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Pathology International 2014; 64: 151–153
doi:10.1111/pin.12137
Letter to the Editor Perivascular epithelioid cell tumor of the uterus To the Editor: Perivascular epithelioid cell tumor (PEComa) is defined by the World Health Organization as ‘a mesenchymal tumor composed of histologically and immunohistochemically distinctive perivascular epithelioid cells’.1 Bonetti et al. first advanced the concept of a family of neoplasms deriving from these distinctive cells in 1992.2 The PEComa family of tumors has subsequently grown to include common angiomyolipomas, clear cell sugar tumors, lymphangioleiomyomatosis, and less common neoplasms of various anatomical sites.3,4 Immunohistochemically, perivascular epithelioid cells (PEC) express melanocytic and myogenic markers, such as HMB45, Melan-A, MiTF and actin. At present, the normal/ physiological counterpart of PEC is unknown, and the histogenesis of PEComa is not fully understood. We report a rare case of uterine PEComa with detailed immunohistochemical and ultrastructural studies. A 62-year-old woman with no known significant past medical or family history presented with abnormal vaginal bleeding. Sagittal T2-weighted MRI of the pelvis showed a mass with slightly high signal intensity at the upper myometrium, and a mass with low signal intensity at the inferior myometrium. Histopathological examination of the biopsy
and cytology specimens obtained from the endometrium suggested an adenocarcinoma. The patient was preoperatively diagnosed with leiomyomas and adenocarcinoma of the uterine corpus and a total hysterectomy and bilateral oophorectomy were performed following this diagnosis. The postoperative course was unremarkable. Grossly, the uterus contained a 12 mm-sized, grayishwhite, solid mass with focal hemorrhage in the right upper myometrium, a 16 mm-sized, white, solid mass in the right lower myometrium, and a polyp in the endocervix (Fig. 1a). Microscopically, the grayish-white mass in the upper myometrium exhibited an expansive growth with no definite capsule (Fig. 1b), and consisted of an alveolar or fascicular arrangement of polygonal to spindle cells with oval to spindle-shaped nuclei and pale to lightly eosinophilic cytoplasm (Fig. 1c). Mild cellular atypia and multinucleated giant cells were observed. No mitotic figures were evident. The stroma contained abundant capillaries and thick-walled vessels (Fig. 1d). A perivascular arrangement of the tumor cells was focally observed. Immunohistochemically, the tumor cells were diffusely positive for HMB-45, Melan-A, microphthalmia transcription factor (MiTF), smooth muscle actin, and cathepsin K, focally positive for HHF-35 and S-100 protein, and negative for AE1/AE3, desmin, estrogen receptor, and transcription factor E3 (TFE3) (Fig. 2a–c). Based on these
Figure 1 (a) Gross appearance of horizontal cut surfaces of surgical specimens. Above: specimen from tumor in upper myometrium. Below: specimen from tumor in lower myometrium. (b–d) Microscopic appearance of upper tumor, with (b, c) HE staining and (d) CD31 immunostaining. © 2014 The Authors Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
152
Letter to the Editor
Figure 2 (a–c) Immunostaining of upper tumor for (a) HMB-45, (b) MiTF, (c) and cathepsin K. (d) Electron microscopic features of upper tumor (x10 000).
pathological findings, the patient was diagnosed with uterine PEComa. Ultrastructural examination using a formalin-fixed specimen revealed that the cytoplasm of the tumor cells contained vesicles with many pigmented granules comparable to stage III melanosomes (Fig. 2d). Smooth muscle differentiation was not observed ultrastructurally. In addition, the white mass in the lower myometrium was identified as a leiomyoma, and the polyp as an endocervical polyp. A 3 mmsized grade 1 endometrioid adenocarcinoma was also detected microscopically. We herein describe a case of uterine PEComa which radiologically and grossly resembled a degenerated leiomyoma. Microscopically, it lacked diffuse cytoplasmic eosinophilia or the cigar-shaped nuclei seen in leiomyomas, and showed, instead, clear to lightly eosinophilic cytoplasm and oval to spindle-shaped nuclei, multinucleated giant cells, a delicate capillary network, and focal hemorrhage. We speculate that PEComas of the uterus have occasionally been mistaken for degenerated leiomyomas on gross examination. Neither the radiological, nor gross appearance of uterine PEComas is sufficiently distinctive to allow diagnosis. In addition, the pathologic features of PEComas, characterized by spindle to epithelioid cells displaying clear to eosinophilic cytoplasms and immunoreactivity for melanocytic markers, significantly overlap with a subset of other uterine mesenchymal tumors. The distinction between uterine PEComas and other mesenchymal tumors, especially epithelioid smooth muscle tumors, should be made chiefly on the basis of morphological evaluation. Among the most important differences is that smooth
muscle tumors lack the delicate and diffuse vascular network seen in PEComas. Pathologists should be aware of the existence of uterine PEComas in order to differentiate them from other similar lesions such as uterine leiomyomas in particular. The normal/physiological counterpart of PEC is unknown. One hypothesis is that PEC derives from undifferentiated cells of the neural crest that can express both smooth muscle and melanocytic phenotypes.3,5 Another hypothesis is that PEC has a myoblastic, smooth muscle origin with a molecular alteration that gives rise to melanogenesis and expression of melanocytic markers. Other hypotheses hold that PEC has a pericytic or telocytic origin. Ultrastructural studies have documented some features indicative of a neural crest origin, such as abundant cytoplasmic glycogen, premelanosomes, neurite-like cytoplasmic processes, fine filaments, and microtubules in PEComa.5 In our case, PEComa cells exhibited both myogenic and melanocytic differentiation immunohistochemically, and melanogenesis ultrastructurally, supporting the hypothesis of a neural crest origin. PEComas have been reported to originate from a wide variety of anatomic locations. The uterus and retroperitoneum have emerged as the two most frequent sites of origin for PEComas leaving aside common renal angiomyolipomas.6,7 To date, more than 50 cases of uterine PEComa have been reported in the English literature. Most of these cases arose in the uterine corpus except four cases of uterine cervix origin. Fadare evaluated 41 previously reported cases of uterine PEComa and found that their cytological features and growth pattern were quite variable, and that their vasculature seemed
© 2014 The Authors Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Letter to the Editor
to be an intrinsic and recurrent property which might be of diagnostic utility irrespective of the growth pattern.7 Concerning the prognostic significance of individual pathological features, Fadare reported that malignant PEComas showed significantly larger tumor sizes than nonmalignant cases. They also reported that the presence of coagulative necrosis was highly associated with malignancy and that the absence of mitotic activity did not rule out malignancy. Some members of the PEComa family have a strong association with tuberous sclerosis. Most sporadic and tuberous sclerosis-associated PEComas demonstrate inactivation of the TSC1 or TSC2 genes with subsequent activation of the mammalian target of rapamycin (mTOR) pathway.8 Recently, a subset of PEComas entirely unassociated with tuberous sclerosis was found to harbor TFE3 gene fusions.9 Conventional PEComas frequently have a spindle cell component, typically label for muscle markers, and lack strong TFE3 immunoreactivity. In contrast, TFE3-rearranged PEComas have predominantly alveolar architecture and epithelioid cytology, show minimal immunoreactivity for muscle markers, and strong TFE3 immunoreactivity, and are thought by some to constitute a distinctive entity. Recent studies have demonstrated that cathepsin K appears to be more powerful than other commonly used markers in diagnosing a wide spectrum of PEComas with or without TFE3 genetic alterations.10 Cathepsin K, a papainlike cysteine protease with high matrix-degrading activity, is under the transcriptional control of MiTF. The mechanism of cathepsin K expression in PEComas remains unexplained, although some researchers have hypothesized that there is a link between the mTOR pathway and the MiTF network and that both are related to the expression of cathepsin K. In summary, we described a case of uterine PEComa. This is one of the few case reports of PEComa containing details of both immunohistochemical and ultrastructural studies. Pathologists should be aware of the existence of uterine PEComas to differentiate them from other mesenchymal uterine tumors especially leiomyomas. Melanin-related
153
features, which were immunohistochemically and ultrastructurally demonstrated in the present tumor, support the hypothesis of a neural crest origin for PEC. Haruka Okada,1,2 Yuichi Terado,2 Masachika Fujiwara,2 Makoto Mochizuki,2 Mitsugu Ishizawa1 and Hiroshi Kamma2 1
Department of Pathology, Tokyo Metropolitan Tama Medical Center, and 2Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan REFERENCES
1 Folpe AL. Neoplasms with perivascular epithelioid cell differentiation (PEComas). In: Fletcher CDM, Unni KK, Merten F, eds. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Soft Tissue and Bone. Lyon: IARC Press, 2002; 221–2. 2 Bonetti F, Pea M, Martignoni G, Zamboni G. PEC and sugar. Am J Surg Pathol 1992; 16: 307–8. 3 Martignoni G, Pea M, Reghellin D, Zamboni G, Bonetti F. PEComas: The past, the present and the future. Virchows Arch 2008; 452: 119–32. 4 Folpe AL, Kwiatkowski DJ. Perivascular epithelioid cell neoplasms: Pathology and pathogenesis. Hum Pathol 2010; 41: 1–15. 5 Fernandez-Flores A. Evidence on the neural crest origin of PEComas. Rom J Morphol Embryol 2011; 52: 7–13. 6 Hornick JL, Fletcher CD. PEComa: What do we know so far? Histopathology 2006; 48: 75–82. 7 Fadare O. Perivascular epithelioid cell tumor (PEComa) of the uterus: An outcome-based clinicopathologic analysis of 41 reported cases. Adv Anat Pathol 2008; 15: 63–75. 8 Kenerson H, Folpe AL, Takayama TK, Yeung RS. Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms. Hum Pathol 2007; 38: 1361–71. 9 Argani P, Aulmann S, Illei PB et al. A distinctive subset of PEComas harbors TFE3 gene fusions. Am J Surg Pathol 2010; 34: 1395–406. 10 Rao Q, Cheng L, Xia QY et al. Cathepsin K expression in a wide spectrum of perivascular epithelioid cell neoplasms (PEComas): a clinicopathological study emphasizing extrarenal PEComas. Histopathology 2013; 62: 642–50.
© 2014 The Authors Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Pathology International 2014; 64: 151–153
doi:10.1111/pin.12137
Letter to the Editor Perivascular epithelioid cell tumor of the uterus To the Editor: Perivascular epithelioid cell tumor (PEComa) is defined by the World Health Organization as ‘a mesenchymal tumor composed of histologically and immunohistochemically distinctive perivascular epithelioid cells’.1 Bonetti et al. first advanced the concept of a family of neoplasms deriving from these distinctive cells in 1992.2 The PEComa family of tumors has subsequently grown to include common angiomyolipomas, clear cell sugar tumors, lymphangioleiomyomatosis, and less common neoplasms of various anatomical sites.3,4 Immunohistochemically, perivascular epithelioid cells (PEC) express melanocytic and myogenic markers, such as HMB45, Melan-A, MiTF and actin. At present, the normal/ physiological counterpart of PEC is unknown, and the histogenesis of PEComa is not fully understood. We report a rare case of uterine PEComa with detailed immunohistochemical and ultrastructural studies. A 62-year-old woman with no known significant past medical or family history presented with abnormal vaginal bleeding. Sagittal T2-weighted MRI of the pelvis showed a mass with slightly high signal intensity at the upper myometrium, and a mass with low signal intensity at the inferior myometrium. Histopathological examination of the biopsy
and cytology specimens obtained from the endometrium suggested an adenocarcinoma. The patient was preoperatively diagnosed with leiomyomas and adenocarcinoma of the uterine corpus and a total hysterectomy and bilateral oophorectomy were performed following this diagnosis. The postoperative course was unremarkable. Grossly, the uterus contained a 12 mm-sized, grayishwhite, solid mass with focal hemorrhage in the right upper myometrium, a 16 mm-sized, white, solid mass in the right lower myometrium, and a polyp in the endocervix (Fig. 1a). Microscopically, the grayish-white mass in the upper myometrium exhibited an expansive growth with no definite capsule (Fig. 1b), and consisted of an alveolar or fascicular arrangement of polygonal to spindle cells with oval to spindle-shaped nuclei and pale to lightly eosinophilic cytoplasm (Fig. 1c). Mild cellular atypia and multinucleated giant cells were observed. No mitotic figures were evident. The stroma contained abundant capillaries and thick-walled vessels (Fig. 1d). A perivascular arrangement of the tumor cells was focally observed. Immunohistochemically, the tumor cells were diffusely positive for HMB-45, Melan-A, microphthalmia transcription factor (MiTF), smooth muscle actin, and cathepsin K, focally positive for HHF-35 and S-100 protein, and negative for AE1/AE3, desmin, estrogen receptor, and transcription factor E3 (TFE3) (Fig. 2a–c). Based on these
Figure 1 (a) Gross appearance of horizontal cut surfaces of surgical specimens. Above: specimen from tumor in upper myometrium. Below: specimen from tumor in lower myometrium. (b–d) Microscopic appearance of upper tumor, with (b, c) HE staining and (d) CD31 immunostaining. © 2014 The Authors Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
152
Letter to the Editor
Figure 2 (a–c) Immunostaining of upper tumor for (a) HMB-45, (b) MiTF, (c) and cathepsin K. (d) Electron microscopic features of upper tumor (x10 000).
pathological findings, the patient was diagnosed with uterine PEComa. Ultrastructural examination using a formalin-fixed specimen revealed that the cytoplasm of the tumor cells contained vesicles with many pigmented granules comparable to stage III melanosomes (Fig. 2d). Smooth muscle differentiation was not observed ultrastructurally. In addition, the white mass in the lower myometrium was identified as a leiomyoma, and the polyp as an endocervical polyp. A 3 mmsized grade 1 endometrioid adenocarcinoma was also detected microscopically. We herein describe a case of uterine PEComa which radiologically and grossly resembled a degenerated leiomyoma. Microscopically, it lacked diffuse cytoplasmic eosinophilia or the cigar-shaped nuclei seen in leiomyomas, and showed, instead, clear to lightly eosinophilic cytoplasm and oval to spindle-shaped nuclei, multinucleated giant cells, a delicate capillary network, and focal hemorrhage. We speculate that PEComas of the uterus have occasionally been mistaken for degenerated leiomyomas on gross examination. Neither the radiological, nor gross appearance of uterine PEComas is sufficiently distinctive to allow diagnosis. In addition, the pathologic features of PEComas, characterized by spindle to epithelioid cells displaying clear to eosinophilic cytoplasms and immunoreactivity for melanocytic markers, significantly overlap with a subset of other uterine mesenchymal tumors. The distinction between uterine PEComas and other mesenchymal tumors, especially epithelioid smooth muscle tumors, should be made chiefly on the basis of morphological evaluation. Among the most important differences is that smooth
muscle tumors lack the delicate and diffuse vascular network seen in PEComas. Pathologists should be aware of the existence of uterine PEComas in order to differentiate them from other similar lesions such as uterine leiomyomas in particular. The normal/physiological counterpart of PEC is unknown. One hypothesis is that PEC derives from undifferentiated cells of the neural crest that can express both smooth muscle and melanocytic phenotypes.3,5 Another hypothesis is that PEC has a myoblastic, smooth muscle origin with a molecular alteration that gives rise to melanogenesis and expression of melanocytic markers. Other hypotheses hold that PEC has a pericytic or telocytic origin. Ultrastructural studies have documented some features indicative of a neural crest origin, such as abundant cytoplasmic glycogen, premelanosomes, neurite-like cytoplasmic processes, fine filaments, and microtubules in PEComa.5 In our case, PEComa cells exhibited both myogenic and melanocytic differentiation immunohistochemically, and melanogenesis ultrastructurally, supporting the hypothesis of a neural crest origin. PEComas have been reported to originate from a wide variety of anatomic locations. The uterus and retroperitoneum have emerged as the two most frequent sites of origin for PEComas leaving aside common renal angiomyolipomas.6,7 To date, more than 50 cases of uterine PEComa have been reported in the English literature. Most of these cases arose in the uterine corpus except four cases of uterine cervix origin. Fadare evaluated 41 previously reported cases of uterine PEComa and found that their cytological features and growth pattern were quite variable, and that their vasculature seemed
© 2014 The Authors Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Letter to the Editor
to be an intrinsic and recurrent property which might be of diagnostic utility irrespective of the growth pattern.7 Concerning the prognostic significance of individual pathological features, Fadare reported that malignant PEComas showed significantly larger tumor sizes than nonmalignant cases. They also reported that the presence of coagulative necrosis was highly associated with malignancy and that the absence of mitotic activity did not rule out malignancy. Some members of the PEComa family have a strong association with tuberous sclerosis. Most sporadic and tuberous sclerosis-associated PEComas demonstrate inactivation of the TSC1 or TSC2 genes with subsequent activation of the mammalian target of rapamycin (mTOR) pathway.8 Recently, a subset of PEComas entirely unassociated with tuberous sclerosis was found to harbor TFE3 gene fusions.9 Conventional PEComas frequently have a spindle cell component, typically label for muscle markers, and lack strong TFE3 immunoreactivity. In contrast, TFE3-rearranged PEComas have predominantly alveolar architecture and epithelioid cytology, show minimal immunoreactivity for muscle markers, and strong TFE3 immunoreactivity, and are thought by some to constitute a distinctive entity. Recent studies have demonstrated that cathepsin K appears to be more powerful than other commonly used markers in diagnosing a wide spectrum of PEComas with or without TFE3 genetic alterations.10 Cathepsin K, a papainlike cysteine protease with high matrix-degrading activity, is under the transcriptional control of MiTF. The mechanism of cathepsin K expression in PEComas remains unexplained, although some researchers have hypothesized that there is a link between the mTOR pathway and the MiTF network and that both are related to the expression of cathepsin K. In summary, we described a case of uterine PEComa. This is one of the few case reports of PEComa containing details of both immunohistochemical and ultrastructural studies. Pathologists should be aware of the existence of uterine PEComas to differentiate them from other mesenchymal uterine tumors especially leiomyomas. Melanin-related
153
features, which were immunohistochemically and ultrastructurally demonstrated in the present tumor, support the hypothesis of a neural crest origin for PEC. Haruka Okada,1,2 Yuichi Terado,2 Masachika Fujiwara,2 Makoto Mochizuki,2 Mitsugu Ishizawa1 and Hiroshi Kamma2 1
Department of Pathology, Tokyo Metropolitan Tama Medical Center, and 2Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan REFERENCES
1 Folpe AL. Neoplasms with perivascular epithelioid cell differentiation (PEComas). In: Fletcher CDM, Unni KK, Merten F, eds. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Soft Tissue and Bone. Lyon: IARC Press, 2002; 221–2. 2 Bonetti F, Pea M, Martignoni G, Zamboni G. PEC and sugar. Am J Surg Pathol 1992; 16: 307–8. 3 Martignoni G, Pea M, Reghellin D, Zamboni G, Bonetti F. PEComas: The past, the present and the future. Virchows Arch 2008; 452: 119–32. 4 Folpe AL, Kwiatkowski DJ. Perivascular epithelioid cell neoplasms: Pathology and pathogenesis. Hum Pathol 2010; 41: 1–15. 5 Fernandez-Flores A. Evidence on the neural crest origin of PEComas. Rom J Morphol Embryol 2011; 52: 7–13. 6 Hornick JL, Fletcher CD. PEComa: What do we know so far? Histopathology 2006; 48: 75–82. 7 Fadare O. Perivascular epithelioid cell tumor (PEComa) of the uterus: An outcome-based clinicopathologic analysis of 41 reported cases. Adv Anat Pathol 2008; 15: 63–75. 8 Kenerson H, Folpe AL, Takayama TK, Yeung RS. Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms. Hum Pathol 2007; 38: 1361–71. 9 Argani P, Aulmann S, Illei PB et al. A distinctive subset of PEComas harbors TFE3 gene fusions. Am J Surg Pathol 2010; 34: 1395–406. 10 Rao Q, Cheng L, Xia QY et al. Cathepsin K expression in a wide spectrum of perivascular epithelioid cell neoplasms (PEComas): a clinicopathological study emphasizing extrarenal PEComas. Histopathology 2013; 62: 642–50.
© 2014 The Authors Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
