Abstract
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) (1–5). 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 (18F-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 (12–64). Previous studies have overwhelmingly reported cases of choriocarcinoma in pregnant females. The current case of primary choriocarcinoma occurring in a male is exceptionally rare.
Table 1
| Case | Authors | Gender | Age | Obstetric history | Medical history | Clinical symptoms | Max β-hCG, mIU/mL | Primary sites | Invasion and metastasis | Max diameter/cm | SUVmax | Management | Outcome |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Lowe et al. (12) | M | 18 | None | Microcytic anemia | Black stools, lethargy, and dizziness | 32,219 | Testicles | Stomach, brain and kidney lungs | NA | NA | Surgery + chemotherapy | Alive |
| 2 | Maruoka et al. (13) | F | 26 y | Molar pregnancy history at 20 y and spontaneous abortion history at 26 y. | NA | NA | 233.8 | Negative | Pulmonary metastasis | 3.0 | 2.0 | Surgery | Alive at 1 mo |
| 3 | Dose et al. (14) | F | 37 y | Abortion at 34 y | Leiomyoma of the uterus, Cystic lesion of the right ovary | Irregular bleedings, and secondary sterility | 8,000 | Uterus | None | 5 | NA | Surgery + chemotherapy | Alive at 13 mo |
| 4 | Gazzilli et al. (15) | F | 36 y | History of 4 spontaneous abortion | NA | Repeated epistaxis | 3,839 | Nasal and ethmoid | Sphenoidal and maxillary sinuses; cervical lymph node | NA | NA | Surgery + chemotherapy | Complete remission |
| 5 | Numnum et al. (16) | F | 22 y | Molar pregnancy history at 16 and a term delivery at 19 y | GTD (gestational trophoblastic disease) | Vaginal bleeding and abdominal cramping | 1,341 | Left pelvis | None | NA | 5.0 | Surgery + chemotherapy | Alive at 8 mo |
| 6 | Hebart et al. (17) | F | 32 y | NA | Irregular menstruation | Irregular periods, intermittent pleuritic chest pains and nonproductive cough | 127,429 | None | Left lung artery and right lung | NA | NA | Chemotherapy | Died within few hours |
| 7 | Hebart et al. (17) | F | 29 y | Term delivery 4 mo ago. | NA | NA | 400 | None | Left and right lung | NA | NA | Surgery + chemotherapy | Alive at 1 y |
| 8 | Huang et al. (18) | F | 40 y | Term delivery 10 y ago | Pseudoaneurysms, GTD | Headache | 4,154 | None | Left frontal lobe in brain and left lung | 1.5 | NA | Chemotherapy | Alive at 3 y |
| 9 | Tripathi et al. (19) | F | 38 y | Term delivery 4 y ago | NA | NA | 33,000 | NA | Right atrium and lung | NA | NA | Chemotherapy + surgery | Alive after 5 cycles |
| 10 | Rao et al. (20) | F | 28 y | Term delivery 4 y ago | NA | Irregular vaginal bleeding | 1,004.69 | Pancreas | None | 5.4 | 3.9 | Surgery + chemotherapy | Alive at 2 y |
| 11 | Huang et al. (21) | F | 46 y | NA | NA | Right upper abdominal pain | 59,283 | Pancreas | Liver and inferior vena cava lymph nodes | 7.4 | 17.7 | Surgery +125I-seed implantation | Died at 10 mo |
| 12 | Trübenbach et al. (22) | F | 33 y | Abortion 10 months ago | Pulmonary embolism, pleural effusion and pulmonary hypertension | Recurrent episodes of exertional dyspnoea and pleuritic chest pain | 129,500 | None | Left pulmonary artery | NA | NA | Methotrexate | Died at 1 d |
| 13 | Zhang et al. (23) | F | 29 y | NA | Recurrent right-sided pneumothoraces | Recurrent right-sided pneumothoraces and episodic menorrhagia | NA | Left lung | NA | NA | 7.2 | Surgery | NA |
| 14 | FCimarelli et al. (24) | M | 23 | None | GCT (germ cell tumors) | Gynecomastia and abdomen pain | 425,000 | Retroperitoneal | Liver, lung and lomboaortic lymph nodes | 14 | NA | Surgery + chemotherapy | NA |
| 15 | Joshua et al. (25) | F | 31 y | Term delivery | Dult polycystic kidney disease and mild hypertension | Pulmonary vein bleeding | 91,348 | Uterus | Lung and liver | NA | NA | Chemotherapy | Alive at 8 mo |
| 16 | Sone et al. (26) | F | 31 y | NA | NA | NA | NA | NA | Lung | NA | 7.3 | Chemotherapy | Died |
| 17 | Kidd et al. (27) | M | 48 y | None | NA | Blurred vision and headache | NA | NA | Brain and lung and | NA | NA | Supportive therapy | Died at 10 d |
| 18 | Aleem et al. (28) | F | 30 y | NA | NA | A lump in right breast and right axilla | NA | Uterus | Right breast | 7 | 5.9 | Surgery + chemotherapy | alive |
| 19 | Goldfarb et al. (29) | F | 50 y | Gravida 3, para 2, abortus 1 | NA | An intra-uterine mass and hemorrhaged during an office endometrial biopsy | 28,725 | Uterus | Lungs | NA | NA | Surgery + chemotherapy + targeted therapy | Disease progression at 2 y |
| 20 | Du et al. (30) | F | 37 y | One term delivery and two miscarriages | Irregular menstruation | Hemoptysis | 279,064 | NA | Lung, renal and brain | 5.8 | 18.3 | Surgery + chemotherapy | Died at 1 y |
| 21 | Wang et al. (31) | F | 21 y | Miscarriage at 20 y. | NA | Chest pain and fever | >10,000 | NA | Lung | NA | 27.5 | Chemotherapy | Alive at 1 y |
| 22 | Sekine et al. (32) | M | 49 y | None | Diabetes mellitus and hepatitis C | Abdominal pain and fever | 5,3,000 | Liver | Lung | NA | NA | None | Died at 60 d |
| 23 | Sironi et al. (33) | F | 38 y | No obstetric history in the past 10 y | NA | NA | 210 | NA | Lung | NA | NA | Surgery + chemotherapy | Alive at 12 mo |
| 24 | Sironi et al. (33) | F | 29 y | Recent molar pregnancy history | NA | NA | 3,471 | NA | Lung | 0.5 | Poor FDG avidity | Surgery | Alive at 6 mo |
| 25 | Sironi et al. (33) | F | 49 y | Molar pregnancy 6 y ago | NA | NA | >10,000 | NA | Left lung and liver | 13 | 7.98 | Surgery + chemotherapy | Alive |
| 26 | Gasparri et al. (34) | F | 37 y | Term delivery 1 y ago | Enhancement of beta-human chorionic gonadotropin levels | Period suspension | NA | NA | Lung | 1.1 | NA | Surgery + chemotherapy | Alive at 2 y |
| 27 | Gvinianidze et al. (35) | F | 42 y | Term delivery 6 mo ago | NA | Cough, shortness of breath on physical exertion and haemoptysis | 3,200 | NA | Lung and brain | NA | NA | Surgery + chemotherapy | Alive at 8 mo |
| 28 | Snoj et al. (36) | F | 35 | Three spontaneous abortions in the past year | NA | Right chest pain | 169,396 | Lung | Brain | 6.4 | 2.7 | Surgery + chemotherapy + radiotherapy | Alive at 1 y |
| 29 | Göksel et al. (37) | M | 27 | None | Anemia and melena | Anemia and melena | NA | Testicles | Stomach | NA | NA | NA | NA |
| 30 | Francischetti et al. (38) | M | 41 | None | Transient ischemic attack and stroke | Recurrent numbness of right finger and arm, left facial weakness and language difficulty | 12,118 | Mediastinum | Brain | 9 | NA | NA | NA |
| 31 | Pakkala et al. (39) | F | 23 | At 28 weeks of gestation | NA | Right hypochondrium pain | 11,875 | NA | Liver and pulmonary, presacral, rectal, and iliac nodal metastasis | 11.6 | NA | Termination of pregnancy + surgery + chemotherapy | Alive at 7 mo |
| 32 | Su et al. (40) | F | 31 | NA | Right ovarian dermoid cyst and bilateral polycystic ovaries | NA | 790,000 | Uterus | Lung | 0.4 | Poor FDG avidity | Surgery + chemotherapy | NA |
| 33 | Lee et al. (41) | F | 15 | None | NA | Uterine bleeding | 76,600 | Right ovary | None | 8.5 | NA | Surgery + chemotherapy | Alive at 6 y |
| 34 | Lehmann et al. (42) | F | 32 | Term delivery 5 mo ago | Gestational choriocarcinoma | Uterine bleeding | 13,575 | Uterus | Lung and brain | NA | NA | Surgery + chemotherapy | Alive at 2 y |
| 35 | Usta et al. (43) | F | 28 | Term delivery 4 y ago | NA | Lower pelvic pain, flank pain, vaginal bleeding and a delayed menstrual period | 70,373 | Renal artery | NA | NA | NA | Surgery + chemotherapy | Alive at 1 y |
| 36 | Clair et al. (44) | F | 30 | A 15-week twin pregnancy consisting of a normal fetus and a suspected molar gestation | NA | NA | 96,952 | Uterus | Lungs | 3.2 | NA | Surgery + chemotherapy + radiotherapy + targeted therapy | Alive at 5 y |
| 37 | Dance et al. (45) | M | 37 d | None | Anemia and thrombocytopenia | A pedunculated, friable red glabellar mass | NA | NA | Cutaneous, liver, and lung | 6.8 | 10.3 | Surgery + liver transplant + chemotherapy | Alive at 3 mo |
| 38 | Shaw et al. (46) | F | 38 y | An abortion 11 mo ago | Pulmonary tuberculosis | Oliguria and leg edema | 382 | Uterus | Stomach | NA | 3.63 | Surgery | Alive at 15 mo |
| 39 | Hyun et al. (47) | F | 38 | Molar pregnancy history 4 y ago | Hydatidiform mole and asymptomatic recurrent pneumothorax | NA | NA | Uterus | Lung | NA | Poor FDG avidity | Surgery + chemotherapy | Alive at 22 mo |
| 40 | Pessanha et al. (48) | M | 14 | None | Tyrosinemia type I, HCC, Budd-Chiari Syndrome with partial occlusion of the hepatic veins and micronodular hepatic cirrhosis | Weight loss, minor edema of the lower limbs, moderate gynecomastia, and morning nausea | 1,984 | Liver | Lung | 6.7 | Poor FDG avidity | Surgery + chemotherapy | Alive at 11 y |
| 41 | Chen et al. (49) | F | 43 | Term delivery 3 y ago | Ectopic pregnancy | Low abdomen pain | 5,241 | NA | Liver, lungs, marrow cavity, thoracic vertebra and brain | 5.8 | 6.4 | Surgery + chemotherapy | Alive at 32 mo |
| 42 | Kohler et al. (50) | M | 64 y | None | NA | Abdomen pain and intra-abdominal bleeding | >5,000 | Liver | Lungs and iliacal lymph nodes | 14.5 | NA | Surgery + chemotherapy | Died at 6 mo |
| 43 | Dlewati et al. (51) | F | 54 | NA | Hypertension and ischemic stroke | Dyspnea, cough, and intermittent hemoptysis | 98,138 | Lung | Right breast and brain | 4.8 | 3.1 | Surgery + chemotherapy + radiotherapy | NA |
| 44 | Dasgupta et al. (52) | M | 29 | None | NA | A lump on the neck | 18 | Testicle | Cervical lymph node | 4.8 | NA | Surgery | NA |
| 45 | Huang et al. (53) | F | 32 | Molar pregnancy 7 mo ago | Hydatidiform mole and GTD | NA | 17,094 | Uterus | Anterior pelvic peritoneal wall | NA | 4.7 | Surgery + chemotherapy | Alive at 30 mo |
| 46 | Chatterjee et al. (54) | F | 41 | Molar pregnancy history | NA | Headache and left eye pain | 7,062 | NA | Endocranium | 3.5 | Poor FDG avidity | Surgery + chemotherapy | Alive at 3 y |
| 47 | Zhou et al. (55) | F | 66 | NA | NA | Abdominal discomfort | 795.14 | Stomach | Liver | 2.0 | NA | Surgery + chemotherapy + radiotherapy | Died at 8 mo |
| 48 | Matsuo et al. (56) | F | 46 | Term delivery 5 y ago | NA | Hemoptysis | 132 | NA | Lung | 4 | NA | Surgery + chemotherapy | Alive at 8 mo |
| 49 | Røge et al. (57) | M | 71 | None | Concurrent goserelin-treated metastasized prostate adenocarcinoma | Back pain | NA | Mediastinum | Lungs | 5.5 | NA | Surgery | Died |
| 50 | Kazemi et al. (58) | F | 49 | Gravida 2, para 2 | Asthma, pulmonary edema, and hyperlipidemia | Cough and right upper quadrant pain | 79,000 | NA | Liver and lungs | NA | NA | Chemotherapy + target therapy | Died |
| 51 | Pan et al. (59) | M | 19 | None | NA | Chest pain and occasional cough | >200,000 | Mediastinum | Lungs, brain, liver, spleen, kidney, and skeletal | 8.8 | NA | Surgery + chemotherapy | Died at 4 mo |
| 52 | Kamata et al. (60) | M | 70 | None | NA | Cough | NA | Lung | NA | 3.8 | 6.5 | Surgery | Alive at 2 y |
| 53 | Iijima et al. (61) | F | 45 | Molar pregnancy history 6 y ago | Hydatidiform mole | Irregular vaginal bleeding | 482.8 | Uterus | Lung | NA | 9.57 | Surgery + chemotherapy | Alive at 7 y |
| 54 | Horotsu et al. (62) | M | 78 | None | NA | NA | 120 | Stomach | Liver | 3 | 5.4 | Surgery + chemotherapy | Died at 10 mo |
| 55 | Rehman et al. (63) | M | 50 | None | NA | Painful bilateral gynaecomastia | 3,756 | Mediastinum | Lung | NA | NA | Surgery + chemotherapy | Alive at 3 y |
| 56 | Guo et al. (64) | F | 61 | Term delivery at 31 y | NA | Vaginal bleeding | 9273.9 | Vagina | Lung | 3 | Poor FDG avidity | Surgery + chemotherapy | Alive at 4 y |
18F-FDG PET/CT and CT manifestations of primary choriocarcinoma.
Case presentation
A 41-year-old man presented with diminished appetite symptoms a year ago, but he did not undergo an examination. His condition deteriorated 2 months ago, marked by malaise, night sweats, and lower back pain, leading to a weight loss of 10.5 kg over 1 year. The patient was hospitalized for a physical examination, revealing bilateral breast development and a palpable mass measuring approximately 12 cm × 10 cm with poor mobility in the right abdomen. Laboratory tests indicated a white blood cell count of 12.00 × 109/L (normal range 3.5–9.5 × 109/L), D-dimer of 5.94 mg/L (normal range 0–0.5 mg/L), fibrinogen of 5.10 g/L (normal range 2–4 g/L), C-reactive protein of 99.90 mg/L (normal range 0–10 mg/L), and CA-reactive protein of 99.90 mg/L (normal range 0–10 mg/L). Additionally, CA-199 was elevated at 47.76 U/mL (normal range 0–37 U/mL), non-small cell lung cancer antigen 21–1 was elevated at 28.16 ng/mL (normal range 0–3 ng/mL), neuron-specific enolase was elevated at 67.66 ng/mL (normal range 0–16.3 ng/mL), prolactin was elevated at 35.62 ng/mL (normal range 2.1–17.7 ng/mL), estradiol was lower than normal at 26.33 pg./mL (normal range 35–245 pg./mL), testosterone was elevated at 179.32 ng/mL (normal range 1.75–7.81 ng/mL), beta-human chorionic gonadotropin (β-hCG) was markedly elevated at 937,268.00 mIU/mL (normal range 0–5 mIU/mL), and EBV antibody IgG was 4.06 (positively expressed).
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.
Figure 1
For staging, the patient underwent further 18F-FDG PET/CT (Figures 2A,B). The 18F-FDG PET/CT scan, performed utilizing Siemens Biograph Truepoint 64 PET/CT machine, was conducted 60 min after the intravenous administration of 18F-FDG (6.1 mCi), revealing multiple soft tissue nodules in both lungs with significantly increased 18F-FDG uptake (SUVmax = 12.7, Figure 2C). The liver exhibited multiple slightly hypodense nodules and masses, characterized by markedly increased 18F-FDG uptake (SUVmax = 38.6). The larger liver mass measured approximately 3.6 cm × 2.1 cm (Figure 2D). In the retroperitoneum, numerous intermingled soft tissue masses with markedly increased 18F-FDG uptake (SUVmax = 13.1) were observed, with the largest dimension measuring about 16.2 cm × 16.3 cm. Additionally, patchy calcifications were evident within this area (Figure 2E). A soft tissue mass of irregular shape was identified in the right pelvis, displaying unevenly increased 18F-FDG uptake (SUVmax = 19.5). The maximum dimensions of this mass were approximately 12.0 cm × 15.2 cm, with areas of cystic necrosis and calcifications noted (Figure 2F). Markedly increased 18F-FDG uptake (SUVmax = 11.8) was detected at the thoracic 11 vertebral attachments (Figure 2G). Notably, no testes were visualized in the bilateral scrotum. The bilateral breast glands exhibited thickening with a slight increase in 18F-FDG uptake (SUVmax = 1.2, Figure 2H).
Figure 2
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.
Figure 3
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 2 weeks later. The patient’s overall survival was a mere 5 months following diagnosis.
Figure 4
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, 68–71). 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.
Histologically, choriocarcinoma is distinguished by a biphasic pattern featuring mononucleated cytotrophoblast cells (including intermediate trophoblast cells) alongside multinucleated syncytiotrophoblasts, with an absence of chorionic villi. The former cells organize lamellarily to form a villous structure, while the latter secrete β-hCG and human placental lactogen (HPL), observable at the tumor progression margin (76–78). Immunohistochemistry plays a crucial role in the differential diagnosis of relevant diseases (79). GATA binding protein 3 (GATA-3), Spalt-like transcription factor 4 (SALL-4), Cytokeratin (CK) AE1/AE3, and 3-beta-hydroxysteroid dehydrogenase type 1 (HSD3B1) have been identified as potential immunohistochemical markers for gestational choriocarcinoma (80, 81). A high Ki-67 proliferation index is noted in over 90% of choriocarcinoma cases (1). Immunohistochemistry holds significance in the differential diagnosis of relevant diseases.
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.
18F-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, 18F-FDG PET/CT provided comprehensive insights into the extent of systemic involvement of the tumor. Another pivotal role of 18F-FDG PET/CT in choriocarcinoma management lies in its ability to monitor treatment response. Radiological assessment using 18F-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 18F-FDG uptake, indicative of robust trophoblastic proliferation and the tumor’s highly aggressive nature (13). However, a subset of cases has demonstrated low 18F-FDG accumulation in metastatic nodules from choriocarcinoma, potentially influenced by hemorrhagic and/or necrotic components affecting 18F-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 prognosis. Factors 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).
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 tumor-infiltrating 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 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.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author contributions
WH: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. ZZ: Conceptualization, Writing – review & editing. ZB: Formal analysis, Supervision, Writing – review & editing. XX: Conceptualization, Data curation, Writing – review & editing. LL: Data curation, Formal analysis, Writing – review & editing. ZS: Conceptualization, Data curation, Writing – review & editing. LK: Data curation, Formal analysis, Funding acquisition, Investigation, Supervision, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Summary
Keywords
male, primary choriocarcinoma, prognosis, computed tomography, 18F-FDG, PET/CT
Citation
Huang W, Zheng Z, Bao Z, Xiao X, Li L, Sun Z and Kang L (2024) A poor prognostic male choriocarcinoma with multiple systemic metastases: a case report and the literature review. Front. Med. 11:1382672. doi: 10.3389/fmed.2024.1382672
Received
06 February 2024
Accepted
08 March 2024
Published
20 March 2024
Volume
11 - 2024
Edited by
Carmelo Caldarella, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
Reviewed by
Mahboubeh Nabavinia, The Research Institute at Nationwide Children’s Hospital, United States
Tanyaluck Thientunyakit, Mahidol University, Thailand
Priscilla Guglielmo, Veneto Institute of Oncology (IRCCS), Italy
Updates
Copyright
© 2024 Huang, Zheng, Bao, Xiao, Li, Sun and Kang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Lei Kang, kanglei@bjmu.edu.cnZhaonan Sun, zhaonan_sun@163.com
†These authors have contributed equally to this work
Disclaimer
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