Case 4 -
Jason L. Hornick
Brigham & Women’s Hospital
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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
Case 4 - Slide 1
Case 4 - Figure 1
Gross photograph showing a well-circumscribed tumor within the body of the pancreas.
Case 4 - Figure 2
The tumor is sharply demarcated from the surrounding pancreatic parenchyma.
Case 4 - Figure 3
The tumor is composed of cells with abundant clear cytoplasm. Note the thin fibrous pseudocapsule surrounding the tumor.
Case 4 - Figure 4
The tumor shows a mixture of spindle cell (left) and epithelioid (right) cytomorphology.
Case 4 - Figure 5
Spindle cells with granular eosinophilic to clear cytoplasm. Note the focal areas of stromal hyalinization (bottom).
Case 4 - Figure 6
In areas, the tumor shows a well-developed fascicular architecture, mimicking a smooth muscle neoplasm.
Case 4 - Figure 7
A more sheet-like area of the tumor. Note the focal perivascular growth pattern (center).
Case 4 - Figure 8
Tumor cells with abundant clear cytoplasm and distinct cell borders, focally associated with blood vessel walls.
Case 4 - Figure 9
Spindle cells with granular eosinophilic cytoplasm. Note the uniform nuclei with fine chromatin and small nucleoli.
Case 4 - Figure 10
Polygonal cells with clear to eosinophilic cytoplasm. Occasional multinucleated cells and focal pleomorphism are present.
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.
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.  This cell type was first proposed in 1992 by
Bonetti and colleagues,  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,  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,  clear cell myomelanocytic
and abdominopelvic sarcoma of perivascular epithelioid cells.  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
The most common anatomic sites are abdomen and pelvis,
retroperitoneum, uterus, and gastrointestinal tract.
A minority (~25%) arises in
somatic soft tissue and skin.
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" ) 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.  A minority of PEComas show striking pleomorphism and resemble pleomorphic
myogenic sarcomas (see below). 
By immunohistochemistry, as indicated above, PEComas often show a mixed melanocytic and myogenic
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.  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%),  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);
the significant of this finding is uncertain.
Recent studies indicate that PEComas frequently show deletions of the TSC2 locus at chromosome
similar to conventional renal AML,  which result in activation of the
mTOR (mammalian target of rapamycin) signaling pathway.
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,  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."  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.  Personal experience suggests that PEComas showing marked
pleomorphism (often resembling a pleomorphic myogenic sarcoma) also have the potential to pursue an
aggressive clinical course. 
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,  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),  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
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