A 44-year-old woman underwent an ultrasound examination for biliary colic that revealed gallstones and an incidental 3-cm solid mass in the left kidney. She subsequently had computed tomographic and magnetic resonance imaging scans that confirmed the presence of a 3-cm mass located centrally in the midportion of the left kidney. The radiologic differential diagnosis was that of renal cell carcinoma versus oncocytoma. Owing to its central location and proximity to the major renal vessels, the mass was resected laparoscopically by complete nephrectomy.
The specimen consisted of a kidney covered by perinephric fat, measuring 9.6 × 6.0 × 6.4 cm, and a segment of ureter measuring 4.5 × 0.4 cm. The renal capsule was intact and smooth. On bivalving the kidney coronally, there was a 2.5 × 2.5 × 2.3-cm, solid, circumscribed, brownish-red mass located in the midportion of the kidney adjacent to, but not extending into, the renal pelvis. Necrosis and hemorrhage were not grossly apparent, and the renal vein was grossly uninvolved. The remaining renal parenchyma was grossly unremarkable.
Sections from the mass showed a highly cellular neoplasm comprising predominantly epithelioid cells with focal spindle cell morphology and scattered, large, thick-walled blood vessels. No fat was identified within the tumor. The mass was nonencapsulated and generally well demarcated from the adjacent renal parenchyma (Figure 1). Only focally did it form an infiltrative border, as evidenced by areas with entrapped renal tubules and glomeruli. The epithelioid cells had abundant clear to lightly eosinophilic granular cytoplasm, large pleomorphic vesicular nuclei, and prominent eosinophilic nucleoli (Figure 2). Histochemical staining for periodic acid–Schiff/periodic acid-Schiff–diastase demonstrated the presence of cytoplasmic glycogen. A particularly striking feature was the presence of numerous huge cells with straplike morphology, eosinophilic cytoplasm, and multiple peripherally distributed nuclei (Figures 1 and 3). These nuclei were markedly pleomorphic and had coarse chromatin and large eosinophilic nucleoli. The straplike cells were typically concentrated around blood vessels and were frequently associated with an admixture of lymphocytes. There were rare foci of necrosis. Mitotic activity was not identified. There was no invasion of the renal capsule or extrarenal soft tissue. Lymphovascular invasion was not identified, and the resection margins were free of tumor. Immunohistochemically, the tumor cells were strongly positive for HMB-45 (Figure 4) and Melan-A (MART-1) and were focally positive for CD68. The spindle cell element stained positively for smooth muscle actin. Staining for cytokeratins AE1/AE3, CAM 5.2, 34βE12, 7, and 20 was negative. The tumor cells also showed negative staining with renal cell carcinoma (RCC), CD10, epithelial membrane antigen, vimentin, desmin, sarcomeric actin, muscle-specific actin, CD45, and S100.
The patient is currently well and shows no evidence of recurrent disease after 8 months of follow-up.
What is your diagnosis?
Pathologic Diagnosis: Atypical Epithelioid Angiomyolipoma
Angiomyolipomas (AMLs) are benign kidney tumors that typically consist of thick-walled blood vessels, smooth muscle, and mature fat admixed in variable proportions. Angiomyolipoma was initially described in 1942 as a hamartomatous lesion associated with the tuberous sclerosis complex (TSC).1 Current evidence demonstrating clonality has revealed that AMLs are truly neoplastic in nature.2 Approximately one half of AMLs occur in association with TSC, while the other half are sporadic. A defining feature of AML is the characteristic positive immunoreactivity of the smooth muscle cells for both muscle markers and the melanoma-associated antigen HMB-45.3 It is now apparent that AMLs contain a fourth cell type that is considered to be their putative cell of origin. This fourth cell type is a vascular smooth muscle cell, or pericyte capable of divergent differentiation, now commonly referred to as the “perivascular epithelioid cell.” In fact, it has been suggested that perivascular epithelioid cells give rise to a spectrum of lesions, which includes renal and extrarenal AML, clear cell “sugar” tumors of the lung and pancreas, and lymphangioleiomyomatosis.4,5 All of these lesions have the common feature of myomelanocytic differentiation, suggestive of a common neural crest origin.
In rare instances, AMLs have unusual morphologic features, such as a predominance of epithelioid cells, the absence of recognizable fat, and striking cytologic atypia that is usually not accompanied by mitotic activity. These lesions have been designated epithelioid AMLs6 and atypical AMLs.7 These unusual AML variants can give rise to diagnostic confusion with RCC, renal sarcomas, or metastases involving the kidney. Delgado et al7 reported 5 examples of atypical AML with essentially the same histomorphologic features as the ones we found in this pathologic quiz case, namely, the presence of bizarre multinucleated straplike cells with an absence of mitotic activity. Four of the 5 cases described by Delgado et al7 were sporadic lesions, as was our case, while 1 was associated with TSC.
To illustrate the diagnostic confusion that can be created by atypical AML variants, Pea et al8 reviewed a series of 5 tumors in TSC cases that were originally classified as RCCs. Three of the 5 tumors were reclassified as epithelioid AMLs based on positive immunohistochemical staining with HMB-45 and negative staining for cytokeratin.
Most of these atypical AML variants appear to behave in a benign manner; however, some will follow a more aggressive course. There are isolated case reports of otherwise typical AMLs having areas of malignant transformation,9,10 which in 1 case was referred to as “sarcoma ex angiomyolipoma.” 9 In addition, 2 of the 3 examples of epithelioid AML reported by Pea et al8 were associated with metastases and death within 12 to 18 months of diagnosis. In contrast, each of the patients with atypical AMLs in the series of Delgado et al7 had no evidence of recurrent disease during follow-up that ranged from 1 to 8 years. The cases described by Pea et al8 and Delgado et al7 shared essentially the same histomorphologic features, including epithelioid and bizarre, large, multinucleated cells. From the aforementioned reports, it would appear that no definitive statement can be made with respect to predicting malignant behavior based on features such as infiltrative tumor borders, vascular invasion, atypia, mitotic activity, or even local recurrence after incomplete resection. It is also tempting to speculate that in the setting of TSC, metastatic AML may not represent true metastases, but rather new primary tumors arising from perivascular epithelioid cells in other organs in a predisposed patient. It is clear that there is a need for more of these cases to be reported in order to determine the optimal treatment and follow-up strategy for a given patient.
As described by Delgado et al,7 the differential diagnosis of atypical/epithelioid AML includes RCC of clear cell type, sarcomatoid RCC, adrenocortical carcinoma, primary pleomorphic renal sarcoma, and even metastatic melanoma. Recognition of the characteristic bizarre straplike cells and their distribution with respect to blood vessels in the tumor, along with an immunohistochemical panel that includes cytokeratins, muscle markers, HMB-45, and S100, should allow the correct diagnosis to be made.
References
The authors have no relevant financial interest in the products or companies described in this article.
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