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A 45-year-old woman with headaches and palpitations was found to be hypertensive and to have a left adrenal gland mass. The resected adrenal gland weighed 120 grams and was largely occupied by an 8.0 cm circumscribed mass with a mottled gray and red cut surface and central cystic change. A compressed rim of adrenal cortex was splayed over the surface.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2005, Case 14 and is a Pheochromocytoma.
Criteria for Diagnosis and Comments:
The histologic sections of this adrenal gland mass show are characteristic of pheochromocytoma. The cells are epithelioid and arranged in a nested, alveolar ("zellballen") pattern with a richly vascular reticulin framework that is typical of pheochromocytoma and other paragangliomas. Some sections show degenerative changes, which were evident grossly; others show focal fibrosis. The cells have abundant eosinophilic cytoplasm and variably sized nuclei with prominent nucleoli. There is regional nuclear pleomorphism and a low mitotic index.
Adrenal gland pheochromocytoma is a paraganglioma, a tumor of neuroendocrine cells. Extra-adrenal retroperitoneal paragangliomas may also be called pheochromocytoma. While pheochromocytoma can occur at any age, it is most frequently seen in adults, equally affects men and women and can be clinically benign or malignant. It has been called the "10% tumor:" 10% bilateral, 10% extra-adrenal, 10% malignant and 10% occurring in children but these estimates probably reflect selection biases in retrospective studies. For example, bilaterality and tumors in childhood occur largely in the familial (genetic disease) setting: pheochromocytoma is a component of Multiple Endocrine Neoplasia (MEN) IIa and IIb syndromes, von Recklinghausen's disease and von Hippel-Lindau disease. In contrast, nearly all sporadic pheochromocytomas are unilateral.
The clinical presentation in this case is typical - headaches caused by paroxysmal hypertension and palpitations resulting from tachycardia. Catecholamines - norepinephrine and epinephrine - are secreted by most pheochromocytomas and cause these characteristic signs and symptoms. Urine tests to detect catecholamines or their catabolites are important in the preoperative evaluation of adrenal masses. Modern imaging by CT scan and MRI demonstrates these vascular masses. Arteriography, which requires adrenergic blockade to prevent hypertensive crisis, is rarely used today.
Pheochromocytomas range in size from 1 - 10 cm (average 3 - 5 cm) in diameter. Clinically benign examples tend to be smaller and lighter, ranging from 75 - 160 grams, while malignant tumors tend to be larger and heavier, weighing 200 - 800 grams. Sporadic examples are unicentric and appear as circumscribed but non-encapsulated masses. Pheochromocytomas originate in the adrenal medulla but obliterate this anatomic structure as they grow. The adrenal cortex tends to flatten and splay over the surface where it may appear grossly as a thin yellow rind or peel. These tumors are firm and gray-white, like the adrenal medulla from which they arise. Rich vascularity makes the tumor liable to hemorrhage, which may be evident grossly and, when marked, can be mistaken for a non-neoplastic hematoma. Focal softening and other degenerative changes may complicate larger examples and do not signify malignancy. Frank invasion of adjacent organs, however, is an ominous gross finding.
Pheochromocytomas have a distinctive microscopic architecture. Cells are typically round or polygonal in shape and grow in a mixed trabecular and alveolar or nested ("zellballen") pattern. Nests may be small or large and the latter may undergo degeneration or necrosis. Approximately 2% have admixed areas of spindle-shaped cells. Reticulum staining serves to highlight the nested pattern as well as rich vascularity. The interface with adrenal cortical cells may be ill-defined despite a gross impression of sharp circumscription. Pheochromocytoma cell cytoplasm exhibits a variety of staining patterns. While usually lightly eosinophilic with a fine granularity, some examples stain quite densely and may resemble oxyphil or "oncocytic" cells. Melanin pigment, intracytoplasmic lipid vacuoles, PAS (+) hyaline globules and intranuclear eosinophilic "pseudoinclusions," the latter created by invaginations of the nuclear membrane, can also be seen. As is true in other neuroendocrine and endocrine tumors, nuclear size, shape, and staining character can vary considerably but does not correlate with clinical behavior. Stromal changes include fibrosis (common) and amyloid (uncommon).
Pheochromocytoma can often be diagnosed on the basis of its distinctive clinicopathologic characteristics: catecholamine-induced manifestations, anatomic location, and microscopic appearance. Further aids to diagnosis include histochemical and immunohistochemical stains. Neuroendocrine cells, both normal and neoplastic, have cytoplasmic granules and vesicles. The former are characteristically argyrophilic and can be identified with a Grimelius stain. Immunohistochemical staining for chromogranin A and synaptophysin is always positive in pheochromocytoma and other paragangliomas. Neuron specific enolase (NSE) is also positive but its wide distribution in other cell types reduces its diagnostic utility. Low molecular weight keratins, inhibin, and melanocytic markers Melan-A and HMB-45 are generally negative in pheochromocytoma, which can help to distinguish it from adrenal cortical neoplasms and metastatic melanoma, respectively.
Pheochromocytoma is reported to be malignant in 10% of cases but the mortality rate ranges from 2.5 - 15% in different series. No specific feature of the primary tumor serves to reliably separate clinically benign from malignant pheochromocytoma except for the presence of metastatic disease at the time of presentation. Aside from this, clinically malignant behavior is more likely if the tumor is large (several hundred grams), has a high mitotic index (> 3/10 hpfs, on average) or exhibits extensive local and vascular invasion. Interestingly, DNA flow cytometry studies have shown that diploid tumors, which account for about one third of cases, behave in a uniformly benign manner.
While distinguishing clinically benign from malignant pheochromocytoma may be a vexing problem, diagnosing adrenal gland pheochromocytoma is usually not difficult. The differential diagnosis may include adrenal cortical adenoma (ACA), a benign neoplasm which, when "functional," may be associated with primary hyperaldosteronism, Cushing's syndrome, virilization and (rarely), feminization. ACAs are usually much smaller than pheochromocytoma, are grossly bright yellow and have a lipid-rich, clear cell microscopic appearance. Their immunohistochemical staining profile (inhibin (+), chromogranin A (-), synaptophysin (-)) contrasts with that of pheochromocytoma.
Diffuse or nodular adrenal medullary hyperplasia (AMH) is defined as "an increase in chromaffin cells with expansion of the adrenal medulla into areas of the gland where it is not normally present." It may manifest itself as catecholamine hypersecretion and usually occurs in MEN IIa and IIb, but can occasionally clinically mimic sporadic pheochromocytoma. In contrast to mass-forming pheochromocytoma, it causes thickening of the medulla and glandular enlargement. The distinction between AMH and pheochromocytoma in persons with MEN syndromes can be difficult - almost arbitrary -- but is usually straightforward in sporadic instances.
Adrenal pseudocyst is a generic term for non-neoplastic cystic masses in the adrenal gland that are usually hematomas with various degrees of organization. Distinguishing them from pheochromocytoma in a patient without evidence of excessive catecholamine secretion relies on generous histologic sectioning to rule out neoplasm.
Last, but not least, in the differential diagnosis of the adrenal mass is metastatic carcinoma. While primary neoplasms of the adrenal gland are unusual, metastatic carcinoma -from any of the most common sites: breast, lung, kidney, etc. -- is not. In fact, metastatic carcinoma is the most common cause of a mass in the adrenal gland. The clinical setting, as well as the distinctive microscopic and immunophenotypic patterns of pheochromocytoma, generally serves to easily set it apart from metastatic carcinoma.