A 50-year-old man presented with nausea and abdominal bloating sensation of a few months' duration and was found to have a large adrenal mass that was resected after computed tomography scan evaluation. The histopathologic examination showed epithelioid and spindle cells having clear to granular eosinophilic cytoplasm, and small, central, round to oval nuclei with small nucleoli. The tumor cells demonstrated reactivity for smooth muscle actin, HMB-45, Melan-A, and vimentin, with focal positivity for desmin and S100 protein and negative staining for inhibin, synaptophysin, and chromogranin. A diagnosis of perivascular epithelioid cell tumor was made. Perivascular epithelioid cell tumors can arise in a variety of locations, including omentum/mesentery, female genital tract, pelvic soft tissues, skin, and falciform ligament, but an adrenal primary tumor has not been previously reported, to the best of our knowledge. The differential diagnosis is broad and site-dependant and in our case includes several neoplasms with clear cells that can involve the adrenal gland, including a primary adrenocortical neoplasm. A review of the related literature and discussion of the differential diagnoses are presented.

Perivascular epithelioid cell tumor (PEComa) is a mesenchymal tumor with perivascular epithelioid clear cell that coexpresses melanocytic and muscle markers. Most of these rare tumors are seen in females.1 Histologically, these tumors are composed of epithelioid and spindle cells having clear to granular eosinophilic cytoplasm, and small, central, round to oval nuclei with small nucleoli. The coexpression of melanocytic and muscle markers in addition to the histologic findings establishes the diagnosis.1 

We report the occurrence of an adrenal PEComa arising in a 50-year-old man. To the best of our knowledge, PEComa of the adrenal gland has not been previously reported in the English literature. Since the adrenal gland is the location for other tumors with clear to granular cytoplasm, other entities that can enter into the differential diagnosis are discussed.

A 50-year-old man presented with nausea and a bloating sensation of the abdomen of a few months' duration. The diagnostic workup led to a computed tomography scan, which demonstrated a 9-cm, left adrenal mass suggestive of malignancy. Biochemical testing showed no evidence of a functioning adrenal neoplasm. Surgical resection was performed and the tumor was excised in its entirety. There was no evidence of invasion into adjacent organs, including the kidney. The patient has no evidence of recurrence or metastasis 2 years postresection.

Gross examination demonstrated a 10 × 8 × 7-cm, brown, lobular tumor with areas of yellow necrosis and hemorrhage. Microscopic examination (Figure, A) showed a vaguely lobulated, well-circumscribed lesion, with a thick fibrotic margin but no true capsule. It was composed of a mixture of spindled and plump epithelioid cells with pale clear to granular eosinophilic cytoplasm (Figure, B). The epithelioid cells had round to oval vesicular nuclei, with 1 or more small eosinophilic nucleoli, and spindled cells had hyperchromatic nuclei and small nucleoli. There was a prominent vascular pattern with many dilated, thin-walled blood vessels and some chronic inflammatory cells at the periphery of the lesion. Scattered multinucleated giant cells were also present. A large necrotic area existed at the center of the lesion, but mitotic figures were not identified. Touch imprint cytology smears showed a cellular lesion with large epithelioid cells having vesicular nuclei with small nucleoli and smaller numbers of bland-appearing spindled cells, with both the epithelioid and spindle cells having a clear to granular eosinophilic cytoplasm. Based on criteria proposed by Folpe et al,2 this tumor meets the criteria for malignancy.

Low-power image demonstrates sheets of neoplastic cells and a large area of tumor necrosis (A). The epithelioid neoplastic cells have round to oval vesicular nuclei, with 1 or more small eosinophilic nucleoli, and pale clear to granular eosinophilic cytoplasm (B). The tumor cells stain positively with antibody against Melan-A (C), as well as staining positively with HMB-45 (D) and smooth muscle actin antibodies (E). Immunostaining pattern for desmin is negative in tumor cells (F) (hematoxylin-eosin, original magnifications ×2 [A] and ×40 [B]; original magnifications ×40 [C through F]).

Low-power image demonstrates sheets of neoplastic cells and a large area of tumor necrosis (A). The epithelioid neoplastic cells have round to oval vesicular nuclei, with 1 or more small eosinophilic nucleoli, and pale clear to granular eosinophilic cytoplasm (B). The tumor cells stain positively with antibody against Melan-A (C), as well as staining positively with HMB-45 (D) and smooth muscle actin antibodies (E). Immunostaining pattern for desmin is negative in tumor cells (F) (hematoxylin-eosin, original magnifications ×2 [A] and ×40 [B]; original magnifications ×40 [C through F]).

Immunohistochemical studies revealed diffuse strong reactivity for Melan-A (Figure, C), HMB-45 (Figure, D), smooth muscle actin (Figure, E), vimentin, and negative staining for inhibin, synaptophysin, chromogranin, calretinin, and AE1/3. Desmin (Figure, F) and S100 protein were focally expressed in scattered cells.

The concept of a perivascular epithelioid cell tumor was first proposed by Bonetti et al3 in 1992. This tumor family includes angiomyolipoma (renal and extrarenal), clear cell “sugar” tumor (lung and extrapulmonary), lymphangioleiomyomatosis, and related tumors of the falciform ligament/ligamentum teres, skin, uterus, and other viscera and soft tissue.4,5 There is no known normal counterpart to the perivascular epithelioid cell.

Among different lesions of the PEComa family, angiomyolipoma, clear cell “sugar” tumor, and lymphangioleiomyomatosis are relatively common and are associated with tuberous sclerosis.1 Conversely, the less common PEComas of the falciform ligament/ligamentum teres, skin, uterus, and other viscera and soft tissue tumors do not appear to be associated with tuberous sclerosis.1 Most patients are females and the median age at presentation is 46 years.2 The tumor size is variable, with a median of 7.8 cm.2 

Histologically, PEComas are composed of epithelioid and spindle cells, with 1 or both cell types arranged in a fascicular or nested pattern. A prominent intrinsic vasculature can be present, with tumor cells often arranged in a radial fashion around blood vessels. Multinucleated tumor giant cells are a frequent finding. PEComas vary significantly in nuclear grade, mitotic activity (including atypical mitotic figures), tumor cell necrosis, and angiolymphatic invasion. Some of these parameters are used to grade PEComas as discussed below.2 

The unique combination of immunoreactivity for melanocytic markers, such as HMB-45 and Melan-A, and myogenic markers, such as smooth muscle actin, is the hallmark of PEComas.2 Most PEComas are also positive for vimentin. Other positive immunostaining patterns are reported with CD1a, CD10, desmin, S100 protein, and caldesmon. PEComas are usually negative for CD68, pankeratin, leukocyte common antigen, CD117, CD34, and inhibin.2,6,7 

Efforts have been made to predict biologic behavior of PEComas, based on morphologic parameters. Folpe et al2 used the previously published criteria (tumor size >5 cm, infiltrative growth pattern, high nuclear grade, necrosis, and mitotic activity greater than 1 mitosis per 50 high-power fields) detailed in the 2002 World Health Organization Pathology and Genetics of Tumours of Soft Tissue and Bone8 to categorize PEComas into 3 groups: benign, with no worrisome features; uncertain malignant potential (either nuclear pleomorphism/multinucleated giant cells or size greater than 5 cm alone), and malignant (2 or more parameters including size greater than 5 cm, infiltrative pattern, high nuclear grade and cellularity, mitotic rate greater than 1 mitosis per 50 high-power fields, necrosis, and vascular invasion). Folpe et al2 stated that clinically aggressive behavior may not be seen in all histologically malignant neoplasms.

The differential diagnosis of PEComa is broad and is guided by morphologic pattern and location.9 A combination of thorough sampling of the tumor, attention to morphologic detail, appropriate use of melanocytic markers and other immunostains, and possibly, molecular markers for characteristic cytogenetic abnormalities, will help differentiate these lesions. Specifically, in the adrenal gland, the primary diagnostic considerations are adrenocortical neoplasm followed by pheochromocytoma. Other uncommon clear cell/spindle cell neoplasms involving the adrenal gland, including renal cell carcinoma, clear cell sarcoma, melanoma, and epithelioid/clear cell smooth muscle tumors, can potentially enter into the differential diagnosis.

Adrenocortical neoplasms have nests of clear cells with occasional giant cells, similar to PEComa. To further complicate the differential diagnosis, adrenal cortical neoplasms are also Melan-A positive.10 However, adrenal cortical neoplasms are inhibin and calretinin positive and occasionally, low-molecular-weight keratin positive and smooth muscle actin negative.11,12 Adrenal oncocytoma and metastatic renal cell carcinoma can present with clear cells, similar to PEComa. They are, however, characteristically cytokeratin positive and HMB-45 negative, and conventional renal cell carcinoma demonstrates positive staining for renal cell carcinoma antigen.13 

Pheochromocytomas (paraganglioma of adrenal medulla) can have a variety of morphologic patterns, including nested clear cells. The clinical history of multiple endocrine neoplasia and symptoms related to catecholamine hypersecretion is a clue to the diagnosis. Pheochromocytoma is readily differentiated from PEComa by positive immunohistochemical staining for chromogranin, synaptophysin, and S100 protein and negative staining for both melanocytic and smooth muscle markers.1 

Clear cell sarcoma (melanoma of soft parts) morphologically mimics PEComa and can express melanocytic markers but demonstrates negative staining for muscle markers. Clear cell sarcoma also demonstrates a characteristic cytogenetic abnormality, t(12;22)(q13;q12), which can be confirmatory.1 Metastatic melanoma to the adrenal gland, although rare, can be confused with PEComas. The “great mimicker,” melanoma, can simulate all patterns of PEComa morphologies and share positivity for HMB-45, Melan-A, and S100 protein.2 An extended immunohistochemical panel including smooth muscle markers, along with the clinical history, will help make this distinction.

On the basis of morphology, epithelioid/clear cell smooth muscle tumors can be mistaken with PEComa: for example, the presence of cells with eosinophilic cytoplasm and positive staining for smooth muscle markers. PEComas, however, have clear to granular, lightly eosinophilic cytoplasm, rather than the dense eosinophilia of true smooth muscle cells. Other morphologic features of smooth muscle tumors, such as perinuclear vacuoles and “cigar shaped” nuclei, are not seen in PEComa. HMB-45, which stains negatively in smooth muscle tumor, will also help in the workup, but there are rare reports in the literature of it demonstrating positive staining; therefore, caution should be exercised.14 

In summary, to the best of our knowledge, we present the first case of a primary PEComa of the adrenal gland, which potentially can be confused with a primary adrenal cortical neoplasm and other uncommon neoplasms involving the adrenal gland, if the histologic features are not appreciated and appropriate immunohistochemical studies are not performed.

The authors would like to acknowledge Christopher D. Fletcher, MD, FRCPath, MBBS, Department of Pathology, Brigham and Women's Hospital–Harvard Medical School, Boston, Massachusetts, for providing consultation on this case.

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Author notes

From the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr Zarineh); and the Department of Pathology and Laboratory Medicine, Allegheny General Hospital/Drexel University College of Medicine, Pittsburgh, Pennsylvania (Dr Silverman). Dr Zarineh is now with the Department of Pathology, New York University, New York, New York.

The authors have no relevant financial interest in the products or companies described in this article.