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    -  Jashnani K
    -  Yagana A
    -  Mahajan N

 
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CASE REPORT
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Double trouble: Extrauterine epithelioid trophoblastic tumor with uterine choriocarcinoma - An autopsy report


1 Department of Pathology, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai, Maharashtra, India
2 Department of Obstetrics and Gynaecology, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai, Maharashtra, India

Date of Submission13-Mar-2019
Date of Decision30-Jun-2019
Date of Acceptance12-Jul-2019
Date of Web Publication05-Aug-2020

Correspondence Address:
Alshifa Yagana,
Department of Pathology, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_220_19

  Abstract 


Gestational trophoblastic tumors (GTTs) include choriocarcinoma, epithelioid trophoblastic tumor, and placental site trophoblastic tumor. The occurrence of mixed GTT is rare. We report such a case in a 24-year-old woman who presented with menorrhagia since 2 months and obstetric history of two abortions, one of which was a molar pregnancy. She was undergoing evaluation for carcinoma cervix and treatment for pulmonary tuberculosis from another hospital when she was admitted at our institute for further workup and treatment. However, she succumbed and an autopsy was performed. Histologic evaluation after the autopsy revealed uterine choriocarcinoma with metastatic epithelioid trophoblastic tumor (ETT) in the lung and spleen.


Keywords: Dual malignancy, dual pathology, Gestational trophoblastic tumor, post-mortem



How to cite this URL:
Jashnani K, Yagana A, Mahajan N. Double trouble: Extrauterine epithelioid trophoblastic tumor with uterine choriocarcinoma - An autopsy report. Indian J Cancer [Epub ahead of print] [cited 2020 Sep 28]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=291409





  Introduction Top


Gestational trophoblastic tumors (GTTs) are a group of fetal trophoblastic neoplasms including choriocarcinomas, epithelioid trophoblastic tumors (ETTs), and placental site trophoblastic tumors (PSTTs).[1] Choriocarcinoma consists of a dimorphic admixture of syncytiotrophoblasts and cytotrophoblasts in addition to a minor component of intermediate trophoblasts (ITs), whereas ETT and PSTT show neoplastic proliferation of chorionic and implantation-type ITs, respectively. Mixed GTTs, consisting of a combination of any of the aforementioned tumors, have also been described.[2],[3],[4],[5]

In this report, we present one such case of mixed choriocarcinoma and ETT.


  Case History Top


A 24-year-old woman (para 0, abortion 2) presented with menorrhagia following her second abortion and dyspnea on exertion (The New York Heart Association [NYHA] class III) since 2 months.

Her first abortus was diagnosed to be a molar pregnancy on dilatation and evacuation (D and E) done at a local hospital at 4 months of amenorrhea. Her second pregnancy also resulted in an abortion at 5 months of amenorrhea. Antitubercular therapy was started 2 months back in view of breathlessness and areas of consolidation noted on chest X-ray.

She was admitted to another hospital where a cervical biopsy was planned for suspected carcinoma of the cervix. However, she left the hospital against medical advice and presented at our institute with the aforementioned history.

On examination, she was poorly built and nourished with severe pallor and bilateral pedal edema. Per-abdominal examination revealed a 14-week-sized mass arising from the pelvis. No side-to-side motility was noted. On per-vaginal examination, multiple blue nodules were noted on the right vaginal wall, the largest measuring 2 × 2 cm. Decreased breath sounds and bilateral coarse crepitations were present on auscultation of the chest.

The urine pregnancy test was positive. Serum β-hCG (beta-human chorionic gonadotropin) value was >300,000 mIU/mL. Ultrasonography of the pelvis showed a mass involving the uterus, ovaries, and bilateral ureters. After 2 days of admission, she became breathless and had a bradycardic arrest. Resuscitation was attempted but the patient succumbed.

At autopsy, the serosa of uterus revealed tumor nodules. The cut surface showed a hemorrhagic, shaggy necrotic mass completely obliterating the endometrial cavity infiltrating the myometrium and the cervix and extending to the cervical wall. The vaginal wall had multiple tumor nodules measuring 1 × 1.5 cm to 1.5 × 2 cm. The right ovary was enlarged and replaced by a hemorrhagic and necrotic tumor mass.

The lungs showed multiple well-circumscribed yellow-white hemorrhagic tumor nodules, the largest measuring 3 cm in diameter.

The spleen revealed multiple whitish tumor nodules, approximately 1.5 cm in diameter.

Histopathological examination of the diffusely infiltrative uterine mass revealed a choriocarcinoma showing proliferation of syncytiotrophoblasts and cytotrophoblasts with areas of necrosis and hemorrhage [Figure 1]. Chorionic villi were absent. This tumor also involved the cervix, vagina, and right ovary. Immunohistochemistry (IHC) was positive for β-hCG (Biogenics, dilution- 1:50). The hemorrhagic lung nodules showed a plexiform dimorphic arrangement of cytotrophoblasts and syncytiotrophoblasts, suggestive of choriocarcinoma metastasis.
Figure 1: (a) Cut section of uterus showing necrotic mass reaching up to the cervix; (b) Cut section of ovary showing parenchyma replaced by a hemorrhagic, necrotic tumor mass; (c and d) Cut section of spleen (c) and lung (d) showing solid, metastatic nodules; (e and f) Histopathological section from uterus showing admixture of cyto, syncytio, and intermediate trophoblasts in choriocarcinoma (H and E, e: 100×; f: 400×)

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Sections from the white nodules in the lung and spleen showed monomorphic tumor cells arranged in cohesive nests. These cells had distinct borders, clear cytoplasm, and relatively uniform nuclei with fine chromatin. There were areas of eosinophilic hyaline-like material deposited at places in between the tumor islands. Necrotic or hemorrhagic areas were not seen. IHC staining was positive for AE1/AE3 (Biogenics; dilution, 1:50), cyclin E (Dako; dilution, 1:40) and negative for p63 (Dako; dilution, 1:40), hPL (Dako; dilution, 1:50). These findings were suggestive of an epithelioid trophoblastic tumor [Figure 2].
Figure 2: (a-c) Histopathological section showing tumor composed of cohesive nests of chorionic-type intermediate trophoblast in lung and splenic metastatic nodules (a and c), and central eosinophilic hyaline-like material (b) (H and E, a, b: 100x; c: 400x); (d) Positive AE1/AE3 (IHC, 100×); (e) Positive cyclin E (IHC, 100×); (f) Negative p63 (IHC, 100×)

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A gestational choriocarcinoma of uterus and cervix with widespread metastasis of epithelioid trophoblastic tumor was the final cause of death.


  Discussion Top


GTTs (choriocarcinoma, ETT, and PSTT) are a group of rare epithelial tumors representing semi-allografts (the trophoblastic cells being of fetal origin). Differences in definition and diagnosis lead to variable data on incidence and prevalence.[6] The incidence of choriocarcinoma is higher in Southeast Asia (9.2 in 40,000 pregnancies) than in the Western world (1 in 40,000).[7] ETT, which originates from extravillous trophoblasts of chorionic leave, has only 110 reported cases.[8] Mixed GTT includes tumors with a combination of any one of the three tumors. Besides our case report, only 16 such cases have been noted in the literature.[2],[3],[4],[9],[10],[11],[12],[13],[14],[15]

The term epithelioid trophoblastic tumor (ETT) was first proposed by Mazur and Kurman[16] in 1994. This tumor was initially found as lung metastasis in patients after chemotherapy for uterine choriocarcinoma. In these tumors, the typical dimorphic pattern of choriocarcinoma disappeared, with residual tumor appearing in an unusual monomorphic pattern. Hamazaki et al.[17] considered ETT a dedifferentiated variant of choriocarcinoma. The detailed clinicopathologic and immunohistochemical features of ETT were described by Shih and Kurman[2] in 1998. ETTs have been reported to coexist with choriocarcinoma in the lung[11] and with placental site trophoblastic tumor in the uterus.[2]

Our case is similar to the first case described by Mazur and Kurman in 1994, though there is no history of chemotherapy in our patient. The literature states that some chemotherapeutic agents might induce phenotypic alterations of trophoblast, including structure, function, and differentiation, since most patients with ETT had a history of chemotherapy. It is possible that chorion-type IT may be more selected in this process.

To elucidate the pathogenesis of GTT, studies use molecular analysis through gene-expression profiling and compare their patterns with those of healthy placentas.[18] As per the proposed model, transformed trophoblastic cells (most likely cytotrophoblast stem cells) retain differentiation plasticity. They are able to differentiate into cytotrophoblast, syncytiotrophoblast, or chorionic or implantation type ITs through various pathways similar to the early stages of placental development.[2],[18],[19],[20] The existence of mixed tumors and response to chemotherapy can both be explained by this model. Choriocarcinoma, which resembles the previllous blastocyst, is the most primitive of all three GTTs and also the most chemoresponsive. On the other hand, ETT and PSTT are more differentiated and, therefore, more chemoresistant.

Any pregnancy event can give rise to GTT but the most common association is seen with molar pregnancies. Thus, serial hCG monitoring in these cases is recommended for early diagnosis.[21] Patients may present early or as late as 15 years after the index pregnancy; sometimes coming to attention only after menopause.[22],[23]

Symptoms range from typical (abnormal uterine bleeding) to uncommon (cardiopulmonary, gastrointestinal, neurological, or endocrine manifestations depending upon the site of metastasis).[24] Local examination may show vulvovaginal masses simulating infected Bartholin's cysts or hemorrhagic cervical masses.[25],[26],[27]

The varied period of presentation, atypical symptoms, and failure to elicit a history of molar pregnancy make the early diagnosis of GTT more challenging. While the confirmatory diagnosis is still by histological morphology, a trophogram using IHC panel including pancytokeratin, cytokeratin-18, HLA-G, HSD3B1, β-hCG, β-catenin, hPL, cyclin E, p63, and Ki-67 can help in establishing a correct diagnosis in difficult cases.

To differentiate between ETT and PSTT, Shih[28] suggests p63 and hPL. In our case, the ETT was p63 negative. This has been noted in 20% of cases reported in the literature.[29] In the cases of intrauterine IT tumors, IHC staining by p16 is used to rule out cervical squamous carcinoma.[29] This was not done in our case as the intrauterine tumor was choriocarcinoma.


  Conclusion Top


Mixed GTTs are rare neoplasms. A high index of suspicion based on obstetric history, serum β-hCG values, and histopathological examination is needed to make a timely diagnosis and start treatment. The presence of ETT in a case of choriocarcinoma may be the reason for the nonresponsiveness of the patient to chemotherapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Shih I-M. Gestational trophoblastic neoplasia--pathogenesis and potential therapeutic targets. Lancet Oncol 2007;8:642-50.  Back to cited text no. 1
    
2.
Shih IM, Kurman RJ. Epithelioid trophoblastic tumor: A neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol 1998;22:1393-403.  Back to cited text no. 2
    
3.
Ramondetta LM, Silva EG, Levenback CF, Burke TW. Mixed choriocarcinoma in a postmenopausal patient. Int J Gynecol Cancer 2002;12:312-6.  Back to cited text no. 3
    
4.
Shen DH, Khoo US, Ngan HY, Ng TY, Chau MT, Xue WC, et al. Coexisting epithelioid trophoblastic tumor and choriocarcinoma of the uterus following a chemoresistant hydatidiform mole. Arch Pathol Lab Med 2003;127:e291-3.  Back to cited text no. 4
    
5.
Baergen RN, Rutgers JL, Young RH, Osann K, Scully RE. Placental site trophoblastic tumor: A study of 55 cases and review of the literature emphasizing factors of prognostic significance. Gynecol Oncol 2006;100:511-20.  Back to cited text no. 5
    
6.
Lurain JR. Gestational trophoblastic disease I: Epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol 2010;203:531-9.  Back to cited text no. 6
    
7.
Smith HO. Gestational trophoblastic disease epidemiology and trends. Clin Obstet Gynecol 2003;46:541-56.  Back to cited text no. 7
    
8.
Horowitz NS, Goldstein DP, Berkowitz RS. Placental site trophoblastic tumors and epithelioid trophoblastic tumors: Biology, natural history, and treatment modalities. Gynecol Oncol 2017;144:208-14.  Back to cited text no. 8
    
9.
Chen B-J, Cheng C-J, Chen W-Y. Transformation of a post-cesarean section placental site nodule into a coexisting epithelioid trophoblastic tumor and placental site trophoblastic tumor: A case report. Diagn Pathol 2013;20:8:85.  Back to cited text no. 9
    
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Sung WJ, Shin HC, Kim M-K, Kim MJ. Epithelioid trophoblastic tumor: Cliaanicopathologic and immunohistochemical analysis of three cases. Korean J Pathol 2013;47:67-73.  Back to cited text no. 10
    
11.
Knox S, Brooks SE, Wong-You-Cheong J, Ioffe O, Meisenberg B, Goldstein DP. Choriocarcinoma and epithelial trophoblastic tumor: Successful treatment of relapse with hysterectomy and high-dose chemotherapy with peripheral stem cell support: A case report. Gynecol Oncol 2002;85:204-8.  Back to cited text no. 11
    
12.
Luk WY, Friedlander M. A fibroid or cancer? A rare case of mixed choriocarcinoma and epithelioid trophoblastic tumor. Case Rep Obstet Gynecol 2013:1-2.  Back to cited text no. 12
    
13.
Zhang X, Zhou C, Yu M, Chen X. Coexisting epithelioid trophoblastic tumor and placental site trophoblastic tumor of the uterus following a term pregnancy: Report of a case and review of literature. Int J Clin Exp Pathol 2015;8:7254-9.  Back to cited text no. 13
    
14.
Imamura Y, Tashiro H, Saito F, Takaishi K, Ohba T, Fukunaga M, et al. Choriocarcinoma coexisting with epithelioid trophoblastic tumor of the uterine horn. Gynecol Oncol Rep 2015;14:31-3.  Back to cited text no. 14
    
15.
Tse KY, Chiu KW, Chan KK, Chu MM, Ngu SF, Cheung AN, et al. 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;150:318-32.  Back to cited text no. 15
    
16.
Mazur MT, Kurman RJ. Gestational trophoblastic disease and related lesion. In: Kurman RJ, ed. Blaustein's Pathology of the Female Genital Tract. 4th ed. New York, NY: Springer-Verlag; 1994. p. 1049-93.  Back to cited text no. 16
    
17.
Hamazaki S, Nakamato S, OkinoT, Tsukayama C, Mori M, Taguchi K, et al. Epithelioid trophoblastic tumor: Morphological and immunohistochemical study of three lung lesions. Hum Pathol 1999;30:1321-7.  Back to cited text no. 17
    
18.
Shih IM, Kurman RJ. Molecular basis of gestational trophoblastic diseases. Curr Mol Med 2002;2:1-12.  Back to cited text no. 18
    
19.
Shih IM, Kurman RJ. The pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol 2001;20:31-47.  Back to cited text no. 19
    
20.
Mao TL, Kurman RJ, Huang CC, Lin MC, Shih IM. Immunohistochemistry of choriocarcinoma. Am J Surg Pathol 2007;31:1726-32.  Back to cited text no. 20
    
21.
Ngan HYS, Seckl MJ, Berkowitz RS, Xiang Y, Golfier F, Sekharan PK, et al. Update on the diagnosis and management of gestational trophoblastic disease. Int J Gynecol Obstet 2018;143:79-85.  Back to cited text no. 21
    
22.
Soper J, Mutch D, Schink J. Diagnosis and treatment of gestational trophoblastic disease: ACOG Practice Bulletin No. 53. Gynecol Oncol 2004;93:575-85.  Back to cited text no. 22
    
23.
Desai NR, Gupta S, Said R, Desai P, Dai Q. Choriocarcinoma in a 73-year-old woman: A case report and review of the literature. J Med Case Rep 2010;4:379.  Back to cited text no. 23
    
24.
Mangla M, Singla D, Kaur H, Sharma S. Unusual clinical presentations of choriocarcinoma: A systematic review of case reports. Taiwan J Obstet Gynecol 2017;56:1-8.  Back to cited text no. 24
    
25.
Bhattacharyya SK, Saha SP, Mukherjee G, Samanta J. Metastatic vulvo-vaginal choriocarcinoma mimicking a Bartholin cyst and vulvar hematoma-two unusual presentations. J Turkish Ger Gynecol Assoc 2012;13:218-20.  Back to cited text no. 25
    
26.
Mitrovic SL, Arsenijevic PS, Kljakic D, Djuric JM, Milosavljevic MZ, Protrka ZM, et al. Gestational choriocarcinoma of the cervix. Arch Iran Med 2014;17:783-5.  Back to cited text no. 26
    
27.
Samantaray S, Rout N, Kakkar S, Pattanayak L. Choriocarcinoma presenting as a vaginal nodule: A rare presentation diagnosed by fine needle aspiration cytology. Acta Cytol 2009;53:364-5.  Back to cited text no. 27
    
28.
Shih I-M. Trophogram, an immunohistochemistry-based algorithmic approach, in the differential diagnosis of trophoblastic tumors and tumorlike lesions. Ann Diagn Pathol 2007;11:228-34.  Back to cited text no. 28
    
29.
Kalhor N, Ramirez PT, Deavers MT, Malpica A, Silva EG. Immunohistochemical studies of trophoblastic tumors. Am J Surg Pathol 2009;33:633-8.  Back to cited text no. 29
    


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  [Figure 1], [Figure 2]



 

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