Primary pulmonary choriocarcinoma in a male that was successfully diagnosed and treated: A case report and review of the literature.

INTRODUCTION: Primary pulmonary choriocarcinoma (PPC) is extremely rare, especially in males. It is characterized by a poor response to therapy and shortened survival times. Here, we report a successful diagnosis and modified treatment for PPC in a male and a review of the literature. CASE
PRESENTATION: This case report describes a 67-year-old male who was discovered to have a left pulmonary mass. The patient underwent a pulmonary lobectomy. Pathological examination showed a poorly biphasic differential tumor. Immunostaining displayed that beta-human chorionic gonadotropin (β-HCG), CD10, and GATA3 were positive, and the increase of postoperative serum β-HCG secretion was also confirmed. Systemic and genital screening was performed, but other abnormal findings were not observed. The diagnosis of PPC was confirmed. Then, the patient received 4 cycles of modified chemotherapy according the condition of his body. The patient has been alive for >13 months without recurrence, and the level of serum β-HCG has already decreased to normal. In addition to reporting this case, we have also summarized the similar previously published cases.
CONCLUSIONS: Currently, there is no standard treatment for PPC. A rapid and correct diagnosis is necessary. Surgery and modified chemotherapy, based on the physical condition of the patient, may currently be the best therapy for PPC.

Introduction

Nongestational choriocarcinoma consisting of cytotrophoblastic and syncytiotrophoblastic cells is an exceedingly rare neoplasm that secretes beta-human chorionic gonadotropin (β-HCG), arises spontaneously, and is primarily located within midline structures such as the retroperitoneum or mediastinum. However, some cases have been reported to emerge in the lung, gastrointestinal tract, brain, and liver. In the literature, only 29 cases of primary choriocarcinoma in lung have been reported in males, including 25 cases of choriocarcinoma,[ 3 cases of choriocarcinoma combined with adenocarcinoma,[ and 1 case of mediastinopulmonary choriocarcinoma,[ which is even rarer and has a very poor prognosis compared to its counterpart in the midline structures according to the literature. Primary pulmonary choriocarcinoma (PPC) in males is easy to misdiagnose or delay the diagnosis; therefore, a potentially curative chemotherapy or surgery may also be delayed. Herein, we reported a 67-year-old male with a large mass in his lung who underwent a surgical resection of the left upper lobe and a section of the left lower lobe. The diagnosis of PPC was confirmed by its morphology and immunotype combined with the postoperative β-HCG level. The patient received a successful and modified treatment plan and is in good condition now. Next, we have described the clinicopathological features, treatment, and prognosis of PPC with a short review of the literature.

Case presentation

A 67-year-old Chinese male was found to have a left pulmonary mass by chest roentgenogram during a routine medical examination. The patient was asymptomatic and was admitted to Peking Union Medical College Hospital (Beijing, China) 15 days later. A high-resolution computer tomography scan of the chest confirmed the presence of a large mass in the left lung adjacent to the pleura that locally compressed the left oblique crack to camber without mediastinal lymphadenopathy (Fig. 1A and B). Pleural thickening and multiple small lymph nodes were detected. The patient was a smoker (1 pack per day) and a drinker (100 g/day) for 40 years and was diagnosed with asthma 15 years ago. Based on the physical examination, he was a typically developed and healthy-appearing man with stable vital signs. The chest was clear of abnormalities during auscultation and percussion. The cardiac and abdominal examination was normal. Physical examination revealed that the testicles were equal in size and without nodules or masses. To determine whether the tumor occurred primarily within the lung, systemic and genital screenings were performed by magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound, and the results displayed no abnormal findings. The results of the routine laboratory examinations were all normal except the tyrosylprotein sulfotransferase (TPS) (>1200 U/L) and Cyfra (21133.86 ng/mL). The preoperative β-HCG levels in the serum and urine were not examined. A cytological diagnosis of non-small cell carcinoma was confirmed by the examination of bronchial brushing cells obtained during bronchoscopy. The cardiopulmonary risk was within acceptable limits for complete resectional therapy. In the absence of distant and regional metastases (stage IIIA, T4 N0 M0), the patient underwent a left whole upper and a partial lower lobectomy.

Figure 1

CT scan of the chest. (A) Soft tissue window: A fairly well demarcated left pulmonary mass is adjacent to the pleura and compressed the left oblique crack to camber. (B) Axial 5-mm-thick reconstructed lung window: A well-defined 8 × 6 cm lobulated inhomogenous mass can be seen in the upper lobe of the left lung.

The macroscopic pathological finding consisted of a large hemorrhagic mass measuring 9 ×7 × 6.5 cm occupying more than one-third of the resected lung with necrosis and a hemorrhage that was adjacent to the lung membrane (Fig. 2A). The specimen was fixed in 10% neutral buffered formalin, routinely processed, and embedded in paraffin. Hematoxylin and eosin-stained sections were examined using optical microscopy and independently reviewed by 2 experienced pathologists. The microscopic examination showed that the majority of the neoplasm was composed of necrotic and hemorrhagic areas. The tumor cells were poorly differentiated and had a characteristic biphasic pattern with polygonal cytotrophoblastic cells growing in a nest-like fashion that were separated or capped by multinucleated giant syncytiotrophoblastic cells (Fig. 2B–D). The tumor was close to the lung membranes and had invaded through the bronchial tubes, but did not exhibit lymph node involvement; the surgical resection margins were clear. Formalin-fixed and deparaffinized sections were examined using immunohistochemistry. A panel of markers in the tumor was detected by an indirect immunoperoxidase method using antibodies against the following markers: ALK-D5F3, CK20, CK7, Napsin A, P40, P63, TTF-1, Ki-67, CD146, HLA-G, β-HCG, HPL, CD10, CAM5.2, and GATA3. The results of the immunohistochemical analysis with the listed antibodies are provided in Table 1. The tumor cells exhibited positivity for HLA-G, CD10 (Fig. 3A), CK7, CAM5.2, and GATA3 (Fig. 3B) and weakly focal positivity for HPL and P63 (Fig. 3C). Staining for β-HCG (Fig. 3D) was strongly positive within the syncytiotrophoblastic cells and weakly positive in the cytotrophoblastic cells. Staining for ALK-D5F3, CD146, CK20, P40, TTF-1 (Fig. 3E), and Napsin A was negative. The Ki-67 labeling index (Fig. 3F) was 75%. Based on these findings, the diagnosis of choriocarcinoma was confirmed.

Figure 2

Macroscopic and histologic features of the tumor. (A) Gross specimen compressing the adjacent lung tissue. (B) At low magnification, the tumor cells grow in clusters with a large area of hemorrhage and necrosis (hematoxylin and eosin; original magnification, ×12.5). (C) The cytotrophoblastic cells grow in clusters separated and capped by giant syncytiotrophoblastic cells, thereby forming the characteristic biphasic pattern surrounded by a hemorrhagic area (hematoxylin and eosin; original magnification, ×100). (D) Higher magnification emphasizes the peripheral palisading by bizarre syncytiotrophoblasts (hematoxylin and eosin; original magnification, ×200).

Table 1

Clones, dilutions, sources and results of antibodies used in the immunohistochemical panel.

Figure 3

Immunohistochemical findings of PPC. (A) The PPC cells are positive for CD10. (B) The PPC cells are positive for GATA3. (C) The tumor cells are weakly focal positive for P63. (D) Syncytiotrophoblastic giant cells and a few cytotrophoblastic cells are positive for β-HCG. (E) The tumor cells are negative for TTF-1. (F) The Ki-67 labeling index is 75% in the tumor cells (immunohistochemical staining; original magnification, ×100). β-HCG = Beta-human chorionic gonadotropin, PPC = primary pulmonary choriocarcinoma, TTF-1 = thyroid transcription factor-1.

After the operation, the serum and urine β-HCG levels were measured for the first time. The serum β-HCG level was 38.41 IU/L (normal, 0–5 IU/L), and the β-HCG level of the urine test was suspiciously positive. The patient then received standard combination chemotherapy (PEB scheme) that consisted of cisplatin (25 mg/m2, intravenous [IV)] drip d1–5), etoposide (120 mg/m2, IV drip d1–5), and bleomycin (30 mg/m2, intramuscular injection d1, d8, d15), but the patient developed a pulmonary ventilation disorder with diffusive dysfunction. Then, vincristine (2 mg/m2, d3) and elemene (600 mg/m2, d1–7) were administered instead of bleomycin. After the first course of chemotherapy, the levels of TPS decreased to 50.55 U/L, Cyfra decreased to 2112.48 ng/mL, and β-HCG markedly decreased to 2.00 IU/L, which was within the normal range, and the patient was found to have bone marrow suppression (grade 3) as well. Fortunately, the suppression relieved after the patient received recombinant human granulocyte colony-stimulating F (300 μg, qd, 3 d) therapy. The dosage was amended to accommodate patient's status during the second course of chemotherapy, which consisted of cisplatin (25 mg/m2, IV drip d1–5), etoposide (110 mg/m2, IV drip d1–5), vincristine (2 mg/m2, IV drip d1) and elemene (600 mg/m2, IV drip d1–7). Unfortunately, the patient was found to be in bone marrow suppression again. The dosage was further amended during the third course of chemotherapy, which consisted of cisplatin (25 mg/m2, IV drip d1–5), etoposide (100 mg/m2, IV drip d1–5), vincristine (2 mg/m2, IV drip d1), and elemene (600 mg/m2, IV drip d1–6). The patient was in good condition during this course of chemotherapy. During the fourth course of chemotherapy, the dosage remained the same as the third course. Dynamic CT evaluation was performed, and no abnormal findings were observed during the 4 cycles of chemotherapy. After the fourth course of chemotherapy, the β-HCG decreased to 0.91 IU/L. At present, the patient has survived >13 months of follow-up without any symptoms.

Discussion

In our case, the patient presented as an older male without any complaints or disease history. Additionally, the preoperative β-HCG level was absent, and the tumor cells were poorly differentiated. The diagnosis of PPC was based on the histological features combined with immunohistochemical detection. A differential diagnosis is required to exclude other β-HCG-positive tumors, such as human chorionic gonadotropin-producing giant cell carcinoma (HCG-producing GCC), epithelioid trophoblastic tumor (ETT), and metastatic choriocarcinoma. HCG-producing GCC is even rare. According to previous reports, the giant cells of HCG-producing GCC may simulate syncytiotrophoblasts, but they lack the overall greater cytological pleomorphism morphologically. Additionally, the multinucleated giant cells are smaller than those in PPC, and lower levels of β-HCG are detected immunohistochemically. Most importantly, thyroid transcription factor-1 (TTF-1), which is an immunohistochemical marker of pulmonary epithelial origin,[ is not expressed in the trophoblast cells of PCC but is strongly positive within the giant cells of HCG-producing GCC.[ ETT is composed of mononucleated epithelioid cells arranged in cohesive sheets and has a hyaline extracellular matrix background. ETT was immunoreactive for AE1/AE3, p63, HLA-G, and HPL, whereas β-HCG and CD146 were typically negative.[ The Ki-67 labeling index of ETT is 7% to 20%. In contrast, PPC includes both cytotrophoblastic-like cells and multinucleated syncytiotrophoblasts. The multinucleated syncytiotrophoblasts of PPC reveal strong immunoreactivity to β-HCG, and the cytotrophoblastic-like cells of PPC exhibit weakly focal positivity to p63, whereas both multinucleated syncytiotrophoblasts and cytotrophoblastic-like cells are negative for CD146. The Ki-67 labeling index in PPC is much higher than ETT. The differentiating points are given in Table 2. The patient in our study lacked evidence of a primary genital tumor and had a thorough check-up by MRT, CT, and ultrasound. No tumors were found in other parts of the body. Therefore, the detailed and rigorous clinicopathological analysis made metastatic choriocarcinoma unlikely.

Table 3

List of all published cases of primary pulmonary choriocarcinoma in males.

Extragonadal primary choriocarcinoma in males is extremely rare and aggressive with a much poorer prognosis than other histological subtypes most likely related to the hematogenous dissemination. Most cases derive from midline structures such as the mediastinum, retroperitoneum[ and pineal body corresponding with the theory of the mismigration of primordial germ cells along the urogenital ridge during embryogenesis. However, cases involving other organs have also been reported, such as the lung, brain, stomach, intestine, kidney, and adrenal gland.[ PPC in males is even more rare, as only 29 cases have been reported.

Our study includes a literature review of PPC in males. The tumorigenesis of PPC remains unclear, although a few theories have been discussed. Some researchers hypothesized that PPC originated from the neoplastic transformation of misplaced primordial germ cells or was generated from an occult primary gonadal neoplasm undergoing spontaneous regression. Other scholars have suggested that the neoplasm could have arisen from metaplasia or the differentiation of somatic tumor cells similar to primary lung cancer. Additionally, Toda et al[ proposed that epidermal growth factor might play an important role in an autocrine manner in tumor cells of PPC.

All PPC cases published from 1953 to 2016 involving males were collected, and all results were examined for applicability. Only 29 cases were found within 26 independently published reports. These cases are included in Table 3.[ We only found 19 unequivocal cases with clinical data in 18 published reports. We could not acquire details from the other 10 reports because these reports were either not accessible or not in the English language. The patients with clinical data in the publications were aged from 4 months to 77 years.[ The age of PPC patients showed a higher prevalence rate in the second and third decades of life. The median age of patients was 58.5 years. Most patients saw their doctors with symptoms, such as pleuritic pain, hemoptysis, dyspnea, cough, or precocious puberty, whereas 3 cases (including the present case) were asymptomatic, and the tumor was discovered by chest roentgenogram. Eight cases were diagnosed by autopsy, and only 1 patient was diagnosed by a urine pregnancy test and bronchoscopic biopsy. One patient was diagnosed by a CT-guided biopsy before the operation. The diagnosis is usually delayed until the patient is in the middle-late stage of the disease. Distant metastases are observed in many cases[ at the time of diagnosis, and the overall prognosis is extremely poor. A total of 18 patients have data about their treatment: 6 patients were treated with surgery and chemotherapy; 4 were treated with chemotherapy alone; 2 were treated with surgery, chemotherapy, and radiotherapy; 1 was treated with surgery and radiotherapy; 2 were treated with surgery alone; and 3 patients did not receive treatment and died quickly. Only 5 patients (including our case) survived for >1 year.

Table 2

Differential diagnosis.

The treatment strategies performed for the patients included complete resection, chemotherapy, radiotherapy, supportive care, or a combination of the above treatments in the published cases.[ There is no evidence-based treatment recommendation at present, making the planning of further therapy difficult. According to the literature, a complete resection followed by adjuvant chemotherapy with 2 or 3 cycles of PEB protocol and close follow-up examinations tended to yield the best survival chance for the patients. Nevertheless, the patients with PPC had a higher metastatic rate and a poorer survival rate. Some reports found that females with PPC were a lot younger than males and had longer survival periods than their male counterparts,[ but the reason for this is unknown. In the present case, the tumor was discovered before the onset of symptoms. A complete resection was performed in a timely manner. After a definite diagnosis of PPC was made, 4 cycles of modified chemotherapy were carried out for the patient based on the systemic status of the patient. The present results support a good response to the chemotherapy. So far, the serum β-HCG level of the patient has remained within the normal range, and no metastatic complications have been discovered. We will continue follow-up with the patient.

Conclusion

The case highlights a rare disease that was successfully diagnosed before the onset of symptoms, and the patient received modified chemotherapy according to the systemic status of the patient following chemotherapeutics after surgery. The key step for the diagnosis of PPC is based on the histological features combined with immunohistochemical detection, β-HCG levels of the patient, and the differential diagnoses. Although the prognosis is poor, such patients would benefit tremendously from early diagnosis and modified therapy. It is necessary to explore novel treatments for patients with PPC, and more reports of similar cases are warranted to establish optimal management.

Acknowledgements

We thank the medical technologists of Department of Pathology, Peking Union Medical College Hospital for vigorous technical assistance.