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2010—September Case of the Month

Posted October 06, 2010


CAP Foundation September 2010 Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A 55-year-old woman, otherwise healthy, presented with flank pain and a renal mass. The resected kidney contained a 10 cm circumscribed yellow and pink-tan tumor that bulged above the renal contour into the perirenal fat but without renal capsular penetration.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 14 and is an angiomyolipoma.

Criteria for Diagnosis and Comments: This lesion is a classical angiomyolipoma (AML), which is the most common mesenchymal tumor of kidney. AML is a benign clonal neoplasm arising in the cortex, medulla, or occasionally in surrounding tissues, and true to its name is typically composed of an intimate admixture of abnormal vessels, smooth muscle, and fat, as in this case.

One third of these patients will have associated tuberous sclerosis which is most strongly suggested if lesions are multiple and/or bilateral. Conversely, eighty percent of those with fully expressed tuberous sclerosis will harbor angiomyolipomas. When associated with tuberous sclerosis, the lesions show no gender preference and tend to be small, bilateral, multifocal, and asymptomatic and therefore require no urgent intervention. Although this tumor is often found incidentally on scan it may clinically present as abdominal pain elicited by hemorrhage from the elastin-deficient vessels inherent in this lesion. The more common sporadic variety typically occurs in adult females from fourth to sixth decade, is rarely discovered prior to puberty, may enlarge rapidly during pregnancy, and is usually progesterone receptor-positive, all suggesting a hormonal influence. Radiographic studies are usually characteristic due to its typical fat content. Treatment is surgical resection or selective arterial embolization to avoid potential life-threatening hemorrhage particularly in those lesions associated with pregnancy or greater than 4 cm.

The gross appearance may be hemorrhagic, myomatous or lipomatous depending upon the relative amount of these three constituents. Microscopically, thick-walled vessels with eccentric lumina and reduced or defective elastic lamina are present within mature-appearing adipose tissue. Smooth muscle cells, which at least focally appear to radiate from vessel walls, will always display a characteristic vacuolated, “moth-eaten” cytoplasmic appearance, likely in part due to its rich glycogen content, and is a helpful clue in establishing the diagnosis. These cells may be spindled and/or epithelioid. The latter correspond to the so-called perivascular epithelioid cell (PEC) which are found in varying amounts in all cases. Less often, diastase-resistant granules and crystalloids (similar to those seen in alveolar soft part sarcoma) may be present in larger epithelioid cells. Multinucleation and minor degrees of nuclear atypia, with occasional mitoses, may be present. Minute stromal, and even glomerular, nodules composed solely of the epithelioid cells (so-called microhamartomas) can often be seen in the adjacent kidney, with or without associated tuberous sclerosis, and likely represent the precursor lesion to AML.

The smooth muscle component has a distinctive immunohistochemical profile in which there is co-expression of both melanocytic and smooth muscle markers, while epithelial markers and S100 (even in the adipose component) are consistently negative. HMB-45 and Mart-1/Melan-1, as well as ultrastructurally detected premelanosomes, may be found in both the spindled and epithelioid cells but tend to be expressed more in the latter while smooth muscle markers (such as smooth muscle actin) are more evident in the former. Why this smooth muscle-type cell contains melanosomes at all remains an enigma. As stated before, AML is typically positive for progesterone receptors. And finally, although some have reported the presence of CD117 in these tumors, other studies have cast doubt on this finding, therefore its diagnostic utility remains uncertain.

We now know that AML is also closely related to certain extra-renal lesions, such as (but not limited to) clear cell sugar tumor of lung and pancreas, lymphangioleiomyomatosis and cardiac rhabdomyoma by virtue of their shared common cell, the HMB45-positive perivascular epithelioid cell (PEC) that now defines this family of tumors as PEComas (formally known as “myomelanocytic” tumors). Interestingly, the normal counterpart of this unique cell has yet to be identified. It is now thought that the PEC is responsible for the histogenesis of these lesions with secondary morphologic differentiation to smooth muscle and fat. Interestingly, many of these extrarenal examples are more monotypic, composed of a population of uncommitted PECs that lack modulation toward either smooth muscle or adipose tissue, and often display an organoid/nested, and somewhat paragangliomatous, growth pattern that requires a high index of suspicion for their diagnosis.

Although benign examples may exhibit lymph node involvement due to multicentricity, true malignant AML can occur. These are almost purely epithelioid (monotypic) and hypercellular, containing highly atypical cells, with either eosinophilic or clear cytoplasm, with atypical mitoses, areas of necrosis and infiltrative growth. Therefore, renal tumors with these features should be considered potentially malignant with the potential for local aggressive growth and metastases. While most of these have been reported as renal cell carcinoma, melanocytic markers now readily allow separation of these two lesions. Similar lesions may also contain pigmented cells raising the possibility of metastatic melanoma. However, melanomas are traditionally negative for both glycogen and smooth muscle markers and, unlike AML, are always S100 positive. Oncocytoma may closely mimic the newly described monotypic oncocytoma-like variant but again HMB45 should be able to distinguish the two. Finally, those cases in which some components overwhelmingly predominate over others also pose a challenge. When fat dominates, or when tumor extends into Gerota’s fat, liposarcoma might be a diagnostic consideration particularly since vacuolated fat cells often occur in AML. The absence of S100 staining in the fat and presence of HMB45 positive cells elsewhere in the tumor would support AML. Those lesions that are solid, with few adipose and vascular elements, may be confused with leiomyosarcoma but while muscle markers are positive in both, only AML would be expected to express melanocytic markers.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. Renal tumors containing melanin pigment are diagnostic of melanoma. A. True
B. False
2. The diagnostic immunoprofile of classic angiomyolipoma is positive for HMB45 and SMA, and negative for S100 and Keratin. A. True
B. False
3. Monotypic epithelioid angiomyolipomas are potentially malignant neoplasms. A. True
B. False


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  2. Cibas ES, Goss GA, Kulke MH, et al. Malignant Epithelioid Angiomyolipoma (`Sarcoma Ex Angiomyolipoma') of the Kidney: A Case Report and Review of the Literature, Am J Surg Pathol. 2001;25(1):121-126.
  3. Eble J. Angiomyolipoma of kidney, Semin Diagn Pathol. 1998;15:1-40.
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  12. 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(2):180-187.
  13. Pea M, Bonetti F, Zamboni G, Martignoni G, Fiore-Donati L, Doglioni C. Clear cell tumor and angiomyolipoma. Am J Surg Pathol. 1991;15(2):199-202.
  14. Ribalta T, Lloreta J, Munne A, Serrano S, Cardesa A. Malignant pigmented clear cell epithelioid tumor of the kidney: clear cell ("sugar") tumor versus malignant melanoma. Hum Pathol. 2000;31(4):516-519.
  15. Stone CH, Lee MW, Amin MB, et al. Renal Angiomyolipoma: Further Immunophenotypic Characterization of an Expanding Morphologic Spectrum. Arch Pathol lab med. 2001;125:751–758.

Arthur Cohen, MD
Surgical Pathology Committee
Presbyterian Hospital
Charlotte, NC