4.
03
ENDOCRINE SYSTEM
A Super Summary brought to you by Team Quacker Oats 
Note: black text: Rubin’s; blue text: Robbin’s
Table 1. Conditions Involving the Pituitary Gland.
Condition Pathogenesis
Pituitary Adenoma  hormonal, environmental and
genetic factors are involved
 rarely, they occur in the
context of multiple
endocrine neoplasia (MEN)
type 1
 Acquired activating
mutations in the stimulatory
subunit of the Gs Protein
 Expression of kinase v
containing variant of
fibroblast growth
factor/receptor (FGFR4)
 Mutations or overexpression
of a number of cyclin D1,
CREB, ras and pituitary
tumor transforming gene.
Lactotroph Adenoma
1 of 15 [Team Quacker Oats ]
Gross Morphology
 Soft and well-circumscribed
 Small adenomas may be
confined to sella turcica, but
with expansion they
frequently erode the sella
turcica and anterior clinoid
process
 Larger lesions- often
compress optic chiasm and
adjacent structures like
cranial nerves
 Invasive adenomas- not
grossly encapsulated and
infiltrate neighboring tissues
(cavernous sinus, sphenoid
sinus, dura, brain)
Microscopic Morphology
 Uniform, polygonal cells
arrayed in sheets and cords
and sparse supporting
reticulin- soft, gelatinous
consistency
 Distinguish pituitary
adenoma from nonneoplastic
anterior pituitary
parenchyma
 Sparse mitotic activity
 hypothalamic input to the
 Chromophobic with
juxtanuclear localization of
transcription factor PIT-1
 contain spheroid nuclei with
prominent nucleoli
 sparsely granulated
 diffuse or papillary growth
patterns
 Endocrine amyloid and
psammoma bodies
April 15, 2017
Clinical Features
 may compress the optic
chiasm, causing severe
headaches, bitemporal
hemianopsia and loss of
central vision
o Oculomotor palsies
 occur when a
tumor invades the
cavernous sinuses
 may interfere with normal
pituitary and lead to loss of
temperature regulation,
hyperphagia and hormonal
syndromes
 radiographic abnormalities
of the sella turcica, visual
field abnormalities, signs
and symptoms of elevated
intracranial pressure, and
occasionally hypopituitarism
 Women
o functional lactotroph
adenomas lead to
amenorrhea,
galactorrhea and
infertility consistently
elevated blood PRL
levels inhibit the surge
of pituitary LH
necessary for ovulation
 (calcospherites) occur but
are not pathognomonic
 Extensive calcification of
entire tumor mass
(“pituitary stone”)stain for
PRL in a dot-like “Golgi
pattern” by
immunohistochemistry
Somatotroph  most are sporadic, but some
arise as part of MEN1 and  densely granulated-
Carney syndrome composed of acidophilic cells
with granular cytoplasm and
a diffuse growth pattern;
usually grow slowly and
remain within the sella
 sparsely granulated
somatotroph adenomas- have
small chromophobe cells with
characteristic spheroid
cytoplasmic inclusions, called
“fibrous bodies,” (contain
keratin intermediate
filaments, especially keratin
8)
 chromophobic variant- grow
and invade faster; shows
cellular and nuclear
pleomorphism
Mammosomatotroph  Resemble the densely
granulated pure somatotroph
adenomas but are
distinguished by having
immunohistochemical
reactivity for prolactin as well
as GH
2 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]
 Men
o tend to suffer from
o decreased libido and
impotence
 Excess PRL secretion
 Lactotroph hyperplasia
 Gigantism
o arise before epiphyses
close in a child or
adolescent
 Acromegaly
o Arise after long bone
epiphyses have fused
and adult height has
been attained
 cause mass effects and
tumor-induced
adenohypophyseal
hypofunction
 gradually develop coarse
facial features, with
overgrowth of the mandible
(prognathism) and maxilla,
broadening of the lower face,
increased space between
upper incisor teeth and a
thickened nose
 Bone density may increase
(hyperostosis) in both the
spine and the hips
 feet and hands are enlarged,
and the fingers become
thickened and sausage-like
 serious complications

Corticotroph Adenoma  intrasellar microadenomas
 intensely basophilic and
periodic acid–Schiff (PAS)
positive
 Functional corticotroph
adenomas
o chromophobic and more
aggressive than their
basophilic counterparts
o show pleomorphic
features and apoptosis
 basophilic adenomas
o contain many secretory
granules and
perinuclear bundles of
fine, keratin-positive,
intermediate filaments
(type I filaments)
 may be abundant
enough to be
visible by light
microscopy as
Crooke
hyalinization,
which reflects
suppression of
ACTH secretion by
high levels of
circulating cortisol
 Crooke adenomas
Gonadotroph Adenoma  chromophobic and PAS
negative
 grow in a diffuse pattern
3 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]
o cardiovascular,
cerebrovascular and
respiratory deaths
 have neurologic and
musculoskeletal symptoms,
including headaches,
paresthesias, arthralgias and
muscle weakness
 Visceral hypertrophy is
common
 Nelson syndrome
o can develop in
patients after surgical
removal of the adrenal
glands for treatment of
Cushing syndrome
o occurs most often
because of a loss of
the inhibitory effect of
adrenal corticosteroids
on a preexisting
corticotroph
microadenoma
o adrenals are absent in
persons with this
disorder,
hypercortisolism does
not develop, and
patients present with
mass effects due to the
pituitary tumor
o there can be
hyperpigmentation
because of the
stimulatory effect of
other products of the
ACTH precursor
molecule on
melanocytes
 include headache, visual
disturbance and
 hypopituitarism

Thyrotroph Adenoma  predominantly  Patients with long-standing

macroadenomas and can be hypothyroidism may develop
invasive and fibrotic hyperplasia of pituitary
 chromophobic, with thyrotrophs (thyroid
polyhedral or columnar cells deficiency cells)- due to
that form collars around inadequate feedback
blood vessels inhibition by thyroid
 stain for α- and β-TSH and hormones
tend to have high
proliferative indices
 electron microscopy:
secretory granules are often
arranged in a single row just
subjacent to the plasma
membrane.

Table 2. Hypothyroidism.
Type Description Pathology/Etiology Clinical features
Primary Autoimmune Idiopathic  More common in women
Hypothyroidism  Circulating Ab to thyroid Ag are present in 75%
of patients
Goitrous Endemic Goiter (due to dietary iodine deficiency); Pathologic evolution of endemic goiter is like that  Enlarged thyroid gland
Hypothyroidism Goiter induced by Antithyroid agents (Lithium of non-toxic goiter. Endemic goiter rarely causes
Phenybutazone P-aminosalycylic acid, turnips, hyperthyroidism.
rutabaga, cassava); Iodide-Induced Goiter
(excessive iodide consumption)
Congenital Crenitism; endemic, sporadic or familial; common Assoc. with mutations in TRH and its receptor,  Apathetic and sluggish
Hypothyroidism in girls; due to thyroid dysgenesis NIS, thyroglobulin and thyroid oxidase  Large abdomen
 Umbilical hernias
 Body temperature below 35 C
 Pale, cold skin
 T3 and T4 (low)
 TSH (high)

4 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]
Table 3. Hyperthyroidism.
Type Description Pathology/etiology Clinical features
Graves’ Disease Basedow disease; from abnormal thyroid IgG antibodies bind to specific domains of the characterized by diffuse goiter, hyperthyroidism,
stimulator; plasma membrane TSH receptor  agonistic exophthalmos, tachycardia, weight loss and
effect of IgG Ab  stimulation of TSH receptor  dermopathy (Pretibial myxedema)
increase TH  hyperplastic and highly vascular
thyroid gland
Toxic Results from functionally; autonomous nodules;
Multinodular common in women; the nontoxic form is common
Goiter in men (50 years old)

Toxic Adenoma Uncommon; displays autonomous function  Common in 4th and 5th decades
(Pituitary independent of TSH; show a solitary focus of iodine  Sx begins when the adenoma is about 3 cm
adenoma) uptake (“hot nodule”)  Spontaneous necrosis and hemorrhage within
the adenoma may relieve the hyperthyroidism
 In that event , the rest of the gland resumes its
normal function and the adenoma becomes a
“cold” nodule simulating thyroid cancer in a
scintigram

Table 4. Thyroiditis.
Type Description Pathology/etiology Clinical features
Acute Thyroiditis Develops during a systemic infection that reaches  Streptococcus  Fever
the thyroid by hematogenous spread; all ages;  Staphylococcus  Chills
Infection may spread into the trachea,  Pneumococcus  Malaise
mediastinum and esophagus  Fungi  Painful, swollen neck
 CMV
 TB

Hashimoto Associated with HLA and CTLA-4 genes; the
Thyroiditis autoimmune process in HT arises from activation
(autoimmune of CD4 (helper) T lymphocytes sensitized to
thyroid antigens; These CD4+ cells stimulate
thyroiditis)
proliferation of autoreactive cytotoxic (CD8) T
cells, which attack thyrocytes
 Diffusely enlarged and firm
 60-200 g
 Cut surface is pale tan and fleshy with
vaguely nodular pattern
 Capsule is intact
 Perithyroid tissues are not involved
 HURTLE or ASKANAZY CELLS
 Lymphoid follicles with germinal centers are
present
 Eventually undergoes atrophy in some
patients
 Symptoms
o Fatigue
o Depression
o Fibromyalgia
 Diffuse thyroid enlargement
 Mild hyperthyroidism or hypothyroidism
 Gradual onset of goiter
 May progress to an overt hypothyroid state
 T4 (low); Thyrotropin and Thyroxine index
(high); TSH (high)
 May coexist with papillary cancer

Subacute Also called de Quervain Granulomatous or Giant  Caused by a viral infection  Pain in the anterior neck
Thyroiditis Cell Thyroiditis o Influenza virus  Presents with fever, malaise, fatigue and pain
o Adenovirus in the neck or radiating to the jaw
o Echovirus  Some patients only experience mild symptoms
5 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]

Silent Thyroiditis Painless subacute thyroiditis or lymphocytic
thyroiditis; mainly affect women (postpartum)
o Coxsackievirus
o Mumps virus (in some cases)
Destruction of gland parenchyma with
lymphocytic infiltration; Associated with HLA-
DR3
 Moderately enlarged thyroid and tender
 Resolves within a few months
 Iodine uptake is suppressed in the early stage
of the disease
 T4 and T3 (high) – due to destruction of
follicles; high enough to cause transient clinical
hyperthyroidism
 TSH (low) –due to negative feedback
 As inflammation resolves – euthyroid state
 ATA (antithyroid antibodies level (low)
 Self-limited hyperthyroidism; Most patients
becomes euthyroid

Riedel Thyroiditis Rare disease; Involves extrathyroidal soft tissues of
the neck and often progressive fibrosis in other
locations, including the retroperitoneum,
mediastinum and orbit; female-to-male ratio (3:1);
Considered manifestation of IgG4-related systemic
disease
 Stony hard and “woody”
 Usually asymmetric (affects only one lobe)
 Fibrosis extends to skeletal muscles and
nerves
 May also surround and infiltrate lymph
nodes and parathyroid glands
 Follicles are normal in unaffected parts
 Eosinophils may also be present
 Gradual onset of painless goiter
 Present with hard thyroid mass
 They may have fibrosing lesions at other sites,
such as the retroperitoneum, mediastinum and
retro-orbital tissues.
 Immunophenotyping shows mostly T cells with
few B cells
 Symptoms are due to compression of neck
organs
o Trachea (stridor)
o Esophagus (dysphagia)
o Recurrent laryngeal nerve (hoarseness)

Table 5. Thyroid Neoplasms.

Condition Pathogenesis Gross Morphology Microscopic Morphology Clinical Features

Adenoma  toxic (functional) adenomas: gain-
of-function somatic mutations of
TSHR or GNAS
 nonfunctioning follicular
adenomas: mutations of RAS or
PIK3CA
 solitary, encapsulated
 gray-white to red-brown
 may have areas of hemorrhage,
fibrosis, calcifications, and cystic
change
 uniform-appearing follicles
containing colloid, distinct from
adjacent non-neoplastic thyroid
 epithelium: little nuclear
variability or mitotic activity
 Hürthle cell adenomas – exhibit
granular eosinophilic cells
 hallmark: intact capsule
 Present as unilateral painless
masses
 Definitive dx can be made only
after histological evaluation of
capsular integrity – suspected
adenomas are then removed
surgically
 do not recur or metastasize;
excellent prognosis

6 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]
 Papillary
 most common thyroid
cancer
 occurs most commonly
between the ages 25 to
50 years, but may arise
at any age  associated with iodine excess,
 most common thyroid
tumor type in children
and young adolescents
 3x more common in
women
 Associated with MAP kinase
pathway mutations through:
- rearrangements of RET or
NTRK1
- gain-of-function BRAF
mutations
exposure to radiation, and genetic
factors (familial forms)
 solitary or multifocal lesions that
may be circumscribed or infiltrate
adjacent parenchyma
 calcification, fibrosis, and cystic
changes are common
 papillary microcarcinomas - <1cm
 Variants: papillary, follicular,
sclerosing, tall-cell
 Psammoma bodies
(Calcospherites)
 Orphan Annie eye (ground
glass) nuclei
 eosinophilic intranuclear
inclusions (cytoplasmic
invaginations)
 vascular invasion is uncommon,
typically invades lymphatics
 present as isolated, asymptomatic
cold thyroid nodules, grossly
indistinguishable from benign
nodules
 hoarseness, dysphagia, cough or
dyspnea – advanced disease
 excellent prognosis in general,
although more serious in men >50
y.o.

Follicular  gain-of-function mutations in RAS  single nodules that may be well-  The nuclear features noted above  present as slowly-growing,
 5% to 15% of thyroid or PIK3CA circumscribed or infiltrative are absent painless, cold nodules
cancers  loss-of-function mutations in the  microfollicular pattern with  lymphatic invasion is rare, but
 3x more common in PTEN tumor suppressor gene relatively uniform, colloid-filled hematogenous metastasis to
women  t(2;3)(q13;p25) translocation follicles bone, lungs and liver is common
 peak incidence between fuses PAX8 with PPARG  invasive FTC: stain positively for  rarely fatal
40 to 60 years  may occur in patients with thyroglobulin and TTF1
 increased incidence in Cowden and Carney syndromes
Carcinoma

areas of dietary iodine

deficiency
Anaplastic  Mutations in RAS or PIK3CA, as
(Undifferentiated)
 aggressive variant most
common in in elderly
patients (>65 y.o.) assoc.
with prior or concurrent
well-differentiated
thyroid cancer
Medullary  germline activating mutations of
 a neuroendocrine
neoplasm from
parafollicular C cells
 secrete calcitonin and
can also produce
serotonin, ACTH, and VIP
 70% sporadic, 30%
MEN-2 syndromes or
FMTC
 Tumors in MEN-2B occur
in infancy; in 2A develop
in adolescents
well as in p53 or β-catenin
the RET protooncogene
 Large, poorly circumscribed
masses
 Cut surface is hard and grayish
white
 Sporadic tumors: usually solitary
 Familial cases: usually bilateral
and multicentric
 firm, gray-tan, and infiltrative,
occasionally with hemorrhage and
focal necrosis
 tumors tend to arise in the
superior portion of the thyroid
(region richest in C cells)
 large, pleomorphic giant cells
 spindle cells with sarcomatous
appearance
 stain positive for cytokeratins and
EMA (epithelial membrane
antigen), TTF1 negative
 cells are polygonal to spindle-
shaped and arrayed in nests,
trabeculae or follicles
 stromal amyloid deposits (altered
calcitonin)
 multifocal C-cell hyperplasia
present in familial cases but
absent in sporadic cases
 present as rapidly enlarging bulky
masses that have already invaded
neck structures or metastasized to
lung at the time of original
diagnosis
 almost uniformly fatal
 death is usually secondary to
aggressive local growth
 present as a thyroid mass (cold
nodules)
 initial manifestations may be
paraneoplastic related to hormone
secretion
 hypocalcemia is uncommon
despite elevated calcitonin levels
 familial cases can present with
thyroid or extra-thyroid
neoplasms
 MEN-2B: more aggressive and
metastasize more often

Lymphoma  most B cell lymphomas arise in  present with dyspnea, hoarseness

 4x more common in women
 Mean age of presentation is
>70 y.o., most common
subtype: diffuse large B-cell
type
glands with chronic thyroiditis and a mass in the neck
 Prognosis of thyroid lymphomas
of the MALT type (mantle zone
lymphomas) is more favorable
than those of some other B-cell
types

7 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]
Table 6. Congenital Adrenal Hyperplasia.
Condition Etiology/ Pathogenesis Morphology Clinical Features
CAH  Results from several autosomal recessive enzyme defects  Enlarged adrenal glands (as much as
in biosynthesis of cortisol 30g)
 Deficiencies vary from mild to complete lack of cortisol  Soft, tan to brown
which leads to unopposed action of ACTH=adrenal  May either be diffusely enlarged or
hyperplasia nodular
 Occurs equally in males and females  Cortex widened between medulla and
 Most common cause of ambiguous genitalia in newborn zona glomerulosa
girls  Hyperplastic zone filled by compact,
granular, eosinophilic cells
 Zona glomerulosa may also be
hyperplastic in most cases but not to
extent of other zones especially
fasciculate
 Ectopic adrenal tissues may also be
hyperplastic and if it persists,
adenomas can develop

21-Hydroxylase  21-Hydroxylase or P450 c21 deficiency is major cause of  Result of cortisol accumulation of steroids
Deficiency CAH  May be classic, Non-classic(milder, late
 90% of cases childhood or early adulthood) or Cryptic
 Gene of P450 c21 (CYP21) is linked to MHC locus on short (biochemical abnormalities occur but
arm of Chromosome 6 (6p21.3 asymptomatic)
 Is closely related to HLA-B and C4A and C4B complement  Glucocorticoids and mineralocorticoids given
genes to suppress ACTH and replace steroids
 P450 C21 converts 17-hydroxyprogesterone to 11-  Reconstructive surgery may be necessary for
deoxycortisol virilized girls with ambiguous genitalia
o Deficiency= accumulated precursors instead of  CLASSIC:
conversion to androgens o Severe form
o Detected in infancy
o P450 C21 deficiency
o May be simple virilizing or salt-wasting
form (HLA-Bw47)
o Simple Virilizing
 Female infants show
pseudohermaphroditism
 males have no abnormalities of
sexual organs
 conversion to androgens is
amplified by the ACTH-dependent
increase in size of gland
 female newborns exposed to a
large excess of adrenal androgens
in utero are born with fused labia,
enlarged clitoris and urogenital
sinus (mistaken for a penile
urethra)
 female external genitalia not
necessarily abnormal at birth, but
may develop a syndrome of
androgen excess, with clitoral
enlargement and pubic hair

8 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]
  Infant boys exhibit sexual
precocity
 High levels of adrenal androgens
lead to premature closure of
epiphyses = short stature.
 Adult women tend to be infertile
due to disturbed menstrual cycle
and inhibited ovulation
 Men may be fertile, but some have
azoospermia
o Salt Wasting
 Aldosterone synthesis may be
impaired = Hypoaldosteronism in
first few weeks in life
 Hyponatremia, hyperkalemia,
dehydration,
 hypotension and increased renin
secretion are typical.
 LATE-ONSET
o nonclassic variants of 21-hydroxylase
deficiency
o no abnormalities at birth but develop
virilizing symptoms at puberty
o In young women, may closely resemble
polycystic ovary syndrome
o Most young men are asymptomatic
o More common than classic
o common in Ashkenazi Jews, Italians and
people from former Yugoslavia
o Treatment: glucocorticoids to reduce
hyperplasia and overproduction of
androgens or mineralocorticoids

11β-Hydroxylase  5% of CAH  high levels of 11-deoxycortisol (weak

Deficiency  uncommon in the general population mineralocorticoid) cause sodium retention
 most common among Jews of Iranian or Moroccan and hypertension
ancestry in Israel  Rare forms include deficiencies of several
 autosomal recessive trait enzymes of adrenocorticosteroid
 gene is on chromosome 8q21-22 and is unrelated to the biosynthesis pathways
HLA locus  Deficiencies lead to diverse combinations of
 11β-Hydroxylase catalyzes terminal hydroxylation in electrolyte abnormalities and anomalies of
cortisol biosynthesis the sex organs
 Rare forms include deficiencies of several enzymes of  Treatment: lifelong glucocorticoid
adrenocorticosteroid biosynthesis pathways replacement sufficient to prevent adrenal
insufficiency

9 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]
Table 7. Adrenal Cortical Insufficiency, Hyperfunction, and Miscellaneous Tumors.
Condition Etiology/Pathogenesis Morphology Clinical Features
 autoimmune destruction of the  90% of the adrenal gland must  First symptom is insidious onset of
adrenals be destroyed before it becomes weakness
 failure of the adrenal glands to symptomatic  Diffuse, tan skin pigmentation usually
Addison’s produce glucocorticoids,  lymphoid infiltrates, develops
Disease mineralocorticoids and predominantly  Dark patches may appear on mucous
androgens T cells membranes
 Hypotension, with blood pressures in
the range of 80/50
 Sudden loss of adrenal cortical  adrenal atrophy that is due to  Initial manifestations – hypotension
Adrenal Cortical function long-term use of steroids and shock
Insufficiency Acute Adrenal  Symptoms are related more to  acute, bilateral, hemorrhagic  Nonspecific symptoms
Insufficiency mineralocorticoid deficiency infarction of the adrenal cortex
 Waterhouse-Friderichsen
syndrome
 Lack of adrenocorticotropic  Any disorder that interferes with  Glucocorticoid response to ACTH
hormone secretion of corticotropin distinguishes secondary from primary
2o Adrenal  Destruction of the pituitary and (ACTH)-releasing hormone adrenal insufficiency
Insufficiency consequent pan- (CRH) by the hypothalamus can
hypopituitarism cause inadequate production of
ACTH
Adrenal Hyperfunction (Cushing’s  chronic corticosteroid  pituitary hyperfunction  clinical features are caused by high
– hypercortisolism, and Conn’s administration  adrenal adenomas or glucocorticoid and mineralocorticoid
Syndrome – hyperaldosteronism)  paraneoplastic syndrome hyperplasia levels of any origin
Adrenal  mixture of mature adipose tissue  Notable for its occasional large size
Myelolipoma and hematopoietic marrow
 Most are actually pseudocysts
that occur as a result of
Adrenal Cysts degenerative changes in benign
Miscellaneous
adrenal tumors or resolution of
Adrenal Tumors
hemorrhage
 usually are from primary lung  The glands may be unilaterally  Sufficient functional adrenal cortex
Metastatic or breast carcinomas, or or bilaterally hugely enlarged, up usually remains so that Addison
Cancers malignant melanomas to 20 to 45 g disease does not develop

10 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]
Table 8. Conditions Involving the Adrenal Medulla and Paraganglia.
Condition Etiology
PHEOCHROMOCYTOMA Associated with autosomal
Dominant MEN Syndromes
PARAGANGLIOMAS - Frequently familial and
inherited as autosomal dominant
traits, with germline mutations
in SDHB, SDHC, SDHA or SDHD
genes
NEUROBLASTOMAS - Germline mutations in PHOX2A
or KIF1B genes may be
responsible for familial cases.
These tumors have also been
linked to copy number variations
within the NBPF10 gene, which
results in the 1q21.1 deletion
syndrome.
11 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]
Pathogenesis Morphology
- Rare catecholamine-secreting - Tend to be encapsulated,
tumors of Chromaffin Cells of the spongy and reddish, with
Adrenal Medulla or elsewhere. prominent central scars,
hemorrhage and foci of cystic
degeneration.
- Circumscribed nests
(zellballen) of polyhedral to
fusiform neoplastic cells contain
granular, amphophilic or
basophilic cytoplasm and
vesicular nuclei
- Eosinophilic cytoplasmic
globules are common. Cellular
pleomorphism may be
prominent, including
multinucleated tumor giant cells.
Not well known - - CAROTID BODY TUMOR
- Round, irregularly lobulated
masses that may weigh 50–150 g
or more. Their cut surfaces are
soft, friable and variegated
maroon in color.
- Necrosis, hemorrhage,
calcification and cystic change
are common.
- CLASSIFICATION OF
NEUROBLASTIC TUMORS
o Neuroblastoma
(Schwannian stroma poor)
o Ganglioneuroblastoma,
intermixed (Schwannian stroma
Clinical features
-Episodic hypertension may
become sustained and evolves
into malignant hypertension.
-Orthostatic hypotension
-Increased basal metabolism,
sweating, heat intolerance and
weight loss may mimic
hyperthyroidism.
-Angina and myocardial
infarction occur in the absence of
coronary artery disease.
-Catecholamine cardiomyopathy
-Increased urinary levels of
catecholamine metabolites,
particularly vanillylmandelic
acid (VMA), metanephrine and
unconjugated catecholamines
Prototypical paragangliomas.
Arises at the carotid bifurcation
and form palpable masses in the
neck.
-HEREDITARY
PARAGANGLIOMA  SDHB-
related syndromes are
associated with malignant
pheochromocytomas that
metastasize to distant organs
such as lung and bone.
- Firm, irregular, nontender
mass.
- Metastases may enlarge the
liver and cause ascites.
- Marked irritability may reflect
pain from bony metastases.
- Respiratory distress
accompanies large masses in the
thorax, and tumors in the pelvis
may obstruct the bowel or
ureters.
- Spinal cord compression may
lead to gait disturbance and
sphincter dysfunction.
 rich)
o Ganglioneuroma
(Schwannian stroma dominant)
o Ganglioneuroblastoma,
nodular (composite Schwannian
stroma rich/stroma dominant
and stroma poor).
- Neuroblastomas contain dense
sheets of small, round to
fusiform cells with scant
cytoplasm and hyperchromatic
nuclei, resembling lymphocytes.
- Characteristic: Homer Wright
rosettes
- Tumor secretion of vasoactive
intestinal peptide may cause
diarrhea.
- Urinary catecholamines and
their metabolites are almost
invariably elevated, particularly
norepinephrine, VMA,
homovanillic acid (HVA) and
dopamine.

Table 9. Conditions Involving the Pineal Gland.

Neoplasm Etiology Morphology Clinical features
Pineal Displaced  Uniform large, round cells with vesicular nuclei and clear or finely  Mass lesions in the pineal region that compress adjacent
germinoma embryonic tissue granular cytoplasm that is eosinophilic. structures result in typical clinical syndromes. One of the
most common presentations is headache, nausea, and
 Typically, the stroma contains lymphocytes and approximately 20% vomiting caused by aqueductal compression and
of patients have sarcoid-like granulomas resultant obstructive hydrocephalus.
Pineocytoma Neuroectodermal  Similar to normal pineal gland’s well differentiated cells but  Compromise of the superior colliculus, either through
cells hypercellular direct compression or through tumor invasion, results in
 Fibrovascular stroma highlights expansive lobules of tumor cells a syndrome of vertical gaze palsy that can be associated
with uniform round nuclei with pupillary or oculomotor nerve paresis (Parinaud’s
 Pinocytomatous rosettes (large, loose, Homer-Wright like rosettes Syndrome).
with central fibrillar zones surrounded by neoplastic cells with  Further compression of the periaqueductal gray region
round nuclei) may cause mydriasis, convergence spasm, pupillary
 May have features of neuronal differentiation (ganglion cells) inequality, and convergence or refractory nystagmus.
 Non-infiltrative, no/rare mitotic figures, no necrosis, no/minimal Impairment of downgaze becomes more pronounced
atypia with tumors involving the ventral midbrain. Patients also
can present with motor impairment, such as ataxia and
dysmetria, resulting from compromise of cerebellar
Malignant  Sheets of densely packed cells with high grade (anaplastic / efferent fibers within the superior cerebellar peduncle.
Pineoblastoma
transformation of undifferentiated) features including high N/C ratio with minimal
pineal parenchymal cytoplasm and large hyperchromatic nuclei
cells/surrounding  Necrosis, frequent mitotic figures
astroglia  Focal nuclear molding
 Homer-Wright or Flexner-Wintersteiner rosettes
 Often infiltrates into surrounding structures

12 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]
 Table 10. Paraneoplastic Syndromes with Endocrine Function.
Condition Etiology Associated conditions Manifestation
Cushing Syndrome ACTH  Small cell lung carcinoma Hypokalemia
 Carcinoid tumors Hyperglycemia
 Pheochromocytoma Hypertension
 Neuroblastoma Muscle weakness
 Medullary thyroid carcinoma
Inappropriate Vasopressin  Small cell lung carcinoma Water intoxication leading to:
Antidiuresis  Prostatic carcinoma  Altered mental status
 GI tract carcinoma  Seizures
 Pancreas with thymoma  Coma
 Lymphoma  Death
 Hodgkin disease
Hypercalcemia Parathormone-like peptide Squamous cell lung carcinoma Hypercalcemia
Breast adenocarcinoma

Osteoclast-activating factor Multiple myeloma

Lymphoma
Prostaglandin
Active metabolites of Vit. D
TGF-α, TGF-β
Hypocalcemia Not known Osteoblastic metastases from cancers of lung, breast, and Hypocalcemia
prostate

Reported associations with calcitonin-secreting

medullary carcinoma of thyroid
Gonadotropic LH, FSH  Germ cell tumors Precocious puberty (children)
Syndromes  Gestational trophoblastic tumors (choriocarcinoma, Gynecomastia (men)
hydatidiform mole) Oligomenorrhea (premenopausal women)
 Pituitary tumors
 Hepatoblastomas (children)
 Cancers of lung, colon, breast, and pancreas (adults)
Hypoglycemia Excessive insulin production  Pancreatic islet tumors Hypoglycemia
 Large mesotheliomas
 Fibrosarcomas
 Primary hepatocellular carcinoma

Somatomedins (IGFs) Nonendocrine tumors

(not yet established)

13 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]
Table 11. Type 1 and Type 2 Diabetes.
Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus
Clinical
Onset: usually childhood and adolescence Onset: Usually adult; increasing incidence in childhood and adolescence
Normal weight or weight loss preceding diagnosis Vast majority are obese (80%)
Progressive decrease in insulin levels Increased blood insulin (early); normal or moderate decrease in insulin (late)
Circulating islet autoantibodies (anti-insulin, anti-GAD, anti-ICA512) No islet autoantibodies
Diabetic ketoacidosis in absence of insulin therapy Nonketotic hyperosmolar coma more common
Genetics
Major linkage to MHC Class II genes; also linked to polymorphisms in CTLA4 and No HLA linkage; linkage to candidate diabetogenic and obesity-related genes (TCF7L2,
PTPN22, and insulin gene VNTRs PARG, FTO, etc.)
Pathogenesis
Dysfunction in T cell selection and regulation leading to breakdown in self-tolerance to Insulin resistance in peripheral tissues, failures of compensation by β-cells
islet autoantigens
Multiple obesity-associated factors (circulating nonesterified fatty acids, inflammatory
mediators, adipocytokines) linked to pathogenesis of insulin resistance
Pathology
Insulitis (inflammatory infiltrate of T cells and macrophages), β-cell depletion, islet No insulitis; amyloid deposition in islets
atrophy Mild β-cell depletion
Note: All from Robbin’s.

Table 12. Pancreatic Neuroendocrine Tumors.

Condition Pathology
Insulinoma  Increased insulin secretion
Most common functioning  Genes involving MEN1 and von Hippel-
PanNET Lindau Syndrome
 Mutations in genes involving:
o mTOR pathway (TSC1, PTEN,
PIK3CA)
o maintenance of telomeres (death-
domain associated protein, DAXX and
α-thalassemia/mental retardation
syndrome, X-linked or ATRX)
Morphology
 Most are solid tumors are small (<2
cm)
o Encapsulated
o Pale to red-brown nodules located
anywhere in the pancreas
o Most often occur in the tail of the
pancreas
 Bona fide carcinomas diagnosed on
the basis of local invasion and distant
metastases
 Deposition of amyloid: characteristic
of many insulinomas
 Focal or diffuse hyperplasia of islets
Clinical Manifestation
 Sweating
 Visual changes
 Nervousness
 Hunger → confusion, lethargy, seizures, coma
 Benign clinical course
 May be mistaken for psychiatric disorder
 Hypoglycemic episodes (blood glucose falls
below 50 mg/dL)
o Characteristic feature
o precipitated by fasting or exercise
o relieved by feeding or parenteral
administration of glucose
 ↑ circulating insulin, ↑ insulin-to-glucose ratio

Gastrinoma (Zollinger-Ellison
syndrome)
 Functioning PanNET
composed of G-cells
 Common between 30-50 y.o.
with slight male
predominance
 Excessive production of gastric acid
due to hypersecretion of gastrin
 Genes involving MEN1 and von Hippel-
Lindau Syndrome
 Mutations in genes involving:
o mTOR pathway (TSC1, PTEN,
PIK3CA)
o maintenance of telomeres (death-
 Arise in the duodenum and
peripancreatic soft tissues
 Gastrinoma of pancreas >2cm,
duodenal <1cm
 Histologically bland and rarely show
marked anaplasia
 Parietal cell hyperplasia
 Zollinger-Ellison Syndrome:
o Intractable gastric hypersecretion
o Severe peptic ulceration of duodenum and
jejunum
o High blood gastrin levels
 Diarrhea (>50%) 30 presenting symptom

14 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]

Glucagonoma (α-cell tumors)
 Occur between 40-70 y.o. with
slight female predominance
Somatostatinoma (δ-cell
tumors)
VIPoma
 Association with
pheochromocytomas and
neural crest tumors, such as
neuroblastomas,
ganglioneuroblastomas, and
ganglioneuromas
PPoma & Pancreatic Carcinoid
Tumors
 Multihormonal hormones
distinguished from MEN
syndromes
15 of 15 [“Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up.” Galatians 6:9]
domain associated protein, DAXX and
α-thalassemia/mental retardation
syndrome, X-linked or ATRX)
 Increased levels of glucagon (30
times above normal)
 Genes involving MEN1 and von Hippel-
Lindau Syndrome
 Mutations in genes involving:
o mTOR pathway (TSC1, PTEN,
PIK3CA)
o maintenance of telomeres (death-
domain associated protein, DAXX and
α-thalassemia/mental retardation
syndrome, X-linked or ATRX)
 Malignant behavior 50-70% of cases
 High somatostatin levels
 Genes involving MEN1 and von Hippel-
Lindau Syndrome
 Mutations in genes involving:
o mTOR pathway (TSC1, PTEN,
PIK3CA)
o maintenance of telomeres (death-
domain associated protein, DAXX and
α-thalassemia/mental retardation
syndrome, X-linked or ATRX)
 Increased VIP
 Genes involving MEN1 and von Hippel-
Lindau Syndrome
 Mutations in genes involving:
o mTOR pathway (TSC1, PTEN,
PIK3CA)
o maintenance of telomeres (death-
domain associated protein, DAXX and
α-thalassemia/mental retardation
syndrome, X-linked or ATRX)
 Made in ganglion cells and nerve fibers
of the pancreas, gut, and brain
 Locally invasive and metastatic
 Secretion of other hormones not
produced by pancreas (ACTH, PTH,
Calcitonin, ADH, Serotonin, MSH,
Norepinephrine)
 Pancreatic polypeptide-secreting
endocrine tumors (PPoma)
 Functioning and nonfunctioning  Mild DM
PanNETs appear similar  Characteristic skin rash (necrolytic migratory
 Solitary, circumscribed masses of pink erythema)
to tan, soft tissue  Anemia
 Large tumors are multinodular with  Diarrhea
areas of hemorrhage  Deep vein thrombosis
 Cystic degeneration may occur, some  Psychiatric disturbances also occur
are firm and fibrotic
 Uniform cells, arranged in so-called
organoid patterns with nests, ribbons,
glands, and festoons.
 Uniform nuclei, coarsely stippled
chromatin
 Low proliferative rate (< 20 mitotic  Mild diabetes
figures in 10hpf and <20% nuclei  Gallstones
positive for immunohistochemical  Steatorrhea
proliferation marker Ki67)  Hypochlorhydria
 PanNET granule morphology matches  Anemia
that of the specific granules in the  Weight loss
nonneoplastic islet cell counterparts  Low blood levels of insulin and glucagon
 WDHA syndrome/Verner-Morrison
syndrome/Pancreatic cholera
o Explosive and profuse watery diarrhea
o Hypokalemia
o Achlorhydria
 High plasma levels of pancreatic polypeptide
fail to cause symptoms