Primary mediastinal choriocarcinoma presenting as cutaneous metastasis with resistance to chemotherapy: case report and literature review

Cutaneous metastases of choriocarcinoma are rare. They may indicate poor prognosis and resistance to chemotherapy. In this report, we present a case of a 25‐year‐old man who presented with central pleuritic chest pain and right upper arm mass for about a week. The patient also had significant weight loss during the last 5 months along with an episode of generalized seizure. Chest computed tomography scan revealed an 8 cm anterior mediastinal mass. A skin punch biopsy from the right upper arm mass revealed a malignant neoplasm with morphology consistent with metastatic choriocarcinoma. Further work‐up revealed multiple lung and brain lesions. Ultrasound of the testes revealed no abnormalities. Several chemotherapy regimens were tried; however, there was no response and the disease showed progression. The patient died 6 months after initial presentation.


| INTRODUCTION
Choriocarcinoma is a malignant trophoblastic tumor that occurs most commonly in women of reproductive age following hydatidiform mole, abortion, or normal pregnancy (gestational choriocarcinoma). In men, however, it usually presents as a component of mixed germ cell tumor usually originating in the testis, or in some cases, in extragonadal sites such as mediastinum and retroperitoneum (non-gestational choriocarcinoma). 1 Choriocarcinoma tends to metastasize to the lungs, brain, liver, and GI tract. 1 However, cutaneous metastases are rare event.  Most of the cases reported in the literature with cutaneous metastasis are testicular choriocarcinomas, [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] and to a lesser extent, gestational choriocarcinomas. [19][20][21][22][23][24][25] To the best of our knowledge, no cases of primary mediastinal choriocarcinoma presenting as cutaneous metastasis have been reported in the literature. We describe an unique case of primary mediastinal choriocarcinoma presenting as cutaneous metastasis. The patient was started on the first cycle chemotherapy with EP protocol (etoposide and cisplatin), which was complicated by thrombocytopenia and febrile neutropenia. In the second cycle, VIP protocol (etoposide, ifosfamide, and cisplatin) was initiated because of extensive lung metastases and restrictive pattern on pulmonary function test. After three cycles of chemotherapy, serum beta-hCG level was dropped from 68000 to 1300 mIU/mL, indicating a good response.

| CASE PRESENTATION
However, MRI of the brain, performed 2 weeks later due to dizziness of new onset, revealed disease progression with new multiple brain lesions. The patient received stereotactic radiosurgery to these new brain metastases. The chemotherapy protocol was changed to TIP protocol (paclitaxel, ifosfamide, and cisplatin) as a salvage therapy. He received only two cycles. However, follow-up positron emission tomography-computed tomography scan revealed increased uptake of mediastinal primary, and rise in serum beta-hCG levels. Discussion regarding autologous stem cell transplant was carried on, but as the disease did not achieve complete remission, the procedure was postponed.
The patient was then started on EMA/CO protocol (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine). MRI of the brain performed 1 week later revealed progression of the disease with multiple small newly developed lesions. Chemotherapy was continued with intrathecal methotrexate and whole brain palliative radiotherapy was administered. A paraffin block was sent to a reference laboratory for further testing to identify any actionable biomarker for  26 and since then, fewer than 50 cases have been reported. [27][28][29][30][31] Primary mediastinal choriocarcinoma with metastasis to the lungs, 28 brain, 29 stomach 30 and choroid 31 (Table 1) with a few reported cases of cutaneous metastasis following gestational choriocarcinoma [19][20][21][22][23][24][25] ( Table 2). Some reported cases in the literature suggest that the presence of cutaneous metastasis in choriocarcinoma may indicate poor prognosis. Chhieng et al reported a case of choriocarcinoma presenting as cutaneous metastasis where the patient died 10 days after the initiation of chemotherapy. 16 Shimizu et al reported a case of metastatic choriocarcinoma to the skin; the patient in that case died 3 months after the appearance of cutaneous metastasis. 15  would indicate a good response for immunomodulatory agents. 32 In addition, next-generation sequencing that was performed on the DNA extracted from the tumor by microdissection technique, detected a pathogenic mutation at exon 2 of PTEN gene with p.A39 protein F I G U R E 2 A, photomicrograph depicting skin in which the dermis is infiltrated by poorly differentiated neoplasm with areas of geographic necrosis (Hematoxylin & Eosin stain, ×40). B, the tumor has biphasic pattern composed of mononuclear cytotrophoblasts and multinuclear syncytiotrophoblasts with extensive necrosis (Hematoxylin & Eosin stain, ×100). C, high power view shows atypical mononuclear cytotrophoblasts (arrowheads) and multinuclear syncytiotrophoblasts (arrows) (Hematoxylin & Eosin stain, ×200). D, the tumor cells demonstrate strong and diffuse staining for cytokeratin AE1/AE3 (IHC, ×100). E, strong nuclear reactivity for SALL4 (IHC, ×100). F, strong diffuse reactivity for beta-hCG (IHC, ×100) alteration. PTEN gene has been found to be mutated in various human cancers. Tumors with PTEN gene mutation were found to respond to poly (ADP-ribose) polymerase (PARP) inhibitors. 33 The patient's condition, however, deteriorated rapidly precluding any kind of immune or targeted therapy.
In summary, we are reporting the first case of primary mediastinal choriocarcinoma presenting as cutaneous metastasis that was resistant to different chemotherapy regimens. The results of our case support the findings of previously reported cases in the literature that cutaneous metastasis in choriocarcinoma may suggest an ominous prognosis; however, further evidence is needed. The findings in our case may contribute in improving and modifying therapeutic modalities for metastatic choriocarcinoma in the future.

ACKNOWLEDGMENT
The publication of this article was funded by the Qatar National Library.