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Hilage P, Damle MN, Sharma RK, Joshi MG. Melanoma Cell Adhesion Molecule (CD 146) in Endometrial Physiology and Disorder. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1474:131-148. [PMID: 39400880 DOI: 10.1007/5584_2024_826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
The human endometrium, the innermost lining of the uterus, is the anatomic prerequisite for pregnancy. It is the only dynamic tissue that undergoes more than 400 cycles of regeneration throughout the reproductive life of women. Key to this function are endometrial stem cells as well as cell adhesion molecules. Melanoma cell adhesion molecule (MCAM/CD146/MUC18) is a membrane glycoprotein of the mucin family and a key cell adhesion protein, highly expressed by endometrial cells. CD146 is a significant molecule pivotal in endometrial physiology, assisting tissue regeneration and angiogenesis. Endometrium also acts as a culprit in causing several endometrial dysfunctions, such as endometriosis, endometrial hyperplasia, and endometrial carcinoma, due to interrupted molecular and functional mechanisms. Though most of the endometrial dysfunctions arise as a result of endocrine disturbance, it has a major pathological role associated with angiogenesis. It has already been proven that CD146 is a potential marker for the diagnosis of angiogenic dysfunctions and malignancy, including endometrial cancer. However, its mechanistic role in causing the pathology is a mystery. This chapter explores the role of CD146 in normal and pathological endometrial conditions and the therapeutic implications of CD146.
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Affiliation(s)
- Priyanka Hilage
- Department of Stem Cells & Regenerative Medicine, D.Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
| | - Mrunal N Damle
- Department of Stem Cells & Regenerative Medicine, D.Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
| | - Rakesh Kumar Sharma
- Department of Obstetrics and Gynecology, D.Y. Patil Medical College, Kolhapur, Maharashtra, India.
| | - Meghnad G Joshi
- Department of Stem Cells & Regenerative Medicine, D.Y. Patil Education Society (Deemed to be University), Kolhapur, Maharashtra, India
- Stem Plus Biotech Pvt. Ltd, Sangli, Maharashtra, India
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Li J, Du Z, Xu T, Li C, Ba S, Zhu H. Epithelioid trophoblastic tumor with lung metastasis: A case report and literature review. Medicine (Baltimore) 2024; 103:e38108. [PMID: 38968534 PMCID: PMC11224836 DOI: 10.1097/md.0000000000038108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 04/12/2024] [Indexed: 07/07/2024] Open
Abstract
RATIONALE Epithelioid trophoblastic tumor (ETT) is an extremely rare variant of gestational trophoblastic neoplasms (GTNs). The biological behavior and therapeutic schedule of ETT remains to be defined which frequently poses diagnostic and therapeutic challenges. Although ETT is a relatively indolent malignancy tumor, the therapeutic efficacy and survival rate decrease significantly when presented with metastases. The lung is the most common site of ETT metastasis. PATIENT CONCERNS A 39-year-old female patient presented with irregular vaginal bleeding and slight distention pain in lower abdomen. DIAGNOSES The patient was diagnosed ETT with lung metastasis after surgery and immunohistochemical staining. INTERVENTIONS A total abdominal hysterectomy plus bilateral salpingectomy and histopathology were performed. The patient received 3 cycles of etoposide, methotrexate, actinomycin-D/etoposide, cisplatin (EMA/EP) regimen chemotherapy after surgery. Due to the presence of lung metastasis, she received pulmonary lesion resection and another cycle of postoperative chemotherapy. OUTCOMES The patients showed a good response to treatment initially. However, the patient did not complete the full initial treatment for family reasons and had signs of recurrence after 2.5 months. The serum β-hCG level gradually elevated and the lung imaging showed that the lesion area gradually expanded. After 15 months of follow-up, the patient declined further treatment due to a lack of presenting symptoms. LESSONS The diagnosis of ETT should be taken into consideration in patients with abnormal vaginal bleeding and low levels of β-hCG. Patients with metastatic disease should be treated with complete surgical resection and intensive combination chemotherapy to maximize the opportunity for cure. Targeted biological agents might be potential therapeutic strategies for chemotherapy-resistant or recurrent patients.
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Affiliation(s)
- Jing Li
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Zhenwu Du
- Department of Orthopaedics, The Second Hospital of Jilin University, Changchun, Jilin, China
- Research Center, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Tianmin Xu
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Chenhong Li
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Shumin Ba
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - He Zhu
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
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Huang LN, Deng X, Xu J. Uterine epithelioid trophoblastic tumor with the main manifestation of increased human chorionic gonadotropin: A case report. World J Clin Cases 2024; 12:2876-2880. [PMID: 38899287 PMCID: PMC11185351 DOI: 10.12998/wjcc.v12.i16.2876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/03/2024] [Accepted: 04/18/2024] [Indexed: 05/29/2024] Open
Abstract
BACKGROUND Epithelioid trophoblastic tumor (ETT) is an extremely rare malignant gestational trophoblastic neoplasm commonly presenting with abnormal vaginal bleeding, abdominal pain, and increased human chorionic gonadotropin (hCG). This study reported a case of uterine ETT with the main manifestation being increased hCG. CASE SUMMARY A 39-year-old female was referred to the Ningbo Maternal and Child Hospital of China in December 2022, complaining of increased hCG levels for 1 month. Magnetic resonance imaging revealed gestational trophoblastic tumor, and hysteroscopic electrotomy and curettage of intrauterine hyperplasia were performed. The patient was diagnosed with uterine ETT through postoperative pathological examination and immunohistochemical results. Total laparoscopic hysterectomy and bilateral salpingectomy were performed, and hCG levels returned to normal. The patient was without recurrence during the postoperative 3-month follow-up. CONCLUSION This study reported a case of uterine ETT with the main manifestation being increased hCG, highlighting that ETT should be considered in the presence of abnormal hCG. A total laparoscopic hysterectomy is recommended.
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Affiliation(s)
- Li-Na Huang
- Department of Gynecology, Ningbo Women and Children's Hospital, Ningbo 315012, Zhejiang Province, China
| | - Xi Deng
- Department of Ningbo Clinical Pathology Diagnosis Center, Ningbo 315021, Zhejiang Province, China
| | - Jian Xu
- Department of Imaging, Ningbo Women and Children's Hospital, Ningbo 315012, Zhejiang Province, China
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Kumar A, Diwan H, Sharma A, Kamboj M. Epithelioid trophoblastic tumors: a diagnostic challenge. Int J Gynecol Cancer 2023; 33:132-134. [PMID: 36423957 DOI: 10.1136/ijgc-2022-004027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Affiliation(s)
- Ankur Kumar
- Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, Delhi, India
| | - Himanshi Diwan
- Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, Delhi, India
| | - Anila Sharma
- Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, Delhi, India
| | - Meenakshi Kamboj
- Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, Delhi, India
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Gorun F, Tomescu L, Motoc A, Citu C, Sas I, Serban DM, Forga M, Citu IM, Gorun OM. Clinical features and management of trophoblastic epithelioid tumors: A systematic review. Medicine (Baltimore) 2022; 101:e29934. [PMID: 35905248 PMCID: PMC9333520 DOI: 10.1097/md.0000000000029934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND This study aimed to systematically review the existing literature on epithelioid trophoblastic tumors (ETTs), the rarest type of gestational trophoblastic neoplasia. METHODS A systematic review according to PRISMA guidelines was performed, using ScienceDirect, Web of Science, and Scopus databases. The only filter used was the English language. Eligibility/inclusion criteria: retrospective observational studies (case reports, case series) including full case description of epithelioid trophoblastic tumor lesions. RESULTS Seventy studies were assessed for synthesis, including 147 cases. 66.7% of patients with ETT presented with irregular vaginal bleeding. Pretreatment β-hCG levels ranged up to 1000 mIU/mL in 58.5% patients. Of most patients, 42.2% had stage I disease, 10.9% stage II, 25.2% stage III, and 21.8% of patients had stage IV. The most common sites of metastatic disease were the lungs, followed by the liver and brain. After treatment, complete remission was achieved in 75.5% of patients, partial remission in 10.2% of patients, and 14.3% of patients died. On univariate and multivariate analyses, stage IV disease was an independent prognostic factor for overall and disease-free survival. CONCLUSIONS Hysterectomy and metastatic lesion resection are essential for controlling ETT. Investigational studies on molecules like EGFR, VEGF, PD-1, CD105, and LPCAT1 are potential therapeutic targets for metastatic ETT.
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Affiliation(s)
- Florin Gorun
- Department of Obstetrics and Gynecology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
| | - Larisa Tomescu
- Department of Obstetrics and Gynecology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
- *Correspondence: Tomescu Larisa- Cristina, Department of Obstetrics and Gynecology, “Victor Babeș” University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041 Timișoara, Romania (e-mail: )
| | - Andrei Motoc
- Department of Anatomy and Embryology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romani
| | - Cosmin Citu
- Department of Obstetrics and Gynecology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
| | - Ioan Sas
- Department of Obstetrics and Gynecology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
| | - Denis Mihai Serban
- Department of Obstetrics and Gynecology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
| | - Marius Forga
- Department of Obstetrics and Gynecology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
| | - Ioana Mihaela Citu
- Department of Internal Medicine I, “Victor Babes” University of Medicine and Pharmacy Timisoara, Timisoara, Romania
| | - Oana Maria Gorun
- Department of Obstetrics and Gynecology, Municipal Emergency Clinical Hospital Timisoara, Timisoara, Romani
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Liu W, Zhou J, Yang J, Huang X. A Multicenter Retrospective Study of Epithelioid Trophoblastic Tumors to Identify the Outcomes, Prognostic Factors, and Therapeutic Strategies. Front Oncol 2022; 12:907045. [PMID: 35677151 PMCID: PMC9169038 DOI: 10.3389/fonc.2022.907045] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 04/18/2022] [Indexed: 11/13/2022] Open
Abstract
Background There is no consensus for the management of epithelioid trophoblastic tumor (ETT) up to date. Objective ETT is the rarest form of gestational trophoblastic neplasia (GTN). Our goal was to assess the outcomes and explore the prognostic factors of patients with ETT through this multicenter retrospective analysis and to devise a risk-adapted approach to clinical management. Methods A total of 31 patients were validated as ETT pathologically between January 2004 and June 2021 from three tertiary hospitals. We retrospectively analyzed the characteristics, treatments, outcomes, and prognostic factors. Results Eight patients experienced a recurrence, and 6 patients died of ETT, resulting in a mortality rate of 19.4%. Five patients with stage I disease had a fertility-preserving treatment. Among them, one patient had a full-term delivery, whereas a 23-year-old patient who declined a hysterectomy died of a recurrent disease. Eight patients of extrauterine ETT with isolated pulmonary lesion were at a young age at diagnosis (median: 30.5 vs. 41, p = 0.003) and had a smaller tumor size (median: 2.4 vs. 4.8 cm, p = 0.003) compared with other patients who had a metastatic disease, and none of them died. The multivariate analyses showed that the number of metastases ≥3 [hazard ratio (HR), 28.16, p = 0.003] was the only significant predictor associated with adverse overall survival, while the number of metastases ≥3 (HR 9.59, p = 0.005) and chemotherapy alone (HR 16.42, p = 0.001) were associated with adverse recurrence-free survival. Patients in stage I or with number of metastases <3 had a favorable prognosis, whereas the prognosis of patients whose number of metastases ≥3 remains poor. Conclusions Chemotherapy alone is insufficient for patients with ETT. Surgical procedures are the mainstay of management for ETT patients. Combined surgery and multi-agent chemotherapy are recommended for patients with metastatic disease and localized disease with persistently positive human chorionic gonadotrophin levels after surgery. The number of metastases at ≥3 is the most critical risk factor for ETT.
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Affiliation(s)
- Wu Liu
- Department of Obstetrics and Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianwei Zhou
- Department of Gynecology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jie Yang
- Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiufeng Huang
- Department of Obstetrics and Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China
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A Review of Current Management of Placental Site Trophoblastic Tumor and Epithelioid Trophoblastic Tumor. Obstet Gynecol Surv 2022; 77:101-110. [DOI: 10.1097/ogx.0000000000000978] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Uterine Epithelioid Trophoblastic Tumor in a 44-Year-Old Woman: A Diagnostic Dilemma. Clin Pract 2021; 11:631-639. [PMID: 34563007 PMCID: PMC8482181 DOI: 10.3390/clinpract11030078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/25/2021] [Accepted: 09/08/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Epithelioid trophoblastic tumor (ETT) is a rare and newly defined disease, which most commonly occurs in women of reproductive age and can be a sequela of any gestational event. ETT can be present in both intrauterine and extrauterine sites. CASE REPORT A woman of reproductive age, without specific comorbidities and with a single pregnancy and natural childbirth eight years ago, was diagnosed initially with poorly differentiated pleomorphic leiomyosarcoma on the hemostatic uterine curettage. CONCLUSION Our case highlights that ETT presents a diagnostic challenge due to its rarity and histologic resemblance to other pathologies. Misdiagnosis delays effective treatment and affects survival. To date, only 8 cases of ETT of the uterus without previous gestational event and normal human chorionic gonadotropin (β-HCG) levels in a 60-year literature survey have been reported.
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Hancock BW, Tidy J. Placental site trophoblastic tumour and epithelioid trophoblastic tumour. Best Pract Res Clin Obstet Gynaecol 2020; 74:131-148. [PMID: 33139212 DOI: 10.1016/j.bpobgyn.2020.10.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 10/06/2020] [Indexed: 01/01/2023]
Abstract
Placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT) are the rarest subtypes of gestational trophoblastic disease (GTD). Their diagnosis is complicated and lacks specific and sensitive tumour markers. They are slow-growing tumours and can occur months to years after any type of antecedent pregnancy. The primary treatment for localised disease is hysterectomy. However, extra-uterine invasion and/or metastasis occur in about one-third of cases and still cause death in a small number. Most patients are young; hence, fertility preservation is a consideration. The major obstacle for prognosis is chemotherapy resistance. The current understanding of these tumours remains elusive and no randomized controlled trials have been done. Even those centres treating a large number of patients with GTD will infrequently manage PSTT/ETT. In this review, we assess progress in the understanding of the disease and discuss four main clinical challenges - establishing conformity of practice, devising a risk-adapted approach to clinical management, establishing long-term follow-up data and evaluating therapies for poor prognosis and multi drug-resistant patients.
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Affiliation(s)
| | - John Tidy
- Director, Sheffield Trophoblastic Disease Centre, UK
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10
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Epithelioid Trophoblastic Tumor: Expanding the Clinicopathologic Spectrum of a Rare Malignancy. Int J Gynecol Pathol 2020; 39:8-18. [PMID: 30480644 DOI: 10.1097/pgp.0000000000000563] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Epithelioid trophoblastic tumor is a malignancy derived from the chorionic laeve-type intermediate trophoblast with sufficient rarity that the vast majority of literature on the topic exists in the form of case reports and small series. Classically, it is regarded as a well-circumscribed tumor with an expansile growth pattern that occurs in reproductive-aged women, usually after a normal pregnancy. However, we recently encountered a case of epithelioid trophoblastic tumor with aggressive spread throughout the abdomen and pelvis in a 68-yr-old female presenting 30 yr after her last delivery. Although to our knowledge this is the first report in a postmenopausal patient to be confirmed by molecular analysis of short tandem repeats, there are multiple similar case reports spanning a variety of clinical settings that deviate from the original description. We therefore sought to synthesize the clinicopathologic data among the available reports in the English literature, with emphasis on pathologic findings. While the overarching themes are largely unchanged, this series of 77 patients reveals a broader spectrum of disease and highlights frequent misdiagnosis. Here we present a clinicopathologic update on this rare entity, with emphasis on a practical approach to diagnosis.
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Zhang S, Tao X, Cao Q, Feng X, Wu J, Yu H, Yu Y, Xu C, Zhao H. lnc003875/miR-363/EGR1 regulatory network in the carcinoma -associated fibroblasts controls the angiogenesis of human placental site trophoblastic tumor (PSTT). Exp Cell Res 2020; 387:111783. [PMID: 31857113 DOI: 10.1016/j.yexcr.2019.111783] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 12/13/2019] [Accepted: 12/15/2019] [Indexed: 11/26/2022]
Abstract
The rare gestational trophoblastic neoplasia placental site trophoblastic tumor (PSTT) frequently demonstrates a high degree of vascularization, which may facilitate the tumor metastasis. However, the underlying mechanisms remain largely unknown. In the present study, we found that early growth response 1 (EGR1) was highly expressed in the carcinoma-associated fibroblasts (CAFs) of PSTT tissues. Further data showed that miR-363 down-regulated EGR1 expression whereas long non-coding RNA NONHSAT003875 (lnc003875) up-regulated EGR1 expression in PSTT derived CAFs. lnc003875 exerted no effect on miR-363 expression, but it recovered the decrease of EGR1 caused by miR-363 mimic. The conditioned media from PSTT CAFs treated with miR-363 mimic abrogated the tube formation capacity of human umbilical vein endothelial cells (HUVECs), which can be partially restored by lnc003875 over-expression. Moreover, over-expression of EGR1 promoted the secretion of Angiopoietin-1 (Ang-1) in PSTT derived CAFs and improved the tube formation of HUVECs, which could be effectively abrogated by Ang-1 siRNAs. In vivo vasculogenesis assay demonstrated that lnc003875/EGR1 in PSTT derived CAFs promoted the vasculogenesis of HUVECs in C57BL/6 mice. Collectively, these findings indicated that lnc003875/miR-363/EGR1/Ang-1 in CAFs may be crucial for the angiogenesis of PSTT.
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Affiliation(s)
- Sai Zhang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China; Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, 200032, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, People's Republic of China
| | - Xiang Tao
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China; Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, 200032, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, People's Republic of China
| | - Qi Cao
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China; Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, 200032, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, People's Republic of China
| | - Xuan Feng
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China; Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, 200032, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, People's Republic of China
| | - Jing Wu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China; Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, 200032, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, People's Republic of China
| | - Huandi Yu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China; Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, 200032, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, People's Republic of China
| | - Yinhua Yu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China; Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, 200032, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, People's Republic of China
| | - Congjian Xu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China; Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, 200032, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, People's Republic of China.
| | - Hongbo Zhao
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, People's Republic of China; Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, 200032, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, People's Republic of China.
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Cho EJ, Chun SM, Park H, Sung CO, Kim KR. Whole transcriptome analysis of gestational trophoblastic neoplasms reveals altered PI3K signaling pathway in epithelioid trophoblastic tumor. Gynecol Oncol 2020; 157:151-160. [PMID: 31954539 DOI: 10.1016/j.ygyno.2019.09.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 09/04/2019] [Accepted: 09/23/2019] [Indexed: 01/07/2023]
Abstract
OBJECTIVE Genomic characteristics of gestational trophoblastic neoplasm (GTN) are mostly unknown. This study reveals the molecular features of malignant GTN, including choriocarcinoma (CC), epithelioid trophoblastic tumor (ETT), and placental site trophoblastic tumor (PSTT), by whole transcriptome sequencing analysis. METHODS Data obtained from the total RNA sequencing of 2 CC, 4 ETT, and 4 PSTT were evaluated for differential gene expression, pathway alteration, fusion gene, infiltrating immune cell type, PD-L1 and PTEN expression level, and mutation analysis was performed. RESULTS The transcriptome data were correlated with known biomarkers, including HDS3B1, p63, hCG, and hPL for all tumor types. ETT and PSTT were more closely clustered compared with CC in clustering analysis using gene expression; however, ETT showed various altered signaling pathways, including PI3K-Akt-mTOR, with frequent loss of PTEN protein expression. This finding was both well correlated with PIK3CA c.3140A > G pathogenic mutation, detected in 1 ETT, and further confirmed using the MassARRAY method. PSTT showed an overexpressed gene cluster associated with muscle contraction and G protein-coupled receptor activity. No significant fusion gene was seen in all 10 cases. In tumor-infiltrating immune cell profiles, CD4 memory T cell and macrophage signature were relatively high in ETT and PSTT. PD-L1 mRNA expression level was high in all cases, which was significantly correlated with the PD-L1 level by immunohistochemistry (p = 0.03) with positivity in all 10 cases. CONCLUSIONS ETT and PSTT were similar at the transcriptome level, with a high level of PD-L1 expression in all tumor types; however, specific pathways, such as PI3K signaling, were altered in ETT.
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Affiliation(s)
- Eun Jeong Cho
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Sung-Min Chun
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Cancer Genome Discovery, Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Hwan Park
- Center for Cancer Genome Discovery, Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Chang Ohk Sung
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea; Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Cancer Genome Discovery, Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.
| | - Kyu-Rae Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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Yang J, Zong L, Wang J, Wan X, Feng F, Xiang Y. Epithelioid Trophoblastic Tumors: Treatments, Outcomes, and Potential Therapeutic Targets. J Cancer 2019; 10:11-19. [PMID: 30662520 PMCID: PMC6329873 DOI: 10.7150/jca.28134] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 10/03/2018] [Indexed: 12/22/2022] Open
Abstract
Background: Epithelioid trophoblastic tumors (ETTs) are the rarest type of gestational trophoblastic neoplasias. We investigated the clinical features, treatments, outcomes, and prognostic factors in patients with ETT, and explored potential therapeutic targets. Methods: We retrospectively analyzed the clinical features, treatments, survival, and prognostic factors of 21 ETT patients treated at our institution between January 2002 and December 2017. Expression levels of programmed cell death 1 (PD-1), PD-1 ligands (PD-L1and PD-L2), B7 family ligands (B7-H3, B7-H4, V-domain Ig suppressor of T cell activation [VISTA], and B7-H6), and CD105 expression were assessed by immunohistochemistry. Results: Fourteen patients with ETT (66.7%) presented with irregular vaginal bleeding. Three stage I patients (14.3%) with normal β-human chorionic gonadotropin (β- hCG) levels underwent hysterectomy alone. Of the remaining 18 patients who had elevated β-hCG levels (85.7%), 1 received chemotherapy and 17 underwent surgery and multi-agent chemotherapy. After treatment, 17 patients (81.0%) achieved complete remission (2 of whom [11.8%] later relapsed) and 4 (19.0%) with stage IV died of their disease. On univariate and multivariate analyses, stage IV disease was an independent prognostic factor for overall and disease-free survival (P < 0.001). PD-L1, B7-H3, and CD105 were detected in 100% of samples, PD-L2 and VISTA in 82%, B7-H6 in 18%, and B7-H4 was undetectable in ETT cells. Conclusions: Hysterectomy and metastatic lesion resection are essential for controlling ETT. Surgery plus chemotherapy are recommended for patients with abnormal β-hCG levels and metastatic disease. PD-L1, PD-L2, B7-H3, VISTA and CD105 are potential therapeutic targets for metastatic ETT.
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Affiliation(s)
- Junjun Yang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, PR China
| | - Liju Zong
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, PR China
| | - Jing Wang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, PR China
| | - Xirun Wan
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, PR China
| | - Fengzhi Feng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, PR China
| | - Yang Xiang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, PR China
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Tse KY, Chiu KWH, Chan KKL, Chu MMY, Ngu SF, Cheung ANY, Ngan HYS, Ip PPC. A Case Series of Five Patients With Pure or Mixed Gestational Epithelioid Trophoblastic Tumors and a Literature Review on Mixed Tumors. Am J Clin Pathol 2018; 150:318-332. [PMID: 29897391 DOI: 10.1093/ajcp/aqy039] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES To review the clinicopathologic features of five patients with epithelioid trophoblastic tumor (ETT). METHODS Characteristics of patients diagnosed with ETT in 2000 to 2012 were reviewed. RESULTS Among 190 patients with gestational trophoblastic neoplasia (GTN), two had pure ETT and three had mixed ETT and choriocarcinoma. The median age was 32.5 years. All the patients had localized disease in the uterus. One patient with pure ETT had a recurrence in the ureter 6 years after the initial treatment. Another patient with pure ETT had two full-term deliveries after fertility-sparing surgery. The three patients with mixed tumors had chemotherapy for GTN before their diseases were completely treated by hysterectomy. At a median follow-up of 102 months, all patients survived. CONCLUSIONS ETT is indolent. Recurrence can happen, but the risk factors are not clear. When patients with GTN fail to respond to chemotherapy, the possibility of mixed GTN should be considered.
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Affiliation(s)
- Ka Yu Tse
- Department of Obstetrics and Gynaecology, the University of Hong Kong
| | | | | | - Mandy Man Yee Chu
- Department of Obstetrics and Gynaecology, the University of Hong Kong
| | - Siew Fei Ngu
- Department of Pathology, the University of Hong Kong
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15
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Fertility-sparing uterine lesion resection for young women with gestational trophoblastic neoplasias: single institution experience. Oncotarget 2018; 8:43368-43375. [PMID: 28108735 PMCID: PMC5522152 DOI: 10.18632/oncotarget.14727] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 01/09/2017] [Indexed: 11/25/2022] Open
Abstract
Purpose To evaluate the oncological safety and pregnant outcomes of fertility-sparing uterine lesion resection in treating gestational trophoblastic neoplasias. Results After the treatment of surgery and chemotherapy, all the patients achieved complete remission. With a median follow-up time of 44 months (range, 6-188), 3 patients (3.85%) relapsed within 3-26 months. Multivariate analysis showed that tumor size was the independent risk factor of recurrence and the cutoff value was 4.2cm. Among 37 patients who attempted to conceive, 31 achieved clinical pregnancy. The rate of pregnancy and live birth were 83.8% and 77.4%. Uterine rupture did not occurred no matter in cesarean section or vaginal delivery. No congenital abnormalities were reported among the live births. Methods From January 1995 to December 2014, 78 patients with gestational trophoblastic neoplasias who underwent fertility-sparing uterine lesion resection at Peking Union Medical College Hospital were reviewed. The complete remission rate, fertility rate, pregnant outcomes and risk factors of recurrence were analyzed. Conclusions Fertility-sparing uterine lesion resection might be considered as a safe and reasonable alternative for high-selected young women to remove uterine lesion in the treatment of gestational trophoblastic neoplasias.
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16
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Extrauterine epithelioid trophoblastic tumor in hysterectomized woman. Obstet Gynecol Sci 2017; 60:124-128. [PMID: 28217684 PMCID: PMC5313356 DOI: 10.5468/ogs.2017.60.1.124] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Revised: 08/15/2016] [Accepted: 08/18/2016] [Indexed: 11/16/2022] Open
Abstract
Epithelioid trophoblastic tumor (ETT) is a very rare variant of gestational trophoblastic disease (GTD) which arises in reproductive age women with prior gestational history. Although abnormal vaginal bleeding is the most common symptom of ETT, there are no reported pathognomonic symptoms of ETT because of its rarity. ETT is similar to placental site trophoblastic tumor in terms of its slow growing characteristic and microscopic findings. Therefore, it could be misdiagnosed as placental site trophoblastic tumor or other types of GTD. Unlike other types of GTD, primary treatment of ETT is surgical resection because of its chemo-resistant nature. Accordingly, immunohistochemical staining is essential for accurate diagnosis and appropriate treatment. Here, we report a case of a 42-year-old hysterectomized woman with pelvic masses who suffered from abdominal pain. Through laparotomy, tumors were resected completely and they were diagnosed as ETT through immunohistochemical stain. This report provides more evidence about its clinical features, diagnosis, and treatment including a brief review of the literature.
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17
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Horowitz NS, Goldstein DP, Berkowitz RS. Placental site trophoblastic tumors and epithelioid trophoblastic tumors: Biology, natural history, and treatment modalities. Gynecol Oncol 2016; 144:208-214. [PMID: 27789086 DOI: 10.1016/j.ygyno.2016.10.024] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 10/17/2016] [Accepted: 10/17/2016] [Indexed: 12/13/2022]
Abstract
Placental site (PSTT) and epithelioid trophoblastic tumor (ETT) are rare types of gestational trophoblastic neoplasia (GTN) that arise from intermediate trophoblast. Given that this cell of origin is different from other forms of GTN, it is not surprising that the clinical presentation, tumor marker profile, and treatment paradigm for PSTT and ETT are quite different as well. The mainstay for therapy for stage I PSTT and ETT is hysterectomy with adjuvant chemotherapy reserved for those presenting greater than four years from the antecedent pregnancy. Surgery is also important for metastatic disease. There is no standardized chemotherapy regimen for advanced stage disease but often consists of a platinum-containing combination therapy, usually EMA-EP or TE/TP. Despite its rarity, PSTT and ETT account for a disproportionate percentage of mortality from GTN likely resulting from their relative chemotherapy resistance. Novel therapeutic modalities therefore are needed to improve the outcomes of women with advanced stage or resistant PSTT and ETT.
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Affiliation(s)
- Neil S Horowitz
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Brigham and Women's Hospital, Dana Farber Cancer Institute, Boston, MA 02115, United States
| | - Donald P Goldstein
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Brigham and Women's Hospital, Dana Farber Cancer Institute, Boston, MA 02115, United States
| | - Ross S Berkowitz
- New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Brigham and Women's Hospital, Dana Farber Cancer Institute, Boston, MA 02115, United States.
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18
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Park JW, Bae JW. Epithelioid Trophoblastic Tumor in a Postmenopausal Woman: A Case Report. J Menopausal Med 2016; 22:50-3. [PMID: 27152314 PMCID: PMC4854661 DOI: 10.6118/jmm.2016.22.1.50] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Revised: 01/26/2016] [Accepted: 03/04/2016] [Indexed: 11/24/2022] Open
Abstract
Epithelioid trophoblastic tumor (ETT) is a rare gestational trophoblastic neoplasm composed of intermediate trophoblasts. Most cases of ETT are reported in women of reproductive age following a prior gestation within 2 weeks to 30 years. ETT is extremely rare in postmenopausal women. It is commonly misdiagnosed as a poorly differentiated carcinoma or another type of gestational trophoblastic tumor. We report a case of ETT in a 56-year-old woman that developed 23 years after the patient's last pregnancy.
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Affiliation(s)
- Jung-Woo Park
- Department of Obstetrics and Gynecology, Dong-A University College of Medicine, Busan, Korea
| | - Jong Woon Bae
- Department of Obstetrics and Gynecology, Dong-A University College of Medicine, Busan, Korea
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19
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20
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Epithelioid trophoblastic tumor: A single institution case series at the New England Trophoblastic Disease Center. Gynecol Oncol 2015; 137:456-61. [DOI: 10.1016/j.ygyno.2015.03.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 03/04/2015] [Indexed: 12/30/2022]
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21
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Mirkovic J, Elias K, Drapkin R, Barletta JA, Quade B, Hirsch MS. GATA3 expression in gestational trophoblastic tissues and tumours. Histopathology 2015; 67:636-44. [DOI: 10.1111/his.12681] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 03/04/2015] [Indexed: 01/13/2023]
Affiliation(s)
- Jelena Mirkovic
- Department of Pathology; Women's and Perinatal Pathology Division; Brigham and Women's Hospital; Boston MA USA
- Harvard Medical School; Boston MA USA
| | - Kevin Elias
- Harvard Medical School; Boston MA USA
- Division of Gynecologic Oncology; Brigham and Women's Hospital; Boston MA USA
| | - Ronny Drapkin
- Department of Medical Oncology; Dana Farber Cancer Institute; Boston MA USA
| | - Justine A Barletta
- Department of Pathology; Women's and Perinatal Pathology Division; Brigham and Women's Hospital; Boston MA USA
- Harvard Medical School; Boston MA USA
| | - Bradley Quade
- Department of Pathology; Women's and Perinatal Pathology Division; Brigham and Women's Hospital; Boston MA USA
- Harvard Medical School; Boston MA USA
| | - Michelle S Hirsch
- Department of Pathology; Women's and Perinatal Pathology Division; Brigham and Women's Hospital; Boston MA USA
- Harvard Medical School; Boston MA USA
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23
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Almarzooqi S, Ahmad Al-Safi R, Fahad Al-Jassar W, Akhter SMJ, Chiab-Rassou Y, Albawardi A. Epithelioid trophoblastic tumor: report of two cases in postmenopausal women with literature review and emphasis on cytological findings. Acta Cytol 2014; 58:198-210. [PMID: 24525845 DOI: 10.1159/000357966] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 12/12/2013] [Indexed: 11/19/2022]
Abstract
BACKGROUND Epithelioid trophoblastic tumor (ETT) is a rare gestational trophoblastic neoplasm of intermediate trophoblasts. It was first described by Shih and Kurman [Am J Surg Pathol 1998;22:1393-1403] who outlined its clinicopathologic characteristics in 14 cases, establishing it as a distinct entity of gestational trophoblastic tumors. It represents 1.39% of all gestational trophoblastic diseases. Most cases are reported in reproductive-age women following a prior gestation with a time interval between 2 weeks and 30 years. ETT is extremely rare in postmenopausal women. It is commonly misdiagnosed as a squamous cell carcinoma (SCC), poorly differentiated carcinoma or another gestational trophoblastic tumor. Limited data is available regarding its cytological features on Pap smears. CASES We report 2 cases of uterine ETT occurring in postmenopausal women. In both cases, an initial diagnosis of an SCC and a poorly differentiated carcinoma was rendered. We highlight the features of ETT helpful in differentiating it from other mimickers with emphasis on rarely reported cytological features of this neoplasm. CONCLUSION ETT is a rare tumor with characteristic cytological features, but is commonly confused with SCC. A high index of suspicion is needed to make the correct diagnosis or to raise the consideration of ETT, especially in cases with an increased β-human chorionic gonadotropin.
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Affiliation(s)
- Saeeda Almarzooqi
- Department of Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
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Moutte A, Doret M, Hajri T, Peyron N, Chateau F, Massardier J, Duvillard P, Raudrant D, Golfier F. Placental site and epithelioid trophoblastic tumours: diagnostic pitfalls. Gynecol Oncol 2012; 128:568-72. [PMID: 23159816 DOI: 10.1016/j.ygyno.2012.11.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Revised: 11/03/2012] [Accepted: 11/08/2012] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To describe the clinical and histological pitfalls in the diagnosis of placental site trophoblastic tumours (PSTT) and epithelioid trophoblastic tumours (ETT), two rare types of gestational trophoblastic neoplasia (GTN). METHODS This retrospective, observational, study was carried out in the French Trophoblastic Disease Reference Centre, Lyon, between 2000 and 2011. Due to the many similarities in the diagnosis, treatment and prognosis of PSTT and ETT, these two types of tumour were investigated together. Twenty-two patients with PSTT or ETT were analysed. RESULTS The clinical presentation of these two types of tumour was irregular vaginal bleeding (55%) or amenorrhoea (27%), with a median plasma hCG level of 205IU/L. Seven of the 22 patients (32%) were initially misdiagnosed as an ectopic pregnancy. Median age at presentation was 35-years, with a median interval of 12months between the antecedent pregnancy and diagnosis of PSTT or ETT. The initial histological diagnosis was incorrect in 7/18 (39%) patients; there was a major disagreement with the referral pathologist in five of these seven patients (28%). CONCLUSIONS PSTT and ETT are the most difficult types of GTN to diagnose clinically and histologically. An incorrect diagnosis can lead to significant therapeutic deviations from the recommended first-line treatment, namely hysterectomy. Clinical and histological expertise is essential to avoid the pitfalls in the diagnosis of PSTT and ETT.
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Affiliation(s)
- Amandine Moutte
- Lyon 1 University, Department of Obstetrics and Gynaecology, Lyon Sud University Hospital, Lyon, France
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