Perivascular epithelioid cell tumors (PEComas) are rare neoplasms that share phenotypic features with angiomyolipomas, clear cell sugar tumors, and lymphangioleiomyomatosis. They presumably represent the neoplastic counterpart of a yet-unidentified perivascular epithelioid cell that expresses smooth muscle and melanocytic immunomarkers. The uterus is the second most common site of origin for perivascular epithelioid cell tumors, after the retroperitoneum. Although most uterine perivascular epithelioid cell tumors are clinically benign and can be cured by a complete surgical excision, there is a subset characterized by both local and distant dissemination. Unfortunately, no single histopathologic or immunohistochemical parameter can accurately predict the clinical behavior of these tumors, which is why the 2012 World Health Organization classification of tumors of the female reproductive organs suggests the use of several criteria to predict the risk of aggressive clinical behavior. Here we review those perivascular epithelioid cell tumors of the uterine corpus with aggressive clinical behavior reported in the literature, and we discuss their most relevant clinical and histopathologic features.
In the early 1990s it was recognized that renal angiomyolipomas, clear cell sugar tumors, and pulmonary lymphangioleiomyomatosis constitute a group of lesions that have similar histopathologic features and share the expression of melanocytic antigens.1–3 Because the aforementioned lesions can be entirely or partially composed of clear to eosinophilic epithelioid cells with a tendency to aggregate around vessels, it was proposed that they might originate from a peculiar muscle cell that expresses melanocyte-associated immunomarkers, that is, the perivascular epithelioid cell.3 The term PEComa, as an acronym for perivascular epithelioid cell tumor, was first introduced in 1996 by Zamboni et al,4 who used it to describe a pancreatic tumor composed of human melanoma black 45 (HMB-45)–positive clear epithelioid cells. Thereafter, neoplasms with an epithelioid cytomorphology and coexpression of smooth muscle and melanocytic immunomarkers have been increasingly reported under the designation of PEComa in a wide variety of anatomic locations. Although PEComas are, in general, rare lesions, the uterus in particular is the second most commonly affected site after the retroperitoneum.5
The latest World Health Organization classification of tumors of female reproductive organs6 defines PEComas of the uterus as mesenchymal tumors typically containing epithelioid cells with clear to eosinophilic, granular cytoplasm demonstrating melanocytic and smooth muscle differentiation by immunohistochemistry. To date, less than 80 cases of uterine PEComa have been reported in the literature.7 Although the majority of these cases show a good overall prognosis and can be definitively cured by a complete surgical excision, locoregional recurrences, distant metastases, and disease-related deaths do rarely occur. In fact, one of the challenges faced by pathologists is how to predict the biological behavior of PEComas, because no single histopathologic feature is in and of itself a marker of an aggressive biology. For the purposes of this review, we considered as clinically aggressive those PEComas that showed evidence of regional or distant dissemination requiring surgery or chemotherapy.
The histogenesis of PEComas is still controversial, because a normal counterpart of the perivascular epithelioid cell has not been identified to date.8 There is a well-established association between PEComas and the tuberous sclerosis complex (TSC), which is caused by mutations in hamartin (TSC1, chromosome 9) and tuberin (TSC2, chromosome 16) in 27% and 73% of cases, respectively.8 The protein products of TSC1 and TSC2, together with TBC1D7 (TBC1 domain family, member 7), form a heterotrimer that promotes the formation of Rheb-GDP (guanidine diphosphate–bound Ras homolog enriched in brain protein) from Rheb-GTP (guanidine trisphosphate–bound Rheb). The active form of Rheb, Rheb-GTP, stimulates the formation of mTORC1 (mTOR complex 1), a multiprotein complex composed of mTOR (mammalian target of rapamycin), Raptor (regulatory-associated protein of mTOR), Deptor (DEP domain–containing mTOR-interacting protein), mLST8/GβL (mammalian LST8/G-protein β-subunit–like protein), and PRAS40 (40-KDa proline-rich AKT substrate).9 In turn, mTORC1 promotes cell growth and metabolism through the activation of ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein (4E-BP). Therefore, TSC1 and TSC2 act as tumor suppressors by inhibiting mTORC1 through an increase in the concentration of inactive, GDP-bound Rheb.
Because of its strategic position within the mTOR signaling pathway, mTORC can function as an integrator of both extracellular and intracellular signals. For example, extracellular stimuli that promote cell growth through the PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) and MAPK (mitogen-activated protein kinase) signaling pathways lead to the activation of Akt (proto-oncogene Akt) and ERK (extracellular signal-regulated kinase) protein kinases, respectively, which results in the inhibition of TSC1/TSC2/TBC1D7.9 In contrast, an increase in the concentration of adenosine monophosphate (AMP) leads to the activation of glycogen synthase kinase 3 (GSK3) and AMP-activated protein kinase (AMPK), both of which can activate TSC1/TSC2/TBC1D7, resulting in decreased cell metabolism and growth.9 In patients with tuberous sclerosis, the loss of functional TSC proteins prevents the formation of the TSC1/TSC2/TBC1D7 heterotrimer. As a result, there is a constitutive Rheb-GTP–mediated activation of mTOR, which leads to increased cell growth and proliferation. Loss of heterozygosity at 16p13, the chromosomal region containing the TSC2 gene, has been described in sporadic and tuberous sclerosis-associated PEComas.8 Mutations of TSC2 have been described in 62% of PEComas overall and in 80% of the PEComa subgroup lacking translocations of the TFE3 gene, as described below.10
Recently, a study10 of 38 PEComas found that 9 (23%) of them harbored translocations of TFE3 (transcription factor E3), a member of the microphthalmia transcription factor (MiTF) gene family located in the short arm of chromosome X. Although the function of the MiTF gene family members as inducers of melanocyte differentiation is well established, providing an elegant explanation for the dual phenotype of PEComas, their mechanistic role in tumorigenesis is still controversial. To date, 3 different models have been proposed to explain the induction of tumor development by TFE3 translocations.11 The first model presumes a wild-type tumor-suppressor activity of TFE3, which is disrupted by the gene fusion. The second model ascribes a novel transforming activity to the TFE3 fusion protein because of altered protein conformation. Finally, the third model attributes a more active and less tightly regulated transcriptional activity to the fusion protein, which displays more promiscuous promoter-binding properties than wild-type TFE3.11 Interestingly, some studies have described an increased activation of mTORC1 signaling in TFE3-fusion RCC cell lines, suggesting a potential link between the 2 major pathways underlying the molecular pathogenesis of PEComas.
A recurrent translocation involving the RAD51B (DNA repair protein RAD51 homolog 2) gene on the long arm of chromosome 14 was also identified in 3 cases.10 Although only 1 of the 9 neoplasms that showed a TFE3 translocation originated in the uterus, translocations involving RAD51 were identified exclusively in uterine PEComas.10 Interestingly, TSC2 mutations seemed to be mutually exclusive with TFE3 translocations, because only TFE3 translocation–negative PEComas showed TSC2 mutations and vice versa.10 Also, 5 of 8 translocation-negative/TSC2-mutated PEComas showed synchronous mutations of TP53 (tumor protein 53).10 Authors12 from the University of Pennsylvania demonstrated increased expression of TP53 by immunohistochemistry in pure epithelioid PEComa, compared with conventional angiomyolipoma. They also documented the presence of TP53 mutations in some cases of pure epithelioid PEComa, but not in angiomyolipomas.12 These findings suggest that alterations in the TP53 pathway may be a possible explanation for the more aggressive biology and unpredictable clinical behavior of pure epithelioid PEComas.
Perivascular epithelioid cell tumors of the uterine corpus can occur in women of any age, including prepubertal pediatric patients.20 While 5% of all uterine PEComas occur in the context of tuberous sclerosis, most tumors seem to be sporadic.7 For published CAPUs in particular, there is only one case affecting a patient with tuberous sclerosis, to the best of our knowledge.14 The mean and median ages at presentation are 47.9 and 44 years, respectively. Most patients have long-standing abdominal pain and vaginal bleeding, but a case with an acute presentation due to uterine rupture has also been documented.19 Most lesions are initially diagnosed by ultrasonography, usually followed by computed tomography or magnetic resonance imaging to evaluate the anatomic extent of the disease.14,15,18–20,23,24
Although intraperitoneal implants are often found at the time of initial diagnosis, distant metastases are most commonly encountered during follow-up.13,14,18,23 For those cases that show localized disease at presentation, the time to distant metastasis seems to be widely variable, ranging from 1 month to 15 years, with median and mean times to distant metastasis of 90 and 51.2 months, respectively.16,18,21,22,25–27 Local dissemination in the form of ovarian and pelvic implants is found in 19% (4 of 21) and 14.3% (3 of 21) of CAPUs, respectively. Distant dissemination affects 62% (13 of 21) of patients, and more often involves the lungs (52.4%; 11 of 21), liver (19%; 4 of 21), and bone (14.3%; 3 of 21). Although CAPUs seem to have a preference for hematogenous dissemination, lymph node metastases are also encountered in almost a fifth of cases (4 of 21).14,17,20,24 Interestingly, 2 patients who developed late metastases, that is, beyond 5 years of initial diagnosis, originally presented with tumors that fell on the lower end of the size spectrum.16,22 In contrast, most cases with peritoneal and pelvic implants have bulky disease at initial diagnosis.15,18,23 It is possible that intraperitoneal dissemination occurs as a consequence of microscopic or macroscopic rupture of the serosa overlying the tumor. In this regard, one report describes the development of multiple pelvic implants after spontaneous intraperitoneal rupture of a uterine PEComa.19 Interestingly, CAPUs that develop intraperitoneal implants or lymph node metastases do not seem to show a tendency for distant dissemination, suggesting that their biology might be different from that of hematogenously metastasizing CAPUs.*
PATHOLOGIC FEATURES AND DIFFERENTIAL DIAGNOSIS
Macroscopically, most CAPUs are described as nodular or multinodular lesions with a myometrial or subserosal localization and a fungating appearance.13–20,22–24 Also, nodules with a submucosal localization can present clinically as pedunculated or sessile polyps (Figure 1, A). Most tumors are bulky, ranging from 5 to 30 cm in greatest dimension, with mean and median sizes of 11 and 12.5 cm, respectively (Table 2). The cut surface is pink to gray and homogeneous, but areas of macroscopic necrosis and hemorrhage are also frequently present (Figure 1, B).6,13–20,22–24
Perivascular epithelioid cell tumors of the uterine corpus are highly vascular and demonstrate an epithelioid, spindle cell, or combined epithelioid–spindle cell cytomorphology (Figure 2, A).13–28 Microscopically, most neoplasms show infiltration of the myometrium, with malignant cells splitting the myometrial fibers or infiltrative tonguelike lesional borders.6,13–27
The epithelioid cells are medium-sized to large, and show a trabecular, nested, and/or solid arrangement, with a characteristic tendency to aggregate around blood vessels. However, less common papillary and pseudoglandular histoarchitectural patterns have also been described.14 Individual cells show well-defined borders and an abundant, granular, eosinophilic to clear cytoplasm that can display diastase-sensitive periodic acid–Schiff positivity.20 Nuclear pleomorphism is usually moderate to marked, but rare cases can show uniform nuclei with bland cytomorphologic features.16 Large nucleoli and atypical hyperchromatic nuclei with coarsely clumped chromatin are commonly found. In contrast, the spindle cell component of CAPUs is characteristically less atypical, and consists of short fascicles and nests of slender fusiform cells in a stromal background with diverse histologic changes, such as myxoid degeneration (Figure 2, B). Both tumor necrosis and lymphovascular invasion are frequently identified, and their presence in an otherwise typical PEComa should always suggest the possibility of CAPU.14,15,19,22,24,27 Bizarre mononucleated and multinucleated giant cells are often recognized scattered among the rest of the neoplastic elements.19,22,24 Also, microscopically apparent intracellular pigment can occasionally be detected in the tumor cells.14 Mitotic activity is usually high, but not invariably so, with some PEComas showing an aggressive clinical behavior in spite of a low mitotic count.16,20,24 However, the presence of even a small number of mitotic figures is worrisome, because nonaggressive PEComas show very rare, if any, mitoses.6 Similarly, the identification of even a single isolated atypical mitotic figure is highly indicative of malignancy. Metastases show histopathologic features similar to those of the primary tumor, with marked nuclear pleomorphism, tumor necrosis, and very high mitotic rates being common findings.22,25,27
Electron microscopy reveals multiple granules that resemble promelanosomes, within a cytoplasm that displays ultrastructural features similar to those of smooth muscle cells.13
Immunohistochemically, PEComas are characterized by the coexpression of smooth muscle and melanocytic markers (Figure 3, A and B). Among the smooth muscle cell markers, smooth muscle actin, muscle-specific actin, and desmin are positive in 84.6%, 66.7%, and 55.6% of cases, respectively.13–16,18–20,22–27 The melanocytic marker HMB-45 is expressed in all cases, and Melan-A is positive in up to 80% of tumors.13–16,18–20,22–27 One case also demonstrated focal nuclear labeling for MiTF, a relatively new melanocyte immunomarker. Although a significant proportion of CAPUs show positivity for estrogen receptor, protein S-100 and cytokeratins are invariably negative.†
The World Health Organization6 classification of tumors of female reproductive organs (2014) proposes the use of 7 parameters to identify those PEComas with a potentially aggressive clinical behavior. Namely, those parameters are size larger than 5 cm, infiltrative margins, high-grade nuclear atypia, high cellularity, mitotic activity greater than 1/50 high-power fields, necrosis, and vascular invasion. Although tumors that show either a size larger than 5 cm or nuclear pleomorphism alone might be considered of uncertain clinical behavior, the presence of 2 or more of the aforementioned histopathologic features portends a high risk for aggressiveness.
The differential diagnosis includes leiomyosarcoma (LMS), low-grade endometrial stromal sarcoma (ESS), and high-grade ESS, all of which are more frequent than CAPUs. In this regard, some uterine tumors originally diagnosed as uterine LMS or ESS are retrospectively found to be CAPUs when they are reviewed in the context of an apparently extrauterine PEComa presenting several years later.22,25 Although all of the aforementioned neoplasms can be positive for sex hormone receptors, an intense estrogen receptor immunolabeling is more often found in low-grade ESS.6 High-grade ESS, which is usually negative for hormone receptors, can be differentiated from CAPUs by its diffuse cyclin D1 positivity, especially if melanocytic immunomarkers are negative.6 In addition, the demonstration of a (10;17) translocation, which results in the YWAEH-FAMM22 (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon family with sequence similarity 22) fusion product, strongly favors the diagnosis of high-grade ESS. Likewise, the presence of a rearrangement of PHD finger protein 1 (PHF1) gene on chromosome 6, or a translocation (7;17)(p15;q21) is highly suggestive of low-grade ESS.6
Coexpression of smooth muscle markers and discovered on gastrointestinal stromal tumor 1 (DOG1), together with a negative immunolabeling for melanocytic antigens, favors a diagnosis of LMS.6 An important pitfall to be aware of is that ESS, LMS, and even leiomyomas can all occasionally show expression of HMB-45.29,30 As a matter of fact, as many as 25% of LMSs and 23.5% of ESSs can be HMB-45 positive.29,30 In LMS, positivity for HMB-45 is more often found in high-grade tumors.29 Although this can be problematic, because such an immunoprofile would be indistinguishable from that of a PEComa, HMB-45 expression in LMS is usually present focally in a minor subset of tumor cells.29 In contrast, PEComas tend to show a more diffuse and intense positivity for melanocytic markers. In difficult cases, immunolabeling for more than one melanocytic marker, as well as the demonstration of TSC2 mutations or TFE3 translocations, might be helpful to differentiate PEComa from LMS. The presence of melanocytic antigens in ESS is probably less problematic, because these tumors show additional immunomarkers that are not usually found in PEComas, and they also harbor specific chromosomal rearrangements.
The diagnosis of metastatic PEComa can often prove to be problematic, because both pelvic lymph nodes and lungs can be affected by lymphangioleiomyomatosis. In this review, we only included cases where lymph node and pulmonary involvement was deemed metastatic by the authors and therefore treated accordingly. For pulmonary metastases, correlation with the clinical course and radiologic findings are elements that can be used to determine their secondary nature. Specifically, the development of new lesions during follow-up that have a solid, nodular appearance on computed tomography—instead of the characteristically cystic look of lymphangioleiomyomatosis—and show an aggressive clinical behavior strongly favors the diagnosis of metastatic PEComa.16,18,27 Also, the presence of overtly malignant features, such as mitoses and necrosis, is highly indicative of tumor implants, especially when those same features were present in the primary tumor.22 For lymph node metastases and abdominopelvic implants, 2 important factors that suggest their secondary nature are the identification of distinctly malignant histologic features and an aggressive, infiltrative growth.14,18,19
TREATMENT AND PROGNOSIS
Surgery, either with a cytoreductive or curative intent, is the mainstay of therapy for CAPUs.13–28 Most patients who show distant metastases or lymph node involvement receive adjuvant treatment in the form of chemotherapy or chemoradiation.14,18,20,21,24,25 However, one patient with lung and kidney metastases who refused adjuvant treatment has been reported to be disease free 1.5 years after a combined metastasectomy.22 Also, 2 patients with ovarian implants and no evidence of lymph node or distant metastases have been treated with surgery alone, remaining recurrence free at 6 and 18 months of follow-up, respectively.14,23 Neoadjuvant chemotherapy has been used in 2 patients who presented initially with bulky local disease, allowing for a subsequent radical surgery.20,24 The use of mammalian target of rapamycin (mTOR) inhibitors for the treatment of CAPUs relies on the rationale that these tumors often harbor TSC2 mutations. Studies on small groups of patients with CAPUs from different anatomic locations have reported a good clinical response to mTOR inhibitors.28,31,32 In fact, individual cases with bulky, unresectable disease at presentation have shown complete or near-complete sustained clinical responses to these drugs.32 Moreover, mTOR inhibitor therapy followed by surgical resection of a single metastasis has proven to be beneficial in at least 2 patients, who have remained disease free at 6 and 9 months after metastasectomy, respectively.28,32 It must be noted, however, that there are several cases where clinical response is either absent or minimal and short-lived because of the development of resistance against mTOR inhibitors. This suggests that, when selective pressure is applied, alternative molecular mechanisms may eventually override the mTOR-driven tumorigenesis.
With regard to prognosis, some cases show an aggressive local disease with early dissemination, whereas others display a more indolent course characterized by late distant metastases. Patients with bulky pelvic disease seem to fare poorly, often exhibiting little response to adjuvant treatment and early disease-related mortality.15,18,19 In contrast, those patients who develop late metastases—several years after the initial diagnosis—appear to have a more protracted clinical course and better overall survival, despite the presence of disseminated disease.21,22,27,28
References 13–15, 17, 19, 20, 23, 24.
References 13–15, 19, 20, 22, 23, 25, 26.
The authors have no relevant financial interest in the products or companies described in this article.