent,27 or in 66.2 percent,27 or in 77.6 percent,88 or
approximately in 90.0 percent.98 Miscellanous benign lesions were in children
in 24.0 percent of 290 ophthalmic specimens of children and adults.99
Other benign orbital tumors such as oxyphillic adenoma of the lacrimal
gland, orbital lymphangioma, osseous, fibro-osseous and histiocytic lesions
are extremely rare in children. For example, of 250 consecutive biopsies there
were only two juvenile ossifying fibromas and only one case of eosinophilic
granuloma.85 Leiomyoma of the orbit, a benign tumor of smooth muscle
occurs in sporadic cases and is very rare orbital pediatric benign tumor.100
In our Department of all age group patients, benign ocular tumors in
children occurred in 35.9 percent but this percentage could be higher, because
in the Department, the most patients with malignant ocular tumors should
be treated.101 In children, benign orbital tumors can masquerade malignant
orbital tumors, inflammatory orbital diseases and even non-tumor disease
such as Echinococcus. Figure 2.3 presents 5-year-old boy with Echinococcus of
the right orbit, which masqueraded orbital tumor.
Fig. 2.3: Echinococcus of the right orbit in a 5-year-old boy,

masqueraded orbital tumor
Ch-2.indd 28 31-08-2012 12:30:46

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J Pediatr Ophthalmol Strabismus 2004;41:338-44.
64. Schmidt D. Retinal angiomatosis. Klin Monasbl Augenheilkd 2005;222:90-109.
65. Singh AD, Nouri M, Shields CL, et al. Retinal capillary hemangioma: a
comparision of sporadic cases and cases associated with von Hippel-Lindau
disease. Ophthalmology 2001;108:1907-11.
66. Gass JD. Cavernous hemangioma of the retina, A neuro-oculo-cutaneous
syndrome. Am J Ophthalmol 1971;71:799-814.
67. Messmer E, Laqua H, Wessing A, et al. Nine cases of cavernous hemangioma of
the retina. Am J Ophthalmol 1983;95:383-90.
68. Labauge P, Krivosic V, Denier C, et al. Frequency of retinal cavernomas in 60
patients with familial cerebral cavernomas: a clinical and genetic study. Arch
Ophthalmol 2006;124:885-6.
69. Davenport WJ, Siegel AM, Dichgans J, et al. CCM1 gene mutation in families
segregating cerebral cavernous malformations. Neurology 2001;56:540-3.
70. Couteulx SL, Brezin AP, Fontaine B, et al. A novel KRIT/CCM1 truncating
mutation in patients with cerebral and retinal angiomas. Arch Ophthalmol
2002;120:217-8.
71. Sarraf D, Payne AM, Kitchen ND, et al. Familial cavernous hemangioma: An
expanding ocular spectrum. Arch Ophthalmol 2000;118:969-73.
72. Reck SD, Zacks DN, Eibschitz-Tsimhoni M. Retinal and intracranial
arteriovenous malformations: Wyburn-Mason syndrome. J Neuroophthalmol
2005;25:205-8.
73. Luo CB, Lasjaunias P, Bhattacharya J. Craniofacial vascular malformations in
Wyburn-Mason syndrome. J Clin Med Assoc 2006;69:575-80.
74. Dayani PN, Sadun AA. A case report of Wyburn-Mason syndrome and review
of the literature. Neuroradiology Jan 18, 2007 [Epub ahead of print].
75. Wachtlin J, Heimann H, Jandeck C, et al. Bilateral vasoproloferative retinal
tumors with identical localization in a pair of monozigotic twins. Arch
Ophthalmol 2002;120:860-2.
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76. Priesemann M, Davies KM, Perry LA, et al. Benefits of screening in von Hippel-
Lindau disease-comparision of morbidity associated with initial tumors in
affected parents and children. Horm Res 2006;66:1-5.
77. Bhende P, Babu K, Kumari P, et al. Solitary astrocytomas in adults. 2004;41:305-
7.
78. Shields JA, Eagle RC Jr, Shields CL, et al. Aggressive retinal astrocytomas in
four patients with tuberous sclerosis complex. Trans Am Ophthalmol 2004;102:
139-47.
79. Volpe NJ, Jakobiec FA. Pediatric orbital tumors. Int Ophthalmol Clin
1992;32:201-21.
80. Sanders BM, Draper GJ, Kingston JE. Retinoblastoma in Great Britain 1969-
1980: incidence, treatment, and survival. Br J Ophthalmol 1988;72:576-83.
81. Sterker I, Frerich B. Orbital disease in childhood. Klin Monatsbl Augenheilkd
2006;223:59-67.
82. Bullock YD, Goldberg SH, Rakes SM. Orbital tumors in children. Ophthal Plast
Reconst Surg 1989;5:13-6.
83. Skladzien J, Olszewski E, Reran E, et al. Primary orbital tumors in children.
Otolaryngol Pol 1996;50:32-6.
84. Ohtsuka K, Hashimoto M, Suzuki Y. A review of 244 orbital tumors in Japanese
patients during a 21-year period: origins and locations. JPN J Ophthalmol
2005;49:49-55.
85. Shields JA, Rakewell B, Augsburger JJ, et al. Space-occupying orbital masses in
children. Ophthalmology 1986;3:379-84.
86. Tatli M, Guzel A, Keklikci U, et al. Pediatric orbital multifocal cavernous
hemangiomas associated with bilateral arachnoid cysts of the middle cranian
fossa. Case report and review of the literature. J Neurosurg 2005;105:454-7.
87. Pollard ZF, Harley RD, Calhoun J. Dermoid cysts in children. Pediatrics
1976;57:379-82.
88. Johansen S, Heergard S, Bogeskov L, et al. Orbital space-occupying lesions in
Denmark 1974-1997.Acta Ophthalmol Scand 2000;78:547-52.
89. Kodsi SR, Shetlar DJ, Campbell RJ, et al. A review of 340 orbital tumors in
children during a 60-year period. Am J Ophthalmol 1994;117:177-82.
90. Gunalp I, Gunduz K. Cystic lesions of the orbit. INT Ophthalmol 1996-
1997;20:273-7.
91. Scat Y, Liolet S, Carre F. Epidemiological study of benign tumors and
inflammatory pseudotumors of the eye and its adnexa. J Fr Ophthalmol 1996;
19:514-9.
92. Char DH. Pediatric orbital tumors. In: Clinical Ocular Oncology. Churchill
Livingstone. New York, Edinburg, London, Melbourn, 1989. pp. 243-77.
93. Lacrimal Gland Tumor Study Group: An epidemiological survey of lacrimal
fossa lesions in Japan: number of patients and their sex ratio by pathological
diagnosis. JPN J Ophthalmol 2005;49:343-8.
94. Riedel KG, Markl A, Hasenfratz G, et al. Epithelial tumors of the lacrimal gland:
Clinicopathologic correlation and management. Neurosurg Rev 1990;13:289-98.
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95. Eggers H, Jakobiec FA, Jones IS. Tumors of the optic nerve. Doc Ophthalmol
1976;41:43-128.
96. Lindegaard J, Heegaard S, Prause JU. Histopathologically verified non-vascular
optic nerve lesions in Denmark 1940-1999. Acta Ophthalmol Scand 2002;80:
32-7.
97. Brovkina AF. Bolezni orbiti. Moscow, Meditsina, 1993. p. 283.
98. Bullock JD. Discussion. Ophthalmology 1986;3:384.
99. Assegid A. Pattern of ophthalmic lesions at two histopathology centres in
Ethiopia. East Afr Med 2001;78:250-4.
100. Jakobiec FA, Howard GM, Rosen M, et al. Leiomyoma and leiomyosarcoma of
the orbit. Am J Ophthalmol 1975;80:1028-42.
101. Mouratova T. Sovershenstvovanie spetsializirovannoi pomoschi vzroslum
i detyam so zlokachestvennimi novoobrazovaniyami organa zreniya v
Uzbekistane. Dissertatsiya na soiskanie uchenoi stepeni Doktora meditsinskih
nauk, Moskwa, Hermann Helmholtz Reseach Institute of Eye Diseases, 1992. pp.
195-7.
MALIGNANT EYELID AND CONJUNCTIVAL TUMORS

Malignant eyelid and conjunctival tumors are very rare in children. For
example, of the 302 cases of epibulbar tumors in children only three cases
(1%) were squamous cell carcinoma.1 Basal cell carcinoma is extremely rare
in children and usually associated with a genetic defect, such as basal cell
nevus syndrome, xeroderma pigmentosum, or nevus sebaceous, or following
radiotherapy treatment.2,3 It is probably the result of a combination of UV
radiation exposure and genetic background. However, there is report about
three children of 8, 11 and 16 years old, from which were 2 boys and 1 girl with
primary isolated basal cell carcinoma unassociated with any other disease or
syndrome.2 Other three cases, reported of de novo is basal cell carcinoma of the
eyelid in children, had no known genetic syndromes and had not undergone
radiotherapy.3 Malignant melanomas of the conjunctiva are extremely rare in
children.4 They are highly malignant tumor that derives from melanocytes.5
There are reports about 6 and 11-year-old children with malignant conjunctival
melanoma.4,5 Strempel and Kroll6 described three cases of 3, 4 and 14-year-
old children, who suffered from this tumors. Of all 5 children, 2 were girls
and 3 were boys. Another rarely reported malignant tumor of conjunctiva
is rhabdomyosarcoma, which was described in a 10-year-old girl, who had
no history of trauma to the eye or other ocular disease.7 Malignant eyelid
and malignant conjunctival tumors are such a rare malignancies that of 800
children treated in the Vladimir Filatov Institute of Eye Diseases (Odessa)
only 2 children (0.3%) were with malignant eyelid and conjunctival tumors.8
Ocular adnexal lymphoma is also rare in children. Only (1.4%) were under 21
years of age and a few cases of pediatric ocular adnexal lymphoma have been
Ch-2.indd 34 31-08-2012 12:30:46

described in the literature. According to author’s opinion, follicular lymphoma
has not been described previously in the ocular adnexa in children.9
Xeroderma pigmentosum is one of the other rare abnormalities, which
is autosomal recessive genetic disorder starting in early childhood and
characterized clinically by cutaneous photosensitivity, pigmentary changes,
photophobia, and propensity for early development of malignancy in sun-
exposed mucocutaneous and ocular structures.10,11,13 In 1968, Cleaver12 was
the first to report that skin cells from patients with xeroderma pigmentosum
have an impaired ability to repair ultraviolet radiation-induced DNA damage.
Xeroderma pigmentosum has a prevalence rate of 1:250000.10,11 45.0 percent
of the patients with xeroderma pigmentosum had basal cell carcinoma or
squamous cell carcinoma of the skin, 5.0 percent of the patients had melanoma,
which occurred in 79.0 percent and 65.0 percent respectively on the face,
head or neck. Neurologic abnormalities were found in 18.0 percent of the
case reported.10 Xeroderma pigmentosum occurred in 0.4 percent (3 of 758
patients with epithelial eyelid and conjunctival tumors) and 2 of 3 patients were
sisters.13 Ocular abnormalities were reported in 40.0 percent of the patients
and included ectropion, corneal opacity leading to blindness, and neoplasms10
Blindness was noted in 26.0 percent of patients with malignant tumors.15
Malignant tumors included squamous cell carcinoma, basal cell carcinoma,
and malignant melanoma was seen in 30.0 percent (3 of 19 patients),14 or in
31.3 percent (10 of 32 patients).15 As a rule, the first symptoms of xeroderma
pigmentisum noted by parents of children with a median age between 1 and
2 years.10,12 Patients died at second or third decade of life from cachexia,
hemorrhoidal meningitis or from dissemination of malignant tumors to the
brain.13 70.0 percent probability of survival was attained at age 40 years, a 28
years reduction in comparison with the US general population.10
In our Department of Ophthalmology of the Institute of Oncology and
Radiology (IOR) of Uzbekistan’s Academy of Science from 1978 to 1989,
5 children with xeroderma pigmentosum were treated. There were 1 male and
4 females, of which 2 females were sisters. The youngest was girl of 1.5 years
old at the time of initial diagnosis.
In Uzbekistan, malignant eyelid and conjunctival tumors in children
are also rare malignancies. Information about patients with malignant ocular
tumors in Uzbekistan has been collected only since 1978. Before 1978, there
was no systematically collected information about the number of patients
with malignant ocular tumors, therefore, epidemiologic aspects of these
malignancies was investigated at first time in Republic. In joint collaboration
with the IOR’s Resource Department and Regional Oncology Dispensaries,
we gathered malignant ocular tumors related information from 1978 to 1999.
The information includes children’s name, age, ethnic background, address,
Ch-2.indd 35 31-08-2012 12:30:46

parents’ occupation, diagnosis, method of treatment, results of treatment,

date and cause of death. Only new cases with biopsy and histopathologically
confirmation of the malignant tumors were registered. Histopathologically
confirmation has been done in the Department of Histopathology of Institute
of Oncology and Radiology (IOR) of Uzbekistan’s Academy of Science.
For statistical purposes, the patients were divided into 0 to 4, 5 to 9 and
10 to 14 age subgroups. We have calculated crude incidence, age-adjusted
incidence and standardized incidence per 100000 children male and female
populations. For standardized incidence, Standard World Population was
used. Population data were obtained from Uzbekistan’s Statistic Committee.
Incidence in different ethnic groups was compared to the number of the same
ethnic groups in Uzbekistan. All rates were statistically tested and considered
statistically significant if intersecting the 95 percent confidence interval (CI 95%,
P< or = 0.05). To analyze malignant ocular tumor incidence, the International
Classification IX, 1984, was used: eyelid skin (172.1, 173.1), conjunctiva
(190.3), retina (190.5), uveal tract (190.6), orbit except for bones (190.1), and
orbital bones (170.0). For statistically purposes, all malignant ocular tumors
were divided into four subgroups: eyelid, conjunctiva, intraocular and orbit.
To calculate mortality rates, only those cases were considered whether death
has been caused by a malignant ocular tumor, i.e. tumor-related death.
Malignant eyelid tumors occurred more frequently than conjunctival
tumors. So, there were 21 children with malignant eyelid tumors including
3 children with xeroderma pigmentosum (14 males and 7 females) and only
11 patients with malignant conjunctival tumors including 2 patients with
xeroderma pigmentosum (7 males and 4 females).
Incidence: In three age subgroups (0–4, 5–9 and 10–14) the highest age-adjusted
incidence of malignant eyelid tumors was in males but only in age subgroup 0 to
4 this incidence (0.5 per 100,000 children population) in males was statistically
significant. In children with malignant conjunctival tumors age-adjusted
incidence was also highest in males but in age subgroup 10 to 14 years (0.4 per
100,000 children population). Comparing age-adjusted incidence of children
with malignant eyelid tumors in urban and rural areas (Table 2.1) we found
that the highest age-adjusted incidence was in urban children both sexes (0.4
per 100,000 urban and rural children population). Because of small number of
patients we calculated annual age-adjusted incidence for both sexes of children
with malignant eyelid tumors together with malignant conjunctival tumors,
which ranged from 0.0 to 0.002 per million children population per year.
Mortality: Overall mortality of children from eyelid tumors in urban areas for
males and both sexes is 0.01 per 100,000 urban males and females children
population and 0.0004 for rural males, females and both sexes per 100,000
rural males, females and both sexes children population, i.e. mortality of
Ch-2.indd 36 31-08-2012 12:30:46

Table 2.1: Number and standardized incidence of children with malignant
eyelid and malignant conjunctival tumors per 100,000 male and female children
population in urban and rural areas
Number of patients Eyelids Conjunctiva
and standardized
incidence Urban Rural Urban Rural
M F B M F B M F B M F B
Number of patients 7 3 10 7 4 11 3 3 6 4 1 5
Standardized incidence 0.2 0.01 0.4 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.01 0.03
Abbreviations: M: Males; F: Females; B: Both sexes
urban children from malignant eyelid tumors 2.5 fold higher than mortality
from this tumors of rural children. Overall mortality of urban children from
malignant conjunctival tumors for both sexes (0.004) is 2.0 fold higher than
that for rural children (0.002) per 100,000 urban and rural both sexes children
population.
Percentage of children died from malignant eyelid tumors less than 1 year,
at 1 year, at 2 years, at 3 years and at 4 years was 0.0 percent, at 5 to 9 years
was 9.5 percent (2 died patients) and at 10 years from initial diagnosis was
also 9.5 percent (2 died patients) including 3 died patients with xeroderma
pigmentosum. Thus, during 10 years there were 19.1 percent died children (4
died of 21 patients with malignant eyelid tumors).
Percentage of children died from malignant conjunctival tumors less than
1 year, at 1 year, at 2 years, at 3 years, and at 4 years was 0.0 percent at 5 to
9 years the rate was 9.1 percent (1 died patient) and at 10 years from initial
diagnosis that was also 9.1 percent (1 died patient). Thus, during 10 years
there were 18.2 percent died children (2 died from 11 children with malignant
conjunctival tumors).
Survival of patients with malignant eyelid tumors less than 1 year, at 1 year,
at 2 years, at 3 years and at 4 years was 100.0 percent, at 5 to 9 years the rate was
90.5 percent (19 survived patients) and at 10 years from initial diagnosis that
was 81.0 percent (17 survived of 21 patients with malignant eyelid tumors).
Survival of patients with malignant conjunctival tumors less than 1 year,
at 1 year, at 2 years, at 3 years, and at 4 years was 100.0 percent, at 5 to 9 years
the rate was 90.9 percent (10 survived patients) and at 10 years from initial
diagnosed that was 81.8 percent (9 survived of 11 patients with malignant
conjunctival tumors).
All of our data concerning age-adjusted incidence, annual age-adjusted
incidence, survival and mortality from malignant eyelid and conjunctival
tumors in children require more epidemiologic investigations. Our work could
be only a basis to compare of our and other future epidemiologic investigations
in Uzbekistan.16
Ch-2.indd 37 31-08-2012 12:30:46

REFERENCES
1. Cunha RP, Cunha MC, Shields JA. Epibulbar tumors in children: a survey of 282
biopsies. J Pediatr Ophthalmol Strabismus 1987;24:248-54.
2. LeSueur BW, Silvis NG, Hansen RC. Basal cell carcinoma in children: report of
3 cases. Arch Dermatol 2000;136:370-72.
3. Al-Buloushi A, Filho JP, Cassie A, et al. Basal cell carcinoma of the eyelid in
children: report of three cases. Eye 2005;19:1313-4.
4. Croxatto JO, Iribarren G, Ugrin C, et al. Malignant melanoma of the conjunctiva.
Report of a case. Ophthalmology 1987;94:1281-5.
5. Polat A, Yildirim C, Isik Y, et al. Conjunctival melanoma in six-year-old female.
Pediatr Blood Cancer Oct 27, 2006 [Epub ahead of print].
6. Strempel I, Kroll P. Conjunctival malignant melanoma in children.
Ophthalmologica 1999;213:129-32.
7. Brichard B, De Potter P, Godfraind C, et al. Embryonal rhabdomyosarcoma
presenting as conjunctival tumor. J Pediatr Hematol Oncol 2003;25:651-2.
8. Barchash SA. Aktualnie voprosi diagnostiki i lecheniya novoobrazovanii organa
zreniya. In: Diagnostika i lechenie opucholei glaza i orbiti. Kiev, 1971. pp. 73-4.
9. Ferry JA, Fung CY, Lucarelli MJ, et al. Lymphoma of the ocular adnexa: A study
of 353 cases. Am J Surg Pathol 2007;31:170-84.
10. Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. Cutaneous,
ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol
1987;123:241-50.
11. Robbins JH, Kraemer KH, Lutzner MA, et al. Xeroderma pigmentosum. An
inherited disease with sun sensitivity, multiple cutaneous neoplasms, and
abnormal DNA repair Ann Intern Med 1974;80:221-48.
12. Cleaver JE. Defective repair replication of DNA in xeroderma pigmentosum.
Nature 1968;218:652-6.
13. Paches AI, Brovkina AF, Ziangirova GG. Klinicheskaya onkologia organa
zreniya. Moskva, Meditsina, 1980;57-9,115-7.
14. Goyal JL, Rao VA, Agrawai K. Oculocutaneous manifestation in xeroderma
pigmentosum. Br J Ophthalmol 1994;78:295-7.
15. Touzri RA, Mohamed Z, Khalil E, et al. Ocular malignancies of xeroderma
pigmentosum: clinical and therapeutic features. Ann Dermatolog Venereol
2008;135:99-104.
16. Mouratkhodjaev NK. Osnovnie etapy razvitiya oncologicheskoy sluzhby v
Uzbekiskoy SSR. Vopr Onkologii 1988;34:3-7.
MALIGNANT INTRAOCULAR TUMORS

Malignant intraocular tumors are represented by such a rare malignant tumor
as malignant medulloepithelioma, melanoma and retinoblastoma.
Medulloepithelioma is so rarely that occurred only in 2 cases during 10
years,1 or only in 6 children during 25 years,2 or in 8 children during 12 years.3
Ch-2.indd 38 31-08-2012 12:30:46

Of all children with benign and malignant medulloepithelioma there were
40.0 percent (6 of 15 children) with malignant medulloepithelioma,2 or
88.9 percent (8 of 9 children).3 Males and females aged from 6 weeks to 2
years,2 or from 0.2 years to 10 years3 were equal affected in both reports.2,3 This
malignancy is locally invasive, but metastatic disease is uncommon.3,4 However,
Broughton and Zimmerman5 found that the prognosis is worse than the results
of their study would indicate, especially among those cases observed to have
extraocular extension. So, of 56 intraocular medulloepitheliomas histologic
evidence of malignancy was observed in 37 tumors (66.1%), and follow-up
studies revealed 4 patients (10.8%) to have died of metastatic disease.5
Malignant melanoma is also rare malignant intraocular tumor in children.
Although this malignancy presenting in birth is extremely rare, 4 cases have
been published before 2005. There were 3 males and 1 female with follow-up
period from 2 years to 10 years. To the end of follow-up period, all of them
were alive.6 In young patients aged 20 or younger uveal melanoma occurred
in 11 (1.4%) of 800 patients,7 or in 0.8 percent (66 of 8000 patients with uveal
melanoma, including adults). The youngest patient was 3 years old.8 In patients
with uveal melanoma under 30 years old patients 20 or younger were in
49.2 percent (6 of 14 patients).9
Retinoblastoma is the most common malignant intraocular tumor in
children. The story of retinoblastoma was described by Dunphy,10 who found
that the first mention in the literature of anything resembling retinoblastoma
goes back to 1597, when Petrus Pawius of Amsterdam reported his autopsy
findings in a case of a young child. 200 years later, Dr Hayes described the
first case of bilateral retinoblastoma and was the first one to write about the
peculiar fundus reflex seen early in this disease “bright look, resembling a cat’s
eye in the dark”. He was also the first to describe optic nerve involvement.
In 1809 James Wardrop of Edinburg published his book “Observation on
Fundus Hematodus or Soft Cancer”, in which he reported 17 cases. He was
the first to advocate early enucleation of affected eye as a life-saving measure.
In 1891 Flexner and in 1897 Wintersteiner described the classical rosettes that
are found in many retinoblastomas rods and cones. They indicated that the
tumor was a neuroepithelioma.10 There are more than forty denominations of
retinoblastoma.11 In 1926 the American Ophthalmological Society officially
accepted the term retinoblastoma, which has become the preferred term.10
Now is well known that retinoblastoma is the most frequent malignant eye
tumor in children comprising 3 percent of registered cases of malignancies
in children under 15 year of age13,14 and 2.5 to 4.5 percent between oncologic
disease in children,15 or 12.1 percent of pediatric malignancies.16
Laterality: Unilateral form of retinoblastoma occurred in 60.0 percent cases
and this form more often is unifocal, sporadic and in much more cases are
Ch-2.indd 39 31-08-2012 12:30:46

with late stage of retinoblastoma’s development. Bilateral form occurs in

40.0 percent cases and this form more often is multifocal, hereditary with
different grade involvement of tissues.15 However, in the literature there is also
another percentage of bilateral cases of retinoblastoma, which ranged from
9.3 percent,17 22 to 30 percent12 to 50.0 percent.18
Age of patients with retinoblastoma: Patients with a positive family history
tend to be diagnosed quite early in life, sometimes within days after birth.19
Patients with bilateral involvement who have a negative family history
are usually diagnosed within the first year, and patients with unilateral
involvement receive a diagnosis within the first 2 years.20 The most patients
with retinoblastoma are diagnosed in the 0 to 4 age subgroup with the peak
incidence in the second year of live,21,22 60.0 percent of the retinoblastoma
presented in the 0 to 4 years subgroup, but 37.5 percent presented later as
neglected, advanced; usually bilateral retinoblastoma diagnosed in the 5 to 9
years age group and the rest in the 10 to 14 years group.23 In the literature,
retinoblastoma in adults has been also described.24-29 A retinoblastoma
occasionally can undergo spontaneous regression. Of 700 eyes with
retinoblastoma there was evidence of spontaneous regression in 8 cases
(1%). Although certain immunologic factors probably play a role, the precise
mechanism of spontaneous regression is poorly understood.12 The gene
responsible for retinoblastoma is located at 13q14.30,31 This gene can mutate
or delete in both nonheritable and heritable forms of retinoblastoma.31,32,39
Retinoblastoma may occur as a germinal mutation or a somatic mutation.
Forty percent of retinoblastoma caused by germinal mutation and included
patients with a positive family history of retinoblastoma. Children with
hereditary forms usually have multifocal, bilateral retinoblastoma, whereas
children with the somatic form have unilateral, unifocal disease. However,
up to 15 percent of cases of sporadic unilateral retinoblastoma may be
hereditary.33 Germline abnormalities were found in 11.0 percent of sporadic
unilateral retinoblastoma and in 86.0 percent of sporadic bilateral or positive
familial history retinoblastoma.34 The direct transmission of an RB1 allelic
loss form a phenotypically normal mother to a retinoblastoma child was
detected.37 The specific marker chromosome i(6p) has been found in 9 tumors
of 15. In 2 cases, trisomy of the short arm of chromosome 6 was present,36
whenever a 13q16 deletion diagnosed, immediate ophthalmologic evaluation
is recommended to ensure prompt diagnosis of retinoblastoma.30 The
alteration of chromosomes in the tumor cells was consisted in monosomia,
threesomia, tetrasomia, partitution of 13 and 6 chromosomes. The markers
of HLA-factors of predisposition to retinoblastoma in Uzbeks population
were: HLA-A25 and HLA-A28. The allocation of HLA-antigenes describes
genetic polymorphism depending on phase of disease and sex of patients.
Ch-2.indd 40 31-08-2012 12:30:46

These findings could be put into requisition on for determination the degree
of risk of retinoblastoma’s formation and diagnostic differentiation, which can
decrease mortality from retinoblastoma.37,38 The clinical syndrome depends,
to a degree, upon the missing portion of long arm of chromosome 13. It is
possible that all retinoblastomas have a tiny segment of this chromosome
missing not detectable by current methods of chromosome analysis.39
According to ‘Histological typing’40 retinoblastomas may be dividing by
differentiated and undifferentiated types. Sometimes good differentiated types
are called retinocytomas.
Retinocytoma: Recently the name of retinocytoma has been recommended as the
most appropriate designation for those rare variants of retinoblastoma that are
so completely differentiated that they are considered totally benign.39 Bilateral
retinocytoma occurred in (13.0%) and the family history of retinocytoma was
positive in (13.0%). The risk for malignant transformation of retinocytoma
into retinoblastoma was (4.0%); therefore, patients with a presumed
diagnosis of retinocytoma should be closely observed.41 Many authors named
retinocytoma as retinoma,39,42-44 which are the most commonly observed
in patients with retinoblastoma and their relatives.44 The new concept of
retinoma, or retinocytoma, brings up the rare “spontaneous regression” long-
reported in the literature. Systematic investigation of all relatives of children
suffering from retinoblastoma is showing up more and more retinoma cases
undetected until now. The average age of the retinoma patients is 23 years.42
There might be an increased risk for patients with retinoma to develop another
primary tumors, necessitating regular follow-up of these patients.43 Majority
of cases of retinoblastoma are sporadic (i.e. disease in patients who have no
family history of retinoblastoma affected family members on comprehensive
familial ophthalmological examination). Positive family history in a newly
diagnosed child with retinoblastoma was found in (7.0%) and negetive family
history in 93.0 percent.45
Gender of patients with retinoblastoma: Many authors found no difference in
retinoblastoma incidence among males and females,11,46,47 no predilection for
right or left eye.48 However, Ben Ezra et al.49 found over representation of girls
among unilateral retinoblastoma in 61.1 percent and of boys among bilateral
cases in 58.9 percent.50 The predomination of girls also found by Bhurgi et
al.51 Gender ratio (M:F) was of 1:5, but male infants had increases rates of
retinoblastoma.52 In both boys and girls the mean incidence of retinoblastoma
was equal being of 0.54 per 100,000 children less than 10 years old.46 The
average annual incidence of retinoblastoma for boys and girls less than 5 years
of age was 9.5 and 8.7 per million respectively with male: female rate of 1.09.53
Another form of retinoblastoma, trilateral retinoblastoma54-56 described below.
Ch-2.indd 41 31-08-2012 12:30:46

Race of patients with retinoblastoma: There is discussion in the literature

regarding retinoblastoma incidence in different ethnic groups. Devesa57 argues
that there were 10.8 cases per million white children, compared to 9.8 cases
per million black children, although no difference in retinoblastoma incidence
for whites and blacks was found, as well as “other non-whites had rates greater
than four times those of whites”. Among all observed patients, more than
50.0 percent of whites and 25.0 percent of blacks have had retinoblastoma
before 2 years of age. Survival rate of blacks is significantly lower than that of
whites.58 Statistically significant excess was seen in Asian children.59
Incidence of retinoblastoma: It is difficult to compare the incidence of
retinoblastoma in different countries as some base their findings upon
retinoblastoma incidence of live births49,61,62 while others consider the age
of patients such as > 5 years,49,62 from 0 to 14,63 0 to 17,61 <5 or <9 years,64
>10 years,46,65 >15 years.20 Moll et al.47 base their study of retinoblastoma
incidence upon both live births and age of patients calculated in a 5-year
birth cohort. Except for that, time period of retinoblastoma incidence in the
literature was from 186247 to 2002,66 to 2003.68 Of interest is the fact that the
offspring of women treated with in vitro fertilization do not have a heightened
risk of retinoblastoma. Relative risks for retinoblastoma were significantly
raised. This possible association of an increased risk of retinoblastoma in a
population-based study needs to be established.60
The number of new retinoblastoma cases per year ranged from 0 to 139 (1
to 13 per birth cohort) in Sweden and from 0 to 10 in Finland (1 to 19 birth
cohort) in 1958 to 1998.67 The average annual number of cases doubled from
3.3 to 6.5 after the implementation of the national health insurance program,
and the age at diagnosis decreased from 29 to 21 months in1978 to 2003.68 The
incidence of retinoblastoma reported in the literature ranged from 1:1000049
Table 2.2: Retinoblastoma incidence in the literature by research period
Reference Period Country Age of patients Incidence
47
Moll et al. 1862–1995 Nederlands >15 years 1: 17000
Lommatzsch et al.46 1961–1980 Germany >10 years 0.54: 100000
Saw et al.64 1968–1995 Singapore <9 years, 2.4: 1 million
<5 years 11.1: 1 million
Sanders et al.61 1968–1980 Gr. Britain 0–17 years 1: 23000
Babior69 1972 Belorussia >14 years 1:34000
Pendegrass et al.20 1974–1976 USA >15 years 3.58: 1 million
Tamboli et al.65 1974–1985 USA >10 years 5.8: 1 million
Ben Ezra et al.49 1975 Malawi >5 years 1: 10000
Tan et al.62 1976–1995 Singapore >5 years 1: 15786
Wessels et al.71 1983–1988 Namibia >15 years 5.8: 1 million
Amozorrutia-Alegria et al.63 1990–1994 Mexico 0–14 years 3.2: 1 million
Khandekar et al.66 1990–2002 Oman >15 years 4.04: 1 million
Ch-2.indd 42 31-08-2012 12:30:46

to 1:34000,69 1 in 17500 births,70 1:18000 live births,71 from 2.4 per million64
to 11.1 per million61 (Table 2.2).
As shown in Table 2.2 age of patients with retinoblastoma ranges widely
and incidence rate of retinoblastoma, which depends on patients’ cohort has
also widely ranged.
The annual incidence of retinoblastoma varies between 7 per million in
African populations to 3 to 6 per million in Europe and US and rates lower
than 3 per million in Asian populations.72 Age standardized incidence rates
per million for both sexes range in Africa from 0.5 to 24.5; in Central and
South America from 2.7 to 7.8; in North America from 2.9 to 9.4; in Asia
from 1.3 to 9.2; in Europe from 1.5 to 7.1; in Oceania from 4.2 to 7.8 and 4.1
per million births according to Automated Childhood Cancer Information
System (ACCIS) in 1978 to 1997. The cumulative incidence of retinoblastoma
was found to be 44.2 and 67.9.73 Cumulative incidence rates per million for
both sexes range in Africa from 7.0 to 339.0; in Central and South America
from 34.0 to 105.0; in North America from 38.0 to 123.0; in Asia from 22.0
to 123.0; in Europe from 19.0 to 92.0; in Oceania from 54.0 to 103.0.74 The
mean annual incidence of retinoblastoma in New South Wales from 1975
to 2001 was 8 per million children aged 0 to 6 years.75 The mean incidence
was 11.8 and 11.2 per million children younger than 5 years of age in Sweden
and Finland respectively and 6.7 and 6.2 per 100,000 live births respectively.
Analysis based on year of diagnosis suggested moderate increase in incidence
since 1990, but by births cohort analysis, incidence rates were stable for both
countries. The pooled incidence by birth cohort was 6.0 per 100,000 live births,
corresponding to 1 in 16642 live births.67
Metastases: Four factors were found to be independently associated with
the development of metastases: involvement of optic nerve to transsection
line, postlaminary optic nerve involvement, choroidal involvement and
enucleation of an affected eye more than 120 days after initial diagnosis.
The 5-year metastatic risks associated with these factors were 57.0 percent,
13.0 percent, 8.0 percent and 4.0 percent, respectively. The relative risk
estimate, calculated from the Cox model, was used for a score classification
with groups of low, medium, and high metastatic risk. The 5-year incidence
of metastases was 4.0 percent, 43.0 percent and 68.0 percent respectively.76
However, Kopelman et al.77 believes that choroidal invasion of retinoblastoma
was not significantly associated with a fatal outcome. At the same time, when
the tumor reached the orbit 95.7 percent of the patients died. In 47 cases of
the 70 cases with orbital invasion, the histologic sections indicated that the
tumor was incompletely excised. In all of these cases, the patients died.77 The
factors for a poor prognosis were an interval between onset and treatment
of >5 months, a lag time before treatment of > 2.5 months, and extraocular
Ch-2.indd 43 31-08-2012 12:30:46

disease.78 In the case of fatal retinoblastoma, the median time to death was
7.7 months. The median time to death in bilateral cases was longer than in
unilateral cases: 14.2 months with bilateral retinoblastoma compared to 6.4
months with unilateral retinoblastoma.77 Metastatic retinoblastoma occurred
within 4 years from diagnosis of the unilaterally affected patients and within
nine years from diagnosis of the bilaterally affected patients.79 8.7 percent of
the patients with neonatal retinoblastoma diagnosed at the age of 1 month or
younger developed metastatic disease and died, 6.5 percent of these patients
had documented metastases in the first month of live (one at birth).19
Mortality of retinoblastoma was reported to be 87.0 percent in 1897 in
children treated by enucleation, and 41.0 percent in 1931 at the dawn of the
modern radiation era. Even today, mortality is enormous in less developed
countries of the world. It was reported to be 95.0 percent in the Phillipine
Islands and, in series of 40 cases, to be 100 percent in Nigeria. Early diagnosis
is as much or more factor in mortality.39 By 25 years after diagnosis more than
50.0 percent of the bilaterally affected children are dead and by 35 years 59.0
percent are dead. Although bilateral patients were seen at significantly lower
ages at diagnosis, they did not have a lower mortality rate from metastatic
retinoblastoma.79 The mortality of retinoblastoma varies in different countries
and research periods. For example, in Sweden in 1958 to 1971 the mortality
from retinoblastoma was 4.5 percent,80 in Australia (Victoria) in 1956 to 2000
from nil to 7.8 percent,81 in the same country, but in other period of 1956 to
1976 that was 8.3 percent,82 in Poland (Krakow) in 1964 to 1984 mortality was
45.0 percent,83 in Cameroon over a period of 4.5 years that was 78.57 percent.84
Survival: Opinions of different authors upon survival of boys and girls are
distinguished. Some of them believe that there was no difference between
survival of girls and boys.72 However, others found significantly higher
survival rate for boys than for girls, this is partly accounted for by difference
in age and stage at diagnosis. Children referred to units specializing in the
treatment of retinoblastoma have a higher three-year survival rate than those
treated at other hospitals.61 Survival rates were higher in children <2 years
because children who present at a younger age may have tumors diagnosed at
earlier stage. Sanders et al. s uppose that older children tend to have a worse
prognosis, which is related to the fact that their tumors are diagnosed at a more
advanced stage.61 However, Saw et al.64 found that there was no difference
in survival rates for sex, race, laterality, family history of retinoblastoma,
treatment, or year of diagnosis The predominant type of eye cancer in
children, retinoblastoma, had a very favorable prognosis.91 Survival rate in the
unilateral cases was significantly higher than in bilateral cases.92 However, the
most researchers found that there was no significant difference in survival rate
between patients with unilateral (88.1±5.6 percent) and bilateral (64.3±14.6
percent) retinoblastoma at 5 years. The 10-year overall survival rates of the
Ch-2.indd 44 31-08-2012 12:30:47

two groups were the same at their 5-year survival rates, and, similarly, the
difference between the groups was not significant.18,78,88,90
Survival of children with retinoblastoma varies in different countries
and research period. So, in Italy for cases diagnosed in 1986 to 1989,
5-year survival rate was 100 percent,85 but for cases diagnosed in 1990 to
1994 that was 87.0 percent. The same 5-year survival rate (87.4%) was in
United State during 1985 to 1989.87 In Mexico another survival rate, the
disease-free survival, at 10 years was 87.5 percent.14 In Turkey between
1963 and 1964 the survival rate of unilateral cases was 82.8 percent and
that of bilateral cases was 81.1 percent at 5 years88 and between 1981 and
2004 the 3-year cumulative survival rate for unilateral cases was 90.74 and
for bilateral retinoblastoma 87.35 percent.89 In Asia, the highest 5-year
cumulative survival rate was in Japan. For unilateral cases survival rate was
93.3 percent at 5 years and 82.3 percent at 10 years. For bilateral cases the
rate was 92.3 percent at 5 years and 86.7 percent at 10 years.30 In Taiwan
between 1982 and 2004 the 5-year overall survival rate was 80.9 percent
(unilateral, 88.1%, bilateral, 64.3%). The survival rate of patients with
intraocular and extraocular disease was an independent factor indicating
a poor prognosis.78 In the same country, Taiwan, but in the other research
period from 1978 to 2003, the survival rate at 5 years increased from 67.0
to 72.0 percent an effect that was obvious in unilateral cases (70–83%) but
not in bilateral cases (50% for both time periods).68 From 0 age group to
1-4 and 5+ age group 100 percent survival rate in all three age groups has
had only Sweden, where long-term survival rates were 96, 92, 91, 89 and 86
percent at 1, 3, 5, 10 and 18 years, respectively.72
The survival of 954 cases of retinoblastoma, diagnosed between 1978 and
1989 in 28 populations belonging to 17 European countries and covered by
cancer registration was analyzed by Sant et al.72 According their investigations
5-year observed survival of 100 percent in 0-age group was in 9 countries
(Austria, Denmark, The Netherlands, France, Germany, Iceland, Slovenia,
Spain, and Sweden). Four countries have had 90 to 94 percent (England and
Wales, Finland, Scotland, and Slovakia). The lowest rate was in Estonia-33.0
percent. In 1 to 4-year of age group, 100 percent of the rate was in 8 countries
(Austria, The Netherlands, Estonia, France, Iceland, Poland, Slovenia, and
Sweden), 90 to 97 percent was in 4 countries (Scotland, England and Wales,
Germany, and Finland). Eighty-two to eighty-nine percent was in 4 countries
(Spain, Denmark, Italy, and Slovakia). In Italy in other period (1990-1994)
5-year survival rate was 87 percent.86 The lowest rate was in Switzerland
(67.0%). In 5+ age group 100 percent, 5-year observed survival was in
8 countries (Denmark, Estonia, Finland, Italy, Scotland, Slovakia, Spain,
and Sweden). Five countries have had no cases in this age group (Austria,
Netherlands, France, Iceland, and Switzerland). European pooled data in all
Ch-2.indd 45 31-08-2012 12:30:47

three age groups ranged from 92 to 94 percent (94% in 0 age group, 92% in 1
to 4 and in 5+ age group and 93% in all ages).
Second primary tumors: Statistically significant excess mortality was found for
second primary cancers of bone, connective tissue, and malignant melanoma
and benign and malignant neoplasms of brain and meninges. Deaths from
second tumors were more frequent among females than males. The relative risk
of mortality was much higher among patients with bilateral retinoblastoma
than with unilateral disease.93 The incidence of second primary tumors in
patients treated without radiation and where tumors developed outside the
field of radiation was 4.8 percent,78 or 10.0 percent at 10 years,94 9.8 percent
at 15 years,78 15.7 percent,78 or 30.0 percent at 20 years and 68.0 percent
at 32 years.94 Hereditary retinoblastoma confers an increased risk for the
development of second primary tumors, especially in patients treated with
external beam irradiation before the age of 12 months. Rather, early external
beam radiotherapy is probably a marker for other risk factors of second
primary tumors,95 which is serious problem for the survivors of hereditary
retinoblastoma and its importance should be recognized in genetic counseling
of patients.
A cumulative incidence of second primary tumors 18 years after
diagnosis was 8.4 percent, at the age of 20 years is 15.7 percent and at the
age of 35 years was 19.0 percent.96 The cumulative incidence for developing
a new cancer at 50 years after diagnosis of retinoblastoma was 36.0 percent
for hereditary and 5.7 percent for nonhereditary retinoblastoma,97 or 51
percent (+/–6.2%) for hereditary and 5 percent (+/–6.2%) for nonhereditary
retinoblastoma.98 The incidence of second nonocular cancer of patients with
neonatal retinoblastoma diagnosed at the age of 1 month or younger reached
54.0 percent by 23.7 years for the patients who received radiotherapy, while the
incidence was 0 percent for the patients who did not.19 More children die from
their second tumor than retinoblastoma itself within 5 years after diagnosis
of bilateral retinoblastoma. By 25 years after diagnosis more than 50 percent
of the bilaterally affected children are dead and by 35 years 59 percent are
dead.79 Thirty-five different types of second primary tumors were reported.
Most of them were octeosarcomas (37.0%), followed by melanomas (7.4%),
soft-tissue sarcomas (6.9%), brain tumors (4.5%), fibrosarcomas (3.3%). Less
frequently reported were leukemias (2.4%), sebaceous cell sarcomas (1.6%),
and non-Hodgkin lymphomas (1.6%).96 Draper et al.99 suggest an association
between retinoblastoma and malignant melanoma. Within the field of
radiation treatment the cumulative incidence rate for all second neoplasm
after 18 years was 6.6 percent and for osteosarcomas alone 3.7 percent. The use
of cyclophosphamide may increase the risk of second primary neoplasms in
patients with genetic retinoblastoma.99
Ch-2.indd 46 31-08-2012 12:30:47

In spite of the improvements in survival, however, childhood cancer
remains a major cause of death in the European Community, affecting
about 15 percent of children between the ages of 1 and 14.100 Abramson and
Servodidio101 found that cooperation of the optometrist, the ophthalmologist,
the pediatric oncologist, and radiation therapist plays an important role
in the long-term survival of children with retinoblastoma. A diagnosis of
retinoblastoma has to be suspected by the ophthalmologist on the first visit.
Parents of the patients with more advanced disease consulted significantly
later. Poor parental education correlated significantly with late consultation.
Socioeconomic factors and access to health care might play a role in delayed
diagnosis.102 The parents of children with retinoblastoma had excess of small
intestinal and rectal cancers and Hodgkin’s disease.103
Trilateral retinoblastoma is another form of retinoblastoma besides
unilateral and bilateral ones,104 that was first reported in 1971 by Jensen et
al.105 At the same year Meur et al.106 described an infant girl aged 10 months
with retinoblastoma of the left eye and a suprasellar tumor, which had “de
rares rosettes”. In 1977, Jacobec et al.107 reported about two patients. The
authors found that patients who develop symptoms of a brain tumor after
a prolonged interval since the treatment of their ocular tumors should be
suspected of harboring a second intracranial primary tumor. In 1980, the
association of retinoblastoma and tumors in the pineal regio was termed
trilateral retinoblastoma by Bader et al.108 who later described eleven patients
with bilateral retinoblastoma presented at a mean age of six months and with
pineoblastoma at 4 years.32 After these reports were published, a number
of case reports appeared that recognized trilateral retinoblastoma as a very
rare condition,15,31,39,109-114 most cases almost always considered fatal,109,110
highly fatal,115 or almost exclusively fatal,110 or the disease with a very poor
outcome.55,116
Pineoblastoma is developed from pineal gland, which shows circardian
oscillation in the mammalian, but these damp out within a few days
in the absence of input from the primary circardian pacemarker in the
suprachiasmatic nuclei.117 In mammals the pineal organ has lost both the
direct light sensitivity and the capacity of generating circardian rhythms, and
melatonin biosynthesis is regulated by retinal photoreceptors and circardian
oscillator located in the suprachiasmatic nucleus of the hypothalamus. In both
diurnal and nocturnal vertebrates, including humans, its main product, the
hormone melatonin, is synthesized and released in rhythmic fashion during
the dark portion of the day-night cycle.118 The two central effects of melatonin,
photoperiodic time measurement and circardian entrainment, are probably
mediated through completely separate mechanisms.119 Melatonin, the major
product of the pineal gland, is also synthesized in the retina of several
Ch-2.indd 47 31-08-2012 12:30:47

vertebrate species.120 In certain lower animals, the pineal gland functions

as a photoreceptor organ and resembles the retina histologically, and is
described as a “third eye”.32 The tumor recalls the function of the pineal gland
as a photoreceptor organ at an earlier stage of its phylogenesis.121 Animal
pineal photoreceptors are functionally and morphologically similar to retinal
photoreceptors. Primary tumors of the pineal gland or its vicinity may be
classified into the tumors of parenchymal, interstitial or germ cell origin.122,123
The WHO classification of the central nervous system neoplasms divides
pineal parenchimal tumors into pineocytoma, pineoblastoma and mixed
pineocytoma-pineoblastoma.124,125 Neoplasms arising from interstitial cells
represent astrocytomas. Pineoblastoma, a poorly differentiated neoplasm,
occurs in childhood, whereas pineocytoma is better differentiated and occurs
in adults.126
In the literature, the tumors of the pineal gland or its vicinity are reffered to as
primitive neuroectodermal tumors (PNET),31,121,134,135 intracranial primitive
neuroectodermal tumors,114,136 pineal parenchymal tumors (PPT),125,126 mid-
line intracranial malignancies or neoplasms or tumors,33,56,128,137-139 intracranial
tumors or neoplasms or malignancies,35,129,140,141 midline pineal tumors,135
pineal neoplasms or paracellar lesions,142 suprasellar retinoblastoma,127 sellar
tumors,111 pineoblastoma,33,128,143,144 pinealoma,145-147 pineal neuroblastic
tumors (PNT),30 pineal retinoblastoma,112 ectopic retinoblastoma,113,130
ectopic intracranial retinoblastoma or ectopic intracranial neuroblastic tumor
(EINT),64,130,148,149 primary neuroblastic tumor or neoplasms,115,132 primary
malignant intracranial tumors.110 The cerebral neoplasm can arise within the
vermis as a medulloblastoma111 or within the third ventricle of patients with
trilateral retinoblastoma.113 Patients with “sellar” trilateral retinoblastoma
have characteristics different from those of the patients with a pineal region
trilateral retinoblastoma: the intracranial mass more often presents initially
and occurs at a younger age. It is more common in females and is more often
associated with unilateral ocular lesion.134 In trilateral retinoblastoma, pineal
tumor, are comparatively more common than suprasellar and parasellar
tumors,32,35,109,128,129,138 but the origin of supra/parasellar and pineal tumors
in retinoblastoma patients is still questionable.35 The pineal region tumors
occur more frequently than suprasellar PNET,114 and suprasellar trilateral
retinoblastoma was diagnosed earlier and may arise earlier than pineal trilateral
retinoblastoma.54 The pineal region has the greater variety of tumor types.152
Some authors suggested that benign variant of trilateral retinoblastoma may
also be possible, describing benign cystic lesion of the pineal gland in patient
with hereditary retinoblastoma.153 The median largest dimension of PNT in
77.0 percent and EINT in 23.0 percent was 30 mm, 18.0 percent were 15 mm
or less in size and 35.0 percent were between 16 and 30 mm in size. The size
Ch-2.indd 48 31-08-2012 12:30:47

of PNT and EINT did not differ in children who were not screened. Of 15
trilateral retinoblastomas detected at screening, 33.0 percent were 15 mm or
less in size and 10.0 percent of patients with trilateral retinoblastoma were
detected after symptoms developed.54
Gender of patients with trilateral retinoblastoma: Of children who developed
trilateral retinoblastoma 40.0 percent,128 or 41.5 percent,114 or 48.0 percent54
were boys, and 52.0 to 53.2 percent,54,154 or 60.0 percent128 were girls. The
male-to-female ratio of children who later developed PNT was similar to
that of those who developed an ectopic intracranial tumor.31,54
Age of patients with trilateral retinoblastoma: The median age at diagnosis of
trilateral retinoblastoma was 26 months56 or 30.7 months.31 There was no
difference between median age at diagnosis of trilateral retinoblastoma of
children with unilateral and bilateral retinoblastoma or between those with
familial and sporadic retinoblastoma.54
Laterality of trilateral retinoblastoma: Since Bader et al.108 termed
trilateral retinoblatoma as a combination of bilateral retinoblastoma with
pineoblastoma more than 25 years ago, some authors demonstrated
that trilateral retinoblastoma can also be found in association with
unilateral retinoblastoma,33,54,107,111,127-133 or occur without intraocular
retinoblastoma.54,128,130 One of the first trilateral retinoblastoma cases was
found in a patient with a unilateral retinoblastoma.106 Bilateral retinoblastoma
was found in 86.0 to 89.0 percent of children with trilateral retinoblastoma and
only 11 to 12.0 percent of children with trilateral retinoblastoma had unilateral
retinoblastoma.31,33,54,111,138 However, in small series of 8 children with trilateral
retinoblastoma and bilateral retinoblastoma, none had unilateral retinoblastoma.56
Trilateral retinoblastoma in siblings: The risk for siblings of retinoblastoma
patients of developing the disease is approximately 2.0 percent if the disease
in the affected child is bilateral and 1.0 percent if it is unilateral, assuming
that there are no other siblings; if there are unaffected siblings the risk for
subsequent children is lower.155 Of 13 patients with midline intracranial tumor,
12 (92.3%) patients had retinoblastoma, 2 patients of 13 (15.4%) were siblings.
The initial twin brother of a patient with trilateral retinoblastoma was found to
have a pinealoblastoma without retinoblastoma described by De Potter at al.128
The median time from retinoblastoma to trilateral retinoblastoma was 21 to
22 months.54,114,128 The time of trilateral retinoblastoma was longer for pineal
tumors than for suprasellar tumors.54 The time of diagnosis of retinoblastoma
varied between 5 months after the intracranial tumor was diagnosed and 4 years
before the intracranial tumor was diagnosed.138 An average interval between
retinoblastoma and trilateral retinoblastoma diagnosed was 24.6 months.31
A latent period of one to several years is typical between the appearance of
retinoblastoma and trilateral retinoblastoma.54
Ch-2.indd 49 31-08-2012 12:30:47

According to Jubran et al.116 who performed a retrospective review of

medical records of all retinoblastoma patients, trilateral retinoblastoma
occurred in 15.0 percent of patients. De Potter et al.128 found trilateral
retinoblastoma in 3.0 percent of retinoblastoma patients. However, report
of Paulino114 showed that 89.0 percent of patients with retinoblastoma will
have developed an intracranial tumor 4 years after the initial diagnosis of
intraocular retinoblastoma.
In the literature, which we reviewed (Table 2.3) this percentage varies
between 0.6 percent78 and 12.7 percent.56
As shown in Table 2.3 of totally number of retinoblastoma cases (2062
cases) trilateral retinoblastoma occur in 2.6 percent (53 cases) and the most
cases of TRB (33 cases) were found in the US.
In literature there are three reports analyzed in total 280 cases of trilateral
retinoblastoma. So, Kivelä54 analyzed 106 cases of trilateral retinoblastoma in
the period of 1966 to 1998, Paulino114 analyzed 80 cases and Marcus et al.31
analyzed 80 cases of trilateral retinoblastoma. Interestingly, that some of cases,
reported in the literature121,127,140,157,159,160 have not been analyzed by Kivela,54
the other cases109,113,134,139,142,158,159,161-165 have not been analyzed by Marcus
et al.31 and some of cases113,121,141,158,160,161,165 have not been analyzed by
Paulino.114 Some of cases33,35,77,110,111,151,166-168 have not been included in the
analysis either by Kivelä,54 or Marcus et al.31 or Paulino.114 From 1999 to 2004,
13 new case of TRB were reported in various countries (Table 2.4) of which
the majority cases of trilateral retinoblastoma (8 cases) were reported in the
US.33,115,116,151,166
Table 2.3: Percentage of trilateral retinoblastoma (TRB) in retinoblastoma (RB)

patients in a research period of 10 years and over in the literature
Authors Research Number of Number of Percentage TRB
period retinoblastoma TRB cases of RB patients
cases
Amoaku et al.109 1957–1994 146 5 3.4
Azar et al.156 1975–2001 123 2* 1.6
Blach et al.157 1979–1990 117 6 5.1
De Potter et al.128 1972–1992 440 13 3.0
Helveston et al.154 1967–1987 74 1 1.4
Kingston et al.130 1954–1984 630 12 1.9
Kopelman et al.77 1922–1959 361 2 0.6
Provenzale et al.56 1985–2002 63 8* 12.7
Scott and Richard135 1970–1990 56 3 5.4
Wu et al.158 1986–1991 52 1 1.9
Total 2062 43 2.6
* no information about number of the TRB patients after 1999
Ch-2.indd 50 31-08-2012 12:30:47

Table 2.4: New cases of trilateral retinoblastoma reported from 1999 to 2004
Authors Country City Year of Number of
publication TRB cases
Amare et al.35 India Bombay 1999 1
Bindlish and LaRoche110 Canada Halifax 1999 1
Cho et al.111 Korea Seoul 2002 1
Elias et al.151 US Charlottesville 2001 1
Halperin166 US Durham 2000 2
Ibarra, O’Brien33 US San Francisco 2000 1
Jubran et al.116 US Los Angeles 2004 3
Kivelä et al.30 Finland Helsinki 2003 1
Shields et al.150 US Philadelphia 2003 1
Tasdemiroglu167 Turkey Istanbul 1999 1
Total: 13 cases

Family history: Most authors found a positive family history of retinoblastoma

in patients with trilateral retinoblastoma,31,54,114,138,154 but only 3 patients
out of 207 patients with retinoblastoma (1.5%) had trilateral retinoblastoma
and none had positive family history of retinoblastoma.116 Children with
familial retinoblastoma have a particularly high incidence of trilateral
retinoblastoma.112,128,129,147,157 The chances of trilateral retinoblastoma
development were less than (0.5%) among unilateral retinoblastoma and 5 to
13 percent among familial retinoblastoma.54,130,135,140,157
Chromosome investigations: An insertion of the q12.3q21.3 segment
of chromosome 13 into chromosome 18 at band q23 in patients with
retinoblastoma was identified in family members of a patient with trilateral
retinoblastoma,151 bur normal chromosomes were found in a case of a
hereditary bilateral retinoblastoma and pinealoma.143 There was no difference
between children with mosaic and non-mosaic chromosomal deletion of
13q14. Only 7 percent of patients who had a mosaic chromosomal deletion,
including 13q14 did not develop trilateral retinoblastoma,54,130,157 but it is not
known which proportion of those who had mosaic deletion did. Deletion of
13q14 is an anxiety symptom and this cases demand to evaluate as urgent as
possible.30
Mortality of patients with trilateral retinoblastoma still remains very high
ranging from 92.3 percent128 to 100 percent.109,130,156,157,166
Median age at death of patients with trilateral retinoblastoma was 37
months (range, 9–142 months and was similar for sporadic and familial
retinoblastoma but lower for ectopic intracranial neuroblastic tumor than for
pineal neuroblastic tumor. Age at death of children whose tumor was diagnosed
by screening was similar to that of children who developed symptoms.54 Death
Ch-2.indd 51 31-08-2012 12:30:47

from an intracranial neoplasm occurs at a mean 11 months after diagnosing

that tumor.128
The causes of death were disseminated neuroaxis disease,138 leptomeningeal
tumor dissemination despite lack of progression in the midline intracranial
mass,112,139 diffuse central nervous system tumor,116,169 subsequent spread
of tumor to other sites within the central nervous system,130 concurrent or
subsequent subarachnoidal dissemination,142 sepsis without evidence of
metastasis or leptomeningial spreading,11 and after intrathecal chemotherapy
without evidence of tumor.154 The most serious complication of anesthesia was
a case of enterobacteria cloacae sepsis in the central venous access line used for
repetitively administering the anesthetic.166 Cranial and spinal leptomeningeal
metastases were invariably followed by a lethal outcome; metastases can also
occur in the ulna.56
Survival: The median survival after a diagnosis of intracranial tumors for
patients with trilateral retinoblastoma was 6 months,114 or 8 months,130 or 11
months,128 or 18 months.32,107,108,112,131,133,138,140,141,145,149 The median survival
for children with tumor of the pineal region and PNET of the suprasellar
region both were 6 months. The median survival for children who received
no treatment for the intracranial tumor was 1 month,109,128 whereas it was 8
months,128 or 15 months109 for children who were treated for the intracranial
tumor.
Marcus et al.31 analyzed the results of treatment of 57 patients with trilateral
retinoblastoma in the literature. In spite of the small number of patients in each
group, chemotherapy alone was the most successful method because the average
survival time was the longest (24.6 months) and percentage of living patients
was the highest (42.9%). Successfully chemotherapy treatment for patients
with trilateral retinoblastoma was described by various authors.31,55,114,170 For
the past years, chemoreduction with vincristine, etoposide, and carboplatin
was used for more than 160 children with intracranial retinoblastoma. Most
of these children were bilaterally affected and would be at risk of trilateral
retinoblastoma. None of these patients developed trilateral retinoblastoma,
although based on published data one would have expected 5 to 16 patients
to do so. In the same period of time, trilateral retinoblastoma has been seen
in children who did not receive chemoreduction.31 Length of survival after
discovery of brain tumor was similar in two groups: an average of 16 months
in the children in whom an intracranial tumor and spinal metastases were
found at the same time and an average 19 months in children whom spinal
metastases were found after discovery of the intracranial tumor.56 Although
patients with trilateral retinoblastoma and suprasellar tumors present and
are diagnosed earlier than trilateral retinoblastoma with pineal tumor, the
prognosis remains poor, patient dying of metastatic disease or postsurgical
Ch-2.indd 52 31-08-2012 12:30:47

complications within 10 months of diagnosis or within a median follow-up
of 68 months.139,149 Trilateral retinoblastoma was the major cause of death,
accounting for 50 percent of deaths. However, Nelson et al.35 in 1992 described
three children with newly diagnosed trilateral retinoblastoma, who have had
partial or complete response of the pineal tumors to chemotherapy, with no
active disease 8 or more years, 33 or more months and 12 or more months,
respectively, after diagnosis of the lesions. Later, in 1999, Bindlish et al.110
presented case of patient with neonatal trilateral retinoblastoma who was
alive and well 26 months after diagnosis and successfully treatment. Another
report deals with a patient with trilateral retinoblastoma who was still alive 30
months after diagnosis of midline brain neoplasm.128
Screening: There is dissonance in the literature about necessity of screening
for trilateral retinoblastoma in patients with unilateral and bilateral
retinoblastoma. Some authors confirm that screening is only useful when
the screened disease is treatable and the rate of incidence is high. Both
conditions may not be met in patients with trilateral retinoblastoma.171
The recommendation of routine screening with imaging studies for early
detection of trilateral retinoblastoma is questionable33 as the low incidence
of this disease may not warrant routine imaging and would not be physically
or economically practical130,170,172 unless pertinent signs are present.129,158,173
One half of trilateral retinoblastoma cases detected by screening were found
during the following year.54 Others believe that it could be rational to screen
every 3 months during the first year of diagnosis of retinoblastoma172 or
every 6 months until the age of 2 years and early until the age of 4 years,128
or twice a year for the next 3 years,54 or every 3 months for the first 2 years,
every 4 months for the next 2 years and then every 6 months until the age
of 5 years.55,150 Monitoring with brain magnetic resonance examination
at 6 to 12 months intervals may be benefit to this small group of patients
with a high propensity for every aggressive intracranial malignant
neoplasm.167 Routine ophthalmoscopy of patients with suprasellar primitive
neuroectodermal tumors (PNET) and other atypically located PNET
may reveal more cases of sellar trilateral retinoblastoma and hereditary
retinoblastoma.111,134 As trilateral retinoblastoma is nearly always observed
in hereditary retinoblastoma (bilateral or multifocal or positive family
history), screening efforts should be applied to the risk cohort.150 A more
aggressive approach toward screening a defined population of childhood
retinoblastoma survivors may be warranted.157 Screening for constitutional
RB1 mutation should become an integral part of current management of
any patient affected by retinoblastoma irrespective of the tumor laterality
and familial background.34 When screening was performed, median
survival after trilateral retinoblastoma was significantly longer. The actuarial
Ch-2.indd 53 31-08-2012 12:30:47

survival of screened children stabilized at 27 percent after 5 years by

which time all those who had not been screened were dead.54 Screening
is recommended for intracranial tumors in children with bilateral and/or
familial retinoblastoma until 4 years128 because 89 percent of patients will
have developed an intracranial tumor 4 years after the initial diagnosis of
intracranial retinoblastoma.114
In Uzbekistan, malignant intraocular tumors in children presented by
retinoblastoma, which occurred approximately in 95 percent of all malignant
intraocular tumors in children. From 1978 to 1999 there were registered 972
children with retinoblastoma (487 males, 50.1% and 485 females, 49.9%). 853
children (87.7%) were treated in the Department of Ophthalmology at the
Institute of Oncology and Radiology of Uzbekistan’s Academy of Sciences and
the rest 119 patients (12.2%) were treated in the Regional Ophthalmologic
Dispenseries or in Russia (Moscow) and Ukraine (Odessa). If dividing number
of patients with retinoblastoma by sex and age subgroups of 0 to 4, 5 to 9, and
10 to 14 years, the highest cumulative incidence falls on age subgroup of 0 to 4
years for males (6.1) and females (5.9) per 100,000 males and females children
population (Table 2.5).
The peak of incidence, however, falling on the second year of life21,22 then
it declined to fourteen years and “ becomes extremely uncommon in children
aged 10 years and over”.72 If calculate retinoblastoma cumulative incidence
per million for both sexes and all age subgroups (54 per million) our results
are similar to the cumulative incidence in Africa (range, 7.0–339.0), in Central
and South Africa (range, 34–105.0), North Africa (range, 38.0–123.0), Asia
(range, 22.0–123.0), and Oceania (range, 54.0–103.0).74
If dividing conditionally all types of malignant ocular tumors by 4 groups
(Fig. 2.4) it is evident that intraocular tumors (retinoblastoma) comes in
first place (69.4%), orbital tumors in second (12.2%), eyelid tumors in third
(12.0%) and conjunctival tumors (6.4%) in the last place for both sexes of all
malignant ocular tumors.22
Table 2.5: Cumulative retinoblastoma incidences by sex and age subgroups per
100,000 males and females children population
0 – 4 Number of patients 459 453 912
Cumulative incidence 6.1 5.9 5.8
Total Number of patients 487 485 972
Ch-2.indd 54 31-08-2012 12:30:47

Fig. 2.4: Intraocular tumors (retinoblastoma) among

other malignant ocular tumors in children
Fig. 2.5: Annual retinoblastoma crude incidence for males (M1) and for females (F1)
and standardized retinoblastoma incidence for males (M2) and females (F2) per 100,000
males and females children population
Annual male retinoblastoma incidence between 1978 and 1999

increased from 0.05 to 0.21(crude incidence) and from 0.02 to 0.11
(standardized incidence) per 100,000 male children population. Annual
female retinoblastoma increased from 0.03 to 0.195 (crude incidence) and
from 0.015 to 0.120 (standardized incidence) per 100,000 female children
population. Thus, annual retinoblastoma incidences have grown by 4.2 times
(crude incidence) and by 5.5 times (standardized incidence) for male. Female
crude incidence in the same period has grown by 6.5 times and standardized
incidence by 8.0 times. Statistically significant difference of annual male
incidence in some years is balanced by annual female incidence in other years
and cumulative incidence for both sexes is, therefore the same (Fig. 2.5).
Both annual incidences for males and females have progressively increased
and the similar result also found by other authors.47,52 For example, Moll et al.47
who studied in the period of 1862 to 1944, i.e. 82 years found that retinoblastoma
Ch-2.indd 55 31-08-2012 12:30:47

incidence has also progressively increased. However, Amozorrutia-Alegria

et al.63 found that in children aged 0 to 14 years incidence of retinoblastoma
shows no increasing trend in shorter period from 1990 to 1994. Fairly stable
incidence rate of retinoblastoma over 28 years was described by Saw et al.64
Survival of children with retinoblastoma in Uzbekistan less than 1 year from
initial diagnosis was 12.2 percent, at 1 year 5.8 percent, at 2 years 5.0 percent,
at 3 years 4.2 percent, at 4 years 1.7 percent, at 5 to 9 years 0.8 percent and at 10
years 0.9 percent. The highest survival was in children less than 1 year and then
survival has decreased. Totally, survival was 25.0 to 30.0 percent. Percentage of
deceased children with retinoblastoma was 75.0 percent (729 deceased children
from the initial diagnosis). There were 73.8 percent of children with intraocular
retinoblastoma growth, 14.2 percent with extraocular retinoblastoma and 12.0
percent with metastases.22 In Singapore62 approximately at the same research
period (1976–1995) of 56 patients with retinoblastoma 8 children (14.3%) died.
This percentage of mortality is significantly less than in Uzbekistan may be
because of late stage of retinoblastoma development, which is not uncommon
in our country showing some signs of secondary glaucoma or leukokoria due
to the tumor filling the hole intraocular space as shown on Figure 2.6 on the
right eye of a 3 years old boy.
Every third child with retinoblastoma does not survive his 5th year
of life because of late diagnosing. We agree with that “early diagnosis is as
much or more factor in mortality”.39 Percentage of deceased children with
retinoblastoma in our work (69.1–75.0%) is similar to the percentage of
deceased patients in Cameroon,84 but significantly higher than in Sweden, 4.5
percent,80 or in Poland, 45.0 percent.83 On the other hand, survival of children
with retinoblastoma in Uzbekistan is much lower than in Turkey,88 or in
Taiwan,78 or in Sweden,72 where survival ranged from 81.1 to 100 percent.
Ethnic factor: Among 123 ethnic groups in Republic Tartars and Uzbeks
have the higest retinoblastoma cumulative incidence per 100000 children
Fig. 2.6: Retinoblastoma of a 3 years old boy showing leukokoria
Ch-2.indd 56 31-08-2012 12:30:48

Table 2.6: Cumulative retinoblastoma incidence by ethnic and age subgroups per
100,000 children population in the same ethnic and age subgroups
Ethnic group Number of patients/cumulative incidence in age subgroups
0–4 years 5–9 years 10–14 years
Uzbeks 597/7.7 21/2.8 7/1.1
Tartars 92/15.9 10/8.4 4/1.7
Russians 138/6.5 4/1.9 3/0.9
Kazaks 54/5.3 3/1.7 2/0.2
Karakalpaks 19/6.2 2/0.3 1/0.2
Others 19/4.4 2/1.8 1/0.8
Total 912/5.9 42/2.4 18/0.5
B C
Figs 2.7A to C: Retinoblastoma with extrabulbar growth in the left eye of a 2 years
old boy (A), in the right eye of a 2 years old boy (B), and in the left eye of a 3 years
old girl (C)
population in the same age and ethnic subgroups. Despite the number of
retinoblastoma among the Tartars was significantly less than in Russian ethnic
subgroup, retinoblastoma cumulative incidence was the highest in Tartars
subgroup (Table 2.6).
Ethnic subgroups of Tartars and Uzbeks have much in common, including
religion and culture, and frequency practice consanguineous marriages that
may affect retinoblastoma incidence and mortality.
Ch-2.indd 57 31-08-2012 12:30:48

Hypotheses of retinoblastoma development: In the literature, there are many

hypotheses of retinoblastoma development, ranging from impact of ambient
erythemal dose of ultraviolet B sunlight radiation,174 poor living conditions
and probably infections etiology175 to water pollution with chemical elements
and industrial waste products.176 Jemal et al.177 found that environmental
factors other than UV-B may be responsible for the geographic patterns
of retinoblastoma. Cowell et al.178 have examined for the presence of a
constitutional RB1 mutation six of eight cases of retinoblastoma previously
identified as having a residential association with West Cumbria, England,
in which the Sellafield nuclear installation is situated. No mutations were
detected, thus authors provided strong evidence against an environmental or
occupational genotoxic effect causing germline mutations in the parents of
these children.
We found a whole set of reasons that could play a role in the occurrence of
retinoblastoma, namely: poor health of parents sometimes because of poverty,
particulary mothers, retinoblastoma in family history, chemical pollution
of water and soil and specifically consanguineous marriages. Consequently,
annual retinoblastoma incidence for both sexes in Uzbekistan has increased
for the last two decades, with male and female incidence varying in different
years. Higher incidence in Tartar and Uzbek ethnic group emphasizes the
importance of taking ethnic dimension into account when making diagnosis
and carrying out research.
Retinoblastoma incidence and mortality are the result of late diagnosis
coupled with unsuccessful treatment and low common culture in some
families. Most children with retinoblastoma in Uzbekistan have had late
diagnosis, which greatly influenced retinoblastoma mortality (Figs 2.7A to C).
We agree with Verma et al.179 who found that most patients presented late and
mortality rate was high and “early diagnosis of this disease when it is localized
to the eye is important to salvage the life of the child’’.180 This could also reflect
the relative paucity of ophthalmic and oncological services in the country
as well as psychosocial attitudes to disease. Many patients live far from
medical services and have no possibility to be treated in certain hospitals,
that have better diagnostic and medical equipment as well necessary
pharmaceuticals. Futhermore, distrust to official medicine and despair
as a result of ineffective treatment force parents of children to approach
healers (tabibs) before coming to the hospital after whom there remains
no hope to help the patients. The lack of a nationalwide computerized
cancer register in Uzbekistan is a key obstacle to the accurate registration
of each case of ocular malignant tumors in children and adults that greatly
hampers epidemiologic research of malignant ocular tumors.
Ch-2.indd 58 31-08-2012 12:30:48

While the 5-year observed actuarial survival rate in the United States
increased from 92.3 percent in 1975 to 1984 to 96.5 percent in 1995 to 2004181
in Uzbekistan survival of children suffered from retinoblastoma dramatically
decreased while retinoblastoma incidence and mortality are progressively
increasing. To change this situation, serious, systematic and long standing
work is needed, particularly from public authorities in Uzbekistan.
Indeed it is true that “early diagnosis is as much or more a factor in
mortality as is expected treatment, and it is a combination of new diagnostic
methods, modern radiological techniques, and effective chemotherapy that
has enable us to save not only life but also affected eyes with useful vision” in
patients suffered from retinoblastoma.182
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101. Abramson DH, Servodidio CA. Retinoblastoma. Optom Clin 1993;3:49-61.
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128. De Potter P, Shields CL, Shields JA. Clinical variation of trilateral retinoblastoma:
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131. Stannard C, Knight BK, Sealy R. Pineal malignant neoplasm in association with
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134. Bejjani GK, Donahue DJ, Selby D, et al. Association of a suprasellar mass and
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135. Scott MH, Richard JM. Retinoblastoma in the state of Oklahoma: A
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138. Pesin SR, Shields JA. Seven cases of trilateral retinoblastoma. Am J Ophthalmol
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139. Skulski M, Egelhoff JC, Kollias SS, et al. Trilateral retinoblastoma with suprasellar
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140. Brownstein S, de Chadarevian JP, Little JM. Trilateral retinoblastoma. Report of
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141. Dudgeon J, Lee WR. The trilateral retinoblastoma syndrome. Trans Ophthalmol
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142. Badley LJ, Hurst RW, Zimmerman RA, et al. Imaging in the trilateral
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143. Michaud J, Jacob JL, Demers J, et al. Trilateral retinoblastoma: Bilateral
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144. Shields JA, Shields CL, De Potter P. Clinical management of retinoblastoma.
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145. Ehlers N, Kaae S, Rasmussen K, et al. Hereditary bilateral retinoblastoma,
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146. Judisch GF, Patil SR. Concurrent heritable retinoblastoma, pinealoma, and
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148. Tarkkanen A, Haltia M, Karjalainen K. Trilateral retinoblastoma. Pineoblastoma
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149. Zimmerman LE, Burns RP, Wankum G, et al. Trilateral retinoblastoma: Ectopic
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150. Singh AD, Shields CL, Shields JA. New insights into trilateral retinoblastoma.
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151. Elias WJ, Lopes MB, Golden WL, et al. Trilateral retinoblastoma variant of the
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152. Edwards MS, Hudgins RJ, Wilson CB, et al. Pineal region tumors in children. J
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153. Beck Popovic M, Balmer A, Maeder P, et al. Benign pineal cysts in children
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154. Helveston EM, Knuth KR, Ellis FD. Retinoblastoma. J Pediatr Ophthalmol
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155. Draper GJ, Sanders BM, Brownhill PA, et al. Patterns of risk of hereditary retino-
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MALIGNANT ORBITAL TUMORS

There are many reports upon orbital tumors in children in the literature.
Most of them originating from the tumor registries of large pathology centers,
others are from medical or pediatric institution or hospitals. The findings also
ranged by the geographic regions of research works.1
Nevertheless, population-based epidemiological reviews deal with
incidence, mortality and survival of children with malignant orbital tumors
remains rare in the literature. Malignant orbital tumors in children occurred
Ch-2.indd 68 31-08-2012 12:30:49

in 5.0 percent,2 or in 10.0 percent,3 or in 22.0 percent,4 or in 33.8 percent5 of all
pediatric orbital tumors. However, of all benign and malignant ocular tumors
in children malignant orbital tumors occurred in 8.9 percent.5
Rhabdomyosarcoma is the most frequently primary orbital malignancy in
children,3,6-8,14,17,21,30 but in Papua New Guinea the most common orbital tumor
was orbital extension of retinoblastoma (40.3%), while rhabdomyosarcoma
was only in 1.7 percent of all orbital malignancies between 1975 and 1996.9
The first rhabdomyosarcoma described in 1854 by Weber and other
reports appeared in the literature over the years. In 1946 Stout published
the first definitive work with particular attention to the problem of orbital
rhabdomyosarcoma. The most recent comprehensive analysis was done by
Porterfield and Zimmerman.21
Morphologically rhabdomyosarcoma has subdivided into three types:
1. a pleomorphic type, 2. an alveolar type, and 3. an embryonal type of
rhabdomyosarcoma. This last subdivision has, as a variant, a tumor of grape like
or polypoid pattern which was called a botryoid variety of rhabdomyosarcoma.10
Later according to “Histological typing of tumors of the eye and its adnexa”11
orbital rhabdomyosarcoma was presented as 1. an embryonal type, 2. an
alveolar type of rhabdomyosarcoma, and 3. others. Rhabdomyosarcoma arises
not from the extraocular muscles, but rather from undifferentiated cells in
the orbit.12 In no of the 34 cases of orbital rhabdomyosarcoma there was any
evidence of the neoplasm having originated in the extraocular muscles.13
Age: Rhabdomyosarcoma is diagnosed at 7 years of age,12,14 or of 8 years at
diagnosis,15 or with mean age of 5.6 years,8 or 10.4 years,16 or with median
age of 6.8 years,18 or from 3 weeks to 13 years,17 or between 2 months
and 17 years,13 or 18 years or younger.19 Ninety percent of children with
orbital rhabdomyosarcoma presented before age 16.20,21 Although orbital
rhabdomyosarcoma is extremely rare in the newborn and not common before
one year of age the case of 5 days aged baby,10 three weeks old boy and one
month of age other boy were described in the literature14 as well as a rare
case of rhabdomyosarcoma of the orbit in pregnancy.22 This malignancy
can also occur in adults. So, a case of primary orbital rhabdomyosarcoma in
34-year-old adult man with a recurrent orbital tumor four years after initial
excision was reported.23 In pediatric population the embryonal and alveolar
types of rhabdomyosarcoma are the most common types, responsible for
approximately two-thirds of cases.20,21 Embryonal rhabdomyosarcoma was
found in 87.5 percent,8 or in 89.5 percent14 of orbital lesions in children, but
only 19 Danish cases of embryonal rhabdomyosarcoma during 22 years were
reported.25 Alveolar type of orbital rhabdomyosarcoma is less frequent than
other forms and occurred only in 10.5 percent,24 or in 12.0 percent.21 In other
words, embryonal rhabdomyosarcoma, including botryoid variants, typically
Ch-2.indd 69 31-08-2012 12:30:49

occurs in young children, alveolar rhabdomyosarcoma typically occurs in

older children and young adults, and pleomorphic rhabdomyosarcoma occurs
in older adults.26
Location or position of tumor’s mass in orbit appeared to be (50.0%)
central behind the globe, 25.0 percent of the cases have a mass above, (12.0%)
below, (6.0%) nasal and (6.0%) temporal. Thus, it has been stated that orbital
rhabdomyosarcomas most commonly lie up and in the orbit. However, some
retrobulbar central orbital growth with outward and downword displacement
of the globe seems to be interpreted as representing a mass up and in21 but
some authors15 found that orbital rhabdomyosarcoma has predilection for the
superior nasal quadrant of the orbit.
Rhabdomyosarcoma occures in 2.5 percent of 121 pediatric orbital
tumors,3 or in 3.0 percent of all orbital masses,27 or in 4.0 percent of 250
consecutive biopsies for orbital space-occupying lesions in children,6 or in 4.9
percent of 102 biopsied cases of orbital tumors in children,17 or in 7.1 of 340
patients with histopathologically verified orbital tumors,19 or in 18.1 percent
of 3476 orbital diseases, including malignant lacrimal gland epithelial tumors,
non-Hodgkin’s disease, secondary nasosinus carcinoma, metastatic tumors,
chloroma, extraocular extension of retinoblastoma and extraocular extension
of choroid melanoma,28 or in 7.0 percent of 24 children with orbital tumors
less than 10 years old.29
Incidence: The crude annual incidence rate of ocular rhabdomyosarcoma
was 0.13/100000, the age standardized rate was 0.3/100000 of cases
resident of Karachi (8 cases in orbit, 1 case eyelid and 1 case conjunctival
rhabdomyosarcoma).16 An annual incidence of rhabdomyosarcoma is 4.3
cases per million children. In the United States an estimated 350 new cases per
year are diagnosed of which 35 cases (10.0%) are orbital rhabdomyosarcoma.15
Gender: Boys are more commonly affected than girls with a ratio of 3:2, or
5:3.7,8,21,30 Ashton and Morgan13 also found predominance of males in 55.8
percent (19 patients) over females in 44.2 percent (15 patients of all 34 patients
with embryonal sarcoma and embryonal rhabdomyosarcoma). However,
Spahn et al.14 found that the male-female ratio varies from one report to
another.
Race: In Caucasians orbital rhabdomyosarcoma occurred in 96.8 percent
(60 cases of 62) and only two cases (3.2%) were in Negro or partly Negro
individuals.21
Survival: The survival time is intimately dependent on the staging and location
of the disease at time of diagnosis as well as the histological type of tumor. The
alveolar type has the worst prognosis and lower survival rate. So, the 5-year
survival rate of children with alveolar rhabdomyosarcoma was 74.0 percent.
Ch-2.indd 70 31-08-2012 12:30:49

All 5 infants diagnosed to have an alveolar type of rhabdomyosarcoma died
before the age of one. The 5-year survival rate for patients with embryonal
rhabdomyosarcoma subtypes combined was 94.0 percent and 97.0
percent. In contrast, for the patients with poorly differentiated embryonal
rhabdomyosarcoma located in extraocular sites had a 66.0 percent survival
estimate.24 However, Jones et al.21 believe that there was no significant difference
in survival among patients with embryonal or alveolar rhabdomyosarcoma.
Moreover, one patient with an original embryonal rhabdomyosarcoma at
recurrence six years later showed an alveolar type. The survival in localized
orbital rhabdomyosarcoma is now more than 90.0 percent at 5 years.20 The
overall survival rate of patients with preserved eye (86.0% of patients) was 96.0
percent31 comparing with 29.0 percent survival rate at 5 years and more in
1965.21 Survival of orbital rhabdomyosarcoma has improved due to advanced
in chemotherapy and radiotherapy.15 So, of 58 patients with orbital tested with
irradiation alone or irradiation and chemotherapy 74.0 percent were alive.
When local sinuses were invaded the survival rate was 55.0 percent.32 Survival
was more favorable in orbital sites than in other sites (head-neck, truk,
paratesticular, etc.). Survival was 20.0 percent (9 of 45 children) before and
52.8 percent (28 children of 53) after chemotherapy and irradiation.33 Survival
of patients with orbital embryonal rhabdomyosarcoma (TNM stage III) at the
end of one year was 70.0 percent, at the end of two years 20.0 percent and there
were no survivors at the end of three years.16 However, Burns et al.8 find that
orbital rhabdomyosarcoma in children has a good prognosis. Children’s Solid
Tumor Group found that in children with rhabdomyosarcoma confined to the
tissue of origin with no evidence of nodal or metastatic spread, a predicted
actuarial 5-year survival rate was (86.0%), in children with “unconfined”
tumors, i.e. those with extension of disease outside the tissue of origin, an
actuarial 5-year survival rate was only 21.0 percent and has much poorer
prognosis.34 Thus, since the best chance for survival lies with early diagnosis
and vigorous treatment, the alertness and energy of the ophthalmologist under
whose care the patients falls will be most critical.21
Recurrence or persistance of the disease tends to become manifest early and
to lead to a rapid demise. However, some individuals will show the disease a
new at longer periods than the commonly stated three-year danger period. The
tumor may recur locally, may recur as seeds along biopsy tracts or may spread
distantly to any part of the body, most frequently brain, skeleton and lungs.21
Reccurence was fatal despite attempt at second look resection and altered
chemotherapy and irradiation.33 For example, of 10 patients with recurrent
localized orbital rhabdomyosarcoma six patients died of tumor (60.0%) and 3
(30.0%) died of other causes.35 Although rare, rhabdomyosarcoma is a highly
malignant tumor and it is important to keep it in mind in order to perform a
Ch-2.indd 71 31-08-2012 12:30:49

Table 2.7: Age-adjusted incidence of primary malignant orbital tumors in males

and females of age subgroups 0–4, 5–9, and 10–14 per 100,000 children males and
females population in the same age subgroups
Age subgroup 0–4 Age subgroup 5–9 Age subgroup 10–14
Gender M F B Gender M F B Gender M F B
Number Number Number
of patients 4 5 9 of patients 1 5 6 of patients 2 4 6
Age- Age- Age-
adjusted adjusted adjusted
incidence 0.3 0.3 0.1 incidence 0.1 0.4 0.3 incidence 0.2 0.4 0.3
Abbreviations: M: Male; F: Female; B: Both sexes
biopsy enabling quick diagnosis and treatment following the modern protocol
giving the highest chances of survival to these patients; about 98.0 percent in 3
years.17
Mortality: The mortality rate of this form of neoplasm is very high10 and as
found in the different series it varies from 26.0 percent,32 or 40.3 percent,21 or
at least 50.0 to close 90.0 percent.10
Other malignant orbital tumors as leiomyoma of the orbit,36 orbital
epitheliod sarcoma,37 adenoid cystic carcinoma and adenocarcinoma of the
lacrimal gland38 are extremely rare, especially in children.
In Uzbekistan, malignant orbital tumors in children are the second most
common malignant tumors of all ocular malignancies.39 Vit41,42 as well as our
studies40,43 also found that malignant orbital tumors took the second place of
all ocular tumors.
Age-adjusted incidence of primary malignant orbital tumors in children
varies from 0.1 to 0.4 per 100,000 children males and females population in
age subgroups 0 to 4, 5 to 9, and 10 to 14 (Table 2.7).
We have not found significant difference between age-adjusted incidence
of primary malignant orbital tumors of males and females in the age subgroup
0 to 4, but in the age subgroup 5 to 9 and 10 to 14 age-adjusted incidence (0.4)
of females four and two times respectively higher than that of males.22 The
crude urban incidence of primary malignant orbital tumors per 100,000 urban
Table 2.8: The crude and standardized urban and rural incidence of primary
malignant orbital tumors in children per 100,000 urban and rural children population
Urban Rural
Male Female Both Male Female Both
Number of patients 3 3 6 4 11 15
Crude incidence 0.2 0.2 0.2 0.2 0.4 0.3
Standardized incidence 0.1 0.1 0.1 0.1 0.1 0.1
Ch-2.indd 72 31-08-2012 12:30:49

Fig. 2.8: The annual crude incidence of primary malignant orbital tumors in children
for males (M1) and females (F1) and standardized incidence for males (M2) and females
(F2) per 100,000 males and females children population
males, females and both sexes children population was 0.2 for males, females
and both sexes. For rural females that was 2 times higher than for rural males.
However, urban and rural standardized incidence was 0.1 for males, females
and both sexes per 100,000 urban and rural males, females and both sexes
children population (Table 2.8).
The annual crude and standardized incidence of primary malignant orbital
tumors in children for males and females per 100,000 males and females
children population ranged in males from 0.0 to 0.05 (crude incidence)
and from 0.0 to 0.025 (standardized incidence). In females both crude and
standardized incidences were higher than in males and ranged from 0.0 to 0.1
(crude incidence) and from 0.0 to 0.025 (standardized incidence).
These incidences had two peaks in 1981, 1984 and tendency to increase in
1987 for both sexes (Fig. 2.8)
A B
Figs 2.9A and B: Late diagnosed patients: (A) Soft-tissue sarcoma of left orbit with
growth to the temporal regio in the left eye of a 4 years old boy after two courses
radiotherapy only (B) Rhabdomyosarcoma in the left orbit of a 11 years old girl with
all orbital bones distruction and metastases to the vertebral bones
Ch-2.indd 73 31-08-2012 12:30:50

Overall mortality from the primary malignant orbital tumors took the first
place following by the mortality from intraocular malignant tumors. Mortality
of rural females was significantly higher (0.3) than mortality of rural males
(0.1). Mortality of urban males and females was similar (0.2) per 100,000
urban and rural males and females children population. From initial diagnosis
8 of 21 children with orbital malignancies (38.1%) died within the first year,
4 children died at 1 year (19.1%), 2 children died at 2 years (9.5%) and there
were no patients who survived more than 3 years.21 Such high mortality of
children with primary malignant orbital tumors as well as all the malignant
ocular tumors could be explained by late diagnosis, which is a reason of late
and unsuccessful treatment as it is shown on Figures 2.9A and B, as well as by
lack of necessary chemotherapeutical medications, aged X-ray equipment and
financial constraints experienced by parents of children patients and related to
the need to undergo treatment only in the big city clinics and hospitals.
Pediatricians and ophthalmologists play a vital role in diagnosis of ocular
tumors in children. They are the first to recognize tumors that may not be
apparent to patients. Both malignant and benign tumors may be vision-
threatening and some malignant tumors may be life-threatening. Most ocular
tumors in children are distinct from tumors that occur in adults.4
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presenting as conjunctival tumor. J Pediatr Hematol Oncol 2003;25:651-2.
3. Bullock JD. Discussion. Ophthalmology 1986;93:384.
4. Johansen S, Heegaard S, Bogeskov L, et al. Orbital space-occupying lesions in
Denmark 1974-1997. Acta Ophthalmol Scand 2000;78:547-52.
5. Barchash SA. Aktualie voprosi diagnostiki i lechenija novoobrazovanii organa
zreniya. In: Diagnostika i lechenie opucholei glaza i orbiti. Kiev 1971. pp. 73-4.
6. Shields JA, Bakewell B, Augsburger JJ, et al. Space-occupying orbital masses in
children. A review of 250 consecutive biopsies. Ophthalmology 1986;93:379-84.
7. Kaliaperumal S, Tiroumal S, Rao V. Orbital rhabdomyosarcoma: A case series.
Indian J Cancer 2007;44:104-7.
8. Burns BJ, McHugh K, McDowell HP, et al. Localized paediatric orbital
rhabdomyosarcoma: Influence of imaging on treatment. Clin Radiol 2001;56:
959-64.
9. Verma N, Murthy DP, Kerek A. Orbital malignancy in Papua New Guinea: A 21
10. Spaeth EB, Cleveland AF. Rhabdomyosarcoma in infancy and childhood. Am J
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11. International Histological Classification of Tumors No 24. Histological
typing of tumors of the eye and its adnexa. WHO Geneva, 1980. In Russian:
Gistologicheskaya klassifikatia opucholei glaza i ego pridatkov. VOZ Geneva,
1984. pp. 44-5.
Am 2003;50:149-72.
13. Ashton N, Morgan G. Embryonal sarcoma and embryonal rhabdomyosarcoma
of the orbit. J Clin Path 1965;18:699-714.
14. Spahn B, Nenadov-Beck M. Orbital rhabdomyosarcoma: Clinicopathologic
correlation, management and follow-up in two newborns. A preliminary report.
Orbit 2001;20:149-56.
15. Karcioglu ZA, Hadjistilianou D, Rozans M, et al. Orbital rhabdomyosarcoma.
Cancer Control 2004;11:328-33.
16. Bhurgri Y, Mazhar A, Bhurgri H, et al. Orbital embryonal rhabdomyosarcoma in
Karachi (1998-2002). J Pak Med Assoc 2004;54:561-5.
17. Ducrey N, Nenadov-Beck M, Spahn B. Update of orbital rhabdomyosarcoma
therapy in children. J Fr Ophthalmol 2002;25:298-302.
18. Oberin O, Rey A, Anderson J, et al. Treatment of orbital rhabdomyosarcoma:
Survival and late effects of treatment- results of an international workshop.
J Clin Oncol 2001;19:197-204.
19. Kodsi SR, Shetlar DJ, Campbell RJ, et al. A review of 340 orbital tumors in
children during a 60-year-period. Am J Ophthalmol 1994;117:177-82.
20. Volpe NJ, Jakobiec FA. Pediatric orbital tumors. Int Ophthalmol Clin
1992;32:201-21.
21. Jones IS, Reese AB, Kraut J. Orbital rhabdomyosarcoma. An analysis of 62 cases.
22. Olurin O. Orbital rhabdomyosarcoma in pregnancy. Cancer 1969;24:1013-6.
23. Othmane IS, Shields CL, Shields JA, et al. Primary orbital rhabdomyosarcoma in
an adult. Orbit 1999;18:183-9.
24. Kodet R, Newton WA Jr, Hamoudi AB, et al. Orbital rhabdomyosarcoma and
related tumors in childhood: Relationship of morphology to prognosis—An
Intergroup Rhabdomyosarcoma study. Med Pediatr Oncol 1997;29:51-60.
25. Fledelius H. Embryonal sarcoma of the orbit. Aclinical review of 19 Danish
cases. Acta Ophthalmol (Copenh) 1976;54:693-703.
26. Folpe AL, McKenney JK, Bridge JA, et al. Sclerosing rhabdomyosarcoma in adult:
Report of four cases of a hyalizing, matrix-rich variant of rhabdomyosarcoma
that may be confused with osteosarcoma, chondrosarcoma, or angiosarcoma.
Am J Surg Pathol 2002;26:1175-83.
27. Shields JA, Shields CL, Scartozzi R. Survey of 1264 patients with orbital tumors
and simulating lesions: The 2002 Montgomery Lecture, part 1. Ophthalmology
2004;111:997-1008.
28. He Y, Song G, Ding Y. Histopathologic classification of 3476 orbital diseases.
Zhonghua Yan Ke Za Zhi 2002;38:396-8.
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patients during a 21-year-priod: Origins and locations. Ipn J Ophthalmol
2005;49:49-55.
30. Shields JA. Rhabdomyosarcoma. In Diagnosis and management of orbital
tumors. Philadelphia: WB Saunders 1989. pp. 244-52.
31. Raney RB, Anderson JR, Kollath J, et al. Late effects of therapy in 94 patients
with localized rhabdomyosarcoma of the orbit: Report from the Intergroup
Rhabdomyosarcoma Study (IRS)-III, 1984-1991. Med Pediatr Oncol 2000;34:
413-20.
32. Abramson DH, Ellsworth RM, Tretter P, et al. The treatment of orbital
rhabdomyosarcoma with irradiation and chemotherapy. Ophthalmology
1979;86:1330-5.
33. Grosfeld JL, Weber TR, Weeman RM, et al. Rhabdomyosarcoma in childhood:
Analysis in 98 cases. J pediatr Surg 1983;18:141-6.
34. Kingston JE, McElwain TJ, Malpas JS. Childhood rhabdomyosarcoma:
Experience of the Children’s Solid Tumor Group. Br J Cancer 1983;48:195-207.
35. Wharam M, Beltangady M, Hays D, et al. Localized orbital rhabdomyosarcoma.
An interim report of the Intergroup Rhabdomyosarcoma Study Committee.
36. Jakobiec FA, Howard GM, Rosen M, et al. Leiomyoma and leiomyosarcoma of
the orbit. Am J Ophthalmol 1975;80:1028-42.
37. White VA, Heathcote JG, Hurwitz JJ, et al. Epitheliod sarcoma of the orbit.
Clinicopathologic correlation and management. Neurosurg Rev 1990;13:289-
98.
39. Mouratova T. Retinoblastoma in Uzbekistan. Bull Soc belge Ophthalmol
2003;289:63-9.
40. Mouratova T. Sovershenstvovanie spetsializirovannoi pomoschi vzroslym
i detyam so zlokachestvennimi novoobrazovaniyami organa zreniya v
Uzbekistane. Dissertatsiya na soiskanie uchenoi stepeni Doktora Meditsinskich
nauk,1992, Moscow, Hermann Helmholtz Reseach Institute of Eye Diseases,
1992. pp. 79-101.
41. Vit VV. Medulloepithelioma glaza. Oftalmolog J 1978;8:612-9.
42. Vit VV. Osobennosti proischozsdeniya pigmentnich novoobrazovanii uvealnogo
tracta glaza cheloveka. Oftalmolog J 1985;7:401-6.
43. Muratova TT, Titov A. Eye tumors in children. Pediatria 1985;9:61-2.
Ch-2.indd 76 31-08-2012 12:30:50

CHAPTER 3
Epidemiology of Ocular Tumors in Adults
EPIDEMIOLOGY OF BENIGN EYELID, CONJUNCTIVAL,

INTRAOCULAR AND ORBITAL TUMORS
Benign eyelid tumors: Eyelid tumors are typically classified into benign and
malignant categories.1 However, histopathologic evaluation then correlated to
determine the accurary of the clinical diagnosis which prospectively categorized
the lesions as benign, premalignant or malignant.2 Space-occupying process
in the eyelids can either be due to lesions, which are specific for the eyelids
such as chalazion or a meibomian carcinoma, or to nonspecific lesions of the
skin or ocular adnexa.3 Beyond this general classification, knowledge of initial
appearance, progression and potential pathologic change is necessary because
delayed diagnosis can lead to extensive surgical intervention and cosmetic
reconstruction.1 On the other hand, some eyelid process can masquerade as
others and one must be aware of the danger of mistaking one space-occupying
process for another.2-4 Agreement between clinical and histopathologic
diagnosis was noted in 84.0 percent of eyelid biopsy specimens5 but in a group of
956 eyelid tumors histologic examination was necessary in 126 cases (13.2%).3
Kersten et al.2 showed that of 153 lesions clinically were thought to represent
malignancies only 140 (91.5%) were found to have malignant histopathologies
and 13 (8.5%) were nonmalignant tumors. Moreover, of 692 lesions clinically
thought to be benign 15 (1.9%) were malignant and 3 (0.4%) were found to
be premalignant. Furthermore, of 153 clinically malignant lesions, 6 lesions
(3.9%) that clinically were highly suspicious for malignancy had initial benign
histologic diagnosis, which suspected by rebiopsy. In other report 10 (11.6%)
clinical diagnoses of suspected malignant eyelid tumor showed benign skin
conditions, and 4 (4.6%) clinical diagnoses presumed benign conditions
proved to be malignant.5 We are agree with the most authors2,9,11 that all eyelid
lesions should be submitted for histopathologic confirmation because it is not
possible to obtain 100 percent accuracy in diagnosing eyelid lesions on clinical
grounds alone. However, strong clinical suspicion of a malignancy is highly
significant, and if initial histopathologic evaluation does not agree with the
malignant clinical diagnosis repeat biopsy should be performed.2
03A.indd 77 31-08-2012 12:31:31

Benign eyelid tumors’ percentage ranges from 25.9 percent3 to

58.9 percent,6 or 59.7 percent,7 or 62.1 percent,8 or 63.2 percent,9 or 71.4,10 or
73.0 percent,11 or 78.2 percent,2 or 82.8 percent,12 or 86.2 percent,13 or about
90.0 percent14,15 of histopathologically diagnosed eyelid lesions. Wide ranged
percentage of benign eyelid tumors of all histopathologically diagnosed eyelid
lesions may be explained by the collected lesions, which included or have not
included tumor-like lesions and inflammatory diseases except eyelid tumors.8
Eyelid skin tumors with dominating of benign tumors were in 80.0 percent
of all ocular tumors and the most common were epithelial (up to 67.0%) and
soft tissue tumors (28.9%). Pigmented tumors occurred in 12.0 percent.16
Most common benign eyelid tumors were papillomas (27.9%), pigmented
nevus (24.4%), cysts (18.1%), angiomas (9.4% including lymphangiomas)
and verrucas (9.0%) of 3510 pathological specimens with eyelid tumors
examined between 1953 and 1992.7 Another results demonstrated by Obata
et al.11 who believe that nevocellular nevi, seborrheic keratosis, epidermoid
cysts, and papillomas were the most common benign eyelid tumors.11 Others
found that papillomas and cysts were most frequent benign eyelid tumors17
or intradermal nevus was more common (44.6%) than seborrheic keratosis
(16.1%) and compound nevus (10.7%) of all benign eyelid tumors, or vascular
tumors were the more common lesions (21.3%), than neural tumors (18.0%),
dermoid cysts (16.4%), squamous cell papillomas (13.1%) and nevi (12.3%)
of the histologically diagnosed tumors and tumor-like lesions.6 Of the
epithelial benign eyelid tumors papilloma and senile verruca (70.0–80.0%),
then keratoacanthoma, trichoepithelioma, adenoma, syringoma were the
most frequent.18 The keratoacanthoma is rare benign eyelid tumor, which
occures in 0.86% (12 cases) of all 1398 eyelid skin biopsies.20 Benign tumors
originating from skin appendages of the eyelid are rare and frequently have
apocrine or eccrine differentiation. So, of 7751 ophthalmic specimens between
1993 and 2002 histopathologically 228 (2.9%) benign adnexal tumors of
apocrine, eccrine or hair follicle origin were obtained. Of 228 benign adnexal
tumors, 182 (79.8%) were diagnosed as apocrine or eccrine hydrocytoma,
12 syringoma (5.3%), 11 trichilemmoma (4.8), 5 syringocystadenomas
papilliferum (2.2%), 3 trichoepithelioma (1.3%) and 3 trichofolliculoma
(1.3%).21 In smaller series of only 17 benign hair-follicle derived eyelid
tumors pilomatrixoma and trichoepithelioma accounted for 16.5 percent,
trichilemmomas, trichoepitheliomas and inverted follicular keratosis were in
the remaining neoplasms (23.5%) of all tumors in this series.22 Eccrine poroma
of the eyelid is extremely rare benign tumor of the intraepidermal sweat duct
unit. A clinicopathological case report of a 71-year-old Caucasoid man with
an unusual right lower eyelid lesion, which proved to be eccrine poroma was
presented.23 We demonstrate a rare benign tumor, cyst of the lower canaliculus
03A.indd 78 31-08-2012 12:31:31

Epidemiology of Ocular Tumors in Adults 79
A B C
Figs 3.1A to C: Cyst of the lower canaliculus lacrimalis in the right eye of a 72-year-old
woman (A) and arteriovenous hemangioma of the right upper lid, frontal and temporal
regios of a 28-year-old woman before operation (B) and after operation (C)
lacrimalis in the right eye of 72-year-old woman and a 28-year-old woman

with arteriovenous hemangioma of the upper right eyelid, right frontal and
temporal regios before and after operation of exision of the tumor with
following plastic surgery (Figs 3.1A to C).
Age: Benign eyelid tumors were usually seen in the first two decades of the life.6
However, Chi et al.18 found that mean age of patients suffering from benign
eyelid tumors was 43.3 years. According to review of other researchers13 the
mean age of such a patients was 41 years. The mean age of benign eyelid
tumor patients was significantly younger than those of malignant eyelid
tumor patients,11 but for cutaneous horn (cornu cutaneum) a mean age was 62
years.24 The peak age for eyelid nevus was 30 to 40 age groups, for angiomas
and granulomas 40 to 50 age group, for papillomas 60 to 70 age group and for
verrucas 70 to 80 age group.17
Location: The lower eyelid was involved in 48.2 percent of all benign eyelid
tumors.18 The lesions occuring in the upper lid are much less likely to be
malignant than those occuring elsewhere.
Gender: A slight preponderance of females with benign eyelid tumors in
51.8 percent of 207 cases with eyelid tumors and tumor-like lesions was found,19
or in 58.9 percent (33 females of 56 patients with benign eyelid tumors).18
Race: Only 4.0 percent were Africans of 2561 patients with benign tumors and
705 inflammatory pseudotumors of the eye and its adnexa.17
Benign conjunctival tumors occupy a large spectrum of conditions.
A number of less common conjunctival lesions can simulate a malignancy.
The most common simulating lesions include pterygium, viral papilloma,
amelanotic nevus, dermolipoma, pyogenic granuloma and corneal pannus. In
most cases these lesions do not require biopsy, but in uncommon presentation
incisional biopsy or cytologic evaluation of surface scraping is necessary.25 The
03A.indd 79 31-08-2012 12:31:32

most tumors of the conjunctiva are benign and they occur in 86.1 percent (669
of 777 primary histopathologically analyzed conjunctival tumors).26 The most
common benign conjunctival tumors in decreasing order of frequency were
pterygium, nevus, dysplasia, and epithelial inclusion cyst.22,27 However, the
most authors found pigmented nevi being the most common tumors.18,26,28
The similar results was found by Toshida et al.29 who histopathologically
analyzed tumors and tumor-like lesions in conjunctiva and cornea during
the 13-year period and showed that pigmented and compound nevi occurred
more frequently (in 37.6%) than cysts (in 20.7%), and dermoids (in 12.9%).
Conjunctival nevus was in 21 to 23 percent of benign conjunctival tumors,16
or in 27.6 percent of 1643 melanocytic and nonmelanocytic conjunctival
tumors,30 or in 31.7 percent of the primary conjunctival neoplasms.26 A
significant increase in the number of conjunctival nevi per annum was
observed in Denmark from 1960 to 1980. According to authors’ opinion, this
may have been caused by an increased exposure to actinic rays.31
Age distribution of the patients with tumors and tumor-like lesions of the
conjunctiva and cornea was 42 to 97 years.29 Patients with benign conjunctival
tumors were younger with the mean age of 29.7 years.18 For patients
with choristomatous, vascular, fibrous, xanthomatous and myxomatous
conjunctival tumors a mean age of <40 years was found.30 In young adults
the most frequent tumors were conjunctival nevus.28 Intrastromal nevi were
excited at a higher median age than compound nevi, and the lowest observed
median age at excision was for junction nevi.31
Gender: In male epithelial tumors of conjunctiva occurred in 80.0 percent,
whereas in males and females the incidence of melanocytic lesions was
equal.18,30 The ratio of males to females was 4:6 in patients with tumors of the
conjunctiva and cornea.29
Race: The white patients with conjunctival nevi were in about 89.0 percent
of all patients with such a tumors, 6.0 percent were African American,
2.0 percent were Asian, 2.0 percent were Indian and 1.0 percent were Hispanic.34
Patients with conjunctival nevi had brown iris color in 55.0 percent, blue in
20.0 percent, and green in 20.0 percent. The nevus was brown in 65.0 percent,
tan in 19.0 percent and completely nonpigmented in 1.0 percent. Change in
tumor color was detected in 13.0 percent. So, the lesion color gradually became
darker in 5.0 percent, lighter in 8.0 percent and was stable in 87.0 percent.34
Location: The anatomical location of the nevus was the bulbar conjunctiva in
72.0 percent, caruncle in 15.0 percent, plica semilunaris in 11.0 percent, fornix
in 1.0 percent, tarsus in 1.0 percent and cornea in < 1.0 percent. The bulbar
conjunctival lesions most commonly abutted the corneoscleral limbus.34
55.0 percent of the papillomas located at the caruncle or semilunar fold, 2
lesions involved the epibulbar conjunctiva as well as the opposite tarsal
03A.indd 80 31-08-2012 12:31:32

conjunctiva (“kissing papilloma”),35 medial conjunctiva was involved in
58.3 percent.18
Recurrence of conjunctival nevi occurred in 2.6 percent (9 of 343 nevi of
the conjunctiva). Eight of recured nevi were located in the limbal area and all
of patients were females, suggesting hormonal factors as a possible cause.31
Transformation of conjunctival nevi to a malignant melanoma was
described in 0.3 percent (1 patient of 343 conjunctival nevi),31 or in 0.7 percent
(3 of 410 consecutive patients).34
Fibrous histiocytomas of the conjunctiva are rare tumors, which can be
benign and malignant. Benign fibrous histiocytomas have been reported in
the orbit, eyelid, episclera and conjunctiva. These tumors can be also named
as fibroxantoma or dermatofibroma, or angiofibroma.6 In 61.1 percent,32 or in
66.7 percent33 fibrous histiocytomas are benign.
Age: The mean age of patients with fibrous histiocytoma was 37 years. All
patients but 1 were males with unilateral tumors, left and right eyes were
affected in equal cases.33
Caruncular tumors are predominantly benign in 93.8 percent (183 of 195
caruncular lesions),36 or in 96.0 percent (550 of 574 caruncular lesions),37 but
the lesions are rare and diverse, making clinical diagnosis difficult. Refferal
or excised lesions for histopathological examination is recommended37
because in 1.1 percent (2 of 191 patients) caruncular tumors clinically thought
to be benign were malignant.36 Twenty-four different types of lesions were
identified in patients with caruncular tumors, but the most common were nevi
and papillomas.36-39
The number of caruncular lesions increased significantly during the 25-
year period (1978-2002) in Denmark. The mean frequency was 11.4 lesions
per year over the first 5-year period, which increased to 34.2 lesions per year
over the last 5-year period. The frequency of caruncular lesions increased due
to an increase in the frequency of benign lesions. A mean age of patients with
nevi and papillomas of caruncle was 40 and 36 years respectively. Males were
186, females 62 with the ratio of male to female 3:1.37
Patients with benign conjunctival tumors treated in our Department
shown in Figures 3.2A to C.
Benign intraocular tumors can be divided into tumors of iris, ciliary body,
tumors of chorioidea, and tumors of retina. Of 476 patients with intraocular
tumors 83.2 percent were patients with iris and ciliary body tumors.16 The
most tumors of iris and ciliary body are benign and of all benign iris and ciliary
body tumors the most common lesions are nevi and cysts. Authors found that
typical iris nevi are less than 4 mm in diameter and generally does not produce
glaucoma.25 The frequency of iris nevi is much less than melanoma of iris. So,
of 100 melanocytic lesions of the iris only 9.0 percent were morphologically
03A.indd 81 31-08-2012 12:31:32

C
Figs 3.2A to C: Benign conjunctival tumors: (A) Conjunctival hemangioma in the left
eye of a 27-year-old women; (B) Caruncular hemangioma and conjunctival papilloma
in the left eye of a 32-year-old man; (C) Conjunctival lymphoma in the left eye of a
46-year-old women.
classified as melanocytic nevi, the rest cases were melanoma (91.0%).40 Of 113
patients with suspicious iris nevi the histologic diagnose was performed in 14
cases (12.4%) and there were no cases with iris nevi,41 or of the 37 cases of the
iris and ciliary body tumors according to the histopathological examination
iris nevi was found only in 5.4 percent,42 or in 2.5 percent,16 or in 9.0 percent.40
Iris nevus can be diffuse and bilateral.43 Except it, iris nevus can be a part of
the “iris nevus syndrome”, which was first described by Klein and Reese. Wolter
and Makley coined the term “Cogan-Reese syndrome” and Scheie and Yanoff
called the “iris nevus (Cogan-Reese) syndrome”. Authors described two types
of pigmented lesions in the iris nevus (Cogan-Reese) syndrome. One of these
types appears clinically as fine, pedunculated nodules on the surface of the
iris. The second type of iris lesions creates a matted appearance on the stroma
of the iris with a velvety whorl-like surface and loss of iris crypts.44 Iris nevus
(Cogan-Reese) syndrome, Chandler’s syndrome and progressive iris atrophy
are altogether named as the iridocorneal endothelial (ICE) syndrome, which
consists of three similar syndromes: (1) iris nevus (Cogan-Reese) syndrome;
(2) Chandler’s syndrome and (3) progressive iris atrophy.45
Melanocytoma or magnocellular nevus of iris is another variant of
melanocytic nevus with distinctive clinical and pathologic features.46 Iris
melanocytoma is a rare diagnosed tumor. So, of 1400 patients with iris
nevus only 47 patients (3.4%) were classified as having iris melanocytoma,
but histopathologic evaluation was performed only in 11 patients (23%).
03A.indd 82 31-08-2012 12:31:33

Estimated tumor growth of all 1400 patients was observed in 0 percent at
1 year, 23.0 percent at 3 and 5 years, 48.0 percent at 10 years, 74.0 percent at
15 years. Increased intraocular pressure was observed in 0 percent at 1 year,
11.0 percent at 3.5 and 10 years, 55.0 percent at 15 years. Development of new
tumors seeds was observed in 5.0 percent at 1 year, 27.0 percent at 3 years,
34.0 percent at 5 years, 63.0 percent at 10 years and 75.0 percent at 15 years.48
Iris melanocytoma can closely simulate iris melanoma.50
Melanocytoma of the ciliary body is unusual melanocytic tumor, which in
85.0 percent had involvement of chamber angle structures and only in 2 cases
of 17 patients preoperative intraocular pressure had elevated. Melanocytoma
may be difficult to differentiate from other pigmented ciliary tumors before
surgery.49
Age of patients with tumors of the iris and ciliary body was 38 years (mean
age).42 The mean age of patients with iris melanocytic lesions was 42.6 years,40
in patients with ciliary body melanocytoma the mean age was 47 years,49 the
mean age of patients with ciliary body nevi was 37 years,48 age of patients with
ciliary body nevi ranged from 28 to 76 years.51
Gender: The prevalence of females with melanocytoma of the ciliary body in
64.0 percent,48 or in 65.0 percent49 and with ciliary body nevi in 83.3 percent51
was found.
Race: Of all ethnic groups the most patients with melanocytoma of the ciliary
body were Whites and only 10.0 percent were Blacks,49 with iris melanocytoma
87.0 percent of patients were Caucasian (Whites), 9.0 percent were African
American, 2.0 percent were Asian and 2.0 percent were Hispanic48 and all of 6
patients with ciliary body nevi were Whites.50
Laterality: No prevalence of laterality in patients wtth melanocytoma of the
ciliary body observed,49 but patients with iris melanocytoma have had more
frequently affected left eye in 64.0 percent, than the right eye in 38.0 percent
and there were no patients with bilateral involvement.48 In patients with nevus
of ciliary body left eye was more frequently affected in 66.7 percent than right
eye in 33.3 percent.51
Epithelial cysts of the anterior chamber (“iris stromal cysts”) is benign
tumor, which occur after penetrating ocular injuries and represent secondary
epithelial ingrowth.52 Primary iris stromal cysts are less common and mostly
congenital. Acquired primary iris stromal cysts in adults are rare and cause
less often symptoms than congenital cysts.46 However, a 41-year-old patient
with primary iris stromal cyst was presented. There was no history of trauma
and no signs of preceding ocular injury.53 The most primary cysts of the iris
pigment epithelium classified as peripheral (73.0%), central (3.0%), midzonal
(21.0%) and dislodged (3.0%) of 234 patients with iris primary epithelial
cysts.54
03A.indd 83 31-08-2012 12:31:33

Age: The mean age for peripheral iris primary epithelial cysts was 33 years,
for midzonal cysts 52 years and for dislodged iris primary epithelial cysts
45 years.54
Gender: In females most often central iris primary epithelial cysts were found
and no gender predilection for midzonal and dislodges tumors was observed.54
Leiomyoma of the uveal tract is also benign uncommon intraocular
tumor that can arise from the iris, ciliary body, or choroids,55-57 the most
reports about this rare tumor described a single case studies. Report of Shields
et al.55 which is the largest recent series in the literature before 1994 deals with
observation on seven patients with intraocular leiomyoma. Of 7 patients 6
were adult from 20 to 80 years old, 4 females and 2 males. Authors found
in the literature more 17 previously published intraocular leiomyoma cases.
Later Kiratly et al.58 presented their experience with 3 patients who had ciliary
body leiomyomas.
Age of patients with intraocular leiomyoma ranged from 16 to 44 years,58
or from 20 to 80 years.55
Gender of patients with intraocular leiomyoma was with significantly
prevalence of females in 100 percent.55,58
Adenoma or benign epithelioma of the iris pigment epithelium is rare
lesion that can simulate iris or ciliary body melanoma, melanocytoma, and
pigment epithelial cyst. Adenoma of the iris pigment epithelium was found by
histopathologically examination in 9.5 percent of all patients (476) with iris
and ciliary body tumors.16
Location: Usually this tumor is unilateral and solitary.16 Adenoma or benign
epithelioma of the iris pigment epithelium located in the peripheral iris in 80.0
percent (16 of 20 lesions), 20.0 percent in the midzone, and 20.0 percent near
the papillary region.16
Age of patients with adenoma of the iris pigment epithelium ranged from 15
to 75 years,16 or the mean age was 60.0 years.59
Gender: Some authors found females being 2 times more often affected
than males,16 but others believe that males and females equal suffered from
adenoma of the iris pigment epithelium.59
Fuchs’ adenoma is age-related hyperplasia60 of nonpigmented epithelium
of ciliary part of the retina,46 or of the peripheral iris,61 or of the pars plicata
of the ciliary body.62 The history of Fuchs’ adenoma described by Iliff et al.63
According to this history, adenoma, first described by Fuchs in 1883 and again
in 1908, has been thought to be a relatively rare occurred. In 1964, Timm and
Fritsch collected 111 cases from the world literature, and Wallnöfer added 48
more in 1967 and stressed the relative frequency of these tumors.63
Ciliary body adenoma was in 20.0 percent of 59 patients, whose 100 eyes
received from two Eye Banks were examined to find Fuchs’ adenoma. As a rule,
03A.indd 84 31-08-2012 12:31:34

Fuchs’ adenoma has no clinical symptoms therefore in most cases this lesion
was found accidentally. For example, of 24 eyes investigated microscopically
in frontal serial studies a typical Fuchs’ adenoma was found in three cases
(12.5%). All eyes were normal macroscopically and all anterior segments
revealed no signs of inflammation or tumor microscopically.62 Of 320 eyes
from 160 nonselected patients 57 benign epitheliomas of Fuchs from the
nonpigmented ciliary epithelium were found in 42 patients (26.4%) as a result
of extremely slow and asymptomatically development of tumor.64
Age of patients with Fuchs’ adenoma ranged from 50 to 96 years,63
therefore Fuchs’ adenoma is disease of adults with an appearance of more than
25.0 percent among older people.64
Gender: In small series of 12 patients slight predominance of males in 7
patients (58.3%) than females in 5 patients (41.7%) was reported.63
Race: Majority of patients with Fuchs’ adenoma were white, and only 1 was
black.63
Neoplasms of the nonpigmented ciliary body epithelium can be divided
into congenital and acquired types. The best was known congenital tumor is
the medulloepithelioma, which was above mentioned.
The more general term “acquired neoplasm of the nonpigmented ciliary
epithelium”, chosed to use by Shields et al.60 is a tumor of ciliary body that has
its clinical onset in adulthood at a mean age of 45 years without predisposition
of sex or race. Because these tumors are only locally aggressive and have no
tendency to metastases, their classification as benign or malignant may be of
little practical importance. Authors-based their investigation on seven patients
with adenoma and two patients with adenocarcinoma of the nonpigmented
ciliary body epithelium. There were 5 females, aged from 24 to 69 years. Six
patients were white and only 1 was black. Right eye was affected in 3 patients
and left eye in 4 patients. There were no patients with bilateral tumor.
Ciliary body neurilemomas seu schwannoma of ciliary body is extremely
rare tumor and it rarely occur intraocularly, being a benign neoplasm of
anterior segment of the eye; they pose a diagnostic dilemma for the physician
and often are mistaken as a malignant lesion, resulting in enucleation.65,66
Choroidal osteoma is an unusual form of intraocular ossification. It is
often found in healthy eyes without signs of inflammation or trauma. The
typical patient with choroidal osteoma is a healthy female in the second
or third decade of life. Typically this tumor is monolateral but it can occur
bilaterally67 in approximately 20 to 25 percent of cases.68 There is no incidence
of choroidal osteoma per number of population in the literature but some
authors believe that choroidal osteoma is a rare tumors of choroids.68,69 The
others do not consider it.70 So, between January 1, 1977 and January 1, 2003
(26 years) in single-center case series there were 61 patients (74 eyes) with
03A.indd 85 31-08-2012 12:31:34

choroidal osteoma (approximately 2 patients per year). In 51.0 percent of eyes

choroidal osteoma showed evidence of growth and in 50.0 percent of eyes was
found decalcification of tumor by 10 years. Decalcified subfoveal choroidal
osteomas displayed a particularly poor visual prognosis.71 During more than
20 years we have observed only one 49-year-old man with choroidal osteoma
of the left eye in temporal part of chorioidea near macular with progressively
decreased vision without evidence of inflammation or trauma.
Choroidal hemangioma is a rare benign vascular intraocular tumor.72
In adults as well as in children choroidal hemangioma occur in two forms: a
circumscribed or solitary type, which is not associated with systemic findings,
and a diffuse type, which is usually associated with ipsilateral facial nevus
flammeus or of the Sturge-Weber syndrome.73 About 70.0 percent of choroidal
hemangiomas were located temporally (at the posterior pole).74
Circumscribed choroidal hemangioma in 38.0 percent of cases is initially
misinterpreted before referal as choroidal melanoma or metastasis. Visual
acuity is poor in more than 60.0 percent of patients at 10 years, despite
successful control of associated subretinal fluid in 76.0 percent.75 A median
age of patients with choroidal hemangioma is 35.2 years; tumor occurs with
the same frequency in males and females more often in the left eye.16
Retinal capillary hemangiomas are multiple in about one-third of patients
and as many as half of the cases,76 or 1 patient of 12 (8.3%) had bilateral
lesions.77 The prevalence of retinal capillary hemangioma in the von Hippel
Lindau disease population has been reported to range from 20.0 to 68.0
percent. On the other hand, the prevalence of underlying von Hippel Lindau
disease in patients with solitary or multiple retinal hemangiomas is reported
to be 20.0 to 58.0 percent.76
Age: The mean age at diagnosis of retinal capillary hemangioma in von Hippel
Lindau disease was 21 years,16 or 25 years48 and the median age at diagnosis in
cases with von Hippel Lindau disease was 17.6 years, but in those without von
Hippel Lindau disease was 36.1 years. New tumors developed before the age of
47 years.78 The most patients with von Hippel Lindau disease present retinal
capillary hemangioma between the ages of 10 and 40 years and it usually
manifested by the age of 30 years.79 Capillary hemangioma of the optic disk
may be associated with von Hippel Lindau disease80 or may be unassociated
with central nervous system involvement.81
Retinal cavernous hemangioma is a rare lesion that was first defined
as a distinct entity by Gass in 1971. It associated with cerebral cavernous
maltiformations syndrome. According to authors’ opinion this syndrome
should be included in the neuro-oculo-cutaneous (phakomatoses) syndrome.82
92.0 percent of familial cavernous malformation (“angioma”) of the central
nervous system and retina were cavernous; 50.0 percent of those subjects
03A.indd 86 31-08-2012 12:31:34

affected had multiple central nervous system and/or retinal malformations
and 68.0 percent were symptomatic. Autosomal dominant inheritance with
high penetrance was confirmed.83 Sporadic ocular angioma can occur in
the absence of von Hippel Lindau disease but appears less prevalently than
von Hippel Lindau itself. Of 32 patients reffered 17 (53.1%) had typically
solitary ocular angiomas,84 and had no evidence of other von Hippel Lindau
complications in themselves or in family members.
Age: The mean age of presentation was 30.9 years,84 or 27 years.85 The age
of presentation, degree of visual morbidity, complications, morphology and
anatomical location of the tumor are similar of those seen in von Hippel
Lindau disease.84
Wyburn-Mason syndrome has been the nomenculature designed for
a distinct clinical entity comprising: 1. arteriovenous malformation of the
midbrain; 2. congenital vascular abnormality of the ipsilateral retina; 3.
facial nervus, and 4. mental change. The most common involved sites are the
orbit and brain, followed by the face.86 This syndrome is phakomatosis with
cerebrospinal arteriovenous aneurism.46
Age: Of 14 patients with Wyburn-Mason syndrome only 4 patients (28.6%)
were adults aged from 28 to 49 years, or adult patients from 16 to 56 years were
in 59.3 percent (16 of 27 pattient).87
Gender: Some authors found the prevalence of males in 100 percent,86 others
found that number of males and females was equal.87
Laterality: Right side was involved in 29.6 percent (8 of 27 patients) and left
side was involved in 25.9 percent (7 of 27 patients) and 1 patient was bilateral.87
Race: With regard to ethnicity Caucasian were in 14.8 percent, and other
ethnicities (Taiwanse, Thai, Indian, Guam, and aboriginal) were in 18.5
percent. Ethnicity of the rest patients was unknown.87
Melanocytoma of the optic disk is intraocular tumors, which generally are
considered to be a benign lesion and may arise wherever uveal melanocytes
are present.88 They may involve part or all optic disk.47
Age: Melanocytoma of the optic disk occures in majority cases in adults
and can apparently develop spontaneously in adulthood.88 The mean age at
diagnosis was 50 years.89
Gender: The predominance of females in 62.0 percent (males 38.0%) was
described.89 Transformation of melanocytoma of the optic disk into malignant
melanoma was reported in several research works91,92 and that found from
1 to 2 percent.90
Laterality: The lesion was unilateral in 99.0 percent and only 1.0 percent of
patients was bilaterally involved.90
Race: The most of patients (65.0%) were White, 29.0 percent were African
American, and 6.0 percent were Asian, Hispanic, Indian, or Arabic.90
03A.indd 87 31-08-2012 12:31:34

Retinal astrocytomas occur more frequently in childhood, a few adult cases

are reported. In approximately 50.0 percent tuberous sclerosis patients occur
retinal astrocytoma.103 However, there are several reports about cases of retinal
astrocytoma in adults.93-103 This tumor is most commonly associated with
tuberous sclerosis6 and less commonly associated with neurofibromatosis.95,99
We have collected consecutive cases of retinal astrocytomas in the literature
to research gender, age and presence or absence of tuberous sclerosis in an
adult patients suffering from retinal astrocytomas (Table 3.1).
Of 11 adult patients with retinal astrocytoma described in the literature
were 5 males and 6 females aged from 21 to 69 years. Tuberous sclerosis found
in 4 patients (36.4%). The patient reported by Pascual-Castroviejo et al.100 was
referred at 3 years of age from the first month of life because of partial seizures,
severe mental retardation and left microphthalmos who was enucleated at age
of 18 years. At 24 years old there was pathologically diagnosed retinal and
cerebral giant cell astrocytoma in both location. This unusual case may be
described as children retinal astrocytoma as well as adult retinal astrocytoma.
5 of 11 cases occurred in USA.
Medulloepithelioma as intraocular type of tumors is very rare lesion in
adults and that is more common in children. So, only 1 adult patient of 10
with ciliary medulloepithelioma was 58 years old.104 Medulloepithelioma in
children was described in Chapter 3.
Benign orbital tumors in adults as well as in children are characterized by
the presence of various tissues. There are multiple types of orbital tumors that
can originate from this region.
Table 3.1: Gender and age of patients with retinal astrocytoma with/without
tuberous sclerosis (TS) or other systemic disease in adults in the literature
Authors Year of Country Number Gender Age of TS
publication of cases of patients patients
Ramsay et al.93 1979 USA 1 Male 41 no
Bornfeld et al.94 1987 Germany 1 Male 56 no
O’Shea, Powers95 1991 USA 1 Female 48 no
Margo et al.96 1993 USA 1 Female 27 yes
Etti et al.97 1993 Austria 1 Male 21 yes
Ikeda et al.98 1995 Japan 1 Female 45 no
Seitz, Jonas99 1995 Germany 1 Female 69 no
Pascual-Castroviejo100 1995 Spain 1 Male 24 yes
Shields et al.101 2004 USA 1 Female 33 no
Rodriguez-Francia et al.102 2005 Spain 1 Male 30 no
Vrabec, Augsburger103 2003 USA 1 Female 47 yes
Total: 11 cases
03A.indd 88 31-08-2012 12:31:34

Approximately all types of tumors are presented in orbit.16 The incidence of
orbital tumors varies widely and has been reported to be different on differences
in geographical areas or the particular race of the subject105 or depending on
the source of the material reviewed,106 or whether histopathologic or clinical
diagnosis is used in diagnosis.118
Of all ocular tumors orbital tumors occurred in 23.0 to 25.0 percent.16
Benign tumors of the orbit of all orbital tumors occur in 27.0 percent,120
or in 48.0 percent,107 or in 58.5 percent,108 or in 62.0 percent,105 or in
64.1 percent,106 or in 80.3 percent16 depending on patients or pathological
data characteristics. Brovkina16 found the prevalence of vascular tumors in
25 percent and neurogenic tumors in 16 percent (neurinoma, neurofibroma,
meningioma and optic nerve tumors). Rare soft-tissue tumors as teratoma,
fibroma, lipoma, mesenchimoma, mixoma, chondroma and leiomyoma
occur in 7 percent, dermoid and epidermoid cysts were in 9.5 percent of all
benign orbital tumors.16 However, Shields et al.106 found other percentage of
benign orbital tumors: of 1264 patients with orbital tumors and simulating
lesions vasculogenic tumors occurred in 13.3 percent, neurogenic tumors in
7.7 percent, fibrocystic tumors in 3.9 percent, osseous and fibro-osseous
tumors in 3.9 percent and lipocystic tumors in 2.6 percent. The percentage
in report of Brovkina16 and Shields et al.106 are not similar due to different
groups of patients, which include or not simulating lesions, primary benign
and malignant tumors, secondary and metastatic tumors in children and
adults, but in both reports vascular and neurogenic benign tumors were the
most common neoplasms developing in orbit.
Benign orbital tumors were mainly seen in the forth or fifth decade
of life.105 The incidence of histologically verified orbital tumors increased
significantly and is about 80 cases per year registred in 1974 to 1997. According
to authors’ opinion, the explanation for this increase may therefore be due to a
combination of more advanced diagnostic techniques, less traumatic surgical
procedures and an incresed patient awareness.108
Cavernous orbital hemangioma in adults is the most frequent vascular
tumor,105,106,108,110,118,120 which account for 36.0 percent,106 or 41.2 percent,118
or 75.0 percent110 of vascular orbital lesions and 6.0 percent,106 or 9.0 percent,110
or 12.3 percent105 of all orbital lesions.
Age: Cavernous orbital hemangiomas have a propensity to affect middle-aged
women.109,113,114 The peak incidence is in early middle age112 with the mean
age of 39.2 years,111 or 46.0 years,118 or 48 years,106 or with median age of 45
years (ranged from 23 to 73 years, median 45 years),110 but in Japanese patients
aged 40 years or older, the most common benign orbital tumors were reactive
lymphoid hyperplasia (24.0%) and pleomorphic adenoma (10.0%), cavernous
hemangioma was only in 9.0 percent and took the forth place of all 244 orbital
03A.indd 89 31-08-2012 12:31:34

tumors.107 Primary intraosseous form of cavernous hemangiomas presented

most frequently in their forth or fifth decade of life.119
Gender: Some authors found that females suffered from orbital cavernous
hemangioma more frequently than males.112,113,118 For example, of 209 patients
with cavernous hemangioma there were 123 females (58.9%) and 86 were
males (41.1%),111 of 85 patients with vascular orbital tumors the prevalence of
females with cavernous orbital hemangioma in 32.9 percent (28 patients) was
reported.118 Others believe that males and females were affected in equal cases
(13 men and 14 women),110 or 14 women and 13 men.111 In small series of 9
patients with cavernous orbital hemangioma were 4 males and 5 females.105
However, light prevalence of males in 55.6 percent (20 of 36 patients with
cavernous hemangioma including children) was found.108
Laterality: Cavernous hemangioma is usually unilateral and single tumor, but
it may also occur bilaterally and as a multiple neoplasm.112,115-117 However, of
35 cases of orbital cavernous hemangioma there were no bilateral or multiple
cases.118 This benign vascular tumor most typically presented as unilateral
painless proptosis.109 Wu et al.111 found that the left orbit was affected more
frequently in 58.6 percent (123 cases) than right orbit (41.1%, 86 cases of 209
patients with orbital cavernous hemangioma) and there were no bilateral cases
of cavernous hemangioma. Predilection for sites lateral to the optic nerve may
be related to origin from arterial rather than venous elements.113 Depending
on whether the tumor was intra or extraconal, the proptosis was either axial
or nonaxial. Twenty-two of 35 tumors (62.9%) were intraconal and 13 (37.1%)
were extraconal. Optic atrophy was detected in patients with a 6-year long
history of proptosis.119
Recurrence: Cavernous hemangioma is recurrent tumor. There is report in the
literature about a case of 35-year-old woman with cavernous hemangioma of
the orbit, which was excised completely without complication and the patient
subsequently regained her vision. Fifteen years later, the patient had recurrent,
multiple cavernous hemangioma in the same orbit.117 Incompletely resected
or excised hemangioma can recur and in these cases it should be excised if it
impairs optic nerve function and causes corneal exposure due to proptosis.118
Complete excision is usually possible and surgical morbidity is low.113 In
13.9 percent of patients with orbital hemangioma (5 of 36 patients including
children) had 5 recurrences.108 However, of 23 cases including tumors located
near apex with at least a 5-year follow-up no recurrences have been seen.118
Race: There was no found a predilection for race.114
Glioma of optic nerve in adults occurs significantly rare than in children.
In adults glioma of optic nerve was in 9.8 percent (13 of 133 adult patients with
optic nerve tumors).123 This percentage ranged from 1.0 percent (3 patients of
300 consecutive children and adults with space-occupying orbital lesions),110
03A.indd 90 31-08-2012 12:31:34

to 2.2 percent (5 of 244 adults and children with primary, secondary and
metastatic orbital tumors),107 to 3.8 percent (48 of 1264 adults and children
with orbital tumors and simulating lesions)106 and to 5.2 percent (50 of 956
adults and children with space-occupying lesions)108 depending on series
characteristics.
Age: In 182 adult patients aged 40 years or older with benign and malignant
orbital tumors glioma of optic nerve has not been observed.107 However, of
72 patients with optic nerve glioma in children and adults there were adult
patients and age of patients ranged from 0 to 45 years,106 or from 0.1 to 67.2
years.108,123
Incidence: Majority of optic nerve gliomas occur in the first two decades of
life, with equal sex incidence in about 1 of 200000 patients presenting with
eye complaints. The incidence is greater in neurofibromatosis.124 Frequency of
glioma increased significantly during the last 25 years.123
Gender: Some authors found this rare tumor only in females,110 or in 62.0 percent
(31 females of 50 adults and children) with optic nerve glioma,108 or in 76.9
percent (10 females of 13 patients including children) with optic nerve glioma.123
Recurrence of optic nerve glioma occurred in 8.0 percent (4 patients with 6
recurrences of 50 patients),108 or in 10.3 percent (6 patients with 6 recurrence
of 58 patients),123 with optic nerve glioma, including children.
Meningioma of optic nerve developed in orbit originating in the optic
nerve sheath, represent 1.2 percent of all meningiomas, and are the second
most common optic nerve tumor after gliomas.126 These tumors arise from the
sheath of the optic nerve in 78.0 percent or extradurally within orbit, remote
from the nerve in 22.0 percent.127 Over 98.0 percent of all meningiomas
originate in the central nervous system including the optic fascicle. Spread
outside this area occurs in 20.0 percent of cases.128 Ectopic (extradural)
meningiomas that do not originate from either the optic fascicle or the
intracranial meninges are exceedingly rare.128 Of all primary orbital tumors
(244 patients) optic nerve meningioma occurred in 2.0 percent (5 patients),107
or in 14.8 percent (35 of 235 optic nerve tumors)123 and in the other series
of 1264 patients with orbital tumors and tumor-simulating lesions were 4.0
percent of orbital meningioma.106 In smaller series of 73 primary orbital
tumors meningioma was in 5.5 percent.105 Calcification in the tumor was in
12.5 percent.127 The most common histologic type is the meningotheliomatous
(syncytial or transitional) meningioma.128
Age: Together with information on patient age and tumor location, the
type of orbital tumor can be estimated before histopathologic examination
because optic nerve sheath meningioma occur in patients over 40 years,107
or predominantly in middle-aged patients.125-127 Up to 80.0 percent of orbital
meningiomas occur in two peaks, 25.0 percent in the first decade, and the
03A.indd 91 31-08-2012 12:31:34

rest in the 5th decade,124 or with mean age of 48 years.106 The mean age at
diagnosis of primary extradural orbital meningioma is 31 years128 and an
average age was 53.0 years.108
Gender: The most of patients (80.0%) with orbital meningioma are
females.108,124,125,127 So, of 31 patients with orbital meningiomas 80.7 percent
were females (25 patients).123 However, in small series of 4 patients with orbital
meningiomas there were 2 males and 2 females.105
Race: Meningiomas, whether primary in the orbit, optic canal or intracranial
areas usually occur in Whites.124,125
Laterality: Optic nerve sheath meningiomas are usually unilateral tumor, but
it is bilateral in about 5.0 percent of cases.126 Tumors in the orbit or optic canal
almost always affect vision unilaterally; intracranial tumors, while usually
causing unilateral visual loss initially, eventually cause bilateral loss of vision,
often with blindness in one eye.125
Frequency of optic nerve sheath meningioma increased significantly during
the last 25 years.123
Recurrence: Orbital meningioma is recurrent tumor. For example, of 23
patients with orbital meningioma 5 patients (21.7%) had 6 recurrences,108 or
of 31 patients there were 4 patients (12.9) with 5 recurrences.123
Metastasis: In spite of orbital meningioma is recurrent neoplasm this tumors
are locally infiltrating but do not metastasize.124
Prognosis: Even when untreated, the prognosis for life is excellent, with an
overal tumor-related mortality of 0 percent.126
Pleomorphic adenoma of lacrimal gland occurred not more than in
2.0 percent of epithelial tumors of lacrimal gland,122 or in 2.4 percent of all
orbital space-occupying lesions,108 or in 7.0 percent of primary, secondary
and inflammatory lesions of orbita,105 or in 9.6 percent of lacrimal gland fossa
lesions,106 or in 9.9 percent of primary benign and malignant orbital tumors,107
or in 12.0 percent of lacrimal gland lesions,121 or in 50.0 percent of all lacrimal
gland tumors.16
Age: The mean age of patients with pleomorphic adenoma was 42.8 years,108 or
44 years,121 or 48 years.106 Median age of 54 years ranged from 39 to 69 years
was in 12 patients with the remaining male outlier being only 21 years old at
the time of surgery,110 or the median age was 52 years.131
Gender: Some authors found the prevalence of males with pleomorphic
adenoma16,105,108 with the male to female sex ratio of 4:8, i.e. in females this
tumor occurs twice as often as in males.16,105 The prevalence of females was
also found in other report with the male to female sex ratio of 26:49 including
children.131 However, Johansen et al.108 argue that of 23 patients with
pleomorphic adenoma of lacrimal gland ratio of males to females was 12:11
including 1 child.
Incidence: The highest yearly incidence of patients with primary pleomorphic
adenoma per 100000 Japanese was in the age group of 50s at 4.3 × 10–²
03A.indd 92 31-08-2012 12:31:34

people.131 Pleomorphic adenoma of lacrimal gland in the left eye of 28 years
old man treated in our Department shown on Figure 3.3.
Lymphangioma of the orbit is a rare benign tumor. The exact nature of the
orbital lymphangiomas is contraversal.129 It occur in 0.3 percent,110 or in 4.3
percent106 of all orbital lesions. Of vasculogenic orbital tumors in adults this
neoplasms were in about 2.5 percent,16 or in 3.1 percent (1 of 32 patients),110
or in 25.3 percent (54 of 213 patients including children).106
The mean age of patients with orbital lymphangioma was 25 years and the
median age was 16 years ranging from 0 to 91 years.106
Other rare benign orbital tumors such as neurolemoma, neurofibroma,
angiofibroma, lipoma, epithelial lacrimal gland lesions and blue orbital nevus
occurred from <1 to 4 percent of total orbital lesions.106 An extremely rare
orbital tumor is germinoma, which according to authors’ opinion should be
considered in the differential diagnosis of primary intraorbital tumors.130
Fibrolipoma of the left orbital in 53-year-old women (A) treated in our
Department and her excited tumor (B) shown in Figures 3.4A and B.
Fig. 3.3: Pleomorphic adenoma of lacrimal gland in the left eye of a 28 years old man
A B
Figs 3.4A and B: Fibrolipoma of the left orbital in 53-year-old women

(A) and her removed tumor (B)
03A.indd 93 31-08-2012 12:31:35

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44. Shields MB. Progressive essential iris atrophy, Chandler’s syndrome, and the
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46. International histological classification of tumours No 24. Histological
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50. Jacobiec FA, Silbert G. Are most iris “melanomas” really nevi? A clinicopathologic
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54. Lois N, Shields CL, Shields JA, et al. Primary cysts of the iris pigment
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55. Shields JA, Shields CL, Eagle RC Jr. Observation on seven cases of intraocular
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56. Toth J, Kerenyi AA, Suveges II, et al. Leiomyoma of the ciliary body and
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58. Kiratly H, Bilgic S, Soylemezoglu F. Ciliary body leiomyomas. Three case reports.
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59. Shields JA, Shields CL, Mercado G, et al. Adenoma of the iris pigment epithelium:
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60. Shields JA, Eagle RC Jr, Shields CL, et al. Acquired neoplasms of the nonpigmented
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61. Zaidman GW, Jonson BL, Salamon SM, et al. Fuchs’ adenoma affecting the
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62. Rohrbach JM, Steuhl KP, Thiel HJ. Cysts and Fuchs’ endothelial adenomas of the
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64. Hilleman J, Nagmann G. Benign epithelioma (Fuchs) of the ciliary body.
65. Pineda R 2nd, Urban RC jr, Bellows AR, et al. Ciliary body neurolemoma. Unusual
clinical findings intimating the diagnosis. Ophthalmology 1995;102:918-23.
66. Kim IT, Chang SD. Ciliary body schwannoma. Acta Ophthalmol Scand
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67. Pamer Z, Kovacs B. A case of a fast-growing choroidal osteoma. Retina
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68. Chen J, Lee L, Gass JD. Choroidal osteoma: Evidence of progression and
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70. Browning DJ. Choroidal osteoma: Observation from a community setting.
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72. Shepkalova VM, Chorosanjan-Tade AA, Disler ON. Intraocular tumors. Atlas.
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74. Witschel H, Font RL. Hemangioma of the choroid. A clinicopathologic study of
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75. Shields CL, Honovar SG, Shields JA, et al. Circumscribed choroidal
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76. Singh AD, Rundle PA, Rennie I. Retinal vascular tumors. Ophthalmol Clin
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77. Kuo MT, Kou HK, Kao ML, et al. Retinal capillary hemangiomas: Clinical
manifestations and visual prognosis. Chang Gung Med J 2002;25:672-82.
78. Singh AD, Nouri M, Shields CL, et al. Retinal capillary hemangioma: A
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79. Schmidt D. Retinal angiomatosis. Klin Monatsbl Augenheilkd 2005;222:90-109.
80. Benson M, Mody C, Rennie I, et al. Hemangioma of the optic disk. Graefes Arch
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81. Takahashi T, Wada H, Tani E, et al. Capillary hemangioma of the optic disk. J
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82. Kushner MS, Jampol LM, Haller JA. Cavernous hemangioma of the optic nerve.
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83. Dobyns WB, Michels VV, Grover RV, et al. Familial cavernous malformations of
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84. Webster AR, Maher ER, Bird AC, et al. A clinical and molecular genetic analysis
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85. Peng X, Wang G, Zhang F, et al. Clinical features of 48 cases with retinal angioma.
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86. Luo CB, Lasajaunias P, Bhattacharya J. Craniofacial vascular malformations in
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87. Dayani PN, Sadun AA. A case report of Wyburn-Mason syndrome and review
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88. Reidy JJ, Apple DJ, Steinmetz RK, et al. Melanocytoma: Nomenculature,
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89. Shields, Shields CL, Piccone M, et al. Spontaneous appearance of an optic disk
melanocytoma in adults. Am J Ophthalmol 2002;134:614-5.
90. Shields JA, Demirci H, Mashayekhi A, et al. Melanocytoma of optic disk in 115
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91. Apple DJ, Craythorn JM, Reidy JJ. Malignant transformation of an optic nerve
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92. Meyer D, Blinder KJ, Sinard J, et al. Malignant transformation of an optic disk
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93. Ramsay RC, Kinyoun JL, Mill CW, et al. Retinal astrocytoma. Am J Ophthalmol
1979;88:32-6.
94. Bornfeld N, Messmer EP, Theodossiadis G, et al. Giant cell astrocytoma of the
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95. O’Shea WF, Powers JE. Solitary retinal astrocytoma. J Am Optom Assoc
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96. Margo CE, Barletta JP, Staman JA. Giant cell astrocytoma of the retina in
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97. Etti A, Phillipp W, Mayer U. Retinal phakomata associated with cerebral
astrocytoma. An incomplete form of Bourneville-Pringle disease?
98. Ikeda T, Ogawa K, Kitanishi K. A case of uncomplicated retinal astrocytoma.
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99. Seitz B, Jonas JB. Solitary retinal astrocytoma with “acoustic shadowing”. Klin
Monatsbl Augenheilkd 1995;206:188-9.
100. Pascual-Castroviejo I, Patron M, Gutierrez M, et al. Tuberous sclerosis
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101. Shields CL, Shields JA, Eagle RC, et al. Progressive enlargement of acquired
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102. Rodriguez-Francia P, Sanchez-Tocino H, Garcia-Cantera M, et al. Optic
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103. Vrabec TR, Augsburger JJ. Exudative retinal detachment due to small
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104. Shields JA, Eagle RC Jr, Shields CL, et al. Congenital neoplasms of the
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105. Shikishima K, Kawai K, Kitahara K. Pathological evaluation of orbital tumors
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108. Johansen S, Heergaard S, Bogeskov L, et al. Orbital space-occupying lesions in
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110. Seregaard S, Sahlin S. Panorama of orbital space-occupying lesions. The 24-year
experience of a refferal centre. Acta Ophthalmol Scand 1999;77:91-8.
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122. Riedel KG, Markl A, Hasenfranz G, et al. Epithelial tumors of the lacrimal gland:
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126. Dutton JJ. Optic nerve sheat meningiomas. Surv Ophthalmol 1992;37:167-83.
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128. Spraul CW, Gareis O, Lang GK. Primary extradural meningioma of the orbits:
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129. Iliff WJ, Green WR. Orbital hemangioma. Ophthalmology 1979;86:914-29.
130. Perrini P, Ventura L, Ricci A. Primary germinoma of the orbit. Neurosurgery
2005;57:E813.
131. Lacrimal Gland Tumor Study Group. An epidemiological survey of lacrimal
diagnosis. Jpn J Ophthalmol 2005;49:343-8.
MALIGNANT EYELID TUMORS

Although malignant tumors are predominantly the cancer of the skin and
are completely treatable if detected early. These malignancies remain to be an
important problem since they represent approximately 5.0 to 10.0 percent of
all skin cancer,1 or of all malignant tumors registred malignant eyelid tumors
represent 1.4 percent.2 At the same time, of all face malignant tumors 15.8
percent represented by malignant palpebral tumors.3
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In the literature, there are varies percentage of malignant eyelid tumors of
all eyelid tumors or lesions. We collected different reports to compare their
datas (Table 3.2).
As shown in Table 3.2, percentage of malignant eyelid tumors ranged
from 10.8 percent4 to 44.2 percent,5 i.e. more than 4 fold. Such a significant
difference may be explained by various clinical characteristics of patients’
group, which included patients with inflammatory conditions,6,7 or eyelid
lesions.8 Futhermore, the location of tumors is also different. Series included
ocular adnexa,5,6 or conjunctiva,9 or all malignant tumors of the eye.10
Malignancies of the eyelid are predominantly cancers of the skin.11 Therefore,
we found that percentage is not accurate index to research epidemiologic
aspects of any disease. Population-based incidences such as age-adjusted or
crude, or standardized incidences are more precise but in the literature they
are not frequently indexes.
Age: Malignant eyelid tumors were usually seen in the age group of 40 to 60
years,7 or in patients with mean age of 62.6 years,12 or from 45 to 92 years
(72+/-12.4 years). 81.6 percent of patients (31 of 38 patients) were over 60
years old14 and 95.0 percent of patients were 40 years of age and above,11 or
the median age at diagnosis was 63.0 years for males and 66 years for females.
To compare with other skin tumors, malignant lesions of the eyelid increase
with age.11 After the age of 60 years, only 18.9 percent of patients was under 60
years of age (21 of 111 patients with palpebral malignant tumors).3 In patients
70 to 79 years of age the peak incidence was observed.13
Gender: There was a slight preponderance of males as male/female ratio
was 1.3:1.7 Men showes statistically significantly higher incidence rates than
women for basal cell carcinoma of the eyelid.25 However, other authors found
a slight predominance of females in 50.2 percent (163 of 325 patients),11 or
in 54.3 percent (69 of 127 patients)12 of all malignant eyelid tumors. Abe
Table 3.2: Percentage of malignant eyelid tumors of all eyelid tumors,

inflammatory conditions, and tumor-like lesions of the eye and adnexa
Authors Research period Number of Number of Percentage
eyelid tumors malignant
(100%) eyelid tumors
Pornpanich, Clindasub4 2000–2004 297 32 10.8
Tesluk8 1980–1982 720 125 17.4
Halon et al.6 1946–1999 2031 433 21.3
Obata et al.9 1990–2004 87 24 27.6
Ni17 1953–1992 3510 1093 31.1
Watanaba10 1964–1984 175 68 38.9
Abdi et al.7 1957–1991 207 85 41.1
Kwang et al.5 1976–1985 52 23 44.2
03A.indd 101 31-08-2012 12:31:35

et al.13 found 26 each of men and woman of total 52 malignant eyelid tumors.
According to results of other reports, males and females were equally affected
by malignant eyelid tumors.14,15
Laterality: The right and the left eyes are involved by malignant eyelid tumors
with equal frequency.6,15,16 However, Takamura and Yamashita14 found that of
38 malignant eyelid tumors 22 cases (57.9%) were on the right eye and 16 cases
(42.1%) were on the left eye.
Race: In Singapore, from 1968 to 1995 of 235 patients with malignant eyelid
cancer 91.1 percent were Chinese (296 patients), 5.2 percent (17 patients)
were Malay, 3.1 percent (10 patients) Indian, and 0.6 percent (2 patients) were
other ethnic groups. The average age standardized incidence of eyelid cancers
in Chinese was 7.8 per million, in Malays that was 5.5 per million, and in
Indians 2.2 per million.11 In other report only 1.5 percent were Blacks (3 of 206
patients with malignant eyelid tumors).18
Incidence: The average annual age standardized incidence rate (The UICC
World population) among male Singapore residents was 6.5 per million
and 5.5 per million among female Singapore residents. This incidence has
increased steadily over the years for females from 4.6 per million in the 1968
to 1972 period to 6.78 per million during 1993 to 1995 period, with a peak of
6.84 per million from 1988 to 1992. The rates for males have remained stable
from 1976 to 1995.11 The same incidence, the average annual age standardized
incidence rate but with other stadardized population 2000 World Standardized
Population was 3.2 per million Chinese population in Taiwan during the study
period of 1979 to 1999. There was an overall increase of incidence rates from
1.5 per million in 1979 to 5.1 per million in 1999 with annual percentage
change of 4.63 percent.19 The incidence of malignant eyelid tumors of
approximately 4.7 per 100000 population found by Lommatzsch et al.2 The
standardized morbidity of eyelid carcinoma was the highest of all malignant
ocular tumors over a period of 10 years and it was significantly higher for
males and rural population.20 The probability of an unrelated malignancy
developing elsewhere in the body was approximately 9.0 percent at 5 years and
15.0 percent at 10 years in patients with malignant eyelid tumors.15
Recurrence: In case of recurrence, malignant palpebral tumors may extend
beyond the clinically visible borders21 but recurrence rate is not high. So, a
5-year recurrence rate of patients with eyelid cancer was 2.0 percent. At 10
years recurrence rate was 3.0 percent and recurrence after surgical excision
is uncommon,15 but malignant eyelid tumors is life-threatening, so further
enlightenment of clinicians is necessary.14 Higher recurrence rate of 7.7
percent and 15.2 percent was found by other researchers.12,13 The mean
interval of recurrence or metastasis after treatment was 26.3 months (range,
4–112 months).12 The 5-year metastasis rate was 11.7 percent.12
03A.indd 102 31-08-2012 12:31:35

Metastasis of malignant eyelid tumors to the regional lymph nodes and to
the lung occurred in 3.9 percent (2 of 52 patients),13 or in 7.1 percent (9 of 127
patients, who had regional lymph node involvement and distant metastases).12
Mortality of patients with malignant eyelid tumors was found in
34.6 percent (18 of 52 patients), or in 42.9 percent (18 of 42 patients with
follow-up information),13 or in 5.5 percent (7 of 127 patients with malignant
eyelid tumors who died from metastasis to lungs, liver or brain. The 5-year
mortality rate was 7.3 percent for all eyelid malignancies.12 Long-term follow-
up is needed after treatment of malignant eyelid tumors.12
There are contradictory results concerning the most common malignant
eyelid tumors in the literature. Some investigators7,11,12,14,22,23 found that basal
cell carcinoma is the most frequently malignant eyelid tumor that occurs from
38.8 percent7 to 90.8 percent15 of all malignant eyelid tumors. Others believe
that sebaceous gland carcinoma,4 or squamous cell carcinoma,13 or malignant
melanoma18 is the most common malignant eyelid tumors. Jahagirdar et al.16
found that sebaceous gland carcinoma approximately in 37.0 percent was
almost as prevalent as basal cell carcinoma approximately in 44.0 percent.
However, Cook and Bartley15 no case of sebaceous gland carcinoma of 174
patients with malignant eyelid tumors during 15 years from 1976 throught
1990 were identified.
The percentage of the leading malignant eyelid tumors such as basal
cell carcinoma (BBC), sebaceous gland carcinoma (SGC), squamous cell
carcinoma (SCC), malignant melanoma (MM) and malignant lymphoma
(ML) of all malignant eyelid tumors in the literature were summarized by us
in Table 3.3.
As shown in Table 3.3, the most common was basal cell carcinoma (BBC),
which occurred in 62.3 percent (1631 patients), then in decreasing order
of frequency is sebaceous gland carcinoma (SGC) (501 patients, 19.1%),
squamous cell carcinoma (SCC) (355 patients, 13.6%), malignant melanoma
(MM) (78 patients, 3.0%) and malignant lymphoma (23 patients, 0.9%) of
total 2619 patients with malignant eyelid tumors in the literature.
Basal cell carcinoma is the most frequent malignant eyelid tumor. This
tumor occurred in 38.8 percent7 and in 72.5 percent6 of all eyelid tumors
and tumor like lesions, or in 20.9 percent9 and 37.6 percent17 of benign
and malignant eyelid tumors, or in 32.7 percent13 and in 39.5 percent14 of
malignant eyelid tumors, or in 65.1 percent of primary eyelid cancers,19 or
in 82.4 percent,8 in 84.0 percent,11 in 88.1 percent22 and in 90.8 percent15 of
the malignant eyelid tumors. Although in such Western country of Europe as
Finland22 and in both East country as China17 and Japan14 basal cell carcinoma
is the most common malignant eyelid tumor, but in Tailand,4 which is also
East country, the most frequently malignant eyelid tumor is sebaceous gland
03A.indd 103 31-08-2012 12:31:36

Table 3.3: Percentage of the leading malignant eyelid tumors of all malignant
eyelid tumors in the literature
Authors BBC SGC SCC MM ML Others Total
N % N % N % N % N % N % N, 100%
Pornpanich4 12 37.5 13 40.6 2 6.3 3 9.4 - - 2 6.2 32
Takamura,
Yamashita14 15 39.5 11a 28.9a 4 10.5 3 7.9 1 2.6 4 10.6 38
Abdi et al.7 33 38.8 23 27.1 19 22.4 3 3.5 - - 7b 8.2b 85
13
Abe et al. 17 32.7 7 12.5 25 48.1 2 3.9 1 1.9 - - 52
Wang et al.12 79 62.2 30 23.6 11 8.7 5 3.9 - - 2 1.6 127
Cook, Bartley15 158 90.8 - - 15 8.6 1 0.6 - - 2 - 174
Saari et al.22 192 88.1 3 1.4 17 7.8 1c 0.4c - - 5 2.3 218
Lee et al.11 273 84.0 33d 10.2d 11 3.4 4 1.2 - - 4 1.2 325
23
Weiner et al. 422 88.8 18 3.8 35 7.4 - - - - - - 475
Ni17 430 39.3 363 33.2 216 19.8 56 5.1 21 1.9 7 0.7 1093
Total: 1631 62.3 501 19.1 355 13.6 78 3.0 23 0.9 31 1.2 2619
a
- basosquamous cell carcinoma; b- premalignant nevus; c- sebaceous adenocarcinoma;
d
- meibomian gland carcinoma
carcinoma. Takamura and Yamashita14 have compared worldwide regional

percentage difference of basal cell carcinoma, sebaceous gland carcinona
and squamous cell carcinoma. The percentage of basal cell carcinoma
was ranged from 29.8 percent to 91.3 percent and that of sebaceous gland
carcinoma was from 0 to 32.7 percent, and squamous cell carcinoma from
2.4 to 29.5 percent. In the United States, Europe, England, Germany, Italy,
Hungary and Australia basal cell carcinoma was the most common as well as
in Africa (North Sudan and Algiria).14 However, there was no recorded basal
cell carcinoma of the eyelid in Southern Sudan.24 We summarized percentage
of basal cell carcinoma in the literature and found that basal cell carcinoma
took the first place and occurred in 62.3 percent (1631 of 2619 patients with
malignant eyelid tumors) (Table 3.3).
Age: Most of the cases of eyelid basal cell carcinoma occurred in eldery
patients from 52 to 88 years, mean 72.7+/- 12.3 years,14 or from 31 to 92
years, mean 69 years.22 However, Cook and Bartley reported cases of basal
cell carcinoma in the age group of 20 to 29 years.15 With age, mean annual
incidence rate of basal cell eyelid carcinoma rose significantly. In age groups of
50 to 80 years, the rate was statistically significantly higher than in age groups
of 30 to 49 years.22 The age-adjusted incidence of basal cell carcinoma of the
eyelid also rose with age.25
Gender: The predominance of females with ratio of males:females 14:24 was
reported by some authors.14 Others found that males showed statistically
higher incidence rates than females,20,25 or there was a slight predominance in
03A.indd 104 31-08-2012 12:31:36

men.12 Thirds believe that between males and females there were no statistically
significant differences in the mean annual rates with basal cell carcinoma of
the eyelid.22
Location: In 8.6 percent,10 in 44.3 percent,12 or in 60.0 percent,26 or in
73.3 percent14 basal cell carcinoma arose in the lower lid and in 34.6 percent
arose in the upper lid,13 the rest in decreasing order of frequency involved the
median canthus, upper lid, and lateral canthus,26 or upper lid in 19.0 percent,
inner canthus in 13.9 percent, outer canthus in 11.4 percent and more than
one region in 11.4 percent.12 Right eye affected by basal cell carcinoma less
frequently than left eye with ratio of 4:11.14
Race: Some authors concluded that racial and geographic factors play
important roles in determining the frequency and pattern of eyelid neoplasms.24
In Caucasians, basal cell carcinoma constituted about 80.0 to 90.0 percent of
the malignant eyelid tumors, whereas in Japan and Asian countries, basal cell
carcinoma constituted about 20.0 to 40.0 percent. In USA all 174 patients with
malignant eyelid tumors were white.15 A racial difference in the incidence of
basal cell carcinoma can be considered in making diagnosis.14
Incidence: The age-adjusted incidence of basal cell carcinoma of the eyelid
varied between 0.7 and 3.0 per 100,000 person-years in males and between 0.5
and 2.8 per 100,000 person-years in females and that increased during 1953 to
1987.25 Both the age-adjusted incidence and the gender-adjusted incidences
for basal cell carcinoma were 14.35 per 100,000 individuals per years.15 Other
incidence, mean annual incidence rate of basal cell eyelid carcinoma was 0.8 in
the age group of 30 to 40 years and rose significantly with age to the maximum
of 17.2 in the age group of 80 to 90 per 100,000 population, but that was lower
in the age group of 80 to 90 years and over.22 This incidence per 100,000
persons showed a statistically significant increase from 0.82 in 1977 to 1979
to 2.88 in 1995 to 1997 with an average incidence of 2.11 per 100000 persons
and it is more than tripled during 1977 to 1997.22 The increase of the mean
annual incidence of basal cell eyelid carcinoma may be due to the increase of
the eldery population because the incidence showed a significant increase with
age,22 or improvements in the diagnosis and registration may partly explain
the increased incidence rates.25 Basal cell carcinoma dominates the incidence
trends and the significant cohort effects give a warning of increasing risk of
basal cell carcinoma in younger girth cohort.19 There were no statistically
significant differences in the mean annual rates among urban, semirural and
rural patients22 or between different social classes and occupation categories
in standardized incidence ratios.25 However, Atanassova-Chilova20 found that
the standardized morbidity of eyelid carcinoma is significantly higher for rural
population. The increasing rates of incidence of eyelid cancer were mainly
given by an increase in the incidence of basal cell carcinoma19 and 60.0 percent
03A.indd 105 31-08-2012 12:31:36

of patients with basal cell eyelid carcinoma had additional unsuspected foci of
basal cell skin carcinoma.27
Recurrence of basal cell carcinoma of the eyelids was seen in 3.9 percent,13
or in 6.7 percent14 of all malignant eyelid tumors. The mean interval of
recurrence or metastasis after primary treatment was 47.7 months and the
recurrence rate at 5 years was 5.2 percent for basal cell eyelid carcinoma. One
case of basal cell eyelid carcinoma recurred after about 10 years.12
Metastasis: At 5 years in 1.5 percent of basal cell carcinoma tumors metastasized.
The 5-year metastasis rate was significantly lower for basal cell carcinoma than
for other malignant eyelid tumors.12
Mortality: The 5-year mortality rate for basal cell carcinoma (1.5%) was the
lowest comparing with that of sebaceous gland carcinoma and squamous cell
carcinoma.12
Etiology of basal cell carcinoma is still unclear. Although UV radiation is
the major cause of basal cell carcinoma, local factors, such as chronic trauma,
irritation or inflammation may also have some role in its etiopathogenesis and
other hypothetic factor such as demodicidosis may be one of the triggering
factors of carcinogenesis in eyelid basal cell carcinoma.28 Moreover, metal dusts
may also be potential carcinogenic agents for non-melanoma skin cancer.25
Sebaceous carcinoma or sebaceous gland carcinoma of the eyelid
is an aggressive malignant tumor derived from the adnexal epithelium
of sebaceous glands. It may arise in ocular or extraocular sites and
exhibits such a variety of histologic growth patterns and diverse clinical
presentation that the diagnosis is often delayed for months to years.30 It
presented as a poorly differentiated lesion, which suggests a possibility of
misdiagnosis because of its similarities to basal cell carcinoma, squamous
cell carcinoma. It can mimic also benign conditions such as recurrent
chalazion and inflammation. Histopathologically, 75.0 percent had
features similar to squamous cell carcinoma, 7.0 percent resembled basal
cell carcinoma.35 27.0 percent of sebaceous gland carcinoma arose from
both meibomian gland and Zeis glands.31 The most frequent site of skin
carcinoma was the eyelid, which occurred in 38.7 percent of 1349 patients
with skin sebaceous carcinoma of all locations.34
We summarized percentage of sebaceous gland carcinoma in the literature
and found that sebaceous gland carcinoma of the eyelid took the second
place of all malignant eyelid tumors and occurred in 19.1 percent (501 of
2619 patients with malignant eyelid tumors) (Table 3.3). Sebaceous gland
carcinoma represents approximately 1 and 5 percent of all malignant eyelid
tumors.29 However, there was other percentage of sebaceous gland carcinoma
in the literature, which occurred in 1.4 percent of malignant non-melanoma
neoplasms,22 or in 13.5 percent,13 in 23.6 percent12 and in 28.9 percent14 of
03A.indd 106 31-08-2012 12:31:36

malignant eyelid tumors, or in 27.1 percent of eyelid tumors and tumor-like
lesions, 7 or in 40.6 percent of benign and malignant tumors and inflammatory
conditions.4 Percentage depends on patients’ series characteristic.
Age: The most of patient suffered from sebaceous gland carcinoma were from
50 to 90 years.29 The mean age of patients with sebaceous gland carcinoma at
diagnosis was 63 years (range, 37–79),36 or 65 years (range 17–90 years),32 or
68.1 years (range 48–91).12 The madian age at refferal was 72 years,31 or 73.8 ±
11.1 years (range, 51–86 years).14
Gender: Females suffered from sebaceous gland carcinoma more frequent
than males.12 In 53.5 percent,36 or 68.8 percent,37 or 72.0 percent,32 or
70.0 percent12 or 73.0 percent31 were females with the ratio of males:females
of 2:9.14
Location: Upper lid involved by sebaceous gland carcinoma in 54.6 percent
and lower lid in 26.7 percent.12 A predilection for upper lid, which is affected
2 to 3 times frequentlier than the lower lid, was also found by Ni,17 Rao
et al.33 Wang et al.12 also found that upper lid involved more frequently by
sebaceous gland carcinoma in 56.7 percent, lower lid in 26.7 percent, outer
canthus in 3.3 percent and more than one region involved in 13.3 percent.
The ratio of right:left eye was 5:6.14 Pagetoid involvement (conjunctival
intraepithelial invasion) was seen in 47.0 percent of 60 patients with sebaceous
gland carcinoma.31
Race: In Japan and Asian countries sebaceous gland carcinoma constituted
about 20.0 to 40.0 percent of all malignant eyelid tumors.14 Primary eyelid
tumors of any type are rare in blacks.18
Incidence: The annual incidence of sebaceous gland carcinoma of the eyelid
in whites older than 20 years was 0.5 per million18 comparing with 2.03 per
million of the crude relative incidence of all locations skin carcinoma for
whites versus 0.48 per million for blacks.34 However, no cases of sebaceous
gland carcinoma in patients residing in Olmsted County, Minnesota during
15 years interval from 1976 to 1990 were identified.15
Recurrence: Local recurrence of sebaceous gland carcinoma of the eyelid was
in 2.3 percent with a median follow-up of 40 months,36 or in 9.4 percent with
a median follow-up of 4.8 years,37 or in 12.0 percent,32 or in 18.0 percent.31 In
many cases pagetoid change appeared to originate in the underlying sebaceous
glands and from there extended to invade the overlying epithelia.33 Metastases
of sebaceous gland carcinoma occurred in 16.0 percent (4 of 25 patients),32 or
in 27.3 percent (3 of 11 patients).14 The 5 years metastasis rate was significantly
higher for sebaceous gland carcinoma (16.1%) than for basal cell carcinoma
(1.5%). The mean interval of recurrence or metastasis after primary treatment
was shortest for sebaceous gland carcinoma, 17.5 months and at 5 years
sebaceous gland carcinoma metastasised in 16.1 percent.12
03A.indd 107 31-08-2012 12:31:36

Mortality: The percentage of patients with sebaceous gland carcinoma of

the eyelid who died from metastatic disease ranged from 6.0 percent,31 9.3
percent,36 22.1 percent,33 and to 31.3 percent.37 Five years mortality has been
estimated at 30.0 percent due to delayed diagnosis and treatment.29 Lower
5 years mortality rate for sebaceous gland carcinoma was 12.1 percent.12 9.3
percent of patients with sebaceous gland carcinoma (4 of 43 patients) died
from the tumor, and 9.3 percent (4 of 43 patients) died of nontumor related
causes.36 The overall tumor-related mortality rate in the west of Scotland was
3.0 percent.37 Rates of sebaceous gland carcinoma recurrence, metastasis, and
mortality were significantly higher than those of basal cell carcinoma.12
Survival: After a median follow-up of 40 months (range 1–148) 30 patients
(69.8%) of 43 were alive without recurrence and one (2.3%) was still alive with
local recurrence and distant metastasis.36
Squamous cell carcinoma of the eyelid is an invasive epithelial malignancy
showing keratinocytic differentiation and comprising 1 to 2 percent of all
eyelid lesions,44 or 3.7 percent (24 of 648)45 and 5 to 10 percent of all eyelid
malignancies.38 There are some investigations in the literature, which show
squamous cell carcinoma as the leading eyelid tumors,39,40 that up to 10 times
less common than basal cell carcinoma38 and that takes the first place of all
malignant eyelid tumors.13 Others found that squamous cell carcinoma is the
second most common eyelid malignancy,42-44 or that squamous cell carcinoma
takes the third place of all malignant ocular tumors in children and adults.41 At
the same time, the true frequency of this tumor has been difficult to estimate
because of a tendency for overdiagnosis (basal cell carcinoma and sebaceous
gland carcinoma) in published reports of eyelid lesions.44 Squamous cell
carcinoma accounted for only 3.7 percent (24 of 648 patients with malignant
eyelid lesions) during the 10 years period,45 or 1 to 2 percent of all eyelid
lesions.44 The tumor was encountered less frequently than in literature reports,
due largerly to the refinement of the pathologic diagnosis. So, of 31 patients
initially diagnosed as squamous cell carcinoma 18 (58.1%) were eliminated
because the diagnoses were changed to sebaceous gland carcinoma, seborrheic
keratosis and papilloma.46 We summarized percentage of squamous cell
carcinoma in the literature and found that squamous cell carcinoma took the
third place of all malignant eyelid tumors and occurred in 13.6 percent (355 of
2619 patients with malignant eyelid tumors) (Table 3.3).
Age of patients with squamous cell carcinoma ranged from 26 to 93.5 years
with a mean age of 65.2 years,38 or 45 to 75 years (62.3 ± 12.7 years),14 or the
mean age and highest incidence decade were 71 years old and 71 to 80 years
old in 45.0 percent.44 The median age of diagnosis was 72 years, range 55 to
96 years.45 The majority of patients (72.0%) were 60 years of age or older.38
However, younger patient aged 26 years old with squamous cell carcinoma was
reported in the literature.38
03A.indd 108 31-08-2012 12:31:36

Gender: Some reports cited a male predominance in patients with squamous
cell carcinoma,38,44 a female predominance,14 or no difference.45
Location: Lower lid was more frequently than upper lid affected by tumor44 in
60.8 percent (31 of 51 cases),38 or in 68.4 percent (54 of 79 patients),47 medial
canthus in 17.7 percent (9 of 51 cases),38 or in 24.1 percent (19 patients),47
and upper lid in 7.6 percent (6 patients),47 or in 9.8 percent38 in patients with
squamous cell carcinoma. Tumors developed most frequently in right eye than
in left eye.44
Incidence of eyelid squamous cell carcinoma has been reported to be
between 0.09 and 2.42 cases per 100,000 population49 and its incidence is
increasing.42
Recurrence occurred in 2.0 percent, i.e. in 1 of 51 cases identified in 50
patients with squamous cell carcinoma in a field of intraepidermal carcinoma,
6 years after excision of a well differentiated tumor,44 or in 3.6 percent (2 of
56 patients with a median follow-up of 73 months (range 42–117).47 Clinical
recurrence of squamous cell carcinoma found in 16.7 percent (4 of 24 patients)
in a median of 7.5 months after surgery.45 In 16.7 percent (3 of 18 patients)
developed orbital invasion.44 The risk of recurrence or persistence of tumor was
increased for patients who delayed seeking medical care after the lesion was
first noticed and when frozen section control was not used during surgery.45
The risk of recurrence of new tumors in all patients with eyelid squamous cell
carcinoma should be advised and encouraged to attend lifelong follow-up.38
Metastasis: 1 of 31 patients (3.2%) experienced tumor metastasis.46 However,
there were no patients, developed lymph node or distant metastases of 50
patients38 and none of 24 patients were known to have developed metastases
of squamous cell carcinoma.45 Despite the low incidence of metastasis,
management recommendations include complete surgical excision using
intraoperative frozen-section monitoring of the surgical margins.46 Prompt
and adequate biopsy can facilitate early diagnosis and thus avoid unnecessary
metastatic spread in the case of squamous cell carcinoma and sebaceous cell
carcinoma, as well as the extensive local destruction that basal cell carcinoma
may produce.48
Mortality: 1 patient of 50 (2.0%) with mean follow-up of 31.1 months,
who declined treatment, died as a result of the tumor,38 or 1 of 31 patients
(3.2%) with tumor metastasis had a tumor-related mortality46 but there were
no tumor-related deaths of 24 patients with squamous cell carcinoma.45
Prevention remains of prime importance in minimizing the mortality of these
tumors.38
Risk factors include ultraviolet light/actinic damage44,49 and exposure to
arsenic, hydrocarbons, radiation, or immunosuppressive drugs. Moreover,
a role for human papillomavirus infection in the case of squamous cell
03A.indd 109 31-08-2012 12:31:36

carcinoma in AIDS patients reported.49 Futhermore, intrinsic risk factors

include albinism, pre-exciting chronic skin lesions and genetic skin disorders
such as xeroderma pigmentosum and epidermodysplasia.38
Prognosis: Although squamous cell carcinoma is a relatively uncommon but
potentially fatal disease, however, if detected early and treated adequately, the
prognosis is generally excellent.38
Malignant eyelid melanoma takes the first place,18 or the third place,4,15
or the forth place,1,14,17 or the fifth place7 of all malignant eyelid tumors, or
there was no even one case of malignant eyelid melanoma of 131 patients
with benign and malignant lesions of eyelid and conjunctival tumors from
1990 to 2004.9 It accounts for 0.6 percent,15 or 0.9 percent,3 not more than 1.0
percent,50 or 4.6 percent,24 or 7.9 percent14 of all malignant eyelid tumors. Of
eyelid tumors and tumor-like lesions malignant eyelid melanoma was in 3.5
percent.7 Melanoma as the cause of pigmented neoplasms is almost 10 times
less common than pigmented basal cell carcinoma.26 We summarized reports
in the literature and found that malignant eyelid melanoma took the forth
place of all malignant eyelid tumors and occurred in 3.0 percent (78 of 1631
patients with malignant eyelid tumors) (Table 3.3).
There are four types of cutaneous melanoma—lentigo maligna, acral
lentiginous, nodular, and superficial spreading melanomas. All melanomas
except the nodular subgroup have a radial (horizontal) growth phase
component.51 17.0 percent,52 or approximately 50.0 percent,55 or 59.0
percent53 of eyelid melanomas are nodular, 22.0 percent,52 or 27.6 percent,54
or 40.0 percent,55 are superficial spreading melanoma, and 19.0 percent,53 or
61.0 percent,52 or 65.5 percent54 were lentigo maligna melanoma. About 40.0
percent of eyelid melanomas are non-pigmented tumors.26 In the literature
described a case of rare and highly malignant type of melanoma, desmoplastic
malignant melanoma of the lower lid.61
Age of patients with malignant eyelid melanoma ranged from 22 to 88
years (mean 65 years)54 or there were 3 patients aged 70, 77, and 89 years old
with malignant eyelid melanoma.14 With the age of patients the frequency of
malignant eyelid melanoma increased and the peak of the incidence is between
40 and 70 years.50
Gender: Malignant eyelid melanoma occurred more frequently in females,50 or
male:female ratio was 2:1.14 However, Vaziri et al.52 found that in 23 patients
with cutaneous eyelid melanomas without conjunctival involvement was not
seen a gender predilection.52
Location: The most common site of malignant eyelid melanoma was the lower
eyelid.14,53,54 The lower eyelid was more frequently involved than upper lid
or canthi52 and in 58.6 percent (17 of 29 cases) malignant eyelid melanoma
arose in the area of pigmentation.54 Left eye affected by malignant eyelid
03A.indd 110 31-08-2012 12:31:36

melanoma more frequently than right eye in 3 of 3 patients with malignant
eyelid melanoma.14
Incidence: The age- and gender-adjusted incidence rates for malignant
eyelid melanoma is 0.08 per 100,000 individuals per year.15 The incidence of
melanomas of the eyelid is unchanged in both sexes in the period of 1966 to
1980.2
Recurrence: In 13.0 percent (3 of 23 patients with cutaneous eyelid
melanomas),52 or in 17.2 percent (5 of 29 patients),54 has local recurrence.
Metastasis: Distant metastases were seen in 3.1 percent (1 of 32 patients),53 or
in 4.4 percent (1 of 23 patients),52 or in 6.9 percent (2 of 29 patients),54 or in
13.8 percent (4 of 29 patients with median postoperative follow-up of 3 years
(range 1 months–9 years 9 months).54
Mortality: Malignant eyelid melanomas with either Clark’s level > or = IV or
Breslow thickness > or 1.5 mm were associated with increased mortality.56 Less
than 1.0 percent tumor-related mortality was in melanomas less than 0.85 mm
thick.58 In 2.9 percent (2 of 29 patients),54 or in 3.1 percent (1 of 32 patients)53
with malignant eyelid melanoma died of the disease.
Survival: For survival age, sex, location, and the histologic type of malignant
eyelid melanoma were not significant prognosis indicators,56 as well as site,
ulceration, regression, and mitotic index. The most important predictor of
prognosis remains tumor thickness.57 Clark’s level > or = IV by itself was a
statistically significant predictor of decreasing survival.56 So, lesions more than
3.65 mm thick have less than 38.0 percent 8-year survival.58 After 120-month
survival, the risk of dying from malignant melanoma is virtually zero.
However, since rare deaths from malignant melanoma occur, lifetime follow-
up is recommended.59 The 5-year survival for those patients with malignant
melanoma involving the lid margins in comparison to those without lid
margin involvement has a significant disadvantage.60
Prognosis: Nodular melanoma patients with the lesion in the lid margin
have a worse prognosis than those with the lesion on the eyelid skin.55 Poor
prognostic indicators for malignant eyelid melanoma are Clark’s level > or
= IV or Breslow thickness > or = 1.5 mm.56 Melanoma involving the eyelid
margin and conjunctiva has a worse prognosis than melanomas of the eyelid
that do not involve the conjunctiva.55,60
Masquerade syndrome: The incidence of eyelid malignant melanoma may
be mistaken because some eyelid processes may masquerade as others,
as a number of conditions of the eyelid43 such as desmoplastic malignant
melanoma, which masquerade chalazion,61 or meibomian carcinoma may
simulate series initially presented as chalazion,62 or inverted follicular eyelid
keratosis clinically mimic malignant melanoma.63 A number of other eyelid
tumors masquerade each other. For example, eyelid sebaceous carcinoma
03A.indd 111 31-08-2012 12:31:36

masquerading as in situ squamous cell carcinoma,64 or sebaceous carcinoma

of the eyelid masquerading as chronic blepharoconjunctivitis,65 or eyelid
sebaceous gland carcinoma presenting as a conjunctival papilloma.66
Desjardins67 described a number of benign pigmented tumors of the eyelids,
simulating a melanoma. An incorrect interpretation on clinical or histological
grounds can lead to mistaken incidence and nonadequate treatment. Wright
et al.68 found that malignant lesions of the eyelid and ocular adnexa may present
with striking inflammatory signs and this has most often been described with
meibomian gland carcinoma and given the name of the masquerade syndrome.
In other words, some eyelid processes masquerade the others.69
Malignant eyelid lymphoma: In the literature, malignant lymphoma of the
eyelids was included in the reports deal with malignant lymphoma of the ocular
adnexa, the conjunctiva, the lacrimal gland and orbital tissue.70 Of malignant eyelid
tumors malignant eyelid lymphoma occurred in 1.9 percent,13,17 or in 2.6 percent.14
However, there was no even one patient with malignant eyelid lymphoma of 174
patients with malignant eyelid tumors.15 Of ocular adnexal lymphoma it occurred
in 5.7 percent,72 or in 8.3 percent,77,78 or in 8.9 percent,76 or in 10.0 percent,77
or in 15.1 percent,71 or in 21.0 percent,73 or in 28.1 percent.78 We summarized
percentage of malignant eyelid melanoma in the literature and found that malignant
lymphoma of the eyelids took the fifth place of all malignant eyelid tumors and
occurred in 0.9 percent (23 of 2619 patients with malignant eyelid tumors) (Table
3.3). According to REAL classification (Revised European American Lymphoma
classification) some authors found that the most frequent type of lymphoma of the
ocular adnexa was mucosa associated lymphatic tissue (MALT) lymphoma.74,75
However, others70-73,77 found that the most common lymphoma of the ocular
adnexa was the extranodal marginal zone lymphoma (EMZL), which occur in the
lid in 20.8 percent (11 of 53 specimens from 46 patients), or in 63.6 percent (7 of
11 eyelid specimens), diffuse large cell B cell lymphoma (DLCL) in 9.1 percent
(1 of 11 eyelid specimens), lymphoplasmocytic lymphoma/ immunocytoma
(LPCI) in 9.1 percent (1 of 11 eyelid specimens), and STL in 9.1 percent
(1 of 11 eyelid specimens).71 In smaller series of patients with malignant eyelid
lymphoma the most common subtype was marginal zone lymphoma, which
occurred in 3 of 4 patients (75.0%).72
Age of patients with malignant eyelid lymphoma ranged from 39 to 87
years with median age of 70 years,76 or ranged from 48 to 82 years.74
Gender: Predominance of females found in 62.1 percent (18 of 29 patients with
malignant eyelid lymphoma).76
Laterality: Eyelid lymphoma occurs as monolateral tumor in the most cases
and it can be bilateral less frequently. So, only 2.2 percent (7 patients with
malignant eyelid lymphoma of 326 patients with lymphoma of the ocular
adnexa) had bilateral disease at the presentation, but this percentage was
03A.indd 112 31-08-2012 12:31:36

higher (24.1%) if calculate 7 patients with bilateral eyelid tumors of 29 patients
with malignant lymphoma of eyelid.76 Left and right eyes were equally affected
by malignant eyelid lymphoma as well as lower and upper lids.74 Anatomic
localization of the lymphoma did not have prognostic significance.73 However,
Jenkins et al.76 showed that in patients with bilateral lymphoma systemic
disease occurred 3.3 times more frequently than in patients with unilateral
lymphoma. Jakobiec et al.78 also found that precise anatomic localization of
the lesion within the ocular adnexa had considerable predictive value, while
eyelid lesions had the worst prognosis.
Prior lymphoma: Patients with eyelid lymphoma have the highest incidence
rate of prior lymphoma in 14.0 percent,72,76 or in 22.2 percent.78
Concurrent extension: The rate of concurrent extension of the eyelid malignant
lymphoma was 10.0 percent usually to the check, forehead or temporal fossa,76
or in 22.2 percent. Future lymphoma developed in 11.1 percent (1 of 9 patients
with malignant eyelid lymphoma).78
Remission: Complete remission of the eyelid malignant lymphoma was
achieved in 18.0 percent of the eyelid malignant lymphoma.71
Mortality: Lymphoma related death of patients with malignant eyelid
lymphoma occurred in 22.2 percent,78 or in 36.4 percent,71 or in 37.9.76
25.0 percent of patients diseased secondary of other cause (1 of 4 patients)
and 25.0 percent of patients with malignant eyelid lymphoma (1 of 4 patients)
diseased of secondary lymphoma.74 At 5 years lymphoma-related death of
patients with malignant eyelid lymphoma was 37.0 percent and at 10 years
45.0 percent.76 Patients with symptoms for a year or more were half as likely to
have systemic lymphoma at diagnosis and were less likely to suffer lymphoma
related death, suggesting that such patients have a lymphoma of relatively
benign phenotype.76
Survival: All 3 patients with marginal zone lymphoma developed in eyelid
were alive at median follow-up period of 58 months.72 50.0 percent of patients
with malignant eyelid lymphoma were alive and well during follow-up period
of 6 to 7 years.74 No evidence of disease during median follow-up of 53 months
(range 11–46 months) was in 33.3 percent (3 of 9 patients) and alive with
disease at median of 32 months follow-up period (range 22–42 months) were
22.2 percent (2 of 9 patients) with malignant eyelid lymphoma.78
Risk of lymphoma-related death was lowest, only 2.0 percent, for marginal
zone lymphoma, which occurred in the eyelid in 3 patients and moderate
(33.0%) for follicular lymphoma, which was in 1 patient with eyelid
lymphoma.72
Systemic disease: In 27.0 percent (10 of 36 patients with a primary
manifestations of ocular adnexal lymphoma) developed systemic involvement
after 95 months on average.71 Systemic lymphoma was present prior to, at
03A.indd 113 31-08-2012 12:31:36

presentation or at subsequent follow-up in 17.0 percent for marginal zone

lymphoma, which occurred in eyelid in 75.0 percent and in 83.0 percent for
follicular lymphoma, which occurred in eyelid in 25.0 percent.72 Systemic
spread of eyelid lymphoma at 5 years was 78.0 percent and at 10 years 89.0
percent. Of patient witn bilateral disease, 46.0 percent had systemic lymphoma
at diagnosis compared to 14.0 percent where signs were unilateral.76
Prognosis: Malignant lymphoma of the eyelid has a worse prognosis compared
with orbital and conjunctival lymphomas.71,78 Prognosis is best for marginal
zone lymphoma with a 17.0 percent risk of systemic disease.72 Coupland
et al.73 found that age and gender did not have prognostic significance during a
follow-up period of 6 months to 16.5 years (mean, 3.3 years). Nola et al.77 also
found that age and sex did not have any prognostic significance, moreover,
side of involvement, clinical stage of disease, and mode of therapy also did not
influence on prognosis of patients with malignant lymphoma during follow-up
period of median 53 months.77 Prognosis of risk of lymphoma-related death
for patients with solely eyelid lymphoma is a worse than those with eyelid and
orbital involvement.76
In Uzbekistan, malignant eyelid tumors are the most common
malignancies in adults, which occurred in 82.9 percent (4039 of 4872 patients
with malignant ocular tumors aged from 15 to 90 years and over).79 There was
a slight predominance of females in 52.4 percent (2115 patients) comparing
with males in 47.6 percent (1924 patients).
Information about patients with malignant ocular tumors in Uzbekistan
has been collected only since 1978. Before 1978, there was no systematically
collected information about the number of patients with malignant ocular
tumors therefore epidemiologic aspects of these malignancies was investigated
at first time in Republic. In our series only primary new cases of malignant ocular
tumors in adults separate from children after histopathologic confirmation
were included. In joint collaboration with the IOR’s Resource Department and
Regional Oncology Dispensaries, we gathered malignant ocular tumors related
information, which includes patient’s name, age, ethnic background, address,
occupation, diagnosis, method of treatment, results of treatment, date and cause
of death. During that period, 79.7 percent (3883 patients) treated in our IOR’s
Department of Ophthalmology. The rest 20.2 percent (983 patients) treated
in Regional Oncology Dispensaries, in Russia (Moscow and St. Petersburg),
Ukraine (Odessa), and one patient was treated in Israel. Histopathologic
confirmation has been done in the IOR’s Department of Histopathology or in
Regional Oncology Dispensaries. For statistical purposes, the patients were
divided into 15 to 19, 20 to 24, 25 to 29, 30 to 34, 35 to 39, 40 to 44, 45 to 49,
50 to 54, 55 to 59, 60 to 64, 65 to 69, 70 to 74, 75 to 79, 80 to 84, 85 to 89, and
90 and over age subgroups. We have calculated crude incidence, age-adjusted
03A.indd 114 31-08-2012 12:31:36

incidence and standardized incidence. For standardized incidence Standard
World Population was used. Population data were obtained from Uzbekistan’s
Statistic Committee. Incidence in different ethnic groups was compared to the
number of the same ethnic groups in Uzbekistan. All rates were statistically
tested and considered statistically significant if intersecting the 95 percent
confidence interval (CI 95%, P< or = 0.05). To analyze malignant ocular
tumor incidence, the International Classification IX, 1984, was used: eyelid
skin (172.1, 173.1), conjunctiva (190.3), retina (190.5), uveal tract (190.6),
orbit except for bones (190.1), and orbital bones (170.0). Other malignant
tumors of eyelid as well as malignant tumors of lacrimal gland and malignant
Meibomian tumors were included in the section 190.1 and 173.1 respectively.
For statistically purposes, all malignant ocular tumors were divided into four
subgroups: eyelid, conjunctiva, intraocular and orbit. For mortality rates, only
those cases were considered where death has been caused by a malignant
ocular tumor, i.e. tumor-related death.
Crude incidence of malignant eyelid tumors (Table 3.4) in females was
slight higher (5.2) than in males (4.3) and both sexes of urban (4.9) and rural
population (4.6) had no statistically significantly difference.
Futhermore, in urban females (5.1) and rural females (4.9) this incidence
was slight higher than in urban males (4.3) and rural males (4.1) per 100,000
populations of males and females in urban and rural areas respectively, but all of
differences were not statistically significant. However, standardized incidence
(Standard World Population)80 per 100,000 populations of malignant eyelid
tumors for males (7.1) was lower than that for females (9.9). In urban females
(10.1) and rural females (9.6) this incidence was higher than in urban males
(7.2) and urban females (9.6). Both sexes of urban (8.7) and rural patients (8.6)
suffered from malignant eyelid tumors (standardized incidence) with equal
frequency. Thus, we found that crude incidence and standardized incidence
for eyelid malignant tumors had no statistically significant difference between
males and females and between urban and rural patients.81
Table 3.4: Crude incidence and standardized incidence of malignant eyelid tumors
in urban and rural populations per 100,000 urban and rural male and female
populations
Incidence Urban population Rural population Total
Male Female Both Male Female Both Male Female Both
Crude 4.3 5.1 4.9 4.1 4.9 4.6 4.3 5.2 5.1
incidence
Standardized 7.2 10.1 8.7 7.0 9.6 8.4 7.1 9.9 8.6
incidence
03A.indd 115 31-08-2012 12:31:36

Fig. 3.5: Annual standardized incidence of malignant eyelid tumors for males and
females per 100,000 male and female populations in Uzbekistan in 1978–1998
Annual standardized incidence of malignant eyelid tumors has increased

for males from 1.3 in 1978 to 1.7 in 1998 per 100,000 male populations
respectively with a peak of incidence of 1.6 in 1982, 1.6 in 1986 and 1.7 in
1998. For females annual standardized incidence has also increased from 1.9
in 1978 to 2.4 in 1998 and this incidence was higher than in males with the
similar peaks in 1982, 1986 and in 1998 (Fig. 3.5).
Lee et al.11 found that average annual age standardized incidence for
females with malignant eyelid tumors has increased steadily over the years
with a peak from 1988 to 1992. The rates for males have remained stable from
1978 to 1995. Authors used other incidence and other Standard of World
Population (UICC) than we, but in both series result is similar: incidences
has increased, they had peaks and females suffered from malignant eyelid
tumors more frequently than males. However, our results contrast a previous
series of Babior,81 who found that standardized incidence of urban patients
with malignant eyelid tumors in both sexes (2.1) higher than that of rural
patients in both sexes (1.5) per 100,000 populations. In our series standardized
incidence of patients with malignant eyelid tumors for both sexes in urban and
rural patients are equal but standardized incidence of urban patients in our
series more than four-fold higher and in rural patients 5.6-fold higher than in
Babior’s report.
Overall mortality of patients with malignant eyelid tumors per 100,000
populations was statistically significant higher in urban females (0.7) than in
urban males (0.2). In rural females and males the rate was equal (0.4) as well
as in urban and rural both sexes patients (0.4).
From initial diagnosis to tumor-related death of 4039 patients with
malignant eyelid tumors were 18 patients (0.5%) deceased less than 1 year,
17 patients (0.4%) deceased at 1 year, 23 patients (0.6%) deceased at 2 years,
31 patients (0.8%) deceased at 3 years, 41 patients (1.0%) deceased at 4 years,
03A.indd 116 31-08-2012 12:31:37

Fig. 3.6: Percentage of deceased patients from malignant eyelid tumors and percentage
of survived patients with malignant eyelid tumors at less than 1 year, at 1 year, at 2
years, at 3 years, at 4 years, at 5–9 years, and at 10 years after initial diagnosis
47 patients (1.2%) at 5 to 9 years, and 61 patients (1.5%) at 10 years. Totally,

there were 238 deceased patients (5.9%) of all 4039 patients with malignant
eyelid tumors. The highest percentage of deceased patients was at 10 years
after initial diagnosis (Fig. 3.6).
As shown in Figure 3.6, the percentage of deceased patients from less than
1 year to 10 years from initial diagnosis significantly increased 3-fold. At the
same time, percentage of survived patients progressively decreased. Both
of these curves formed so-called “scissors”, which shows that percentage of
deceased patients has to be decreased and percentage of survived patients with
malignant eyelid tumors in Uzbekistan has to be increased.
Although the number, percentage and incidences in patients with
malignant eyelid tumors of all patients with malignant ocular tumors were
the highest mortality of these patients was the lowest.79 Percentage of deaths
(34.6%) in patients with malignant eyelid tumors (18 deceased of 52 patients
with malignant eyelid tumors during 22-year period from 1960 to 1981)
reported by Abe et al.13 is 5.9-fold higher than percentage of deceased patients
(5.9%) in our series. Comparing the percentage of deceased patients at 5-year
(7.3%) reported by Wang et al.12 we found that this rate is 1.2-fold higher than
percentage of deceased patients with malignant eyelid tumors at 5 to 9 years in
our series (5.3%).
Survival of patients with malignant eyelid tumors (Fig. 3.6) was 99.6 percent
less than 1 year from initial diagnosis (4021 patients), 99.1 percent at 1 year
(4004 patients), 98.6 percent at 2 years (3981 patients), 97.8 percent at 3 years
(3950 patients), 96.8 percent at 4 years (3909 patients), 95.6 percent at 5 to 9
years (3862 patients), and 94.1 percent at 10 years (3801 patients). Survival of
patients with malignant eyelid tumors was the highest at the first two years
from initial diagnosis.
03A.indd 117 31-08-2012 12:31:37

A B
C D
Figs 3.7A to D: Basal cell carcinoma: (A) In the lower lid of the right eye of a 82-year-
old man; (B) In the upper lid of the left eye of a 76-year-old woman; (C) Medial
canthal ulcerative basal cell carcinoma invading left orbit of a 48-year-old man;
(D) Sebaceous cell carcinoma in the lower lid of the left eye of a 45-year-old woman 1
month later after radiotherapy only
Some of patients with malignant eyelid tumors treated in our Department

are presented in Figures 3.7A to D.
Our experience and literature datas “demonstrate the considerable
difficulty associated with the clinical diagnosis of eyelid lesions, and highlight
the importance of histological confirmation, preferably by excisional biopsy,
for all suspicious eyelid lesions”.38
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03A.indd 122 31-08-2012 12:31:38

MALIGNANT CONJUNCTIVAL TUMORS
Tumors of the conjunctiva and cornea comprise a large and varied spectrum of
conditions. These tumors are grouped into two major categories of congenital
and acquired lesions. The acquired lesions are further subdivided based on
origin of the mass into surface epithelial, melanocytic, vascular, fibrous,
neural, histiocytic, myxoid, myogenic, lypomatous, leukemic, metastatic
and secondary tumors. Melanocytic lesions include nevus, racial melanosis,
primary acquired melanosis, melanoma, and other ocular surface conditions
like ocular melanocytosis and secondary pigmentary deposition.1
Many different names have been applied to primary dysplastic and
carcinomatous lesions, e.g. corneal or conjunctival intraepithelial neoplasia
and ocular surface epithelial dysplasia,2 or conjunctival carcinoma in situ,
dyskeratosis and intraepithelial epithelioma. Conjunctival intraepithelial
neoplasia (CIN) usually connotes a partial to full thickness intraepithelial
neoplasia whereas carcinoma in situ has full-thickness involvement.3 Lee and
Hirst4 suggested the “umbrella” term for ocular surface squamous neoplasia
(OSSN) presenting as a spectrum from simple dysplasia to carcinoma in situ
to invasive squamous cell carcinoma involving the conjunctiva as well as the
cornea. Malignant tumors accounted for only 7.9 percent (10 of 126 cases) of
all tumors and tumor-like lesions in conjunctiva and cornea.5 In other series of
benign and malignant eyelid and conjunctival tumors malignant conjunctival
tumors were in 20.9 percent (41 of 128 cases) and of benign and malignant
conjunctival tumors in the same series malignant conjunctival tumors
occurred in 21.9 percent (9 cases of 41).6 In a lager series of 777 primary
conjunctival neoplasms with histopathologic analysis malignant conjunctival
tumors found in 13.9 percent (108 cases),7 or in 30.0 percent (134 of 447
conjunctival specimens).8
The most common conjunctival malignancy in adults was squamous
cell carcinoma,9,11 followed by melanoma, and pagetoid change associated
with sebaceous gland carcinoma.9 Of nonmelanocytic neoplastic lesions the
most frequent tumor were squamous cell carcinoma and lymphoma.1 On the
other hand, there were no patients with malignant conjunctival melanoma in
Tanzania from 1976 to 1997.13
Age: The mean age of conjunctival malignant tumor patients was significantly
older than those of benign tumor patients.6 The age at diagnosis ranged from
47 to 92 years.2,5
Gender: There was a slight predominance of males with the ratio of females to
males of 4:6.2,5
Risk of conjunctival cancer increased with increasing time spent in culti-
vation and therefore in direct sunlight, but decreased with decreasing age
03B.indd 123 31-08-2012 12:32:16

at leaving home perhaps reflecting less exposure to sunlight consequent

to working in towns, although both results were of borderline statistical
significance.24 The 10-fold increased risk of conjunctival cancer in HIV
infected individuals is similar to results from other studies.26
Additional malignant tumors. An additional malignant tumors elsewhere in
the body found in 13.0 percent,11 or in 20.0 percent.4
Squamous (cell) carcinoma of the conjunctiva. These tumors have a low
malignant potential but may behave more aggressively in the spindle cell and
mucoepidermoid variant.1,9,15 The percentage of the squamous cell carcinoma
of the conjunctiva ranges from 1.6 percent,5 to 4.7 percent,6 7.5 percent,7 25.1
percent,8 and to 26.0 percent11 depending on patients group characteristics. For
example, of ocular surface squamous neoplasia it occurred in 21.5 percent,19
of all conjunctival carcinomas in 32.4 percent,16 and of a total conjunctival
biopsies in 45.8 percent.13
Age: The mean age of patients with squamous cell carcinoma was 45.3 years,
the median age 39.0 years, range 16 to 86 years and the change in mean age
from year to year did not show any significant trend.13 The patients were older
in the report of Tune et al. between 26 and 84 years old with a mean age of 64
years old,14 or mean age was 60.4 years,20 or mean age was 63± 13 years,11 or
> 60 years.10,14,21 The average age of the human papillomavirus (HIV)-positive
patients with squamous cell carcinoma was 41 years compared to the HIV
negative patients with 58 years. Thus, HIV positive patients with a squamous
cell carcinoma were on average 17 ages younger.16
Gender: The most authors found a great or slight prevalence of males in
patients with squamous cell conjunctival carcinoma. So, the incidence rate was
approximately 5-fold,17 or 2.8-fold14 higher for males, and a prevalence of males
shown in 51.7 percent,13 or in 55.0 percent,20 or in 76.9 percent21 of patients
with squamous cell conjunctival carcinoma. However, in other reports found a
prevalence of females suffered from squamous cell conjunctival carcinoma in
36.8 percent of patients with ocular malignancies in children and adults,12 or
in 67.6 percent of patients with conjunctival carcinomas.16
Laterality and location: Squamous cell carcinoma involved the right eye in 45.0
percent,14 or in 46.1 percent,21 the left eye in 51.7 percent,14 or in 53.8 percent,21
and bilateral tumors were in 16.7 percent (1 of 60 patients with intraepithelial
and invasive squamous cell carcinoma).14 In 80.8 percent tumor involved
limbus, or limbus and cornea, and only in 19.2 percent tumor involved fornix,
medial canthus and bulbar conjunctiva. Corneal and/or scleral invasion was in
30.0 percent and orbital invasion was noted in 15.0 percent.21
Race: White patients had more frequently conjunctival squamous cell
carcinoma because all 26 patients with squamous cell carcinoma were whites
with none in the Aboriginal population.21 Among whites, incidence rate was
03B.indd 124 31-08-2012 12:32:16

approximately 5-fold higher than that among other ethnic groups.17 The most
of patients (53 patients) were Whites (88.3%), 6.7 percent (4 patients) were
Hispanic, and 3.3 percent (2 patients) were Asian of 60 patients with squamous
cell conjunctival carcinoma.14 More than half patients (57.1%) had fair skin,
47.6 percent were with blue or green eyes and only 2 patients of 21 (9.5%) were
with brown eyes. The others were described as olive skinned.21
Occupation: Most of patients were retired at the time of diagnosis, but 23.3
percent (14 patients) had a previous outdoor occupation and 75.0 percent (45
patients) of 60 patients with squamous cell conjunctival carcinoma had an
indoor occupation.14
Incidence: The frequency of conjunctival carcinoma in Germany was 1:20000,16
in USA 0.03 per 100,000 populations.17 Comparing to the average annual
incidence of squamous cell carcinoma developed in all body, this rate was 118
per 100,000 white residents in Hawai, USA. It is estimated that over 100,000
new cases of this malignant tumor’s all localizations are diagnosed in the USA
annually.18 There was a sharp rise in the incidence of conjunctival squamous
cell carcinoma in the last 3 years of the study (1995–1997) in Tanzania.13
Recurrence: Recurrence of squamous cell conjunctival carcinoma ranged from
23.3 percent19 to 27.0 percent,21 but there was no one of cases recurred after
eye wall resection, enucleation, or exenteration, and overall recurrence rate
for conjunctival squamous cell carcinoma was 5.3 percent (2 of 38 patients
with a mean follow-up of 55 months (range, 18–226 months). The rate of new
or recurrent tumors was 4.5 percent for intraepithelial squamous carcinoma
of conjunctiva and 5.3 percent for invasive squamous cell carcinoma of
conjunctiva.14 Evidence of local extension of the tumor was found in 52.0
percent (150 of 286 patients) with the cornea being most frequently involved
in 38.0 percent (108 cases).20 The main predictor for recurrence include
histological grade of the lesion, corneal location and larger size (>2 mm).19
Significant factors affecting recurrence included positive surgical margins, size
and increased age.21
Metastasis: There were no patients suffered from squamous cell carcinoma of
the conjunctiva with metastatic disease or were lost to follow-up.14 However,
in other report, regional metastasis was found in 0.7 percent (2 of 286 patients
with squamous cell conjunctival carcinoma) to a submandibular lymph node
in one and to a preauricular lymph node in other.20 Mc Kelvie et al.21 also found
that of 26 patients with squamous cell conjunctival carcinoma in 2 patients
(7.7%) developed metastases in cervical lymph node at 4 months and parotid
metastasis at 16 months after exenteration in one and cerebral metastasis and
death at 13 months.21
Risk of a second malignancy after squamous carcinoma of the conjunctiva
was not increased overall although a significant excess of salivary gland cancer
and a borderline excess of lung cancer were noted.17
03B.indd 125 31-08-2012 12:32:16

Mortality: Some authors found that there were no patients with tumor-related
death of 60 patients with intraepithelial and invasive squamous cell carcinoma
of the conjunctiva.14 However, in other report shown 2 of 26 patients (7.7%)
died of metastatic disease.21
Etiology of squamous cell conjunctival cancer is not well known. A
possible role of ultraviolet radiation is suggested by an excess of squamous cell
conjunctival carcinoma in tropical countries and by the association between
this carcinoma and exposure to UV radiation.4,8,17,21,22 The lower incidence in
dark-eyed population may also suggest a lower sensitivity to solar radiation.12
The incidence of squamous cell carcinoma of the eye declined by 49.0
percent of each 10 degrees increased in latitude, falling from more than 12
cases per million per year in Uganda to less than 0.2 per million per year in the
UK. Solar ultraviolet (UV) radiation decreased with increasing latitude, and
the incidence decreased by 29.0 percent per unit radiation in UV exposure.23
Histological evidence of solar injury, which was recognized as a major risk
factor for conjunctival squamous cell carcinoma found in all cases.21 The
number of new cases of squamous cell carcinoma increased concern over
the ozone layer depletion and the continued sunbathing behavior of many
individuals.18
Human papillomavirus type 16 may also be involved.17 An increases
incidence of conjunctival squamous cell carcinoma in patients with HIV
infection, especially in young individuals and Africans was reported.25
However, percentage of positive (33.3%) and negative HIV patients (31.3%)
with squamous cell carcinoma in authors’ series was approximately equal.16
HIV has been detected in benign and malignant conjunctival lesions.17 It may
be that HIV infection has a permissive effect on cellular changes brought about
by ultraviolet light and previous conjunctival disease that would normally
be corrected by a properly functioning immune system.13 As with other UV
light-related conditions, preventive measures must remain the key to disease
control.19
Malignant melanoma of the conjunctiva is an extremely rare tumor, but
when developed may be fatal27 or it is potentially deadly tumor.28 Malignant
melanoma of the conjunctiva is such a rare tumor that “ few clinicians have the
opportunity to manage more than 1 case of conjunctival malignant melanoma
during their years of clinical practice”.28 It accounts for 1.0 to 3.0 percent of
all ocular malignant tumors in adults29 and 2.0 percent30,31 or 2.9 percent32
or 5.0 percent,33 or 6.6 percent35 of all ocular malignant melanoma. Of uveal
and conjunctival malignant melanoma it occurred in 4.6 percent34 and of
all noncutaneous melanomas malignant melanoma of the conjunctiva was
in 4.8 percent.35 It occurs only 1/40th as often as choroidal melanoma and
approximately 500 times less often than cutaneous melanoma.36 Malignant
03B.indd 126 31-08-2012 12:32:16

melanoma of the conjunctiva can evolve from nevus with ranging percentage
from 0.7 percent,50 2.0 percent,29 4.0 percent,28 17.0 percent,43 18.0 percent,46
26.0 percent,44 27.1 percent,39 and to 28.4 percent.31 From primary acquires
melanosis (PAM) it developed in 24.7 percent,31 25.0 percent,43 55.2 percent,39
56.0 percent,44 57.2 percent,29 and in 57.4 percent.46 de novo it was seen in 18.0
percent,44 22.3 percent,46 25.7 percent,29 46.9 percent,31 and in 59.5 percent37
of all malignant melanoma of the conjunctiva. Some authors39,51 found that in
more than 50.0 percent of cases malignant conjunctival melanomas developed
from primary acquired melanosis. However, Lommatzsch et al.31 found that
the melanomas had developed with almost equal frequency from a pre-
existing nevus, from primary acquired melanosis and de novo. A combination
of a nevus and PAM is also possible.46 The predominant morphologically cell
type for malignant conjunctival melanoma was epithelioid in 55.0 percent of
cases, followed by mixed in 14.0 percent and spindle in 12.0 percent.37
Age: Malignant melanomas of the conjunctiva typically arise in adults at a
mean age at presentation of 53 years,27 or 56 years,43 or 57 years,44 or 58 to 64
years,33 or at median age of 62 years.28 At presentation 1.0 percent of patients
(2 patients) were under 20 years of age, 12.0 percent (18 patients) were 21 to
40 years, 33.0 percent (49 patients) were 41 to 60 years and 54.0 percent (80%)
were older than 60 years.28 Approximately the same age groups of patients
with malignant conjunctival melanoma was in the report of De Potter et al.44
who found 24.0 percent (16 patients) younger than 40 years, 26.0 percent (18
patients) between 40 and 60 years and 50.0 percent (34 patients) were older
than 60 years. Patients in the age interval 50 to 74 years accounted for 61.0
percent of the tumors.33 The average age of female patients was 60 years and it
was higher than that of the male patients with 51 years.31
Although malignant melanoma of the conjunctiva was found predominantly
in middle-aged and more senior adults between the forth and seventh decades
of life30 rate cases occurred in children described in Chapter 3 of the recent
book.
Gender: The predominance of males or females with malignant melanoma
of the conjunctiva in the literature is questionable. Some authors found
predominance of females in 66.7 percent in small series of 15 patients suffered
from these malignancies.27 Predominance of females has also registred in
the National Cancer Registry of the GDR31 and by Desjardins et al.43 in 60.7
percent. In other report this percentage was 59.6 percent46 and 64.2 percent.31
However, a slight preponderance of males with malignant conjunctival tumors
in 54.4 percent demonstrated by De Potter et al.44 The male-to-female ratio of
47:38 did not differ statistically from unit39 and no difference between males
and females also found by other authors.28,33,35,36 However, interestingly, that
in males with unifocal tumor malignant conjunctinal melanoma occurred
more frequently than in females (69.9%), but multifocal melanoma was more
common for females in 41.8 percent.46
03B.indd 127 31-08-2012 12:32:16

Laterality and location: Usually, conjunctival malignant melanoma is termed

as unilateral malignancy28,30 and none were bilateral.27,44,46 It involved the
right eye in 40.0 percent,27 or in 40.6 percent,46 or in 54.0 percent,44 or in 60.0
percent.27 This tumor can be unifocal in 62.9 percent and multifocal in 36.7
percent.46 Location of tumor was the most important factor for development
of local recurrence.29 Some authors found that the most frequently location
of the conjunctival malignant melanoma is bulbar conjunctiva.31,28 Others
believe limbal area or limbus, or limbal conjunctiva being the most frequent
part of the conjunctiva to develop this rare malignant tumor.29,37,39 We
calculated the number and percentage of patients with malignant melanoma
of the conjunctiva in the literature to know which of tumor’s location is the
most frequently location for these tumors (Table 3.5).
According to our calculation based on the previous literature reports,
the most frequently location of malignant melanoma of the conjunctiva is
bulbar conjunctiva (42.2%) and limbal area (28.8%), but perhaps “bulbar
conjunctiva” and “eyeball conjunctiva” as well as “contiguous location”
and “diffuse melanoma” are the similar location of the tumor. Paridaens et
al.46 identified location of conjunctival melanoma as favorable (cornea,
corneolimbal location, bulbar conjunctiva <2 mm from limbus and >2
mm from limbus) and unfavorable location (palpebral conjunctiva, fornix,
caruncle, plica semilunaris and eyelid). Werschnik and Lommatzsch52 found
that favorable locations are only bulbar and limbal conjunctiva and they added
to unfavorable location plica semilunaris. In the favorable location malignant
conjunctival melanoma occurred in 44.8 percent,44 or in 56.5 percent,51 or in
55.9 percent46 and in unfavorable areas that accounted for 41.5 percent,51 or
44.1 percent.46 According to our calculation, favorable locations (bulbar and
limbal) occurred significantly frequent in 71.6 percent than unfavorable one.
Race: In rare cases malignant melanoma of the conjunctiva occurred in
Blacks.30,33,47 For example, all 68 patients with these malignancies were Whites
and there were no black or oriental patients,44 or there was only 1 African-
American patient of 150 (0.7%).28 A few cases of conjunctival malignant
melanoma in Blacks have been reported in detail. Because epibulbar
conjunctival melanoma is a much rare malignant tumor than malignant
melanoma of skin or intraocular melanomas, statistical comparison between
races is difficult to be obtained. In Africans and Asians conjunctival melanoma
is almost unknown.30 The racial and ethnic differences in the incidence of
conjunctival melanoma in a large population-based study from 1992 through
2003 provided by SEER program (the National Cancer Institute’s Surveillance,
Epidemiology, and End Results) was investigated by Hu et al.42 According to
their results, the annual age-adjusted incidence rates per million populations of
conjunctival melanoma was 0.18 for Blacks, 0.17 for American Indians, 0.15 for
03B.indd 128 31-08-2012 12:32:16

03B.indd 129
Table 3.5: Patients’ number and percentage of conjunctival malignant melanoma primary location in the literature
Authors Bulbar Limbal Palpebral Caruncle Tarsal Eyeball Fornix Cornea Conb+ Plicasemc Contiguous Diffuse Total
conb conb conb conb fornix number
Missotten et al.29 23 110 - 5 11 - 2 - - - - 43 194
28
Shields et al. 138 - 6 1 - - 4 - - 1 - - 150
Tuomaala et al.39 11 50 8 3 - - - 4 - - - 9 85
Lommatzsch et al.31 59 - - 5 6 - 6 4 1 - - - 81
De Potter et al.44 31 - 2 2 - - 1 - - - 32a - 68
Norregaard et al.37 - 18 5 2 - 14 - - - - - - 39
Total 262 178 21 18 17 14 13 8 1 1 32 52 617
Percentage 42.4 28.8 3.4 2.9 2.8 2.3 2.1 1.3 0.2 0.2 5.2 8.4 100
a
- bulbar conjunctiva and cornea – 20 patients + bulbar conjunctiva and carruncle – 2 patients + bulbur conjunctiva and fornix – 4 patients + with and without
lid margin involvement – 6 patients = 32 patients; b- conjunctiva; c- semilunaris
129
31-08-2012 12:32:16
Asians, 0.33 for Hispanics, and 0.49 for non-Hispanic Whites. The difference in
the incidence between White and Blacks or Asians was statistically significant,
but was not significant between Blacks and Asians. Of interest is the fact, that
skin complexion of the white patients ranged from judged light (fair) in 99.0
percent and dark (olive) in 1.0 percent.28 In white 32-year-old man extremely
rare case of amelanotic conjunctival melanoma was described.49
Incidence: The annual incidence of malignant conjunctival melanoma was
0.0240 per 100,000. On average, only 2 new cases were diagnosed each year
from 1969 to 1991 (22.5 years) in Sweden,38 or 2.5 patients per year between
1967 and 2000 in Finland,39 or 2.6 new cases were seen per year from 1960 to
1980 in Denmark,37 or approximately 40 patients with conjunctival melanoma
were diagnosed each year in the USA (period was not shown).30 A minimum
incidence of premalignant and malignant lesions of 0.052 cases a year per
100,000 was in Denmark.37 Age-standardized incidence rate (World Standard
Population) during the period 1943 to 1997 ranged from 0.02 to 0.06 in men,
and from 0.00 to 0.07 in women per 100,000 person/year in Denmark.33 The
same incidence, age-standardized incidence, but adjusted for the 2000 US
standard million populations is 0.54, the crude incidence was 0.51 per million
and the age-specific incidence was 0.06 for those under 30 years of age, and
0.48, 1.05 and 1.57 for age groups of 30 to 49 years, 50 to 70 years, and more
than 70 years respectively between 1967 and 2000 in USA.39 The incidence
of malignant conjunctival melanoma between 1960 and 1985 in GDR was
0.08 per 100,000 populations per year.31 Another incidence rate, the annual
average age-adjusted incidence rate was 0.012 per 100,000 persons in USA.40
In 2002 Tuomaala et al.39 in their population-based assessment wrote that
more population-based data are needed to determine whether the incidence
of conjunctival melanoma is increasing globally and in 2004 Isager et al.33
reported about population-based incidence rate, which was investigated
during 55 years not globally but in Denmark. That incidence rate had neither
increased no decreased. No increase of frequency was also noted during 1960
to 1985 in GDR.31 The smoothed, age-standardized incidence, which remained
stable until 1975, then showed increase there after from 0.4 to 0.8 per million
in Finland.39 The significant elevated age-standardized incidence rate for
white men, but not for white women with conjunctival malignant melanoma
was observed from 1973 to 1999 in USA.41 All of above-mentioned incidences
such as annual average age-adjusted incidence rate,30 the incidence,31 age-
standardized incidence rate,33 a minimum incidence,37 annual incidence,38
and the crude incidence,39 could not been compared with each other due to
their heterogeneity.
Recurrence: In spite of bulbar and limbal locations of the malignant conjunctival
melanoma are the most frequently locations, epibulbar involvement (bulbar
03B.indd 130 31-08-2012 12:32:16

and limbal) showed significantly fewer local recurrence, which was not
associated with age at time of diagnosis, tumor origin (PAM or non-PAM),
sex, unilocular/multilocular location, tumor thickness or basal diameter.29,39
The size of the primary tumor was strongly associated with recurrence,
mainly because palpebral location predicted frequent and rapid recurrence.39
However, Shields C et al.28 believe that the factors predictive of recurrence of
conjunctival melanoma in a series of univariate analysis included melanoma
not touching the limbus, melanoma 2 mm or more from limbus, extent of
PAM for 7 to 9 o’ clock hours, melanoma color (red), gross tumor thickness
on pathologic examination 4 mm or more, melanoma located in the superior
quadrant, lateral and base margins of specimen involved with tumor on
pathologic examination, and corneal involvement with melanoma 2 mm or
more. Others defined tumor thickness, lagest basal diameter, contact area and
adjuvant treatment statistically did not associated with local recurrence.39
De Potter et al.44 found that the only risk factors statistically associated with
local recurrence were the primary method of tumor management and the
eventual development of distant metastases. The risk of recurrence in the first
5 years was 39.0 percent and in the 10 years it was 43.0 percent.37 Percentage
of conjunctival malignant melanoma recurrence ranged from 23.4 percent,31
or to 35.0 percent,28 or 39.0 percent,43 or 47.6 percent,37 or 56.0 percent,44 or
62.0 percent,38 or to 62.6 percent,29 and even all 15 patients with malignant
conjunctival melanoma had experienced at least one recurrence.27 The
recurrence was detected in 26.0 percent of patients at 5 years, 51.0 percent at 10
years, and 65.0 percent at 15 years follow-up.28 The tumor recurred at least once
in 29 patients.39 The mean time interval between the first treatment and the
first recurrence was 2.4 years,29 or 2.5 years.44 The mean time until recurrence
was 3.5 years,37 or 56 months (4.7 years).43 19.0 percent of patients have had
1 recurrence, 7.0 percent had 2 recurrence, 3.0 percent had 3 recurrence, 2.0
percent had 4 recurrence, and 3.0 percent had 5 and more recurrences. The
mean interval from first recurrence to second recurrence was 15 months, and
the mean interval from second recurrence to third recurrence was also 15
months.37 A short time to local recurrence was predicted by nonlimbal location
of the primary tumor.39 Tumor recurrence involving favorable sites was seen
in 54.4 percent of male and in 56.9 percent of female patients. In 27.0 percent
of patients the melanoma recurred at the previous site, and in 28.1 percent a
recurrence locus of tumor was detected at a new site. In 5.5 percent of patients
there was evidence of orbital recurrence.46 The percentage of patients without
a local recurrence was 39.9 percent after 5 years, 33.2 percent after 10 years,
and 27.8 percent after 15 years.29
Risk and prognostic factors for metastasis included pathological tumor
margins (lateral margin involved) and melanoma location (not touching
03B.indd 131 31-08-2012 12:32:16

limbus), or nonepibulbar location, thick >2 mm and multilocular tumors.29

Except it, factors pertinent to fatal metastasis are epithelial cells, from presence
of atypical melanin cells in case of development from PAM (primary acquired
melanosis), pagetoid invasion (the presence of atypical melanocytes within
the epithelium), in situ’ growth pattern, development in the caruncle and
palpebral conjunctive, reduced small polygonal cells, and meld inflammation
and abundant mitoses.27,53 Sex, age and clinical origin of the tumor (PAM,
pre-existing nevus or de novo) were not useful prognostic indicators.46 The
presence or absence of nevi had no effect of prognosis,53 which was not related
to the type of melanoma, mitotic rate, cell type, and degree of pigmentation.54
Prognostic factors are tumor size and tumor location. Tumor growing
extralimbal especially at the fornix, plica semilunaris and caruncle have a
significantly poorer prognosis than limbal tumors.2,55 An increase incidence
of distant metastasis was statistically associated with the presence of one or
more recurrence of conjunctival melanoma in 68 patients, but in the subgroup
of 25 patients treated exclusively in the authors’ institution, the presence of one
or more recurrence of conjunctival melanoma was statistically not associated
with development of metastases.49
Metastasis: Tumor metastasis was present in 16.0 percent of patients at 5 years,
26.0 percent of patients at 10 years, and 32.0 percent of patients at 15 years.28
Metastasis was located in the regional lymph nodes in 11.3 percent,28 or in 20.0
percent,27 or in 21.1 percent,29 or in 45.0 percent;51 in the lungs in 1.3 percent,28
or in 9.3 percent;29 in brain in 2.7 percent,28 or in 5.7 percent;29 skin in 6.7
percent;29 spinal cord in 2.6 percent;29 ilenium in 1.5 percent;29 mesentery in
1.5 percent,29 skeletal bones in 1.5 percent;29 thyroid gland in 1.0 percent;29
jaw bone in 1.0 percent,29 and it was disseminated in 0.7 percent.28 In 13.3
percent (2 of 15 patients with conjunctival malignant melanoma) metastases
were in the nasal cavity throught the nasolacrimal duct.27 Median times to
initial regional and systemic metastasis were 2.3 and 3.4 years respectively, and
the median time from regional to systemic metastasis was 1 year.51 The mean
time to local lymph node metastasis was 3.5 years and to systemic metastasis
was 9.3 years.27 In 45.0 percent of patients with regional lymph node metastasis
were detected before systemic ones. The 10-year cumulative incidence of
initial regional metastasis was 0.11 and it tended to be higher for tumors more
than 2 mm thick. The corresponding incidence of initial systemic metastasis
was 0.18 and it was higher for nonlimbal tumors and for tumors more than 2
mm thick.51 Up to now there is no effective treatment of metastatic disease.55
Prognostic factors for death from metastatic conjunctival melanoma were
identified as patients age greater than 55 years, higher TNM category, and
unfavorable tumor location.52 Metastatic death was 4.0 times greater in
patients with histological evidence of lymphatic invasion compared with those
03B.indd 132 31-08-2012 12:32:17

without. This phenomenon was observed in patients with melanomas growing
at both favorable and unfavorable areas of the conjunctiva.46 The risk of death
to be significantly higher for tumors more than 2 mm in thickness that may
be close to critical thickness of clinically risk of metastasis and death.39 An
important factor to preventing eventual tumor recurrence, metastasis and
death is technique of initial surgery.27 Surgical technique is characterized by
so-called “no-touch” method avoiding any direct manipilation of the tumor
to prevent tumor cell seeding into a new area.55 Proper surgical planning with
wide tumor-free margins is important. The finding of tumor extension to the
surgical margins imposed risk on the patients for local tumor recurrence,
metastasis and death.28
Mortality: Tumor-related death of patients with malignant melanoma of the
conjunctiva occurred in 7.0 percent of patients at 5 years,28 in 27.1 percent at
6.3 years,39 in 18.0 percent at 7.5 years,44 in 13.0 percent at 8 years,27 and in
38.3 percent at 26 years.31 There was 33.3 percent of tumor-related death with
no fixed period of follow-up.27 The mortality rate of malignant conjunctival
melanoma was 25.0 percent,43 or 25.5 percent,53 or 29.0 percent,44 or
approximately 30.0 percent.29,48 The overall mortality rate was 26.0 percent
and that due to melanoma without PAM was 27.3 percent.53 The overall
mortality rate from metastasis in 81 cases presented was 18.5 percent and from
all cases of death was 38.3 percent.31 Other report showed the mortality rate
of malignant conjunctival melanoma ranging between 0.0 percent (maximum
tumor thickness <1 mm) and 50.0 percent (maximum tumor thickness >2
mm). The melanoma-specific 5- and 10 years mortalities were 0.20 and 0.38
respectively. Increased mortality was associated with non-limbal location of
the primary tumor and increasing tumor thickness as well as with the presence
of local recurrence.39 Other mortality rate, the 10-year cumulative incidence of
metastatic death from conjunctival malignant melanoma was 32.0 percent and
after adjusting for tumor size, risk of death from conjunctival melanoma was
higher than from uveal melanoma.45 Mortality rate of tumors in unfavorable
locations, involving the palpebral conjunctiva, fornices, plica semilunaris,
caruncle, and lid margins, were associated with 2.2 times higher than
mortality compared with epibulbar or bulbar melanomas.46 2.91 times higher
mortality had patients with mixed cell type tumors compared with those with
pure spindle cell melanomas, and histological evidence of lymphatic invasion
by tumor cells was also a prognostic feature, carrying a 4.0 fold increase in
the mortality rate. Multifocal tumors were associated with 5 fold increase in
mortality among those with tumors in favorable epibulbar or bulbar locations,
but were not prognostic in patients with melanomas in unfavorable sites. The
mortality was significantly higher in those with initial tumor thickness of more
than 4 mm, but only among patients with unfavorable located melanomas.46
03B.indd 133 31-08-2012 12:32:17

The median follow-up period for patients who died from metastatic
melanoma was 4.1 years,46 or 5.5 years.31 18.0 percent44 or 24.6 percent46 of
patients died of metastatic melanoma and 12.0 percent,44 or 15.6 percent46
died of other causes including other cancers. The most of patients died within
5 years of their first treatment. Death from metastasis occurred at average of
6.2 years after the first treatment of the lesion. The average age of patients was
67 years.31
The median time from diagnosis of primary tumor to death from metastatic
disease was 4.0 years, median time from diagnosis of metastasis to death was
1.3 years.39
Survival: While patients with epibulbar or bulbar melanomas have a 92.0
percent 5-year survival probability, those with melanomas involving other
conjunctival sites have only a 72.0 percent chance of surviving 5 years
following diagnosis of their tumor. The 5-year survival probability for all
patients was estimated at 82.9 percent, the 10-year survival probability at 69.6
percent, and the 15 and 20 years survival probabilities were both calculated at
67.7 percent.46 The 5-year survival rate was estimated at 82.9 percent,46 or at
86.0 percent,37 the 10-year survival rate at 69.3 percent,46 or at 84.0 percent.37
Tumor-related survival was 86.3 percent at 5 years, 72.0 percent at 10 years and
67.0 percent at 15 years.29
The cumulative survival rate was 90.0 percent at 30 months (2.5 years) and
56.6 percent at 70 months (5.8 years),27 or 84.0 percent,37 or 86.3 percent,29
and 87.6 percent31 at 5 years; 71.2 percent,29 or 76.3 percent31 at 10 years
and 67.2 percent at 15 years.29 The overall cumulative survival rate was 76.0
percent after 5 years and 60.0 percent after 10 years. As regards deaths caused
by metastasis only, the cumulative survival rates were 87.6 percent after 5 years
and 76.3 percent after 10 years.31 The cumulative melanoma-specific survival
rate was 84.4 percent at 5 years, 77.7 percent at 5 years, and 75.0 percent at
15 years.55 The 5- and 10-year relative survival for conjunctival malignant
melanoma for men was 83.0 percent and 70.0 percent and for women 93.0
percent and 82.0 percent respectively.34
The overall survival rates were 74.0 percent,56 or 77.0 percent43 at 5 years
and 41.0 percent,56 or 64.0 percent49 at 10 years.
The cumulative melanoma-specific survival proportions were 0.80 at 5
years, and 0.62 at 10 years.39
All of these survival rates are different and to compare them is impossible
due to their heterogenesis.
The survival rates in Japan were 95.1 percent after 1 year, 72.9 percent
after 3 years, and 53.4 percent after 5 years and by authors’ opinion survival
rates are relatively low compared with those reported in Europe and United
States.57 95.0 percent (20 of 21 patients) with small localized bulbar neoplasms
03B.indd 134 31-08-2012 12:32:17

and 67.0 percent of patients with diffuse bulbar melanomas (4 of 61 patients)
have survived with no evidence of secondary spread. By contrast, only 1 of
6 patients with neoplasms involving the fornix (17.0%) and 2 of 4 (50.0%)
with caruncular melanomas had survived.54 A significantly reduced survival
due to tumor-related death was noted in patients with tumors with high
mitotic indices, many epitheliod cells and in lesions exceeding 10 mm in
diameter.38 Tumor thickness is also an important predictor of survival, as well
as of regional and distant metastasis.29 Overall survival was longer after initial
regional metastasis than after systemic metastasis.51 Small tumors give a better
chance of survival than larger ones31 and patients suffering from malignant
melanoma of the conjunctiva have better prognosis for survival compared
with those who have mucosal melanomas at other sites.46 On the other
hand, nonepibulbar tumors more often recur locally and are associated with
a shorter survival independent of other risk factors.58 Clinical observations
show longer survival after primary conjunctival melanoma than after primary
uveal melanoma. However, a primary conjunctival melanoma of a given size
is more deadly than a uveal melanoma of equivalent size because primary
conjunctival melanoma tends to recur after treatment and, possibly, because
additional lymphatic dissemination occurs with conjunctival melanoma.45
The most important factors in improving survival of conjunctival melanoma
is the systematic investigation for regional lymph node metastases, and
probably the use of sentinel node biopsies in high-risk patients (tumor height
2 mm, diameter larger than 10 mm, multiple recurrences). Although little
information is available on distant metastases, lung and liver seem to be the
most important first localization, and screening with liver ultrasound, serum
tests and RX thorax may be advised every 6 months.58
Malignant lymphoma of the conjunctiva. In the second edition of Hogan
and Zimmerman,59 which was the mainstay for ophthalmic pathology
reference for over two decades, the following points were made with respect
to conjunctival lymphoma. “Lymphomas of the conjunctiva may appear
independently, be associated with generalized lymphosarcoma, or be due
to one of the leukemias”. Indeed, 70.0 percent,64 or 87.5 percent of patients
with ocular adnexal lymphoma (21 of 24 patients) had primary lymphoma
and prior or concurrent systemic disease was seen in 12.5 percent (3 of 24
patients).65 Systemic lymphoma was known to exist before ocular diagnosis
in 13.8 percent (16 of 117 patients with conjunctival lymphoid tumors) for
a mean of 51 months and was found subsequent to ocular diagnosis in 1.7
percent (20 patients) at a mean of 21 months. Thus, 30.8 percent (36 of 117
patients) had or eventually developed systemic lymphoma and 69.2 percent
did not manifest systemic lymphoma during the mean follow-up of 38
months. Systemic lymphoma was eventually discovered in 7.0 percent of
03B.indd 135 31-08-2012 12:32:17

patients at 1 year, 12.0 percent at 2 years, 15.0 percent at 5 years, and 28.0
percent at 10 years.63 Past history of systemic lymphoma was noticed in
6.8 percent,69 or in 19.4 percent.61 Malignant lymphoma of the conjunctiva
occurred in 8.3 percent,65 or in 21.4 percent,64 or in 28.5 percent,61 or in 34.0
percent66 of patients with ocular adnexal lymphoma. Of 112 patients with
lymphoproliferative lymphoma of the ocular adnexa 28.6 percent (32 patients)
were with conjunctival lesions67 and of patients with ophthalmologic (orbit
and/or adnexa) or intraocular involvement conjunctival lymphoma occurred
in 35.2 percent (51 of 145 patients).68
Age: The age of patients is 4 to 5th decade of life,60 or the mean age at ocular
presentation was 61 years,63 or 64 years (range, 35–89 years), or 25 to 85 years.61
Gender: A slight predominance of males in 53.4 percent (14 males of 26 patients)
versus 46.2 percent for females (12 females of 26 patients with lymphocytic
tumors of the conjunctiva) was found.61 In contrast, in larger series of 117
patients with lymphoid conjunctival tumors a slight predominance of females
in 53.0 percent (62 females) versus 47.0 percent of males (55 males) reported
by Shields et al.63
Laterality: Slight predominance of the right eye in 57.7 percent found in 15 of
26 patients with lymphocytic tumors of the conjunctiva.61 Unilateral tumor
had 62.0 percent of patients and 10.0 percent68 or 38.0 percent63 had bilateral
lymphoma of the conjunctiva. Of the patients with unilateral conjunctival
involvement 17.0 percent manifested systemic lymphoma, and of the patients
with bilateral involvement 47.0 percent manifested systemic lymphoma. In 8
patients (6.8%), initial unilateral disease evolved into bilateral involvement
over a mean of 32 months.63
Race: The most of patients in 94.0 percent were white and only 6.0 percent
were African American.63
Incidence: The incidence of prior conjunctival lymphoma is the lowest (1.0 %) of
other ocular adnexal lymphomas61 and no increased frequency of conjunctival
involvement by low-grade B-cell lymphoma of mucosa-associated lymphoid
tissue (MALT type) was found.62
Recurrence: Local relapse of conjunctival malignant lymphoma in one patient
with marginal zone lymphoma in conjunctiva occurred 3 times during the
follow-up period of 24 to 62 months.69 Future spread of conjunctival lymphoma
was in 21.0 percent of patients, these lymphomas most often spreading to
lymph nodes in 24.0 percent and only rarely showing direct extraorbital
invasion in 3.0 percent.61
Metastasis: Of 26 patients with lymphocytic tumors of the conjunctiva
four patients (15.4 %) had metastases, of which widespread metastases
03B.indd 136 31-08-2012 12:32:17

(1 patients) and other 3 patients had metastases in the spleen, liver, and lymph
nodes (1 patient), in the liver and spleen (1 patient) and in iliac fossa (1 patient).71
Mortality: Lymphoma-related death for patients with lymphoproliferative
lymphoma was significantly associated with advanced clinical stage, an age
>60 years and large tumor growth fractions.70 Death related to lymphoma was
the final course in 22.0 percent,66 or in 23.1 percent71 or in 23.4 percent60,61 of
patients with lymphomas located at the conjunctiva. Lymphoma-related death
was also commoner and earlier in patients with bilateral disease. Conjunctival
lymphoma had the lowest rate of lymphoma-related death and extra-orbital
spread.61 Only 1 patient (<1.0%) died of systemic lymphoma, at 28 months
after the diagnosis of the ocular disease.63
Survival: Complete remission was achieved in 39.0 percent of patients with
conjunctival lymphoma.66 The 5-year disease-free survival and overall survival
were 65.0 percent and 83.0 percent respectively.73
Prognosis: Age, sex, anatomical location of the conjunctival lymphoma, clinical
stage of disease and mode of therapy did not have any prognostic significance
during the follow-up period of 9 to 131 months,65 or 6 months to 16.5 years.67
The only significant predictors of all causes of mortality were the histological
type of lymphoma and the stage of disease at presentation66,69 and it seems to
have a better prognosis compared with lymphomas of the lid.66 Interestingly,
that prognosis for patients with conjunctival lymphoma was relatively good,
whether including or excluding orbital involvement.61 The most conjunctival
lymphomas are of MALT type and that explains their uniformly favorable
prognosis.72 A significant correlation was also noted between the final outcome
and tumor cell expression for K1-67 antigen and p53 protein.66 Prognosis for
patients with malignant conjunctival lymphoma is unfavorable in cases of
systemic disease developing.74
In Uzbekistan, malignant tumors of the conjunctiva including caruncle
occurred in 350 patients aged from 15 to 90 years and over excluding
conjunctival lymphomas (7.2% of 4872 patients with malignant ocular tumors
in Uzbekistan), which treated in the Institute of Hematology. There was a slight
predominance of females in 56.9 percent (199 females) versus males in 43.1
percent (151 males). Crude incidence of malignant conjunctival tumors per
100,000 male and female populations as well as urban and rural populations,
and in total have no had statistically significant difference between sexes and
between urban and rural population. In spite of the standardized incidence
(Standard World Population)75 for females of urban and rural population
and in total was slight higher this incidence was not statistically significant
(Table 3.6).
Overall mortality of males and females suffered from malignant con-
junctival tumors was equal, 0.04 per 100,000 males and females populaton.
03B.indd 137 31-08-2012 12:32:17

Table 3.6: Crude incidence and standardized incidence of malignant tumors of

the conjunctiva per 100,000 male, female and urban and rural populations
Incidences Urban population Rural population Total
Crude 1.5 1.8 1.7 1.2 1.7 1.8 1.6 1.8 1.9
incidence
Standardized 2.9 3.8 3.7 2.5 3.2 3.1 2.5 3.3 3.4
incidence
Fig. 3.8: Percentage of deceased patients and survival of patients with malignant
tumors of the conjunctiva excluding lymphomas at less than 1 year, 1 year, 2 years, 3
years, 4 years, 5–9 years, and 10 years from initial diagnosis
Of 350 patients less than 1 year from initial diagnosis deceased 3.1 percent (11
patients), at 1 year 4.9 percent (17 patients), at 2 years 3.4 percent (12 patients),
at 3 years 8.3 percent (27 patients), at 4 years 6.3 percent (22 patients), at
5 to 9 years 7.7 percent (27 patients) and at 10 years 4.3 percent (15 patients).
The most patients died at 5 to 9 years (27 patients, 7.7%). Total, 122 of
350 patients with malignant tumor of the conjunctiva (34.8%) excluding
lymphomas deceased from initial diagnosis to 10 years due to their malignant
conjunctival tumors (Fig. 3.8).
Survival of patients with malignant conjunctival tumors less than 1 year
from initial diagnosis was 96.9 percent (339 patients), at 1 year 92.0 percent
(322 patients), at 2 years 88.6 percent (310 patients), at 3 years 84.4 percent
(292 patients), at 4 years 77.1 percent (270 patients), at 5 to 9 years 69.4 percent
(243 patients), and at 10 years 65.1 percent (228 patients). Total 228 of 350
patients with malignant conjunctival tumors (65.1%) excluding lymphomas
survived to 10 years and the most patients survived less than 1 year and at 1
year from initial diagnosis (Fig. 3.8).
Although percentage of females with malignant conjunctival tumors in our
studies had a slight predominance this result is similar with other reports.2,5
However, crude incidence and standardized incidence for both sexes (1.9
and 3.4 per 100,000 populations, respectively) in patients with conjunctival
03B.indd 138 31-08-2012 12:32:17

Fig. 3.9: Late diagnosed squamous cell carcinoma of the bulbar and pulpebral
conjunctiva, upper and lower fornixes involving orbita in the left eye of 78-year-old
women
malignant tumors were much higher in Uzbekistan than population-based

age-adjusted incidence rate of squamous cell conjunctival cancer in US.17
Although conjunctival malignant tumors could frequently be seen “by eye”
late diagnosed patients are common in Uzbekistan and one of such patient
with squamous cell carcinoma of bulbar, palpebral conjunctiva and upper and
lower fornixes involving orbita treated in our Department demonstrated in
Figure 3.9.
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43. Desjardins L, Puncer P, Levy C, et al. Prognostic factors in malignant melanoma
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44. De Potter P, Shields CL, Shields FA, et al. Clinical predictive factors for
development of recurrence and metastasis in conjunctival melanoma: a review
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52. Werschnik C, Lommatzsch PK. Long-term follow-up of patients with
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57. Matsumoto A, Inatomi T, Kinoshita S, et al. Analysis of the long-term prognosis
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cycle markers in ocular adnexal lymphoma: An assessment of 230 cases. Graefes
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Histopathology 1993;23:417-24.
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1960.
MALIGNANT INTRAOCULAR TUMORS

The iris and ciliary body malignant tumors arising from the non-pig-
mented ciliary epithelium located on the radix iridis or/and ciliary body is
adenocarcinoma, malignant variant of adenoma, which occurs extremely
rare in adults.1 Other extremely rare malignant intraocular tumor is
medulloepithelioma, typically tumor of children, but it may be also in adults.2,3
For example, of 16 patients with benign and malignant medulloepithelioma
there was only one 48-year-old male (6.2%),4 or of 9 patients with malignant
medulloepithelioma was only one 58-year-old female (11.1%) with malignant
medulloepithelioma.5
Malignant melanoma of the iris and/or ciliary body. The most frequently
malignant tumor of the iris and/or ciliary body is malignant melanoma
occurred in 5.6 percent (141 of 2504 patients with a melanoma in ocular
region),6 or in 9.8 percent of all 476 patients with iris and ciliary body tumors.7
The recognition of malignant melanoma of the iris “is very important because
number of benign lesions clinically resemble these tumor”8 but the reason of
malignant iris melanoma is not known although exposure to the rays may be
a factor.9 There is also hypothesis about a role of previous nevus in developing
of malignant melanoma of the iris.7
03B.indd 143 31-08-2012 12:32:18

Age: The mean age of patients with iris or/and the ciliary body melanoma was
43.0 years,10 or 44.6 years,8 or 49.0 years,11 or 59.0 years.12 The median age was
45.0 years,10 or 53.0 years,9 or 63.0 years.12
Gender: Some authors found a slight prevalence of females with malignant
iris melanoma in 51.2 percent,8 or in 54.1 percent.7 Others showed that there
was a slight prevalence of males in 51.3 percent (41 males) than females
in 48.7 percent (39 females) of 80 patients with malignant iris melanoma.9
Thirds found equal number of males (20 males) and females (21 females) of 41
patients with malignant iris melanoma.8
Variant of the iris and/or ciliary body melanoma: The most common clinically
variants of growing of malignant iris melanoma are nodulous and mixed
form.8 A rare variant of iris melanoma and/or anterior chamber angle are
diffuse melanoma of the iris and ring melanoma of the anterior chamber angle
that manifests as circumferential.13 Diffuse iris melanoma has a flat growth
pattern as well as ring melanoma of the anterior chamber angle, which occupy
trabecular meshwork and angle structures. Both of them are a variant of
diffuse malignant melanoma.11,13 Of 8800 patients with uveal melanoma 0.2
percent (14 patients) were classified clinically as ring melanoma of the anterior
chamber angle and there were no cases appreciable involvement of the iris
or ciliary body on clinical examination.13 Only 0.3 percent (23 patients) had
ring melanoma of the ciliary body of 8800 patients with uveal melanoma,12
or 1.3 percent (10 patients) were with ring melanoma of the iris of 80 patients
with malignant melanoma of the iris).9 Ring melanoma of the trabecular
meshwork and angle structures often masquerades as unilateral glaucoma and
can be difficult to recognize clinically unless careful comparative gonioscopy
is performed.13
Some authors found that histopathologically there have been shown a
prevalence of epithelioid cell type in diffuse iris melanoma,11 others found a
prevalence of mixed cell type in ring melanoma of the ciliary body12 and thirds
revealed a prevalence of spindle cell type8,14 in malignant iris melanoma. So,
histopathologic examination revealed spindle cell melanoma in 28.6 percent
of ring melanoma of the anterior chamber angle,13 or in 50.0 percent9 and
65.9 percent8 of malignant melanoma of the iris. Mixed cell melanoma was
in 14.6 percent8 and in 25.0 percent9 of malignant iris melanoma, or in
64.3 percent of ring melanoma of the anterior chamber angle,13 or in 68.0
percent of diffuse iris melanoma,11 or in 73.9 percent of ring melanoma of
the ciliary body.12 Epithelial cell melanoma was in 5.7 percent of malignant
iris melanoma,8 or in 7.1 percent of diffuse iris melanoma,11 or in 9.0 percent
of ring melanoma of the ciliary body,12 or in 12.0 percent of diffuse iris
melanoma,11 or there were “a few epithelioid or nevoid in cell morphology”
of malignant iris melanoma.9
03B.indd 144 31-08-2012 12:32:18

Local invasion was found in the trabecular meshwork in all 22 enucleated
cases,11 invasion of Schlemm’s canal in all 13 enucleated cases,13 or in 81.8
percent,11 minor pars plicata in 54.6 percent and episclera in 23.1 percent,13
or in 31.5 percent.11 Extraocular extension was presented in 5.9 percent of
patients with iris melanoma10 and in 34.8 percent of patients with ring
melanoma of the ciliary body.12
Race: All of patients with malignant iris melanoma were Caucasian.10
Incidence: An average of 3.2 cases per year with an average population of 4.9
million were with malignant melanoma of the iris in Denmark from 1961 to
1985 (over a 25-year period)9 and during the period of 1943 to 1947 (54 years)
in Denmark the incidence of iris melanoma increased substantially.15
Recurrence: For local recurrence may be such a risk factors as the proliferation
of melanocytes of the anterior iris surface (iris plaque) and diffuse stromal
invasion.14
Metastasis: Metastasis in patients with malignant iris melanoma was found to
be 3.0 percent at 5 years, 5.0 percent at 10 years and 10.0 percent at 20 years.10
In patients with ring melanoma of the ciliary body metastasis developed in
52.2 percent after a mean follow-up of 55 months.12 One of 41 patients (2.4%)
with malignant melanoma of the iris who died of metastasis had epithelioid
cell type melanoma of the iris.8 Liver metastasis developed in 12.0 percent (3
of 25 patients with diffuse iris melanoma) with a mean time of observation of
78 months.11 In patients with ring melanoma of the anterior chamber angle
distant metastasis to the liver was detected in 25.0 percent (3 of 12 patients)
after a mean follow-up of 78 months.13 Metastases are more likely to develop in
those patients who are older and show tumor features of iris root/angle location
with elevated intraocular pressure and extraocular extension; the influence of
the method of management (resection, radiotherapy, or enucleation) did not
have on an impact on metastasis.10
Mortality: Death of patients with iris malignant melanoma was found in 10.0
percent (8 of 80 patients with malignant melanoma of the iris) at 30 years
follow-up period. Four of these were patients with ring melanoma and 4 with
melanoma invading the ciliary body.9 The mortality rate was found to be 2.4
percent during the mean follow-up of 3.2 years.8 Jensen9 showed a case of
metastatic death as a result of incomplete resection of malignant iris melanoma.
Survival: The 5- and 10-year relative survival for the iris malignant melanoma
was for men 90.0 percent and 85.0 percent and for women 99.0 percent and
101.0 percent respectively. The highest observed and relative survival was
found for iris melanoma.6
Prognosis: Ring melanoma of the ciliary body can remain hidden from
ophthalmoscopic examination and has a poor life prognosis.12 However,
prognosis is favorable in patients with spindle cell melanomas of the iris.8
03B.indd 145 31-08-2012 12:32:18

Despite the relatively small tumor volume, life prognosis for patients with ring
melanoma of the anterior chamber angle is guarded with distant metastasis in
25.0 percent at mean 6 years follow-up.13 The prognosis of iris melanoma is
better than that of melanoma of the ciliary body and choroid, but the reason
for that difference is unclear. One possible explanation is that iris melanoma
is smaller than its posterior segment counterparts at the time of diagnosis.14
Malignant choroidal melanoma is an uncommon malignancy.16 It is
lethal tumor,17 and in the ocular region malignant choroidal melanoma is
the most frequent melanoma, which has been found in 87.0 percent in large
series of 2504 patients with uveal and conjunctival malignant melanoma,6 or
in 86.0 percent in smaller series of 136 patients with ocular melanoma.18 Of
intraocular malignant tumors choroidal and ciliary body melanomas occurred
in 74.6 percent19 and of all patients with the suspicion of choroidal melanoma
this malignancy was diagnosed in 43.3 percent (212 of 458 patients). It is
very important that of 58 eyes without a fundus view, ultrasound revealed
an intraocular tumor in 8.6 percent (5 eyes), and in these cases choroidal
melanoma was found by vitrectomy/cataract extraction.20
Diffuse choroidal melanoma occurred in 3.0 percent (111 of 3500 patients
with choroidal melanoma,21 juxtapapillary choroidal melanoma was found in
7.1 percent (265 of 3706 patients with choroidal malignant melanoma).24 Small
melanoma of the chorioidea occurred in 13.0 percent22 or in 18.9 percent,23
medium sized melanoma was in 51.0 percent and large choroidal melanoma
was in 36.0 percent22 of all choroidal melanoma.
Histologically, the most frequent was spindle cell type in 45.0 percent, then
mixed cell type in 37.0 percent, epithelioid cell type in 15.0 percent and
necrotic type in 1.0 percent of all 293 cases with choroidal and ciliary body
melanomas.25
Age: From the age of 30 to the age of 70 the age-specific incidences of choroidal
malignant melanoma showed a steep rise. The peak incidence was in the age
group 70 and over.19 The most numerous group of patients with choroidal
melanoma consisted of patients between 60 and 70 years of age (22.7%).22
With age there was noticed an increase of relative frequency in both female
and male patients.26 Choroidal melanoma is seen most commonly in the 6th
to 7th decades of life.30 The mean age of patients with posterior choroidal
melanoma was 47 ± 16 years (range 22–70 years).28
Gender: The number of females and males was found to be approximately
equal without statistically prevalence in the sex distribution among patients
with choroidal melanoma.19,22,23 However, Lommatzsch and Dietrich26 and
De Potter et al.24 believe that the frequency of this tumor turns out to be higher
in males than in females, but slight predominance of females in 53.6 percent
was found by Isager et al.27 in 209 patients with choroidal and ciliary body
03B.indd 146 31-08-2012 12:32:18

melanomas during 1955 to 2000. In small series of 20 patients with medium-
sized posterior choroidal melanoma predominance of males in 65.0 percent
(13 patients) versus females in 35.0 percent (7 patients) was reported.28
Laterality and location: Usually, choroidal melanoma is an unilateral tumor
with slight prevalence of occurrence in the left eye in 51.3 percent versus
right eye in 48.7 percent,24 or in 50.5 percent left eye versus 49.5 percent in
right eye,25 but it may be bilateral according to calculated risk of developing a
second primary melanoma in other eye in 1 person per 50 million whites, or in
other words, a bilateral case is expected to occur every 18 years in the United
States.31 Of choroidal melanoma bilateral choroidal melanoma occurred in 2.2
percent (42 of 1898 patients with choroidal melanoma)8 and of 2461 patients
with primary uveal melanoma 0.2 percent (5 patients) were identified as
having bilateral melanoma.33
Race: Among the general population the reported incidence of choroidal
melanoma is low and is especially low among blacks being most commonly
in whites.30 One of 2500 whites will develop a choroidal melanoma during
his or her lifetime.31 Patients with blue or gray irises appear to be at increased
risk of metastatic death from choroidal melanoma, independent of other risk
factors.32
Incidence: The age standardized to the World Standard Population incidence
per 100.000 person/year of choroidal/ciliary body malignant melanoma in
Denmark was stable for both sexes during the period 1943 to 1997; for males
in was 0.68 and for females 0.55.15 No significant increase of the choroidal
age-adjusted incidence in Finland during 1973 to 1980 was also found.19 The
incidence of the choroid and ciliary body melanoma in an area of the Swedish
west coats during the period 1956 to 1975 was 0.72 per 100,000 inhabitants.
Recurrence: Recurrent melanomas are associated with an increased rate of
metastatic disease therefore treatment of melanomas should be directed
toward minimizing the potential for recurrences.17
Metastasis: The occurrence of very late metastases up to 36 years after initial
surgery has been reported.40 Coupland et al.41 described metastasis from
choroidal melanoma to the contralateral orbit 40 years after enucleation. We
observed 48-year-old woman and 62-year-old man with choroidal melanoma
who had metastasis in liver 21 and 28 years, respectively after enucleation.
Choroidal 5-, 10-, and 12-year melanoma metastasis rates of death with
histopathologically confirmed melanoma metastasis were 10.0 percent, 18.0
percent, and 21.0 percent respectively, in the (125I) brachytherapy arm and
11.0 percent, 17.0 percent and 17.0 percent respectively in the enucleation
arm.42 In the patients with primary choroidal melanoma treated with proton
beam irradiation (70 cobalt-gray equivalent in 5 fraction) the 5- and 10-year
metastatic death rates were 12.8 percent and 20.7 percent respectively. Death
03B.indd 147 31-08-2012 12:32:18

of melanoma metastasis occurred in 16.0 percent (193 of 1204 patients).43

According to COMS’ assessment of metastatic disease status at death in
435 patients with large choroidal melanoma 61.8 percent patients (269 of
435 deaths) had histopathologically confirmed melanoma metastasis at the
time of death. The common metastatic sites were liver in 83.3 percent (5 of
31 patients with choroidal and ciliary body melanoma),50 or in 93.0 percent
of 269 patients with metastases of large choroidal melanoma,44 lung in 16.7
percent,50 or in 24.0 percent,44 and bone in 16.0 percent; multiple sites were
identified in 87.0 percent of patients with metastasis.44 71.0 percent of patients
who died had metastasis mainly in liver, bones and lungs.26 Diffuse choroidal
melanoma carries a metastatic potential of 24.0 percent at 5 years. The
probability of metastasis developing was 16.0 percent at 3 years, 24.0 percent
at 5 years, and 36.0 percent at 10 years.21 Overall metastatic disease was seen
in 11.0 percent of 90 patients with choroidal melanoma treated by iodine 125
(125I) brachytherapy, local excision or enucleation.52 However, much lower
metastasis rate, 1.1 percent (1 of 91 patients with malignant melanoma of the
choroid and the ciliary body) was found at the time of primary diagnosis in
only one patient, with a 10 years survival.29
The clinical factors predictive of metastasis by univariate and multivariate
analysis included tumor basal dimension 18 mm or more, poorly defined
tumor margins, transcleral extension, and optic nerve invasion.21
Risk of dying from malignant choroidal melanoma: A low risk of dying within
5 years have patients average age of 60 years, without a previous diagnosis
of malignant disease who have small choroidal melanoma.35 Patients with
choroidal melanoma who had blue or gray irises have an increased risk of
dying from metastatic disease.31 The primary predictors of time to death
with melanoma metastasis were older age and larger maximum basal tumor
diameter.42 Except largest basal diameter and high age, an increased risk of
death from choroidal and ciliary body melanomas found for men versus
women, anterior tumor margin and nonspindel cell type. Age and gender gave
additional risk factors for death.46 For patients with juxtapapillary choroidal
melanoma age of patients, tumor thickness (>3 mm), treatment (enucleation),
treatment by age interaction, and treatment by thickness interaction were the
most significant risk factors for death.24 Besides it, an important predictor of
death in choroidal melanoma is monosomy 3. However, without monosomy 3
in a significant number of patients death also occurred from metastatic disease.
There is no significant difference in time until death between metastatic
melanomas, with and without monosomy 3.46 Prediction of disease-specific
mortality after treatment enhances cytogenic analysis of chromosomes 3 and
8 but must be interpreted together with tumor diameter and cell type.49
03B.indd 148 31-08-2012 12:32:18

Mortality: In the literature, there are a number of reports concerning mortality
following a diagnosis of choroidal melanoma. Diener-West et al.34 have
analyzed 76 reports published in the period 1966 to 1988. 38.2 percent of
reports excluded from meta-analyses because there were no cases treated by
enucleation alone, mortality was not reported by time from enucleation, fewer
than 10 cases were reported, or 5-year mortality rates were not reported or
derivable from the data presented and only eight articles (10.5 percent) reported
5-year mortality rates by tumor size were included in a pooled analysis. The
combined weighted estimates of 5-year mortality rates following enucleation
were 16.0 percent for small tumors, 32.0 percent for medium tumors and 53.0
percent for large melanomas.34 Interestingly, no deaths occurred in patients
with tumors less than 7 mm in diameter and 3 mm in elevation. Authors
found than tumor size may be of more prognostic significance than cell type
in the case of small choroidal melanoma.23 2.9 percent of patients with small
choroidal melanoma (6 of 204 patients with small choroidal melanoma), who
were offered participation in the COMS (Collaborative Ocular Melanoma
Study) in period 1986 to 1989 died due to metastatic melanoma. The 5-year
and 8-year tumor-specific mortality rates were only 1.0 percent and 3.7
percent, respectively.35 Estimated 5-year mortality rate for patients with
medium choroidal melanoma, who had subsequent melanoma treatment was
approximately 30.0 percent. For the COMS medium melanoma trial, 5-year
mortality was 18.0 percent, not statistically significantly different from the
natural history study patients.36 In the enucleation group of patients with
medium-size choroidal melanoma 28.5 percent (188 of 660 patients) had
died, and in the brachytherapy group 26.8 percent of patients (176 of 657
patients) had died. Five-year rate of death with histopathologically confirmed
melanoma metastasis were 11.0 percent and 9.0 percent following enucleation
and brachytherapy, respectively.37 However, in small series of 20 patients with
medium-sized posterior choroidal melanoma only 1 patient died (5.0%) of
metastasis to the liver with the mean follow-up period of 89.55 months ± 38.4
months (7.5 ± 3.2 years).28 The mortality after 15 years in all the 91 cases of
enucleated malignant melanoma of the choroid and ciliary body during the
period 1956 to 1975 was 50.0 percent. Tumors of the epithelioid type showed a
surprisingly low mortality (29.0%).29 COMS randomized clinical trial showed
that 43.4 percent died (435 of 1003 patients with large choroidal melanoma).
The risk of death among patients treated with pre-enucleation radiation relative
to those treated with enucleation alone.38 Complications were infrequent
during the 5-year period following enucleation surgery in patients with large
choroidal melanoma according to report of COMS. Five-year incidence rates
and prevalence at the 5-year examination of most complications were similar
in the two treatment arms (enucleation alone or pre-enucleation radiation).
03B.indd 149 31-08-2012 12:32:18

There was no indication that pre-enucleation radiation had resulted in more

serious complications.39
Two peaks in mortality of patients with choroidal melanoma found by
Packard.51 One of two peaks was at 3 to 4 years following treatment and the
other was at 9 to 10 years. The explanation of the peaks was possible that
immunological factors were important, such that in those patients dying in
the earlier peak they might be less able to cope with any outflow of metastatic
cells from the tumor at the time of enucleation than those patients dying in
the later peak. In their case only foci of metastases may well be controlled
immunologically for a time, but eventually this become inadequate and leads
to death from the melanoma.51
The last melanoma-related death occurred 26 years after enucleation. 13.0
percent of melanoma-related deaths occurred after 10 years and 6.0 percent
after 15 years.25
Survival: Survival of patients with choroidal/ciliary body malignant melanoma
was stable during the 55 years study period from 1943 to 1997 in Denmark.
The 5- and 10-year relative survival for men was 66.0 percent and 55.0
percent, and for women 69.0 percent and 57.0 percent respectively. The lowest
observed and relative survival was found for patients with choroidal/ciliary
body melanomas comparing with observed and relative survival of patients
with iris and conjunctival malignant melanomas.6 The 5-, 10-, 15-, 20-, and
25-year melanoma-specific survival was 70.0 percent, 53.0 percent, 47.0
percent, 45.0 percent and 41.0 percent respectively. For patients enucleated
before the introduction brachytherapy in 1988, the 5-, 10-, 15-, 20-, and 25-
year melanoma-specific survival was approximately the same: 71.0 percent,
54.0 percent, 48.0 percent, 46.0 percent and 41.0 percent respectively.25 The
5-year survival rate of patients with spindle cell choroidal melanoma yield
an 85.0 percent chance.26 For the metastatic group of patients with choroidal
melanoma the 5-year survival rate was only 10.0 percent with an average
follow-up period of 64 months (range, 5–172 months); the 5-year survival
is encouraging with all forms of therapy and it is important to monitor the
effects of conservative therapy.52 In conservatively treated patients with small
choroidal melanoma compared with enucleated tumors the 10-year survival
was approximately the same: 81.3 percent and 81.4 percent respectively.51 In
patients with large choroidal melanoma according COMS report the estimated
5-year survival rates was lower (57.0%) for the enucleation alone group of
patients comparing with 62.0 percent for pre-enucleation radiation group of
patients.38 On the contrary, patients with juxtapapillary choroidal melanoma
in the enucleation group had a better survival rate when the thickness of the
tumor was less 3 mm compared with a tumor of more than 3 mm. There were
no apparent effects of tumor thickness on survival for patients treated with
03B.indd 150 31-08-2012 12:32:18

plaque radiotherapy.24 Increasing age is a strongly depressing influence on
survival after enucleation, the 15-year relative survival being 80.0 percent for
those less than age 40 and only 30.0 percent for patients aged 70 and over.45
Survival of patients with choroidal melanoma displaying monosomy 3 is
generally short,46 and can be predicted only in patients with large epithelioid
melanomas. The absence of monosomy 3 is predictable only in patients who
have small, spindle-cell tumors. In most patients, prediction of monosomy 3
according to tumor size and histology is unreliable.47 Loss of chromosome
3, loss of 6q, and gain of 8q were significantly associates with poor overall
survival of patients with choroidal and ciliary body melanoma.50 Survival of
patients with uveal melanoma treated by Gamma knife radiosurgery was 88.8
percent at 3 years and 81.9 percent at 5 years. Authors found that Gamma knife
radiosurgery can be considered an alternative to enucleation for the treatment
of choroidal melanoma.53
Prognosis: Greer et al.45 found that extension into a scleral emission appeared
to exert an unexpectedly depressing effect on prognosis and that the choroidal
melanomas have a better prognosis than ciliary body melanomas. However,
prognosis after diagnosis of metastasis was poor.52 In patients with large
choroidal melanoma reported by COMS randomized trial, for statistically
significant prognosis for survival were only age and longest basal diameter
of the melanoma.53 In the cases of delay and/or other treatment preceded
enucleation the prognosis was not worse than for those who underwent
immediate enucleation.29 Cell type may be less prognostic significance than
tumor size in the case of small melanoma.23 Submacular melanomas had a
very good prognosis for patients’ survival due in part to their small size
and benign cytology.45 Significant predictor of both relapse-free and overall
survival is monosomy 3.48
Uveal melanoma: It is well known that uveal melanoma is the most frequently
primary intraocular malignant tumor in adults. Uveal melanomas are slowely
growing neoplasms, which arises from melanocytes located in the choroid,
the layer between the sclera and the retina. An average of seven to eight years
is required for small tumors to become large and an additional period of four
years before metastatic diseases might be anticipated.55 Uveal melanoma is the
only primary malignancy of the eye that can be considered life-threatening to
the population above the age of 15 years.56
The most commonly site of all uveal melanomas is choroid, where
malignant melanoma occurred in 73.7 percent,57 or in 76.6 percent,58 or in
83.9 percent,59 or in 84.5 percent,60 or in 87.37 percent.61 Malignant melanoma
affected the ciliary body less frequently in 13.1 percent,59 or in 13.2 percent,60
or in 21.1 percent57 and in iris it occurred in only 2.3 percent,59,60 or in 5.3
percent57 of all malignant uveal melanomas. Of 169 cases of primary invasive
cutaneous melanoma intraocular melanoma was in 2.96 percent (5 cases).65
03B.indd 151 31-08-2012 12:32:18

Age of patients with uveal melanoma at the first visit ranged from 25 to
89 years with an average of 58.6 years,59 or average age was 60.09 years,60 or
64.6 years ± 9 years,57 or the age at the time of diagnosis ranged from 21 to 87
years (mean 61.0 years).69 The most often uveal melanoma diagnosed in the
6th decade of life.70 Only 1.1 percent of patients with uveal melanoma (40 of
3706 patients) were aged 20 years or younger at the time of diagnosis but the
majority of patients (78.0%) were between 15 and 30 years old.75 Up to age 55
incidence of uveal melanoma noticeably increased68,70 but leveled off after age
75.71 The mean age of patients with uveal melanoma was 45.7± 14.2 years.61 The
median age of patients with uveal melanoma was 60.09 years60 and the median
age of patients with disseminated or metastatic uveal melanoma was 56 years
(range 17–67 years),72 or 55 years (range, 24–74 years), of which 58.4 percent
were 24 to 60 years and 35.6 percent were >60 years.74 However, Rietschel et
al.73 had shown a prevalence of patients >60 years in 60.5 percent (72 of 119
patients with metastatic uveal melanoma). In China strikingly younger age
distribution was observed. Almost 20.0 percent of 65 cases of uveal melanoma
involved patients between the age of 19 and 30. The largest number of cases
was seen in the 5th decade and only 8.0 percent were seen in the 6th decade
of life.93 The mean age of Asian Indian patients with uveal melanoma was 43.7
± 14.2 years,61 comparable with the age of Caucasian paitents with an average
age at the first visit of 58.6 years,59 or an average age of 60.09 ± 1.67 years.60
Gender: A prevalence of females affected by uveal melanoma in 54.9 percent,57
on in 55.7 percent,59 or in 55.8 percent60 found by some investigators. Others
showed a slight predominance of males in 55.3 percent,56 or in 55.8 percent.69
Egan et al.70 and Graell et al.60 are also sure that uveal melanoma in males is
somewhat more common in males than in females, especially in patients 50
and over. Age-adjusted incidence rate of uveal melanoma had also significant
variation between genders being in males 4.9 and in females 3.7 per million
over a 25 years period from 1973 to 1997 in the United States.67 Standardized
incidence rate was also higher in males than in females during the years
1983 to 1994 in 16 European countries.71 In patients with disseminated uveal
melanoma the prevalence of males in 54.2 percent was also found by Kath et
al.72 However, a slight prevalence of females in 56.3 percent (67 women) in
other report of 119 patients with metastatic uveal melanoma was found73 but
the male/female ratio of 1:1 in consecutive patients with liver metastasis from
uveal melanoma treated by fotemustine was reported.74
Laterality and location: In 51.0 percent of patients with primary uveal melanoma
the tumor affected their right eye and in 47.3 percent,60 or in 48.0 percent,58
or in 49.0 percent59 the left eye. The occurrence of bilateral uveal melanoma
is an extremely rare event, but in 0.2 percent (5 patients) were identified
as having bilateral melanoma.33 The same percentage (0.18%) in 8 patients
03B.indd 152 31-08-2012 12:32:18

with bilateral melanoma of 4500 patients with primary uveal melanoma was
found.76 The probability of any one individual developing bilateral melanoma
is estimated to be 1 to 50 million. The estimated probability for patients
with unilateral primary uveal melanoma of developing bilateral melanoma
is 0.2 percent.77 However, Augsburger78 declared that primary intraocular
malignant melanoma is almost exclusively a monocular, unifocal disease
without hereditary transmission.
Familial uveal melanoma is a rare disease and a few cases have been
described in the literature. An autosomal dominant inheritance was proposed.
Only 11 patients from 9 families of 2169 patients with uveal melanoma were
identified and at least 2 members of them (0.1 percent) were affected. According
to authors’ opinion, uveal melanoma occurring at least in two members of the
same family is not due to chance alone. Genetic factors associated to external
factors are probably responsible.79 The family uveal melanoma accounts for
only 0.6 percent of patients with uveal melanoma. Since the first description
by Silcock in 1892 of the case of a mother and her two daughters affected
by uveal melanoma, only 51 families had been reported until 1996.80,81 A
family history of uveal melanoma was in 1.2 percent (56 of 4500 patients with
uveal melanoma). In 17 cases the second affected relative was a first-degree
relative and rarely affects more than two persons in a family, and may be
associated with a generalized inherited predisposition to cancer.80 Unusual
familial histopathologically proved uveal melanoma involving first generation
members of the same family (siblings) was analyzed by Krygier et al.81 Because
of no previous evidence of family members with uveal melanoma in the
genealogical tree, either an environmental factor that remains undisclosed
might be suspected or a new mutation may have arisen. Either way careful
monitoring of the remaining siblings would be of a great interest. The
statistical likelihood of such an uncommon tumor occurring independently
in two or more family members lead us to believe that some cases of familial
uveal melanoma may go unrecognized, and appropriate tissue samples, such
as blood and tumor samples, should be obtained and conserved for present or
future cytogenic or molecular genetic studies.82 Although no specific genes
have been linked to the pathogenesis of uveal melanoma, which differs from
that of cutaneous melanoma, progress has been made in identifying potential
targets involved in uveal melanoma apoptosis, proliferation, invasion,
metastasis, and angiogenesis.54
Race: Most cases (97.8%) of uveal melanoma (2493 patients) occurred in the
white population.67 Fair-skinned individuals have a much higher risk of ocular
melanomas than dark-skinned individuals. In Whites ocular melanoma was in
6.9 percent (1587 patients) and in Blacks only in 0.04 percent (11 patients) of
25184 melanoma cases (cutaneous, ocular, visceral and others). Otherwise, of
03B.indd 153 31-08-2012 12:32:18

all ocular melanoma cases (1598 cases) in Whites ocular melanoma occurred
in 99.3 percent and in Blacks only in 0.7 percent.83,84 The annual age-adjusted
incidence of uveal melanoma per million populations according to SEER
program (Surveillance, Epidemiology, and End Results) was 0.31 for Blacks,
0.38 for Asians, 1.67 for Hispanics, and 6.02 for non-Hispanic whites. If the
non-Hispanic white population and the Hispanic population were combined,
than the overall white: black ratio was 18:1.85 In rare cases of 0.5 percent
(4 of 873 histologically confirmed uveal melanoma,) uveal melanoma occurred
in black non-Hispanics, more frequently in 5.4 percent in white Hispanics
(47 cases), and there were no cases of uveal melanoma in black Hispanics.
White Hispanics were less likely to develop uveal melanoma than white non-
Hispanics.86 The ethnic group is an important factor as far as age of onset,
and thus it has been described that in Japanese patients with uveal malignant
melanoma the average patients age was younger (55.2 years) than that for
white population.91 The Hispanic patients with choroidal melanoma were
younger than the white patients at the time of diagnosis.92
Incidence: Uveal melanoma was notified in about 90.0 percent of all records
of ocular malignant melanoma between 1943 and 1982 in Denmark and
although the annual number of incident cases increased from 30 to 50, but the
age-adjusted incidence rate remained stable at 0.75 per 100,000 in males and
0.60 in females62 and in the period 1943 to 1997 age-standardized incidence
rate (World Standard Population) was 0.72 for men and 0.60 for women per
100,000 persons per years in Denmark.68 In the United States in 79.3 percent
was reported melanoma of the choroid and ciliary body (2539 of 3202 ocular
melanomas) during the period 1974 to 1998.63 Uveal melanoma in adults
was identified in 67.0 percent of 4308 patients with ocular melanoma.64 Of
primary invasive cutaneous melanoma patients only 2.96 percent (5 of 169
cases) had uveal melanoma.65 In large series of 84836 patients with cutaneous
and noncutaneous melanoma between 1985 through 1994 in accordance to
the National Cancer Date Base report in the United States ocular melanoma
was in 5.3 percent (4522 patients), of which uveal melanoma was in 85.0
percent (3846 patients), while in the period of 1985 to 1989 there were 35.5
percent (1365 of 3846 patients), and in the period of 1990 to 1994 there were
64.5 percent (2481 of all 3846 patients with uveal melanoma for all years were
diagnosed). The number of patients with uveal melanoma in the period of
1985 to 1989 (1365 patients) increased in the period of 1990 to 1994 (2481
patients) 1.8 fold, i.e. 81.8 percent comparing with 1365 patients in 1985 to
1989.66 In the same country (United States), but in the other research period
of 1973 to 1997, 2493 patients with primary uveal melanoma derived from
the SEER program database (Surveillance, Epidemiology, and End Results)
and the mean age-adjusted incidence of uveal melanoma was 4.3 per million.
03B.indd 154 31-08-2012 12:32:18

The age-adjusted incidence rate of uveal melanoma has remained stable for
the past 25 years.67 The incidence of uveal melanoma is 6 cases per million
populations per year in United States,70 and 0.7 per 100,000 populations in
1992 in France.117 Uveal melanoma affected from 6 to 12 patients per million/
year in Caucasian population in Sweden.118 In Europe an age-standardized
incidence rate (World Standard Population) is up to 1.0 per 100,000 persons
per year.122 Estimated incidence rate of uveal melanoma in Europe from 1943 to
1994 by EUROCARE Working Group standardized incidence rates increased
from south to north across registries, from Spain and Southern Italy up to
>8 per million in Norway and Denmark. Rates were stable during the study
period, but in cohort effect was evidenced, accounting for higher incidence
rates in people born during the period 1910 to 1935. Incidence increased with
latitude, which explained most differences in rates among areas.71 The average
annual age-adjusted incidence rate of ocular melanoma was 4.9 per million
among men and 3.7 per million among women in New York State among New
York State residents, this incidence was 1.5 fold higher for men and women.120
Uveal melanoma incidence rates remained quite stable during the period
1983 to 1997. The important fact is that the interpretation of uveal melanoma
incidence trends is complicated by missing data on topography within the eye,
morphology and basis of diagnosis.121
Uveal melanoma and other primary cancers development: There are several
reports about the presense of multiple primary cancers in patients with
uveal melanoma, which suggested a greater risk of developing other types of
tumors in these patients. Data from SEER program in 1973 to 1998 showed
that persons with uveal melanoma went on to develop cutaneous melanoma
4.6 times more often than the population at large. In contrast, persons with
cutaneous melanoma were not subsequently diagnosed with uveal melanoma
at an elevated rate.123 The overall prevalence of nonbasal cell cancers diagnosed
in uveal melanoma patients was over two times greater than the expected
prevalence. In uveal melanoma female patients gynecologic cancers tended to
be more common than in the comparison population and hormonal factors
may play a role in the genesis of this malignancy; there may be a link between
cutaneous and uveal melanoma.124 An increased risk of second primary
cancers was observed among 2995 Swedish patients with uveal melanoma
during the period 1960 to 1998125 and one or more additional neoplasms in 7.9
percent (24 of 305 patients with uveal melanoma) was reported.59 However, the
findings of other authors do not support an association between prior cancer
and increased risk of uveal melanoma.126 In Canadian cohort no increased
risk of a second cancer, overall or by organ site, in male or female patients with
uveal melanoma between 1990 and 2002 was indicated.127
Recurrence: The initial retinal detachment appears to be a risk factor for local
recurrence.142 Local recurrence occurred in 3.3 percent (4 of 120 patients with
primary intraocular malignant tumors) between 1993 and 1997.156 Orbital
03B.indd 155 31-08-2012 12:32:18

recurrence was found in 2.5 percent of 302 patients who were followed up and
evaluated 25 years after enucleation and 8.0 to 12.0 percent of the same series
with extrascleral extension had orbital recurrence at an average of 2 years after
enucleation.162
Metastases of uveal melanoma occurred in 10.0 percent,139 or in 15.9 percent,140
or in 17.0 percent,141 or in 19.5 percent,142 or in 27.0 percent143 of patients
with uveal melanoma. Estimated median time from initial diagnosis of uveal
melanoma until detection of metastatic disease for all patients was 53 months
ranging from 0 to 359 months73 or between 7 weeks and 8.3 years.144 The mean
age at diagnosis of metastatic malignant melanoma of the uvea was 63 years
ranging from 23 to 86 years.148 Clinical evidence of metastasis occurred 5 to 240
months after initial therapy with median relapse-free follow-up of 36 months.72
It is possible that some clinically silent metastases remained undiagnosed145
and metastases from uveal melanoma were misclassified as cutaneous
melanoma or as primary liver cancer.125 Zimmerman et al.55 conclused that
the enucleation may have had an adverse effect, accelerating dissemination
and lethal outcome, especially among patients whose tumors were large/or
contained epithelioid cells, however, recent results strengthen the idea of
dissemination taking place before the primary tumor is treated.148 Clinically
evident metastatic disease at the time of initial presentation is uncommon,
indicating that there is early subclinical metastasis in most cases.146 Ciliary
body involvement profoundly increased the risk for metastases within the first
3 years140 and the higher risk of death resulting from melanoma metastasis.157
Patients with ciliary body involvement are candidates for future adjuvant
therapeutic intervention.140
The liver is the most common site of uveal melanoma metastases, which
occurred in 60.5 percent,73 or in 75.0 percent,117 or in 77.4 percent,133 or in
85.5 percent,145 or in 87.5 percent,72 or in 95.7 percent.148 Second to the liver
site of uveal melanoma metastases is lung, wherein metastases occurred in 3.6
percent,145 or in 4.2 percent,72 or in 4.3 percent,148 or in 6.5 percent,133 or in
16.7 percent,117 or in 24.4 percent.73 Some authors found that skin metastases
from uveal melanoma are more frequent than bone metastases in 10.9 percent
versus 8.4 percent,73 but others believe that bone metastases are rarer and
occurred from 0 to 9.7 percent and only in 33.3 percent (8 of 24 patients) it was
the sole manifestation of metastatic disease in the liver.72 However, Rietschel et
al.73 found that 89.0 percent of patients had a single organ involved as the first
metastatic site and almost 40.0 percent of all patients presented with nonliver
sites as first metastasis. 85.5 percent (94 of 110 patients) had liver involvement
when first seen and 54.5 percent (60 of 110 patient) had no clinical or
radiologic evidence of other metastatic disease at that time.145 In 88.1 percent
the liver was the only site of metastases. This specific oculo-hepatic tropism
03B.indd 156 31-08-2012 12:32:19

remains yet unexplained. Moreover, the prevalence of hepatic metastases can
not be explained only on the basis of lymphatic of venous drainage alone,
and undoubtedly, many contributory factors exist.145 Metastatic melanoma
of patients with posterior uveal melanoma to the liver develop approximately
in 40.0 percent,131 or 50.0 percent146 within 10 years131 or within 15 years146
after initial diagnosis. Peters et al.74 found that the time from diagnosis of
the primary uveal melanoma to the diagnosis of liver metastases from uveal
melanoma was highly variable ranging from 3 to 332 months (27.7 years) with
almost half of patients developing metastatic disease after 3 years, and in one
patients distant spread occurred as late as 28 years. Late metastases to the liver
are well recognized complication of this disease and metastases for 29 and 30
years before sole metastases to the liver developed. Lorigan et al.145 described
patients with diffuse hepatic metastases who was free from disease for 36
years. Clinically evident metastatic disease at the time of initial presentation
is uncommon, indicating that there is early subclinical metastasis in most
cases.146 Rare site of uveal melanoma metastasis is contralateral choroid149
and contralateral orbit.150,151 Only 8 cases of metastatic uveal melanoma to the
contralateral orbit having been reported before 1998 and there is a presentation
of a case of metastatic melanoma from choroid to the contralateral orbit that
occurred 40 years after enucleation for primary uveal melanoma.152 Shield et
al.153 described a case of orbital recurrence and hepatic metastases 42 years
after enucleation because of previously unsuspected posterior uveal melanoma.
In 2000 Rosario et al.154 presented uncommon case of cardiac metastasis from
ocular melanoma 9 years after treatment, presenting as a left ventricular
intracavitary pedunculated mass. However, studies based on autopsy series,
indicate, that cardiac metastasis from uveal melanoma is not uncommon.
Of patients who died of disseminated uveal melanoma, 19.0 percent to 24.0
percent had macroscopic cardiac metastasis at autopsy.155 More cases of heart
metastases (5 patients) described by Lindegaard et al.138
We analyzed location sites, number and percentage of patients with
uveal melanoma metastases in the literature to know percentage of the most
common metastasis of uveal melanoma (Table 3.7).
The results of our calculation is similar to the most literature reports, which
show that liver is the most frequently site of uveal melanoma metastases and
our calculated percentage of uveal melanoma metastases in liver is also the
highest, 50.4 percent (290 patients) of all 576 patients with uveal melanoma
described in the literature. If calculate metastases in liver only together with
metastases to liver and other sites percentage of metastases would be much
higher, 55.6 percent. The second most common site is lung, 15.3 percent (88 of
576 patients) and in other sites metastases of uveal melanoma are less common
and occurred from 0.2 percent (1 patient) in colon and 0.2 percent (1 patient)
03B.indd 157 31-08-2012 12:32:19

03B.indd 158
158
Table 3.7: Location sites, number and percentage of uveal melanoma metastases in the literature
Location sites Kath Rietschel Vidal Coleman Lindegaard Lorigan Eskelin148 Total number Percentage
145
of metastases et al.72 et al.73,d et al.117 et al.133 et al.138 et al. of patients
Liver only 8 72 9 14 49 101 37 290 50.4
Liver with other sites 13 – – 10 – – 7 30 5.2
Lung 1a 29 2b 2 18 34 2 88 15.3
Bone 1 10 1 1 10 25 1 49 8.5
Skin – 13 – – 8 19 2* 42 7.3
Lymph node – 2 – – 5 15 1 23 4.0
Brain or CNS – 5 – 1 6 5 – 17 3.0
Adrenal gland – – – – 5 3 – 8 1.4
Heart 1c – – – 5 – – 6 1.0
Kidney – – – – 6 – – 6 1.0
Spleen – – – – – 2 – 2 0.3
Orbit – – – 2 – – – 2 0.3
Epidemiology of Ocular Tumors in Children and Adults
Colon – – – 1 – – – 1 0.2
Pancreas – – – – – – 1 1 0.2
Other sites – – – – – 2 9 11 1.9
– – – – – – – –
576 100.0
a
- pleuropulmonal metastasis; b -1 patient with metastasis to the lung and 1 patient with metastasis to the lung and bone; c - patient with metastasis to the
mediastinum ; d - 13 of 119 patients presented with multiple first sites of metastasis; * - subcutaneous metastasis
31-08-2012 12:32:19
in pancreas, 0.3 percent (2 patients) in orbit to 7.3 percent (42 patients) in skin
and 8.5 percent (49 patients) in bone.
Mortality of patients with uveal melanoma depends on the size and location
of tumor, not only on the cell type. In the tumor extended more than 15 mm in
at least one direction death of patients followed in spite of enucleation. There
were no cases of metastases among patients with relatively small tumors under
5 mm. At the same time, the outcome was worse for tumors of the iris, ciliary
body and at posterior pole. The tumors adjacent to the optic nerve, though
small, i.e. at their early stage of development, had a tendency to metastases. The
most favorable outcomes were observed in pre- and postequatorial tumors.128
Kujala et al.68 compared mortality rates for uveal melanoma and conjunctival
melanoma by adjusting for differences in tumor size and local recurrence. They
found that survival after primary uveal melanoma is shorter than after primary
conjunctival melanoma. However, a primary conjunctival melanoma of a given
size is more deadly than a uveal melanoma of equivalent size because primary
conjunctival melanoma tends to recur after treatment and, possibly, because
additional lymphatic dissemination occurs with conjunctival melanoma.68
Men and women have essentially the same mortality from melanoma of the
choroid and ciliary body.129 The 5-year melanoma-related mortality rate of
patients treated by ruthenium plaque radiotherapy was 6.0 percent for small
and medium tumors and 26.0 percent for large tumors. The 5-year and 10-year
melanoma-related mortality rates for balanced set of tumors with small and
large tumors being present in similar proportion were 14.0 percent and 22.0
percent respectively.130 There was no significant difference in the mortality
rate between patients treated by radical surgical techniques (enucleation,
block-excision) and patients treated by episcleral applicator. The mortality rate
was 25.0 percent,58 or 40.5 percent,133 or 40.7 percent134 in the enucleation
only group and 33.0 percent in the beta-irradiation group.58 In patients with
uveal melanoma treated by irradiation before enucleation melanoma-related
death occurred in 32.3 percent versus 40.7 percent in enucleation only group
with mean follow-up of 9.25 years.134 By way of comparison, from 120 patients
treated by enucleation or exenteration for uveal melanoma, only 18.3 percent
had died.135 In the secondary enucleation group the 5-, 10-, and 15-year all
cause death rates were 24.7 percent, 51.5 percent and 52.0 percent respectively
and those in the ocular preservation group were 7.4 percent, 32.9 percent and
48.1 percent respectively.136 Melanoma-related mortality might have been
greater in patients with postlaminar invasion of melanoma because the tumors
were larger and the frequency of orbital recurrence was greater. Only choroid
and ciliary body melanoma of all uveal melanomas were found to invade the
optic nerve.138 However, despite high accuracy of diagnosis and availability
of various methods of treatment; the mortality due to uveal melanoma has
03B.indd 159 31-08-2012 12:32:19

remained unchanged over a period of 25 years from 1973 to 1997 in the United
States132 and approximately half of all patients with melanoma of choroid or
ciliary body will die of the disease within 15 years of enucleation.137 Death from
uveal melanoma metastatic disease was in 7.4 percent,156 or in 17.0 percent,141
or in 20.6 percent,157 or in 53.0 percent.138 The 10-year cumulative incidence
of metastatic death from uveal melanoma was 39.0 percent.68 The 5- and 10-
year estimates for probability of metastatic death were 16.1 percent and 21.8
percent respectively.141 Nevertheless, 94.5 percent of patients with metastases
uveal melanoma had died by close of the study in spite of the majority of
patients received some form of treatment for metastases.144 The predetection
of ocular melanoma to metastaze to the liver must be remembered even in
patients who have been free from disease for many years.145
Survival of patients with uveal melanoma after 5 years of follow-up was
estimated to be 60.3 percent (the crude survival rate). The 10-year crude
survival rate was 42.5 percent, the relative survival rate, which was estimated
for the deaths due to uveal melanoma was 70.1 percent for the first 5 years,
after 10 years, the rates were 59.4 percent in Swedish survey, covering a 39-year
period from 1960 to 1998.56 In the United States the relative 5-year survival
calculated for 2054 patients diagnosed over a 25-year period between 1973
and 1997 ranged from 77.0 to 84.0 percent but without a statistically significant
variation.159 Five-year disease-specific survival for uveal melanoma according
to the National Cancer Data Base report on cutaneous and noncutaneous
melanoma 1, 2, 3, 4, and 5 years after diagnosis was 97.3 percent, 90.5 percent,
86.6 percent, 80.6 percent, and 75.7 percent respectively.66 Cause-specific
survival at 10 years was calculated to 72.6 ± 1.9 percent for patients with
controlled tumors compared to 47.5 ± 6.5 percent for those with recurrent
tumors. Authors’ results strongly support that improvement of the local
tumor control rate results in a better survival rate160 but the local methods
of treatment of primary uveal melanoma have not led to an improvement
in survival.159 Relative survival from uveal melanoma was 95.0 percent at 1
year and 72.0 percent at 5 years.64 Tumor-related 5-year survival rate of 72.0
percent was also found by Coleman et al.133 between 1964 and 1987 being
the first survival analysis of uveal melanoma in the Republic of Ireland. The
occurrence of metastases and presence of more than one metastatic site were
significantly correlated with shortened survival. The 5-year progression free
survival of patients with uveal melanoma was 79.0 percent for the whole
patients cohort.140 Overall survival rate was 76.3 percent for patients with
conservative management with iodine 125 brachytherapy, or proton beam
therapy and those patients who had enucleation only.142 The 5- and 10-year
all-cause survival rates for patients with uveal melanoma after radiation
therapy were 75.6 percent and 62.3 percent respectively141 and for patients
03B.indd 160 31-08-2012 12:32:19

with (cilio)-choroidal melanoma who had high-dose.106 Ruthenium plaque
brachytherapy the 5-year survival rate was 91.0 percent.139 The estimated 15-
year survival rates for patients with uveal melanoma in the pre-enucleation
radiotherapy group and enucleation only group were 63.7 percent and 51.0
percent respectively. After 48 months of follow-up a significant difference in
survival became evident in favor of the pre-enucleation radiotherapy group.134
However, Shargal and Pe’er161 showed that in survival studies no therapeutic
method was found to be superior and there was no relationship between
method of treatment and survival, nor did any clinical risk factor influence
survival. Moreover, the presence of extrascleral spread or retinal detachment
were not shown to significantly influence metastatic-free survival following
treatment, either stereotactic radiosurgery or enucleation.143 A better 5-year
relative survival for women as the tendency, which was not reach statistical
significance, shown by Bergman et al.56 Male gender was identified to be
one of other main factors impairing local tumor control.160 On the contrary,
there was no statistically significant variation by sex in 1- or 5-year survival of
patients with uveal melanoma.64
Analyzing survival of patients with uveal melanoma with relation to age,
no statistically significant differences was found. So, the 2-, 5- and 10-year
survival of patients less than 50 years of age at diagnosis was 91.41 percent,
81.93 percent and 61.45 percent respectively. The 2-, 5- and 10-year survival
of patients equal to or older than 50 years was 90.86, 73.18 percent and 58.28
percent respectively. No significant difference was found between these two
groups but there was a higher survival in men than in women in patients
equal or older than 50 years of age.60 Older patients with uveal melanoma
had significantly worse survival.64 However, Gragoudas et al.144 found that
significantly longer survival of patients with metastases from uveal melanoma
occurred among young patients. Survival time of approximately 9 months,163
or with a median survival of less than 6 months132 can be expected in patients
with disseminated uveal melanoma.72 Median survival was 2.0 months for
patients receiving no treatment for metastases and the overall 1-year survival
rate was poor, 13.0 percent.144 After diagnosis of liver metastases the median
overall survival was 15 months. It reached 25 months for selected patients
with complete resection of liver metastases.147 Observed median survival of
91 patients who died of uveal melanoma in 1985 to 2000 for Stage IV Ba was
14.9 months, for Stage IV Bb 8.9 months, and for Stage IV Bc 2.0 months and
the median survival period of these patients was 8.4 months.158
Survival of a pregnant women suffering from posterior uveal melanoma
comparing with survival of nonpregnant women with posterior uveal
melanoma was 71.0 percent and was similar in these two groups of patients.163
Benjamin et al.164 in 1948 described interesting results of survival rates
with historical aspects, receiving by Hirschberg, who gives the survival rate
03B.indd 161 31-08-2012 12:32:19

as 25.0 percent in 1882, 35.0 percent in 1985, and 56.0 percent in 1903. To
compare these results of survival rate with recent results in the literature from
1993 to 2007 we summarized them in Table 3.8.
In spite of the name of survival rates in the recent literature shown in
Table 3.8 are differently and although some authors believe that survival of
patients with uveal melanoma has not improved in the last century165 survival
rate of patients with uveal melanoma became approximately in 3.6, 2.6 and
1.6 fold higher than in 1882 (25.0%), 1895 (35.0%) and in 1903 (56.0%)
respectively comparing with Hirschberg’s results of survival rate have been
written by Benjamin et al.164 Seemingly, modern methods of diagnosis,
treatment and management of patients with uveal melanoma have increased
survival rate of these patients. Ocular oncologists can continue to offer globe
sparing treatment modalities as long as uveal melanoma survival and quality
of life studies do not show a more favorable outcome following enucleation.143
Geographic location: There was no significant variation of age-adjusted
incidence rate of primary uveal melanoma by the geographic location of the
registry and over the entire period of observation (1973–1997) in the United
States.67
Risk factors for developing of uveal melanoma: Among various risk factors,
Caucasian race seems to be the most significant with light skin color, blond or
red hair, and blue eyes being specific risk factor.88-90 The relative risk of uveal
melanoma was 1.2 for Asian and Pacific Islander patients, 5.4 for Hispanic
patients, and 19.2 for non-Hispanic white patients as compared with black
Table 3.8: Survival of patients with uveal melanoma in the literature

Authors Number The name of survival rate Survival rate, %
of patients 5-year 10-year
Bergman et al.56 2997 The crude (observed) 60.3 42.5
survival rate
Bergman et al.56 2997 The relative survival rate 70.1 59.4
Burr et al.64 3698 Relative survival 72.0 –
Coleman et al.133 111 Tumor related survival 72.0 –
Egger et al.160 2435 Cause-specific survival – 72.6 ± 1.9
Kroll et al.141 731 All-cause survival rate 75.6 62.3
Chang et al.66 1062 Disease specific survival 75.7 –
Cohen et al.143 196 Cumulative metastasis-free 74.0; 51.0 * –
survival –
Singh, Topman.159 2054 The relative survival 77.0–84.0 –
Schmittel et al.140 271 Progression-free survival 79.0 –
Graell et al.60 303 Survival 81.93 61.45
Heindl et al.139 100 Survival rate 91.0 –
* – cumulative metastasis-free survival of 74.0 percent was in stereotactic radiosurgery group
and 51.0 percent in the enucleation group
03B.indd 162 31-08-2012 12:32:19

patients.85 Non-Hispanic white men had 72 times the risk of uveal melanoma
compared to black men; non-Hispanic white women experienced a 22-fold
risk compared to black women. The reason for lower risk of uveal melanoma
in White Hispanics than in white non-Hispanics is not known but could be
related to the protective effects associated with dark skin pigmentation or may
be because of unknown cultural-environmental exposures or socioeconomic
factors.86
Sunlight has been proposed as a risk factor in melanoma and non-
melanotic skin cancer (i.e basal cell and squamous cell carcinoma, lip cancer
and eye melanoma).94,95 Some studies indicate the role of sunlight with
development of intraocular melanoma96 and ocular melanoma.97 A tendency
to sunburn after 0.5 hours midday summer sun exposure increased risk for
uveal melanoma, as did exposure to UV or black lights and welding burn,
sunburn of the eye, or snow blindness.90 Increased risk for occupational groups
who had intense exposure to ultraviolet light also found by Holly et al.98 For
chronic ultraviolet exposure, meta-analysis found occupational sunlight
exposure to be a borderline non-significant risk factor for development
of uveal melanoma.99 With increasing latitudes from 20 to 22 degrees to
47 to 48 degrees the incidence of uveal melanoma increased 4.91 fold. The
latitudinal patterns of uveal melanoma may reflect protective effect of sunlight
exposure for uveal melanoma, which is similar to the sun radiation protective
effects for various internal malignant tumors that are not exposed to the
sunlight.100 However, a population based case-control study in 1995 to 1997
in nine European countries does overall not support an association between
occupational sunlight exposure and risk of uveal melanoma.101 The findings of
other authors do also not support the hypothesis that exposure to the sunlight
has relation to the development of ocular melanoma.102-104 Singh et al.87 found
that although there is ample evidence in support of the hypothesis in regard
to skin melanoma, the evidence in regard to uveal melanoma is insufficient
and contradictory. Futhermore, only a small percentage of ultraviolet light
incident to the eye actually reaches the choroid, where most ocular melanoma
arise, because there are intraocular filters that effectively filter different parts
of ultraviolet spectrum and allow only of the order of 1.0 percent or less to
actually reach the retina and choroid. Nevertheless, this small fraction of
energy- if phototoxic- could still be of concern.105 The degree of lid opening
limits ocular exposure to rays entering at angles near the horizon,106 but the
lens capsule transmits greater than 90.0 percent of the incident ultraviolet
light and thus does not appear to provide significant protection for the retina
from ultraviolet radiation and in aphakic eyes with intact posterior capsule
ultraviolet light does not be adsorbed by the lens capsula.107 Althought some
03B.indd 163 31-08-2012 12:32:19

authors have stressed the protective role of sunglasses,63 the findings of others
postulated that sunglasses wearing was not found to be protective.60
Occupational risk of uveal melanoma developing linked to uveal melanoma
was analyzed in Germany between 1995 and 1998 and the relevant occupations
were the food industry and the chemical and pharmaceutical industry among
men and machine production among women. This analyses support the
potential role of occupational exposure as a risk factor for uveal melanoma.108
There is also showed increased risk of ocular melanoma among male cooks,
and among female metal workers and material handling operators as well as
in welders.89 An excess risk in welders was restricted to the French part of
nine European countries. Cooks, cleaners, and laundry workers were also at
increased risk of uveal melanoma.101 Holly et al.98 and Shah et al.99 have also
found an evidence implicating welding as a possible risk for uveal melanoma
as well as asbestos exposure.98 Indoor workers appeared to be at elevated risk
for ocular melanoma88 and on the contrary, outdoor work was associated with
a lower risk.109 Guenel et al.89 also showed that in outdoor occupational groups
exposed to sunlight was no increased risk of ocular melanoma. A significantly
increased risk of ocular melanoma in occupational groups was exposition to
artificial ultraviolet radiation.89 Using sunlamps was a risk determinant as was
intense sun. However, birthplace below latitude 40 degrees and associated with
low risk of uveal melanoma developing.109 In Australia from 1990 to 1998
higher incidence of ocular melanoma in rural than in urban areas was found.97
Stang et al.110 found that 3 fold increased risk of uveal melanoma to
radiofrequency radiation as transmitted by radio sets and mobile phones.
Other sources of electromagnetic exposure radiation such as high-voltage
lines, electrical machines, or radar units were not associated with uveal
melanoma. However, Inskip in 2001111 and later, Inskip et al. in 200363
analyzed an association of radiofrequency radiation from cellular telephones
with an increase in the incidence of ocular melanoma and their results provide
no support for hypothesis that use of cellular telephones caused ocular
melanoma. In 2001,112 2002113 and 2006114 in Denmark was to investigate
cancer risk among Danish cellular phone users. During the period 1982
through 1995 subscriber lists from two operating companies identified 420095
cellular telephone users. The results of this investigation do also not support
the hypothesis of an association between use of these telephones and other
cancers.112 However, in 2004 the similar research work was to be planned in
Essen, Germany.119 Such as brain tumors, acoustic neuromas, salivary gland
tumors, eye tumors or leukemias among either short or long-term cellular
telephone users was not associated with increased risk of tumor developing.114
Bullimore115 named “anecdotal” reports, which have suggest that there may
be additional dangers associated with cell phone use. Increasing trend in the
incidence rate of malignant melanoma of the eye is in sharp contrast to the
03B.indd 164 31-08-2012 12:32:19

exponentially increasing number of mobile phone subscribers and there was
no support for an association between mobile phones and ocular melanoma.113
Prognosis of patients with metastatic uveal melanoma was poor, especially
when melanoma disseminated to the liver.72 Women had a better prognostic
outcome than men134 and women below the age of 40 had a better prognosis
than women above that age. Small tumors, spindle shaped cells, no invasion
and low pigment content of tumor were all in favor of a good prognosis.162
Greater age,64,164 but not gender or lever of poverty, is associated with a poorer
prognosis of patients with uveal melanoma.64 The two independent favorable
prognostic factors are fewer than ten metastases at screening and the absence of
ciliary body involvement.147 In addition to prognostic factors, socioeconomic
factors were found to be associated with survival.66 In analyzing prognostic
factors, considerable information may be lost if analyses are based on all-cause
mortality rather than cause-specific mortality.140
In Uzbekistan, the primary malignant intraocular tumors from 1978 to
1998 occurred in adults in 326 patients (6.7% of 4872 patients with malignant
ocular tumors in Uzbekistan). There were 209 males (64.1%) and 117 females
(35.9%) aged from 15 to 90 years and over. Primary intraocular melanomas
were in approximately 90.0 to 95.0 percent of the primary malignant intraocular
tumors. The most patients were treated by enucleation with or without pre-
enucleation radiotherapy and with adjuvant chemotherapy in patients with
metastases from intraocular melanoma.
Crude incidence of malignant intraocular tumors per 100,000 urban and
rural male and female populations for urban (2.6) and rural (2.3) females was
higher than that for urban (2.0) and rural (1.9) males but these incidences
were not statistically significant. There were also no differences between urban
(2.5) and rural (2.0) both sexes patients. Totally, we have no had statistically
significant differences in crude incidence between males and females in urban
and rural area but the standardized intraocular malignant tumor incidence
(World Standard Population) per 100,000 urban and rural male and female
populations for urban females (5.3) was statistically significant higher
than that for urban males (2.9). In rural patients there was no statistically
significant difference between males (3.0) and females (3.9). However, totally,
standardized incidence showed that females (4.7) suffered from malignant
intraocular tumors more frequently than males (3.1) (CI 95%)166 (Table 3.9).
The annual standardized incidence of malignant intraocular tumors for
males per million male populations was 0.03 in 1978 and that increases to 0.06
in 1998 with a peak in 1987 (0.07) and in 1986 (1.0). For females this incidence
per million female populations was 0.05 in 1978 and that increased steadly
without peaks to 1.1 in 1987.167
Overall tumor-related mortality of patients with malignant intraocular
tumors per 100,000 urban and rural male and female populations in urban
03B.indd 165 31-08-2012 12:32:19

Table 3.9: Crude incidence and standardized incidence of the primary malignant
intraocular tumors in urban and rural male and female populations per 100,000
urban and rural male and female populations in Uzbekistan, 1978–1998
Incidences Urban population Rural population Total
Crude 2.0 2.6 2.5 1.9 2.3 2.0 2.1 2.4 2.3
incidence
Standardized 2.9 5.3 3.8 3.0 3.9 3.9 3.1 4.7 3.8
incidence
males was statistically significant higher (0.1) than that in urban females
(0.04). On the contrary, in rural females (0.1) overall tumor-related mortality
was 3.3 fold higher than that in rural males (0.03). However, totally, overall
tumor-related mortality was statistically significant higher in males (0.1) than
in females (0.04) per 100,000 urban and rural male and female populations167
(Table 3.10).
Percentage of patients with malignant intraocular tumors deceased at less
than 1 year from initial diagnosis was 2.1 percent (7 patients), at 1 year 3.4
percent (11 patients), at 2 years 4.6 percent (15 patients), at 3 years 8.3 percent
(27 patients), at 4 years 8.3 percent (27 patients), at 5 to 9 years 9.2 percent (30
patients), and at 10 years 11.3 percent (37 patients). Totally 47.2 percent (154
patients) has died of malignant intraocular tumors to 10 years and the most of
patient deceased at 10 years from initial diagnosis (Fig. 3.10).
Table 3.10: Overall tumor-related mortality of urban and rural patients with mali-
gnant intraocular tumors per 100,000 urban and rural male and female populations
Urban Rural Total
0.1 0.02 0.1 0.03 0.1 0.1 0.1 0.04 0.1
Fig. 3.10: Percentage of deceased patients and survival of patients with malignant
intraocular tumors at less than 1 year, at 1 year, at 2 years, at 3 years, at 4 years, at
5 – 9 years, and at 10 years from initial diagnosis
03B.indd 166 31-08-2012 12:32:19

Survival of patients with malignant intraocular tumors at less than 1
year from initial diagnosis was 97.8 percent (319 patients), at one year 94.5
percent (308 patients), at 2 years 89.9 percent (293 patients), at 3 years
81.6 percent (266 patients), at 4 years 73.3 percent (239 patients), at 5
to 9 years 64.1 percent (209 patients), and at 10 years 52.8 percent (172
patients). Thus, survival of patients with malignant intraocular tumors was
the highest at less than 1 year (97.8%) and at 1 year (94.5%) and then that
has falled from 52.8 percent at 10 years from initial diagnosis, i.e. 1.9 fold.
Both curves of overall tumor-related mortality and survival of patients
with malignant intraocular tumor formed so-called “scissors” when two
curves aspire to each other and it means that the ideal curves should be
approximately parallel if mortality is low and survival is high. As far as
approximately 90 to 95 percent of malignant intraocular tumor in our
series was malignant melanoma we compared our results and results in the
literature concerning malignant uveal melanoma. We found significantly
prevalence of males in 64.1 percent but standardized incidence for males
was lower than that for females especially for urban patients. These results
in our series are similar to the results in other reports.52,56,57,68-71,144
Coleman et al.133 found that 40.5 percent of enucleated patients with uveal
melanoma died at the end of the study from 1964 to 1987. Although in our
series patients with intraocular tumors were treated by different methods
including enucleation and pre-enucleation radiotherapy this percentage
was slight higher, 47.2 percent. On the other hand, survival at 5 to 9 years
in our series (64.1%) was much lower comparing to 5-year survival of 91.0
percent in the series of Heindl et al.139 and 81.93 percent in the report
of Graell et al.60 Survival at 10 years in our series (52.8%) was also lower
(61.45%) than in series of Graell et al.60 Among 117 females treated in
our department was a 56-year-old woman with extraocular extension of a
ciliary body melanoma (Fig. 3.11).
Fig. 3.11: Extrascleral extension of right eye’s ciliary body melanoma of a

56-year-old woman
03B.indd 167 31-08-2012 12:32:19

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Dissertarsiya na soiskanie ichenoy stepeni Doktora meditsinskich nauk, 1992,
Moskwa, Hermann Helmholtz Research Institute of Eye Diseases 1992;62:64-6.
MALIGNANT ORBITAL TUMORS

There are a lot of different tissues in the orbit such as extraocular muscles,
vessels, optic nerve and peripheral nerves of central system, adipose tissue,
exocrine gland tissue, lymphoid tissue, periosteum and bone. Various types
of orbital benign and malignant tumors can develop from these structures but
malignant orbital tumors are less common than benign tumors.1 Although
in the literature there are a number of reports deal with orbital tumors a few
reports are concrete related to only primary malignant orbital tumors in adults.
Some publications investigate cases of space-occupying tumors of the orbit
in adults combined with children including benign primary and metastatic
malignancies.1-7 In other reports malignant orbital tumors analyzed with
malignant tumors of the eye and its adnexa,8 or with malignant lacrimal gland
tumors.9 Thirds failed to show only cases from pathology laboratory examined
all orbital disease including inflammatory lesions, benign and malignant
tumors5,10 even with traumatic orbital problems.11 Moreover, there are reviews
have not indicated anatomically site of the orbital tumors. For example,
“pleomorphic adenocarcinoma, adenoid cystic carcinoma”,12 which perhaps
should be a tumor of lacrimal gland. Sometimes there is no information
about tumors if they are primary, secondary or metastatic origin.13 Absence
of gender1,6 and age distribution11 of patients with orbital tumors should not
allow to research incidence of malignant orbital tumors in adults separate from
children, in males separate from females. It is indeed true that “even though
we could not comprehensively assess the age distribution, there appeared to be
no apparent differences among cases for each of these series”.12 Furthermore,
histological types of malignant tumors differ in different reports.5,12,13 As a
result of these variables, it is difficult to attain the true incidence of primary
malignant orbital tumors in adults, which varies widely and has been reported
to be dependent on differences in number and percentage of malignant
orbital tumors. In the literature, primary malignant orbital tumors in adults
described together with orbital tumors and simulating lesions,1 or with all
orbital cases,11 or with orbital space-occupying lesions,2-5 or with orbital
tumors, including benign tumors, inflammatory, miscellaneous lesions,
mucoceles, primary, secondary, metastatic tumors,1,4,5,11 or with leukemic
conditions,4,12 or with trauma of the orbit,11 Mikulicz’s syndrome,5 Erdheim
Chester syndrome,1 Sjögren’s syndrome,5 Letter Siwe disease,14 Wegener’s
granulomatosis,5 Paget’s disease,11 Kimura disease,1,12 Waldenström’s disease,5
Ewing’s sarcoma,1,6 or finally with systemic inflammation/granuloma and
thyroid related orbitopathy.11 Moreover, primary malignant orbital tumor
03B.indd 177 31-08-2012 12:32:20

cases in adults reported together with children cases.1,4,6,8,10,11,13,14,21,23 We are

agree with that “the interpretation of these results is difficult because reported
cases vary in histological and tumor size, patients’ characteristics, treatment
and follow-up”.23 Therefore we calculated percentage of primary malignant
orbital tumors in adults apart from children and from other orbital diseases
to receive primary malignant orbital tumors’ percentage of primary orbital
tumors in the literature.22 Our calculation showed that primary malignant
orbital tumors (PMOT) of primary orbital tumors (POT) in adults occurred
from 26.3 percent5 to 44.8 percent4 (Table 3.11).
As shown in Table 3.11, totally, primary orbital tumors (2404 patients)
occurred in 48.4 percent of all 5076 patients with orbital diseases, benign and
malignant tumors, which we analyzed in the literature. On the other hand,
primary malignant orbital tumor of all 2404 patients with primary orbital
tumors occurred in 15.4 percent.
The most authors1,5,11,12 found that of all orbital tumor histological
types the most frequently type is malignant lymphoma, which occurred
from 55.7 percent14 to 88.0 percent6 following by malignant lacrimal gland
tumors1,4-6,11,12,14 occurred from 9.0 percent6 to 22.7 percent4 and primary
malignant melanoma1,4,14 occurred from 0.4 percent12 to 6.3 percent.1 We
analyzed percentage of histological types of primary malignant orbital tumors
in adults in the literature to account for an average percentage of the most
common histological type of malignant orbital tumors in adults (Table 3.12).
According to our calculation based on the previous reports in the literature
(Table 3.12) the most frequent orbital malignant tumor is lymphoma, which
was in 67.0 percent (713 of 1064 patients), the second common tumor is
lacrimal gland malignancies, which occurred in 18.8 percent (200 of 1064
patients) and the third common tumor is primary orbital melanoma, which was
in 4.2 percent (45 of 1064 patients). The rest histological types of the primary
malignant orbital tumors such as hemangiopericytoma, peripheral and optic
Table 3.11: Number of patients and percentage of primary malignant orbital

tumors (PMOT) of primary orbital tumors (POT) in adults in the literature
Authors Research Number of Number of Number of Percentage
period all cases POT, 100% PMOT PMOT of POT
Seregard, Sahlin5 1974–1998 300 175 46 26.3
Shields J et al.4 1971–2002 1264 565 159a 28.1
Kennedy11 1949–1984 820 384 118 30.7
Ontsuka et al.6 1981–2002 244 213 67 31.5
Shikishima et al.12 1983–2002 1483 703 230 32.7
Johansen et al.4 1974–1997 965 364 163 44.8
Totally 5076 2404.100% 783 32.6
a
- including 14 patients with adenoid cystic carcinoma aged 9 to 80 years
03B.indd 178 31-08-2012 12:32:20

03B.indd 179
Table 3.12: Histological types of the primary malignant orbital tumors in adults in the literature
Histological type Seregard, Ohtsuka Kennedy11 Shields Johansen Shikishima Margo, Mulla14 Number of Percentage
6
of the tumor Sahlin5 et al. et al.1 et al.4 et al.12 patients
Number* Number* Number* Number* Number* Number* Number*
Malignant lymphoma 33 59 87e 95 112 170 157 713 67.0
a b c
Lacrimal gland tumors 8 6 17 36g 37 48 48h 200 18.8
Primary melanoma – – 1 10 7 1 26 45 4.2
Hemangiopericytoma 1 1 9d 8 3 4 4 30 2.8
Optic nerve and – – – 3 1 – – 4 0.4
peripheral nerve tumors
Sarcoma 1 – 4 1 – – 3 9 0.8
Fibrocytic tumors 1 1 – – 3 – 2 7 0.7
Liposarcoma 2 – – 1 – 1 1 5 0.5
Plasmocytoma – – – 5 – 1 1 7 0.7
Carcinoma – – – – – 5 39 44 4.1
Total 46 67 118f 159 163 230 281 1064 100
* - number of patients; a - including malignant lymphoma; b - lacrimal fossa tumors; c- excluding malignant lymphoma; d - 7 cases of hemangiopericytoma and
2 cases of hemangioepithelioma; e - 56 cases of lymphoma and 31 cases of lymphosarcoma; f - no age and gender of patients; g - including 14 patients with
adenoid cystic carcinoma aged 9 to 80 years; h – including 4 patients with mucoepidermal carcinoma aged 6 to 59 years
179
31-08-2012 12:32:20
nerve tumors, fibrocytic tumors, liposarcoma, plasmocytoma, and carcinoma

occurred from 0.4 to 4.1 percent. However, He et al.10 found malignant lacrimal
gland epithelial tumors being the most common malignancy of the orbit.
Age of patients with primary malignant orbital tumors ranged from 15 to
95 years,14 or from 17.3 to 95.8 years,4 or from 18 to 92 years,1 or from 38 to 91
years.5 The age-specific incidence was less than 1.0 per million until the fifth
decade of life, but then that increased progressively each decade. The maximum
age-specific incidence was 10.0 cases per million for persons older than the age
of 80.14 In the senior adult population orbital tumors are malignant in 63.0
percent.16 The age of the studied group is an important factor affecting relative
incidence of orbital tumors.17 With increasing age, malignant orbital tumors
became more common.15
Gender of patients with primary malignant orbital tumors was found to
have a slight predominance of males in 56.3 percent.4 The ratio of male:female
was 2,7:1,43 or 12:5.12 However, in other reports found a slight predominance
of females suffered from malignant orbital lymphoma in 54.6 percent5 and in
57.4 percent.14
Race: 89.0 percent of malignant orbital tumors recorded in whites and 11.0
percent in nonwhites. This corresponds to race-specific incidences of 2.1 cases
per million in whites and 1.5 cases per million in nonwhites, a difference
that approaches statistical significance.14 87.3 percent of patients with orbital
lesions were Whites, 10.0 percent African American, 1.5 percent Hispanic and
1.2 percent Asian.1
Incidence: The average annual incidence for all orbital malignancies was 2.0
cases per million populations and there was a steady increase in the annual
incidence of orbital malignancies during the 13 years of study;14 this is
approximately one-third the annual incidence of uveal melanoma, that is 6.0
cases per million,18,19 or 0.7 per 100,000.20 From 1981 through 1993 the annual
incidence for all malignant orbital tumors reached a nadir in 1983 with 0.8
case per million.14
Recurrence: Local recurrence in patients having undergone orbital exenteration
for malignant orbital tumors (64 children and adult patients) occurred in 4
adult patients (6.3%). All of them were with clear surgical margins.21,22 Clear
surgical margins confirmed histologically were found in 23.7 percent (9 of 38
patients) with local recurrence of patients treated by orbital exenteration and
local recurrence appeared in 54.6 percent (24 of 44 patients).23,24 Furthermore,
in the group with transected margins in patients with malignant orbital tumors
treated by exenteration local recurrence was significantly more common, than
in the group with free margins, which on histological examination was in
59.0 percent (26 patients).23 Recurrent tumors in the orbit have shown the
tendency to infiltrate the surrounding tissues and the bone, rendering complete
03B.indd 180 31-08-2012 12:32:20

secondary excision more difficult.21 For patients with transected margins the
median time for appearance of recurrence was 12 months23 and 11 months for
patients with free margins.23
Mortality of 64 patients with orbital exenteration during a 13-year period
20.3 percent (13 patients) died as a direct result of the orbital tumor, 14.0
percent (9 patients) died of unrelated medical conditions, and 3.1 percent
(2 patients) succumbed to malignant processes originating elsewhere in the
body. An overall mortality rate was 38.0 percent over 12 years.21 Mortality rate
in patients who had clear resection margins was 18.4 percent (7 of 38 patients
with orbital exenteration).24 However, Rahman et al.21 found that the presence
of clear surgical margins, although reassuring for the surgeon, should not be
regarded as an indication of cure.
Survival: The overall 1-year survival postexenteration was highest at 93.0
percent, followed by 57.0 percent after 5 years, and 37.0 percent at 10 years.
There was no difference in survival rate at 3 years and at 5 years between those
with clear resection margins and those without.21 In the group of patients
without local recurrence or metastasis, the 1-year survival was 90.0 percent
and the 4-year survival was 70.0 percent. In contrast, in the group of patients
with local recurrence or metastasis, 1-year survival was 63.0 percent and
the 4-year survival was 24.0 percent with statistically significant difference
between these two groups of patients.23
Malignant orbital lymphoma is the most common orbital malignant
tumor, which occurred in 6.8 percent of all orbital cases including tumor
and nontumor diseases,11 or in 11.1 percent5 and in 11.4 percent4 of orbital
space-occupying lesions, or in 24.2 percent12 and 27.7 percent6 of primary
orbital tumors, or in 55.1 percent of malignant tumors of the orbit,14 or in 73.1
percent of lymphoid and leukemic lesions.1 This malignancy in the older adult
population was also the most frequent and occurred in 23.5 percent (47 of 200
patients of 60 years and older with orbital space-occupying lesions).16 On the
other hand, of histologically verified ophthalmic lymphoma the most cases
(56.8%) located in the orbit.26 Orbit-only disease occurred in 45.8 percent (22
of 48 patients with orbital non-Hodgkin’s lymphoma).27 Of ophthalmologic
and intraocular malignant lymphoma orbital lymphoma was in 42.0 percent
(61 of 145 patients).28 However, Gunalp et al.7 found percentage of orbital
lymphoma being significantly lower of only 2.5 percent (10 of 429 cases of
orbital exenteration) due mainly to various types of cases in this series, which
included primary, secondary, benign, malignant tumors, and inflammatory
pseudotumors in children and adults.7
Of ocular adnexal lymphomas the orbital lymphoma was in 46.4 percent
(52 of 112 patients),30 or in 54.3 percent (38 of 70 patients),29 or in 60.0
percent (12 of 20 patients),53 or in 83.3 percent (20 of 24 patients),31 or in
03B.indd 181 31-08-2012 12:32:20

89.6 percent (69 of 77 patients).32 The orbit most commonly was involved
by MALT lymphoma (extranodal marginal zone B-cell lymphoma).28,29,35,53
However, Bhatia et al.36 believe that follicular lymphoma is the most common
histological type of lymphoma in the orbit and Yap et al.33 postulated
that almost all orbital lymphomas consisted of B-cell lymphomas. Other
histological types of malignant lymphoma in orbit described in the literature
were less frequent. So, diffuse large B-cell lymphoma was in 15.0 percent,28 or
in 19.1 percent,37 or in 22.2 percent,34 or in 25.5 percent,36 or in 30.0 percent;53
mantle cell lymphoma was in 7.2 percent,37 or in 11.1 percent,34 or in 12.8
percent;36 B-small lymphocytic lymphoma in 3.1 percent;37 follicular center
lymphoma in 5.0 percent53 and there were no cases of other types orbital
lymphoma except MALT lymphoma, diffuse, large B-cell lymphoma and
follicular center lymphoma in small series of 20 patients with ocular adnexal
lymphoma.53 However, in Nigeria the most common orbital lymphoma was
Burkitt’s lymphoma.38
Systemic disease at presentation was in 21.4 percent (15 of 70 patients with
ocular adnexal lymphoproliferative disease) and the lowest incidence (only
9.0%) registered in extranodal malignant zone lymphoma (MZL) group.
Thirty-five point one percent (13 of 37 patients with orbital lymphoma),32
or 39.0 percent of all lymphoma patients (26 of 68 patients)29 had prior,
concurrent or subsequent systemic lymphoma. The MZL group had the lowest
frequency of developing systemic disease but other histological types as mantle
cell lymphoma, B-cell chronic lymphocytic leukemia/small lymphocytic
leukemia, peripheral T-cell lymphoma and natural killer cell lymphoma in 100
percent were presented by systemic lymphoma.29 Deep orbital lymphomas had
the lowest incidence (13.0%) of systemic lymphoma at diagnosis. Extraorbital
disease was detected in 19.0 percent at the time of presentation and patients
with symptoms for a year or more were half as likely to have systemic lymphoma
at diagnosis.39 Percentage of systemic involvement at presentation was higher
in patients with natural killer/T-cell lymphoma involving the orbit or ocular
adnexa. Sixty-two point five percent (5 of 8 patients) had concurrent sinonasal
involvement whereas 37.5 percent (3 patients) had orbital involvement alone.40
The frequency of previous or subsequent systemic nonocular non-Hodgkin’s
lymphoma in patients with bilateral ocular adnexal lymphoma is comparable
to that of patients with unilateral disease.48
Age: Lymphoid tumors of the orbit usually occur in middle-aged to elderly
adults.45 The average age of patients with malignant orbital lymphoma was 61.5
± 12.3 years.41 The mean age was 60 years at diagnosis (range, 37–90 years46
with the youngest patient being 41 and the oldest patient 78,46 or mean age of
patients was 67 years.46 The median age was 68 years (range, 34–91 years),27 or
69 years (range, 32–89 years).36 Patients with ocular and adnexal natural killer/
03B.indd 182 31-08-2012 12:32:20

T-cell lymphoma were younger with the mean age at presentation of 45 years
(range, 26–65 years),40 but the patients with lymphoid orbital tumors were
older with an average age of 63 years.47 McNally et al.48 found no differences in
the age, sex, or ophthalmic findings between patients with unilateral and those
with bilateral ocular adnexal lymphoid neoplasms.48
Gender: The frequency of males or females with malignant orbital lymphoma
is dependent on the number of patients, characteristics of patients’ group and
histological type of lymphoma. So, in small series of 9 patients34 and in lager
series of 47 patients36 with orbital lymphoma a predominance of women in
55.6 percent and 61.7 percent respectively was found. However, in Japanese
series of 14 patients41 and 17 patients43 with primary orbital lymphoma a
predominance of men was in 64.3 percent (9 patients) and in 76.5 percent (13
patients) respectively, or there were 2.7 male patients for each female patient.43
In ophthalmic lymphoma cases an equal number of men and women patients
found,26 but a prevalence women than men was in the histologically high-
grade malignancies group of primary orbital malignant lymphomal.42 On the
contrary, the prevalence of men than women found in the same high-grade
lymphoma subtypes by Sjo et al.26 A predominance of females was found in
63.0 percent (34 females) of 54 patients with malignant and benign lymphoid
lesions of the orbit.46 In patients with orbital and conjunctival lymphoma a
prevalence of male patients reported in 59.2 percent (58 of 98 patients).44
According to histological type of malignant lymphoma of ocular adnexal female
patients suffered from MALT lymphoma more frequently in 61.9 percent (26
females of 42 patients) than male patients37 but in small series of 8 patients
with natural killer/T-cell lymphoma of the ocular adnexal male patients were
more frequently than female patients in 62.5 percent (5 patients).40 However,
in larger series of 326 patients with ocular adnexal lymphoma 154 males
(47.2%) were less common than females.39
Laterality: Usually malignant orbital lymphoma appears unilaterality. For
example, of 9,34 or of 14 cases41 no bilateral lymphoma found, but in 10.0
percent,28 or in 10.6 percent,36 or in 16.6 percent49 malignant lymphoma
was bilateral. In approximately 80.0 percent of bilateral cases the lymphoma
developed simultaneously and in 20.0 percent of cases subsequently.48 46.0
percent of patients with bilateral orbital lymphoma had systemic lymphoma
at diagnosis compared to 14.0 percent where signs were unilateral with
contradiction to the view that unilateral and bilateral diseases are clinically
similar.30 Left orbit was involved more frequently in 64.3 percent (9 of 14
patients with malignant orbital lymphoma).41
Race: Malignant lymphoma is most common in Caucasian patients, but
Ohtsuka et al.6 and Shikishima et al.12 found that the incidence of malignant
lymphoma among Japanese patients was two or three times higher than
03B.indd 183 31-08-2012 12:32:20

that among Caucasian patients. The reason of this difference is not clear. It
may result from racial or environmental differences between Japanese and
Caucasians.
Incidence: Incidence of orbital lymphoma is secondary to any overall change
in incidence of systemic non-Hodgkin’s lymphoma, which the 6-year average
annual incidence increased by 17.0 percent during the last half of study (1981–
1986 and 1988–1993).14 An increase in the incidence of orbital non-Hodgkin’s
lymphoma has also been observed over the last three decades due mainly to
MALT lymphoma.26,34,35 Incidence rates were highly dependent of patients’
age. For all ages a statistically significant annual average incidence increase
of 3.4 percent during the 26-year period was found. Since an indeterminate
number of unreported and isolated cases have occurred, meaningful data
regarding incidence is not avalible.26,35
Recurrence. One-third of patients with ophthalmic lymphoma had a relapse
or progression of disease after initial therapy and relapses were frequently
found at extraocular sites.35 Late relapse occurs in sites other than the treated
orbit, even in patients with early-stage disease. Ten-year relapse-free survival
in patients with orbital lymphoma stage I or stage II was 66.0 percent.27 In
patients with malignant orbital lymphoma treated with radiotherapy only (28
patients) in 17.9 percent (5 patients) local and distant relapses developed.52
Local recurrence occurred in 75.5 percent (74 patients) in non-disseminating
group and in 24.5 percent (24 patients) in disseminating tumors of 98
conjunctival and orbital lymphocytic tumors of indeterminate nature. Both
non-disseminating and disseminating tumors have either very similar or
identical histopathological features and the nature of the nondisseminating
tumors is unknown.44 However, there were no recurrences in small series of
16 patients with primary orbital malignant lymphoma since the completion
of the initial therapy with ranging follow-up period from 16 months to 10
years.42
Metastasis: Ocular adnexal lymphoma spread to lymph nodes, bone marrow,
spleen and subcutis.29 Involvement of paranasal sinuses or temporal fossa was
present at the time of diagnosis in 33.3 percent (11 of 33 patients with orbital
lymphoma)39 and at presentation there were 15.7 percent patients (18 of 115
of patients with orbital and conjunctival lymphoma treated by radiotherapy
alone to the orbit) who had disseminated lymphoma.56 Extraorbital lesions
developed in 25.0 percent in patients with reactive lymphoid hyperplasia, in
50.0 percent in atypical lymphoid hyperplasia, and in 75.0 percent in malignant
lymphoma cases.47 In 5.0 percent (1 of 20 patients with Stage I primary orbital
lymphoma treated by radiation therapy alone) developed disseminated disease
with minimum follow-up of 24 months (median, 4-year).55 A distant relapse
experienced in 4.8 percent (1 patient with aggressive lymphoma treated with
03B.indd 184 31-08-2012 12:32:20

radiotherapy alone of 21 patients with orbital lymphomas treated by using
combination chemotherapy with or without radiotherapy).54 Jakobiec et al.47
postulated that no clinical or radiographic findings helped to distinguish the
cases of disseminated disease from located disease.
Mortality: Extend of lymphoma at the time of presentation correlated with
increased risk ratios of having persistent disease and with lymphoma-related
death.30 The most of patients 87.5 percent (7 patients) with natural killer/T-
cell lymphoma in ocular adnexa (3 of 8 patients, 37.5%) in small series of 8
patients died 5 weeks to 13 months after presentation in spite of treatment
by steroids, surgical intervention, and radiation and only 1 patient was alive
without disease during the 5-year follow-up.40
In patients with orbital lymphomas lymphoma-related death was in 5.9
percent (1 of 17 patients)42 and in 11.1 percent (1 of 9 patients).34 In patients
with ocular adnexal lymphoma that was in 16.7 percent (7 of 42 patients)37 but
in patients with lymphocytic tumors of indeterminate nature of 98 patients
only 1 (1.0%) died after the onset of the original ocular tumor with a 5-year
follow-up.44 In patients with ocular adnexal lymphoma this percentage was
higher, 22.4 percent (32 of 143 patients).39 Coupland et al.50 found that
lymphoma-related death in 25.0 percent of patients with ocular adnexal
lymphoma was significantly associated with age > 60 years, advanced clinical
stage and large tumor growth fraction. However, the 5-year mortality rates
of orbital lymphoid malignancies were significantly different for each type
of tumors: 6.0 percent for reactive lymphoid hyperplasia, 19.0 percent for
atypical lymphoid hyperplasia and 58.0 percent for malignant lymphoma.47
In patients with ocular adnexal lymphoma lymphoma-related death was 19.0
percent by 5 years. The rate of tumor-related death was slightly less where
symptoms have been presented for more than a year and slightly greater in
the elderly. Lymphoma-related death was sequentially greater for patients with
predominantly deep orbital lymphoma.39
Remission: The absence of regrowth after a follow-up period of six months
indicates complete remission.57 A 9-year remission was achieved in 16.7
percent (1 of 6 patients), an 8-year in another (16.7%) and a 7-year remission
in 2 (33.3%) more out of the total of 6 patients with orbital lymphoma and
one is living without relapse for 6 years.25 A complete remission was achieved
in 93.7 percent (15 of 16 patients with primary orbital malignant lymphoma)
after chemotherapy with or without radiotherapy with follow-up from 16
months to 10 years,42 or in 52.2 percent (24 of 46 patients with ocular adnexal
lymphoma) with average follow-up time of 85 months (7.1 years).51 However,
one of 37 patients (2.7%) with complete remission from a stage I low-grade
orbital malignant lymphona died from chemotherapy-induced marrow
aplasia.43
03B.indd 185 31-08-2012 12:32:20

Survival: The overall cause-specific survival for stage I patients with primary
orbital non-Hodgkin’s lymphomas at 10 years was 100.0 percent for each
group and at 20 years was 100.0 percent for radiotherapy group, 67.0 percent
for surgery alone group and 0 percent for chemotherapy group.43 Hasegawa
et al.52 compared survival rates of orbital malignant lymphoma according
to the original classification and the working formulation and the WHO
classification. As a result of their comparison, the 5- and 10-year overall survival
rates of patients with low-grade orbital lymphoma according to the original
and the working formulation were 94.0 percent and 73.0 percent, respectively.
The corresponding rates for those with intermediate-grade lymphoma were
67.0 percent and 67.0 percent. In contrast, the WHO classification showed a
significant difference in the survival rates. So, the 5- and 10-year overall survival
rate of patients with MALT lymphoma of the orbit was 100.0 percent and 88.0
percent respectively; for diffiuse large B-cell patients, the rates were both 0
percent. Authors found that a precise histopathologic diagnosis using the
WHO classification and long-term follow-up for >10 years is recommended.
The 5-year local control, progression-free, and overall survival rates were
100.0 percent, 100.0 percent and 75.0 percent respectively for the patients
with orbital lymphomas.54 At 2 and 5 years, actuarial disease free survival
was 100.0 percent and 90.0 percent respectively.55 Survival of patients with
stage I low-grade lymphoma was similar to that of a normal population of
the same age distribution.56 Patients with stage I or II of orbital lymphoma
treated by radiotherapy alone have better overall and cause specific survival
than patients with stage III or IV disease. Median overall survival and cause
specific survival were 6.5 and 15.5 years, respectively.27 However, Bhatia et
al.36 found that the 5-year overall survival and relapse-free survival rate was
73.6 percent and 65.5 percent respectively and tumor grade and location of the
primary orbital lymphoma did not predict for overall survival or relapse-free
survival in patients treated by radiotherapy alone. Since, lymphomas are the
most frequent malignant orbital tumor, and can be successfully treated in many
cases, it is important for the ophthalmologists to be aware of this condition.34
Overall survival was not significantly poorer for patients with relapse.35
Prognosis: Statistically significant good prognostic features were: complete
remission in response to initial treatment, primary radiotherapy and older
age. Primary orbital lymphoma is an indolent, usually stage I disease showing
low to intermediate-grade histology.43 Some authors found that age, gender,
and anatomical location of the lymphomas, clinical stage of disease, methods
of therapy did not have prognostic significance during a follow-up period
of 6 months to 16.5 years (mean, 3.3 years)30 or during median follow-up
period of 53 months range, 9 to 131 months.31 On the contrary, statistically
significant prognosis factors were early stage, low-grade histology and primary
03B.indd 186 31-08-2012 12:32:20

radiotherapy43 and clinical signs also provide a useful guide to the probability
of systemic disease, disease relapse, and mortality as a result of lymphoma.39
Very important to know, that it is not possible to make a definitive diagnosis
when the lesions are first seen, and a conclusion can be reached only after a
prolonged follow-up.44 The majority of patients with MALT lymphoma were
alive and had a better prognosis comparing with patients suffering from other
types of lymphoma.53
Malignant lacrimal gland tumors of all primary malignant orbital tumors
occurred in 14.4 percent,71 or in 17.0 percent,14 or in 17.4 percent,6 or in
20.6 percent,12 or in 22.7.4 Of benign and malignant tumors of the lacrimal
gland malignant tumors were in 44.8 percent (13 of 29 patients underwent
surgery)62 and in 65.85 percent of 41 patients with primary epithelial lacrimal
gland tumors.66 As shown in Table 3.12, according to our calculation based on
the previous literature reports of 1064 patients with primary malignant orbital
tumors malignant lacrimal gland tumors occurred 18.8 percent (200 patients)
and they are the second common orbital tumors.
Of all epithelial lacrimal gland tumors arising in the palpebral lobe of the
lacrimal gland malignant tumors occurred in 17.0 percent.58 Contraversal
results concerning the most common histological type of the primary malignant
lacrimal gland tumors were published in the literature. Some authors found
adenoid cystic carcinoma being the most frequent type of malignant lacrimal
gland tumor,4,59,65,66,68 although Ohtsuka et al.6 have not found even one case of
adenoid cystic carcinoma of 40 patients with malignant lacrimal gland tumors.
Other authors believe that malignant lymphoma was the most common
tumor in patients with malignant lacrimal gland tumors.1,19 However, thirds
have postulated that adenocarcinoma of lacrimal gland,5,63 then pleomorphic
adenocarcinoma and adenocarcinoma63 were the most frequently malignancy
of lacrimal gland. Primary epithelial tumors of the lacrimal gland classified
pathologically were the most frequently malignancies and accounted for 69.7
percent (272 cases of 390 lacrimal fossa lesions), adenocytic carcinomas and
malignant mixed tumors were less common, occurring in 25.0 percent and 9.0
percent respectively. From the other less common types 3 polymorphous low-
grade adenocarcinomas (1.1%) and 1 carcinosarcoma (0.4%) were identified.60
However, Shields and Shields61 in a review of 142 lacrimal gland biopsies
performed during a 25-year period revealed that 22.0 percent were primary
epithelial neoplasms, of which malignant epithelial tumors were only in 4.0
percent. Riedel et al.62 also found that epithelial tumors of the lacrimal gland
are rare seen, even in an institution with frequent referes of orbital diseases. So,
in 27 years there were only 29 epithelial lacrimal gland tumors, representing
10.0 percent of all orbital lesions (291) surgically removed during this time.
Of the epithelial tumors collected in the Ophthalmic Pathology Laboratory
03B.indd 187 31-08-2012 12:32:20

adenoid cystic carcinomas arising de novo occurred in 29.3 percent (12

of 41 cases), malignant mixed tumors were in 17.1 percent (7 cases), and
adenocarcinomas arising de novo were only in 4.9 percent (2 cases).64 In the
other smaller series with malignant lacrimal gland tumors the most frequently
tumors were adenoid cystic carcinomas accounted for 44.4 percent (12 of 27
patients),66 or 61.5 percent (8 of 13 patients),62 following by malignant mixed
tumors in 33.3 percent (9 patients),66 adenocarcinoma in 15.4 percent (2
patients),62 malignant transformation from pleomorphic adenomas in 15.4
percent (2 patients), other lacrimal gland carcinomas in 22.2 percent66 and
one patient showed an oxyphilic adenocarcinoma (7.7%).62
We analyzed literature reviews to calculate number and percentage of the
most frequently malignant lacrimal gland tumor (Table 3.13).
As shown in Table 3.13 and according to our calculation of number and
percentage of histological types of malignant lacrimal gland tumors in adults
in the literature the most frequently type is malignant lymphoma, which was
found in 44.1 percent (135 of 306 patients). The second and third common
histological types occurred in patients were adenoid cystic carcinoma and
adenocarcinoma occurred in 30.1 percent (92 patients) and in 8.9 percent (26
patients), respectively.
Age: The median age of patients with malignant epithelial tumors of lacrimal
fossa lesions was 53 years and with malignant lymphoma 61 years with the
largest number of malignant lymphoma cases in the 70s and older age groups.59
All patients with malignant lacrimal fossa lesions were older than 20 years
ranging from 21 to 80 years,5 or older than 17 years, ranging from 18.8 to 87
years,4 or from 18 to 89 years.14 Patients with adenoid cystic carcinomas tended
to be younger than those with adenocarcinoma or malignant mixed tumors
and 60.0 percent (9 of 15 patients with basaloid adenoid cystic carcinoma of
the lacrimal gland) were over 40 years of age.65
Gender: Malignant lacrimal gland tumors were declared by some authors more
frequently tumors in males than in females. So, the prevalence of males was
in 57.6 percent,59 or in 59.6 percent,65 or in 62.5 percent.5 Malignant epithelial
lacrimal gland tumors were also significantly more common in males in 76.9
percent.62 On the contrary, others found that females suffered from malignant
lacrimal gland tumors more frequently than males with a slight preponderance
of females in 51.4 percent,4 or in 60.4 percent.14
Incidence: An overall incidence of orbital soft tissue and lacrimal gland tumors
was 2.0 per million population.14 The highest yearly incidence per 100,000
was the ages 60 to 75 years at 2.4x 10-2 people in patients with malignant
epithelial lacrimal gland tumors and the 70s at 4.8x 10-2 people in patients
with malignant lymphoma of lacrimal fossa lesions.59
03B.indd 188 31-08-2012 12:32:21

03B.indd 189
Table 3.13: Histological types of malignant lacrimal gland tumors (MLGT) in adults in the literature
Histological types Seregard Shields Johansen Ohtsuka Wright Margo, LGT Study Number/
of MLGT et al.5,h et al.1 et al.4 et al.6 et al.65 Mulla14 Group59,h percent**
Number* Number* Number* Number* Number* Number* Number*
Malignant lymphoma 3 16 9 34 – 18 55 135/44.1
Adenoid cystic carcinoma 2 14a 15 – 35 7 19 92/30.1
Adenocarcinoma 1 – 3 6 4 1b 11 26/8.9
Pleomorphic adenocarcinoma – 4 6 – – 6c 7 23/7.5
Mucoepidermoid carcinoma 2 1 4 – 1 4d – 12/3.9
Squamous carcinoma – – – – – 8 8/2.6
Malignant melanoma – – – – – 1 1/0.3
f e
Others – – – – 6 3 – 9/2.9
Total MLGT 8 35 37 40 46 48 92g 306/100
* - Number of patients; ** – total number of histological types / percentage; a - patients aged 9–80 years; b - 1 patient with carcinoma not otherwise specified,
1 patient with large cell carcinoma and 4 patients with transitional cell carcinoma; c – adenocarcinoma not otherwise specified; d– patients aged 6–59 years;
e
- 1 patient with malignant mixed tumor and 2 patients with malignant neoplasm not otherwise specified; f – malignant mixed tumors; g – no age described;
h
- lacrimal fossa lesions
189
31-08-2012 12:32:21
Recurrence: The recurrence rate of malignant lacrimal gland tumors was

4.6 percent (12 of 261 patients with benign and malignant tumors of the
lacrimal gland)63 or 45.9 percent (17 of 37 patients,4 or all of patients with
adenoid cystic carcinoma had local recurrences.64 Tumors recurred in the
soft tissues or bones near site of the primary tumors in 50.0 percent (26
of 52 primary malignant lacrimal gland tumors, including 4 children).
Adenocarcinoma or malignant mixed tumor of the lacrimal gland had a
high recurrence rate within 2 to 3 years of treatment. The risk of recurrence
of adenoid cystic carcinoma continues for many years after treatment and
cranio-orbital resection does not reduce the estimated rate of recurrence
of adenoid cystic carcinoma.65 On the other hand, no recurrences in small
series of 3 patients with malignant lacrimal gland tumor and with short
time of follow-up being only 6 months to 7 years (mean 26 months) were
detected.58 Primary lacrimal epithelial tumors show high recurrence
rate. So, recurrence rate of adenoid cystic carcinoma and malignant
mixed tumors was 18.2 percent and 27.8 percent respectively68 and the
highest recurrence rate of 100.0 percent was in patients with adenoid
cystic carcinoma.64 As compared with radiotherapy alone, local resection
with radiotherapy for adenoid cystic carcinoma delayed significantly the
recurrence of the tumor with interval between treatment and recurrence
of tumor of 0.79 years (range, 0.2–1.8 years) in 8 patients and 6.2 years
(range, 3.1–9.3 years) in 2 patients, respectively.65 Malignancy degree of
lacrimal gland epithelial tumors is revealed by its ability to recur, locally
destructive growth leading to the tumor spreading into cranial cavity and
the patient’s death as a result of a damage of vital brain centers as well
as by its hematogenic metastasizing. Moreover, the frequency of tumors
recurrence depends on the degree of anaplasia of the tumor and its stage
of development determined by the clinicoanatomic classification by TNM-
system.69 To determine the true recurrence rate of malignant tumors
arising in the lacrimal gland a long follow-up period is necessary.58
Metastases to regional lymph nodes or distant sites are less frequent
(25.0%) and occurred later in the course of the disease.65 Distant metastases
from lacrimal gland tumors accounted for 65.85 percent including adenoid
cystic carcinoma in 44.4 percent (12 cases), malignant mixed tumors in
33.3 percent (9 cases) and other lacrimal gland carcinomas in 22.2 percent
(6 cases) of 27 patients with malignant lacrimal gland tumors.66 However,
much higher percentage (80.0%) of adenoid cystic carcinoma distant
metastases arising from lacrimal gland in 16 of 20 patients between 1952
and 2002 found by Esmaeli et al.67 To minimize early dissemination via
bone, en bloc, one-stage removal of malignant lacrimal gland tumors with
attached periorbita and underlying bone is recommended.70
03B.indd 190 31-08-2012 12:32:21

Mortality: The mortality rate of patients with malignant epithelial
lacrimal gland tumors was 1.5 percent (4 of 261 patients with benign and
malignant lacrimal gland tumors),63 or 80.0 percent (four of five patients
with malignant epithelioid lacrimal gland tumors ultimately died of wide-
spread disease).5 Mortality rate of patients with adenoid cystic carcinona
of the lacrimal gland was 16.7 percent (1 of 6 patients with adenoid cystic
carcinoma with short follow-up period of 25 months),71 or 60.0 percent,64
or 65.0 percent during the median follow-up time of 34 month (range,
6–264 months).67 There is report in the literature about patient with
adenoid cystic adenoma who died due to disease six years after the first
surgery.71
Survival of patients with adenocarcinoma or malignant mixed tumors
of the lacrimal gland is poor.65 Only 2 of 12 patients with adenoid cystic
carcinoma (16.7%) were alive 13 and 16 years after the initial surgery, both
of whom had radical surgical procedures for recurrence following orbital
exenteration.64 Patients with malignant lacrimal gland tumors who had
undergone biopsy prior to excision had a 5-year survival rate of 29.0 percent
compared to a 5-year survival rate of 70.0 percent in those patients whose
malignant tumor was totally excised during the initial surgical procedure.73
Patients with a basaloid pattern in their tumor had a 5-year survival rate of
21.0 percent and median survival of 3 years, whereas patients whose tumor
contained no trace of a basaloid component had a 5-year survival rate of
71.0 percent and median survival rate of 8 years.72 In patients with adenoid
cystic carcinoma of the lacrimal gland the median disease-free survival
was 18 months.67 In the survival of patients with lacrimal gland tumors
histopathology is the most significant factor. However, the relatively high
proportion of cranio-orbital resections among patients surviving for more
than 10-year suggests that this treatment might lead to improved survival;
this will be evident only with prolonged follow-up after another 10 years.65
Prognosis of adenoid cystic carcinoma arising de novo is dismal64 but
the average lifetime of patients with malignant epithelial tumors of the
lacrimal gland twice prolonged when the treatment of these tumors is
combined.69 Adenoid cystic carcinoma of the lacrimal gland is a malignant
tumor with a reserved prognosis.71
In Uzbekistan, the primary malignant orbital tumors occurred in
157 patients (3.2% of 4872 patients with malignant ocular tumors in
Uzbekistan) in the period of 1978 to 1998. There were 93 males (53.2%)
and 64 females (40.8%) aged from 15 to 90 years and over.
The combination of treatment methods including removal of tumors by
different methods of orbitotomy and lateral orbitotomy using the Krönlein
technique, total, subtotal, and extended orbital exenteration with or without
03B.indd 191 31-08-2012 12:32:21

lid sparing procedures and plastic and reconstructive surgeons, with or

without removal of the periosteum, radiotherapy, chemotherapy have been
used. Only new cases with biopsy and histopathologically confirmation
of the primary malignant orbital tumors, including new cases of primary
malignant lacrimal gland tumors were registered. Histopathologically
confirmation has been done in the Department of Histopathology of
Institute of Oncology and Radiology (IOR) of Uzbekistan’s Academy of
Science.
The most of patients with malignant orbital tumors as well as with benign
orbital tumors have been treated in our Department of Ophthalmology of
IOR.
We analyzed crude and standardized incidence of malignant orbital
tumors in Uzbekistan in 1978 to 1998 (Table 3.14).
Crude incidence of malignant orbital tumors per 100,000 urban and
rural male and female populations was in urban (0.9) and rural (0.7) female
patients higher than in urban (0.5) and rural (0.4) male patients. Difference
between urban (0.8) and rural (0.6) both sexes patients was not statistically
significant although totally females suffered from malignant orbital tumors
more frequently (0.8) than males (0.5). Standardized incidence with using of
Standard World Population74 showed that urban (1.9), rural (1.6) and totally
females (0.8) had malignant orbital tumors more frequently than urban, rural
and totally males suffered from these malignancies.75
Mortality: Although percentage and incidences of the primary malignant
orbital tumors of all primary malignant ocular tumors were the lowest
percentage of deceased patients who died due to their malignant orbital
tumors was the highest, 51.6 percent (81 of 157 patients with the primary
malignant orbital tumors). Percentage of patients deceased less than one
year after initial diagnosis was 4.5 percent (7 patients), at 1 year 8.9 percent
(14 patients), at 2 years 6.4 percent (10 patients), at 3 years 6.4 percent (10
patients), at 4 years 7.0 percent (11 patients), at 5 to 9 years 9.6 percent (15
patients), and at 10 years 8.9 percent (14 patients) of all 157 patients with
Table 3.14: Crude incidence and standardized incidence of the primary malignant
orbital tumors in adults per 100,000 urban, rural male and female population in
1978–1998 in Uzbekistan
Incidences Urban Rural Total
Crude 0.5 0.9 0.8 0.4 0.7 0.6 0.5 0.8 0.7
incidence
Standardized 1.2 1.9 1.7 0.9 1.6 1.2 1.1 1.7 1.5
incidence
03B.indd 192 31-08-2012 12:32:21

malignant orbital tumors. Totally 51.6 percent of patients with the primary
malignant orbital tumors (81 of 157 patients) died due to their disease.
The most patients with the primary malignant orbital tumors died at first
year and at 5 to 9 years after initial diagnosis and percentage of deceased
patients increased from 4.5 percent at less than one year to 8.9 percent at 10
years, i.e. 2.0 fold. The curve of deceased patients with primary malignant
orbital tumors less than one year, at one year, at two years, at three years, at
four years, at five to nine years, and at 10 years shown in (Fig. 3.12).
Survival of patients with primary malignant orbital tumors less than 1
year was 95.5 percent (150 patients), at 1 year 86.6 percent (136 patients),
at 2 years 80.3 percent (126 patients), at 3 years 73.9 percent (116 patients),
at 4 years 66.9 percent (105 patients), at 5 to 9 years 57.3 percent (90
patients), and at 10 years 48.4 percent (76 patients). Totally, 48.4 percent
of patients (76 patients) was alive of 157 patients with primary malignant
orbital tumors and the highest survival was at less than 1 year and at 1 year
from initial diagnosis.
The curves of survival and percentage of deceased patients with the
primary malignant orbital tumors less than one year, at one year, at two
years, at three years, at four years, at five to nine years, and at 10 years
after initial diagnosis shown in Figure 3.12. Both of deceased and survived
patients’ curves formed so-called “scissors”, which means that ideale curves
should be approximately parallel if percentage of deceased patients is lower
and tumor-related survival is higher.
Decreasing survival of patients with orbital malignant tumors had
also demonstrated by the previous studies.21,23 Result indicated tumor-
related survival at 1 year in our studies (86.6%) is between overall one-year
survival of 75.0 percent in the report of Mouriaux et al.23 and 93.0 percent
in the report of Rahman et al.21 After 3 years both of these incidences
in Rahman’s report and in our work has fallen to 67.0 percent and 73.9
percent, respectively and after 5 years to 57.0 percent and to 57.7 percent,
respectively (in our report after 5 to 9 years). At 10 years survival was 37.0
percent in Rahman’s report and 48.4 percent in our series. The reason of
difference in both reports was due to difference of patients’ cohort in our
work and in previous report of Rahman et al.21 where children together
with adults were included and survival of post-exenteration patients was
observed.
Figures 3.13A to C demonstrates patients with the primary malignant
orbital tumors treated in our Department in 1978 to 1998.
03B.indd 193 31-08-2012 12:32:21

Fig. 3.12: Survival and percentage of deceased patients with the primary malignant
orbital tumors less than 1 year, at 1 year, at 2 years, at 3 years, at 4 years, at 5–9 years,
and at 10 years after initial diagnosis in 1978–1998
A B C
Figs 3.13A to C: Patients with the primary malignant orbital tumors: (A) Osteosarcoma
in the right orbit of a 42-year-old man; (B) Angiosarcoma in the right orbit of a 45-year-
old man; (C) Recurrence of fibrosarcoma in the left orbit of a 36-year-old woman
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MALIGNANT OCULAR TUMORS IN ADULTS IN UZBEKISTAN

Before 1978 in Uzbekistan was no information about the number of patients
with malignant ocular tumors therefore all of statistically datas such as
incidences, survival and mortality rates, relation between incidences and age,
gender, race, occupations, climate in various regions of Republic, incidences
of malignant ocular tumors in urban and rural patients were analyzed by us
at the first time in Uzbekistan. Patients’ group characteristics and statistically
methods were described in previous Chapter 2 for children and Chapter 6 for
adults. 79.7 percent (3883 adult patients) have been treated in our Department
of Ophthalmology at the Institute of Oncology and Radiology (IOR) of
03B.indd 198 31-08-2012 12:32:22

Uzbekistan’s Academy of Science, which is the only medical institution in
Uzbekistan where all conditions for early diagnosis and treatment of cancer,
including ocular benign and malignant tumors are met. Climatic and
geographical characteristics of malignant ocular tumors incidence have been
studied by plotting incidence and climatic zone data presented in single scale
on Uzbekistan’s maps. Climatic maps and maps of water and soil pollution
were obtained from the Bugaev AA Central Asian Regional Research
Hydrometeorological Institute in cooperation with Candidate of Geographical
Science Ikhtibor Yuldasheva; the results of the study conducted by that
Institute (36) was used. A total of 72 maps were developed. Air pollution data
were provided by the State Committee of Nature Protection of Uzbekistan.
Computer application for statistical data manipulation was developed by
the Central Asian Regional Computing Center and the Institute of Nuclear
Physics.
Gender: From 1978 to 1998, 4872 adult patients aged from 15 to 90 and over
have been registered. There were 48.8 percent males (2377 patients) and 51.2
percent females (2495 patients). The similar percentage of males (48.8%)
and females (51.2%) found by Thakur et al.1 although in their report adults
together with children were studied.
Anatomical sites: Of 4872 patients with malignant ocular tumors the percentage
of eyelid malignant tumors was highest, 82.9 percent (4039 patients), of which
were 39.5 percent males (1924 patients) and 43.4 percent females (2115
patients), followed by conjunctival tumors in 7.2 percent (351 patients), of
which males were 3.1 percent (151 patients) and females 4.1 percent (199
patients). Then in decreasing order were patients with malignant intraocular
tumors in 6.7 percent (326 patients), of which males were 4.3 percent (209
patients) and females were 2.4 percent (117 patients) and patients with
malignant orbital tumors 3.2 percent (157 patients), of which males were 1.9
percent (93 patients) and females 1.3 percent (63 patients). In Figure 3.14
shown percentage of malignant ocular tumors by anatomical sites in males,
females and both sexes.
Our results relating to eyelid malignant tumors, which are the most
common malignancies of all malignant ocular tumors in our series contradict
results of Marshall,2 who found that the most frequent anatomical site of
ocular cancer is the eye, followed by the orbit, the conjunctiva, and the lacrimal
gland. The main reason of the difference between our results and Marshall’s
result is that we studied epidemiology of malignant ocular tumors in adult
patients separately from children but in Marshall’s report epidemiology of
malignant ocular tumors of children together with adults was investigated.
The other previous report of Scat et al.3 who studied and children and adults
with malignant tumors of the eye and adnexa has also contrasted our results
03B.indd 199 31-08-2012 12:32:22

Fig. 3.14: Percentage of patients with malignant eyelid tumors (1), malignant
conjunctival tumors (2), malignant intraocular tumors (3), and malignant orbital
tumors (4) in males, females and both sexes of all malignant ocular tumors
concerning eyelid malignant tumors being the most common anatomical site
of malignant ocular tumors in adults in our series. They found that the most
common anatomical site is the endo-ocular site, then in decreasing order were
lids, conjunctiva, orbit, and so on, whereas we found primary malignant eyelid
tumors being the most common site of all primary malignant ocular tumors
in our series. According to Poso et al.4 of all malignant tumors of the eye and
adnexa in adults together with children epibulbar and intraocular tumors were
the most frequent malignancies, following by orbital tumors, which contrasts
with our results based on only in children aged 0 to 14 years or only in adults
aged 15 to 90+ years.
Incidence: The age-adjusted incidence of malignant ocular tumors in children
and adults had the first statistically significant peak at the age of 2 years, and
the second statistically significant peak was from 60-64 to 80-84 age subgroups.
From 15 to 30-34 years age subgroups the age-adjusted incidence was minimal
and from 35-39 to 60-64 age subgroups significant increase of these incidences
in both males and females was observed. The second peak was from 60 to 64
age subgroups in females and 65 to 69 age subgroups in males and then that
declined in both sexes to 90+ age subgroups. We found that the first peak
occurred due to retinoblastoma in children and the second peak occurred due
to malignant eyelid tumors in adults. However, Ud-Din et al.6 found that the
second peak was due mainly to both conjunctival squamous cell carcinoma
and malignant eyelid tumos. In Figure 3.15 shown bimodal age-adjusted
incidences in males, females and both sexes with malignant ocular tumors.
Thakur et al.1 Sunderraj,5 Ud-Din et al.6 and Osterlind7 came to the same
conclusion deals with bimodal incidence of malignant ocular tumors but in
their results the second peak of incidence was between 40 or 41 and 60 years,
(5.7) or above 50 years, (1.6) or in the 75 to 84 age subgroup,8 or in the 80 to 84
age subgroup in males and in the 85+ age subgroup in females.9 We analyzed
annual standardized incidence, annual crude incidence and annual overall
03B.indd 200 31-08-2012 12:32:22

Fig. 3.15: Bimodal age-adjusted incidence of malignant ocular tumors of children

aged from <1 to 14 years due to retinoblastoma and adults from 15-19 to 90+ years
age subgroups due to malignant eyelid tumors per 100,000 male and female children
population and per 100,000 male and female adults populations
mortality for both sexes of patients with malignant ocular tumors in 1978 to
1998 to compare incidences of malignant ocular tumors with mortality from
these malignancies and we found that annual standardized incidence of both
sexes statistically significant increased from 0.9 in 1978 to 2.1 in 1998, i.e. 2.3
times with peaks in 1982 (3.1) and in 1986 (3.5) per 100.000 populations.
Annual crude incidence also statistically significant increased from 0.2 in 1978
to 0.8 in 1998, i.e. 4.0 fold with two peaks in 1982 (1.4) and in 1986 (1.8) per
100,000 populations. However, the annual mortality increased without any
statistically significant peaks from 0.1 to 0.6 per 100,000 populations, i.e. 6.0
fold. Interestingly, that mortality rate from malignant neoplasms of the eye in
Japan (averaged from 1950–1972) has also had bimodal form with the first
peak approximately at 2 to 3 years of patients and the increasing of curve was
begun from 30 years of patients to the second peak at 80 to 90 years of patients.
Adjusted mortality rate from malignant neoplasms of the eye in patients over
45-year-old group of 18 countries was the highest in Finland, Norway and
Denmark and it was the lowest in France and Japan.10
03B.indd 201 31-08-2012 12:32:23

Fig. 3.16: Annual standardized incidence (1), annual crude incidence (2) and annual
mortality for both sexes of patients with malignant ocular tumors per 100,000 male
and female populations in 1978–1998.
In Figure 3.16 shown curves of annual standardized incidence, annual

crude incidence and annual mortality for both sexes of patients with malignant
ocular tumors per 100,000 male and female populations in 1978 to 1998.
For urban females (Table 3.15) crude incidence of malignant ocular tumors
(2.0) was statistically significant higher than for urban males (1.2) but this
incidence had no difference between rural males and females and between
both sexes of urban and rural patients. Totally, this incidence was slight higher
for females (1.5) than for males (1.0) per 100.000 urban and rural male and
female populations.
Comparing our results of standardized insidence in males (3.0) and females
(4.9) per 100,000 male and female population with review of Bhurgri et al.13
who studied in 1998 to 2002 epidemiology of ocular malignancies in Karachi
in children and adults we found that age-standardized incidence in males (0.5)
and in females (0.4) per 100,000 populations was significantly lower than that
in our series. It was due mainly to patients’ cohort, which included in series of
Bhurgri et al.13 children together with adults.
Geographical distribution: To know region with the highest incidence
of malignant ocular tumors comparing with mortality in each region of
Table 3.15: Crude incidence and standardized incidence of urban and rural
patients with malignant ocular tumors per 100,000 urban and rural male and
female populations in 1978–1998
Incidences Urban Rural Total
Crude 1.2 2.0 1.9 1.9 1.7 1.8 1.0 1.5 1.6
incidence
Standardized 3.2 5.1 4.3 2.7 2.7 3.4 3.0 4.9 3.8
incidence
03B.indd 202 31-08-2012 12:32:23

Uzbekistan we studied crude incidence and overall tumor-related mortality in
each 13 regions (wiloyats) per 100,000 populations of each wiloyat (Fig. 3.17).
As shown in Figure 3.17, crude incidence of malignant ocular tumors
ranged from 2.7 to 5.9 in various wiloyats and the highest crude incidence in
Uzbekistan was in KKAR (5.9) following by Khorezm (4.8) and Samarkand
(4.7) wiloyats. To compare with wiloyats with the lowest incidence (0.6 in
Kashkadarya wiloyat) in KKAR crude incidence was 2.2 fold higher. On the
contrary, the lowest incidence of malignant ocular tumors was in Surhandarya
(2.7) and Kashkadarya (2.7) wiloyats per 100,000 populations in each wiloyats.
Overall tumor-related mortality ranged from 0.6 to 2.2 in various wiloyats
and the highest mortality was in KKAR, (2.2) following by Khorezm (1.6) and
Samarkand (1.3) wiloyats; the lowest overall tumor-related mortality was in
Surhandarya (0.7) and Kashkadarya (0.6) wiloyats per 100,000 population
of each wiloyats. We found that the highest crude incidence and the highest
overall tumor-related mortality in KKAR as well as in Khorezm wiloyat can
be explained by unique geographically disposition in the estuary of Amu
Darya river and on the shore of the Aral Sea, the site of the world’s worst
environmental disaster for the past 20 years. Khorezm Wiloyat is the only
Uzbekistan region, which is situated along both banks of the river Amu Darya
(Fig. 3.18) and which is also polluted by salt, herbicides and pesticides from
the surrounded fields especially cotton fields.14
Intensive agriculture and abundant irrigation have resulted in land
degradation and salinization and contamination of water with salt and
agricultural chemicals.14 The Amu Darya, especially its estuary, is still
polluted with organo-chloride pesticides and a total of 84 tons of salt, fertilizer,
herbicides and pesticides found their way to the rivers as a return flow from
the cotton fields.14,15 In the 80s-90s, pesticide pollution load per 1 ha exceeds
the USSR’s average limits by 15 times and per capita permissible pollution load
Fig. 3.17: Geographical distribution of ocular malignant crude incidence and overall
tumor-related mortality by Uzbekistan’s regions (wiloyats) per 100,000 populations of
each wiloyat
03B.indd 203 31-08-2012 12:32:23

by 3.5 times16 thought for the past 10 years the contamination of soil with
pesticides tends to decrease in Uzbekistan. Of 28 cities having statistically
significant high crude incidence of malignant ocular tumors compared to
respective wiloyat’s urban incidence, 39.3 percent (11 cities) were situated
in the rivers with the highest level of pesticide pollution (Muynak, Chimbay,
Khodjeyli, Bustan, Beruni, Karmana, Shakrisyabz, Sherabad, Baysun, Shurchi
and Akkurgan) and 14 cities (50.0%) were situated on the DDT polluted soils
(Kagan, Aktash, Nurabad, Chelek, Djuma, Krasnogvardeysk, Yangier, Shirin,
Almalyk, Yangiabad, Chirchik, Chinaz, Kokand, and Leninsk). We found
that water and soil pollution plays specific role of the development malignant
ocular tumors and development malignant tumors of other sites, such as skin,
liver, stomach.
Fig. 3.18: Administrative map of Uzbekistan (Provided by Author)
03B.indd 204 31-08-2012 12:32:23

We analyzed air pollution with dust, sulfur dioxide, carbon dioxide and
nitrogen oxide. The content of these pollutants in the air varied from 1.3 to 4.8
(duat), 1.3 to 15.9 (sulfur dioxide), 0.3 to 5.2 (carbon dioxide) and 0.5 to 2.3
(nitrogen oxide) of maximum tolerance dose units. However, no relationship
between air pollution and malignant ocular tumors incidence was found.
Comparing malignant ocular tumors incidence rate to Uzbekistan’s climate
in various areas, we found that the highest incidence rate was in the southern
Surkhandarya wiloyat, where the highest annual average soil temperature
(over 12°C) and air temperature (over 18°C) and the longest sunshine duration
(more than 3,000 hours per annum) has been registered. Hakulinen et al.17
have postulated that both incidence and mortality rates of eye cancer in adults
were positively correlated to the latitude of the country or area.
We found that pollution of water and soil and warm climate with long-
term sunshine duration are very important factors but not the only reason of
increasing of the incidence and mortality of malignant ocular tumors in the
Republic.
Race: In the literature, published series have demonstrated that some types of
malignant ocular tumors, especially malignant melanoma, are more common
for Whites than for non-Whites or Blacks.17-27 Furthermore, malignant
skin cancer was also found to be more common in individuals of European
nationality groups or in Whites.13,19,28 We have also studied crude incidence
of malignant ocular tumors in various ethnic groups in Uzbekistan where
approximately 125 ethnic groups resided in 1978 to 1987. The highest crude
incidence of malignant ocular tumors in adults per 100,000 populations
of each ethnic group was in Jews, Germans, and Russians, followed by
Ukrainians, Tartars, Armenians, Turkmens, Aseris, Koreans, Uzbeks,
Karakalpaks, Kazakhs, Tajiks and Kyrgyz. If dividing patients into “local”
(Uzbeks, Karakalpaks, Tajiks, Kyrgyz and Turkmens) and “non-local” (Russian,
Ukrainians, Germans, Jews, Koreans, Aseris, and Armenians) ethnic groups,
it is evident that the malignant ocular tumors incidence of “non-local” ethnic
subgroups has increased 3.5 times compared to “local” ethnic subgroups.
From 1988 to 1998 the number of population of “non-local” subgroups has
decreased and incidence of malignant ocular tumors of “non-local” subgroup
also decreased but continued to be 1.8 times higher than the one in “local”
subgroup. Individuals of “local” subgroup are more frequently dark-skinned
persons than individuals of “non-local” subgroup therefore our results are
similar to the previous results in the literature. Moreover, we believe that fair
skin and blue eyes are one of most important factor of the ocular malignancies
development although several generations of fair-skinned individuals resided
for a long time and became “local” persons.
03B.indd 205 31-08-2012 12:32:23

Occupational risk: To find out which occupation or group of occupations

have the majority malignant ocular tumors we have studied the patients’
occupational activities. As a result of these investigations manual workers were
found having 1.9 times more frequently malignant ocular tumors than non-
manual workers. Interestingly that medical doctors and nurses had malignant
ocular tumors only in 2.0 percent of all patients with malignant ocular tumors
(Fig. 3.19).
However, our results that manual workers suffered from malignant ocular
tumors approximately 2 times more frequenly than non-manual workers
contrast a previous series11 that proportional registration ratios were generally
higher for non-manual than for manual social classes and notably high for
electrical and electronical workers. Nevetheless, our results are similar to the
others that malignant ocular tumors were more common for manual workers.29
It probably can be explained by the fact that individuals with manual works are
the most frequently between all other occupations and they accounted for 77.0
percent in Uzbekistan.30
Mortality: Annual mortality between 1978 and 1987 exceeded not more than 0.2
and from 1988 to 1998 it increased from 0.1 to 0.6 per 100,000 populations, i.e.
sixfold. Overall mortality for males was 0.5, for females 0.7, and for both sexes
0.6 per 100,000 populations in Uzbekistan. In different countries mortality for
males ranged from 0.3 in Thailand to 3.0 in Finland and in females that ranged
from 0.2 in Thailand to 2.6 in Finland per million populations.12 If calculate
overall mortality in Uzbekistan per million then the rate should be 5.0 for
males and 7.0 for females, i.e. 1.7 fold higher for males and 2.7 fold higher for
females than in Finland.17
Percentage of patients with malignant ocular tumors deceased less than 1
year after initial diagnosis was 0.9 percent (43 patients), at 1 year 1.2 percent
(59 patients), at 2 years 1.2 percent (60 patients), at 3 years 1.8 percent (86
patients), at 4 years 2.1 percent (101 patients), at 5 to 9 years 2.4 percent
(119 patients), and at 10 years 2.6 percent (127 patients). Thus, 12.2 percent
of patients (595 of 4872 patients with malignant ocular tumors) deceased
and percentage of deceased patients due to their malignant ocular tumors
increased from 0.9 percent at less than one year to 2.6 percent at 10 years
from initial diagnosis, i.e. approximately 3 fold in Uzbekistan. Our results,
which demonstrated increasing mortality due to malignant ocular tumors
contrast a previous series from Canada8 that age-standardized death rate of
eye cancer declined significantly for both males and females. According to
author’s opinion, the significant reduction in age-standardized death rates for
males and females were mainly attributable to significant reduction for males
aged 24 years or less, 45 to 54 and 65 to 74 and for females aged 24 years or
less and 55 to 64. Decrease of estimated eye cancer deaths was for male from
03B.indd 206 31-08-2012 12:32:23

Fig. 3.19: Percentage of malignant ocular tumors by patients’ occupational activities
125 and for female also from 125 patients in 199431 to 100 for male and 100
for female patients in 2003.32 Decreasing of mortality rate from malignant
neoplasms of the eye between 1950 and 1972 was also registered in Japan10
whereas in Uzbekistan during 20 years mortality of patients with malignant
ocular tumors has been increased.
Survival of patients with malignant ocular tumors less than 1 year after
initial diagnosis was 99.1 percent (4829 patients), at 1 year 97.9 percent (4770
patients), at 2 years 96.7 percent (4624 patients), at 3 years 94.9 percent (4624
patients), at 4 years 92.8 percent (4523 patients), at 5 to 9 years 90.4 percent
(4404 patients), and at 10 years 87.8 percent (4277 patients). Thus, there were
87.8 percent survived patients (4277 of 4872 patients with malignant ocular
tumors) and their survival decreased from 99.1 to 87.8 percent (Fig. 3.20).
As shown in Figure 3.20, percentage of patients with malignant ocular
tumors deceased from their disease increased progressively and faster than
survival.
Analyzing cases of malignant ocular tumors in Uzbekistan we found the
classical features characterizing such a malignancies: early arising, intensive
03B.indd 207 31-08-2012 12:32:23

Fig. 3.20: Survival and percentage of deceased patients with malignant ocular tumors
less than 1 year, at 1 year, at 2 years, at 3 years, at 4 years, at 5–9 years, and at 10 years
after initial diagnosis
A B
Figs 3.21A and B: Eyelids squamous cell carcinoma involving left orbit of a 53-year-
old man 1 year after exenteration without prothesis (A) and with prothesis (B)
development, late diagnosing and treatment. Such crippled operation as orbital

exenteration is not rare surgery in Uzbekistan due mainly to late diagnosis. In
Figures 3.21A and B shown a 53-year-old patient with eyelids squamous cell
carcinoma involving left orbit 1 year after exenteration without prothesis and
with prothesis.
Risk of malignant ocular tumors development: Our studies have demonstrated
that incidence of malignant ocular tumors as well as mortality of these
malignancies to the large extend depend on ethnic, environmental, economic
and even political factors except other factors described in the literature such
as sunlight expose, outdoor occupation, advanced age and so on.34
Ethnic factors include hygiene, marriage between family members, literacy
level and cultural level of an ethnic group. According to our results 65.5
percent of patients with malignant ocular tumors are manual workers and of
this percentage more than half patients are agricultural workers. In Uzbekistan
03B.indd 208 31-08-2012 12:32:24

up to now marriage between family members is not rare and in urban and
especially in rural population lids to increasing incidence and mortality of
hereditary diseases, including hereditary cases of retinoblastoma. Literacy
level and cultural level are the basis of early or late diagnosis and as result of
low or high mortality and incidence of malignant tumors.
The environmental situation in Uzbekistan continues to be alarming. So,
according to Uzbekistan’s Academy of Sciences, only 8.0 percent of Uzbekistan’s
river are “clean”, around 15.0 percent of river water is of “satisfactory” quality,
and 51.0” is “bad”. In 1996, over 10 million people (about 50.0% of the
population in 1996) resided in the river basins that fell into the latter category.
Around 36.0 percent of river water is considered “dangerous” or “extremely
dangerous”, particularly in the KKAR and in the Uzbek population lives. In
many cases, rural dwellers are forced to drink irrigation water, being the only
water available, with all health risk involved.33,36 Chemical water pollution
coupled with a long-term ultraviolet light exposure is likely to play significant
role in the development of skin cancer in Uzbekistan, in particular such
“visuale” malignancies as eyelid and conjunctival malignant tumors.
Economical factors influence literacy, culture, level of staffing with
qualified experts and hospital facilities and, most importancy, early diagnosis
of ocular malignant tumors. We are agree with Augsburger35 that “in countries
with a well-developed health care system and reasonable good patients access
to that system, patients with a particular disease or condition are likely to be
diagnosed on average at a less advanced stage of their disease. In contrast, in
countries that have a poorly developed health care system and limited patients
access to that system, patients tend to seek health care service later on average
following recognition of symptoms and likely to have more advanced disease
in average at the time of diagnosis”.
Political situation as a result of the collapse of the formed Soviet Union
has brought in a dramatic impoverishment. For people living in the rural
area, this means lack of opportunity to find money to buy necessary and often
very expensive medicines, e.g. chemotherapeutic drugs, and to visit a central
hospital, while there are no conditions for diagnosing and treating patients
not only with malignant ocular tumors but with all other malignant tumors,
especially in rural hospitals. Taken in total, these factors have led to the
increase of malignant ocular tumors incidence in Uzbekistan. This view is also
supported by the fact that the malignant ocular tumors mortality has grown
sixfold in Uzbekistan.
To treat patients with benign and malignant tumors in Uzbekistan
successfully, substantial planning efforts and massive funding of local, rayon,
oblast and national medical institutions are needed. In addition, one single
03B.indd 209 31-08-2012 12:32:24

computerized registration system of patients with malignant tumors needs to

be set-up to establish an eye cancer registry in Uzbekistan.
Administrative and territorial formations are given as of 1987, although
they have been changed partially or in whole in current Uzbekistan. For
instance, in 1988 some regions were enlarged that led to the abolishment
of Navoi and Djizak Oblasts, which were subsequently re-established. After
1991, Uzbek Soviet Socialist Republic, which was one of 15 Republic of Soviet
Union turned into the independent Republic of Uzbekistan, many medical
institutions including Institute of Oncology and Radiology have also changed
their names along with the names of Uzbek cities and towns and their streets.
In the past two decades, major political and economic changes occurred in
Uzbekistan. Yet there remain problems related to modernization of eye clinics
and hospitals, regular supply of medicines, organizational efforts for early
diagnosis, timely and effective treatment of cancer patients and especially
children and adult patients with malignant ocular tumors.
ACKNOWLEDGMENTS
I am highly indebted to Professor Nariman Muratkhodjaev, MD, Academician
of the Uzbekistan’s Academy of Sciences; Professor Alevtina Brovkina, MD,
Academician of the Russian Academy of Medical Sciences; Professor Elena
Kremkova, Ophthalmological Chair of Russian State Medical University;
Professor Raimund Hennekes, Vrij Universiteit Brussel; Valery Votrin,
PhD, Environmental Resourses Management (ERM); Ikhtibor Yuldasheva,
Candidate of Geographical Science, Scientific Secretary of the Central Asian
Regional Research Hydrometeorogocal Institute; Dr Galina Kozlovskaya, Dr
Marfua Nigmanova, Dr Damira Khakimova, Candidate of Medical Sciences;
Dr Naphisa Ubaidullaeva, Candidate of Medical Sciences, Department of
Ophthalmology, Research Institute of Oncology and Radiology of Uzbekistan’s
Academy of Science; Natalya Griva, Mentral Regional Computing Center;
Mikhail Chuprinin, the Institute of Nuclear Phisics; Boris Konyukhov,
Candidate of Geographical Sciences, the State Committee of Natural
Protection; Alexei Tolmachev and Vladimir Rukavitsin for computer support,
to all of my colleagues in the Department of Ophthalmology and in IOR,
to my husband Guenrikh Votrin, to my brother Alexander, to our daughter
Elena, our son Valery, our grand-daughter Ester, our grandson Matvei and to
all of our friends whose contribution made this book possible.
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03B.indd 212 31-08-2012 12:32:24

Index
Page numbers followed by f refer to figure and t refer to table
A Causes of death 51
Abramson staging system for retinoblastoma Cavernous
hemangioma 27f
4
orbital hemangioma 89
Additional malignant tumors 124
Cephalocele 14
Adenocarcinoma 189
Cervical lymph node extension 5
Adenoid cystic carcinoma 14, 189
Chandler’s syndrome 82
Adenoma of iris pigment epithelium 21, 84
Chorioretinal atrophy 13
Administrative map of Uzbekistan 204f
Choroidal
American Joint Committee on Cancer 10 capillaries 8
Angioma 86 hemangioma 24, 86
Angiosarcoma 194f osteoma 23, 85
Apocrine gland cyst 14 Ciliary body
Arteriovenous hemangioma 79f adenoma 84
melanoma 144, 167f
B neurilemomas 85
Basal cell Clark’s classification 10
carcinoma 103, 118f Classifications of ocular tumors 1
nevus syndrome 34 Cogan-Reese syndrome 82
Basosquamous cell carcinoma 104 Collaborative ocular melanoma study 149
Benign Colobomatous cyst 14
conjunctival tumors 79, 82f Congenital cystic eye 14
epithelioma of iris pigment epithelium Conjunctival
84 cancer 123
eyelid tumors 20, 77 carcinoma in situ 123
intraocular tumors 21, 81 dermoid cyst 14
orbital tumors 26, 88 epithelial cyst 14
hemangioma 82f
tumors of conjunctiva and cornea 21
intraepithelial neoplasia 123
Biopsy-proven orbital tumor 4
lymphoma 82f
Bruch’s membrane 8
papilloma 82f
tumors in children 35
C Cotton-wool spots 13
Capillary Cumulative retinoblastoma 57t
hemangioma 26 Cutaneous
of optic disk 86 epithelial cyst 14
telangiectasia 25 photosensitivity 35
Carcinoma 179 Cyst of
Caruncular lower canaliculus lacrimalis 79f
hemangioma 82f surface epithelium 14
tumors 81 Cysticercosis 14
Index.indd 213 31-08-2012 12:33:47

D Hemorrhagic lymphangioma 26
Dentigerous cyst 14 Human papillomavirus 124, 126
Dermoid cyst 14 Hypotheses of retinoblastoma development
Developing of uveal melanoma 162 57
Distant disease 6
I
E Incidence of retinoblastoma 42
Echinococcal cyst 14 Inflammatory cysts 14
Ectopic International
brain tissue 14 Classification of
Childhood Cancer 11
intracranial retinoblastoma 48
Disease for Oncology 11
retinoblastoma 48
Histologic Classification of Tumors 1
Epidemiology of
Intracranial
benign eyelid 20, 77
metastasis 4
ocular tumors in
primitive neuroectodermal tumors 48
adults 77
tumors 48
children 19
Intraepithelial epithelioma 123
Epidermal dermoid cyst 14
Intraocular
Epidermoid cyst 14
disease 4
Epithelial cysts of anterior chamber 83 metastasis 4
Extrachoroidal extension 6 tumors 55f
Eyelid Iridocorneal endothelial syndrome 82
squamous cell carcinoma 208f Iris
tumors 101t and ciliary body malignant tumors 143
cysts 22
F melanocytoma 22
Familial nevus 82
cavernous malformation 86 syndrome 82
malformations 25 stromal cysts 83
uveal melanoma 153
Fibrocytic tumors 179 L
Fibrous Lacrimal gland
dysplasia 26 epithelial tumors 27
histiocytomas of conjunctiva 81 tumors 179
Follicular lymphoma 35 Lamina cribrosa 4
Fuchs’ adenoma 84, 85 Large cell carcinoma 189
Leiomyoma 23
G of uveal tract 84
Ghost vessels 13 Leptomeningeal disease 5
Glioma of optic nerve 27, 90 Liposarcoma 179
Grabowski-Abramson pathologic staging Local nodal involvement 4
system of retinoblastoma 4 Lymphangioma 14
of orbit 93
H
Hemangioblastoma 24 M
Hemangiomas of orbit 26 Magnocellular nevus of iris 82
Hemangiopericytoma 179 Malignant
Hematogenous metastasis 4, 5 choroidal melanoma 146, 148
Index.indd 214 31-08-2012 12:33:47

Index 215
conjunctival tumors 123, 200f N
eyelid Neoplasms of nonpigmented ciliary body
and conjunctival tumors 34 epithelium 85
lymphoma 112 Neural cysts 14
melanoma 110 Neuroectodermal cyst with microphthalmia
tumors 100, 104t, 114, 117, 200f 14
intraocular tumors 38, 143, 166f, 166t, Neuro-oculocutaneous syndrome 25, 86
200f Nevus sebaceous 34
in children 54 Noncystic orbital lesions 14
lacrimal gland tumors 187, 189t
lymphoma 179, 189
O
of conjunctiva 135
medulloepithelioma 39 Ocular surface epithelial dysplasia 123
melanoma 39, 103, 189 Optic
of conjunctiva 126 disk 9
of iris 143 nerve 4, 6, 9, 179
ocular tumors 200f, 208f disease 4
glioma 26, 27
development 208
head 6
in adults in Uzbekistan 198
meningiomas 28
in children 55f
Orbital
orbital
cellulitis, inflammatory pseudotumor
lymphoma 181
26
tumors 68, 72, 177, 200f
disease 4
tumors 35
embryonal rhabdomyosarcoma 71
of conjunctiva 138f
optic nerve meningocele 14
Mantle cell lymphoma 12
tumor 4
Masquerade
Osteosarcoma 194f
orbital tumor 28f
Overt orbital disease 5
syndrome 111
Mass
CNS section 4 P
lesion in central nervous system 4 Parasitic cyst 14
Medulloepithelioma 22, 38, 88 Pathologic staging of retinoblastoma 4
Meibomian gland carcinoma 104 Pathology of scattered episcleral cells 4
Melanocytoma of Pediatric ocular adnexal lymphoma 34
ciliary body 83 Percentage of
optic disk 87 conjunctival malignant melanoma 129t
Meningioma 92 leading malignant eyelid tumor 104t
of optic nerve 91 malignant
Metastatic eyelid tumors 101t
conjunctival melanoma 132 ocular tumors 207f
disease 5 primary malignant orbital tumors 178t
Mid-line trilateral retinoblastoma 50
intracranial malignancies 48 Peripheral nerve tumors 179
pineal tumors 48 Pigment epithelium-choroid stage 8
Milliary aneurysm of Leber 24, 25 Pineal
Mucocele 14 neuroblastic tumors 48
Mucoepidermoid carcinoma 189 parenchymal tumors 48
Multiple tumors 3 retinoblastoma 48
Index.indd 215 31-08-2012 12:33:47

Pinealoma 48 Sellar tumors 48

Pineoblastoma 47, 48 Simple epithelial cyst 14
Plasmocytoma 179 Soft-tissue sarcoma 73f
Pleomorphic Solitary tumor 3
adenocarcinoma 189 Sporadic ocular angioma 87
adenoma of lacrimal gland 92, 93f Squamous
Position of tumor’s mass 69 carcinoma 189
Positive cerebrospinal fluid 4 of conjunctiva 124, 125
Premalignant nevus 104 cell
Primary carcinoma 103, 108, 139f
cancers development 155 conjunctival carcinoma 125
malignant neoplasia 123
intraocular tumors 165 Sturge-Weber syndrome 24
orbital tumors 72t, 179t, 191, 192t, Submandibular lymph node 125
194f Suprasellar
melanoma 179 primitive neuroectodermal tumors 53
orbital tumors 178t retinoblastoma 48
Primitive neuroectodermal tumors 48 Systemic disease 182
Progressive iris atrophy 82
T
R Taxonomy of neoplasms 11
Reese-Ellsworth classification 3, 6 Teratomatous cyst 14
Respiratory epithelial cyst 14 Transformation of melanocytoma of optic
Retinal disk 87
astrocytoma 88, 88t Trilateral retinoblastoma 49
benign tumors 24 Tuberous sclerosis 88t
capillary hemangioma 86 Tumor
cavernous hemangioma 25, 86 mass 4
hemorrhages 13 with extraocular extension 9
ischemia 13
microaneurysms 13 U
neovascularization 13 Uveal
tumor 4 extension 4
vasoprolipherative tumors 25 melanoma 151, 155, 159, 160
Retinoblastoma 39-41, 55f
Retinocytoma 41 V
Revised European American Lymphoma
Vitreous hemorrhage 13
Classification 12
von Hippel Lindau
Rhabdomyosarcoma 14, 68, 73f
complications 87
disease 24, 86, 87
S
Scattered episcleral cells 4 W
Sebaceous Wyburn-Mason syndrome 24, 25, 87
adenocarcinoma 104
carcinoma 106
gland carcinoma 103 X
of eyelid 106 Xeroderma pigmentosum 34, 35
Index.indd 216 31-08-2012 12:33:47

Epidemiology of Ocular Tumors 2013

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Epidemiology of

Prelims.indd 1 04-10-2012 10:00:53

Prelims.indd 3 04-10-2012 10:00:54

Jaypee Brothers Medical Publishers (P) Ltd.

© 2013, Jaypee Brothers Medical Publishers

Inquiries for bulk sales may be solicited at: jaypee@jaypeebrothers.com

Epidemiology of Ocular Tumors in Children and Adults

First Edition: 2013

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Every expert ophthalmologist who treats patients with ocular tumors

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Specialists of environmental areas, Journalists who are interested in relationship

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survival of ocular tumors in different geographical areas and countries across

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I am highly indebted to Professor Nariman Muratkhodjaev, Academician

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1. Classification of Ocular Tumors 1

2. Epidemiology of Ocular Tumors in Children 19

3. Epidemiology of Ocular Tumors in Adults 77

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“A broadly accepted tumor classification system is a powerful clinical tool. It

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CRITERIA FOR SUITABILITY FOR TREATMENT

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PATHOLOGIC STAGING OF RETINOBLASTOMA

Abramson Staging System for Retinoblastoma

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Stage I–Tumor Confined to the Retina

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Stage II–Tumor Confined to the Globe/ Extraretinal

Stage III–Extrachoroidal Extension

Stage IV–Distant Disease

Group A–Very Low Risk

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Group C–Moderate Risk

Group D–High Risk

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Stage I: Only retinal pigment epithelium involved, the Bruch’s membrane

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established, must remain unchanged, 3. After assigning T, N and M categories,

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In the literature, there is no classification for lacrimal sac melanoma,

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REAL classification40 Working Formulation38 Updated Kiel classification43

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A prognosis related classification for radiation retinopathy is the Finger

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In Russian: Gistologicheskaya klassifikatsiya opycholei glaza i ego pridatkov,

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42. Cahill M, Barness C, Moriarty P, et al. Ocular adnexal lymphoma—comparison

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Epidemiological study of the ocular tumors is very important in identifying

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The incidence of benign and malignant ocular tumors has a great

EPIDEMIOLOGY OF BENIGN EYELIDS, CONJUNCTIVAL,

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