Primary retroperitoneal choriocarcinoma with lung and liver metastasis in a male patient: case report

Introduction

Choriocarcinoma is a highly malignant trophoblastic tumor that may be gestational or non-gestational in origin [1, 2]. Diagnosis is challenging and serious damage to local tissue may result from delay, followed by metastasis from the blood to multiple organs causing death [3, 4]. Choriocarcinoma is extremely rare in male patients, in whom it usually occurs in the central nervous system, mediastinum, retroperitoneum, lung or liver [5], [6], [7]. There are no typical clinical symptoms but elevated serum β-hCG is a significant indicator [8, 9]. In our reported case, the current patient was a young man diagnosed with primary retroperitoneal choriocarcinoma with multiple lung metastases. He presented with intense abdominal pain due to the large retroperitoneal tumor and the metastatic tumor of liver which were incompletely removed during palliative surgery. However, the tumor remains well-controlled after systemic chemotherapy.

Case report

A 27-year-old male presented to the general surgery department of our hospital with abdominal pain that had gradually worsened over two weeks. He had unremarkable medical, personal and family histories. The abdomen was found to be slightly distended during examination, abdominal muscles were soft on palpation with mild tenderness but there was no rebound pain or mobility dullness.

Chest and abdominal Computed Tomography (CT) and Positron Emission Tomography/Computed Tomography (PET/CT) scans showed obvious masses in the lungs, liver and retroperitoneum. Morphological examination indicated that the primary retroperitoneal tumor was more likely to come from the reproductive system with metastases in lung and liver. Abdominal CT showed that the retroperitoneal tumor was lobulated with a maximum cross-sectional diameter of 7.2×6.0 cm. The tumor tissue had uneven density with enhanced tumor margins, blurred peripheral adipose space and multiple enlarged lymph nodes (Figure 1A). A circular mass with a maximum diameter of 5.4×4.6 cm and unclear boundaries was observed in the left liver. Nodular enhancement of the lesion edge was seen during the arterial phase of enhanced scanning (Figure 1B). Multiple nodules of an approximate maximum diameter of 2 cm could be seen in both lungs. However, the hilum and mediastinum appeared normal and no enlarged lymph nodes could be found (Figure 1C and D).

Figure 1:

Imaging of the soft tissues of malignant tumor. (A) Abdominal CT showed a lobulated soft tissue mass in the posterior peritoneum with uneven density on plain scan and enhanced edge; (B) abdominal CT showed a round mass in the left lobe of the liver with unclear borders which the nodular enhancement at the edges; (C and D) chest CT scan showed multiple bilateral pulmonary nodules at the soft-tissue window (C) and the lung window (D).

Further, ¹⁸F-FDG PET/CT showed that the retroperitoneal hypermetabolic mass was accompanied by multiple locally enlarged lymph nodes. The maximum cross-sectional diameter of the tumor was about 7.3×6.0 cm and SUVmax was about 17.4, suggesting a primary retroperitoneal tumor (Figure 2A). The mass in the left lobe of the liver showed marginal hypermetabolism and had a cross-sectional diameter of 5.9×4.8 cm and a SUVmax of 5.2 (Figure 2B). Many diffuse hypermetabolic nodules, ranging from 0.2 to 3.0 cm in diameter with a SUVmax of 2.2 were identified in both lungs (Figure 2C and D). Lung and liver tumors were considered to be metastatic malignancies. Serum human chorionic gonadotropin (β-hCG) was found to be significantly increased to 383,641 mIU/mL. Pathological investigations were initiated.

Figure 2:

Images of the ¹⁸F-FDG PET/CT. (A) Abdominal PET/CT showed a retroperitoneal mass with hypermetabolic; (B) PET/CT showed a borderline hypermetabolic mass in the left lobe of the liver; (C and D) PET/CT showed numerous diffuse hypermetabolic nodules in both lungs.

Palliative surgery was performed to reduce the burden of the large abdominal tumor that was responsible for the abdominal pain. Resection of the left outer lobe of the liver, radiofrequency ablation of the retroperitoneal tumor and ligation of the inferior vena cava were performed during a series of operations under general anesthesia. Due to the severe adhesion of the abdominal tumor, complete resection was not possible but only a partial resection was performed. The patient recovered well after surgery. Pathological analysis of post-operative specimens showed cancer cells in the tumor tissue, consistent with choriocarcinoma. The 9.5×7.3×5.3 cm tumor was accompanied by hemorrhagic necrosis, showing vascular invasion but no definite nerve invasion and no (0/8) lymph node metastasis was found (Figure 3A and B). And, chorionic cancer cells were also found in retroperitoneal tumor tissue (Figure 3C and D). Immuno-histochemical analysis of tumor markers suggested hCG (+), CK7 (+), GPC-3 (partial +), inhibin-α (+), SALL4 (partial +), GS (partial +), CK8/18 (+), hepatocyte (focus +), Ki-67 (75 %+), HSP70 (−), Arg-1 (−), CD34 (−), EMA (−), AFP (−), CD117 (−), CD30 (−) and PLAP (−) (Figure 3E–M).

Figure 3:

A gross specimen removed surgically and the pathology. (A) A gross specimen of the liver tumor, the size was 9.5×7.3×5.3 cm, which there was extensive bleeding in the tumor; (B) H&E staining of the liver tumor tissue; (C) tissue specimen of a partial retroperitoneal tumor; (D) H&E staining of the retroperitoneal tumor tissue; (E–M) immunohistochemical staining of relevant markers in the tumor tissue, including hCG (C), CK7 (F), GPC-3 (G), inhibin-α (H), SALL4 (I), GS (J), CK8/18 (K), hepatocyte (L), Ki-67 (M).

Six cycles of penpulimab combined with VIP regimen (penpulimab 200 mg d1+isocyclophosphamide 1.2 g/m² d1-4+etoposide 75 mg/m² d1-4+cisplatin 20 mg/m² d1-4) at 3 weeks intervals were completed between November 2022 and April 2023 after the patient had recovered from surgery. Imaging after three cycles of systemic chemotherapy suggested a partial response (PR) (Figure 4). Lung metastases decreased in number and size (Figure 4A, B, D and E). and the retroperitoneal tumor decreased from 8.6×6 cm to 6.5×6.1 cm (Figure 4C and F). A health check after six cycles of chemotherapy indicated continued shrinkage of the metastatic tumor and that the retroperitoneal tumor had shrunk to 4.8×4.4 cm (Figure 4G–I). Serum β-hCG showed a temporary decrease after surgery but increased again quickly, and dropped to normal levels after six cycles of chemotherapy (Figure 4J). The patient continued with three cycles of treatment after β-hCG had returned to normal levels, in accordance with guidelines. At the time of writing, the patient continues to be treated with pembrolizumab monotherapy and the tumor appears well-controlled.

Figure 4:

The changes in the size of multiple tumors and in β-hCG before and after treatment. (A–C) The size of multiple lung tumors (A–B) and abdominal soft tissue tumors (C) before the chemotherapy; (D–F) the size of multiple lung tumors (D–E) and abdominal soft tissue tumors (F) after three cycles of chemotherapy; (G–I) the size of multiple lung tumors (G–H) and abdominal soft tissue tumors (I) after six cycles of chemotherapy; (J) the β-hCG expression levels of this patient before and during the treatment of choriocarcinoma.

Discussion

Primary choriocarcinoma is a low-incidence malignancy that is highly angio-invasive and aggressive with a poor prognosis and occurs extremely rarely in males. Gestational choriocarcinoma is primarily associated with pregnancy during which it may occur at any point. It is extremely rare for non-gestational choriocarcinoma to develop as a component of germ cell tumors or to be associated with poorly differentiated somatic cancers. Most non-gestational primary choriocarcinoma originate from the midline structures such as mediastinum or retroperitoneum [10], which is consistent with the theory that primordial germ cells migrate along the genitourinary ridge during the embryogenesis. Three potential hypotheses for the pathogenesis of male choriocarcinoma have been proposed [11]. First, abnormal migration of primordial germ cells was retained during embryogenesis. Second, metastasis of spontaneously regressing testicular choriocarcinoma. And third, an initial non-trophoblastic tumor transforms into choriocarcinoma.

The atypical clinical symptoms make early diagnosis of primary retroperitoneal choriocarcinoma challenging and it is easily misdiagnosed as another type of cancer, allowing metastasis to multiple organs, such as the lungs or liver, by the time of first diagnosis [12]. However, the β-hCG positive expression is one of the keys to diagnosis [13], so differential diagnosis is required to exclude other β-hCG positive tumors, such as hCG-producing giant cell carcinoma (GCC), epithelioid trophoblastoma (ETT). It has been reported that compared with primary choriocarcinoma, GCC is smaller and lacks greater cytological pleomorphism in morphology, and the elevation of β-hCG is lower levels. More importantly, the immunohistochemical marker of thyroid transcription factor-1 (TTF-1) was not expressed in primary chorionic cancer cells, but was strongly positive in GCC that produces β-hCG [14]. In ETT, the immunohistochemistry of markers AE1/AE3, p63, HLA-G, or HPL are positive, but β-HCG and CD146 are often negative or lower expression, and the proliferation-associated Ki-67 is expressed positively in 7–20 %. In contrast, the immune response of β-hCG was strongly positive in primary chorionic cancer cells, and the Ki-67 labeling index was much higher than that of ETT [15].

The non-gestational choriocarcinoma that occurs in males is a high-risk disease with poor prognosis and high mortality and limited treatment measures [16, 17]. Review of past cases, the treatment strategies performed surgery, chemotherapy, radiation therapy, and symptomatic supportive care [18, 19]. Studies have shown that adjuvant chemotherapy with two or three cycles after surgery or β-hCG is at normal levels often yields the best survival chance for the patients. However, advanced male primary choriocarcinoma is insensitive to chemotherapy with a median overall survival of only about half a year [20]. Currently, there is no standard treatment for male patients with primary choriocarcinoma. Immunotherapy has been shown to play a key therapeutic role in recent years, and immune checkpoint inhibitors (ICIs) have also been used to treat choriocarcinoma [21, 22]. Interestingly, the therapeutic efficacy of PD-1/PD-L1 inhibitors is thought to depend on clinicopathological characteristics, such as PD-L1 overexpression or the presence of tumor-infiltrating lymphocytes. Studies have shown that the expression of PD-L1 in choriocarcinoma is significantly higher than in other germ cell tumors, which is associated with poor prognosis [23]. Clinical studies also have found that chemotherapy can enhance anti-tumor immune responses by upregulating tumor antigens [24], suggesting that Immune Checkpoint Inhibitors (ICI) combined with chemotherapy may be a potential strategy for the treatment of choriocarcarcinoma.

In this case report, the patient was forced to undergo palliative surgery due to acute abdominal pain and post-surgical systemic chemotherapy combined with immunotherapy was given. The size of the tumor was significantly reduced after 3–6 treatment cycles, achieving more than partial response (PR) and β-hCG values declined to the normal range. Mild to moderate gastrointestinal reactions and grade II myelosuppression occurred but returned to normal after symptomatic treatment. It has been one year since the diagnosis of choriocarcinoma, and the patient continues to receive maintenance therapy. We will continue to follow up the patient regularly and hope that he can have a good prognosis. In summary, the anti-tumor treatment described in the current case report was very effective for primary choriocarcinoma and Penpulimab maintenance therapy continues to control the tumor. The current report may inform clinical treatment of male primary choriocarcinoma in the future.