Adrenocortical carcinoma

* We report a combination of unusual myxoid change and extensive lipomatous metaplasia of an adrenocortical carcinoma. The patient was a 38-year-old man with hypertension and heart failure. Radiographic examination revealed the presence of a left adrenal tumor, and adrenalectomy was performed. The tumor weighed 380 g and appeared encapsulated. The cut surface was predominantly gelatinous. Histologically, the tumor was composed of atypical round cells with eosinophilic to vacuolated cytoplasm. The tumor was diagnosed as adrenocortical carcinoma. The stroma accumulated copious mucinous material. In addition, individual to nodular mature adipocytes were admixed throughout the tumor. The transition from carcinoma cells to mature adipocytes was recognized. Myxoid change is a very rare phenomenon in adrenocortical carcinoma, and only 10 similar cases have been reported to date. Lipomatous metaplasia is another peculiar feature of adrenocortical lesions that has been reported only in benign conditions. To our knowledge, this is the first reported case of adrenocortical carcinoma with lipomatous metaplasia.

(Arch Pathol Lab Med. 2003;127:227-230)

Myxoid change or degeneration in adrenocortical tumors is a rare phenomenon. This condition may be defined as the presence of copious mucinous material in the stroma associated with a gelatinous macroscopic appearance. Since Tang et al1 reported the first case of myxoid adrenocortical carcinoma in 1979, 9 additional cases have been described in the literature.2,3 Lipomatous metaplasia (LM), although rare in the neoplastic state, is observed as a stromal reaction in malignant tumors of the ovary, testis, breast, kidney, and other organs.4 In the adrenal gland, LM is also a very rare phenomenon, but in contrast to the tumors arising in other organs, this change has been noted only in benign lesions, such as cortical hyperplasia,5 adrenocortical adenoma,6 and other disorders.7,8 To the best of our knowledge, LM in adrenocortical carcinoma has not been reported previously.

We report a case of adrenocortical carcinoma with local recurrence and multiple metastases, which histologically exhibited marked myxoid change and extensive LM of the tumor.

REPORT OF A CASE

A 38-year-old man was admitted to the Emergency Ward of Tokyo Medical University Hospital, Tokyo, Japan, because of congestive heart failure and hypertension. Examination on admission revealed that the patient was moderately obese (88 kg and 170 cm) and hypertensive (190/110 mm Hg). The patient's serum adrenaline level was 300 pg/mL (normal

PATHOLOGIC FINDINGS

Gross Findings

The resected left adrenal gland weighed 380 g and measured 13.5 x 7.5 x 5.0 cm. The adrenal gland was almost totally replaced by a well-encapsulated, vaguely bosselated tumor. The compressed nonneoplastic adrenal gland was barely recognizable on the surface. The cut surface of the tumor bulged and was confluent tan, yellow, to flesh-- colored with a diffuse, gelatinous, glittering appearance in the major part of the lesion (Figure 1). Foci of hemorrhage and necrosis also were detected on the cut surface.

Microscopic Findings

The tumor was entirely encapsulated by a fibrous capsule of variable thickness. The predominant tumor cells were round to polygonal with eosinophilic to vacuolated cytoplasm. The tumor cells grew in solid and trabecular patterns. The nuclei of the tumor cells were pleomorphic and exhibited mild to severe atypia with hyperchromasia and prominent nucleoli. Mitotic figures were readily identifiable, and capsular and vascular invasions were apparent. The findings satisfied the criteria of Weiss et a19 for malignant adrenocortical tumors. Mucinous degeneration was intense, and in several areas tumor cells were present in small clusters floating in mucin lakes (Figure 2, a). In areas where the degeneration was not prominent, the tumor cells were arranged in sheets separated by sinusoids, into which tumor invasion was readily recognizable. Another distinctive morphologic change was the admixture of adipocytes throughout the tumor nodule (Figure 2, b). The ratio of adipocytes to tumor cells varied markedly among the areas, ranging from those in which individual adipocytes were scattered within sheets of the tumor cells to the lipoma-like nodules. In the region in which adipocytes were prominent, the tumor cells were mainly composed of vesicular-type cells associated with stromal myxoid degeneration of various degrees. Vacuoles in the cytoplasm of the tumor cells varied from fine granular structures in cells with small amounts of cytoplasm to large vesicles with reticular septa in cells with large amounts of cytoplasm. As the size of the tumor cells increased, the cytoplasms merged, and the cells appeared to undergo a transition into mature adipocytes (Figure 2, c). Alcian blue/periodic acid-Schiff double-staining highlighted tumor cell cytoplasm in pink and mucinous background in blue. Fat staining by Sudan black IV confirmed the presence of abundant lipids in the vacuolated tumor cell cytoplasm and mature adipocytes.

Immunohistochemistry

Details of the commercially available reagents used for immunohistochemistry are summarized in the Table. The tumor cells were positive for cytokeratin (CK), synaptophysin, cl-inhibin, and melan-A, but were negative for chromogranin. The CK was present in the tumor cell cytoplasm intensively just below the cytoplasmic membrane. The larger tumor cells, with confluent vacuoles, preserved their CK intensity mainly along the cell membrane. In the transition from small tumor cells to large vacuolar cells, the intensity of the CK weakened, and in the mature lipocytes there was no reaction (Figure 3, a). A number of the large vacuolated tumor cells expressed S100 protein in their nuclei and cytoplasms (Figure 3, b). All mature lipocytes were highlighted by S100 protein. Almost all the tumor cells also exhibited immunoreactivity for adrenal 4 binding protein, a transcription factor of steroidogenesis and an immunohistochemical marker of steroidogenic cells.10 This finding indicated an adrenocortical origin of the lesion. Among the enzymes involved in steroidogenesis, P450 side-chain cleavage enzyme, 3(beta)-hydroxysteroid dehydrogenase, P450 11(beta)-hydroxylase, P450 21-hydroxylase, and P450 17(alpha)-hydroxylase were positive in most of the tumor cells. On the other hand, dehydroepiandrosterone sulfotransferase was only rarely expressed. The Ki-67 labeling index was 7%.

COMMENTS

Myxoid change of adrenocortical carcinoma is a remarkably rare phenomenon, with a total of 10 cases reported in the literature since the original report by Tang et al in 1979.1 Brown et al2 and Forsthoefel3 reported the presence of myxoid change in 6 adrenocortical adenomas, in addition to 8 cases of carcinoma. These reports have shown that the severity of the myxoid change did not have any effect on clinical behavior.

The possible explanation for the myxoid change is that there may be a correlation between the functional status of the tumor and the degree of myxoid change. In the case reported by Tang et al,1 the tumor was nonfunctional and exhibited extensive myxoid change. In the case reported by Forsthoefel,3 the myxoid change was limited to only 10% of the tumor and was associated with Cushing syndrome.3 In the cases reported by Brown et al,2 the average size of the myxoid area in the nonfunctional adrenocortical neoplasms was approximately 61%, whereas it was 43% in the cases associated with overt adrenocortical dysfunction.2 In our case, both cortisol and aldosterone levels were markedly elevated, with expression of steroidogenic enzymes in the tumor cells. Hypertension can be attributed to elevated aldosterone and epinephrine/norepinephrine levels, which was most likely caused by secretion from the compressed adrenal medulla.

Until now, LM in the adrenal gland has only been associated with benign disorders, including pseudocyst,7 hyperplasia,5 primary pigmented nodular adrenocortical disease, and adenoma.6 Therefore, LM has been regarded as one of the hallmarks of benignity in adrenocortical diseases.5 To the best of our knowledge, this is the first reported case of adrenocortical carcinoma with extensive LM. In our case, the adipocytes were admixed throughout the tumor nodule, and the tumor was entirely surrounded by the fibrous capsule. We, therefore, suggest that the adipocytes were not entrapped by tumor invasion, but rather an intrinsic component of the tumor itself.

It has not been determined whether the cells capable of metaplastic transformation are tumor cells or parenchymal cells. It has been speculated that LM represents metaplastic change of altered parenchymal cells.4,7 In our case, the area of extensive LM coincided with that of myxoid degeneration, and this fact might raise the possibility of LM being a reactive process. However, the direct relationship between degeneration and myxoid change has not been adequately proven, and other degenerative features, such as hemorrhage and necrosis, were not related to the severity of the myxoid changes. In addition, in the case of adrenocortical carcinomas, which may elicit a more severe reactive process than benign conditions, LM has not been reported. Also, 10 cases of reported adrenocortical carcinoma with demonstrated myxoid changes did not exhibit LM. Taking these findings into consideration, the phenomenon of LM cannot be fully explained as a simple reactive process. As an alternative explanation, our case raised the possibility of the metaplasia of the neoplastic cells. Our case contained cells at various stages of metaplasia, ranging from atypical cancer cells to mature adipocytes. As lipid accumulated in the cytoplasm of the cancer cells, the cytoplasm expanded and filled with coarse vacuoles. These cells merged into larger cells with vesicular cytoplasm and eventually may have become mature adipocytes.

Immunohistochemistry for CK and S100 protein successfully demonstrated the transition. Immunostaining for CK was intensely positive in the small eosinophilic cytoplasm of the cancer cells. The large, confluent, vacuolated cells with confluent vacuoles exhibited submembranous CK positivity, and eventually mature lipomatous cells lost all CK reactivity. On the other hand, staining for S100 protein highlighted lipocytes well, but only marginally in the vacuolated cancer cells. Therefore, the cancer cells themselves may have undergone transition into adipocytes in this case, but further investigations are required for clarification.

We have reported a case of adrenocortical carcinoma with unusually extensive myxoid degeneration and extensive LM. The myxoid type is a rare variant of adrenocortical carcinoma; the pathogenesis of the change is not well understood. Myxoid change is not correlated with the degree of malignancy or functional activities of adrenocortical tumors. Because extensive LM previously has been recognized only in benign adrenocortical lesions, this case uniquely suggests that carcinoma cells may turn into metaplastic adipocytes.

This study was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan.

References

1. Tang CK, Harriman BB, Toker C. Myxoid adrenal cortical carcinoma: a light and electron microscopic study. Arch Pathol Lab Med. 1979;103:635-638.

2. Brown FM, Gaffey TA, Wold LE, Lloyd RV. Myxoid neoplasms of the adrenal cortex: a rare histologic variant. Am J Surg Pathol. 2000;24:396-401.

3. Forsthoefel KF. Myxoid adrenal cortical carcinoma: a case report with differential diagnostic considerations. Arch Pathol Lab Med. 1994;118:1151-1153. 4. Helenon 0, Merran S, Paraf F, et al. Unusual fat-containing tumors of the kidney: a diagnostic dilemma. Radiographics. 1997;17:129-144.

5. Finch C, Davis R, Truong LD. Extensive lipomatous metaplasia in bilateral macronodular adrenocortical hyperplasia. Arch Pathol Lab Med. 1999;123:167169.

6. Feldberg E, Guy M, Eisenkraft S, Czernobilsky B. Adrenal cortical adenoma with extensive fat cell metaplasia. Pathol Res Pract. 1996;192:62-65; discussion, 66.

7. Gaffey MJ, Mills SE, Medeiros LJ, Weiss LM. Unusual variants of adrenal pseudocysts with intracystic fat, myelolipomatous metaplasia, and metastatic carcinoma. Am J Clin Pathol. 1990;94:706-713.

8. Park YK, Kim YW, Kim JW, et al. Bilateral primary pigmented nodular adrenocortical disease: a case of Isid report describing a rare cause of Cushing's syndrome J Korean Med Sci. 1994;9:450-457.

9. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic significance in adrenocortical carcinoma, Am J Surg Pathol. 1989;13:202-206.

10. Sasano H. Localization of steroidogenic enzymes in adrenal cortex and its disorders. Endocr]. 1994;41:471-482.

Miki Izumi, MD; Hiromi Serizawa, MD; Keiichi Iwaya, MD; Kazuhiro Takeda, MD; Hironobu Sasano, MD; Kiyoshi Mukai, MD

Accepted for publication May 14, 2002.

From the Department of Pathology (Drs Izumi and Mukai), Division of Hospital Pathology (Drs Serizawa and Iwaya), and Department of Cardiology (Dr Takeda), Tokyo Medical University, Tokyo, Japan; and the Department of Pathology (Dr Sasano), Tohoku University School of Medicine, Sendai, Japan.

Reprints: Kiyoshi Mukai, MD, Department of Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402 Japan (e-mail: kmukai@tokyo-med.ac.jp).

Copyright College of American Pathologists Feb 2003
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