In this report, we describe a case of unusual epithelioid tumors in the kidney and the lung seven years after the initial diagnosis of uterine leiomyosarcoma, with pathological and immunohistochemical features entirely compatible with those of a PEComa. PEComas are characterized by epithelioid to spindle cells with eosinophilic to clear cytoplasm, an intimate relationship with blood vessels, and demonstrate positive immunostaining for markers of both melanocytic (HMB45, Melan-A, tyrosinase, microphthalmia transcription factor) and myoid (desmin, smooth muscle actin, muscle-specific actin, caldesmon, calponin) differentiation . PEComas-NOS have now been reported in almost every body site and the growing list of reported sites include gynecological, genitourinary, gastrointestinal, extremities and the skin, as well as single reports in the heart, breast, oral cavity, orbit, and skull base [1, 5–17]. The uterus is the most prevalent reported site of involvement of PEComa-NOS (accounting for 38 out of about 100 reported cases). The other common sites are the gastrointestinal tract, genitourinary tract and retroperitoneum, whilst rare sites include somatic soft tissue, skin and bone. Almost all the reported non-uterine PEComas-NOS have been in women [1, 5–17]. The vast majority of PEComas-NOS have been described in females (as in the case herein presented) [1, 5–17], and therefore hormones may play a role in their pathogenesis and/or phenotypic cellular manifestations. Estrogen receptor (ER) and progesterone receptor (PR) expression, that have been reported primarily in the spindle cell component of PEComas [5, 10], may play a role in the development of this morphologic pattern. The case herein presented showed moderate-to-strong positive nuclear staining for both ER and PR in both the spindle and epithelioid cell components of all three lesions (uterine, renal and pulmonary), although the ER staining was always more intense than PR staining.
PEComas are of interest primarily because of their immunoreactivity with melanocytic and myoid markers. They are also almost always negative for S-100 protein and cytokeratins. Folpe and colleagues  recently reviewed all reported cases of PEComa up to 2005 (61 cases). In their review, 100% were HMB-45 positive, 59% were smooth muscle actin positive, 41% were Melan-A positive, 33% were CD117 positive, 31% were desmin positive, 11% were S-100 positive, and 0% was cytokeratin positive. Therefore, nearly all PEComas are immunoreactive for HMB-45 and/or Melan-A, and many are positive for smooth muscle actin, whereas desmin staining appears to be somewhat less common. Elongated spindle cells in PEComas are characterized by prominent smooth muscle-specific filaments, while the epithelioid component does not usually contain high numbers of such filaments . The case herein presented showed strong and diffuse staining for both HMB-45 and MelanA in both the spindle and epithelioid cell components of all three lesions (uterine, renal and pulmonary), with more intense staining in the epithelioid cells compared to the spindle cells. In the present case, staining for muscle-specific actin, smooth muscle actin, and desmin was more evident in the area adjacent to the cytoplasmic membrane, with more intense staining in the spindle cells compared to the epithelioid cells.
Not unexpectedly, the uterine tumor of the case herein presented was initially misdiagnosed as a uterine leiomyosarcoma at an outside institution seven years prior. Myomelanocytic marker expression was found to be prominent in both components of all the three lesions in the case herein presented. Controversy exists regarding the minimum criteria for the diagnosis of malignant PEComa [18, 19]. In studies of uterine tumors demonstrating epithelioid morphology, clear cell areas and HMB-45 positivity, these authors [18, 19] argued that these lesions represented epithelioid smooth muscle tumors with focal melanocytic differentiation and not PEComas. This view was based largely on the fact that the tumors looked like classic leiomyosarcomas with spindled and epithelioid areas, and stained with desmin. Nevertheless, these authors [18, 19] still advocated performing immunohistochemistry for HMB-45 in all uterine epithelioid smooth muscle tumors, in order to identify patients who should be investigated for TSC. It is also noteworthy that only focal HMB-45 staining was seen in their cases, unlike the diffuse expression in the case herein presented and nearly all the reported cases of uterine PEComa [1, 5–11]. Additionally, 31% of PEComas showed at least focal desmin staining in a recent review of all reported cases up to 2005 (61 cases) , and therefore desmin staining of uterine epithelioid tumors with clear cell areas and HMB-45 positivity does not exclude the diagnosis of PEComa. We are therefore of the view that tumors with diffuse myomelanocytic differentiation should be regarded as being related to the PEComa family irrespective of site of origin or desmin positivity, and that it is the characteristic morphology and immunophenotype that warrants separating these tumors from classic leiomyosarcoma that exhibit only muscle differentiation. However the clinicopathological significance of HMB-45 positivity in uterine epithelioid smooth muscle tumors is not known.
In addition to epithelioid smooth muscle tumors (epithelioid leiomyosarcoma and epithelioid leiomyoma), the other important differential diagnosis of PEComa include malignant melanoma, clear cell sarcoma of tendon and aponeuroeses (melanoma of the soft parts), alveolar soft part sarcoma, endometrial stromal sarcoma with clear cell features, uterine tumor resembling sex cord tumor, carcinoma (especially renal cell and adrenocortical carcinoma), paraganglioma, angiomyolipoma, and any other tumor with focal or prominent clear cell change. Malignant melanoma and clear cell sarcoma of tendon and aponeuroeses can be differentiated from PEComas based on S-100 positivity; however, up to 11% of PEComas express S-100 as well . The additional important features for the diagnosis of PEComa in this context include negative history for melanoma, visceral location of tumor, perivascular accentuation of tumor cells, immunoreactivity for myoid markers (smooth muscle actin, muscle-specific actin, and desmin), and absence of the t(12:22) translocation. Although S-100 negative melanomas have rarely been described, tumors with S-100 negativity, strong and diffuse melanocytic marker positivity, and actin immunoreactivity should be designated as PEComas based on morphology and immunophenotype. Pitfalls in the diagnosis of PEComas include aberrant staining of cells with melanocytic markers. However, diffuse and multiple melanocytic marker expression is highly reliable for melanocytic differentiation. Focal or weak positivity can be disregarded, however, and do not warrant the diagnosis of PEComa. The case herein presented was strong and diffusely positive with at least two melanocytic markers (HMB45 and Melan-A), which is not a finding in other sarcomas. Angiomyolipoma can be ruled out because the present case lacked lipomatous elements and showed a biphasic cellular population. However, PEComa and monophasic epithelioid angiomyolipoma are probably very closely related, if not the same entity. Endometrial stromal sarcoma and uterine tumor resembling sex cord tumor can be ruled out because of the presence of prominent perivascular accentuation of tumor cells and diffuse, rather than focal, positive staining of HMB-45 in PEComa. PEComa can be distinguished from paraganglioma in that the former is negative for chromogranin A, synaptophysin, and S-100 protein, and the latter shows more organoid growth. The expression of melanocytic markers (HMB-45 and MART-1/Melan-A) and the lack of immunoreactivity for cytokeratins and RCC marker argue against the diagnosis of carcinoma.
Clinically, most PEComas follow a benign course . Malignant PEComas-NOS are being increasingly reported, several originating in the uterus and others arising in the jejunum, ileum, prostate, pelvis, skull base, broad ligament and somatic soft tissue [1, 5–17]. Since relatively few malignant PEComas have been reported, firm criteria for malignancy have yet to be established. However, Folpe and colleagues  recently suggested criteria for malignancy including a size of >8.0 cm, mitotic count of >1 per 50 high power fields (HPFs) and necrosis, with benign, uncertain malignant potential and malignant categories based on the presence of none, 1 or ≥ 2 of these three criteria, respectively. Infiltrative growth or edges, marked hypercellularity and marked nuclear pleomorphism/atypia may be secondary features suggesting aggressive behaviour or malignancy [1, 8, 11]. A Ki-67 labeling index of 5% of neoplastic cells has been observed in a uterine PEComa that have behaved aggressively . In the case herein presented, the size of the primary uterine tumor seven years prior was <8 cm, mitotic count was >1 per 50 HPFs and necrosis was absent. Retrospectively, this uterine tumor would be categorized as of uncertain malignant potential according to the above suggested criteria. Additionally, the uterine tumor showed all the three secondary features suggestive of aggressive behaviour or malignancy. Furthermore, the Ki-67 labeling index was greater than 5% in the uterine tumor (also in the renal and pulmonary metastases), and thus the uterine tumor was destined to behave aggressively, which it did seven years later. Dimmler and colleagues have also reported late pulmonary metastases occurring seven years after the diagnosis of a case of uterine PEComa . Therefore, metastatic spread of PEComas may, in some cases, be a late complication, presenting after many years. This highlights both the need for criteria that more accurately predict the behavior of PEComas and the need for long-term follow-up of patients with PEComas, as widespread metastases may present as a late complication.
Optimal treatment for PEComas is not well established at this time. Currently, surgery is the mainstay of treatment for primary PEComa at presentation as well as for local recurrences and metastases, with the aim of obtaining clear resection margins. The role of adjuvant therapy remains unclear. Metastases have been successfully managed by resection alone . Primary excision is usually curative, as most PEComas are benign. However, locally advanced or metastatic disease portends a poor prognosis and treatment strategies incorporating surgery, radiotherapy and chemotherapy have been reported . Given the uncertainty of PEComa tumor biology, adjuvant therapies, including chemotherapy and immunotherapy, may be considered for patients with locally advanced or metastatic PEComa.