A poor prognostic male choriocarcinoma with multiple systemic metastases: a case report and the literature review

Background Non-gestational choriocarcinoma, also known as primary choriocarcinoma, is extremely rare in men, manifesting with specific signs such as breast feminization, testicular atrophy, and loss of libido. The presentation typically includes elevated serum β-hCG levels, widespread metastatic disease, and a rapid progression of the condition. Case report We present a rare case of a 41-year-old man diagnosed with choriocarcinoma, exhibiting a unique combination of multiple metastases, including lung, brain, bone, and retroperitoneal lymph node metastases, as confirmed by 18F-FDG PET/CT imaging. The patient was treated with aggressive chemotherapy and pembrolizumab, and the prognosis remained poor. The patient’s overall survival was a mere 5 months following diagnosis. Conclusion Non-gestational choriocarcinoma represents a rare entity in clinical practice and should be considered in young men presenting with gynaecomastia and elevated β-hCG levels alongside normal gonads. Thus, we advocate for a more comprehensive inquiry into medical history and a systematic examination. The 18F-FDG PET/CT examination not only visually delineates the lesion’s location and extent but also serves as a cornerstone for clinical tumor staging, providing valuable support for treatment monitoring and subsequent follow-up.


Introduction
Choriocarcinoma, a rare trophoblastic tumor, exhibits high invasiveness and is characterized by the proliferation and interstitial transformation of abnormal chorionic trophoblast cells.It is distinguished by the absence of a chorionic structure, accompanied by hemorrhage and necrosis, and has the capability to secrete beta-human chorionic gonadotropin (β-hCG).The condition can be classified into two main categories: gestational choriocarcinoma and non-gestational choriocarcinoma (primary choriocarcinoma) (1)(2)(3)(4)(5).Gestational choriocarcinoma originates from the trophoblast of various gestational events, such as hydatidiform mole, spontaneous abortion, and normal pregnancy.On the other hand, non-gestational choriocarcinoma, also known as primary choriocarcinoma, is extremely rare in men, manifesting with specific signs such as breast feminization, testicular atrophy, and loss of libido (2,6,7).This type of choriocarcinoma can be further categorized into gonadal choriocarcinoma (testis) and extragonadal choriocarcinoma (such as mediastinum and retroperitoneum) based on its origin and primary site (8,9).The presentation typically includes elevated serum β-hCG levels, widespread metastatic disease, and a rapid progression of the condition (10,11).
In this report, we present a rare case of a 41-year-old man diagnosed with choriocarcinoma, exhibiting a unique combination of multiple metastases, including lung, brain, bone, and retroperitoneal lymph node metastases, as confirmed by 2-Deoxy-2-[fluorine-18]fluoro-D-glucose ( 18 F-FDG) positron emission tomography combined with computed tomography (PET/CT) imaging.Through an extensive literature search on the PubMed database, covering the period from 1996 to 2023 and utilizing keywords related to choriocarcinoma and CT, the search was carried out with and without the addition of filters, such as English language only, type of article, and subjects, excluding duplicate papers.We identified a total of 53 relevant publications.The summarized findings are presented in Table 1 .Previous studies have overwhelmingly reported cases of choriocarcinoma in pregnant females.The current case of primary choriocarcinoma occurring in a male is exceptionally rare.
The patient underwent an enhanced CT examination, revealing bilateral enlarged breasts (Figure 1A), empty scrotums bilaterally, with the testes not visualized (Figure 1B).A roundish mass with heterogeneous density was observed in the pelvis, post-enhancement, the mass exhibited heterogeneous mild enhancement (Figures 1C,D).Multiple enlarged lymph nodes were identified in the retroperitoneum, merging with one another, encircling the abdominal aorta and vessels, resulting in displacement of surrounding organs (Figure 1E).Additionally, multiple hypodense foci, characterized by ring-shaped and mild enhancement, were detected in the liver (Figure 1F).Furthermore, multiple rounded hyperdense nodules were observed in both lungs (Figure 1G).Following a thorough physical examination, laboratory tests, and CT imaging, the clinician initially suspected the presence of seminomas and metastases.
The patient underwent CT-guided puncture biopsy of a lesion on the liver, extensive hemorrhage was seen microscopically with typical features of choriocarcinoma.The tumor consists of mononuclear cytotrophoblasts and multinucleated syncytiotrophoblasts (Figures 3A,B).Immunohistochemistry showed positive expression of HPL (Figure 3C), β-HCG (Figure 3D), CD34 (vascular), CK7, CK19 and SALL-4.In addition, Ki-67 was observed to be positive in 90% of the tumor cells.The pathologic diagnosis confirmed choriocarcinoma metastasis.
After confirming the absence of contraindications to chemotherapy, the patient underwent treatment with an eight-cycle regimen consisting of etoposide (200 mg/d1-4), cisplatin (40 mg/d1-3), and bleomycin (30 U/d1,5).According to RECIST guidelines, subsequent CT examinations indicated stable disease (SD) in the patient's status.Considering the patient's chemotherapy tolerance, a collaborative decision was made to initiate a four-cycle course of anti-tumor therapy using the PD-1 antibody (pembrolizumab).Unfortunately, the patient experienced adverse effects of diarrhoea during this treatment phase.At the conclusion of the Avelumab treatment, follow-up CT scans revealed an increase in size of metastatic lesions in both lungs and liver, accompanied by the emergence of multiple metastases in the vertebral body (Figure 4A).Due to an inadequate response to pembrolizumab, the patient was subsequently treated with the regimen of "methotrexate (1.5 g) + actinomycin (0.4 mg)." Two weeks post-treatment initiation, the patient presented with dizziness and headache.A cranial MRI disclosed a rounded lesion in the left frontal lobe with high signal on T2WI (Figure 4B), measuring approximately 1.7 cm in diameter, and exhibiting inhomogeneous annular enhancement (Figure 4C).Nine days later, the patient's secondary epileptic symptoms exacerbated, with a repeat MRI showing an enlarged frontal lobe lesion surpassing its previous size (Figure 4D).Additionally, new bilateral occipital lobe metastases were evident (Figure 4E).Despite medical recommendations, the patient declined further treatment and succumbed to the illness

Discussion
Germ cell tumors encompass various cell types, broadly categorized into seminoma and non-seminoma.Non-seminomatous germ cell tumors (NSGCTs) exhibit four subtypes: embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, often displaying a combination of seminomatous and non-seminomatous components.Choriocarcinoma, the rarest subtype, lacks a clear etiology in males, potentially associated with various risk factors such as Klinefelter syndrome, cryptorchidism, exposure to radiation, and more.Cryptorchidism may be one of the significant factors contributing to testicular choriocarcinoma.It has been reported that the likelihood of choriocarcinoma in cryptorchidism patients is 20-40 times higher compared to individuals with normal testes (65,66).The absence of the testicle in this particular case may be a significant factor contributing to the development of testicular choriocarcinoma.Due to its pronounced invasiveness into blood vessels and tissues, extensive hemorrhage, necrosis, and lymphovascular invasion are common findings (67).Choriocarcinoma primarily metastasizes hematogenously, resulting in early and extensive dissemination to sites such as the lungs, liver, skin, retroperitoneal lymph nodes, gastrointestinal tract, and central nervous system (37,(68)(69)(70)(71).In this case, the diagnosis of choriocarcinoma was established at an advanced stage, with multiple metastases already present throughout the body.A thorough medical history and examination are necessary to detect the primary lesion.Characteristics of the typical choriocarcinoma patient history include pregnancy-relatedness, elevated β-hCG levels, abnormal uterine bleeding, and vaginal bleeding.Patients with choriocarcinoma usually have a history of multiple pregnancies.Primary choriocarcinoma is extremely rare in men, manifesting with specific signs such as breast feminization, testicular atrophy, and loss of libido.
The determination of serum tumor markers, specifically serum β-hCG and AFP, proves beneficial in choriocarcinoma diagnosis as they are elevated in approximately 80% of cases.Our case report demonstrates markedly elevated serum β-hCG, produced by syncytiotrophoblasts, indicating its diagnostic relevance.Monitoring the serum concentration of β-hCG also aids in assessing treatment response.According to the International Cooperative Organization for Germ Cell Cancer, a β-hCG level exceeding 50,000 mIU/mL signifies a poor prognosis.Some patients may manifest hyperthyroidism or bilateral gynecomastia, attributed to markedly elevated serum β-hCG levels, often exceeding 50,000 mIU/mL (66,72).In our case, elevated β-hCG levels stimulated supraphysiological testosterone secretion, subsequently aromatized to estradiol, resulting in gynecomastia.Following chemotherapy, a substantial decrease in β-hCG levels was observed, aligning with existing literature.In addition to the abnormal laboratory results, elevated white blood cell count may indicate an underlying infection or inflammation.Elevated levels of D-dimer, C-reactive protein, and fibrinogen may suggest a hypercoagulable state, which could be related to the patient's malignancy.Elevated tumor markers and neuron-specific enolase levels may indicate an underlying malignancy.Elevated prolactin and testosterone levels and a low estradiol level may suggest an endocrine disorder, potentially related to the patient's breast development and gynecomastia.Furthermore, positive EBV antibody IgG suggests a previous Epstein-Barr virus infection, which may have contributed to the patient's condition.
The pathogenesis of extragonadal choriocarcinoma has been a subject of prolonged debate, currently revolving around three hypotheses (73).First, the tumor is postulated to arise from retained primordial germ cells that undergo abnormal migration during embryogenesis (74).Second, it is proposed that the lesion originates from the transformation of a nontrophoblastic neoplasm (75).The third hypothesis suggests that the tumor results from the metastasis of choriocarcinoma from the gonads, accompanied by the spontaneous regression of the primary choriocarcinoma in the gonads.
The imaging characteristics of choriocarcinoma lack distinctive features that differentiate it from other types of germ cell tumors, making its initial diagnosis challenging.However, a comprehensive pre-operative workup, including clinical imaging assessments, remains crucial.There is a scarcity of studies reporting imaging features of retroperitoneal choriocarcinoma in men (82).On CT scans, the lesion typically exhibits a large central necrosis with common occurrences of bleeding and ring enhancement of solid components at the tumor margins.MRI findings include a mixed high signal on T1WI and T2WI associated with combined hemorrhage.Striped hypointensity on both T1WI and T2WI at the tumor margin suggests the possibility of old hemorrhage.In our presented case, CT revealed a cystic solid tumor with eggshell-like calcification at the margin, and an enhancement scan displayed circumferential enhancement, with patchy non-enhanced necrotic areas within the lesion.Due to the rapid growth of choriocarcinoma, histologically, the lesion lacks interstitial blood vessels, relying on the invasion of blood vessels for nutrition, leading to frequent internal necrosis.While CT served as the initial diagnostic modality in our case study, it proved insufficient in revealing metastatic details. 18 F-FDG PET/CT emerges as a noninvasive tool, showcasing its exceptional utility in discerning the metabolic activity of tumors.It proves particularly advantageous in delineating the staging of choriocarcinoma, tracking relapse, and assessing therapeutic response (18, 24,33,47).PET/ CT effectively identifies occult choriocarcinoma lesions that may elude detection through conventional imaging methods such as MRI or CT (30).In the case under scrutiny, 18 F-FDG PET/CT provided comprehensive insights into the extent of systemic involvement of the tumor.Another pivotal role of 18 F-FDG PET/CT in choriocarcinoma management lies in its ability to monitor treatment response.Radiological assessment using 18 F-FDG PET/CT should be incorporated at the end of treatment and annually during follow-up.The existing literature on choriocarcinoma is predominantly comprised of case reports, highlighting its heightened metabolic state with significant 18 F-FDG uptake, indicative of robust trophoblastic proliferation and the tumor's highly aggressive nature (13).However, a subset of cases has demonstrated low 18 F-FDG accumulation in metastatic nodules from choriocarcinoma, potentially influenced by hemorrhagic and/or necrotic components affecting 18 F-FDG avidity (83).The reported SUVmax range for choriocarcinoma spans from 2.0 to 27.5, encompassing various studies (13, 16, 20, 21, 23, 26, 28, 30, 31, 33, 36, 45-47, 49, 51, 53, 54, 60-62, 64, 83).
The treatment approach for choriocarcinoma is contingent upon the disease's stage (66).Non-gestational choriocarcinomas often receive a diagnosis in advanced or metastatic stages.Inaba et al. propose neoadjuvant chemotherapy to reduce tumor volume or high-dose chemotherapy before cytoreductive surgery (84).Currently, there is no standardized chemotherapy regimen for primary choriocarcinoma in males, with high-intensity chemotherapy regimens commonly employed, similar to those used for female choriocarcinoma.Frequently utilized chemotherapy protocols include EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) and TP (paclitaxel and cisplatin).It is acknowledged that male patients often develop resistance to cytotoxic chemotherapy, leading to a grim As the medical field advances, ongoing exploration and application of new treatment modalities persist.In a pre-clinical model, PD-L1 overexpression was identified in gestational trophoblastic specimens, suggesting the potential role of this ligand in tumor-immune evasion (92).Veras et al. (93) reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma.Ghorani et al. (92) documented four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab.Among these cases, all displayed PD-L1 overexpression, and three out of four patients achieved remission.The lack of response in one patient was attributed to the absence of tumor-infiltrating lymphocytes.In a recent phase II, single-arm, prospective trial (CAP 01), the efficacy and safety of camrelizumab (PD-1 inhibitor) combined with apatinib (vascular endothelial growth factor (VEGF) receptor inhibitor) were evaluated in patients with high-risk chemo-refractory or relapsed gestational trophoblastic neoplasia.The study included 20 patients (19 with gestational choriocarcinoma and one with placental site trophoblastic tumor).Notably, 50% of enrolled patients achieved a complete response with the combination of the two drugs, and none of the patients with a complete response experienced disease recurrence after discontinuation of the treatment (94).Contrastingly, in a study by Adra et al. (95), only one of three male patients with choriocarcinoma exhibited PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment.These findings suggest that PD-1/ PD-L1 blockade therapy may not be universally effective in all male patients.It is posited that the therapeutic efficacy of PD-1/ PDL1 blockade varies based on clinicopathological features such as PD-L1 overexpression and the presence of tumorinfiltrating lymphocytes.

Conclusion
In conclusion, non-gestational choriocarcinoma represents a rare entity in clinical practice and should be considered in young men presenting with gynaecomastia and elevated β-hCG levels alongside normal gonads.Thus, we advocate for a more comprehensive inquiry into medical history and a systematic examination.Male primary choriocarcinoma is often associated with widespread metastatic disease, rapid disease progression, and a poor prognosis.Early diagnosis is paramount for formulating an optimal management strategy and minimizing widespread metastasis to achieve the best clinical outcome.The case elucidated in this report contributes to a deeper understanding of the disease for clinicians.The 18 F-FDG PET/CT examination not only visually delineates the lesion's location and extent but also serves as a cornerstone for clinical tumor staging, providing valuable support for treatment monitoring and subsequent follow-up.

FIGURE 1
FIGURE 1 Computed tomography (CT) images of male choriocarcinoma with multiple systemic metastases (December 15, 2018).(A) The transverse image reveals bilaterally enlarged breasts (long arrows).(B) The transverse image displays empty scrotums bilaterally, with the testes not visualized (long arrows).(C) A roundish mass with heterogeneous density is observed in the pelvis, featuring eggshell-like calcifications at its margins (long arrows).(D) The transverse image in the arterial phase shows heterogeneous mild enhancement of the lesion, with evident thickening of blood-supplying arteries, areas of necrotic cystic degeneration in the interior, and tortuous, dilated veins in the surrounding area (long arrows).(E) The coronal image in the venous phase reveals multiple enlarged lymph nodes in the retroperitoneum, merging with one another (dashed arrows).(F) The transverse image in the venous phase exhibits multiple hypodense foci in the liver, characterized by ring-shaped and mild enhancement (arrowheads).(G) The transverse image depicts multiple rounded hyperdense nodules in both lungs (arrowheads).

FIGURE 2 18F
FIGURE 2 18 F-FDG PET/CT images of male choriocarcinoma with multiple systemic metastases (December 20, 2018).(A) The anteroposterior 3-dimensional maximum intensity projection (MIP) image demonstrates increased metabolic activity in the both lungs, abdominal cavity, and pelvic cavity.(B) The sagittal fusion image demonstrates increased metabolic activity in the liver, retroperitoneum and pelvis.(C) Transverse images reveal multiple soft tissue nodules in both lungs with significantly increased 18 F-FDG uptake (SUVmax = 12.7).(D) Transverse images reveal the liver exhibiting multiple slightly hypodense nodules and masses, characterized by markedly increased 18 F-FDG uptake (SUVmax = 38.6).(E) Transverse images depict, in the retroperitoneum, numerous intermingled soft tissue masses with markedly increased 18 F-FDG uptake (SUVmax = 13.1).(F) Transverse images identify a soft tissue mass of irregular shape in the right pelvis, displaying unevenly increased 18 F-FDG uptake (SUVmax = 19.5).The maximum dimensions of this mass are approximately 12.0 cm × 15.2 cm, with areas of cystic necrosis and calcifications noted.(G) Transverse images reveal markedly increased 18 F-FDG uptake at the thoracic 11 vertebral attachments (SUVmax = 11.8).(H) Transverse images show the bilateral breast glands exhibiting thickening with a slight increase in 18 F-FDG uptake (SUVmax = 1.2).

FIGURE 4 CT
FIGURE 4 CT images and magnetic resonance images after treatment for choriocarcinoma (May 5 & 14, 2020).(A) The sagittal bone window CT image reveals multiple metastases in the vertebral body.(B,C) The T2-weighted imaging (T2WI) and enhanced images indicate the development of brain metastases in the patient.(D,E) Subsequent scans after 9 days demonstrate an enlargement and increased size of the patient's brain metastatic lesions compared to the previous images in both T2WI and enhanced sequences.

TABLE 1 18
F-FDG PET/CT and CT manifestations of primary choriocarcinoma.

TABLE 1 (
Continued) (76)ors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis correlate with shorter survival times in male primary choriocarcinoma patients, with a median overall survival of approximately 6 months and a 1-month mortality rate of 23.8% (85-90).In this study, the patient received treatment with etoposide, cisplatin, and bleomycin; however, metastases remained uncontrolled, resulting in the patient's demise due to increased intracranial pressure and secondary epilepsy exacerbated by enlarged brain metastases.The overall survival was only 5 months.A consistent phenomenon observed in patients with poor prognoses was a rapid decrease in β-hCG to a lower level during treatment, followed by a sharp rise during disease relapse (91).Liu et al. suggest that, for advanced patients, a combination of adjuvant chemoradiotherapy with palliative surgery is recommended.If serum β-hCG drops to a normal level and residual lesions persist, salvage surgery to achieve an R0 status is considered worthwhile(76).