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Perivascular epithelioid cell tumors of the uterine cervix
Pathology – Research and Practice 212 (2016) 667–671
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Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Review
Perivascular epithelioid cell tumors of the uterine cervix E. Kudela a,∗ , K. Biringer a , P. Kasajova a , M. Nachajova a , M. Adamkov b a b
Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovakia Institute of Histology and Embryology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovakia
a r t i c l e
i n f o
Article history: Received 30 January 2016 Received in revised form 9 March 2016 Accepted 29 March 2016 Keywords: Cervix PEComa Tuberous sclerosis
a b s t r a c t The World Health Organization (WHO) defines PEComas as mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular cells. Uterus is the most common site of a subgroup of PEComas not otherwise specified(NOS). PEComas of the uterine cervix are extremely rare, and only thirteen cases have been described in the English literature to date. In this review, we summarize the available data concerning diagnostics, immunohistochemical analysis, genetics and treatment of cervical PEComas. Radical hysterectomy with bilateral salpingooophorectomy is the best surgical approach available. Adjuvant therapy in its present form is not efficient. Therefore, further studies are needed to evaluate the newest treatment strategies. © 2016 Elsevier GmbH. All rights reserved.
Contents 1. 2.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667 PEComas of uterine cervix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668 2.1. Symptoms and diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668 2.2. Surgery and outcome of cervical PEComas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670
1. Introduction Perivascular epithelioid cell tumor (PEComa) was first described in 1943 by Apitz et al. [1] as an abnormal myoblast in renal AML. PEComas are found in different sites with different dignity. The World Health Organization (WHO) defines PEComas as mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular cells. [2]. The PEComa family of tumors consists of: angiomyolipoma, clear-cell “sugar” tumor of the lung and extrapulmonary sites, lymphangioleiomyomatosis, clear-cell myomelanocytic tumor of the falciform ligament and rare clear-cell tumors of other anatomical sites [3]. The prevalence of these tumors is most often in middle-aged women with an overall female-to-male ratio of 7:1 [4]. Uterus is the most common site of
∗ Corresponding author at: Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University, Kollarova 2, 03601 Martin, Slovakia. E-mail address: [email protected] (E. Kudela). http://dx.doi.org/10.1016/j.prp.2016.03.010 0344-0338/© 2016 Elsevier GmbH. All rights reserved.
a subgroup of PEComas not otherwise specified (NOS), and the first case of uterine PEComa was reported by Pea et al. [5]. PEComas of the uterine cervix are extremely rare, and only thirteen cases have been reported in the English literature so far. Other gynecological PEComas also have a rare incidence: uterus—78 cases, vagina—seven cases, adnexa—six cases, broad ligament—five cases and just one case of vulvar PEComa [6]. The normal counterpart of PEComas is still unknown, and there are three hypotheses available explaining the origin of PEComas (origin in undifferentiated cells of neural crest, molecular alteration of smooth muscle origin and pericytic origin) [4,7]. Morphologically, PEComas have an epithelioid appearance of cells with clear to granular cytoplasm, and a round to oval nucleus with mild or no atypia. There is a great variation regarding the shape of cells: from epithelioid to spindled and lipid-like cells. The tumors, in general, are localized in perivascular space. [8]. PEComas, in general, express melanocytic and myogenic markers: HMB-45, HMSA-1, Melan A, microophthalmia transcription factor (Mitf), actin and, less commonly, desmin [8]. In the study
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of Folpe et al., all cases expressed at least 1 melanocytic marker; HMB45 was the most sensitive reagent (92% positive), followed by Melan-A (72% positive) [4]. Due to the uniform expression of melanocytic markers, it is not surprising that PEComas are frequently confused with conventional melanoma and clear cell sarcoma. In most cases, melanomas and clear cell sarcomas are characterized by S100 overexpression and missing actin expression. In problematic cases Folpe et al. suggest the use of the following markers: HMB-45, melan A, smooth muscle actin and desmin [4]. Some members of PEComa family are seen with high frequency in the genetic syndrome Tuberous Sclerosis Complex (TSC) [10] with the inactivation of the TSC1 and TSC2 genes [10,11] and with subsequent activation of the mammalian target rapamycin (mTOR pathway) [12]. Loss of heterozygosity (LOH) of TSC 2 with loss of expression of the protein tuberin (encoded by TSC2), is frequently found in PEComas [11]. Other studies have found chromosomal changes in PEC family: losses of chromosomes 1p, 17p, 18p, 19; and gains of chromosomes 2q, 3q, 5q, 12q and X [13]. Recently, there was identified a subgroup of lesions that harbor TFE3 gene fusions [14]. TFE 3 is a member of the MiT family of transcription factors (microopthalmia-associated transcription factor family localized on chromosome Xp11.2), which includes MiTF, TFEB, TFEC and TFE3 [Haq]. TFE3 gene fusions are also found in other neoplasms, such as alveolar soft part sarcoma (ASPS) [11]. The true significance of TFE3 gene in PEComas is still unknown. TFE3-mutated PEComas appear in younger patients. These are not associated with TSC complex and immunohistochemically present only minimal positive staining for muscle markers. TFE3 gene re-arrangements are increasingly described in PEComas, including tumors with SFPQ/PSF-TFE3 fusions and one with a novel DVL2—TFE3 fusion [15]. The other mutations in PEComa group include RAD51B gene rearrangements with complex fusion patterns (RRAGB/OPHN1), HTR4—ST3GAL1 and RASSF1—PDZRN3 gene fusions [15]. Methylation of genes in PEComas is not as clearly defined as it is in endometrial cancer [16]. Lesma et al. showed that methylation of promoter TSC2 leads to loss of tuberin in cells, and that the pathogenesis of angiomyolipomas could be connected with epigenetic changes [17]. 2. PEComas of uterine cervix Cervical PEComas are extremely rare tumors of uncertain dignity. In our study, we searched the PubMed and Medline databases for PEComas of uterine cervix. We identified thirteen cases published between the years 2004 and 2015. The average age at the time of the diagnosis was 41 years; 3 women were postmenopausal. Just two patients were diagnosed with TSC; intraabdominal PEComatosis was present in both patients. [18,19]. The first cervical PEComa was presented by Fadare et al. in 2004 [18]. It was a case characterized by the intraabdominal PEComatosis associated with TSC complex. All available cases of cervical PEComas are included in Tables 1 and 2, which focus on the dignity of tumors, immunohistochemistry, treatment and follow-up. According to the Folpe classification, we can identify five malignant cervical PEComas and six benign tumors in our study. One tumor [4] fits in the group of tumors with uncertain malignant potential. 2.1. Symptoms and diagnostics The most frequent clinical symptoms are vaginal bleeding, abdominal pain and uterine compromise [20]. It is very difficult to diagnose PEComas from cytological smear due to its rarity. The first reported case of cervical PEComa detected by a routine cervical
smear was published by Stone et al. in 2013 [21]. The smear was reported as possible HSIL lesion with a more specific diagnosis of clear cell carcinoma. The cells were discohesive, with the size of metaplastic squamous cells, with a pale, fragile cytoplasm and no mitotic figures present. The second case of cervical PEComa identified on a conventional smear was published by Tajima et al. in 2015 [22]. Discohesive cells with epithelioid morphology, weakly eosinophilic cytoplasm and rare mitotic figures were present on the cytological slide. The authors considered the lesion as lowgrade sarcoma at first, but the final histopathological evaluation of biopsy confirmed a PEComa of the uterine cervix. The differential diagnosis, as far as the cytological evaluation is concerned, has to include reactive endocervical cells, adenocarcinomas and clear cell carcinoma as well. A delicate fibrovascular network frequently described on the cytological sample of lung PEComa was not present on the cervical smear. The vessels were identified only on histological sample after cervical conisation. The discrepancy could be explained by the fact that the cervical cells are just exfoliated, whereas the lung cells are part of an aspiration cytology [21]. Interestingly, the average size of cervical PEComa is 4.5 cm (average value from all studies) and the cervical smear identified the smallest tumors (0.9 cm) of all thirteen published cases. Colposcopic examination of the cervix is the essential part of the accurate diagnostics of cervical dysplasias and carcinomas. Of thirteen reported cases, there is only one study that describes cervical PEComa during colposcopy as a dark-red neoplasm located in the center of the cervix. Tajima et al. reported PEComa arising from the endocervix that is not visible for colposcopy, which has a very poor sensitivity for the screening of glandular lesions—only 9.8% [23]. HPV (human papillomavirus) infection by approximately 14 high-risk types is the cause of virtually all carcinomas of the cervix. If HPV infection is not present, the risk of malignancy is extremely low. This is why the HPV DNA test is a perfect predictor of cervical cancers and its precursors [24]. On the other hand, the connection of HPV and cervical PEComas was never identified in all thirteen published cases. Compared to squamous carcinoma, there is no specific oncomarker for PEComas. In the study of Natella et al., the serum levels of Ca 125 and Ca19-9 were within normal limits [20]. On ultrasound, the tumor appears to be a well vascularized cervical mass, but the finding is not typical. Uterine and cervical PEComas have similar characteristics, and they mimic fibroids and leiomyosarcomas on CT/MRI (homogenous enhancement and sharp margins). On MRI, PEComas represent hyperintense mass typical also for other mesenchymal tumors as cellular myomas and sarcomas [25]. F18FDG PET/CT should be used to exclude distant metastases especially in malignant PEComas. 2.2. Surgery and outcome of cervical PEComas Treatment and outcome of PEComas depend on prognostic indicators. Folpe et al. classified PEC tumors as benign, as well as of uncertain malignant potential and malignant [4,8]. • Benign: <5cm, non-infiltrative, mild nuclear grade and cellularity, mitotic index ≤1/50HPF (high power fields), no necrosis and vascular invasion. • Uncertain malignant potential (nuclear pleomorphism/multinucleated giant cells only or size >5 cm only). • Malignant: size of the tumor >5cm, infiltrative, high nuclear grade and cellularity, mitotic rate ≥1/HPF, necrosis and vascular invasion). The classification was modified by Schoolmeister et al. in 2014. The tumor is considered as malignant when there are more than four unfavorable prognostic indicators (size ≥5 cm, mitoses
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Table 1 Cervical PEComas according to their treatment, dignity and follow up. Reference
Age
Treatment
PEComa classification (Folpe et al. [8])
Follow-up
Fadare et al. [18]
41
Benign
Folpe et al. [8]
28
Abdominal hysterectomy with bilateral salpingo-oophorectomy Abdominal hysterectomy and pelvic lymphadenectomy
Folpe et al. [8]
48
Excision
Azad et al. [32]
25
Radical hysterectomy and pelvic lymphadenectomy
35 months— no recurrence 36 months— no recurrence 21 months— no recurrence Not available
Yamamoto et al. [27]
24
Local excision (2×)
Bradshaw et al. [33]
46
Yang et al. [34]
46
Abdominal hysterectomy, bilateral salpingo-oophorectomy and regional lymph node dissection Total hysterectomy and bilateral salpingo-oophorectomy
Stone et al. [21]
41
Laparoscopic radical hysterectomy and pelvic node sampling
Benign
Natella et al. [20]
52
Radical pelvectomy
Malignant
Zhang et al. [35] Celik et al. [36]
57 41
Total hysterectomy and bilateral salpingo-oophorectomy Total hysterectomy and bilateral salpingo-oophorectomy
Malignant Benign
Liu et al. [19]
34
Not available
Malignant
Tajima et al. [22]
51
Total hysterectomy with bilateral salpingo-oophorectomy
Benign
Benign Uncertain malignant potential Missing tumor characteristics Malignant Benign
Malignant
Recurrence 4 and 7 months after excisions 42 months— no recurrence 12 months— no recurrence Solitary inguinal node metastasis after 60 months 12 months— no recurrence Not available 36 months—no recurrence Recurrence after 2 months (reexcision), after 5 months pelvic lymph node metastases 30 months—no recurrence
Table 2 Cervical PEComas—microscopic and immunohistochemical analysis. Reference
Size (cm)
Histopathology
Staining
Fadare et al. [18]
2.2
Circumscribed; epithelioid, spindled, mild to moderate nuclear grade, no necrosis, mitotic activity <1/50HPF
Folpe et al. [8]
3
Folpe et al. [8]
2
Azad et al. [26]
4
Circumscribed; epithelioid; intermediate nuclear grade, no necrosis and mitotic figures Circumscribed; epithelioid; high nuclear grade, no necrosis and mitotic figures Infiltrative; epithelioid; mild nuclear grade
Positive: HMB-45, Melan A, ER,Aktin, desmin focally positive Negative: S100CD67, CD118, EMA Not available
Yamamoto et al. [26]
10
Infiltrative; epithelioid, mild nuclear grade
Bradshaw et al. [27]
2.5
Circumscribed; epithelioid and spindled cells; mild nuclear grade
Yang et al. [28]
3
Circumscribed; epithelioid, mild to moderate nuclear atypia, mitotic activity 1–4/50HPF, no necrosis
Stone et al. [21]
0.9
Circumscribed; epithelioid, mild nuclear atypia, no necrosis, absence of mitotic activity
Natella et al. [20]
12
Circumscribed; epithelioid; bizarre nuclei, focal hemorrhage and necrosis, mitotic activity <1/50HPF
Zhang et al. [35]
3.2
Circumscribed; epithelioid, spindled cells; bizarre nuclei, hemorrhagic and necrotic areas, mitotic activity 2/50HPF
Celik et al. [36]
4
Circumscribed; epithelioid+ mild nuclear grade, focal necrosis and hemorrhage (5%), mitotic activity 1/50HPF
Liu et al. [19]
9
Infiltrative; epithelioid; uniform nuclei, intratumoral hemorrhage, necrosis, stromal calcifications, occasional mitotic activity
Tajima et al. [22]
2.8
Circumscribed; epithelioid; no necrosis and vascular invasion, rare mitotic figures
Not available Positive: HNM-45 Negative: Cytokeratins, EMA, desmin, ASMA, S-100 Positive: HMB-45, CD34, MIB positive in 2–3% cells Negative: S100, SMA, desmin, c-kit, CD 31, CS1a Positive: HMB-45 Negative: S100, Melan A, CD10, ER, MNF116, CK7, CK20, TTF-1 SMA, vimentin, p53 Positive: HMB-45, calponin, ER, PR, SMA Negative: CD34, CD10, S100, p53 Positive: SMA, Melan A, gp100 Negative: S100 Positive: HMB-45, caldesmon, actin focally positive, Ki-67 positive in <10% cells Negative: Keratin, S100, desmin Positive: HMB-45, PAS, S100, CD34 weakly positive, Ki-67 staining positive in 5% cells Negative: EMA, cytokeratins, vimentin, melan-A, SMA, CD117 Positive: HMB-45, vimentin, desmin, caldesmon, SMA focally positive, Ki-67 positive in 3–4% cells Negative: Cytokeratin, CD10, S100,CD68, CD34 Positive: TFE3, HMB-45, Melan A, Ki-67—moderate proliferation rate Negative: Ckpan, SMA,S100,PAX8,PAX2 Positive: Melan-A, HMB-45 (5%), SMA, Ki-67—3.6% Negative: S-100
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≥1/50HPF, significant nuclear atypia, necrosis and lymphovascular invasion). If the tumor has none of the malignant criteria, it is classified as a benign lesion. If the tumors fulfill just 1–3 characteristics, it is difficult to predict its behavior [26]. On the other hand, Bleeker et al. concluded that primary tumor size more than 5 cm and high mitotic rate (more than 1/50HPF) were the only factors significantly associated with recurrence [9]. Surgical excision is the main choice of therapy for both benign and malignant PEComas with the need for clear resection margins. The uncertain behavior of these tumors favors radical hysterectomy in most cases. The management is questionable especially in small sized tumors and in young women. Yamamoto et al. [27] performed a fertility-sparing surgery in woman aged 24. The tumor had malignant characteristics, and the recurrence appeared twice after the local excision. According to the available data, conservative surgery could be efficient only in benign small-sized lesions. Treatment in general varied between thirteen published cases, but the most common surgical procedure was the radical hysterectomy with pelvic lymphadenectomy (Table 1). Only one patient underwent radiotherapy after excision procedure [8]. Surgery seems to be the only approach for aggressive cases, as chemotherapy and radiotherapy have not shown significant results [28]. Regardless of the postoperative strategy, long-term surveillance is necessary because of the possibility of recurrence and distant metastases. The average follow-up was 28 months (12–42 months), and in two cases, there was recurrence after local excision [19,27]. The future of adjuvant therapy is still questionable, but the latest findings indicate the important role of mTORC1 activation in both TSC-associated and non-TSC-associated PEComas. Clinical trials are therefore examining the benefit of mTORC1 inhibitors (sirolimus-rapamycin) for these tumors [8]. Sirolimus/everolimus act as cytostatic agents and are very effective in reducing the tumor mass. Pollizzi et al. observed 99% reduction of tumor size after the one-month treatment [29]. Despite their effectiveness, there are cases of recurrence after the discontinuation of inhibitor use [30]. TFE3 rearrangements are connected with resistance to sirolimus therapy, but these genetic changes were not seen in one patient not responding to therapy [31]. This fact shows possible multigene predictive factors involved in PEComa therapy. 3. Conclusion In summary, cervical PEComas constitute a very rare group of lesions with an unpredictable outcome and high percentage of malignant tumors. Radical hysterectomy with bilateral salpingooophorectomy is the best surgical approach available. Adjuvant therapy in its present form is not efficient. Therefore, further studies are needed to evaluate the newest treatment strategies. Conflict of interest We declare that we have no conflict of interest. Acknowledgements This work was supported by the project “Molecular diagnostics of cervical cancer” (ITMS: 26220220113), Project “Increasing opportunities for career growth in research and development in the field of medical sciences”, ITMS 26110230067, Comenius University Grants 287/2015. References [1] K. Apitz, Die Geschwulste und Gewebsmissbildungen der Nierenrinde: II Midteilung. Die mesenchymalen Neubildungen, Virchow Arch 311 (1943) 306–327 (Article in German).
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[34] W. Yang, G. Li, Z. Wei-qiang, Multifocal PEComa (PEComatosis) of the female genital tract and pelvis: a case report and review of the literature, Diag. Pathol. 7 (2012) 23. [35] C. Zhang, F. Pan, J. Qiao, et al., Perivascular epithelioid cell tumor of the cervix with malignant potential, Int. J. Gynaecol. Obstet. 123 (2013) 72–80. [36] H. Celik, M. Kefeli, M. Cetinkaya, et al., Perivascular epithelioid cell tumor (PEComa) of the uterine cervix in a patient with tuberous sclerosis complex: a literature review, Turk. Patoloji Derg. 11 (2014) 1–5.
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Pathology – Research and Practice journal homepage: www.elsevier.com/locate/prp
Review
Perivascular epithelioid cell tumors of the uterine cervix E. Kudela a,∗ , K. Biringer a , P. Kasajova a , M. Nachajova a , M. Adamkov b a b
Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovakia Institute of Histology and Embryology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovakia
a r t i c l e
i n f o
Article history: Received 30 January 2016 Received in revised form 9 March 2016 Accepted 29 March 2016 Keywords: Cervix PEComa Tuberous sclerosis
a b s t r a c t The World Health Organization (WHO) defines PEComas as mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular cells. Uterus is the most common site of a subgroup of PEComas not otherwise specified(NOS). PEComas of the uterine cervix are extremely rare, and only thirteen cases have been described in the English literature to date. In this review, we summarize the available data concerning diagnostics, immunohistochemical analysis, genetics and treatment of cervical PEComas. Radical hysterectomy with bilateral salpingooophorectomy is the best surgical approach available. Adjuvant therapy in its present form is not efficient. Therefore, further studies are needed to evaluate the newest treatment strategies. © 2016 Elsevier GmbH. All rights reserved.
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667 PEComas of uterine cervix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668 2.1. Symptoms and diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668 2.2. Surgery and outcome of cervical PEComas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670
1. Introduction Perivascular epithelioid cell tumor (PEComa) was first described in 1943 by Apitz et al. [1] as an abnormal myoblast in renal AML. PEComas are found in different sites with different dignity. The World Health Organization (WHO) defines PEComas as mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular cells. [2]. The PEComa family of tumors consists of: angiomyolipoma, clear-cell “sugar” tumor of the lung and extrapulmonary sites, lymphangioleiomyomatosis, clear-cell myomelanocytic tumor of the falciform ligament and rare clear-cell tumors of other anatomical sites [3]. The prevalence of these tumors is most often in middle-aged women with an overall female-to-male ratio of 7:1 [4]. Uterus is the most common site of
∗ Corresponding author at: Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University, Kollarova 2, 03601 Martin, Slovakia. E-mail address: [email protected] (E. Kudela). http://dx.doi.org/10.1016/j.prp.2016.03.010 0344-0338/© 2016 Elsevier GmbH. All rights reserved.
a subgroup of PEComas not otherwise specified (NOS), and the first case of uterine PEComa was reported by Pea et al. [5]. PEComas of the uterine cervix are extremely rare, and only thirteen cases have been reported in the English literature so far. Other gynecological PEComas also have a rare incidence: uterus—78 cases, vagina—seven cases, adnexa—six cases, broad ligament—five cases and just one case of vulvar PEComa [6]. The normal counterpart of PEComas is still unknown, and there are three hypotheses available explaining the origin of PEComas (origin in undifferentiated cells of neural crest, molecular alteration of smooth muscle origin and pericytic origin) [4,7]. Morphologically, PEComas have an epithelioid appearance of cells with clear to granular cytoplasm, and a round to oval nucleus with mild or no atypia. There is a great variation regarding the shape of cells: from epithelioid to spindled and lipid-like cells. The tumors, in general, are localized in perivascular space. [8]. PEComas, in general, express melanocytic and myogenic markers: HMB-45, HMSA-1, Melan A, microophthalmia transcription factor (Mitf), actin and, less commonly, desmin [8]. In the study
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of Folpe et al., all cases expressed at least 1 melanocytic marker; HMB45 was the most sensitive reagent (92% positive), followed by Melan-A (72% positive) [4]. Due to the uniform expression of melanocytic markers, it is not surprising that PEComas are frequently confused with conventional melanoma and clear cell sarcoma. In most cases, melanomas and clear cell sarcomas are characterized by S100 overexpression and missing actin expression. In problematic cases Folpe et al. suggest the use of the following markers: HMB-45, melan A, smooth muscle actin and desmin [4]. Some members of PEComa family are seen with high frequency in the genetic syndrome Tuberous Sclerosis Complex (TSC) [10] with the inactivation of the TSC1 and TSC2 genes [10,11] and with subsequent activation of the mammalian target rapamycin (mTOR pathway) [12]. Loss of heterozygosity (LOH) of TSC 2 with loss of expression of the protein tuberin (encoded by TSC2), is frequently found in PEComas [11]. Other studies have found chromosomal changes in PEC family: losses of chromosomes 1p, 17p, 18p, 19; and gains of chromosomes 2q, 3q, 5q, 12q and X [13]. Recently, there was identified a subgroup of lesions that harbor TFE3 gene fusions [14]. TFE 3 is a member of the MiT family of transcription factors (microopthalmia-associated transcription factor family localized on chromosome Xp11.2), which includes MiTF, TFEB, TFEC and TFE3 [Haq]. TFE3 gene fusions are also found in other neoplasms, such as alveolar soft part sarcoma (ASPS) [11]. The true significance of TFE3 gene in PEComas is still unknown. TFE3-mutated PEComas appear in younger patients. These are not associated with TSC complex and immunohistochemically present only minimal positive staining for muscle markers. TFE3 gene re-arrangements are increasingly described in PEComas, including tumors with SFPQ/PSF-TFE3 fusions and one with a novel DVL2—TFE3 fusion [15]. The other mutations in PEComa group include RAD51B gene rearrangements with complex fusion patterns (RRAGB/OPHN1), HTR4—ST3GAL1 and RASSF1—PDZRN3 gene fusions [15]. Methylation of genes in PEComas is not as clearly defined as it is in endometrial cancer [16]. Lesma et al. showed that methylation of promoter TSC2 leads to loss of tuberin in cells, and that the pathogenesis of angiomyolipomas could be connected with epigenetic changes [17]. 2. PEComas of uterine cervix Cervical PEComas are extremely rare tumors of uncertain dignity. In our study, we searched the PubMed and Medline databases for PEComas of uterine cervix. We identified thirteen cases published between the years 2004 and 2015. The average age at the time of the diagnosis was 41 years; 3 women were postmenopausal. Just two patients were diagnosed with TSC; intraabdominal PEComatosis was present in both patients. [18,19]. The first cervical PEComa was presented by Fadare et al. in 2004 [18]. It was a case characterized by the intraabdominal PEComatosis associated with TSC complex. All available cases of cervical PEComas are included in Tables 1 and 2, which focus on the dignity of tumors, immunohistochemistry, treatment and follow-up. According to the Folpe classification, we can identify five malignant cervical PEComas and six benign tumors in our study. One tumor [4] fits in the group of tumors with uncertain malignant potential. 2.1. Symptoms and diagnostics The most frequent clinical symptoms are vaginal bleeding, abdominal pain and uterine compromise [20]. It is very difficult to diagnose PEComas from cytological smear due to its rarity. The first reported case of cervical PEComa detected by a routine cervical
smear was published by Stone et al. in 2013 [21]. The smear was reported as possible HSIL lesion with a more specific diagnosis of clear cell carcinoma. The cells were discohesive, with the size of metaplastic squamous cells, with a pale, fragile cytoplasm and no mitotic figures present. The second case of cervical PEComa identified on a conventional smear was published by Tajima et al. in 2015 [22]. Discohesive cells with epithelioid morphology, weakly eosinophilic cytoplasm and rare mitotic figures were present on the cytological slide. The authors considered the lesion as lowgrade sarcoma at first, but the final histopathological evaluation of biopsy confirmed a PEComa of the uterine cervix. The differential diagnosis, as far as the cytological evaluation is concerned, has to include reactive endocervical cells, adenocarcinomas and clear cell carcinoma as well. A delicate fibrovascular network frequently described on the cytological sample of lung PEComa was not present on the cervical smear. The vessels were identified only on histological sample after cervical conisation. The discrepancy could be explained by the fact that the cervical cells are just exfoliated, whereas the lung cells are part of an aspiration cytology [21]. Interestingly, the average size of cervical PEComa is 4.5 cm (average value from all studies) and the cervical smear identified the smallest tumors (0.9 cm) of all thirteen published cases. Colposcopic examination of the cervix is the essential part of the accurate diagnostics of cervical dysplasias and carcinomas. Of thirteen reported cases, there is only one study that describes cervical PEComa during colposcopy as a dark-red neoplasm located in the center of the cervix. Tajima et al. reported PEComa arising from the endocervix that is not visible for colposcopy, which has a very poor sensitivity for the screening of glandular lesions—only 9.8% [23]. HPV (human papillomavirus) infection by approximately 14 high-risk types is the cause of virtually all carcinomas of the cervix. If HPV infection is not present, the risk of malignancy is extremely low. This is why the HPV DNA test is a perfect predictor of cervical cancers and its precursors [24]. On the other hand, the connection of HPV and cervical PEComas was never identified in all thirteen published cases. Compared to squamous carcinoma, there is no specific oncomarker for PEComas. In the study of Natella et al., the serum levels of Ca 125 and Ca19-9 were within normal limits [20]. On ultrasound, the tumor appears to be a well vascularized cervical mass, but the finding is not typical. Uterine and cervical PEComas have similar characteristics, and they mimic fibroids and leiomyosarcomas on CT/MRI (homogenous enhancement and sharp margins). On MRI, PEComas represent hyperintense mass typical also for other mesenchymal tumors as cellular myomas and sarcomas [25]. F18FDG PET/CT should be used to exclude distant metastases especially in malignant PEComas. 2.2. Surgery and outcome of cervical PEComas Treatment and outcome of PEComas depend on prognostic indicators. Folpe et al. classified PEC tumors as benign, as well as of uncertain malignant potential and malignant [4,8]. • Benign: <5cm, non-infiltrative, mild nuclear grade and cellularity, mitotic index ≤1/50HPF (high power fields), no necrosis and vascular invasion. • Uncertain malignant potential (nuclear pleomorphism/multinucleated giant cells only or size >5 cm only). • Malignant: size of the tumor >5cm, infiltrative, high nuclear grade and cellularity, mitotic rate ≥1/HPF, necrosis and vascular invasion). The classification was modified by Schoolmeister et al. in 2014. The tumor is considered as malignant when there are more than four unfavorable prognostic indicators (size ≥5 cm, mitoses
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Table 1 Cervical PEComas according to their treatment, dignity and follow up. Reference
Age
Treatment
PEComa classification (Folpe et al. [8])
Follow-up
Fadare et al. [18]
41
Benign
Folpe et al. [8]
28
Abdominal hysterectomy with bilateral salpingo-oophorectomy Abdominal hysterectomy and pelvic lymphadenectomy
Folpe et al. [8]
48
Excision
Azad et al. [32]
25
Radical hysterectomy and pelvic lymphadenectomy
35 months— no recurrence 36 months— no recurrence 21 months— no recurrence Not available
Yamamoto et al. [27]
24
Local excision (2×)
Bradshaw et al. [33]
46
Yang et al. [34]
46
Abdominal hysterectomy, bilateral salpingo-oophorectomy and regional lymph node dissection Total hysterectomy and bilateral salpingo-oophorectomy
Stone et al. [21]
41
Laparoscopic radical hysterectomy and pelvic node sampling
Benign
Natella et al. [20]
52
Radical pelvectomy
Malignant
Zhang et al. [35] Celik et al. [36]
57 41
Total hysterectomy and bilateral salpingo-oophorectomy Total hysterectomy and bilateral salpingo-oophorectomy
Malignant Benign
Liu et al. [19]
34
Not available
Malignant
Tajima et al. [22]
51
Total hysterectomy with bilateral salpingo-oophorectomy
Benign
Benign Uncertain malignant potential Missing tumor characteristics Malignant Benign
Malignant
Recurrence 4 and 7 months after excisions 42 months— no recurrence 12 months— no recurrence Solitary inguinal node metastasis after 60 months 12 months— no recurrence Not available 36 months—no recurrence Recurrence after 2 months (reexcision), after 5 months pelvic lymph node metastases 30 months—no recurrence
Table 2 Cervical PEComas—microscopic and immunohistochemical analysis. Reference
Size (cm)
Histopathology
Staining
Fadare et al. [18]
2.2
Circumscribed; epithelioid, spindled, mild to moderate nuclear grade, no necrosis, mitotic activity <1/50HPF
Folpe et al. [8]
3
Folpe et al. [8]
2
Azad et al. [26]
4
Circumscribed; epithelioid; intermediate nuclear grade, no necrosis and mitotic figures Circumscribed; epithelioid; high nuclear grade, no necrosis and mitotic figures Infiltrative; epithelioid; mild nuclear grade
Positive: HMB-45, Melan A, ER,Aktin, desmin focally positive Negative: S100CD67, CD118, EMA Not available
Yamamoto et al. [26]
10
Infiltrative; epithelioid, mild nuclear grade
Bradshaw et al. [27]
2.5
Circumscribed; epithelioid and spindled cells; mild nuclear grade
Yang et al. [28]
3
Circumscribed; epithelioid, mild to moderate nuclear atypia, mitotic activity 1–4/50HPF, no necrosis
Stone et al. [21]
0.9
Circumscribed; epithelioid, mild nuclear atypia, no necrosis, absence of mitotic activity
Natella et al. [20]
12
Circumscribed; epithelioid; bizarre nuclei, focal hemorrhage and necrosis, mitotic activity <1/50HPF
Zhang et al. [35]
3.2
Circumscribed; epithelioid, spindled cells; bizarre nuclei, hemorrhagic and necrotic areas, mitotic activity 2/50HPF
Celik et al. [36]
4
Circumscribed; epithelioid+ mild nuclear grade, focal necrosis and hemorrhage (5%), mitotic activity 1/50HPF
Liu et al. [19]
9
Infiltrative; epithelioid; uniform nuclei, intratumoral hemorrhage, necrosis, stromal calcifications, occasional mitotic activity
Tajima et al. [22]
2.8
Circumscribed; epithelioid; no necrosis and vascular invasion, rare mitotic figures
Not available Positive: HNM-45 Negative: Cytokeratins, EMA, desmin, ASMA, S-100 Positive: HMB-45, CD34, MIB positive in 2–3% cells Negative: S100, SMA, desmin, c-kit, CD 31, CS1a Positive: HMB-45 Negative: S100, Melan A, CD10, ER, MNF116, CK7, CK20, TTF-1 SMA, vimentin, p53 Positive: HMB-45, calponin, ER, PR, SMA Negative: CD34, CD10, S100, p53 Positive: SMA, Melan A, gp100 Negative: S100 Positive: HMB-45, caldesmon, actin focally positive, Ki-67 positive in <10% cells Negative: Keratin, S100, desmin Positive: HMB-45, PAS, S100, CD34 weakly positive, Ki-67 staining positive in 5% cells Negative: EMA, cytokeratins, vimentin, melan-A, SMA, CD117 Positive: HMB-45, vimentin, desmin, caldesmon, SMA focally positive, Ki-67 positive in 3–4% cells Negative: Cytokeratin, CD10, S100,CD68, CD34 Positive: TFE3, HMB-45, Melan A, Ki-67—moderate proliferation rate Negative: Ckpan, SMA,S100,PAX8,PAX2 Positive: Melan-A, HMB-45 (5%), SMA, Ki-67—3.6% Negative: S-100
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≥1/50HPF, significant nuclear atypia, necrosis and lymphovascular invasion). If the tumor has none of the malignant criteria, it is classified as a benign lesion. If the tumors fulfill just 1–3 characteristics, it is difficult to predict its behavior [26]. On the other hand, Bleeker et al. concluded that primary tumor size more than 5 cm and high mitotic rate (more than 1/50HPF) were the only factors significantly associated with recurrence [9]. Surgical excision is the main choice of therapy for both benign and malignant PEComas with the need for clear resection margins. The uncertain behavior of these tumors favors radical hysterectomy in most cases. The management is questionable especially in small sized tumors and in young women. Yamamoto et al. [27] performed a fertility-sparing surgery in woman aged 24. The tumor had malignant characteristics, and the recurrence appeared twice after the local excision. According to the available data, conservative surgery could be efficient only in benign small-sized lesions. Treatment in general varied between thirteen published cases, but the most common surgical procedure was the radical hysterectomy with pelvic lymphadenectomy (Table 1). Only one patient underwent radiotherapy after excision procedure [8]. Surgery seems to be the only approach for aggressive cases, as chemotherapy and radiotherapy have not shown significant results [28]. Regardless of the postoperative strategy, long-term surveillance is necessary because of the possibility of recurrence and distant metastases. The average follow-up was 28 months (12–42 months), and in two cases, there was recurrence after local excision [19,27]. The future of adjuvant therapy is still questionable, but the latest findings indicate the important role of mTORC1 activation in both TSC-associated and non-TSC-associated PEComas. Clinical trials are therefore examining the benefit of mTORC1 inhibitors (sirolimus-rapamycin) for these tumors [8]. Sirolimus/everolimus act as cytostatic agents and are very effective in reducing the tumor mass. Pollizzi et al. observed 99% reduction of tumor size after the one-month treatment [29]. Despite their effectiveness, there are cases of recurrence after the discontinuation of inhibitor use [30]. TFE3 rearrangements are connected with resistance to sirolimus therapy, but these genetic changes were not seen in one patient not responding to therapy [31]. This fact shows possible multigene predictive factors involved in PEComa therapy. 3. Conclusion In summary, cervical PEComas constitute a very rare group of lesions with an unpredictable outcome and high percentage of malignant tumors. Radical hysterectomy with bilateral salpingooophorectomy is the best surgical approach available. Adjuvant therapy in its present form is not efficient. Therefore, further studies are needed to evaluate the newest treatment strategies. Conflict of interest We declare that we have no conflict of interest. Acknowledgements This work was supported by the project “Molecular diagnostics of cervical cancer” (ITMS: 26220220113), Project “Increasing opportunities for career growth in research and development in the field of medical sciences”, ITMS 26110230067, Comenius University Grants 287/2015. References [1] K. Apitz, Die Geschwulste und Gewebsmissbildungen der Nierenrinde: II Midteilung. Die mesenchymalen Neubildungen, Virchow Arch 311 (1943) 306–327 (Article in German).
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