Pheochromocytoma

* Adrenal tumors often present with clinical features that are specific and unique to their endocrine metabolism. When these features are in conflict with the pathologic appearance of the tumor, there can be great consternation for both the pathologist and the surgeon. In the case reported herein, an adrenalectomy was performed for clinical features of pheochromocytoma that on gross and histologic examination had the pathologic features of an adrenal cortical adenoma. Electron microscopy subsequently revealed that the tumor cells contained adrenalin-type granules, explaining the clinical outcome. It is crucial for both the surgeon and the surgical pathologist to be aware of this possibility when the clinical and pathologic features of an adrenal tumor are not congruent.

(Arch Pathol Lab Med. 2002;126:1530-1533)

The relationship between the adrenal cortex and medulla has been intensively studied, and coexpression of cortical and medullary features in individual cells has been described.1,2 Of note, cells with a bipotential or intermediate phenotype have been recognized since 1960, leading to terms such as mixed cells and corticomedullary cells.2

Although initially described during development, these features can also present in neoplasms of the adrenal cortex.1,2 The largest series of 5 adrenal cortical tumors with medullary features was published by Alsabeh et all in 1995. To our knowledge, there has been no case to date that describes the clinical signs and symptoms of a pheochromocytoma combined with the radiologic and pathologic features, and postsurgical symptomatic confirmation, of an adrenal cortical adenoma with neuroendocrine granules. Cases such as these can be a diagnostic dilemma for the pathologist and surgeon, and thus the importance of recognition of these entities is emphasized.

REPORT OF A CASE

The patient was a 57-year-old white man who presented with a 3-year history of severe refractory chronic hypertension with associated palpitations, diaphoresis, and flushing in the absence of precipitating factors. On physical examination, no appreciable abdominal mass was noted and the blood pressure ranged from 160/98 to 192/120 mm Hg while sitting. Orthostatic hypotension was not noted.

Twenty-four-hour urine studies were obtained following an episode of hypertension and revealed increased norepinephrine (93.6 (mu)g/24 h; normal,

The patient subsequently underwent laparoscopic left adrenalectomy for a presumptive pheochromocytoma. Intraoperative pathologic consultation revealed a 3-cm tumor within the cortex with a yellow cut surface, characteristic of an adrenal cortical tumor.

Removal of the tumor led to a resultant decrease in intraoperative blood pressure, and the postoperative course was characterized by blood pressures ranging from 176/94 to 130/45 mm Hg, measured immediately and for 4 days postoperatively. The patient was last examined 12 months postoperatively and was without hypertensive signs or symptoms. At this time, a blood pressure of 132/72 mm Hg was recorded.

MATERIALS AND METHODS

Histochemical and Immunohistochemical Analysis

Histologic examination was performed on 5-(mu)m, hematoxylineosin-stained sections from paraffin-embedded tissue. Immunohistochemical studies were performed using the avidin-biotin method with 3,3'-diaminobenzidine as the chromogen and included the following antibodies and dilutions: chromogranin (1: 50; Dako Corporation, Carpinteria, Calif), synaptophysin (1:100; Dako), and inhibin (1:100; Serotec, Oxford, United Kingdom). The periodic acid-Schiff (PAS) stain was applied with and without diastase (laboratory made).3

Electron Microscopy

Electron microscopy was performed on formalin-fixed tissue postfixed in 1% osmium tetroxide. Subsequent dehydration of the tissue in methanol was followed by embedding in Epon-Araldite. Ultrathin sections were examined on a Hitachi 600 transmission electron microscope (Hitachi Instruments, San Jose, Calif).

PATHOLOGIC FINDINGS

Gross Findings

The left adrenal lesion consisted of a 2.3 x 2.2 X 1.5-- cm yellow-orange to red nodule within the cortex of a 3.0 x 2.9 x 1.9-cm yellow-red adrenal gland with yellow, focally hemorrhagic cut surfaces and associated fibroadipose tissue. These findings were suggestive of an adrenal cortical adenoma. No additional lesions were identified. The entire specimen was submitted for microscopic evaluation.

Microscopic Findings

On light microscopy, the tumor was composed of nests, cords, and trabeculae of tumor cells, separated by delicate fibrovascular septae. These cells were present as uniform polyhedral cells with pale-to-eosinophilic, vacuolated cytoplasm, and centrally located, round-to-ovoid vesicular nuclei containing small, pink nucleoli (Figure 2, A). The special stain for PAS revealed scant PAS-positive, diastase-- resistant cytoplasmic granules. Immunohistochemical studies revealed the tumor cells to be focally positive for synaptophysin and inhibin and negative for chromogranin. Internal controls of PAS, synaptophysin, inhibin, and chromogranin in the adrenal medulla were positive.

Electron microscopy performed on formalin-fixed tissue demonstrated lipid vacuoles and smooth endoplasmic reticulum, consistent with adrenal cortical differentiation, along with multiple intracytoplasmic, adrenalin-type, dense core neurosecretory granules (Figure 2, B).

COMMENT

The pathogenesis and pathophysiology of adrenal tumors are closely related to the embryologic development of the adrenal gland. The adrenal cortex is of mesodermal origin, whereas the adrenal medulla is derived from the neural crest. The detection of adrenal tumors by radiologic imaging studies has become increasingly common, and most of these tumors are nonhypersecreting.4

Adrenal cortical adenomas appear grossly as well-circumscribed or encapsulated, 2- to 4-cm masses with yellow cut surfaces. These tumors can originate from all 3 cortical layers (zona glomerulosa, fasciculata, and reticularis), resulting in a possible hypersecretion of hormones (mineralocorticoids, glucocorticoids, and sex steroids) with the associated clinical syndromes (Conn syndrome, Cushing syndrome, and androgenital syndromes). In addition, hyposecreting tumors characterized by the absence of hormone overproduction have been documented. On electron microscopy, adrenal cortical adenomas express distinct cortical features, including tubulovesicular mitochondria characteristic of the zona fasciculata and reticularis, lipid vacuoles, and abundant, predominantly smooth endoplasmic reticulum. Therefore, the findings of cytoplasmic lipid vacuoles and smooth endoplasmic reticulum in our case are consistent with adrenal cortical differentiation. Surgical resection is indicated in a functional adrenal cortical adenoma. The discussion regarding the criteria for resection of nonfunctional adrenal cortical adenomas is still in progress, with discussions focusing on tumor size, with cutoff values for surgery ranging from 3.5 to 6 cm.4,5

In contrast, pheochromocytomas usually present as encapsulated, 3- to 5-cm, gray-tan to brown masses that are hemorrhagic and cystic. Prominent clinical signs and symptoms, associated with overproduction of catecholamines (mostly a combination of adrenalin and noradrenaline with predominance of noradrenaline), include paroxysmal, refractory hypertension, headaches, tachycardia, palpitations, sweating, anxiety, chest and abdominal pain, postural hypotension, tremor, nausea, vomiting, and flushing. Urine and serum studies usually reveal increased catecholamine levels. The histologic, immunohistochemical, and electron microscopic features are characteristic of medullary chromaffin cells and include intracytoplasmic PAS-positive, diastase-resistant hyaline globules and positivity for chromogranin, synaptophysin, and inhibin. Membrane-bound dense core neurosecretory granules, mitochondria of the tubulolamellar type, and predominantly rough endoplasmic reticulum are characteristic features on electron microscopy.

Eranko and Hanninen first described the coexistence of cortical and medullary features in adrenal cells in 1960, and terms such as mixed cells and corticomedullary cells have since been introduced.2 Some authors have argued that these findings are due to technical artifacts in tissue processing, with the neurosecretory granules being transferred from medullary into cortical cells during slicing and fixation.2 In our case, the clinical presentation and increased urine catecholamines make artificial transfer of neurosecretory granules into cortical cells unlikely.

The presence of cortical and medullary features within the same neoplastic cells as seen in our case has been previously described in approximately 97 cases.1,2,6-11 In these cases, most inferences were made through the identification of a single positive immunohistochemical stain for synaptophysin (52 cases).1,9-12 In 38 cases, various levels of study were performed to confirm the bipotential nature of the tumors, either by multiple immunohistochemical studies, messenger RNA studies for synaptophysin, or in one case, purification of catecholamines.1,7,8,10,11 In one case, the diagnosis was supported only by histologic examination.6 Electron microscopy was performed in only 6 cases. 12 8 This is the first report, to our knowledge, in which the presence of bipotential differentiation in an adrenal cortical tumor is examined by immunohistochemical analysis and electron microscopy and confirmed by the study of clinical signs and symptoms both preoperatively and postoperatively.

Two case reports have been published before the introduction of immunohistochemical analysis and electron microscopy, suggesting the existence of mixed cortical and medullary tumors, based on clinical signs and symptoms characteristic of pheochromocytomas, combined with microscopic features of cortical differentiation.6,7 In both cases, no medullary differentiation within the tumor was recognized histologically.6,7

Kovacs and Horvath2 describe a case of an aldosterone-- secreting cortical adenoma, consisting mostly of fasciculata cells but also containing cells with mixed cortical (smooth endoplasmic reticulum, lipid droplets, and mitochondria of the tubulovesicular type) and medullary features (rough endoplasmic reticulum and electrondense, membrane-bound granules). In the only series to examine this issue, Alsabeh et al1 studied 2 adrenal cortical carcinomas and 3 adrenal cortical adenomas, all clinically imitating pheochromocytomas, and showed immunohistochemical and electron microscopic evidence of medullary features in these tumors. The clinical follow-up showed distant metastatic spread in the 2 carcinomas at 15 and 12 months after operation.1 In 2 cases with adenoma, the patients were well with normal urine catecholamine levels and normal blood pressure 10 and 7 months after operation, similar to the clinical findings in our case. One patient was lost to clinical follow-up. Although all 5 patients presented with preoperatively elevated catecholamine secretion in serum or urine, none of these cases demonstrated persistent, preoperative, clinical catecholamine-associated signs and symptoms along with radiologic and microscopic features, as presented in this case report.

Although the histologic features favor a diagnosis of adrenal cortical adenoma in this case, the presence of increased catecholamine secretion necessitates the consideration of other tumor types as sources of the clinical signs. Tumors of neural crest origin, including neuroblastoma, ganglioneuroma, pheochromocytoma, extraadrenal paraganglioma, chemodectoma, medullary carcinoma of the thyroid, and carcinoid tumor, are capable of catecholamine production and can arise in various sites and organs and metastasize, with the adrenal gland as a possible target for distant metastasis. The presence of bilateral adrenal masses or the clinical evidence of a pulmonary mass, features not present in this case, should lead to the correct diagnosis, whereas the histologic features of copious eosinophilic granular cytoplasm and the insular or trabecular pattern may mimic a primary adrenal tumor. Tumor-associated hypertension related to catecholamine hypersecretion has also been reported in a patient with malignant schwannomatosis with increased serum catecholamine levels and electron-dense neurosecretory granules. The lack of a spindled fascicular architecture or S100 protein positivity help exclude this diagnosis in our case. In addition, there is a reported case of a noradrenaline-producing renal cell carcinoma, associated with markedly increased noradrenaline serum levels, chromogranin and synaptophysin positivity, and membrane-bound electron-dense granules. Due to the proximity of and propensity for renal cell carcinoma to spread to the adrenal cortex, this possibility should be excluded. Although similar histologic features make differentiation difficult, the use of immunohistochemical analysis, in particular inhibin staining in adrenal cortical tumors, as in this case, supports the correct diagnosis. In our patient, a careful clinical and radiologic examination failed to detect an occult primary tumor, and the resolution of catecholamine-related symptoms on surgery also supported the notion of this being the only source of the tumor. Elevated catecholamine levels can alIo be related to pressure on the splanchnic nerves by the tumor10 or adrenomedullary hyperplasia. However, the relatively small tumor size and absence of medullary hyperplasia rule this out in our case. Increased blood pressure in association with tumors can also be indirectly induced by certain tumor proteins, potentiating catecholamine-induced pressor activity, as seen in fibrosarcoma, hepatoma, and mammary carcinoma, although predominantly demonstrated in animal experiments.

The gross appearance, histochemical ana ysis, immunoprofile, and electron microscopy in our case revealed cortical (lipid vacuoles and smooth endoplasmic reticulum) and medullary features (PAS-positive, diastase-resistant cytoplasmic granules, synaptophysin and inhibin positivity, and dense core neurosecretory granules), a combined profile that would be incongruous with a metastatic neuroendocrine tumor. The presence of smooth endoplasmic reticulum and the absence of fegenerative changes preclude a diagnosis of lipid degeneration in a pheochromocytoma.

In summary, an adrenal cortical adenoma can clinically mimic a pheochromocytoma and should be considered when the gross and microscopic impressions are in conflict with the clinical presentation. Immunohistochemical analysis and electron microscopy can elucidate the true biphasic nature of these tumors. The surgical pathologist should be aware of this potential diagnostic dilemma and describe these findings in the accompanying report.

References

1. Alsabeh R, Mazoujian G, Goates J, Medeiros Li, Weiss LM. Adrenal cortical tumors clinically mimicking pheochromocytoma. Am J Clin Pathol. 1995;104: 382-390.

2. Kovacs K, Horvath E. Ultrastructural features of corticomedullary cells in a human adrenocortical adenoma and in rat adrenal cortex. Anat Anz. 1973;134: 387-393.

3. McManus JFA. Stain Techniques. Vol 23. Baltimore, Md: Williams & Wilkins Co; 1948:99-108.

4. Barzon L, Boscaro M. Diagnosis and management of adrenal incidentalomas. ) Urol. 2000;163:398-407.

5. Ross NS, Aron SC. Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med. 1990;323:1401-1405.

6. Robinson PL, Baker-Bates ET. Adrenal cortical carcinoma simulating a pheochromocytoma. Br J Surg. 1954;41:399-403.

7. Walters G, Wyatt GB, Kelleher J. Carcinoma of the adrenal cortex presenting as a pheochromocytoma: report of a case. J Clin Endocrinol. 1962;22:575-580. 8. Miettinen M. Neuroendocrine differentiation in adrenocortical carcinoma:

new immunohistochemical findings supported by electron microscopy. Lab Invest. 1992;66:169-174.

9. Schroder S, Padberg BC, Achilles E, Holl K, Dralle H, Kloppel G. Immunohistochemistry in adrenocortical tumors: a clinicomorphological study of 72 neoplasms. Virchows Arch. 1992;420:65-70.

10. Komminoth P, Roth J, Schroder S, Saremaslani P, Heitz PU. Overlapping expression of immunohistochemical markers and synaptophysin mRNA in pheochromocytomas and adrenocortical carcinomas: implications for the differential diagnosis of adrenal gland tumors. Lab Invest. 1995;72:424-431.

11. Haak HR, Fleuren G. Neuroendocrine differentiation of adrenocortical tumors. Cancer. 1995;75:860-864.

Tomislav Ivsic, MD; Richard A. Komoroski, MD; Gary S. Sudakoff, MD; Stuart D. Wilson, MD; Milton W. Datta, MD

Accepted for publication January 8, 2002.

From the Departments of Pathology (Drs Ivsic, Komorowski, and Datta), Radiology (Dr Sudakoff), and Surgery (Dr Wilson), Medical College of Wisconsin, Milwaukee, Wis.

Reprints: Milton W. Datta, MD, Department of Pathology, Medical College of Wisconsin, Dynacare Bldg LL69, 9200 W Wisconsin Ave, Milwaukee, WI 53226 (e-mail: mdatta@mcw.edu).

Copyright College of American Pathologists Dec 2002
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