ENDOCRINE

Organ Type of disorder

• PITUITARY • NON-NEOPLASTIC
– ANTERIOR – HYPER-function
– POSTERIOR – HYPO-function
• THYROID • NEOPLASTIC
• PARATHYROID – NON-FUNCTIONAL
• ADRENAL – FUNCTIONAL
– CORTEX – Functional endocrine
malignancies are
– MEDULLA
RARE.
Positive/negative feedback systems
• CORTEX, SUBCORTEX?->
• HYPOTHALAMUS ->
• ANTERIOR PITUITARY ->
• ENDOCRINE GLAND ->
• END ORGAN ->
• HYPOTHALAMUS ->
 Adenohypophysis
• ACIDOPHILIC cells (growth)
– GROWTH HORMONE
(somatotrophs)
– PROLACTIN (mammotrophs)
– PRL+GH (mammosomatotrophs)
• BASOPHILIC cells (endocrine
organs)
– TSH (thyreotrophs)
– ACTH (corticotrophs)
– LH, FSH (gonadotrophs)
• Chromophobic: no secretion
 POSTERIOR PITUITARY
• OXYTOCIN (contracts uterine
smooth muscle)

• VASOPRESSIN (ADH)
(vasoconstriction, gluconeogenesis,
platelet aggregation, release of Factor-
VIII and vWb factor, concentrates urine,
main effects on kidney and brain)
Hormones are sysnthesyzed in the
hypothalamus and stored within the axon
terminals that reach the neurohypophysis
Posterior pituitary: pituicytes, modified glial cells (neurohypophysis)
 PITUITARY PATHOLOGY
• CLINICAL FEATURES depend on:
– endocrine effects (hyper- or hypofunction, one
or more hormones)
– optic chiasm compression (bitemporal
hemianopsia)
– mass effects (elevated intracranial pressure,
headache, etc)
Pituitary adenoma and hyperpituitarism
• The most common cause of hyperpituitarism
is an adenoma arising in the anterior lobe.
• Pituitary adenomas are classified on the
basis of hormone(s) produced by the
neoplastic cells, which are detected by
immunohistochemical stains
• Some pituitary adenomas can secrete two
hormones (GH and prolactin being the most
common combination), and rarely, pituitary
adenomas are plurihormonal.
Pituitary adenomas can be functional (associated
with hormone excess and clinical manifestations
thereof) or nonfunctioning (immunohistochemical
demonstration of hormone production at the tissue
level, without clinical symptoms of hormone
excess). Clinical symptoms primarily depend on the
type and amount of secreted hormones
 Nonfunctioning pituitary adenomas
• Nonfunctioning pituitary adenomas are a
heterogeneous group that constitutes
approximately 25% to 30% of all pituitary tumors.
Their lineage can be determined by
immunohistochemical staining for specific lineage
markers, or, partially, for hormones
• Typical presentation of nonfunctioning adenomas
is mass effects (visual field abnormalities, signs
and symptoms of elevated intracranial pressure)
• Large nonfunctioning pituitary adenomas may
cause hypopituitarism as they compress and
destroy adjacent anterior pituitary parenchyma
Prolactinoma Corticotroph cell adenoma

Non functioning adenoma

FSH LH
 HYPO-pituitarism: causes
• Pituitary tumors, functional or not.
• Hypothalamic tumors, primary or metastatic
• Iatrogenic: pituitary surgery, radiation
• Traumatic brain injury and subarachnoid
hemorrhage
• “Apoplexy”, i.e., sudden hemorrhage
• Sheehan’s syndrome (post-partum ischemic
necrosis)
• Expansion of cysts (Rathke cleft)
• Empty sella syndrome
• Genetic defects (pit-1 gene mutations)
• Inflammatory diseases
 clinical manifestations of anterior pituitary
hypofunction
• Can be protean, and depend on the specific hormone(s) that
are lacking.
• Children can develop growth failure (pituitary dwarfism) due
to growth hormone deficiency.
• Gonadotropin (LH and FSH) deficiency leads to amenorrhea
and infertility in women and decreased libido, impotence, and
loss of pubic and axillary hair in men.
• TSH deficiency results in symptoms of hypothyroidism
• ACTH deficiency results in symptoms of hypoadrenalism,
• Prolactin deficiency results in failure of postpartum lactation.
• The anterior pituitary is also a rich source of MSH,
synthesized from the same precursor molecule that produces
ACTH; therefore, one of the manifestations of hypopituitarism
includes pallor due to a loss of stimulatory effects of MSH on
melanocytes
POSTERIOR pituitary dysfunction
• Hypofunction: (central) DIABETES
INSIPIDUS
– Causes: head trauma, tumors,
inflammation of hypothamus or
hypophisis (sarcoidosis, Langerhans
cell histiocytosis, IgG4 hypophysitis)
• Hyperfunction: SIADH (Syndrome of
Inappropriate Anti-Diuretic Hormone)
– Causes: paraneoplastic synd., posterior
pituitary injury
15-25
grams
 HYPER-THYROIDISM
(thyrotoxicosis)
• Primary thyroid hyperfunction
# Hyperfunction of the gland
– Diffuse toxic hyperplasia (Graves disease)
– Hyperfunctioning multinodular goiter
– Hyperfunctioning adenoma
# Excessive release of preformed thyroid
hormones
– Thyroiditis
• Secondary (TSH-secreting pituitary
adenoma)
HYPER-THYROIDISM
• HYPERMETABOLISM
• Tachycardia, palpitations
• Increased T3, T4
• Goiter
• Ophtalmopathy
• Tremor
• GI hypermotility
• Thyrotoxic crisis, life threatening
 HYPO-THYROIDISM
• Primary:
– Developmental (genetically determined, inborn errors of
thyroid hormone metabolism, thyroid hormone resistance
syndrome)
– Iatrogenic (surgery, I-131, external irradiation, Li+, iodides,
p-aminosalicylates)
– Auto-immune (Hashimoto’s thyroiditis)*
– Chronic iodine deficiency (can be congenital or acquired)*
– Congenital biosynthetic defect (dyshormonogenetic goiter)
*
*Associated with enlargement of the thyroid

• Secondary (pituitary TSH hyposecretion)

• Tertiary (hypothalamic defect of TRH, rare)

"Chretinism": hypothyroidism that develops in infancy

or early childhood
Mixedema: develops in older children or adults
 THYROIDITIS
Inflammatory disorders of the thyroid
• Hashimoto (Auto-immune), MOST
COMMON cause of acquired
hypothyroidism
• Subacute Granulomatous (DeQuervain)
• Subacute Lymphocytic often post-partum
• Sclerosing (Riedel’s) thyroiditis
Clinically, some forms are associated with
hyperthyroidism, others with
hypothyroidism
 Hashimoto Thyroiditis
• Gradual thyroid failure because of autoimmune
destruction of the thyroid gland.
• Most prevalent between age 45 and 65, more common
in women (F:M 10 : 1 to 20 : 1). Although it is primarily a
disease of older women, it can occur in children
• Strong genetic component (polymorphisms in multiple
immune regulation–associated genes, including
cytotoxic T lymphocyte–associated antigen-4 and
protein tyrosine phosphatase-22 (negative regulators of
T-cell responses)
• Induction of thyroid autoimmunity is accompanied by a
progressive depletion of thyrocytes by apoptosis and
replacement by mononuclear cell infiltration and fibrosis
• Enlarged, painless thyroid with progressive
hypothyroidism
• Increased risk of other autoimmune diseases, both
endocrine (type 1 diabetes, autoimmune adrenalitis) and
nonendocrine (SLE, myasthenia gravis, and Sjögren s).
Also increased risk for the development of B-cell non-
Hodgkin lymphomas, especially MZL or MALTomas.
Some morphologic and molecular studies suggest a
predisposition to papillary carcinomas.
 Morphology
• The thyroid is often diffusely enlarged
• The capsule is intact, and the gland is well
demarcated from adjacent structures.
• The cut surface is pale, yellow-tan, firm, and
somewhat nodular.
• Microscopic examination reveals extensive
infiltration by a mononuclear inflammatory
infiltrate containing small lymphocytes, plasma
cells, and well-developed germinal centers
• Thyroid follicles are atrophic and often lined by
epithelial cells with abundant eosinophilic,
granular cytoplasm, called Hürthle cells
(oncocytes).
• Interstitial fibrosis
 Subacute Lymphocytic (Painless)
Thyroiditis
• Mild hyperthyroidism and goitrous enlargement of the
gland, painless
• Middle-aged women
• A disease process resembling painless thyroiditis can
occur during the postpartum period in up to 5% of women
(postpartum thyroiditis)
• Subacute and postpartum thyroiditis are variants of
Hashimoto thyroiditis: the majority of patients have
circulating anti-thyroid peroxidase antibodies or a family
history of other autoimmune disorders
• As many as a third of cases can evolve into overt
hypothyroidism over time
 Histology
• “Incomplete” Hashimoto’s features:
– lymphocytic infiltration with hyperplastic
germinal centers
– patchy disruption and collapse of thyroid
follicles
– Minimal Hürthle cell metaplasia
– Absent fibrosis
 Granulomatous Thyroiditis

• Autoimmune response triggered by a viral

upper respiratory infection (coxsackievirus,
mumps, measles, adenovirus)
• The immune response is not self-
perpetuating, so the process is limited
• There is a variable enlargement of the
thyroid. The thyroid is painful and
hyperfunctioning (hyperthyroidism)
• The gland may be unilaterally or bilaterally enlarged and firm, with an intact
capsule
• Early in the active inflammatory phase, follicles may be entirely disrupted and
replaced by neutrophils forming microabscesses. Later, the more characteristic
features appear in the form of aggregates of lymphocytes, activated
macrophages, and plasma cells around collapsed and damaged thyroid
follicles. Multinucleate giant cells enclose naked pools or fragments of
colloid, hence the designation granulomatous thyroiditis. In later stages of
the disease a chronic inflammatory infiltrate and fibrosis may replace the foci of
injury.
 Riedel thyroiditis
» Extensive fibrosis
involving the thyroid
and contiguous neck
structures (simulates a
thyroid carcinoma)
» Diffuse plasmacellular
infiltration, IgG4+
» Thyroid manifestation of
systemic autoimmune
IgG4-related disease
 GRAVES DISEASE
(diffuse toxic goiter)

• Most common cause of endogenous hyperthyroidism

• Autoimmune: activating autoantibodies to TSH
receptors on thyrocytes
– Hyperthyroidism
– Exophtalmos
– Localized infiltrative dermopathy (myxedema)
• Gross: symmetric enlargement of the gland
• Morphology: “activated” thyrocytes (taller cells, cell
crowding, larger nuclei, nucleoli); evidence of active
thyroglobulin resorption (colloid “scalloping”)
 NON-TOXIC GOITER
(thyromegaly, diffuse or nodular)
• Result of impaired thyroid hormone
synthesis, mostly caused by dietary iodine
deficiency
• Feed-back: increased TSH secretion
• TSH stimulates the disordered growth of
thyrocytes and follicles -> hyperplasia,
nodules
• Most patients are euthyroid by
compensation; hypothyroidism can
develop over time
G
O
I
T
E
R
• Endemic goiter occurs in geographic areas where the
soil, water, and food supply contain low levels of iodine
(mountainous areas). The term endemic is used when
goiters are present in more than 10% of the population in
a given region
• Sporadic goiter occurs less frequently. There is a striking
female preponderance and a peak incidence at puberty or
in young adult life. Sporadic goiter can be caused by
several conditions, including the ingestion of abnormal
amounts of substances that interfere with thyroid hormone
synthesis. In other instances, goiter may result from
hereditary enzymatic defects that interfere with thyroid
hormone synthesis, all transmitted as autosomal-
recessive conditions (dyshormonogenetic goiter)
• The ingestion of substances that interfere with thyroid
hormone synthesis at different level, such as vegetables
belonging to the Brassicaceae (Cruciferae) family (e.g.,
cabbage, cauliflower, Brussels sprouts, turnips, and
cassava), has been documented to be goitrogenic and
interact with other factors
• Diffuse nontoxic (simple) goiter: enlargement of the entire
gland without nodularity. Because the enlarged follicles are filled
with colloid, the term colloid goiter has been applied to this
condition
• With time, recurrent episodes of hyperplasia and involution
combine to produce a more irregular enlargement of the thyroid,
termed multinodular goiter
• Nodularity: Multinodular goiters arise because of variations
among follicular cells in their response to stimuli, such as trophic
hormones. When some cells in a follicle have a growth
advantage, perhaps because of intrinsic genetic abnormalities,
they can give rise to clones of proliferating cells. This may result
in the formation of a nodule whith autonomous continued growth,
without any external stimulus
• Remodeling: Follicular hyperplasia, generation of new follicles,
and uneven accumulation of colloid produce physical stress that
leads to rupture of follicles and vessels followed by
hemorrhages, scarring, and sometimes calcifications, increasing
the multinodular appearance of the gland
• The dominant clinical features of multinodular goiter are
caused by the mass effects of the enlarged gland (airway
obstruction, dysphagia, and compression of large vessels
in the neck and upper thorax (superior vena cava
syndrome))
• Most patients are euthyroid or have subclinical
hyperthyroidism (identified only by reduced TSH levels),
• In a substantial minority of patients an autonomous
nodule may develop within a long-standing goiter and
produce hyperthyroidism (toxic multinodular goiter). This
condition, known as Plummer syndrome, is not
accompanied by the infiltrative ophthalmopathy and
dermopathy of Graves disease.
• It is estimated that clinically apparent autonomous
nodules can develop in approximately 10% of
multinodular goiters over a 10-year follow-up.
• Dominant nodules in a multinodular goiter can present as
a “solitary thyroid nodule” (“hot” nodule on radioidine
scan), mimicking a thyroid neoplasm
 Thyroid neoplasms present as palpable
nodules
Nodules can have different nature:
– Dominant nodule in multinodular goiter
– Cyst
– Focus of thyroiditis
– Adenoma
– Carcinomas
Clinical characters of malignant nodules
– Solitary > Multiple
– Younger > Older
– Male > Female
– Previous neck radiation
– Non functional (“cold”) nodule in imaging studies
with radioactive iodine
 Thyroid Neoplasms
• FOLLICULAR • CARCINOMA
ADENOMA – FOLLICULAR
– Classic – PAPILLARY
– HÜRTHLE
cell – POORLY
(oxyphilic, DIFFERENTIATE
oncocytic) D
– MEDULLARY
– ANAPLASTIC
US-guided FNA is the diagnostic
approach to thyroid nodules

Cytology can
not
distinguish
between
dominant
nodule in
multinodular
goiter,
follicular
adenoma and
follicular
carcinoma
 Follicular adenoma
• Clinically, follicular adenomas can be difficult to
distinguish from dominant nodules of follicular
hyperplasia in goiter (functional “hot”
adenomas) or from the less common follicular
carcinomas (non functional). This distinction is
also not possible on FNA cytology
• From the molecular point of view, some f.a. can
be considered the progression of a dominant
nodule, some other the precursor of f.
carcinoma
 Dominant nodule <-> f. adenoma
• Somatic mutations of the TSH receptor signaling
pathway that lead to constitutive activation have been
found in a subset of autonomous thyroid nodules in
toxic multinodular goiter as well as in toxic adenomas.
• Gain-of-function mutations allow follicular cells to
secrete thyroid hormone independently of TSH
stimulation (“thyroid autonomy”). This causes
symptoms of hyperthyroidism and produces a “hot”
thyroid nodule on imaging.
• Overall, mutations in the TSH receptor signaling
pathway seem to be present in slightly over half of
toxic thyroid nodules (dominant nodule or adenoma).
• Notably, these mutations are rare in follicular
carcinomas; thus toxic adenomas and toxic
multinodular goiter do not seem to progress to
malignancy
 F. Adenoma <–> F. carcinoma
• <20% of nonfunctioning follicular adenomas have
activating mutations of RAS or PIK3CA, or bear a
PAX8-PPARG activating fusion gene, all of which are
genetic alterations shared with follicular carcinomas
• These F.A. are genetically precursors of F.C.
• Can we recognise them with non-invasive methods?
Molecular analysis is increasing the diagnostic
accuracy of cytology for the diagnosis of STN. At
present, surgery and histological examination are still
indicated for all non-hyperplastic solitary thyroid
nodules
 Gross features
• A solitary, spherical,
encapsulated lesion that is
well demarcated from the
surrounding thyroid
parenchyma
• Average diameter about 3
cm, but some are much larger
(≥10 cm in diameter)
• The color ranges from gray-
white to red-brown,
depending on the cellularity of
the adenoma and its colloid
content.
 Microscopic examination
• Uniform-appearing follicles that contain colloid;
uniform cells, small, regular, round nuclei
• The follicular growth pattern within the adenoma
is usually quite distinct from the adjacent non-
neoplastic thyroid (mostly smaller,
microfollicular).
• Occasionally, the neoplastic cells acquire brightly
eosinophilic granular cytoplasm (oxyphil or
Hürthle cell change -> oncocytes) . These cells
can have higher degree of nuclear atypia, that
however has no biological correlation
The hallmark of all FA is the presence of an intact,
well-formed capsule encircling the tumor. Careful
and complete evaluation of the integrity of the
capsule is critical in distinguishing FA from FC,
which demonstrate capsular and/or vascular invasion
 Follicular carcinoma
clinical features
• 5% to 15% of primary thyroid cancers.
• More common in women (3 : 1)
• Older age than papillary carcinomas, (peak
incidence 40 - 60 year)
• More frequent in areas with dietary iodine
deficiency (25% to 40% of thyroid cancers)
• Relevant histopathological features:
presence of capsular and/or vascular
invasion (DD FA); absence of nuclear
characters of papillary carcinoma
 Follicular carcinoma
genetic background
• 1/3-1/2 FC show activation of the PI-3K/AKT
signaling pathway,
– gain-of-function point mutations of RAS and PIK3CA,
– PIK3CA amplification
– loss-of-function mutations of PTEN, negative regulator
of the pathway
• 1/3 harbor the (2;3)(q13;p25) translocation
creating a fusion gene between PAX8, a paired
homeobox gene important in thyroid
development, and the peroxisome proliferator-
activated receptor gene (PPARG), whose gene
product is a nuclear hormone receptor implicated
in terminal differentiation of cells
 Papillary carcinoma
clinical features
• 85% of primary thyroid cancers.
• More common in women
• 25-50 yrs
• Associated with exposure to ionizing radiations
• Excellent prognosis (10-year survival rate > 95)
• 5%-20% of patients have local or regional recurrences;
10%-15% have distant metastases.
• The prognosis depends on several factors including age
(less favorable if patients older than 40 years), the
presence of extra-thyroid extension, and of distant
metastases (stage).
 Nuclear “grooves”

Empty or ground glass nuclei = “ORPHAN ANNIE”

CELLS in PAPILLARY CARCINOMA
 Papillary carcinoma
genetic background
Activation of the MAP kinase pathway in most cases,
through mutually exclusive molecular events.
1. 30-50%: gain-of-function mutation in the BRAF gene,
which is most commonly a valine-to-glutamate change at
codon 600 (BRAFV600E)
2. 20-40%: rearrangements of the gene coding for RET
tyrosine kinase receptor (paracentric inversion of
chromosome 10 or a reciprocal translocation between
chromosomes 10 and 17 ). The resulting RET/PTC
fusion protein leads to constitutive expression of the
tyrosine kinase in thyroid follicular cells, with resultant
activation of the MAP kinase pathway
3. 5-10%: rearrangements of the gene coding for NTRK1
tyrosine kinase receptor
 High grade thyroid carcinomas
» Poorly differentiated and anaplastic (=
undifferentiated carcinoma)
» Can arise ex novo or originate from
transformation of a preexisting low grade
tumor
» Rapid invasion and extra-thyroid extension
(vessels, lymphnodes, trachea, larynx),
and distant metastasis
» Anaplastic ca frequently have sarcomatoid
morphology
 Medullary thyroid carcinoma
• Neuroendocrine neoplasm derived from the parafollicular cells, or
C cells
• 5% of thyroid neoplasms
• Medullary carcinoma cells, similarly to normal C cells, secrete
calcitonin
• About 70% of tumors arise sporadically. The others occurs in the
setting of MEN syndrome 2A or 2B or as familial tumors without
an associated MEN syndrome
• Activating point mutations in the RET proto-oncogene play an
important role in the development of both familial and sporadic
medullary carcinomas
• Microscopically, medullary carcinomas are composed of
polygonal to spindle-shaped cells, which may form nests,
trabeculae, and even follicles.
• Calcitonin and neuroendocrine markers are readily demonstrable
within the cytoplasm of the tumor cells by immunohistochemical
methods
35-50 mg
 PARATHYROID DISORDERS
• HYPERFUNCTION
– PRIMARY (autonomous
overproduction of PTH)
– SECONDARY (chronic hypocalcemia)
• HYPOFUNCTION
– Surgical, congenital, familial,
idiopathic, autoimmune
• PSEUDO-HYPOFUNCTION
– (end organ resistance)
 Hyperparathyroidism
• Primary
– Parathyroid adenoma (85-95%), sporadic or
familial (MEN1, MEN2)
– Parathyroid hyperplasia (5-10%)
– Parathyroid carcinoma (1%)
 Parathyroid adenoma
• Almost always solitary
• 0.5 to 5.0 gm; is a well-circumscribed, soft, tan to reddish-
brown nodule
• In contrast to primary hyperplasia, the glands outside the
adenoma are usually normal in size or somewhat shrunken
because of feedback inhibition by elevated levels of serum
calcium
• Microscopically, parathyroid adenomas are mostly
composed of fairly uniform, polygonal chief cells with small,
centrally placed nuclei
• Mitotic figures are rare, but it is not uncommon to find bizarre
and pleomorphic nuclei even within adenomas (so-called
endocrine atypia); this is not a criterion for malignancy.
• diagnosis of carcinoma based on cytologic detail is
unreliable, and invasion of surrounding tissues and
metastasis are the only reliable criteria.
4 g.
ADRENAL CORTEX
• Glomerulosa, mineralocorticoids
– ALDOSTERONE
• Fasciculata, glucocorticoids
– CORTISOL
• Reticularis, gonadocorticoids
– ANDROGENS, ESTROGENS
ALDOSTERONE

CORTISOL

ESTROGENS
ANDROGENS

Catecholamines
 HYPERADRENALISM
• HYPERALDOSTERONISM (g)
• CUSHING SYNDROME
(CORTISOL) (f) (most common of the three)
• ADRENOGENITAL
(VIRILIZING) SYNDROME (r)
 CUSHING SYNDROME
Clinical manifestations
• CENTRAL OBESITY
• MOON FACIES
• WEAKNESS
• HIRSUTISM
• HYPERTENSION
• DIABETES
• OSTEOPOROSIS
• STRIAE
 CUSHING SYNDROME
Causes
• Pituitary ACTH hypersecretion (adenoma)
(70%)
• Paraneoplastic ACTH hypersecretion (10%)
• Adenoma of adrenal cortex (10%)
• Carcinoma of adrenal cortex (5%)
• Hyperplasia of adrenal cortex (5%)
– Sporadic macronodular hyperplasia
– McCune-Albright s.
– PRKR1A and PDE11A gene mutations
• Iatrogenic: prolonged STEROID therapy (90%)
 HYPERALDOSTERONISM

• Na+ RETENTION
• K+ EXCRETION
• HYPERTENSION
 PRIMARY HYPERALDOSTERONISM
(Conn’s Syndrome)
• Cortical adenomas (35%, Conn s.)
• Bilateral nodular hyperplasia (60%)
• familial (rare)

SECONDARY HYPERALDOSTERONISM
Activation of the renin-angiotensin system
• DECREASED RENAL PERFUSION
• Hypovolemia and EDEMA (HEART, LIVER,
KIDNEY)
• PREGNANCY
 ADRENOGENITAL SYNDROMES
VIRILIZATION
• Androgen secreting adrenal carcinomas
(less frequently adenomas)
• Congenital adrenal hyperplasia
– 21-Hydroxylase deficiency and other
inherited defects of enzymes involved in
the biosynthesis of cortical steroids
ADRENAL INSUFFICIENCY
• PRIMARY ACUTE (ADRENAL
CRISIS)
• PRIMARY CHRONIC (auto-immune:
ADDISON DISEASE)
• SECONDARY (PITUITARY
hyposecretion of ACTH)
 NEOPLASMS
• Only a minority of adrenocortical adenomas elaborate
steroid hormones; carcinomas are most frequently
functional
• Functional adrenal neoplasms may be responsible for
any form of hyperadrenalism.
• Functional adenomas are most commonly associated
with hyperaldosteronism and Cushing syndrome;
virilizing neoplasm are more likely carcinomas;
• Adenomas and carcinomas are about equally
common in adults; in children, carcinomas
predominate.
• Most cortical neoplasms are sporadic, familial cases
are associated with Li-Fraumeni s.
• Functional and nonfunctional adrenocortical
neoplasms cannot be distinguished on the basis of
morphologic features.
 Adrenocortical adenoma
• Well-circumscribed, capsulated nodular lesion up
to 2.5 cm in diameter that expands the adrenal.
Aldosterone-secreting adenomas tend to be
smaller (<2cm),
• In adenomas associated with Cushing s. the
adjacent cortex and the controlateral gland are
usually atrophic (ACTH suppression), while in
aldosterone-secreting and in non-functioning
adenomas, the adjacent cortex is normal.
• On cut surface, adenomas are usually yellow to
yellow-brown because of the presence of lipids.
 Histology
• Adenomas are composed of
cells similar to those of the
normal adrenal cortex. The
nuclei tend to be small,
although some degree of
pleomorphism may be
encountered even in benign
lesions (“endocrine atypia”).
The cytoplasm of the
neoplastic cells ranges from
eosinophilic to vacuolated,
depending on their lipid
content. Mitotic activity is
generally inconspicuous.
• Tumor cells most closely
resemble cells of the normal
zona fasciculata
 Adrenocortical carcinomas
• Overt carcinomas are large, invasive lesions, many
exceeding 20 cm in diameter, which efface the native
adrenal gland
• On cut surface are typically variegated, poorly demarcated
and contain areas of necrosis, hemorrhage, and cystic
change.
• Adrenal cancers have a strong tendency to invade the
adrenal vein, vena cava, and lymphatics. Metastases to
regional and periaortic nodes are common, as is distant
hematogenous spread to the lungs and other viscera
• Microscopically, may be composed of well-differentiated
cells, resembling those seen in cortical adenomas, or
bizarre, monstruous giant cells, which may be difficult to
distinguish from those of an undifferentiated carcinoma
metastatic to the adrenal. Between these extremes are
cancers with moderate degrees of anaplasia, some
composed predominantly of spindle cells.
 ADRENAL MEDULLA
• PHEOCHROMOCYTOMAS, neoplasm composed of
chromaffin cells, synthesizing and releasing
cathecolamines
– 10% arise in MEN (other 10% are familial, non-
MEN syndromes)
– 10% are extra-adrenal (“paragangliomas”)
– 10% are bilateral
– 10% are biologically malignant
– 10% are in childhood
The only criterion for malignancy is metastasis
 Histology
• Pheochromocytomas are paragagliomas originating in the
adrenal gland
• Their histologic pattern is quite variable. The tumors are
composed of polygonal to spindle-shaped chromaffin cells
or chief cells, clustered in small nests or alveoli
(zellballen) surrounded by sustentacular (hormonally
inactive) cells and by a rich vascular network
• The cytoplasm has a finely granular appearance, best
demonstrated with silver stains, due to the presence of
granules containing catecholamines. The nuclei are
usually round to ovoid, with a stippled “salt and pepper”
chromatin that is characteristic of neuroendocrine tumors
• Chief cells express neuroendocrine markers, while
sustentacular cells are S100+
 Multiple endocrine neoplasia
syndromes
Inherited conditions resulting in proliferative lesions
(hyperplasia, adenoma, carcinoma) of multiple
endocrine organs
Tumors occur at younger age than the sporadic
counterpart
Multiple lesions can be synchronous or
metachronous
Can be multifocal even at a single site
Are preceded by asymptomatic hyperplasia
More aggressive behaviour than sporadic cases
 MEN-1, Wermer Syndrome
• Primary
HYPERPARATHYROIDISM,
(hyperplasia>adenoma) – 100%
• Duodenopancreatic endocrine
tumors (gastrinomas)
• Pituitary adenoma, usually
prolactinoma
Caused by germline mutations in the MEN1 tumor
suppressor gene, which encodes a 610–amino acid
product (menin). How menin acts is poorly
understood, but it is clear that it plays a part in
regulating normal gene transcription in several
different pathways
 MEN-2
• MEN-2A (SIPPLE):
– medullary thyroid ca (100%)
– pheochromocytoma (40-50%)
– parathyroid hyperplasia (10-20%)
Activating mutations in the RET oncogene
• MEN-2B:
– Pheochromocytoma, medullary thyroid ca,
neuromas
A different, single activating mutation in the RET
oncogene
• Familial Medullary Thyroid CA