Pathology (dr.

Yabut)
Endocrine Pathology – Part 3 (from
Book)
09 January 08

ADRENAL INSUFFICIENCY (AI) 2) Waterhouse-Friderichsen Syndrome

 Primary adrenal disease ( primary  Uncommon but catastrophic syndrome

hypoadrenalism)
 Characteristics:
 Decreased stimulation of the adrenals owing to a
deficiency of ACTH (secondary hypoadrenalism) 1.Overwhelming bacterial infection

Patterns of Adrenal Insufficiency • Usually associated with

Neisseria meningitides
1) Primary Acute AdrenocorticalInsufficiency septicemia

 Caused by any lesion of the adrenal

• Occasionally by highly
cortex that impairs corticosteroid
production or may be secondary to virulent organisms:
corticotrophin deficiency Pseudomonas,
pneumococci,
 Occur as a crisis in patients with chronic Haemophilus influenza, or
staph
adrenocortical insufficiency precipitated
by any form of stress - immediate
2.Rapidly progressive hypotension
increase in steroid output from glands
leading to shock
incapable of responding
3.DIC with widespread purpura –
 In patients maintained on exogenous
SKIN
corticosteroids, owing to the inability of
the atrophic adrenals to produce 4.Rapidly developing adrenocortical
glucocortioid hormones insufficiency associated with
massive bilateral adrenal
 Result of massive adrenal hemorrhage,
hemorrhage
which destroys the adrenal cortex
sufficiently to cause acute adrenal  Occurs at any age – BUT more common in
insufficiency children

 Occurs in newborns following  Adrenal hemorrhage is uncertain but

prolonged and difficult delivery could be attributable to:
with considerable trauma and
hypoxia 1.Direct bacterial seedling of small
vessels in the adrenal
 Newborns are vulnerable because
they are often deficient in 2.Development of DIC
prothrombin
3.Endotoxin-induced vasculitis
 Also occurs in:
4.Some form of hypersensitivity
• Patients maintained on vasculitis
anticoagulation therapy
 Whatever the basis, the adrenals are
• Postsurgical patients who converted to sacs of clotted blood
develop DIC with virtually obscuring all underlying detail
consequent hemorrhagic
 Morphology: massive, bilateral adrenal
infarction o the adrenals
hemorrhage, which begins in the medulla
• Waterhouse-Friderichsen
 Histologic exam:
Syndrome

Pwets 1 of 10
Pathology – Endocrine Pathology by Dr. Yabut Page 2 of 10

Hemorrhage starts within the i. Autoimmune

medulla I relationships to thin- polyendocrine
walled venous sinusoids  syndrome type 1 (APS1)
suffuses peripherally in the cortex
 Also known as
 leaving islands of recognizable
autoimmune
cortical cells
polyendocrinopathy,
 Clinical course is usually devastatingly candidiasis, and
abrupt, and prompt recognition and ectodermal
appropriate therapy must be instituted dystrophy (APECED)
immediately, or death follows within
 Characterized by
hours to a few days
chronic
3) Addison Disease/ Primary Chronic mucocutaneous
Adrenocortical Insufficiency candidiasis and
abnormalities of
 Uncommon disorder skin, dental enamel,
and nails
 Progressive destruction of the adrenal (ectodermal
cortex dystrophy)

 Clinical manifestations appears until at  Occurring in

least 90% of the adrenal cortex has been association with a
compromised combination of
organ-specific
 All races and both sexes may be affected autoimmune
disorders resulting
 Certain cause of Addison (such as
in immune
autoimmune adrenalitis) are much
destruction of target
common in whites, particularly in women
organ
 Pathogenesis:
a. Autoimmune
adrenalitis
 90% of all cases are attributable
to one of four disorders:
b. Autoimmune
hypoparathyr
1. Autoimmune adrenalitis
oidism
• 60% to 70% of cases of
c. Idiopathic
Addison disease
hypogonadis
m
• Most common cause of
primary AI in developed d. Pernicious
countries anemia

• Autoimmune destruction  Caused by

of steroidogenic cells mutations in the
autoimmune
• Autoantibodies to several
regulator (AIRE)
key steroidogenic
gene on
enzymes (21-hydroxylase,
chromosome 21q22
17-hydroxylase) are
detected in these patients ii. Autoimmune
polyendocrine
• Occurs in 3 clinical syndrome type 2 (APS2)
settings:
 Starts in early
adulthood
Pathology – Endocrine Pathology by Dr. Yabut Page 3 of 10

 Presents as a  Disseminated infections caused by

combination of AI Histoplasma capsulatum and Coccidioides
with autoimmune immitis may result in Adisson disease
thyroiditis or type 1
diabetes  Patients with AIDS are at risk for
developing AI from several infections
 Characteristics of (CMV, Mycobacterium avium-
APS1 do not occur intercellulare) and non-infectious
complications (Kaposi sarcoma)
 Unlike APS1, it is
not a monogenic  Metastatic neoplasms involving the
disorder, although adrenals are another potential cause of AI
some studies have
suggested a  Adrenals are a fairly common site
possible association for metastases in patients with
with polymorphisms disseminated carcinomas -
in the HLA loci destroy enough adrenal cortex to
produce a degree of AI
iii. Isolated autoimmune
Addison disease  Carcinomas of the lung and
breast are source of a majority of
 Presents with
metastases in the adrenals,
autoimmune
although many other neoplasms,
destruction
including GI carcinomas,
restricted to the
malignant melanoma, and
adrenal glands
hematopoietic neoplasms, may
also metastasize to this organ
 Overlaps with APS2
in terms of age and  Genetic disorders of AI
linkage to HLA and
other susceptibility  Includes adrenal hypoplasia
loci congenital (AHC) and
adrenoleukodystrophy
 Variant of APS2
 Not commonly included in the
 Infections, particularly tuberculosis and causes of Addison disease
those produced by fungi may cause
Addison  Morphology:

 Tuberculous adrenalitis – once accounted  Depends on the underlying

for as much as 90% of Addison; become disease
less common with development of
antituberculous agents  APS1 – characterized by
irregularly shrunken glands which
 With resurgence of tuberculosis is difficult to identify within the
in most urban centers and the suprarenal adipose tissue
persistence of the disease in
developing countries, however, • Histologically: cortex
this cause of AI must be kept in contains only scattered
mind residual cortical cells in a
collapsed network of
 When present, tuberculous connective tissue; a
adrenalitis is associated with variable lymphoid
active infection in other sites – infiltrate is present in the
lungs and genitor-urinary tract cortex and may extend
into the subjacent
medulla
Pathology – Endocrine Pathology by Dr. Yabut
 In cases of tuberculous and
fungal disease – adrenal
architecture is effaced by a
granulomatous inflammatory
reaction identical to that
encountered in other sites of
infection
 Caused by metastatic carcinoma
– adrenals are enlarged, and their
normal architecture is obscured
by the infiltrating neoplasm
Autoimmune adrenalitis – usually
produces small glands, lipid
depletion of adrenal cortex, and a
variable lymphocytic infiltrate in
cortex; medulla is spared
 Clinical course:
 Includes weakness, fatigue,
anorexia, hypotension, nausea,
vomiting and cutaneous
hyperpigmentation
 Laboratory values include
elevated levels of corticotrophin,
hyperkalemia, and hyponatremia,
associated with volume depletion
and hypotension
4) Secondary Adrenocortical Insufficiency
 Caused by any disorder of the
hypothalamus or pituitary causing a
decreased corticotrophin production
 With secondary disease, the
hyperpigmentation of primary Addison
disease is lacking because melanotropic
hormone levels are low
 Characterized by deficient cortisol and
androgen output but normal or near-
normal aldosterone levels
 Sever hyponatremia and hyperkalemia
are NOT features of 2o adrenocortical
insufficiency
 Corticotrophin deficiency may be isolated
or associated with hypopituitarism
 Morphology: variable degrees of atrophy
of the adrenal cortex, with sparing of the
zona glomerulosa and medulla
Page 4 of 10
ADRENAL NEOPLASMS
 Functional and nonfunctional
adrenocortical neoplasms cannot be
distinguished on the basis of morphologic
features
 Morphology:
 Adrenal adenomas – clinically silent
 Typical cortical adenomas are
well-circumscribed, nodular lesion
up to 2.5cm in diameter that
expands the adrenal
 Inc contrast to functional
adenomas, which are associated
with atrophy of the adjacent
cortex, the cortex adjacent to
nonfunctional adenomas is of
normal thickness
 Yellow to yellow-brown on cut
surface – presence of lipid within
tumor cells
 Microscopically: composed of cells
similar to those populating the
normal cortex; nuclei small,
although some degree of
pleiomorphism may be
encountered even in benign
lesions (“endocrine atypia”);
cytoplasm of the neoplastic cells
ranges from eosinophilic to
vacuolated, depending on lipid
content; mitotic activity is
inconspicuous
 Adrenocortical carcinomas – rare
 Occur at any age more likely to be
functional than adenomas
 associated with virilism or other
clinical manifestations of
hyperadrenalism
 two rare inherited causes: Li-
Fraumeni syndrome and
Beckwith-Wiedermann syndrome
 large, invasive lesions, may
exceed 20 cm in diameter, that
efface the native adrenal gland
Pathology – Endocrine Pathology by Dr. Yabut Page 5 of 10

 typically variegated, poorly  Composed of specialized neural crest cells

demarcated lesions containing (chromaffin cells) and their supporting
areas of necrosis, hemorrhage, (sustentacular) cells
and cystic change
 Most important diseases of the adrenal medulla
 invasion of contiguous structures, are neoplasms
including the adrenal vein and
IVC, is common 1. PHEOCHROMOCYTOMA (PCM)

 microscopically: well-  Uncommon neoplasms composed

differentiated cells resembling of chromaffin cells
those seen in cortical-adenomas
or bizarre, monstrous giant cells; Associated with catecholamine
cancers with moderate degrees of production and hypertension
anaplasia, some composed (account for 0.1%-0.3% of all
predominance of spindle cells; cases of hypertension
they may be difficult to
differentiate from metstatic cells  Usually subscribe to a convenient
“rule of 10s”
 commonly invade the adrenal
vein, vena cava, and lymphatics, • 10% of PCM arise in
with metastases to regional and association with one o
periaortic lymph nodes and to several familial
viscera, especially lung syndromes – includes
MEN-2A and MEN2B
OTHER LESIONS OF THE ADRENAL
syndromes, type 1
neurofibromatosis, von-
 Advancements in medical imaging and
Hippel Lindau syndrome
greater utilization of abdominal CT scans
and Sturge-Weber
have led to the incidental discovery of
syndrome
adrenal masses in asymptomatic
individuals
• 10% of PCM are extra-
 Adrenal myelolipomas – unusual benign adrenal – occurs in sites
lesions composed of mature fat and such as the organ of
hetopoietic cells Zuckerkandl and the
carotid body
 Histology: mature adipocytes are
admixed with aggregates of − Usually called
hetopoietic cells belonging to all paragangliomas
three lineages; foci of
myelolipomatous change may be • 10% of nonfamilial
seen in cortical tumors and in adrenal PCM are bilateral
adrenals with cortical hyperplasia – may rise to 70% in
cases that are associated
 Adrenal incidentaloma – half-facetious with familial syndromes
moniker that has crept into the medical
lexicon as advancements in medical • 10% of adrenal PCM are
imaging have led to the incidental biologically malignant,
discovery of adrenal masses in although the associated
asymptomatic individuals hypertension represents a
serious and potentially
 Nonsecreting cortical adenomas lethal complication of
even “benign” tumors

− Frank malignancy
Adrenal Medulla
- more common
Pathology – Endocrine Pathology by Dr. Yabut Page 6 of 10

(20-40%) arising • Aggressive tumor – large

in extra-adrenal tumor; extensive
sites vascular, capsular, or
periadrenal adipose tissue
• 10% of adrenal invasion; inc. mitotic
pheochromocytomas index (>3/10hpf) or
arise in childhood – atypical mitotic figures;
usually familial subtypes confluent (“sheetlike”)
tumor necrosis; high
− M>F cellularity and large tumor
nest cells; cellular
− Non-familial PCM monotony; and spindle-
occurs in adults cell morphology
between 40-60;
F>M • Metastasis most
commonly to lymph
 Morphology: nodes, live, lung, and
bones
• Vary in size (1g -4kg)
 Clinical features:
• Cut surface appears
usually pale gray or • Hypertension – dominant
brown clinical feature

• Associated with − Abrupt,

hemorrhage, necrosis, or precipitous
cystic change elevation in BP,
associated with
• Highly vascular tachycardia,
palpitations,
• Dichromate fixative ( e.g. headache,
Zenker) causes it to turn sweating, tremor,
brown-black because of and a sense of
oxidation of apprehension
catecholamines hence
the term chromaffin − May be assoc with
organ dysfunction
 Microscope:
• Paroxysmal release of
• Composed of polygonal to catecholamines
spindle-shaped
chromaffin cells or chief − Associated with
cells episodic
headache.
• Clustered with the Anxiety, sweating,
sustentacular cells into tremor, visual
small nests or alveoli disturbances,
(zallballen), by a rich abdominal pain,
vascular network and nausea

• Cellular and nuclear • Cardiac complications –

pleiomorphism (common) due to ischemic
myocardial damage
• There is no single 2ndary to catecholamine-
histologic feature that can induced vasoconstriction
reliably predict clinical  catecholamine
behavior in PCMs cardiomyopathy
Pathology – Endocrine Pathology by Dr. Yabut Page 7 of 10

• Dx: based on lab studies –  multiple endocrine organs, either

measuring urinary
catecholamine and their
metabolites, plasma
catecholamine assays,
and radiographic imaging
studies
TUMORS OF EXTRA-ADRENAL PARAGANGLIA
synchronously (at the same time) or
metachronously (at different times)
 multifocal
 preceded by an asymptomatic stage of
endocrine hyperplasia involving the cell
of origin of the tumor

 PCMs that develop in paraganglia other than the

adrenal medulla
 Px with MEN-1 syndrome develop
varying degrees of islet cell
 Arise in any organ that contains paraganglionic hyperplasia  some progress to
tissue pancreatic tumors

 Carotid body tumors – tumor arising in the carotid  More aggressive and recur
body
1. MEN-1
 Chemodectomas – originating in the jugulo-
 Wermer syndrome
tympanic body
 Characterized by 3 P’s
 Common in teens to 20s

i. Parathyroid hyperplasia or
 Multicentric (15-25%)
multiple adenomas (90-95%) of
cases – 40 to 50 y/o
 Malignant (20-40%)

 10% metastasize widely

ii. Pancreatic lesions – endocrine
tumors which may usually secrete
 Morphology: a variety of peptide hormones
(pancreatic peptide (most
 Usually firm common), gastrin and insulin
(associated with clinical
 1cm to 6cm lesion symptoms)

 Densely adherent to adjacent tissues iii. Pituitary adenomas (10-15%) –

usually prolactinoma
 Composed of well-differentiated
neuroendocrine cells arrayed in nests or iv. Additional tumors include
cords duodenal gastrinomas, carcinoid
tumors, and thyroid and
 Prominent fibrovascular stroma adrenocortical adenomas

 Microscope: may contain mitotic figures and may  Etiology – involves germ line mutations in
exhibit substantial pleiomorphism
the MEN-1 gene on c-some 11q11-13 
encoding for menin (610-a.a)
MULTIPLE ENDOCRINE NEOPLASIA (MEN)
SYNDROMES
 Clinical manifestations – defined by the
 Group of genetically inherited disease resulting in peptide hormones
proliferative lesions (hyperplasia, adenomas, and
− Recurrent hypoglycemia in
carcinomas) of multiple organs
insulinomas and recurrent peptic
 Distinct features: ulcers in patients with gastrin-
secreting neoplasms (Zollinger-
 younger age Ellison syndrome)

2. MEN-2
Pathology – Endocrine Pathology by Dr. Yabut
 Subclassified into 3 distinct syndromes:
MEN-2A, MEN-2B, and familial medullary
thyroid cancer
i. MEN-2A, or Sipple syndrome
 Characterized by
pheochromocytoma,
medullary carcinoma, and
parathyroid hyperplasia.
 Medullary carcinomas of
the thyroid occur in
almost 100% of patients.
 They are usually
multifocal and are
virtually always
associated with foci of C-
cell hyperplasia in the
adjacent thyroid.
 The medullary
carcinomas may
elaborate calcitonin and
other active products and
are usually clinically
aggressive.
 40 to 50% of patients with
MEN-2A have
pheochromocytomas,
which are often bilateral
and may arise in extra-
adrenal sites.
 As in the case of
pheochromocytomas in
general, they may be
benign or malignant.
 10 to 20% of patients
have parathyroid
hyperplasia and evidence
of hypercalcemia or renal
stones.
 clinically and genetically
distinct from MEN-1
 Linked to germ-line
mutations in the RET
(rearranged during
transfection)
protooncogene on
chromosome 10q11.2.
Page 8 of 10
 In MEN-2A (as well as in
MEN-2B), germ-line
mutations constitutively
activate the RET receptor,
resulting in gain of
function.
ii. MEN-2B
 significant clinical overlap
with MEN-2A
 Patients develop
medullary thyroid
carcinomas, which are
usually multifocal and
more aggressive than in
MEN-2A, and
pheochromocytomas
 Unlike in MEN-2A, primary
hyperparathyroidism is
not present
 Accompanied by
neuromas or
ganglioneuromas
involving the skin, oral
mucosa, eyes, respiratory
tract, and gastrointestinal
tract, and a marfanoid
habitus, with long axial
skeletal features and
hyperextensible joints.
 A single amino acid
change in RET
(RETMet918Thr), appears to
be responsible for
virtually all cases of MEN-
2B and affects a critical
region of the tyrosine
kinase catalytic domain of
the protein.
iii. Familial medullary thyroid
cancer
 variant of MEN-2A
 There is a strong
predisposition to
medullary thyroid cancer
but not the other clinical
manifestations of MEN-2A
or MEN-2B.
 Pathology – Endocrine Pathology by Dr. Yabut
 Majority of cases of
medullary thyroid cancer
are sporadic, but as many
as 20% may be familial.
 Develop at an older age
than those occurring in
the full-blown MEN-2
syndrome and follow a
more indolent course.
Pineal Gland
 Minute, pinecone-shaped organ
 100 to 180 mg
 lying between the superior colliculi at the base of
the brain
 composed of a loose, neuroglial stroma enclosing
nests of epithelial-appearing pineocytes, cells
with photosensory and neuroendocrine functions
(hence the designation of the pineal gland as the
"third eye")
 Silver impregnation stains reveal that these cells
have long, slender processes reminiscent of
primitive neuronal precursors intermixed with the
processes of astrocytic cells.
Pathology
 All tumors involving the pineal are rare
 Include both germ cell tumors
(resembling those arising in the gonads)
and neoplasms of pineal parenchymal
origin
Page 9 of 10
PINEALOMAS
 Divided into two categories,
pineoblastomas and pineocytomas,
based on their level of differentiation,
which, in turn, correlates with their
neoplastic aggressiveness
 Morphology:
 Pineoblastomas
 Encountered mostly in the first
two decades of life
 appear as soft, friable, gray
masses punctuated with areas of
hemorrhage and necrosis
 Typically invade surrounding
structures, such as the
hypothalamus, midbrain, and
lumen of the third ventricle.
 Histologically:
 they are composed of masses of
pleomorphic cells 2-4 times the
diameter of an erythrocyte
 Large hyperchromatic nuclei
appear to occupy almost the
entire cell, and mitoses are
frequent.
 The cytology is that of primitive
embryonal tumor ("small blue cell
neoplasm") similar to
medulloblastoma or
retinoblastoma.
 Pineoblastomas, like
medulloblastomas, tend to spread
via the cerebrospinal fluid
 As might be expected, the
enlarging mass may compress the
aqueduct of Sylvius, giving rise to
 Internal hydrocephalus and all its
consequences.
 Survival beyond 1 or 2 years is
rare.
PINEACYOMAS
Pathology – Endocrine Pathology by Dr. Yabut Page 10 of 10

 occur mostly in adults and are  The manifestations are the

much slower-growing than
pineoblastomas
 well-circumscribed, gray, or
hemorrhagic masses that
compress but do not infiltrate
surrounding structures
 Histologically:
 may be pure pineocytomas
or exhibit divergent glial,
neuronal, and retinal
differentiation
consequence of their pressure
effects and consist of visual
disturbances, headache, mental
deterioration, and sometimes
dementia-like behavior.
 The lesions being located where
they are, it is understandable that
successful excision is at best
difficult.

 composed largely of
pineocytes having darkly
staining, round-to-oval, fairly
regular nuclei

 Necrosis is unusual, and

mitoses are virtually absent.

 neoplastic cells resemble

normal pineocytes in their
strong immunoreactivity for
neuro-specific enolase and
synaptophysin

 Particularly distinctive are the

pineocytomatous
pseudorosettes rimmed by
rows of pineocytes

 The centers of these rosettes

are filled with eosinophilic
cytoplasmic material
representing tumor cell
processes.

 These cells are set against a

background of thin,
fibrovascular, anastomosing
septa, which confer a lobular
growth pattern to the tumor

 Glial and retinal

differentiation is detectable
by immunoreactivity for glial
fibrillary acidic protein and
retinal S-antigen, respectively.

 The clinical course of patients

with pineocytomas is prolonged,
averaging 7 years.