Adrenal Flashcards
Deficiency of 21-hydroxylase: Laboratory finding.
Elevated 17-hydroxyprogesterone.
Congenital lipoid adrenal hyperplasia: Definition.
Severest form of congenital adrenal hyperplasia: All gonadal and adrenal cortical steroids are markedly underproduced.
Congenital lipoid adrenal hyperplasia: Genes (2).
StAR (steroidogenic acute regulatory) protein.
P-450scc.
Classic presentation of congenital adrenal hyperplasia in females:
A. Newborn.
B. Older (3).
A. Virilization.
B. Postpubertal: Oligomenorrhea, hirsutism, acne.
Classic presentation of congenital adrenal hyperplasia in males:
A. Newborn.
B. Older (3).
A. Salt-losing crisis.
B. Prepubertal: Precocious puberty.
Non-classic presentation of congenital adrenal hyperplasia (3).
Newborns: Normal.
Around puberty: Virilization.
Pregnancy: May present with adrenal insufficiency.
Congenital adrenal hyperplasia: Histopathology (3).
All three cortical layers are thickened, but especially the zona reticularis.
Loss of zonation.
Lipid-poor cells.
Congenital lipoid adrenal hyperplasia: Histopathology.
Cholesterol-overloaded cells with rupture and cholesterol esters.
Congenital adrenal hyperplasia: Complication.
Adrenal cortical adenoma or carcinoma.
Congenital adrenal hyperplasia: Effect on adrenal medulla.
Glucocorticoid deficiency can impair development of the medulla, resulting in epinephrine deficiency and hypoglycemia.
Autoimmune adrenal insufficiency:
A. Frequency.
B. Antibodies (3).
A. Accounts for 75-90% of cases of primary adrenal insufficiency.
B. 21-hydroxylase, 17-hydroxylase, P-450scc.
Primary vs. secondary adrenal insufficiency: Biochemical differences (3).
Primary: Low ACTH, low aldosterone, high renin.
Secondary: High ACTH, normal aldosterone, normal renin.
Primary vs. secondary adrenal insufficiency: Gross-pathology difference.
Primary: Small, pale adrenal gland.
Secondary: Enlarged gland.
Adrenal insufficiency: How much adrenal tissue is essential to normal function?
About 10%.
Autoimmune polyglandular syndromes.
APS-1: Includes candidiasis and alopecia; mutation in AIRE-1.
APS-2: Schmidt’s syndrome.
Primary adrenal cortical hyperplasia: Types (3).
ACTH-independent macronodular hyperplasia.
Primary pigmented nodular adrenal cortical disease.
Other.
ACTH-independent macronodular hyperplasia: Syndrome that can cause it, and its gene.
McCune-Albright syndrome, GNAS1.
Primary pigmented nodular adrenal cortical disease: Syndromes (2).
Carney’s complex.
Isolated primary pigmented nodular adrenal cortical disease.
Primary pigmented nodular adrenal cortical disease: Genes (2).
PRKAR1A.
PDE11A.
Other syndromes (2) that can cause bilateral adrenal hyperplasia.
MEN-1.
FAP.
Secondary adrenal cortical hyperplasia: Causes (2).
Pituitary adenoma or hyperplasia.
Ectopic ACTH.
Adrenal cortical hyperplasia: Presentation.
Primary: Various endocrine abnormalities.
Secondary due to pituitary: Severe, typical Cushing’s syndrome.
Secondary due to ectopic ACTH: Severe, atypical Cushing’s syndrome.
Adrenal cortical hyperplasia: Pharmacological therapy.
Ketoconazole and similar drugs.
Adrenal cortical hyperplasia: Degree of enlargement (3).
Severe: Ectopic ACTH, AIMAH.
Mild or moderate: Pituitary disease, PPNAD.
Grossly inapparent: Conn’s syndrome due to hyperplasia of zona glomerulosa.
Enlargement may be nodular or diffuse.
Hyperplasia of zona glomerulosa: Histopathology (3).
Involvement limited to the periphery of the gland.
Abnormal continuity of the zona.
More than 5 nests thick.
ACTH-independent macronodular adrenal cortical hyperplasia: Histopathology (2).
Mixture of large clear cells and small compact cells.
Nodules of cells containing dark brown pigment.
Primary pigmented nodular adrenal cortical disease: Histopathology.
Cortical tissue between nodules is atrophic and disorganized.
Adrenal cortical hyperplasia: Immunohistochemistry.
AIMAH: 3β-hydroxysteroid dehydrogenase.
PPNAD: Synaptophysin, 17α-hydroxylase.
Clinical findings that favor adrenal adenoma over adrenal hyperplasia (2).
Solitary, unilateral nodule.
Evidence of autonomous growth.
Adrenal cortical adenoma: Familial syndromes (3).
MEN-1.
Familial hyperaldosteronism.
Congenital adrenal hyperplasia.
Spoardic adrenal cortical adenoma associated wth Conn’s syndrome: Genes (3).
KCNJ5: Potassium channel.
ATP1A1, ATP2B3: Na/K-ATPases.
Adrenal cortical adenoma: Most common hormonal excess.
None: Most adenomas are nonfunctioning.
Adrenal cortical adenomas: Presentations of the functioning types (4).
Cushing’s syndrome.
Conn’s syndrome.
Virilization (rare).
Feminization (strongly suggests adenocarcinoma).
Adrenal cortical adenomas: Possible colors (3).
Golden yellow: Conn’s syndrome.
Mahogany: Oncocytic.
Black: Pigmented (lipofuscin).
Adrenal cortical adenoma associated with Conn’s syndrome: Histopathology (2).
Clear, lipid-rich cytoplasm.
Spironolactone bodies (if spironolactone has been given).
Adrenal cortical adenoma: Histopathology of non-adenomatous tissue (2).
Cushing’s syndrome: Atrophy of zona reticularis.
Conn’s syndrome: Paradoxical hyperplasia of zona glomerulosa.
Electron microscopy of adrenal cortical adenomas: General (3).
Much lipid.
Much smooth endoplasmic reticulum.
Many mitochondria.
Electron microscopy of adrenal cortical adenomas: Mitochondria (2).
Aldosterone-producing cells: Lamellar cristae.
Steroid-producing cells: Tubulovesicular cristae.
Epithelioid angiomyolipoma: Biological behavior.
Can be malignant.
Epithelioid angiomyolipoma: Histopathology (2).
Polygonal epithelioid cells with much cytoplasm and sometimes with a large nucleolus, forming nests or sheets.
Some cells may be multinucleate or bizarre.
Epithelioid angiomyolipoma:
A. Immunohistochemistry.
B. Electron microscopy.
A. Cells express melanocytic and myoid markers.
B. Melanosomes and pre-melanosomes.
Adrenal cortical carcinoma: Hereditary syndromes (5).
Li-Fraumeni.
Beckwith-Wiedemann.
MEN-1.
Carney’s complex.
Hereditary isolated glucocorticoid deficiency.
Adrenal cortical carcinoma: Genes mutated in sporadic tumors (6).
TP53.
β-Catenin.
Menin.
PRKAR1A.
IGF-II.
MC2-R.
Adrenal cortical carcinoma:
A. How many are functional?
B. What is the most common function?
A. About 79%.
B. Virilization due to secretion of 17-ketosteroids and DHEA.
Adrenal cortical carcinoma: Treatment (2).
Complete resection if possible; otherwise, mitotane.
Adrenal cortical carcinoma: Typical size and weight.
14-15 cm; 100-1000 g.
Adrenal cortical carcinoma: Features diagnostic for malignancy (3).
Weight greater than 100 g.
Vascular invasion.
Metastasis.
ACTH-independent macronodular hyperplasia: Other associated genes.
ACTH receptor.
GIP, β-adrenergic receptor, LH receptor.
Adrenal cortical carcinoma: Diagnostic immunohistochemistry (4,2,2).
Positive: Inhibin-α, steroidogenic factor-1, Melan-A, D11.
Negative: β-Catenin (aberrant loss), chromogranin,
Variable: Cytokeratins, synaptophysin.
Adrenal cortical carcinoma: Prognostic immunohistochemistry (2).
Ki-67.
Cyclin E: Positive staining implies advanced stage.
Vascular invasion by adrenal cortical carcinoma:
A. Definition.
B. Sites of metastasis.
A. Thrombus must accompany tumor cells.
B. Liver, lung, lymph nodes.
Adrenal medullary hyperplasia: Associations (4).
MEN 2a, MEN 2b.
Beckwith-Wiedemann syndrome.
Cystic fibrosis.
Not: VHL syndrome, neurofibromatosis.
Adrenal cortical carcinoma: Histopathologic features suggestive of malignancy (5).
Necrosis.
Cellular atypia.
Increased mitotic activity.
Invasion beyond the adrenal gland.
Broad fibrous bands.
MEN 2a:
A. Synonym.
B. Inheritance.
C. Components.
A. Sipple’s syndrome.
B. Autosomal dominant.
C. Pituitary hyperplasia, medullary carcinoma of the thyroid, pheochromocytoma.
MEN 2a and MEN 2b: Gene and its location.
RET on chromosome 10q11.2.
MEN 2b:
A. Inheritance.
B. Components.
A. Autosomal dominant.
B. Same as those of MEN 2a, plus mucosal neuromas.
Adrenal medullary hyperplasia: Gross pathology (3).
Usually bilateral.
Nodular or diffuse.
By definition, nodules are less than 1 cm.
Adrenal medullary hyperplasia: Histopathology (2).
Cells may be enlarged or pleomorphic; may show increased mitotic activity.
Hyperplasia is histopathologically indistinguishable from pheochromocytoma.
Adrenal medullary hyperplasia: Special histopathologic feature.
Hyaline globules in MEN 2 syndromes.
Pheochromocytoma: How many are hereditary?
Almost half.
Pheochromocytoma: Genes (7).
VHL.
RET.
NF.
SDHA, SDHB, SDHC, SDHC.
Pheochromocytoma: How many are asymptomatic?
Up to 25%.
Pheochromocytoma: Instigators of symptoms (4).
Anesthesia.
Manipulation of the tumor.
Certain foods, drugs.
Pheochromocytoma: Diagnostic tests (4).
Urinary and plasma catecholamines.
Urinary metanephrines.
Urinary vanillylmandelic acid.
Pheochromocytoma: Histologic architecture.
Zellballen surrounded by sustentacular cells.
Pheochromocytoma: Cytology of tumor cells (3).
Granular cytoplasm.
Large nucleoli.
Intranuclear cytoplasmic inclusions.
Composite pheochromocytoma.
Also contains areas resembling neuroblastoma, ganglioneuroblastoma, or typical ganglioneuroma.
Pheochromocytoma: More specific immunohistochemical stains (2).
Tyrosine hydroxylase.
SDHB: Expression is lost in any tumor exhibiting a mutation of any of the genes for succinate dehydrogenase.
Pheochromocytoma: Significance of SDHB (2).
Usually mutated in extra-adrenal paraganglioma rather than in pheochromocytoma.
Mutation in pheochromocytoma suggests malignancy.
Pheochromocytoma: Electron microscopy.
Neurosecretory granules.
Pheochromocytoma: How to recognize a malignant one.
Only by the demonstration of distant metastases.
Histology does not help, even when there are bizarre tumor giant cells.
Ganglioneuroma: Origin (2).
De novo.
Maturation of neuroblastoma or ganglioneuroblastoma.
Ganglioneuroma: Possible laboratory findings (4).
Elevated HVA, VMA, VIP, and/or serotonin.
Ganglioneuroma: Cellular components (3).
Ganglion cells.
Schwann cells.
Mature fibroblasts.
Ganglioneuroma: Possible source of difficulty in histologic diagnosis.
Scarcity of ganglion cells can cause confusion with neurofibroma.
Ganglioneuroma: Immunohistochemistry (3).
Positive: S-100, synaptophysin, neurofilament.
Ganglioneuroma: Electron microscopy of ganglion cells (2).
Peripheral rough endoplasmic reticulum.
Neurosecretory granules.
Ganglioneuroma: Clinical behavior.
Benign, unless it undergoes transformation to an MPNST.
Ganglioneuroblastoma: Epidemiology.
Occurs mainly in toddlers.
Ganglioneuroblastoma: Most common site.
Abdomen.
Ganglioneuroma: Posterior mediastinum.
Ganglioneuroblastoma: Components.
Ganglioneuromatous component: Usually more than 50%.
Neuroblastomatous component.
Ganglioneuroblastoma: Subtypes (3).
Nodular classic.
Nodular atypical.
Intermixed.
Ganglioneuroblastoma: Nodular classic subtype.
Sharp demarcation between neuroblastomatous nodule and surrounding ganglioneuromatous component.
Ganglioneuroblastoma: Nodular atypical subtype (3).
No gross or microscopic nodules.
Ganglioneuromatous component forms a thin rim.
Metastases resemble neuroblastoma.
Ganglioneuroblastoma: Intermixed subtype (2).
No gross or microscopic nodules.
Microscopic foci of neuroblastomatous component.
Ganglioneuroblastoma: Prognostic difference among subtypes.
Intermixed: Better.
Nodular: Worse.
Ganglioneuroblastoma: Biochemical difference among subtypes.
Nodular subtype secretes more catecholamines.
Neuroblastoma: Most common sites (2).
Adrenal gland.
Posterior mediastinum.
Neuroblastoma: Classic signs of metastasis (3).
Periorbital ecchymoses.
Proptosis.
“Blueberry-muffin” skin.
Neuroblastoma: Paraneoplastic syndromes (2).
Intractable diarrhea due to secretion of VIP.
Opsoclonus-myoclonus syndrome.
Neuroblastoma: Histologic architecture.
Cells are arranged in vague lobules and may form Homer Wright rosettes (filled with pink fibrillary matter).
Pheochromocytoma: Prognosis.
Five-year survival rate
− Benign: 95%.
− Malignant: 44%.
Neuroblastoma: Subtypes.
Undifferentiated.
Undifferentiated and pleomorphic.
Poorly differentiated.
Differentiating.
Neuroblastoma: Undifferentiated (2).
Neuroblasts show no differentiation toward ganglion cells.
No neuropil.
Neuroblastoma: Undifferentiated and pleomorphic.
Same as undifferentiated neuroblastoma, except that neuroblasts are larger and more pleomorphic and have more cytoplasm.
Neuroblastoma: Poorly differentiated.
Fewer than 5% of neuroblasts show differentiation toward ganglion cells.
Neuroblastoma: Differentiating.
More than 5% of neuroblasts show differentiation toward ganglion cells.
Mitosis-karyorrhexis index: Number of cells to be counted.
5000.
Mitosis-karyorrhexis index: Ranges.
Low: Less than 2%.
Intermediate: 2-4%.
High: More than 4%.
Neuroblastoma: Mutation that confers poor outcome.
Amplification of MYCN (more than 10 copies).
Prognosis of neuroblastoma: Patient over 5 years of age.
Any neuroblastoma is considered to have unfavorable histology.
Prognosis of neuroblastoma: Patient between 18 months and 5 years of age, inclusive (3).
Undifferentiated or poorly differentiated: Unfavorable histology.
Differentiating: Favorable as long as the MKI is low (i.e. not intermediate or high).
Prognosis of neuroblastoma: Patient under 18 months of age (3).
Undifferentiated: Unfavorable histology.
Poorly differentiated or differentiating: Favorable as long as the MKI is low or intermediate.
Any tumor with a high MKI: Unfavorable.
Prognosis of neuroblastoma: DNA index.
A. Use.
B. Interpretation.
A. Used in patients under 1 year of age.
B. Hyperdiploidy or near-triploidy is better than near-diploidy or near-tetraploidy.
Prognosis of neuroblastoma: Expression of TRK.
TRK A, B, and C: Low or absent expression imparts poorer prognosis.
Neuroblastoma: Extracellular components (2).
Fibrillar matrix resembling neuropil.
Delicate fibrovascular septa separating the lobules.
Neuroblastoma: Definition of stage 4S.
Small, localized primary tumor with metastases to liver, skin, or bone marrow that nearly always spontaneously regress.
Neuroblastoma: Immunohistochemistry of tumor cells (5,2).
Positive: NSE, synaptophysin, chromogranin, neurofilament, Neu-N.
Negative: Cytokeratins and other non-neural markers.
Neuroblastoma: Associated hereditary syndromes (4).
Hirschsprung’s disease.
Congenital central hypoventilation.
Neurofibromatosis-1.
Neuroblastoma: Electron microscopy (3).
Cytoplasmic filaments.
Dense-core granules.
Microtubules.
Primary melanoma of the adrenal gland: Criteria (4).
Unilateral.
No previous melanoma.
No endocrine disorder.
No doubt about histology.
Primary melanoma of the adrenal gland: Gross pathology.
Often locally advanced at presentation, with renal adhesions.
Primary melanoma of the adrenal gland: Prognosis.
Death within 2 years.
Primary melanoma of the adrenal gland vs. pigmented adrenal cortical adenoma: Immunohistochemistry (3).
Both are positive for Melan-A.
Adenoma is negative for S100, HMB-45.
Primary melanoma of the adrenal gland vs. pheochromocytoma: Immunohistochemistry.
Both are positive for HMB-45.
The sustentacular cells of pheochromocytoma are positive for S-100.
Myelolipoma: Age group.
Middle-aged.
Myelolipoma: Presentation (2).
Usually asymptomatic.
Rarely causes Cushing’s syndrome or Conn’s syndrome.
Myelolipoma:
A. Gross pathology.
B. Histopathology.
A. Red and yellow cut surface.
B. Mature bone marrow and mature fat.
Myelolipoma: Variant.
Adenolipoma combines myelolipoma and adrenal cortical adenoma.
Myelolipoma: Extraadrenal sites (3).
Liver.
Retroperitoneum.
Stomach.
Adrenal cyst: Size and structure.
Usually small and unilocular.
Adrenal cyst: Types (4).
Endothelial (most common).
Pseudocyst.
Epithelial.
Parasitic.
Endothelial adrenal cyst: Types (3).
Lymphangioma.
Angioma.
Hamartoma.
Adrenal pseudocyst:
A. Etiology.
B. Histopathology.
A. Previous hemorrhage.
B. Fibrous wall; no epithelial or endothelial lining.
Epithelial adrenal cyst: Types (3).
Adenoma.
Glandular cyst or retention cyst.
Embryonal.
Parasitic adrenal cyst:
A. Etiology.
B. Histopathology.
A. Parasites, esp. Echinococcus.
B. May contain fat or bone marrow.
Adrenal cysts: Radiography (2).
Pseudocyst: Mural calcification.
Endothelial cyst: Septal calcification.
Metastasis to the adrenal gland: Most frequent primary sites (4).
Lung.
Stomach.
Esophagus.
Liver.
Metastasis to the adrenal gland: Gross pathology (2).
Usually multifocal but can be solitary.
Usually involve the cortex.
Metastasis to the adrenal gland: Renal-cell carcinoma.
May mimic adrenal cortex histologically but does not express inhibin A or SF-1.
Metastasis to the adrenal gland: Hepatocellular carcinoma (2).
May mimic adrenal cortex histologically but can show bile staining.
Positive for HepPar-1, canalicular polyclonal CEA, canalicular CD10.
