Surgical Pathology

PEComa

Jason L. Hornick
Brigham & Women’s Hospital
Boston, MA


Clinical History:
A 60 year-old female presented to her primary care physician complaining of a painless "bulge" in the mid abdomen. A CT scan revealed a well-circumscribed mass in the body of the pancreas, around which the pancreatic duct deviated. Endoscopic ultrasound showed a 3 cm round, hypoechoic, solid mass in the body of the pancreas at the junction with the tail, with no enlarged lymph nodes. A distal pancreatectomy was performed.


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Figure 1
Gross photograph showing a well-circumscribed tumor within the body of the pancreas.
Figure 2
The tumor is sharply demarcated from the surrounding pancreatic parenchyma.
Figure 3
The tumor is composed of cells with abundant clear cytoplasm. Note the thin fibrous pseudocapsule surrounding the tumor.

Figure 4
The tumor shows a mixture of spindle cell (left) and epithelioid (right) cytomorphology.
Figure 5
Spindle cells with granular eosinophilic to clear cytoplasm. Note the focal areas of stromal hyalinization (bottom).
Figure 6
In areas, the tumor shows a well-developed fascicular architecture, mimicking a smooth muscle neoplasm.

Figure 7
A more sheet-like area of the tumor. Note the focal perivascular growth pattern (center).
Figure 8
Tumor cells with abundant clear cytoplasm and distinct cell borders, focally associated with blood vessel walls.

Figure 9
Spindle cells with granular eosinophilic cytoplasm. Note the uniform nuclei with fine chromatin and small nucleoli.
Figure 10
Polygonal cells with clear to eosinophilic cytoplasm. Occasional multinucleated cells and focal pleomorphism are present.

Immunohistochemical Results:
The tumor cells were positive for smooth muscle actin, desmin, HMB-45, melan-A, and microphthalmia transcription factor (MiTF), and were negative for EMA, keratins, S-100 protein, KIT, CD34, DOG1, chromogranin, and synaptophysin.

Diagnosis:
PEComa

Discussion/Differential Diagnosis:
PEComa belongs to a family of related neoplasms, which also includes angiomyolipoma (AML), lymphangiomyomatosis (LAM), and clear cell sugar tumor of the lung (CCST), all sharing a morphologically and immunophenotypically distinctive cell type, the so-called "perivascular epithelioid cell" (PEC), which lacks a normal cellular counterpart. [1] This cell type was first proposed in 1992 by Bonetti and colleagues, [2] who recognized the similarities among the aforementioned tumor types. The "PEC" characteristically shows evidence of both myogenic (smooth muscle) and melanocytic differentiation. The term "PEComa" was then coined by Zamboni and colleagues in 1996 in a case report of a pancreatic tumor indistinguishable from pulmonary CCST, [3] similar to the case presented here. Various other terms have since also been used to describe this distinctive tumor type, including monotypic epithelioid AML, primary extrapulmonary sugar tumor, [4] clear cell myomelanocytic tumor, [5, 6] and abdominopelvic sarcoma of perivascular epithelioid cells. [7] Most PEComas are benign or indolent, although a subset pursues an aggressive clinical course. Criteria for malignancy in PEComas have only recently been proposed (see below). The remainder of this discussion applies to PEComas exclusive of AML and LAM.

Clinically, PEComas show a marked female predominance (approximately 7:1) and most often affect middle-aged adults. [1, 8] The most common anatomic sites are abdomen and pelvis, retroperitoneum, uterus, and gastrointestinal tract. [1, 8, 9] A minority (~25%) arises in somatic soft tissue and skin. [6, 8, 10] Although AML and LAM are strongly associated with the tuberous sclerosis complex (TSC), most PEComas are sporadic; only a small subset arises in TSC patients.

Morphologically, PEComas most often show a nested architecture, with the nests surrounded by a delicate capillary vasculature, or, less frequently, a more sheet-like growth pattern, similar to the presented case. Tumor cells are usually large and epithelioid with sharply-defined cell borders, with a similar proportion of cases composed predominantly of clear cells and cells with granular, eosinophilic cytoplasm; a minor spindle cell component is relatively common. PEComas composed chiefly of spindle cells (formerly "clear cell myomelanocytic tumor" [5]) are much less common. A careful search will often reveal focal areas in which the epithelioid cells are associated with the walls of blood vessels, which is a helpful diagnostic clue. Approximately 20% of PEComas show marked stromal hyalinization ("sclerosing PEComa"); this subset has a predilection for the (pararenal) retroperitoneum. [11] A minority of PEComas show striking pleomorphism and resemble pleomorphic myogenic sarcomas (see below). [1]

By immunohistochemistry, as indicated above, PEComas often show a mixed melanocytic and myogenic phenotype. [1, 8] Nearly all PEComas are at least focally positive for HMB-45, which is the most sensitive marker for PEComa. Most PEComas are also positive for microphthalmia transcription factor (MiTF), and a smaller subset is positive for melan-A (MART1). The most sensitive myogenic marker for PEComa is smooth muscle actin (SMA); desmin is less commonly positive. The smooth muscle marker h-caldesmon may also be positive. [11] We now recognize that co-expression of smooth muscle and melanocytic markers is not required to confirm the diagnosis of PEComa; some cases show HMB-45 reactivity in the absence of SMA or other myogenic markers. S-100 protein expression is seen in a small subset of PEComas (<10%), [8] and, when present, is generally focal, which is helpful to distinguish PEComa from metastatic melanoma (see below). A minority of PEComas is positive for TFE3 instead of MiTF (homologous transcription factors); [8, 12] the significant of this finding is uncertain.

Recent studies indicate that PEComas frequently show deletions of the TSC2 locus at chromosome 16p13, [13] similar to conventional renal AML, [14] which result in activation of the mTOR (mammalian target of rapamycin) signaling pathway. [13, 15] These findings have therapeutic implications for patients with clinically aggressive malignant PEComas, as mTOR inhibitors have already shown efficacy in clinical trials of some human malignancies in which this pathway has been implicated.

Criteria for malignancy in PEComas have only recently been evaluated. Based on a recent study including a comprehensive literature review, [8] any combination of the following features likely warrants designation as a malignant PEComa: tumor size >5 cm, mitotic activity >1 per 50 high power fields, coagulative necrosis, high nuclear grade, and infiltrative growth. The authors of this study suggested that PEComas showing only one of the above features should probably be regarded as of "uncertain malignant potential." [8] However, some large PEComas (such as those involving the retroperitoneum) showing a low level of mitotic activity but no other malignant histologic features appear to be clinically benign. [11] Personal experience suggests that PEComas showing marked pleomorphism (often resembling a pleomorphic myogenic sarcoma) also have the potential to pursue an aggressive clinical course. [1]

The usual differential diagnosis for solid, cellular tumors of the pancreas includes acinar cell carcinoma, pancreatoblastoma, solid pseudopapillary tumor, and pancreatic endocrine tumors. However, these tumor types do not resemble PEComas, and are not realistic diagnostic options.

Instead, the chief differential diagnostic considerations for PEComa are metastatic clear cell (particularly renal cell) carcinoma, clear cell sarcoma (CCS), metastatic (including "balloon cell") melanoma, and gastrointestinal stromal tumor (GIST).

Distinguishing metastatic carcinoma from PEComa is usually straightforward, since PEComas are generally negative for keratins and EMA. CCS and metastatic melanoma show some immunophenotypic overlap with PEComa and can therefore be more problematic. Although first recognized in deep somatic soft tissues of the extremities, CCS is now known to arise primarily in the GI tract as well, most commonly the small intestine, followed by stomach. The neoplastic cells in CCS are usually more compact than those in PEComa (lacking voluminous cytoplasm), and, despite the nomenclature, the majority of CCS cases are composed of eosinophilic (not clear) cells. Unlike conventional CCS (and PEComa), GI tract examples often completely lack expression of melanocytic markers, [16] and are only positive for S-100 protein. In contrast to PEComa, CCS is generally negative for myogenic markers. Detection of EWS gene rearrangement (by FISH or RT-PCR, which can be performed on paraffin sections) can confirm the diagnosis of CCS. Of note, GI tract examples often show a different EWS fusion partner, CREB1, resulting in the translocation t(2;22), [16] rather than the typical t(12;22) with the ATF1 fusion partner found in the majority of somatic soft tissue cases. Although metastatic melanoma with epithelioid morphology is often positive for HMB-45, melan-A, and MiTF (like PEComa), melanoma usually shows strong, diffuse reactivity for S-100 protein, which is not seen in PEComa, and lacks expression of myogenic markers. GISTs may show mixed epithelioid and spindle cell morphology, similar to PEComa. However, GISTs usually lack the clear to granular cytoplasm typical of PEComa, instead showing fibrillary cytoplasm, and most GISTs show indistinct cell borders with a syncytial appearance (with the exception of a subset of epithelioid examples). The vast majority of GISTs are positive for KIT and DOG1, and ~70% are positive for CD34; these markers are generally negative in PEComas.

References
  1. Hornick JL, Fletcher CD. PEComa: what do we know so far? Histopathology. 2006;48:75-82.

  2. Bonetti F, Pea M, Martignoni G et al. PEC and sugar. Am J Surg Pathol. 1992;16:307-308.

  3. Zamboni G, Pea M, Martignoni G et al. Clear cell "sugar" tumor of the pancreas. A novel member of the family of lesions characterized by the presence of perivascular epithelioid cells. Am J Surg Pathol. 1996;20:722-730.

  4. Tazelaar HD, Batts KP, Srigley JR. Primary extrapulmonary sugar tumor (PEST): a report of four cases. Mod Pathol. 2001;14:615-622.

  5. Folpe AL, Goodman ZD, Ishak KG et al. Clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres: a novel member of the perivascular epithelioid clear cell family of tumors with a predilection for children and young adults. Am J Surg Pathol.2000;24:1239-1246.

  6. Mentzel T, Reisshauer S, Rutten A et al. Cutaneous clear cell myomelanocytic tumour: a new member of the growing family of perivascular epithelioid cell tumours (PEComas). Clinicopathological and immunohistochemical analysis of seven cases. Histopathology.2005;46:498-504.

  7. Bonetti F, Martignoni G, Colato C et al. Abdominopelvic sarcoma of perivascular epithelioid cells. Report of four cases in young women, one with tuberous sclerosis. Mod Pathol. 2001;14:563-568.

  8. Folpe AL, Mentzel T, Lehr HA et al. Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol. 2005;29:1558-1575.

  9. Vang R, Kempson RL. Perivascular epithelioid cell tumor ('PEComa') of the uterus: a subset of HMB-45-positive epithelioid mesenchymal neoplasms with an uncertain relationship to pure smooth muscle tumors. Am J Surg Pathol. 2002;26:1-13.

  10. Liegl B, Hornick JL, Fletcher CD. Primary cutaneous PEComa: distinctive clear cell lesions of skin. Am J Surg Pathol. 2008;32:608-614.

  11. Hornick JL, Fletcher CD. Sclerosing PEComa: clinicopathologic analysis of a distinctive variant with a predilection for the retroperitoneum. Am J Surg Pathol. 2008;32:493-501.

  12. Righi A, Dimosthenous K, Rosai J. PEComa: another member of the MiT tumor family? Int J Surg Pathol. 2008;16:16-20.

  13. Pan CC, Chung MY, Ng KF et al. Constant allelic alteration on chromosome 16p (TSC2 gene) in perivascular epithelioid cell tumour (PEComa): genetic evidence for the relationship of PEComa with angiomyolipoma. J Pathol. 2008;214:387-393.

  14. Henske EP, Neumann HP, Scheithauer BW et al. Loss of heterozygosity in the tuberous sclerosis (TSC2) region of chromosome band 16p13 occurs in sporadic as well as TSC-associated renal angiomyolipomas. Genes Chromosomes Cancer.1995;13:295-298.

  15. Kenerson H, Folpe AL, Takayama TK et al. Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms. Hum Pathol. 2007;38:1361-1371.

  16. Antonescu CR, Nafa K, Segal NH et al. EWS-CREB1: a recurrent variant fusion in clear cell sarcoma -- association with gastrointestinal location and absence of melanocytic differentiation. Clin Cancer Res. 2006;12:5356-5362.