A Complex Case of Testicular Choriocarcinoma in Cryptorchidism and Choriocarcinoma Syndrome: Clinical and Treatment Insights

Introduction

Testicular cancer is a rare malignancy that accounts for 1% of all male tumors [1]. According to the National Cancer Registry Report of Malaysia (2012–2016), testicular cancer represented 1.2% of all cancers diagnosed in Malaysian men [2]. About 95% of testicular malignancies are germ cell tumors (GCTs), which comprise both non-seminomatous germ cell tumors (NSGCTs) and seminomatous germ cell tumors (SGCTs) [1]. Testicular cancers with SGCTs are the most prevalent and often have a favorable prognosis [3]. NSGCTs comprise various histological subtypes, such as embryonal carcinoma, yolk sac carcinoma, teratoma, choriocarcinoma and mixed testicular choriocarcinoma [1,4]. Of all NSGCTs, testicular choriocarcinoma is the rarest subtype and is aggressive and known for its poor outcomes [4]. Testicular choriocarcinoma, making up less than 1% of all testicular tumors, is an exceptionally rare and aggressive malignancy characterized by rapid hematogenous spread [5]. Diagnosis is typically confirmed through histology of the testicular mass, supported by elevated human chorionic gonadotropin (bhCG) level [6].

Testicular choriocarcinoma is suspected when it has a very high value of bhCG that usually occurs in a young man with testicular swelling. bhCG serves as a pivotal marker to monitor treatment response. The aggressive nature of testicular choriocarcinoma, characterized by hematogenous dissemination to various organs such as the lungs, lymph nodes, bone, skin, liver, and brain, often leads to rapid and profound deterioration. This progression can culminate in the fatal complication known as choriocarcinoma syndrome, ultimately resulting in patient mortality. Choriocarcinoma syndrome is a life-threatening complication of testicular choriocarcinoma testis, in which patient can have spontaneous hemorrhages from the metastatic sites due to high vascularization of the neoplasm and its invasion into small vessels [6–8].

The clinical understanding of testicular choriocarcinoma, including its clinicopathological features, radiological characteristics, and optimal treatment strategies, remains limited due to its low prevalence. The scarcity of clinical data has led to a lack of clear guidelines for its definitive management. Testicular choriocarcinoma is typically associated with a poor prognosis, frequently involving metastasis to critical organs such as the lungs and brain [4,7]. The rarity of this condition underscores the need for further research and case documentation to enhance our understanding and improve patient outcomes.

Case Report

This report presents the case of a 52-year-old Malay man with an untreated cryptorchidism (undescended testis), despite earlier recommendations for medical attention. He was aware of the diagnosis of the undescended testis made by a visiting nurse at his school at age 7 years. He was advised to attend an appointment at the hospital with his parents at that time, but they did not follow through as it did not cause him any issues. This continued into adulthood until he was married, during which he had a stable personal and sexual life. He did not smoke, drink alcohol, or use illegal drugs, and had no other health problems. He had 3 healthy children. His marriage, however, ended in divorce 2 years ago. He worked as a clerk at a government office.

At age 51 years, he finally decided to seek medical attention at a primary care center when he noticed a painless swelling in the right inguinal region, which was progressively increasing in size over 3 months prior to his visit. Two weeks prior to this presentation, the swelling started to cause him discomfort, which he described as a heavy sensation over the right inguinoscrotal region, particularly noticeable during walking. Despite the swelling, he reported no fever, nausea, vomiting, night sweats, abdominal pain or distension, urinary issues, constipation, loss of weight, or loss of appetite. He was also able to continue his routine daily activities, including going to work. However, he had not engaged in any sexual activities for the previous 2 years before his presentation, following a divorce from his wife. Additionally, there was no family history of malignancies.

Physical examination revealed a swelling in the right groin region, originating from the inguinal canal, measuring 20 cm (length)×11 cm (width)×10 cm (depth), extending into the scrotum. Superiorly, the swelling encompassed the whole region along the inguinal ligament up to the anterior superior iliac spine (ASIS). Inferiorly, the swelling extended close to, but did not involve, the femoral canal. The overlying skin appeared normal, with no erythema. On palpation, the skin over the swelling was not hot to touch, and the swelling was firm, irregular, hard, non-tender, and non-mobile. It was irreducible and exhibited a negative cough impulse. A palpable right inguinal lymph node measuring 1.5×1 cm was noted superior and lateral to the main swelling, distinctly separate upon palpation. Examination showed the contralateral side was normal. There was no abnormal swelling in the left inguinal region or in the left testis. Abdominal examination revealed no abnormal masses or organomegaly. Results of examination of other systems, including the cardiovascular, respiratory, neurological, skin, and musculoskeletal systems, were unremarkable.

The patient’s clinical presentation and physical examination findings were highly suggestive of a malignancy. Differential diagnoses considered included hydrocele, varicocele, spermatocele, epididymal cyst, and inguinal hernia. Hydrocele was deemed unlikely, as the swelling was firm and non-trans-illuminable. Varicocele was excluded due to the absence of the characteristic “bag of worms” feel on palpation. Similarly, spermatocele and epididymal cyst were ruled out because the swelling was not localized to the head of the epididymis. Inguinal hernia was excluded, as the swelling was irreducible and did not exhibit a positive cough impulse. The size, firmness, immobility, and irreducibility of the swelling strongly suggested a tumor.

Thus, he was urgently referred to the urologist, who arranged for serum bhCG, alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH) levels to be tested. Following this, a contrast-enhanced computed tomography (CECT) scan of the abdomen and pelvis was performed to confirm the diagnosis and evaluate the extent of metastasis. The results showed markedly elevated bhCG level of 236,335 IU/L. High bhCG level of >50 000 IU/L supports a diagnosis of non-seminomatous germ cell tumor (NSGCT), particularly choriocarcinoma, which is known to have predominantly raised bhCG levels. Additionally, the LDH level was elevated at 445 U/L, indicative of a high tumor burden, while AFP was slightly elevated at 2.6 ng/mL, remaining within the low range, which is sometimes seen in NSGCTs such as choriocarcinoma. CECT scans of the abdomen and pelvis confirmed a testicular tumor measuring 13.3 cm (anteroposterior)×15.9 cm (width)×17.4 cm (craniocaudal), with metastasis to the lymph nodes and lungs. Notably, the lymph nodes were matted and appeared to encase the right common iliac artery and vein, as shown in Figure 1.

The markedly elevated bhCG and LDH levels along with the imaging findings of a large metastatic testicular mass, strongly supported the diagnosis of NSGCT, specifically advanced stage testicular choriocarcinoma. The patient was clinically diagnosed as having NSGCT at clinical stage IIIC. He was then urgently seen by an oncologist, who initiated neoadjuvant chemotherapy. The BEP regimen was used, which includes cisplatin, etoposide, and bleomycin. He received a total of 6 cycles of this regimen, with each cycle lasting 3 weeks. After completing 6 cycles, his bhCG significantly decreased from an initial level of 236 335 IU/L to 1008 IU/L, indicating a partial response to therapy. At this stage, he reported feeling better, with a noticeable reduction in tumor size and significant relief from the discomfort and heavy sensation he experienced during his initial presentation.

Upon completion of chemotherapy, he underwent a right orchidectomy. Intraoperatively, a well-defined, lobulated tumor measuring 10×70×55 mm was found, encompassing nearly the whole testicular parenchyma. The cut section was predominantly hemorrhagic, with small solid, whitish areas, and a nodular area. Histopathological results confirmed testicular choriocarcinoma with the presence of lymphovascular invasion, indicating a poor prognosis. Figure 2 shows a section from the testicular tumor showing cystic hemorrhagic spaces lined by malignant cells. Immunohistochemical staining of the tumor cell was positive for bhCG, indicating it was a germ cell tumor (GCT). However, it was negative for AFP, CD30, and CD117, which supports the diagnosis of pure testicular choriocarcinoma, as these markers are typically associated with other germ cell tumor subtypes.

Following an uneventful postoperative course, he began the first cycle of adjuvant chemotherapy with the same BEP regimen approximately 6 weeks after surgery, after he had sufficiently recovered from the operation. Following his surgery and adjuvant chemotherapy, he continued to receive support from his primary care physician. Regular virtual consultations were conducted to monitor his health and address any emerging concerns. During these calls, he reported being well taken care of at home by his 2 daughters, who assumed the role of his main caregivers. He mainly stayed at home, and was able to ambulate independently and manage his personal care needs.

Unfortunately, 70 days postoperatively and 24 days after the first adjuvant chemotherapy, he experienced an abrupt onset of seizures. He was brought to the emergency department at a different hospital nearer to his house. CT imaging of the brain revealed several well-defined hyperdense lesions predominantly located in the cortical grey-white matter junction in the left frontal and occipital lobes. The largest lesion in the left frontal lobe measured 1.5×1.4×1.3 cm, associated with marked surrounding perilesional edema (Figure 3). CT brain results were consistent with hemorrhagic metastatic foci. He was hemodynamically stable without any residual weakness. On day 3 of admission, he was transferred to the treating hospital for his cancer under care of the urology team. After the transfer, he again developed multiple episodes of seizures and regrettably, after 2 days, he died due to his illness 10 months 3 days after the testicular cancer diagnosis, 2 months postoperatively, and 1 month after adjuvant chemotherapy. The cause of death was right testicular choriocarcinoma syndrome.

Discussion

Testicular cancer is frequently diagnosed in men aged 20–34 years. It is a rare type of malignancy, comprising only 1% of all tumors in men [1]. According to the National Cancer Registry Report of Malaysia (2012–2016), testicular cancers accounted for 1.2% of all cancers diagnosed in Malaysian men [2]. In the United States, data from the National Cancer Institute (NIH) for 2018–2021 indicate that about 0.4% of men are diagnosed with testicular cancer at some point in their lives [9].

Testicular cancer is 5–10 times more likely to be associated with cryptorchidism. This condition significantly increases the likelihood of developing testicular cancer, contributing to approximately 10% of all testicular cancer cases [10]. Other than cryptorchidism, risk factors for testicular choriocarcinoma are not well-defined in the literature. Generally, risk factors also include environmental factors (24%) such as exposure to chemicals and radiation, family history with genetic predisposition (37–44%), and infections such as EBV and HIV (OR 7.38, 95% CI 1.89–28.75, P=0.004; OR 1.71, 95% CI 1.51–1.93, P<0.00001) [11,12]. In this case report, several risk factors potentially contributed to the development of testicular choriocarcinoma, including a history of an undescended testis, which had been untreated during his childhood. He was eventually diagnosed with testicular cancer at the age of 52 years and the CECT scan confirmed a testicular tumor with metastases to the lymph nodes, liver, and lungs. Understanding these risk factors is crucial for early detection and management, especially in patients with known predisposing conditions such as cryptorchidism. Early treatment of the undescended testis, particularly through corrective surgery before puberty, might have prevented germ cell damage and reduced the risk of malignant transformation, especially into NSGCTs such as choriocarcinoma, which is rare and aggressive [10,12].

With regards to the types of testicular cancers, ~95% are GCTs, which include both SGCTs and NSGCTs. GCTs have a better relative survival rate of 95% over 50 years compared to NSGCTs. Among NSGCTs, testicular choriocarcinoma is exceptionally rare, comprising 0.3–1% of all testicular germ cell tumors and 0.2–0.6% of testicular cancers. It is also the most aggressive form of testicular cancer, and the prognosis is often poor. Testicular choriocarcinoma originates from trophoblastic cells, characterized by their ability to invade and metastasize rapidly [4,6,7]. The marked elevation of the bhCG level of >200 000IU/L is a hallmark of this malignancy, as seen in our patient. According to the IGCCG classification, NSGCTs are categorized into good-, intermediate-, and poor-prognosis groups based on tumor site, serum tumor marker levels, and the presence of extra-pulmonary visceral metastases [4,13]. Approximately 56% of patients with NSGCTs are in the good-prognosis group, where there is a high curability rate of over 90%. On the contrary, those in the poor-prognosis group have a 5-year survival rate of only 48% [14,15]. Our patient was presented with severely elevated bhCG level of 236 335 IU/L. On the contrary, patients with SGCTs do not usually have elevated level of bhCG of >1000 IU/L [16].

Radical orchidectomy should be promptly conducted following a clinical diagnosis to ensure accurate diagnosis and primary tumor control. Following this, chemotherapy is essential for managing both early and advanced stages of the disease [16]. For advanced disease, chemotherapy remains the cornerstone of treatment, complemented by surgical intervention for residual disease. Timely initiation of chemotherapy and radical orchidectomy following clinical diagnosis are crucial for prognosis and primary tumor control in metastatic choriocarcinoma. First-line chemotherapy for testicular cancer involves cisplatin-based regimens like BEP (cisplatin, etoposide, bleomycin) or VIP (cisplatin, etoposide, ifosfamide) [4,17].

In this case, despite an initial positive response to surgery and chemotherapy, the patient’s rapid progression to brain metastasis underscores the poor prognosis associated with testicular choriocarcinoma. Patients with a very high level of bhCG are at risk of a severe complication known as choriocarcinoma syndrome [18]. This condition was first described in 1984 by Logothetis et al, and it is characterized by hemorrhage from the metastatic sites in patients with advanced GCT containing a high volume of choriocarcinoma elements, especially those with choriogonadotropin levels over 50 000 IU/L [19]. In this case, our patient succumbed to death due to choriocarcinoma syndrome resulting in hemorrhagic metastasis. One of the triggering factors for choriocarcinoma syndrome is the prescription of chemotherapy, which leads to massive lysis of tumor cells and consequent release in cytokines that aggravate cell damage [5,7,18].

This report presents a rare case of testicular choriocarcinoma with the rare complication of choriocarcinoma syndrome, which occurred in the setting of untreated cryptorchidism. Through this case, it is evident that early intervention of cryptorchidism via orchiopexy would have optimized the patient’s testicular health by reducing the risk of atrophy and cancer [20]. A systematic review by Gates et al highlighted the importance of orchiopexy to be performed before 1 year of age, which can markedly reduce long-term cancer risk. Delayed treatment, particularly beyond puberty, increases cancer risk by up to 22-fold compared to the general population [21]. Thus, awareness of the complications that can develop from undescended testes needs to be increased in the male population to improve future health outcomes.

In managing patients with aggressive malignancy, continuous monitoring and multidisciplinary care are essential to ensure that patients are managed holistically. As demonstrated in this case, a primary care physician played a crucial role in recognizing a red flag for malignancy – large right inguinal swelling extending into the scrotum – resulting in an urgent referral to the urologist. Prompt recognition and referral to a secondary or tertiary care center for urgent management are paramount to improving patient outcomes [21–23]. Furthermore, primary care physicians can play a significant role in providing ongoing psychosocial support and advice during the postoperative recovery and chemotherapy period, as in the present case.

Conclusions

This case underscores the necessity of prompt and comprehensive diagnostic workups in patients presenting with atypical testicular masses, especially in those with a history of undescended testes. Testicular choriocarcinoma poses a significant clinical challenge due to its rarity and aggressiveness, compounded by the lack of established treatment guidelines. Due to its rapid proliferation and vascular invasion, testicular choriocarcinoma tends to exhibit hematogenous spread to the lungs, liver, and brain at an early stage. Overall, it illustrates the value of early detection, timely intervention, and coordinated care from primary care to specialized follow-ups, which can significantly improve outcomes for patients with rare and aggressive conditions like testicular choriocarcinoma.