Remarkable Response to Cisplatin-Based Chemotherapy and Long-Term Remission in a Young Male with Widespread Extragonadal Choriocarcinoma: A Case Report and Literature Review

Abstract

Introduction

Choriocarcinoma is a rare and aggressive germ cell tumor that presents significant diagnostic challenges, particularly in males, where it is typically found in the gonads. Most patients present with advanced disease, often exhibiting symptoms related to metastatic spread, such as shortness of breath, cough, and hemoptysis. The rarity of extragonadal choriocarcinoma and its non-specific presentation make early diagnosis difficult, emphasizing the need for a multidisciplinary approach to treatment.

Case Presentation

A 31-year-old male presented with progressive shortness of breath, cough, and hemoptysis for over a month. Initial imaging revealed multiple pulmonary nodules and a large necrotic retroperitoneal mass, along with liver metastases. The patient’s β-human chorionic gonadotropin (β-hCG) levels were markedly elevated, raising suspicion of choriocarcinoma, subsequently confirmed through biopsy. Given the rapid clinical deterioration, chemotherapy with cisplatin and etoposide was initiated. The patient responded well to treatment, with a significant reduction in tumor and metastasis size. Over 30 months of follow-up, the patient showed continued clinical improvement with no evidence of disease recurrence.

Conclusion

Extragonadal choriocarcinoma is a highly aggressive and rare malignancy that poses significant diagnostic and therapeutic challenges. This case underscores the importance of early intervention and the need for ongoing research to improve outcomes in these patients. A multidisciplinary approach is crucial for optimal management.

Introduction

Choriocarcinoma is a highly aggressive and rare form of germ cell tumor (GCT). It is challenging to detect at early stages and often discovered at advanced metastatic stages at the time of diagnosis. In males, it represents less than 5% of all GCTs, is classified as a non-seminomatous GCT, and commonly develops in the gonads (testes). However, extragonadal choriocarcinoma is an exceedingly rare form of the disease that is difficult to treat and has an abysmal prognosis. Patients with extragonadal choriocarcinoma typically present with progressive shortness of breath (SOB), cough, chest pain, hemoptysis, and significantly elevated β-human chorionic gonadotropin (β-hCG) hormone levels [1–4].

Several cases have been reported in the literature of male patients with metastatic choriocarcinoma describing the diagnostic challenges and rapid progression [5–9]. However, only a few have reported favorable responses [10, 11]. Here, we present an interesting case of a young male with extragonadal choriocarcinoma with a large, necrotic retroperitoneal mass with metastasis to the lung, liver, and brain who achieved a remarkable response to cisplatin-based chemotherapy and remained disease-free over a follow-up period of more than two and a half years.

Case Presentation

A 31-year-old male presented with a 1-month history of increasing SOB, cough, and hemoptysis. The symptoms worsened 2 days before his presentation to the emergency room with more SOB and hemoptysis. The patient’s medical and surgical history was significant for cystinuria (homozygous SLC3A1 gene mutation) with multiple urologic invasive interventions, including ureteroscopic and percutaneous nephrolithotomy procedures. Physical examination findings upon initial assessment included tachycardia (heart rate of 113 beats per minute), a respiratory rate of 20 breaths per minute, and slightly elevated blood pressure (137/96 mm Hg) with normal temperature.

Chest X-ray revealed multiple bilateral pulmonary nodules as shown in Figure 1. Urgent chest computed tomography (CT) was arranged and demonstrated bilateral scattered innumerable pulmonary rounded nodules and masses, with the largest mass in the left lower lobe measuring 4.3 × 3.8 cm. Based on the clinical and radiological findings, metastatic disease was suspected. Additional tests were performed to investigate further, including CT scan of the neck, abdomen, and pelvis. The patient was found to have a large retroperitoneal hypoattenuating and necrotic mass within the lower aortocaval region, invading the infra-renal inferior vena cava and encasing the abdominal aorta; it measured 6.3 × 5.8 × 6.9 cm. Another retroperitoneal mass measuring 1.3 × 2.1 cm was noted at the confluence of the common iliac veins with the inferior vena cava. In addition, a few indeterminate subcentimeter lymph nodes were also noted.

Fig. 1.

Chest X-ray on admission (a) showing multiple lung nodules with worsening (b) 2 weeks later. CT revealed bilateral lung nodules (c, d) and retroperitoneal mass (e, f).

Scrotal ultrasonography showed no significant abnormalities except for the presence of microlithiasis foci in the right testicle. Cranial MRI revealed a small focus of hemorrhagic metastasis in the right occipital cortical-subcortical region. Bone scan showed no evidence of active metastatic skeletal disease. Laboratory investigations were within normal ranges except for a significantly elevated β-hCG at 12,253,227 mIU/mL, increased lactate dehydrogenase (LDH) at 1,377 IU/I, Erythrocyte Sedimentation Rate (ESR) at 68 mm/h, and C-reactive protein (CRP) of 89 mg/dL.

A CT-guided abdominal lymph node Tru-Cut biopsy was performed; however, it was inconclusive as it showed extensive necrosis without any viable tissue for analysis. A subsequent review of the CT scans with the radiologist revealed that all the masses demonstrated varying degrees of necrosis, making it unlikely that a repeat biopsy would provide different results.

Given the patient’s rapid clinical deterioration, marked by increasing SOB and hemoptysis, and the presumptive diagnosis of a high-risk GCT with significantly elevated β-hCG, the case was discussed in our multidisciplinary tumor board as well as with his family. Considering the potential for bleomycin to exacerbate pulmonary issues, the tumor board recommended initiating first-line chemotherapy with cisplatin and etoposide (EP), initially forfeiting bleomycin. This aligns with international guidelines where cisplatin-based regimens are standard for high-risk GCTs [12]. However, to explore the possibility of obtaining a biopsy from an accessible lesion, a liver ultrasound was performed. The ultrasound revealed multiple diffusely distributed hyperechoic well-defined lesions, with the largest lesion measuring 4.2 × 3.3 cm. Two ultrasound-guided Tru-Cut biopsies were obtained from these lesions. The initial histologic examination of the biopsy samples was suggestive of metastatic choriocarcinoma, likely representing a component of a mixed GCT as shown in Figure 2.

Fig. 2.

a A photomicrograph depicts the infiltration of cytotrophoblastic proliferation (arrow), which is accompanied by areas of necrosis (arrowhead) (hematoxylin and eosin, ×100 and ×200 magnifications). b Multinucleated, enlarged syncytiotrophoblasts (arrow) with a few mitotic figures present (arrowhead) (hematoxylin and eosin, ×100 magnification). c, d Immunohistochemical staining for β-hCG and CAM5.2 demonstrating strong positivity in neoplastic cells (H&E, ×100). e SALL4 stain showing heterogeneous nuclear expression (H&E, ×100). f Diffuse positivity for HPL in tumor cells (×100 magnification).

Immediately following the biopsy procedure, the patient was started on EP chemotherapy. The patient tolerated the initial cycle of chemotherapy well. However, on the fourth day of the first cycle, the patient experienced a rapid deterioration in respiratory status (severe hypoxia and increasing hemoptysis), necessitating endotracheal intubation and admission to the intensive care unit. Repeat chest X-ray revealed worsening bilateral pulmonary opacities and new and enlarging nodules suggestive of possible acute respiratory distress syndrome secondary to hospital-acquired pneumonia or alveolar hemorrhage due to metastatic disease. Extensive septic workup including bronchoalveolar lavage was negative.

Over time, there was a gradual improvement in the patient’s condition and he was eventually extubated and transferred out of the intensive care unit. The patient remained in the hospital to continue therapy. After the third EP chemotherapy cycle, he was discharged in good condition following a 72-day hospital stay.

Over the next 5 months, the patient underwent an additional 5 cycles of etoposide and cisplatin chemotherapy (a total of 8 cycles). Bleomycin was added to the regimen on cycle 4 after performing a pulmonary function test that showed no significant deficits. Re-staging CT scans completed after the sixth cycle of chemotherapy revealed a positive disease response. There was a reduction in the size of the aortocaval mass (3.4 × 3.5 cm compared to 6.3 × 5.8 × 6.9 cm on admission) as well as the hepatic segment VIII lesion (1 cm compared to 1.6 × 2 cm), along with a significant decrease in the size of the bilateral pulmonary metastatic lesions, indicating a favorable response to the treatment. Cranial MRI was also repeated and showed resolution of the previously seen right occipital cortical lesion with no evidence of new metastasis. Additionally, the level of β-hCG started to decline steadily as illustrated in Figure 3.

Fig. 3.

β-human chorionic gonadotropin (β-hCG) level in relation to chemotherapy.

The patient continued to do well in terms of respiratory and functional status. Subsequent measurements of β-hCG revealed consistently low levels over the several months after completing chemotherapy. He was followed for approximately two and a half years after diagnosis with follow-up PET MRI scans showing no evidence of disease recurrence.

Discussion

Extragonadal choriocarcinoma is an extremely rare phenomenon in males, and it is characterized by a highly angioinvasive, rapidly growing, and aggressive early metastatic malignancy with no primary testicular tumor. Due to the rarity of the disease, the data regarding extragonadal choriocarcinoma in males are scarce, and most of the literature about this disease has been merely case reports and case series.

It is unclear how extragonadal choriocarcinoma develops. There were several proposed hypotheses, one of which is that extragonadal choriocarcinoma represents metastasis from a primary testicular tumor that regressed spontaneously [3, 12]. Another term used to describe this hypothesis is “Burned-Out” GCT, which refers to the presence of a metastatic tumor with the histological regression of the primary lesion. Obtaining serial sectioning of the testes was proposed as a requirement before establishing extranodal choriocarcinoma as a diagnosis [13, 14]. However, there are some doubts and conflicting evidence regarding the validity of this theory, and describing them is beyond the scope of this report.

Early diagnosis of extragonadal choriocarcinoma can be exceptionally challenging for many reasons. Patients’ presentation is often non-specific and atypical and mimics more common malignancies. Moreover, there are difficulties associated with obtaining diagnostic tissue biopsies, often necessitating multiple biopsy procedures [4–6]. In a study conducted by Qiu et al. [6], a patient was admitted to the hospital 1 month after the onset of symptoms. It took 25 days to reach a final diagnosis, which was only possible after a third biopsy was performed. Similarly, in our case, a definitive diagnosis was confirmed on the 26th day following a second biopsy. Another reported case by Payne et al. [4] involved a patient presenting with progressive cervical lymphadenopathy and tonsillar enlargement, where three biopsies were ultimately required to establish the diagnosis.

Given its rare occurrence and the lack of clinical trials, there is currently no definitive consensus regarding the optimal therapeutic approach for extragonadal choriocarcinoma. However, cisplatin-based chemotherapy has emerged as the standard of care for extragonadal choriocarcinoma [3, 7–10]. This is often followed by surgical resection of any residual tumor. The most commonly utilized regimens are BEP (bleomycin, etoposide, and cisplatin) and VIP (vinblastine, ifosfamide, and cisplatin).

Zhang et al. [5] and Qiu et al. [6] reported two cases similar to our patient. On both, the patients presented with cough, SOB, and hemoptysis for 2 weeks to 1 month prior to hospital admission. There was evidence of a large mediastinal mass and bilateral pulmonary metastasis, and an ultrasound of the testes showed no abnormalities. The first biopsy obtained in both cases failed to yield any precise diagnosis, and the choriocarcinoma diagnosis was established only by the second biopsy. Both patients were treated with EMA-CO chemotherapy, which consisted of a combination of etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine. Unfortunately, the health of the patients worsened, resulting in the cessation of chemotherapy treatments. Subsequently, both patients passed away soon after.

On the other hand, Uematsu et al. [10] and Koilpillai et al. [11] both reported a favorable response after four cycles of cisplatin-based chemotherapy in 2 patients with primary retroperitoneal choriocarcinoma and distant metastasis. In our case, the patient was found to have a large retroperitoneal mass, metastatic pulmonary nodules, and a significantly elevated β-hCG level. The patient was treated with eight cycles of cisplatin-based chemotherapy with excellent response. After his hospital discharge, he was followed up in the clinic without receiving any further treatment. Routine clinical assessments, measurement of β-hCG levels, and regular re-staging PET/CT scans have consistently shown no signs of disease recurrence or significant neurotoxicity two and a half years after his diagnosis. Table 1 compares clinical features, diagnostic challenges, and outcomes of our case with prior reports of male extragonadal choriocarcinoma.

Table 1.

Comparative analysis of reported cases of male extragonadal choriocarcinoma

Study	Age/sex	Primary site	Metastases	Biopsies, n	Treatment regimen	Prognosis
Present case (2023)	31/M	Retroperitoneal	Lung, liver, brain	2	EP ×3 → BEP ×5	Alive, NED at 30 months
Zhang et al. [5] (2014)	20/M	Mediastinal	Lung, lymph nodes	3	EMA-CO	Died at 3 months
Qiu et al. [6] (2019)	26/M	Mediastinal	Lung, liver	3	EMA-CO	Died at 6.5 months
Uematsu et al. [10] (2020)	33/M	Retroperitoneal	Brain, lung	1	BEP ×4 → TIP ×4 → VIP × 3	Alive, NED at 12 months
Koilpillai et al. [11] (2022)	24/M	Retroperitoneal	Lung	1	VIP ×4	Alive, NED at ≥4 months

NED, no evidence of disease; EP, etoposide/cisplatin; BEP, bleomycin/etoposide/cisplatin; EMA-CO, etoposide/methotrexate/actinomycin D/cyclophosphamide/vincristine; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin.

Conclusions

Extragonadal choriocarcinoma is an extremely rare entity in men. It is an aggressive malignancy with a poor prognosis. Diagnosis is often challenged by the atypical presentation, fulminant course, and difficulties in obtaining a diagnostic tissue biopsy. Nevertheless, early detection and prompt initiation of treatment can result in better survival. Continued research and collaboration among healthcare professionals are necessary to enhance our understanding of this rare disease and develop more effective therapeutic strategies.

Acknowledgments

We sincerely acknowledge the staff of the Departments of Medicine, Medical Oncology, Critical Care, Thoracic Surgery, Interventional Radiology, and Pathology at King Saud University Medical City for their invaluable contributions.

Statement of Ethics

The patient has given written informed consent to publish his case (including publication of images). The Institutional Review Board (Research Ethical Committee, King Saud University) approved the study protocol and patient follow-up (KSU-REC 006CR-E, August, 22, 2022). The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546751).

Conflict of Interest Statement

All authors declare that they have no competing interests.

Funding Sources

No funding was received for this article.

Author Contributions

Abdulmajeed Alshabanat, Waad Aldahlawi, and Siham Hussein acquired, analyzed, and interpreted the data. Abdulmajeed Alshabanat, Waad Aldahlawi, and Siham Hussein contributed to writing, reviewing, and editing the original manuscript. Wajd Althakfi contributed to analyzing the pathology data. Ahmed Ibrahim contributed to the follow-up data. Wajd Althakfi and Ahmed Ibrahim participated in interpreting and revising the data and editing the final manuscript. Abdulmajeed Alshabanat, Waad Aldahlawi, Siham Hussein, and Ahmed Ibrahim followed up the patient. All authors read and approved the final manuscript.

Funding Statement

No funding was received for this article.

Data Availability Statement

All data in this study are included in the article and its online supplementary material. For additional inquiries, please contact the corresponding author.