Adrenal Neoplasms MBBS pheochromocy.pptx

ANATOMY • 2 Adrenal gland also
called suprarenal gland.
• Each adrenal gland is found in
the epigastrium at the top of
the kidney opposite the 11th
intercostal end of the
vertebral space and the 12th
rib.
• In humans each adrenal gland
weighs about 5 grams and
measures about 30 mm wide,
50 mm long, and
10 mm thick.

ZONA GLOMERULOSA (5%)
Cells arranged in irregular ovoid
clusters separated by delicate
fibrous trabeculae.
ZONA FASICULATA (70%)
Middle and broadest zone.
Consists of narrow columns and
cords of cells. Cell cytoplasm is
abundant and pale staining due
to large no. of lipid droplets
present.
ZONA RETICULARIS (25%)
Consists of irregular network of
branching cords and clusters of
glandular cells.

• Adenomas and carcinomas are about equally common in adults.
• In children, carcinomas predominate.
• Most cortical neoplasms are sporadic.
• Two familial cancer syndromes are associated with a predisposition
for developing adrenocortical carcinomas: Li-fraumeni syndrome,
germline TP53 mutations and Beckwith- wiedemann syndrome, a
disorder of epigenetic imprinting.

• Functional adenomas are most commonly associated with
hyperaldosteronism and Cushing syndrome
• A virilizing neoplasm is more likely to be a carcinoma.
• Functional and nonfunctional adrenocortical neoplasms cannot be
distinguished on the basis of morphologic features.
• Determination of functionality is based on clinical evaluation and
measurement of hormones or hormone metabolites in the blood.

Adrenal cortical adenoma
Adrenal cortical adenoma - neoplasm of adrenocortical cell derivation
that lacks morphologic features of malignancy.
ACAs may be hormonally inactive or synthesize/secrete steroid
hormones.
Most frequent hormones produced :
• Cortisol – Cushing syndrome
• Aldosterone - Primary aldosteronism
Clinically silent.
Incidental findings at autopsy or during abdominal imaging for an
unrelated cause.

GROSS
Well- circumscribed
Nodular lesion up to 2.5 cm in
diameter that expands the
adrenal
Functional adenomas associated
with atrophy of the adjacent
cortex
Cortex adjacent to nonfunctional
adenomas is normal.
• Cut surface
Yellow to yellow- brown because
of the presence of lipid.

MICROSCOPY
composed of cells similar to
those populating the normal
adrenal cortex.
Small nuclei
some degree of pleomorphism
may be seen (“endocrine
atypia”).
cytoplasm of the neoplastic
cells ranges from eosinophilic
to vacuolated, depending on
their lipid content.
Mitotic activity is generally
inconspicuous.

lipid-rich clear cells
Adrenal cortical adenomas

Adrenocortical Carcinoma
• Rare neoplasms
• Occur at any age, including childhood.
• More functional than adenomas
• Associated with virilism or other clinical manifestations of
hyperadrenalism.
• Strong tendency to invade the renal vein, vena cava, and lymphatics.
• Metastases to regional and periaortic nodes are common, as is distant
hematogenous spread to lungs & other visceras.

GROSS
Large,
Invasive lesions,
Many exceeding 20 cm in
diameter, which efface the
native adrenal gland.
• Cut surface
Variegated,
 Poorly demarcated lesions
Containing areas of necrosis,
hemorrhage, and cystic
change.

MICROSCOPY
• composed of well-
differentiated cells,
resembling those seen in
cortical adenomas.
• Or bizarre, monstrous giant
cells which may be difficult to
distinguish from those of an
undifferentiated carcinoma
metastatic to the adrenal.
• moderate degrees of
anaplasia, some composed
predominantly of spindle
cells.
Figure 24-53 Adrenal carcinoma revealing marked anaplasia
contrasted with normal adrenal cortical cells

• Most important diseases of the adrenal medulla are neoplasms,
which include
Neoplasms of chromaffin cells (pheochromocytomas)
Neuronal neoplasms (neuroblastic tumors).

PHEOCHROMOCYTOMA
• Neoplasms composed of chromaffin cells, which synthesize and
release catecholamines and peptide hormones.
• The features of pheochromocytomas have been summarized by the
“rule of 10s”.
10 % of pheochromocytomas are extra-adrenal, occurring in sites
such as the organs of Zuckerkandl and the carotid body.
• Pheochromocytomas that develop in extra-adrenal paraganglia are
designated paragangliomas.
10 % of sporadic adrenal pheochromocytomas are bilateral.

10% of adrenal pheochromocytomas are biologically malignant,
Malignancy is more common (20% to 40%) in extra- adrenal
paragangliomas and certain germline mutations.
10% of adrenal pheochromocytomas are not associated with
hypertension.

25% of individuals with pheochromocytomas and paragangliomas harbor
a germline mutation in one one of at least six known genes.

• The affected genes fall into two broad classes, those that enhance
growth factor receptor pathway signaling (e.g., RET, NF1), and those
that increase the activity of the transcription factor HIF-1α.
• VHL gene encodes a tumor suppressor protein that is needed for the
oxygen-dependent degradation of HIF-1α and is mutated in patients
with von Hippel-Lindau (VHL) syndrome, which is associated with a
number of tumors, including pheochromocytoma.

• Other familial cases of pheochromocytoma are associated with
germline mutations in genes encoding components of the succinate
dehydrogenase complex (SDHB, SDHC, and SDHD).
• This complex is involved in mitochondrial electron transport and
oxygen sensing, and it is believed that these mutations also lead to
upregulation of HIF-1α, which appears to be a key oncogenic driver in
this type of tumor.

CLINICAL FEATURES
• Hypertension (90% of patients).
• More common: Chronic, sustained elevation in blood pressure
punctuated by the aforementioned paroxysms (precipitated by
emotional stress, exercise, changes in posture, and palpation in the
region of the tumor)
• Two thirds of patients with hypertension demonstrate paroxysmal
episodes (abrupt, precipitous elevation in blood pressure, associated
with tachycardia, palpitations, headache, sweating, tremor, and a
sense of apprehension).
• Associated with pain in the abdomen or chest, nausea, and vomiting.

GROSS
 Small to large hemorrhagic masses
 Circumscribed lesions confined to the adrenal
 Weighing kilograms.
 Average weight of a pheochromocytoma is 100 gm
(weights from 1 gm to 4000 gm).
 Larger tumors are well demarcated by either connective
tissue or compressed cortical or medullary tissue.
 Richly vascularized fibrous trabeculae within the tumor
produce a lobular pattern.
 Remnants of the adrenal gland can be seen, stretched
over the surface or attached at one pole.
 Cut surfaces
 Smaller are yellow-tan.
 Larger lesions tend to be hemorrhagic, necrotic & cystic
and efface the adrenal gland.
 Incubation of fresh tissue with a potassium dichromate
solution turns the tumor a dark brown color due to
oxidation of stored catecholamines.

MICROSCOPY
• Composed of clusters of polygonal
to spindle- shaped chromaffin cells
or chief cells
• Surrounded by supporting
sustentacular cells, creating small
nests or alveoli (zellballen) that are
supplied by a rich vascular network .
• Cytoplasm has a finely granular
appearance, best demonstrated
with silver stains, due to the
presence of granules containing
catecholamines.
• Nuclei are usually round to ovoid,
with a stippled “salt and pepper”
chromatin that is characteristic of
neuroendocrine tumors.

ELECTRON MICROSCOPY
• Reveals variable
numbers of
membrane-bound,
electron-dense
secretory granules.

IMMUNOHISTOCHEMISTRY
• Chromogranin and
synaptophysin is seen in the
chief cells.
• Peripheral sustentacular cells
stain with antibodies against S-
100, a calcium-binding protein
expressed by a variety of
mesenchymal cell types.
S100 Staining

• There is no histologic feature that reliably predicts clinical behavior.
• The definitive diagnosis of malignancy in pheochromocytomas is
based exclusively on the presence of metastases.
• Sites of metastasis: Regional lymph nodes, liver, lung, and bone.

COMPLICATIONS
• The elevations of blood pressure are induced by the sudden release of
catecholamines may lead to:
Congestive heart failure
Pulmonary edema
Myocardial infarction
Ventricular fibrillation
Cerebrovascular accidents.
• Cardiac complications called catecholamine cardiomyopathy, or
catecholamine-induced myocardial instability

LAB DIAGNOSIS
• Based on the demonstration of increased urinary excretion of free
catecholamines and their metabolites, such as vanillylmandelic acid
and metanephrines.

TREATMENT
• Isolated benign tumors are treated with surgical excision.
• After preoperative and intraoperative medication of patients with
adrenergic-blocking agents to prevent a hypertensive crisis.
• Multifocal lesions require long-term medical treatment for
hypertension.

NEUROBLATIC TUMORS
• The term neuroblastic tumor includes tumors of the sympathetic ganglia and
adrenal medulla that are derived from primordial neural crest cells populating
these sites.
• Neuroblastoma is the most important member of this family.
• Most common extracranial solid tumor of childhood.
• Most frequently (40%) diagnosed tumor of infancy.
• Prevalence is about one case in 7000 live births.
• Median age at diagnosis is 18 months.

• Most occur sporadically
• 1% to 2% are familial and may involve both of the adrenals or
multiple primary autonomic sites.
• Germline mutations in the anaplastic lymphoma kinase (ALK)
gene is identified as a major cause of familial predisposition
to neuroblastoma.
• Somatic gain-of-function ALK mutations are observed in less
than 10% of sporadic neuroblastomas.

• Sites of occurence:
• Adrenal medulla(40%).
• Paravertebral region of the abdomen (25%) and
• Posterior mediastinum (15%).
• Pelvis, the neck, and within the brain (cerebral neuroblastomas).
In situ neuroblastomas are reported to occur 40 times more
frequently than clinically overt tumors.

CLINICAL FEATURES
• Under age 2 years: large abdominal masses, fever, and weight loss.
• In older children, metastases produce manifestations, such as bone pain, respiratory symptoms,
or gastrointestinal complaints.
• Proptosis
• Ecchymosis due to spread to the periorbital region, a common metastatic site.
• Bladder and bowel dysfunction (due to paraspinal neuroblastomas that impinge on nerves).
• In neonates, multiple cutaneous metastases (disseminated neuroblastomas) that cause deep blue
discoloration of the skin ( “blueberry muffin baby”).

Pheochromocytoma Neuroblastoma
Produce catecholamines. 90% of neuroblastomas produce
catecholamines.
Elevated blood levels of
catecholamines and elevated urine
levels of the metabolites
vanillylmandelic acid [VMA] and
homovanillic acid [HVA])
Elevated blood levels of
catecholamines and elevated urine
levels of the metabolites
vanillylmandelic acid [VMA] and
homovanillic acid [HVA])
Hypertension is more common Hypertension is less common

GROSS
Minute nodules (so-called in situ
lesions) to large masses
More than 1 kg in weight.
Often sharply demarcated by a
fibrous pseudo-capsule
Some are infiltrative and invade
surrounding structures, including the
kidneys, renal vein, and vena cava,
and envelop the aorta.
Cut surface:
Soft, gray-tan
Larger tumors have areas of necrosis,
cystic softening, and hemorrhage.
Occasionally, foci of punctate intra-
tumoral calcification seen

MICROSCOPY
• composed of small, primitive-
appearing cells with dark nuclei,
scant cytoplasm, and poorly defined
cell borders growing in solid sheets.
• Mitotic activity, nuclear breakdown
(“karyorrhexis”) and pleomorphism
may be prominent.
• Background demonstrates a faintly
eosinophilic fibrillary material
(neuropil) which are neuritic
processes of the primitive
neuroblasts.
• Homer- Wright pseudorosettes
(tumor cells are concentrically
arranged about a central space filled
with neuropil )

ELECTRON MICROSCOPY
• small, membrane-bound,
cytoplasmic
catecholamine-containing
secretory granules
• the latter contain
characteristic central
dense cores surrounded
by a peripheral halo
(dense core granules).
Synaptic vesicle in a neuroblastoma cell. These vesicles are larger
and more irregular than the normal presynaptic terminals.
Numerous dense core neurosecretory granules are present.

IMMUNOHISTOCHEMISTRY
• positive reactions for
neuron-specific enolase.

• Metastases appear early and widely.
• Local infiltration and lymph node spread
• Hematogenous & lymphatic spread to liver, lungs, bone marrow, and
bones.

The International Neuroblastoma Staging
System
• Stage 1: Localized tumor with complete gross excision, with or without
microscopic residual disease; representative ipsilateral nonadherent
lymph nodes negative for tumor (nodes adherent to the primary tumor
may be positive for tumor).
• Stage 2A: Localized tumor with incomplete gross resection;
representative ipsilateral nonadherent lymph nodes negative for tumor
microscopically.
• Stage 2B: Localized tumor with or without complete gross excision;
ipsilateral nonadherent lymph nodes positive for tumor; enlarged
contralateral lymph nodes, which are negative for tumor
microscopically.

• Stage 3: Unresectable unilateral tumor infiltrating across the midline
with or without regional lymph node involvement; or localized
unilateral tumor with contralateral regional lymph node involvement.
• Stage 4: Any primary tumor with dissemination to distant lymph
nodes, bone, bone marrow, liver, skin, and/or other organs (except as
defined for stage 4S).
• Stage 4S (“S” = special): Localized primary tumor (as defined for
stages 1, 2A, or 2B) with dissemination limited to skin, liver, and/or
bone marrow; stage 4S is limited to infants younger than 1 year.

PROGNOSTIC FACTORS:
based on the collection
of prognostic factors,
classified either as low,
intermediate or high
risk.

Ganglioneuroma
• Better differentiated lesions
• Containing many more large cells resembling mature ganglion cells
• Presence of few residual neuroblasts.
• Either asymptomatic mass lesions or symptoms related to
compression.

Ganglioneuroblastoma
• Larger cells having more abundant cytoplasm, large vesicular nuclei, and a
prominent nucleolus, representing ganglion cells in various stages of
maturation admixed with primitive neuroblasts.
• Maturation of neuroblasts into ganglion cells is usually accompanied by the
appearance of Schwann cells.
• Presence of schwannian stroma composed of organized fascicles of neuritic
processes, mature Schwann cells, and fibroblasts is a histologic prerequisite
for the designation of ganglioneuroblastoma and ganglioneuroma.

LAB DIAGNOSIS
• Screening for asymptomatic tumors in children.
• Based on the demonstration of increased urinary excretion of free
catecholamines and their metabolites, such as vanillylmandelic acid
and homovanillic acid.

TREATMENT
• Use of retinoids as an adjunct therapy for inducing the differentiation
of neuroblastoma.
• Targeted inhibitors ALK and such agents are currently undergoing
evaluation in clinical trials.

Myelolipoma
• Unsual benign tumor
• Composed of mature fat and hematopoietic cells.
• Incidental findings
• Foci of myelolipomatous change may be seen in cortical tumors and in adrenals
with cortical hyperplasia.
• Occasional myelolipomas may reach massive proportions.

MICROSCOPY
 mature adipocytes are
admixed with
aggregates of
hematopoietic cells
belonging to all three
lineages.

Adrenal incidentaloma
• Incidental discovery.
• Asymptomatic individuals.
• In individuals in whom the presenting complaint is not directly related
to the adrenal gland.
• Estimated population prevalence of “incidentalomas” discovered by
imaging is approximately 4%,
• Age-dependent increase in prevalence.
• Majority are small nonsecreting cortical adenomas of no clinical
importance.

Adrenal Neoplasms MBBS pheochromocy.pptx

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