College of American Pathologists

2011—May Case of the Month

Posted May 20, 2011


CAP Foundation May 2011 Online Case of the Month

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Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, and Case 14 is adrenal cortical carcinoma.

Criteria for Diagnosis and Comments: This is an adrenal cortical carcinoma, a rare tumor that occurs at a frequency of one per million population per year or 0.2% of all malignancies. It has a bimodal age distribution with a small peak in the first and second decade and a larger peak in the fifth decade. There is also an increased frequency seen in patients with Li Fraumeni syndrome, Beckwith-Wiedemann syndrome and congenital adrenal hyperplasia.

Adrenal cortical carcinomas occur slightly more frequently in females. They are functional in 62% of cases at initial presentation which is defined as showing clinical endocrine manifestations or elevated hormone levels. In adults, Cushing syndrome is the most common syndrome associated with adrenal cortical tumors. Sex steroid overproduction or mixed syndromes are less common. Mineral corticoid overproduction rarely occurs. The remaining 38% of patients have nonfunctional tumors and commonly present with abdominal pain and sometimes a palpable mass.

Adrenal cortical carcinoma cells grow in trabecular, nested (or acinar) and diffuse patterns. Admixtures of these patterns are common, but characteristically they are trabecular with anastomosing cords and thick columns of cells separated by a delicate vascular sinusoidal network. Some tumors have a prominent myxoid pattern. A diffuse growth pattern is more commonly seen in adrenal cortical carcinomas than adenomas. The cells are usually lipid depleted with eosinophilic cytoplasm rather than foamy or vacuolated clear cytoplasm; nuclear atypia and pleomorphism are usually conspicuous. Occasionally the eosinophilic cells form intracytoplasmic hyaline globules which may be a source of confusion with pheochromocytoma. Adrenal cortex is immunoreactive to vimentin, however, reactivity to cytokeratins may be variable depending on fixation characteristics of the tissue used for testing (i.e. frozen or formalin fixed) and antigen retrieval techniques. Adrenal cortical tumors are negative for cytokeratins in formalin fixed tissue unless antigen retrieval techniques are utilized and then the tumors are only focally weak positive. Melan-A, inhibin and calretinin are usually positive and useful in differentiating adrenal cortical neoplasms from other tumors. Most adrenal cortical carcinomas are positive for synaptophysin but negative for chromogranin.

The principal entities in the differential diagnosis of adrenal cortical carcinoma include adrenal cortical adenoma, pheochromocytoma, renal cell carcinoma and metastatic carcinoma. Careful analysis will be diagnostic in most cases; however, there is no single criterion that is diagnostic of adrenal cortical carcinoma.

At one time the importance of tumor weight was overemphasized. Adrenal cortical tumors less than 50 grams were considered benign while those more than 100 grams were considered malignant. Although tumor weight is a useful, it is not a totally dependable parameter. Tumors less than 50 grams have metastasized and tumors more than 1,000 grams have not metastasized during long follow-up. In adults, carcinomas average 510 to 1,210 grams from several series of cases.

The development of the histologic criteria for differentiating adrenal cortical adenomas from carcinomas was encumbered by the rarity of carcinomas. Some of the early criteria utilized clinical symptoms, biochemical data and tumor weight. A system proposed by Weiss utilizes only histologic criteria. This is not to say that the clinical data are not useful, but they may be incomplete or not be available. The nine histologic features used by Weiss are listed in Table 1.

Table 1 (from Medeiros & Weiss 1992)

1. High nuclear grade (criteria of Fuhrman and coworkers)

2. Mitotic rate greater than 5 per 50 high-powered fields (HPF)

3. Atypical mitotic figures

4. Eosinophilic tumor cell cytoplasm ( > 75% of tumor cells)

5. Diffuse architecture ( > 33% of tumor)

6. Necrosis

7. Venous invasion (smooth muscle in wall)

8. Sinusoidal invasion (no smooth muscle in wall)

9. Capsular invasion

If there are less than two of these features, the tumors do not metastasize; while if there are three or more features, the tumors can recur or metastasize. The three most important criteria are mitotic activity of > 5 per 50 HPF, atypical mitoses and venous invasion which are found only in malignant tumors. Evaluation of multiple sections may be necessary to adequately evaluate for malignancy. Some of the sections in this case only show focal areas of striking nuclear pleomorphism and mitotic counts may vary from slide to slide. Additionally, vascular invasion is only focal and not represented on each slide. Therefore a single slide analysis may not be sufficient to make an unequivocal diagnosis of malignancy.

Both MIB-1 and p53 show a significant difference in their expression in benign and malignant adrenal cortical tumors. However, they are not recommended as yet for routine use.

Pheochromocytoma is an important entity in the differential diagnosis; the age range of cases is similar to adrenal cortical carcinoma. Pheochromocytomas may grow in a trabecular, alveolar (nesting or zellballen) or solid pattern; many show a mixture of these patterns. Intracytoplasmic eosinophilic hyaline globules are found within tumor cells of up to 45% of cases, but they may also be seen in up to 10% adrenal cortical tumors. Lipid degeneration and ACTH overproduction by a pheochromocytoma may also cause confusion with an adrenal cortical tumor. Immunohistochemistry is helpful in distinguishing adrenal cortical tumors from pheochromocytoma. It is important to keep in mind that both pheochromocytoma and adrenal cortical carcinoma are immunoreactive for synaptophysin, although pheochromocytoma is much stronger. Adrenal cortical carcinoma is chromogranin (-), inhibin (+), melan A (+), calretinin (+) and S-100 (-), while pheochromocytoma is chromogranin (+), inhibin (-), melan A (-) and calretinin (-); S-100 is immunoreactive only in the nuclei of the sustentacular cells.

Renal cell carcinoma may involve the adrenal gland by direct extension or metastasis. Histologic features that favor renal cell carcinoma include the formation of glands and abundant cytoplasmic glycogen. Immunohistochemistry can be very helpful. Adrenal cortical carcinoma is usually inhibin (+), melan A (+), cytokeratin (-), CD10 (-), RCC (-); however, conventional/clear cell renal cell carcinoma is usually inhibin (-), melan A (-), cytokeratin (+), CD10 (+), RCC (+). Recently PAX-2 and PAX-8 have been shown to be sensitive markers for renal cell carcinoma.

Metastatic carcinoma may pose significant challenges. There is a wide range of tumors that metastasize to the adrenal gland; lung and breast carcinoma are among the most common. Melanoma, gastric and colonic adenocarcinoma, and renal cell carcinoma are other contenders. Typically adrenal cortical carcinomas are negative or only focally weak positive for cytokeratin. Most carcinomas metastatic to the adrenal gland are strongly positive for cytokeratin and positive for other markers also such as CEA and EMA. Adrenal cortical carcinoma is also inhibin (+), and melan A (+), while metastatic carcinoma is inhibin (-), and melan A (-). If a specific primary tumor is suspected, immunohistochemical stains can be chosen for a tumor from that specific primary site.

The prognosis of adrenal carcinoma is very poor. At the time of initial diagnosis, 7% have the tumor confined to the adrenal, 41% have locally advanced disease and 52% have distant metastasis. The overall median survival is 14 months and the 5 year survival is 24%. Cases with > 20 mitoses per 50 hpf have a median survival of 14 months while those cases with < 20 mitosis per 50 hpf have a median survival of 58 months.

Supplementary Questions:
A. True
B. False

Question Diagnostic Set
1. The three most important histologic features used in differentiating adrenal cortical carcinoma from adrenal cortical adenoma are: mitotic activity of > 5 per 50 hpf, atypical mitoses and venous invasion. A. True
B. False
2. Tumor weight is a reliable means of determining if an adrenal cortical tumor is benign or malignant. A. True
B. False
3. Adrenal cortical carcinomas are usually positive for both synaptophysin and chromogranin by immunohistochemistry. A. True
B. False


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  7. Mazal PR, Stichenwirth M, Koller A, Blach S, Haitel A, Susani M. Expression of aquaporins and PAX-2 compared to CD10 and cytokeratin 7 in renal neoplasms: a tissue microarray study. Mod Pathol. 2005; Apr; 18(4):535-540.
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Robert H. Knapp, MD, FCAP
Surgical Pathology Committee
Pathology Laboratory, PC
Grandville, MI