Oncocytoma

* We report the clinical, pathologic, and immunohistochemical features of an unusual tumor of the kidney composed of densely eosinophilic, polygonal epithelioid cells. The patients were a 56-year-old woman and a 35-year-old man. The renal tumors were discovered during follow-up for breast carcinoma and evaluation for abdominal pain, respectively. The tumors closely resembled oncocytoma in routine sections, but were negative for epithelial markers and positive for HMB-45, a pattern of reactions characteristic of angiomyolipoma. In the woman, a single additional microscopic angiomyolipoma was present in the renal parenchyma at a distance from the main tumor. Both patients are alive without recurrence 7 and 10 years after surgery, respectively. Based on clinical, morphologic, and immunophenotypic features, we conclude that these tumors are oncocytoma-like angiomyolipomas.

(Arch Pathol Lab Med. 2002;126:610-612)

Incocytoma is a renal epithelial neoplasm composed of polygonal cells with abundant, finely granular, eosinophilic cytoplasm filled with densely packed mitochondria. Typical architectural patterns include sheets, islands, and tubules.1-3 Immunohistochemical studies have confirmed the epithelial nature of renal oncocytoma, showing the expression of a variety of epithelial markers and the absence of vimentin.4 Hundreds of oncocytomas have been studied during the past 25 years, and it is clear that oncocytoma is benign.5

In this study, we report the clinical, pathologic, and immunohistochemical features of 2 unusual angiomyolipomas of the kidney composed of densely eosinophilic epithelioid cells resembling oncocytoma.

REPORT OF CASES

Case 1

This 56-year-old woman was seen in routine follow-up for breast carcinoma, which had been resected 5 years earlier. A sonogram showed a 25-mm tumor in the lateral aspect of the right kidney. Surgical enucleation was performed. During this surgical procedure, an additional 5-mm subcapsular nodule was found and removed. Subsequently, the patient was evaluated for cutaneous and neurological findings of tuberous sclerosis, and none was found. Seven years later, the patient is well and without recurrence.

Case 2

A 35-year-old man presented with abdominal pain. Radiographic evaluation revealed a 50-mm renal tumor. Nephrectomy was performed. The patient was evaluated for cutaneous and neurological findings of tuberous sclerosis, and none was found. Ten years later, the patient is well and without recurrence.

MATERIALS AND METHODS

The 2 cases we describe are from the files of the Dipartimento di Patologia-Sezione Anatomia Patologica dell' Universita' di Verona, Verona, Italy. Tissue specimens were fixed in formalin (10%) for 24 to 48 hours and routinely processed for paraffin embedding. The original sections were examined, and new sections were prepared from the blocks and stained with hematoxylin-eosin, periodic acid-Schiff (with and without diastase), and immunohistochemically with the avidin-biotin method and a panel of antibodies recognizing the following molecules: vimentin (Amersham, Buckinghamshire, England; dilution 1:10), cytokeratin AEl/AE3 (Boehringer, Mannheim, Germany; 1:500), cytokeratin CAM5.2 (Becton Dickinson, Mountain View, Calif; 1:10), epithelial membrane antigen (Dakopatts, Glostrup, Denmark; 1: 50), chromogranin (Enzo Diagnostics, New York, NY; 1:10), HMB-45 (gp100 protein; Dakopatts; 1:40), S100 protein (Dakopatts; 1:500), desmin (D33; Dakopatts; 1:500), and smooth muscle actin (1A4; Dakopatts; 1:100).

Ten oncocytomas and 30 angiomyolipomas from the files of the Dipartimento di Patologia-Sezione Anatomia Patologica dell' Universita' di Verona were compared with the study tumors.

PATHOLOGIC FINDINGS

Gross Pathology

The tumors were well circumscribed, approximately spherical, and 25 mm (case 1, Figure 1) and 50 mm (case 2) in diameter. Their cut surfaces were homogeneous, glistening, and tan.

Microscopic Pathology

The 2 tumors were histologically similar. The tumors were composed of sheets of densely packed, mediumsized and large, deeply eosinophilic cells (Figure 2, A). Neither tumor had a fibrous pseudocapsule. The neoplastic cells had regular polygonal contours and resembled epithelial cells (Figure 2, B). No glandular architecture was present. The neoplastic cells had single, nearly spherical nuclei with single central nucleoli (Figure 2, C). Occasional nuclei contained eosinophilic cytoplasmic pseudoinclusions. Mitotic figures were rare. Necrosis was absent. Neither fascicles of smooth muscle cells nor thick-walled tortuous blood vessels were present. Fat cells were not present in the tumors. In the tumor of case 1, a 5-mm synchronous subcapsular angiomyolipoma also was present.

Immunohistochemical Findings

Immunohistochemical results were the same for both tumors. Approximately 10% of their cells had strong cytoplasmic immunoreactivity for HMB-45 (gp100 protein) (Figure 2, D and E). In the tumor of case 1, the reaction with antibody to smooth muscle actin showed focal staining at the cytoplasmic membrane (Figure 2, F). Reactions with antibodies to vimentin, desmin, and 5100 protein were negative. Reactions with antibodies to epithelial markers (AEl/AE3, CAM5.2 [Figure 2, G], and epithelial membrane antigen) were negative in the tumor cells and strongly positive in nearby normal renal parenchyma.

Oncocytomas and Angiomyolipomas

The oncocytomas were composed of a homogeneous population of polygonal cells with deeply eosinophilic cytoplasm. The cells were arranged in sheets and formed microscopic cysts. Their small, uniform nuclei lacked mitotic activity. Neither necrosis nor papillae were present. All of the oncocytomas reacted with antibodies to the epithelial markers and failed to react with HMB-45 (gp100 protein), actin, desmin, 5100 protein, and vimentin. The control angiomyolipomas were composed of mixtures of abnormal blood vessels, spindle and epithelioid smooth muscle cells, and fat. In 2 of the control tumors, scattered epithelioid smooth muscle cells had deeply eosinophilic cytoplasm closely resembling the cells in the 2 tumors described in this article (Figure 2, H). The angiomyolipomas displayed positive reactions for HMB-45 and actin in the smooth muscle component in a variable percentage of cells and S100 protein immunoreactivity in the adipose tissue.

COMMENT

Renal oncocytoma is a benign epithelial tumor with well-characterized morphology that makes up approximately 5% of surgically resected renal neoplasms in adults. The differential diagnosis of renal oncocytoma has included other epithelial neoplasms, principally the eosinophilic variant of chromophobe renal cell carcinoma and occasionally clear cell renal cell carcinoma with diffuse areas of cells with finely granular eosinophilic cytoplasm.1-3 The present tumors add angiomyolipoma to the differential diagnosis of renal oncocytoma.

Immunohistochemistry can be helpful in arriving at the correct diagnosis. In contrast with the epithelial immunohistochemical phenotype typical of oncocytomas,4 the tumors we describe did not react with antibodies to cytokeratins or epithelial membrane antigen. Conversely, the tumors reacted with HMB-45, and one of them reacted with antibody to actin, reactions typical of angiomyolipoma6 and not found in oncocytoma. One of the tumors occurred in a kidney that also contained a 5-mm classic angiomyolipoma, indicating a presumptive diagnosis of tuberous sclerosis, according to the criteria of Gomez.7 Based on the clinical, morphologic, and immunohistochemical data, we conclude that these tumors are angiomyolipomas that resemble renal oncocytomas in routine sections.

Recently, a monotypic epithelioid variant of angiomyolipoma closely resembling high-grade or sarcomatoid renal cell carcinoma has been described in patients with and without tuberous sclerosis and has been given the name "epithelioid angiomyolipoma."8-15 Several of the patients with these tumors have died of metastases and recurrence. Since the present tumors lack the atypical features of epithelioid angiomyolipoma and both have shown no sign of malignancy, we conclude that it would be inappropriate to call them epithelioid angiomyolipomas and favor the term oncocytoma-like angiomyolipoma.

Recognition of oncocytoma-like angiomyolipoma is significant because oncocytomas in the same kidneys as angiomyolipomas have been reported repeatedly, and in patients with tuberous sclerosis there is some evidence that oncocytomas occur more frequently than in the general population.16 Some of these cases could be oncocytomalike angiomyolipomas rather than oncocytomas. In 1985, Srinivas et al17 reported an oncocytoma in a patient with tuberous sclerosis who surprisingly was without angiomyolipomas. The photomicrographs showed a morphology overlapping the tumors reported here, suggesting that this neoplasm could be an oncocytoma-like angiomyolipoma. This tumor was later recognized to be an angiomyolipoma.3 That oncocytomas can also resemble angiomyolipoma is underscored by an unusual case of renal oncocytoma with islands of fat within it, mimicking angiomyolipoma.18 We have had the opportunity to examine this tumor and immunohistochemically confirm that it is an oncocytoma.

In conclusion, these tumors demonstrate that angiomyolipoma may resemble renal oncocytoma and, because of the adverse prognostic significance of epithelioid angiomyolipoma, we suggest the name oncocytoma-like angiomyolipoma for these tumors. Immunohistochemistry is useful in making the diagnosis, and we suggest that a panel of markers, including epithelial markers and HMB-45 (gp100 protein), be applied to oncocytic tumors in patients with tuberous sclerosis.

This study was supported by Progetto Sanita 96/97 Fondazione Cassa di Risparmio di VR-VI-BL-AN, Verona, Italy, and Progetti Finalizzati Regione Veneto, Italy.

The authors thank Giuseppe Zamboni, MID, for helpful discussion; Janice Lage, MD, for providing materials from the oncocytoma with islands of fat reported in reference 18; and Licia Montagna, Paola Piccoli, Bertilla Magnaguagno, and Giorgio Bettio for their skillful technical assistance.

References

1. Eble JN, Hull MT. Morphologic features of renal oncocytoma: a light and electron microscopic study. Hum Pathol. 1984;15:1054-1061.

2. Amin MB, Crotty TB, Tickoo SK, Farrow GM. Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol. 1997;21:1-12.

3. Perez-Ordonez B, Hamed G, Campbell S, et al. Renal oncocytoma: a clinicopathologic study of 70 cases. Am] Surg Pathol. 1997;21:871-883.

4. Pitz S, Moll R, Stoerkel S, Thoenes W. Expression of intermediate filament proteins in subtypes of renal cell carcinoma and in renal oncocytomas: distinction of two classes of renal cell tumors. Lab Invest. 1987;56:642-653.

5. Eble JN. Neoplasms of the kidney. In: Bostwick DG, Eble JN, eds. Urologic Surgical Pathology. St Louis, Mo: Mosby; 1997:83-147.

6. Pea M, Bonetti F, Zamboni G, et al. Melanocyte-marker-HMB-45 is regularly expressed in angiomyolipoma of the kidney. Pathology. 1991;23:185-188.

7. Gomez MR. Definition and criteria for diagnosis. In: Gomez MR, ed. Tuberous Sclerosis Complex. 3rd ed. New York, NY: Oxford University Press; 1999: 10-23.

8. Martignoni G, Pea M, Bonetti F, et al. Renal epithelioid oxyphilic neoplasms (REON): a pleomorphic monophasic variant of renal angiomyolipoma [abstract]. Int] Surg Pathol. 1995;2(suppl):539.

9. Mai KT, Perkins DG, Collins JP. Epithelioid variant of renal angiomyolipoma. Histopathology. 1996;28:277-280.

10. Eble JN, Amin MB, Young RH. Epithelioid angiomyolipoma of the kidney: a report of five cases with a prominent and diagnostically confusing epithelioid smooth muscle component. Am] Surg Pathol. 1997;21:1123-1130.

11. Pea M, Bonetti F, Martignoni G, et al. Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. Am J Surg Pathol. 1998;22:180-187.

12. Martignoni G, Pea M, Bonetti F, et al. Carcinoma-like monotypic epithelioid angiomyolipoma in patients without evidence of tuberous sclerosis: a clinicopathologic and genetic study. Am I Surg Pathol. 1998;22:663-672.

13. L'Hostis H, Deminiere C, Ferriere JM, Coindre JM. Renal angiomyolipoma: a clinicopathologic, immunohistochemical, and follow up study of 46 cases. Am I Surg Pathol. 1999;23:1011-1020.

14. Leroy X, Moukassa D, Gosselin B. Renal epithelioid angiomyolipoma: a clinicopathological and immunohistochemical study of three cases. J Urol PathoL 1999;11:59-67.

15. Lento P, Brown K, Unger P. Epithelioid angiomyolipoma presenting as flank pain in a pregnant woman. J Urol Pathol. 2000;12:123-131.

16. Jimenez RE, Eble JN, Reuter VE. Concurrent angiomyolipoma and renal cell neoplasia: a study of 36 cases. Mod Pathol. 2001;3:157-163.

17. Srinivas V, Herr HV, Hajdu EO. Partial nephrectomy for a renal oncocytoma associated with tuberous sclerosis. I Urol. 1985;133:263-265.

18. Curry NS, Schabel SI, Garvin AJ, Fish G. Intratumoral fat in a renal oncocytoma mimicking angiomyolipoma. AIR Am J RoentgenoL 1990;154:307308.

Guido Martignoni, MD; Maurizio Pea, MD; Franco Bonetti, MD; Matteo Brunelli, MD; John N. Eble, MD

Accepted for publication September 14, 2001.

From the Dipartimento di Patologia-Sezione Anatomia Patologica, Universita' di Verona, Verona, Italy (Drs Martignoni, Pea, Bonetti, and Brunelli); and Roudebush VA Medical Center, Indiana University, Indianapolis (Dr Eble).

Reprints: Franco Bonetti, MD, Dipartimento di Patologia-Sezione di Anatomia Patologica, Policlinico G. B. Rossi, Via delle Menegone, 10, Verona, 37134 Italy (e-mail: francobonetti@katamail.com).

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