Syndrome Components

MEN, type 2A Medullary thyroid carcinomas and C-cell hyperplasia

Pheochromocytomas and adrenal medullary hyperplasia

Parathyroid hyperplasia

MEN, type 2B Medullary thyroid carcinomas and C-cell hyperplasia

Pheochromocytomas and adrenal medullary hyperplasia

Mucosal neuromas

Marfanoid features

von Hippel-Lindau Renal, hepatic, pancreatic, and epididymal cysts

Renal cell carcinomas

Pheochromocytomas

Angiomatosis

Cerebellar hemangioblastomas

von Recklinghausen Neurofibromatosis

Café au lait skin spots

Schwannomas, meningiomas, gliomas

Pheochromocytomas

Sturge-Weber Cavernous hemangiomas of fifth cranial nerve distribution

Pheochromocytomas

MEN, multiple endocrine neoplasia.

Data from Silverman ML, Lee AK: Anatomy and pathology of the adrenal glands. Urol Clin North Am 16:417, 1989.

Morphology.

Pheochromocytomas range from small, circumscribed lesions confined to the adrenal ( Fig. 24-55 ) to large hemorrhagic masses weighing kilograms. The average weight of a

pheochromocytoma is 100 gm, but variations from just over 1 gm to almost 4000 gm have been reported. The larger tumors are well demarcated by either connective tissue or

compressed cortical or medullary tissue. Richly vascularized fibrous trabeculae pass into the tumor and produce a lobular pattern. In many tumors, remnants of the adrenal gland can be

seen, stretched over the surface or attached at one pole. On section, the cut surfaces of smaller pheochromocytomas are yellow-tan. Larger lesions tend to be hemorrhagic, necrotic, and

cystic and typically efface the adrenal gland. Incubation of fresh tissue with a potassium dichromate solution turns the tumor a dark brown color owing to oxidation of stored

catecholamines, thus the term chromaffin.

The histologic pattern in pheochromocytoma is quite variable. The tumors are composed of polygonal to spindle-shaped chromaffin cells or chief cells, clustered with the sustentacular

cells into small nests or alveoli (zellballen) by a rich vascular network ( Fig. 24-56 ). Uncommonly, the dominant cell type is a spindle or small cell; various patterns can be found in any

one tumor. The cytoplasm has a finely granular appearance, best demonstrated with silver stains, owing to the appearance of granules containing catecholamines. The nuclei are usually

round to ovoid, with a stippled "salt and pepper" chromatin that is characteristic of most neuroendocrine tumors. Electron microscopy reveals variable numbers of membrane-bound,

electron-dense granules, representing

Figure 24-55Pheochromocytoma. The tumor is enclosed within an attenuated cortex and demonstrates areas of hemorrhage. The comma-shaped residual adrenal is seen below.

Figure 24-56Pheochromocytoma demonstrating characteristic nests of cells ("zellballen") with abundant cytoplasm. Granules containing catecholamine are not visible in this

preparation. It is not uncommon to find bizarre cells even in pheochromocytomas that are biologically benign, and this criterion by itself should not be used to diagnose malignancy.

Figure 24-57Electron micrograph of pheochromocytoma. This tumor contains membrane-bound secretory granules in which catecholamines are stored (30,000X).

TABLE 24-12-- Multiple Endocrine Neoplasia (MEN) Syndromes

MEN-1 MEN-2A MEN-2B

Pituitary Adenomas

Parathyroid Hyperplasia +++ Hyperplasia +

Adenomas +

Pancreatic islets Hyperplasia ++

Adenomas ++

Carcinomas +++

Adrenal Cortical hyperplasia Pheochromocytoma ++ Pheochromocytoma +++

Thyroid C-cell hyperplasia +++ C-cell hyperplasia +++

Medullary carcinoma +++ Medullary carcinoma +++

Extraendocrine changes Mucocutaneous ganglioneuromas

Marfanoid habitus

Mutant gene locus MEN1 RET RET

Relative frequency: +, uncommon; +++, common.

MEN-1 syndrome is caused by germ-line mutations in the MEN1 gene at 11q13. This gene encodes a 610-amino acid product known as menin, which localizes primarily to the nucleus.

MEN1 is a classic tumor suppressor gene ( Chapter 7 ) in that both alleles are inactivated in the MEN-1-associated tumors.[131] The precise role of menin in tumor suppression remains

elusive, although recent studies have shown that it may be important in regulating the cell cycle and transcription. [132]

The dominant clinical manifestations of MEN-1 are usually defined by the peptide hormones that are overproduced and include such abnormalities as recurrent hypoglycemia due to

insulinomas, intractable peptic ulcers in patients with Zollinger-Ellison syndrome, nephrolithiasis caused by PTH-induced hypercalcemia, or symptoms of prolactin excess from a

pituitary tumor. As expected, malignant behavior by one or more of the endocrine tumors arising in these patients is often the proximate cause of death.

Date: 2016-04-22; view: 694