Mustafa Fuat Acikalin md, Gültepe Mah, Üniversite evleri, C3 Blok Daire 6, Eskisehir, Turkey. Email: firstname.lastname@example.org
Abstract Epithelioid angiomyolipoma is a recently recognized variant of angiomyolipoma, which is characterized by the presence of polygonal cells with densely eosinophilic cytoplasm and varying degrees of nuclear atypia. Only a relatively small number of cases of epithelioid angiomyolipoma of the kidney have been reported in the literature. We report a case of epithelioid angiomyolipoma of the kidney that occurred in a 38-year-old woman. The tumor was composed of diffuse sheets of epithelioid cells, adipocytes and only scattered thick-walled blood vessels. The epithelioid cells had pleomorphic and hyperchromatic nuclei with densely eosinophilic cytoplasm. Hemorrhage, necrotic foci and clusters of foamy macrophages were present. HMB-45, CD117 (c-kit) and CD68 were detected in the epithelioid cells. There was no expression of cytokeratin, epithelial membrane antigen or desmin. The patient showed no evidence of recurrence or metastatic disease 9 months after nephrectomy.
Angiomyolipoma is an unusual, generally benign tumor composed of differing amounts of smooth muscle, adipose tissue and blood vessels. Angiomyolipoma is considered by many authors to be a hamartomatous lesion. Recent detection of clonal genomic alterations and rare case reports of malignancy in renal angiomyolipomas are features that favor a neoplasm.1–3 Angiomyolipomas occur in a sporadic form or in association with tuberous sclerosis. The smooth muscle component of angiomyolipoma typically consists of fascicles of elongated spindle cells with cigar-shaped nuclei. Rarely, epithelioid smooth muscle cells predominate. Epithelioid angiomyolipoma is a recently recognized variant of angiomyolipoma that is characterized by the presence of polygonal cells with densely eosinophilic cytoplasm and varying degrees of nuclear atypia.2,4–7 Although the diagnosis of angiomyolipoma is usually easy, the epithelioid variant might simulate carcinoma both clinically and pathologically, which often poses problems in diagnosis.
Herein we report a case of angiomyolipoma in which the smooth muscle component consists entirely of epithelioid cells.
A 38-year-old woman presented with left abdominal pain. The medical and family histories were unremarkable. Ultrasonography and computerized tomography (Fig. 1) of the abdomen demonstrated a solid mass occupying the lower middle portion of the left kidney. No fat density was appreciated radiologically and renal cell carcinoma was suspected. Radical nephrectomy was performed. After the pathological diagnosis of epithelioid angiomyolipoma was established, the patient was evaluated for stigmata of tuberous sclerosis, and none was found.
At the 9-month follow-up, the patient showed no evidence of recurrence or metastatic disease.
The tumor was well circumscribed and located in the lower middle portion of the kidney. The largest diameter of the tumor was 6.5 cm. Its cut surface was solid and tan, with focal yellowish areas admixed with hemorrhagic foci. The tumor was confined within the renal capsule. No extension into the renal pelvis was observed. Microscopically, the tumor was composed of diffuse sheets of epithelioid cells, adipocytes and only scattered thick-walled blood vessels (Fig. 2). The epithelioid cells had pleomorphic and hyperchromatic nuclei with densely eosinophilic cytoplasm (Fig. 3). Some of these cells had multilobated nuclei. In addition, there were numerous multinucleated giant-cells. Mitotic figures were rare (less than 1 per 10 high-power fields). No spindle-shaped smooth muscle cells were seen. Hemorrhage, necrotic foci and clusters of foamy macrophages were present. No capsular, vascular and lymphatic invasion was seen. Perihilar lymph nodes were negative for metastases.
Immunohistochemical study was performed on sections of paraffin-embedded tissue using monoclonal antibodies for HMB-45 (Neomarkers, Fremont, USA), CD68 (Neomarkers), actin (Novocastra, Newcastle, UK), desmin (Novocastra), cytokeratin AE1/AE3 (Neomarkers), epithelial membrane antigen (Neomarkers), CD117 (c-kit) (Neomarkers) and p53 (DAKO, Carpinteria, USA). Epithelioid cells showed intense and diffuse immunoreactivity for CD117 (c-kit). Melanoma-associated antigen HMB-45 (Fig. 4a) and CD68 demonstrated a strong cytoplasmic reaction in some of the epithelioid cells. Epithelioid cells were focally positive for actin. There was no expression of cytokeratin (Fig. 4b), epithelial membrane antigen, desmin or p53 in the epithelioid cells.
Angiomyolipoma is characterized by an admixture of blood vessels, smooth muscle cells and adipose tissue in varying proportions. The diagnosis of angiomyolipoma is usually easy, and because of its distinctive radiological and histological appearance, angiomyolipoma cannot be easily confused with any of the well-recognized renal neoplasm. However, in some cases the diagnosis might be difficult for several reasons. Radiologically, renal angiomyolipomas usually demonstrate areas of different tissue density, which might represent fatty and non-fatty parts of the tumors; however, in some cases the fatty component might not be evident, and the fat density might not be appreciated radiologically, as in the present case. Histologically, the spindle smooth muscle cells might display considerable nuclear pleomorphism, mitotic activity and tumoral necrosis, and these features might cause confusion with leiomyosarcoma. In addition, some cases might show smooth muscle component that consists either predominantly or exclusively of epithelioid cells. Epithelioid angiomyolipoma is a recently identified variant of angiomyolipoma that is characterized by the presence of epithelioid smooth muscle cells, producing an appearance distinctly different from that usually associated with angiomyolipoma. This variant often posed problems in diagnosis, because the adipose tissue and tortuous thick-walled blood vessels are not evident, in contrast to the ordinary angiomyolipoma. Microscopically, epithelioid angiomyolipoma consists of sheets of polygonal cells with abundant eosinophilic cytoplasm and pleomorphic and hyperchromatic nuclei. Extensive intratumoral hemorrhage and necrosis are more common in this variant than in the classic histological type. All these features might prompt a mistaken diagnosis of malignancy. Another confusing feature that might be observed in these tumors is the extension into perirenal soft tissue and involvement of the regional lymph node. The latter is generally regarded as an expression of multicentricity rather than metastases.
Only a relatively small number of cases of epithelioid angiomyolipoma of the kidney have been reported. However, because it is frequently misdiagnosed as renal cell carcinoma (for the reasons just mentioned), this tumor might occur more frequently than reported in the literature. Four of five cases of epithelioid angiomyolipoma reported by Eble et al. were diagnosed as carcinoma at the initial radiological and pathological examination.4 Pea et al. have studied five tumors previously reported as carcinoma and they observed that, among these five tumors, three exhibit a phenotype compatible with the epithelioid angiomyolipoma.3
Histologically, the lesions most commonly confused with epithelioid angiomyolipomas are renal cell carcinoma, oncocytoma, medullary carcinoma, and renal sarcomas. Epithelioid angiomyolipoma is distinguished from renal cell carcinoma by the lack of delicate vascular network and alveolar and tubular architectural patterns, all of which are characteristics of renal cell carcinoma. Additionally, immunohistochemistry ap-pears to be particularly useful for distinguishing epithelioid angiomyolipoma from renal cell carcinoma. Renal cell carcinomas are immunoreactive with cytokeratins and epithelial membrane antigen, which is not seen in the case of epithelioid angiomyolipoma. In contrast, the latter stains for HMB-45 and smooth-muscle actin. Moreover, the immunoreactivity with CD68, albeit non-specific, is considered a feature of angiomyolipoma.2 Recently, CD117 (c-kit) was reported to be a useful marker for the diagnosis of angiomyolipoma.8 In contrast to epithelioid angiomyolipoma that consists of cells showing diffuse cytoplasmic acidophilia and pleomorphic nuclei, oncocytomas are composed of cells with acidophilic granular cytoplasm and regular nuclei. Furthermore, oncocytomas differ from epithelioid angiomyolipoma by their architectural patterns and immunophenotypic profiles (cytokeratins +, epithelial membrane antigen +, HMB-45 –). Medullary carcinomas are composed of cells arranged in solid nests or irregular tubules, and microcystic or reticular growth is common. Careful attention to these architectural characteristics with clinical features (association of this disease with young patients with the sickle cell trait) readily distinguish medullary carcinoma from epithelioid angiomyolipomas. In addition, large cells resembling ganglion cells and multinucleate giant cells, which are generally present in epithelioid angiomyolipomas, are not features of medullary carcinoma. Renal sarcomas differ from epithelioid angiomyolipomas by their distinct morphoimmunophenotype. In the present case, although the tumor was composed largely of epithelioid cells, the presence of foci of mature adipose tissue and scattered thick-walled blood vessels was helpful in reaching the correct diagnosis. Further supportive evidence for the diagnosis was the positive immunostaining for HMB-45, actin, CD117 (c-kit) and CD68, and negative immunoreactivity with epithelial markers.
Previous reports in the literature suggest that epithelioid angiomyolipomas are potentially aggressive tumors.2,3,9,10 It is difficult to diagnose a malignancy in renal angiomyolipoma because not all cases with cytologic atypia correlate with poor prognosis.9 There is no reliable morphological criteria of malignancy for these tumors, other than the presence of metastases. The patient with epithelioid angiomyolipoma reported by Yamamoto et al. died 3 months after presentation because of widespread metastasis.10 Among the three cases reported by Martignoni et al., one patient showed recurrence after 6 years and died 1 year later of cardiorespiratory failure, without evidence of distant metastases.2 Two out of three cases reported by Pea et al. died of distant metastases.3 Kawaguchi et al. reported a case of renal epithelioid angiomyolipoma with malignant transformation and detected p53 mutations in the malignant epithelioid areas, which suggests that the p53 mutation might play an important role in malignant transformation of renal epithelioid angiomyolipoma.9 In the present case, the epithelioid cells had pleomorphic and hyperchromatic nuclei, but mitotic figures were rare. There was no expression of p53 in the epithelioid cells and the patient has remained free of recurrent or metastatic disease in the 9 months since the operation.
In conclusion, epithelioid angiomyolipoma is a recently identified variant of angiomyolipoma, closely simulating high-grade carcinoma. The awareness of this entity and careful interpretation of histopathological and immunohistochemical features are needed to accurately classify this tumor.