Case 77 - Discussion

Uploaded: 2007-08-07, Updated: 2007-08-16

• Pheochromocytoma (Intra-adrenal paraganglioma)

Microscopic Description

• Microscopically, the tumor consists of a thick dense fibrotic capsule and internal septa. Areas of hemorrhage, degeneration, fibrosis and cystic changes are identified. The tumor cells are arranged in trabecular, solid and alveolar patterns in a vascular-rich network. Perivascular palisading of the tumor cells is identified. The tumor cells are large, polygonal to spindle-shaped with mildly variable sizes and are clustered with sustentacular cells. The tumors cell have abundant finely granular cytoplasm that is basophilic, eosinophilic or amphophilic. The tumor cells have one single round to oval or spindle nucleus with one prominent nucleolus. The chromatin are closely clumped in a salt and pepper pattern. In focal areas the tumor cells appear polymorphic with giant cell and multinucleation formation. No vascular, nerve or capsule invasion is identified, and no marked necrosis or atypical mitosis is present. No tumor beyond the capsule is noted.

Immunohistochemistry

• The tumor cells show diffusely strong positivity of NSE, chromogranin and weak reaction to synaptophysin. S100 highlights the sustentacular cells (very focal). The tumor cells are negative for CKAE1/3, inhibin, and NF. This pattern supports a diagnosis of pheochromocytoma. The Ki67 index of the tumor cells is very low (<1%).

Electron Microscopy

Cytogenetics

• Pending

Pheochromocytoma

Clinical Futures

• Intra-adrenal paraganglioma: pheochromocytoma arises from catecholamine-producing chromaffin cells in the adrenal medulla. Extra-adrenal paraganglioma: pheochromocytoma arises from extra-adrenal sympathetic and parasympathetic paraganglia, commonly occur below the diaphragm, most frequently in the organ of Zuckerkandl.;

• Classical symptoms: recurring episodes of Headaches (severe), Excess sweating (generalized), Racing heart (tachycardia and palpitations), Anxiety / nervousness (feelings of impending death), Nervous shaking (tremors), Pain in the lower chest or upper abdomen and Nausea;

• Laboratory diagnosis of pheochromocytoma: 24 hour urinary catacholamines and metanephrines.

• rule of 10s:

  10% associated with l familial syndromes: MEN-2A and MEN-2B, NF I, VHL, and Sturge-Weber syndrome. 10% extra-adrenal: most commonly in the organ of Zuckerkandl and the carotid body. 10% bilateral:  10% of nonfamilial adrenal pheochromocytomas are bilateral; this figure may rise to 70% in cases that are associated with familial syndromes. 10%  malignant: 20% to 40% of extra-adrenal tumor are malignant. 10%  in childhood: 10% of intra-adrenal pheochromocytomas arise in childhood, usually the familial subtypes, and with a strong male preponderance. The nonfamilial pheochromocytomas most often occur in adults between 40 and 60 years of age, with a slight female preponderance.

• Associated with several syndromes:

  Syndrome	Components	Notes
  MEN, type 2A (Sipple syndrome)	Medullary thyroid carcinomas and C-cell hyperplasia Pheochromocytomas and adrenal medullary hyperplasia Parathyroid hyperplasia Hirschsprung disease	95% of cases are associated with mutations in the ret proto-oncogene affecting 1 of 5 codons in exon 10 (codons 609, 611, 618, 620) or exon 11 (codon 634). The ret proto-oncogene, located on chromosome 10, encodes a tyrosine kinase receptor involved in the regulation of cell growth and differentiation.
  MEN, type 2B	Medullary thyroid carcinomas and C-cell hyperplasia; Pheochromocytomas and adrenal medullary hyperplasia; Mucosal neuromas, intestinal ganglioneuromatosis; Marfanoid features;  Hirschsprung disease.	A germline missense mutation in the tyrosine kinase domain of the ret proto-oncogene (exon 16, codon 918) has been reported to be present in 95% of patients with MEN 2B.
  von Hippel-Lindau	Renal, hepatic, pancreatic, and epididymal cystadenomas; Renal cell carcinomas; Pheochromocytomas; Angiomatosis; Cerebellar hemangioblastomas.	One study found that this syndrome was present in nearly 19% of patients with pheochromocytomas. More than 75 germline mutations have been identified in a VHL suppressor gene located on chromosome 3.
  von Recklinghausen (Neurofibromatosis)	Neurofibromatosis; Café au lait skin spots; Schwannomas, meningiomas, gliomas; Pheochromocytomas;	Only 1% of patients with neurofibromatosis have been found to have pheochromocytomas, but as many as 5% of patients with pheochromocytomas have been found to have neurofibromatosis.
  Sturge-Weber	Cavernous hemangiomas of 5th cranial nerve distribution; Pheochromocytomas
  Tuberous sclerosis (Bourneville disease, epiloia)
  PGL1, PGL3 and PGL4		Paraganglioma syndromes type 1 (PGL1), type 3 (PGL3), and type 4 (PGL4) are caused by mutations in the SDHD, SDHC and SDHB genes, respectively

Gross Findings

• The tumors are well-circumscribed and may produce a lobular pattern. The cut surfaces of smaller pheochromocytomas are yellow-tan. Larger lesions tend to be hemorrhagic, necrotic, and cystic.

Microscopic Findings

• Histologically, the tumor cells are arranged into trabecular, solid or alveolar (zellballen) pattern in a rich vascular network. Some tumor cells may be arranged in a glandular or acinar pattern. Large tumors commonly display hemorrhage and necrosis;

• The tumors are polygonal to spindle-shaped  and are clustered with the sustentacular cells. Some tumors may be composed of spindle cells or relatively small cells. The tumor cells vary in size and shape and have finely granular basophilic or eosinophilic or amphophilic cytoplasm. Some tumor cells may contain abundant cytoplasmic vacuoles.

• The tumor cells have one round or oval nucleus with one prominent nucleolus. The chromatin may be coarsely clumped (salt and pepper chromatin). Nuclear pseudoinclusions may be prominent in some tumors. Nuclear giantism and hyperchromasia are common.

• PAS+ (resistant to diastase) cytoplasmic hyaline globules are noted in up to 60% cases.

• Some tumors may have prominant sclerosis. Amyloid is present in some tumors.

• The 2004 WHO criteria define malignancy by the presence of metastases. No histologic feature can—by itself—identify metastatic potential, including local invasion, capsular or vascular invasion, cytologic atypia, or areas resembling pediatric neuroblastoma. Suspicous features: extra-adrenal location, larger tumor, confluent necrosis, and vascular invasion or extensive local invasion.

Subtypes

• Familial pheochromocytoma
• Composite pheochromocytoma
• Childhood pheochromocytoma
• Pseudopheochromocytoma
• Malignant pheochromocytoma

Differential Diagnosis

Immunohistochemistry Straining

• Positive: chromogranin, synaptophysin, neurofilament and NSE;
• Negative: cytokeratin and vimentin;
• S-100 is restricted to the peripheral sustentacular cells (not tumor cells).

Election Microscopy

• Electron microscopy reveals variable numbers of membrane-bound, electron-dense granules, representing catecholamines and sometimes other peptides.

Cytogenetics

Patricia L.M. Dahia. Evolving concepts in pheochromocytoma and paraganglioma. Current Opinion in Oncology 2006, 18:1–8

Treatment and Prognosis

Reference

• http://www.emedicine.com/med/topic1816.htm

• Bravo EL, Gifford RW Jr. Pheochromocytoma: diagnosis, localization and management. N Engl J Med 1984;311:1298-1303

• N Engl J Med. 2002 May 9;346(19):1486-8.

• http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=171300

• Curr Urol Rep. 2007 Jan;8(1):83-8.

• Nature Clinical Practice Endocrinology & Metabolism (2007) 3, 92-102.

• Robbins & Cotran Pathologic Basis of Disease

• Essentials of anatomic pathology, Liang Cheng

• AFIP, 3rd series, 19