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Malignant Perivascular Epithelioid Cell Tumor Mimicking Renal Cell Carcinoma: A Diagnostic Pitfall

Chornenkyy, Yevgen MD, MSc; Hakim, Natalya MD; Qasem, Shadi A. MD

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doi: 10.1097/PCR.0000000000000414
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Abstract

Perivascular epithelioid cell tumors (PEComas) are defined by the World Health Organization as mesenchymal tumors arising from perivascular epithelioid cells with a myomelanocytic immunophenotype.1 This growing family includes angiomyolipoma (AML), lymphangiomyomatosis (LAM), clear cell “sugar” tumors (CCST), and a number of other tumors.2 Angiomyolipomas of the kidney are typically benign and rarely metastasize; however, the epithelioid type (also known as epithelioid PEComa) has a more aggressive clinical course. Tumors in older patients, larger tumor size (>7 cm), higher percentage of epithelioid component, severe atypia, higher percentage of atypical cells, higher mitotic count, atypical mitotic figures, necrosis, lymphovascular invasion, and renal vein invasion have been found to be associated with worse prognosis.3,4

CASE REPORT

A 56-year-old male, with previous history of malignant melanoma of skin, presented with a 3-month history of flank pain and hematuria. The initial abdominal computed tomography (CT) scan identified bilateral necrotic heterogeneous enhancing kidney masses, the right one being significantly larger (16 cm) than the left (3.8 cm). The patient underwent a right radical nephrectomy. Histology demonstrated a poorly differentiated tumor with clear cell features and extensive rhabdoid and focal sarcomatoid pleomorphic cells with frequent giant, bizarre multinucleated forms. Most of the cells contained abundant clear cytoplasm. The nuclei were enlarged and pleomorphic with prominent nucleoli. Multifocal tumor necrosis and extensive lymphovascular invasion were also observed. The tumor was surrounded by a prominent desmoplastic response and chronic inflammation (Fig. 1A). Based on histomorphology alone, an initial diagnosis of renal cell carcinoma (RCC), Fuhrman grade 4, with extensive rhabdoid and focal sarcomatoid features was made.

FIGURE 1
FIGURE 1:
The renal and hepatic masses demonstrate similar morphology and immunophenotype. The renal mass is composed of sheets of markedly pleomorphic cells with frequent bizarre forms. Most cells have abundant clear cytoplasm (A). HMB45 (B) and Melan-A (C) demonstrate strong positive staining in the renal mass, whereas TFE3 demonstrates focally positive staining (D). The hepatic mass shows infiltrative pleomorphic cells with cleared cytoplasm and prominent epithelioid morphology (E). HMB45 (F) and Melan-A (G) showing strong positive staining in the liver mass. Axial abdominal scan demonstrating liver lesion (H) (A–C and E–G, original magnification ×10; D, original magnification ×20).

A follow-up CT scan, 3 years later, identified a large ill-defined area of hypodensity within the right hepatic lobe involving segments 6 and 7 and measuring 13 × 9 × 8 cm (Fig. 1H). Clinical considerations included residual direct kidney tumor invasion, metastatic disease, or metastatic melanoma. The patient underwent partial liver resection. The histomorphology of the mass was identical to the renal mass, identified 3 years ago, except for focal areas of prominent epithelioid cells with abundant eosinophilic cytoplasm (Fig. 1E). The histomorphology and the clinical history of malignant melanoma prompted additional immunohistochemical staining. Both tumors (kidney and liver) were positive for Melan-A (Figs. 1B, F), HMB-45 (Figs. 1C, G), and epithelial membrane antigen (EMA) but negative for PAX8, SOX10, S100 protein, smooth muscle actin (SMA), desmin, inhibin, calretinin, BRAF V600E, and cytokeratin. Additional testing demonstrated that the renal lesion was focally positive for TFE-3 (ARUP Laboratories, Salt Lake City, Utah) (Fig. 1D) and negative for TFE3 rearrangement (Break-Apart Probe; Xp11.23 [3′ TFE3, 5′ TFE3], XCEN [DXZ1]; Mayo Clinic Laboratories, Rochester, Minn). The initial diagnosis of RCC was amended to malignant epithelioid AML with hepatic metastasis.

DISCUSSION

The concept of neoplasms with perivascular epithelioid cell (PEC) differentiation was developed by Bonetti and colleagues in 1992.5–7 They observed a group of neoplasms consisting of cells, likely originating from blood vessel walls with morphologic, immunohistochemical, and ultrastructural characteristics of both smooth muscle and melanocytic differentiation. The descriptive term “PEC” was proposed to describe these cells. Overtime, neoplasms composed of these cells were grouped under the term PEComa. This family of tumors now includes renal and extrarenal AML, lymphangio(leio)myoma and lymphangio(leio)myomatosis (LAM), CCST of the lungs and extrapulmonary sites, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres, and abdominopelvic sarcoma of PECs.2,6–11 Most cases are benign; however, malignant variants have been reported.12

Angiomyolipoma presents as a solitary mass with a median size of 9 cm and commonly occurs in middle-aged patients (median age, 40–50 years) with a female predominance. It commonly presents with pain, hematuria, and fever. Angiomyolipoma may be detected incidentally as a CT, surgical, or autopsy finding. Most cases develop in the kidneys, whereas few are found at extrarenal sites.13–16 Perivascular epithelioid cell tumors, other than AML and LAM, are rare neoplasms described as either benign extrapulmonary “sugar” tumor, clear cell myomelanocytic tumor, and abdominopelvic sarcoma of PECs.2,8–10,17 They tend to occur in middle-aged patients with a female predominance. Up to 40% are found in the retroperitoneum, soft tissue, and skin. Remaining cases are found in the gastrointestinal tract; however, any anatomic site may be involved.2,8–10,17

Grossly, AMLs present as a yellow-to-gray unencapsulated mass consisting of adipose tissue, smooth muscle, and blood vessels. Sometimes, the neoplasm can contain infiltrative margins and necrosis. Histologically, conventional AML is composed of mature fat, thick-walled blood vessels, and smooth muscle in varying proportions. An epithelioid AML is composed predominantly of epithelioid cells. Pure epithelioid (“monotypic”) AMLs are identical to (and synonymous with) PEComa, and the tumor cells are large and polygonal, with abundant pale eosinophilic granular-to-clear cytoplasm. Blood vessels and mature adipose components are focal or absent. When present, blood vessels are usually muscular and thick walled, with hyalinization of the media. Nests of tumor cells are typically surrounded by delicate capillary vessels, similar to RCC. Nuclear atypia is common, and areas of hemorrhage and tumor necrosis may be seen. Mitotic activity is usually minimal but is seen in malignant cases.2,8–10,13,17

In comparison to AML/renal PEComa, the morphologic features of PEComa outside the kidney are very broad.2,8–10,17 The majority are indistinguishable from epithelioid (monotypic) AML. They are composed of large polygonal epithelioid cells that contain abundant granular eosinophilic-to-clear cytoplasm. Structurally, they are arranged in nests surrounded by capillaries. The tumor cells often show focal association with blood vessel walls. In addition, the tumor cells may be spindled, with clear cytoplasm, resembling CCST of the lung. Clear cell morphologic features often predominate in tumors of the falciform ligament/ligamentum teres18 and cutaneous PEComas, making it important to differentiate them from RCC.19,20

Angiomyolipomas/PEComas are characteristically reactive for smooth muscle markers (SMA in ~80% of cases) and melanocytic markers (most often HMB-45 in ~90% of cases). They can also stain positive for Melan-A (~70%) and microphthalmia-associated transcription factor.2,8–10,17 The cytoplasmic positivity for HMB-45 is typically finely granular. Approximately 80% of cases coexpress SMA and HMB-45 or Melan-A. Predominantly epithelioid tumors can express melanocytic markers more strongly than myogenic markers, and the opposite is seen in spindled PEComas.8 Desmin (~30%) and S-100 protein (10%) are expressed less often. Occasional PEComas (especially those with clear-cell features) express melanocytic markers without SMA and desmin. Keratins, EMA, KIT, and CD34 are rarely expressed, making them useful to rule out PEComas and rule in carcinomas and other tumors in the differential. Estrogen and progesterone receptors can frequently be expressed in AML but less often in other types of PEComas.8 Approximately 20% of PEComas show nuclear staining for TFE-3, many of which harbor TFE-3 gene rearrangements.10,21

Box 1. Differential Diagnosis of Renal and Extrarenal Epithelioid AML

Carcinoma (Especially RCC)

  MiT family of translocation carcinomas

Metastatic melanoma

Rhabdomyosarcoma

 Liposarcoma

Epithelioid leiomyosarcoma

Epithelioid sarcoma

ASPS

Epithelioid gastrointestinal stromal tumor

The differential diagnosis is broad and includes more common entities especially clear cell RCC and melanoma (Box 1). Although morphology based on hematoxylin-eosin stain is crucial, immunohistochemistry plays an important role in differentiating PEComas from their mimickers. The two top differential diagnoses in the kidney include carcinomas, especially RCC (positive for PAX8 and EMA and negative for melanocytic markers) and MiT family translocation carcinomas (RCCs with translocations involving a member of MiT transcription factor gene family, most commonly, TFE3 gene at Xp11.23).22,23 In the MiT family, it is important to consider t(6;11) RCC as this entity can have morphologic overlap with epithelioid AML, be negative for PAX8, and require TFEB FISH for diagnosis.22,23 Additional differential diagnoses include epithelioid metastatic melanoma (strong and diffuse S-100 reactivity and negative staining for SMA and desmin), epithelioid leiomyosarcoma (positive staining for SMA and desmin but negative staining for melanocytic markers), liposarcoma (negative staining for melanocytic markers), epithelioid sarcoma (reactivity for epithelial markers and CD34, loss of expression of INI1, and negative staining for melanocytic markers), and epithelioid gastrointestinal stromal tumor (reactivity for c-KIT, CD34, and DOG1 and negative staining for melanocytic markers). The distinction between alveolar soft part sarcoma (ASPS) and PEComa may be difficult because both neoplasms show a nested growth pattern and may show nuclear staining for TFE3; however, unlike PEComa, ASPS is consistently negative for melanocytic markers24 (Table 1).

TABLE 1 - Immunohistochemical Stains in the Differential Diagnoses of AML/PEComa
eAML RCC t(6;11) eMM RMS eLMS eSarc GIST ASPS
TFE-3 +/− −/+ + +/−
HMB-45 + +
PAX8 + −/+*
EMA −/+ + +
Keratins −/+ + − (f) +
SMA + + −/+
Desmin +/− + +
S100 −/+ + (d) −/+
CD34 + +
cKIT + −/+ +
DOG1 +
*Fifty percent can be positive for PAX8.22
eAML, epithelioid AML; t(6;11), t(6;11) RCC; eMM, epithelioid metastatic melanoma; RMS, rhabdomyosarcoma; eLMS, epithelioid leiomyosarcoma; eSarc, epithelioid sarcoma; GIST, gastrointestinal stromal tumor; f, focal positive22; d, diffuse.

Conventional AMLs are typically benign.13 In contrast, a significant subset of epithelioid AMLs/PEComas can be aggressive. These are characterized by local recurrences and metastatic disease commonly to the lungs, bone, and liver.13 Factors predicting aggressive behavior for epithelioid AMLs/PEComas appear similar to those for other extrarenal sites and include nuclear atypia, pleomorphism, and high mitotic rate, in addition to extrarenal extension or renal vein involvement.4 Brimo et al3 published a predictive model of 4 atypical features that included: (1) ≥70% atypical epithelioid cells, (2) ≥2 mitotic figures per 10 high-power fields, (3) atypical mitotic figures, and (4) necrosis; the presence of 3 or all of the features was highly predictive of malignant behavior and metastasis.3

There are no standardized treatment protocols for PEComas; resection is usually the primary treatment modality associated with reduced rates of recurrence. Additionally, sirolimus (and the derivatives temsirolimus and everolimus) demonstrates some efficacy in renal AMLs and pulmonary LAM. Some patients with metastatic malignant PEComas demonstrate response to sirolimus.8,25,26 In this case, the patient received temsirolimus, everolimus (Afinitor), and radiotherapy postresection, and he was stable for a while; however, he subsequently developed lung metastasis. He is currently alive with disease, 4 years after initial diagnosis, receiving radiotherapy for his lung metastasis.

CONCLUSIONS

The differential diagnosis for epithelioid AML/PEComas is broad and includes more common tumors such as RCC, melanoma, and epithelioid leiomyosarcoma. Their rarity and the wide differential diagnoses render the diagnosis challenging. Renal cell carcinoma, clear cell type, can be difficult to distinguish from AML/PEComa of the kidney as they share a common location and similar morphologic features. In addition, RCC is far more common. The presence of spindle and epithelioid histology with eosinophilic cytoplasm in RCC should prompt additional immunohistochemical workup (HMB45, Melan-A, SMA, PAX8, and EMA) in order to exclude PEComa/AML and confirm RCC. The prevalence of AML/PEComa might be underestimated in the literature, and some cases called RCC may represent a monotypic, epithelioid variant of AML.

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Keywords:

angiomyolipoma; PEComa; renal cell carcinoma

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