Herein, we describe three PEComas of the nasal cavity (two cases) and larynx (one case) all of which occurred in females, consistent with the sex predilection of all PEComas, who ranged from 18 to 71 years of age. Other than a mass effect, no other specific signs or symptoms were noted. PEComas are rare in the head and neck [7
], and those arising in the nasal cavity and larynx are even more unusual [7
]. The common morphologic features observed in all three tumors included: large polygonal to epithelioid cells with clear or eosinophilic granular cytoplasm, centrally located nuclei with vesicular chromatin, and occasional nucleoli; a predominantly nested growth pattern associated with a delicate vascular stroma, similar to the vessels seen in clear cell renal cell carcinomas and paragangliomas; and a zone of subepithelial sparing. Except for Case 1, which showed extensive surface ulceration, the other two cases had an intact overlying surface. In Case 2, the vessels were more variable and a subpopulation of tumor cells demonstrated a faint brown cytoplasmic melanin pigment. Only Case 3 had the characteristic perivascular distribution of tumor cells, although only focally present. In addition, no case revealed significant cytological atypia, necrosis, infiltrative growth, vascular invasion, or mitotic activity. Moreover, by immunohistochemistry, all three cases reacted positively with melanocytic markers (HMB45 and/or Melan-A) and myoid markers (SMA or calponin).
The two patients with nasal PEComas were women 18 and 71 years of age, respectively. Not surprisingly, given the strong uniform expression of the melanocytic markers HMB45 and/or Melan-A, a differential of sinonasal melanoma was considered in both cases. Only two previous cases of nasal PEComas have been reported, expressing characteristic histologic and immunophenotypic features diagnostic of this tumor [7
]. The first case, reported in 2001 by Banerjee et al. [7
], presented as a polyp in the left nasal cavity of a 34-year-old woman who complained of nasal obstruction and occasional epistaxis. There was no personal or family history of tuberous sclerosis. Twelve months after an intranasal polypectomy, the patient was well without evidence of disease. In 2009, Kuroda et al. [12
] reported the second case of nasal PEComa in a 79-year-old Japanese woman who presented with a firm polypoidal mass in the nasal cavity. Notably, this was the first case of nasal PEComa expressing TFE3 protein. Follow-up information was not available for this patient, thus the prognosis could not be assessed.
In Case 3, the PEComa was originally misdiagnosed as paraganglioma and only correctly diagnosed as PEComa after subtotal laryngectomy. To our knowledge, this is the first reported case of PEComa of the larynx, although case reports of AML arising in the larynx and the epiglottis have been reported previously by Stodulski et al. [18
] and Zhang et al. [19
The descriptive term perivascular epithelioid cell (PEC) was proposed by Bonetti et al. [1
] to describe a novel cell type demonstrating HMB45 immunoreactivity and the presence of premelanosomes ultrastructurally, and which morphologically resembled the CCST of lung, AML of the kidney and liver, and LAM [21
]. They hypothesized that the PEC may originate from the walls of blood vessels, given the perivascular association and the fact that there is no known normal cellular counterpart to the PEC. The PEComa family of tumors has grown to include AML (renal and extrarenal variants), LAM, CCST of the lung, clear cell myomelanocytic tumor (CCMMT) of the falciform ligament/ligamentum teres, primary extrapulmonary “sugar” tumor and clear cell tumors of diverse sites [10
Epidemiologically, this tumor has a distinct female predominance, as observed in our three cases. Although most cases occur in middle aged patients [10
], two of our three patients were under the age of 30. The role of sex hormones has been speculated in the pathogenesis of some PEComas since estrogen or progesterone receptors have been found in renal AML and LAM [5
]. However, the absence of estrogen and progesterone receptor expression in other PEComas could not confirm this hypothesis [10
]. Although there is an association of AML and LAM with tuberous sclerosis complex, this association has been documented in less than 10% of patients with PEComas of soft tissue and gynecologic origin [10
Histologically, PEComas are characterized by predominantly epithelioid and/or spindled cells. Tumor cell nuclei range from round or ovoid in epithelioid cells to more elongated in the spindle cells. PEComa cells have a characteristic glycogen-rich, clear to lightly eosinophilic granular cytoplasm with vesicular nuclei and inconspicuous nucleoli. The nuclei are generally uniform with occasional cells exhibiting striking degenerative-type nuclear hyperchromasia and pleomorphism. Multinucleated giant cells may also be focally present and variable degrees of melanin pigmentation can be seen (as in Case 2). Mitotic figures are rare, though abundant and atypical mitotic figures can be seen in malignant examples. The cells have a focally nested, trabecular, or sheet-like growth pattern and may be intimately arranged around and within blood vessel walls. The vasculature ranges from a delicate capillary network to hyalinized arterioles and small arteries, best demonstrated in Case 2. At scanning magnification, the lesions may be well circumscribed or infiltrative.
Immunohistochemically, PEComas characteristically coexpress melanocytic and myoid markers [10
]. Folpe et al. [10
] evaluated 26 PEComas of soft tissue and gynecologic origin, and identified expression of melanocytic markers in all cases, with HMB45 being the most sensitive (92%) followed by Melan-A (72%). SMA was seen in 80% and desmin positivity in 8 (36%). Calponin was not used in this study but one case did express caldesmon. Case 1 was unusual in that there was no expression of SMA, but myoid differentiation was confirmed by immunoreactivity with calponin, another myoid marker; otherwise, this was a histologically typical PEComa with melanocytic differentiation (both HMB45 and Melan-A positive). Calponin has not been very well studied in PEComas but there are reports of calponin positive and SMA negative PEComas [11
Based on the review by Hornick et al. [6
] PEComas (excluding renal AML, LAM, and CCST of lung) most commonly involve the retroperitoneal, visceral, abdominal, and pelvic sites. The gastrointestinal tract and the uterus are the most common extrarenal organs involved with soft tissue and skin being less frequently involved. Case reports and small series have also described PEComas in unusual sites including the vulva, heart, breast, common bile duct, urinary bladder, and a variety of head and neck sites.
Based on our review of the English literature, we identified 13 cases [7
] of primary head and neck PEComas (excluding examples described as AML). Including our three cases, this number now consists of 16 tumors (Table ). There is less of a female predilection among this series (F: M = 10:6), compared to non-head and neck PEComas, and patients ranged in age from 7 to 80 years with both a mean and median of 48 years. The nasal cavity and ocular sites accounted for four cases each, representing half of the head and neck sites. The next most frequent sites of occurrence were scalp (three), intraoral (two), and one case each in cervical soft tissue, skull base, and larynx, respectively. Similar to PEComas at other body sites, these tumors tend to behave in an indolent fashion. Adequate follow-up was reported in 14 patients. Two patients (one skull base and one scalp) behaved in an aggressive fashion with distant or loco-regional metastases and one patient (skull base) died of disease-related causes [8
]. Therefore, 14% of head and neck PEComas, with available follow-up, behaved aggressively with loco-regional or distant metastases and only 7% died of disease. The patient with cervical lymph node metastasis was alive and disease-free at last follow-up. The remaining twelve patients were all reported as alive and free of disease following surgical resection.
Clinicopathologic findings of previously reported head and neck PEComas
The malignant potential of PEComas remains unknown. A vast majority of reported PEComas seem to behave in a benign fashion, although a malignant course with local recurrences and distant metastases has been reported [8
]. Predicting the behavior of PEComas based on histology alone is challenging. However, criteria for risk classification of non-AML PEComas based on histopathologic features have recently been proposed [10
]. Tumors with two or more of the following atypical features are considered malignant: size >5 cm, infiltrative growth, high nuclear grade, necrosis, mitotic rate ≥1/50 hpf and vascular invasion. Tumors with nuclear pleomorphism or multinucleated giant cells only, or those >5 cm are considered to be of uncertain malignant potential. All other tumors can be considered benign. However, this study was based on tumors of gynecologic origin and soft tissue (including two head and neck tumors), so application to all head and neck sites may not be appropriate.
Although size was known in only one of our cases (Case 1), all seemed to be much smaller than 5 cm based on review of the tumor dimensions on the glass slides (all tumor tissue was submitted in each case). None of our cases demonstrated an infiltrative growth pattern, vascular invasion, high nuclear grade, necrosis or mitotic activity. Twenty-six months (Case 1) and 8 years (Case 3) into follow-up, both patients are alive with no evidence of recurrence and/or metastases; the other patient (Case 2) was lost to follow up. These observations are consistent with the finding reported by Folpe et al. [10
] regarding the benign clinical behavior of these tumors. Still, the prognostic features of these tumors are largely unpredictable since occasional cases have demonstrated metastatic potential even though malignant histopathological features of the tumor were not observed [10
The differential diagnosis for head and neck PEComas is broad and somewhat site dependent. The differential diagnosis may include primary or metastatic melanoma, paraganglioma, clear cell sarcoma (malignant melanoma of soft parts), clear cell carcinoma, clear cell variants of salivary gland carcinomas, alveolar soft part sarcoma, granular cell tumor, clear cell oncocytoma, metastatic renal cell carcinoma and rhabdomyoma. By immunohistochemistry, negative S-100 staining and positive myoid marker expression are useful in differentiating PEComas from melanomas (primary and secondary). It must be noted, however, that some studies have shown that up to 33% of PEComas demonstrate S-100 positivity [10
], although most studies indicate positivity rates of about 10%, and characterized by only focal and usually cytoplasmic (not nuclear) staining. Furthermore, these S-100 positive PEComas typically also express myoid markers, a finding not generally seen in true melanocytic lesions [10
]. Spindle cell variant of melanoma may show limited SMA expression [29
]. Malignant melanomas generally tend to have more significant nuclear pleomorphism and increased mitotic activity which was not seen in any of our cases. In addition, prior history of melanoma or an in situ component would support this diagnosis.
Few PEComas (13%) of the soft tissue and gynecologic origin may show focal cytokeratin expression [10
] but the lack of diffuse cytokeratin expression combined with the coexpression of melanocytic and myoid markers should help to exclude the differential of clear cell carcinoma, clear cell oncocytoma, clear cell variants of salivary gland carcinoma, and metastatic renal cell carcinoma. A “Zellballen” architecture and a vascular stroma may resemble a paraganglioma, as seen in Case 3 which was initially misdiagnosed as such on incisional biopsy. But the lack of staining for chromogranin, synaptophysin, and S-100 (sustentacular distribution), as well as the expression of melanocytic and myoid markers makes this distinction straightforward. Alveolar soft part sarcoma (especially the solid type) may resemble PEComas and often show TFE3 nuclear expression. Although they may show positivity for muscle markers, they will lack expression of melanocytic markers. In addition, characteristic cytoplasmic PAS positive (diastase resistant) crystals may be identified and a recurring t(X;17) translocation resulting in a ASPL
fusion protein can be demonstrated. However, use of TFE3 immunostaining to separate these two neoplasms may not be helpful since nearly one-third of PEComas also express nuclear TFE3 [17
]. Moreover, this same study showed that five of 29 (17%) PEComas also had TFE3
gene rearrangements (four) or TFE3
amplification (one), thus limiting the utility of molecular testing in this differential diagnosis. Granular cell tumors have more abundant and granular cytoplasm coupled with characteristic positivity for S-100 and negativity for muscle markers thereby excluding this diagnosis. Clear cell sarcoma (also known as malignant melanoma of soft parts) has a nested growth pattern with clear cells and stains positively with melanocytic markers, but the cells do not express myoid markers, which can help distinguish them from PEComas. However, it may be difficult to distinguish them from the rare PEComas that are SMA negative and S-100 positive. As reported by Folpe et al. [10
] not all PEComas express smooth muscle markers: 80% of PEComas of soft tissue were SMA positive in their study. Therefore, the most specific test to distinguish these two entities in challenging cases is cytogenetic and/or molecular genetic confirmation of the characteristic t(12;22) seen in clear cell sarcoma that results in EWS
fusion protein [10
]. Finally, adult rhabdomyoma can be excluded based on strong desmin reactivity, lack of melanocytic markers and characteristic large cells with, at least occasional, foci of cytoplasmic striation.
The pathogenesis of PEComas is still not completely understood and is being explored owing to their rarity. However inactivation of TSC1
] with subsequent activation of mammalian target of rapamycin (mTOR) pathway has been associated with the pathogenesis of both syndromic and sporadic PEComas [32
]. Recent studies highlighting genetic events, including chromosome losses (1p, 17p, 18p, 19p) and gains (2q, 3q, 5q, 12q and X) have been indicated in the development of some PEComas [32
The optimal treatment for this group of tumors is not well established, but surgical resection with adequate margins seems to be the gold standard. The role for adjuvant radiation is not fully appreciated but may be indicated for those tumors that qualify as histologically malignant or of uncertain malignant potential. Given the role of mTOR pathway activation, inhibitors of this pathway (such as sirolimus) may prove helpful in treating malignant PEComas, as well as unresectable, histologically benign PEComas. In our cases, surgical excision with negative margins resulted in adequate treatment in the two cases with follow-up.