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Nasopharyngeal carcinoma: Epithelial dysplastic changes-useful clue to

infiltrating malignancy

Article · December 2007

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Nasopharyngeal Carcinoma: Epithelial Dysplastic Changes — Useful Clue
to Infiltrating Malignancy

Mudassar Majeed and Anwar Ul Haque

Department of Pathology, Pakistan Institute of Medical Sciences, Islamabad

Introduction: Nasopharyngeal carcinoma (NPC) refers to a poorly differentiated small blue cell type
squamous cell carcinoma which microscopically closely mimics lymphoma. As the management of the
two lesions is quite different their separation is essential. Ancillary studies such as histochemical
tests, immunostains and flow cytometry are generally employed to differentiate between the two.
As infiltrating carcinomas usually follow dysplastic changes in the overlying mucosa, a significant
dysplastic change in the overlying mucosa or in the adjacent glands would definitely be associated
with carcinoma rather than lymphoma. A careful examination of the mucosa and the glands will thus
obviate ancillary studies which may be laborious, time consuming, unnecessary and costly and thus
may not be afforded by the poor patients and public sector institutions.
Objective: To determine the spectrum of dysplastic changes in the overlying epithelium of the cases
of infiltrating Nasopharyngeal Carcinoma that would be of help to differentiate invasive carcinoma
from lymphoma without resorting to special histochemical and immunostaining thus avoiding
unnecessary expenses, labor and time wasting.
Materials and Methods: It is a descriptive retrospective study spanning January 2004 to June 2007
at Pathology Department, Pakistan Institute of Medical Sciences (PIMS), Islamabad.
Inclusion criterion: All diagnosed cases of Nasopharyngeal carcinoma (Lymphoepithelioma).
Exclusion criterion: All cases of large cell keratinizing and non-keratinizing carcinoma. Cases without
overlying intact mucosa were also excluded.
27/35 cases fulfilled the inclusion criterion. Dysplasia in the overlying mucosa with intact basement
membrane was evaluated. The dysplasia was graded as mild, moderate, severe, and carcinoma in
situ. Whenever the glands were identified in the biopsies their epithelia were also evaluated on the
same lines.
Results: All cases showed significant dysplasia in the overlying mucosa. 74% cases revealed severe
dysplasia to carcinoma in situ. 7 biopsies contained glands and except one all showed dysplastic
changes of variable intensity in the glandular cells.
Conclusion: A diagnosis of infiltrating nasopharyngeal carcinoma as opposed to lymphoma could be
easily made based on dysplastic changes in the overlying mucosa in most if not in all cases and
hence time, energy and money wasting ancillary studies could be avoided in these cases.
Keywords: Nasopharyngeal carcinoma, Lymphoepithelioma, Squamous cell carcinoma,
undifferentiated carcinoma, Basaloid carcinoma, Basaloid squamous cell carcinoma, EBV,
Lymphoepithelial carcinoma

Introduction

Nasopharyngeal carcinoma (NPC) which is also known as lymphoepithelioma, is uncommon tumor of

nasopharynx in Western Hemisphere but it is a leading cause of death in Southeast Asia especially in
Chinese southern provinces of Kwantung, Kwangsi, and Fukien. Native populations in Canada,
Alaska, Greenland, and Africa also have elevated rates compared with those of the rest of the world.
NPC most frequently affects individuals aged 40-60 years. In African Americans, the disease peaks in
10-20 years age group. In some African populations, NPC is responsible for approximately 15% of
childhood malignancies. In fact, in Sudan, it is the most common malignancy of children. The incidence
of nasopharyngeal carcinoma is less than 1 per 100,000 in USA while it is over 28 per 100,000 in
Hong Kong. The NPC is quite distinct form sinonasal undifferentiated tumors.1-3 Because of small cell
size some authors have used the term basaloid squamous cell carcinoma for NPC. 4-6.

NPC is a small cell non-keratinizing squamous cell carcinoma as opposed to large cell keratinizing and
large cell non-keratinizing types. The tumor cells are small because of lack of differentiation and rapid
turn over as seen in several other small cell tumors. As the small cells have scant cytoplasm, they
closely mimic lymphocytes. When the tumor cells infiltrate underlying stroma after breaking basement
membrane they become intermixed with dense population of lymphocytes which is present in the
submucosa as part of Waldeyer ring of small “tonsilar” tissue in the nasopharynx. This close intimacy
and intermixing led to the name of “lymphoepithelioma” for these tumors; which is a misnomer as
lymphocytes are reactive or innocent bystander and certainly not malignant. Intermixing of small blue
cells of squamous origin with lymphocytes create diagnostic difficulties in separating these from
lymphomas. In order to separate the two a battery of ancillary studies are carried out including
several immunostains. Varieties of keratins have been demonstrated in these cells while lymphomas
have their own immune markers. These ancillary tests may be laborious, time consuming and
expensive especially for poor people and in public sector hospitals. As frankly infiltrating carcinoma is
frequently associated with dysplasia and carcinoma in situ in the overlying or adjacent surface
epithelium, we studied overlying epithelium as well as glandular epithelium when present in the
biopsy to determine the presence and extent of intraepithelial neoplasia as a guide and indicator for
invasive malignancy.

Materials and Methods

It was a descriptive retrospective study spanning January 2004 - June 2007 at Pathology
Department, Pakistan Institute of Medical Sciences (PIMS), Islamabad. We examined 27 biopsies of
infiltrating nasopharyngeal carcinoma (NPC). Other forms of squamous cell carcinoma i.e. large cell
keratinizing and large cell non keratinizing types and other malignancies e.g. adenocarcinoma and
lymphoma were excluded. The slides were reviewed by a postgraduate pathology resident and a
senior pathologist. Depending on the severity of the dysplastic changes in the nuclei, N/C ratio and
hypercellularity the alterations in the overlying mucosa and glands were graded from mild dysplasia
to carcinoma in situ. As various dysplastic transformations go hand in hand, the dysplastic grades
were assigned on the basis of multiple parameters. Mild dysplasia was granted when the cells
contained slightly enlarged nuclei and minor changes in nuclear contours and chromatin distribution.
It was noted that the normal pseudostratified ciliated columnar cells were pushed upwards while the
reserve cells underneath first underwent squamous metaplasia and then dysplasia. The overlying
columnar epithelium persisted till severe dysplasia (Figure 1).

Figure 1: The overlying epithelium Mild dysplasia with persistent top ciliated columnar layer. (H & E X
100)

At carcinoma in situ level this layer was lost. The moderate dysplasia was used when cells
underwent moderate dysplastic changes. Certainly the atypical cells were present throughout the
epithelium. The dysplastic nuclei became larger and more distorted in moderate dysplasia (Figure 2).
In severe dysplasia almost entire epit helium was full of dysplastic cells except the top most layer
which was either ciliated columnar or keratinized. The N/C ratio was quite high with corresponding
hypercellularity and abnormal chromatin distribution and irregular nuclear contours. At carcinoma in
situ level all layers were completely studded by highly dysplastic cells. Similar changes were
observed in the otherwise intact glands (Figure 3)

Results

All 27 cases displayed significant dysplasia in the overlying mucosa (Table I). 23 /27 cases showed
more than mild dysplasia. As a matter of fact the Carcinoma in situ was the commonest mucosal
lesion
followed by severe dysplasia, both accounting for 20/27 (74%) cases. The glands were present only
in seven biopsies and they displayed spectrum of dysplasia from none to severe (Table 2).

Discussion

The most frequent site of origin of NPC is the fossa of Rosenmüller which is over 10 mm deep with an
opening of less than 5 mm.This fossa is an out pouching of nasopharyngeal mucosa, anterior and
superior to the entrance of the eustachian tube and between the skull base and the muscular layers
of the nasopharynx.

Table 1: Grades of dysplasia in the

overlying mucosa

No
Dysplasia Mild Moderate Severe CIS
dysplasia

Overlying
epithelium
(n=27) 0 4 3 7 13

Table 2: Grades of dysplasia in the

glands

No
Dysplasia Mild Moderate Severe CIS
dysplasia

Glands
1 1 3 2 0
(n=7) d

Blind biopsy is obtained because of suspected occult primary in patients with lymph node metastsis
or unilateral serous otitis media, nasal obstruction, epistaxis, hearing loss, headache, and
involvement of the cranial nerves.
Nasopharynx is lined by ciliated pseudostratified columnar cells which due to various influences may
undergo squamous metaplasia. Dysplasia in the squamous metaplastic epithelium is a forerunner of
squamous cell carcinoma. The reserve or basal cells are the only cells capable of generating waves of
dysplastic cells and sending them upwards.
In large cell malignancies, as the cells go upwards, they become large and may or may not develop
keratinization giving rise to respectively large cell keratinizing and large cell non keratinizing
squamous cell carcinoma.

Figure 2: High power view showing moderate dysplasia (H &E X 400)

Figure 3: Mild dysplasia in glands : Note the polarity of the cells had been lost and the disoriented
cells have variable sized nuclei.
(H & E X 100)

In small cell squamous cell carcinoma i.e. NPC the cells do not differentiate and hence do not enlarge
as they go upwards or downwards in the form of infiltration. This explains the terms used for these
cells e.g., poorly differentiated, small cell, basaloid or basaloid squamous. Initially the damage is mild
and relatively few dysplastic cells are produced. As the damage persists and gets intensified perhaps
due to more mutations, the population of dysplastic cells increases along with parallel increase in
nuclear and chromatin irregularities. When almost all cells become dysplastic the term carcinoma in
situ is applied. It is obvious that the theory of monoclonal origin of cancer does not hold water here
as a wide area of epithelium is exposed to carcinogen e.g. EBV virus and a wide area displays
dysplastic changes of variable intensity. Additionally all dysplastic cells are usually pushed upwards.
The notion that mild dysplasia affects only lower 1/3rd and the moderate dysplasia 2/3rd of the
epithelium does not make much sense as the cells migrate upwards and regularly shed off. As a
matter of fact often normal ciliated columnar epithelium can be seen for some time above the layers
of metaplastic and/or dysplastic cells except in carcinoma in situ where it is already shed. However in
a few instances the dysplastic cells go downward piercing the basement membrane before even
reaching to the top. 7 In such cases the dysplastic cells will not be occupying the entire thickness of
the mucosa. However significant dysplastic cells in the mucosa will indicate infiltrating component
being nasopharyngeal carcinoma rather than lymphoma. Unlike malignancies of the oral cavity and
oropharynx, NPCs often metastasize to level V lymph nodes. Bilateral metastases are common (with
rates as high as 50%) on presentation. Fiberoptic endoscopic biopsies are usually performed to find
out the primary site. 8
Current epidemiologic and experimental data suggest at least 3 major etiologic factors, namely, viral,
environmental, and genetic. The marked variation between different geographic region and strong
racial differences point out to genetic predisposition and to some extent such environmental factors
as diet e.g. Nitrosamine-rich fish. There is 2-3 times preponderance among men over women and
there is bimodal pattern in terms of a ge in Asian countries as opposed to single peak in Western
countries. The histocompatibility locus human leukocyte antigen (HLA)-A2 may be a marker for
susceptibility to this tumor. Other loci also being considered include HLA-hence do not enlarge as
they go upwards or B17 and HLA-Bw46.
The nasopharyngeal carcinomas have elevated Epstein Barr Virus (EBV) antibody titers and over
expression of BCL2 oncogene protein. EBV is a DNA-containing herpes virus that has been implicated
in at least 5 distinct malignancies: endemic Burkitt lymphoma, NPC, Hodgkin disease, T-cell
lymphoma, and immunoblastic lymphoma. In the case of NPC, malignant epithelial cells harboring EBV
have been demonstrated on in situ hybridization, PCR tests, immunohistochemical analysis, and
ultrastructural studies. 9-13.
The overexpression of gene p53 protein is seen in some cases. 14, 15 The association with Human
Papilloma Virus is not as strong as seen in other types of squamous cell carcinoma.16
The tumor may directly or indirectly damage the nerves with corresponding symptoms. The 5 year
survival after radiation therapy is 36-58%. The additional chemotherapy shows slightly better results
over 3 year survival only. Severe complications occur due to large volume of radiation treatment.17-
20
In conclusion, meticulous examination of overlying surface mucosa and of the glands if present will
reveal significant dysplasia (severe dysplasia to carcinoma in situ) confirming the carcinomatous
nature of the infiltrating carcinoma and differentiating it from lymphoma. This will help to avoid
unnecessary ancillary tests and initiation of prompt treatment of the patient.

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