Clinical Features and Treatment Outcomes in Patients with Extracranial Germ Cell Tumors: A Tertiary Centre Experience

Background: Germ cell tumors are histologically heterogeneous group of tumors with high cure rate if diagnosed early. The aim of study was to evaluate the extracranial germ cell tumors presenting to our institute with regards to gender, age, clinical presentation, pathology, management, acute toxicity and


Introduction
Germ cell tumors (GCT) are a heterogeneous group of tumors, which are curable. They arise from primordial germ cells that migrate during embryogenesis from yolk sac to the gonads. They are broadly classified into gonadal and extragonadal based on anatomy. Again, it can be classified into the following groups depending on pathology. i.
Malignant germ cell tumor iii.
Mixed GCT: a separate entity, which houses two different types Teratoma can be divided into mature teratoma and immature teratoma. Malignant GCT is classified as seminomatous (ST) and nonseminomatous (NST) in males, dysgerminoma, and nondysgerminomas in females that include yolk sac tumors, embryonal carcinoma, gonadoblastoma and choriocarcinoma.
Various registries throughout the world have different reported incidences of testicular GCT varying from 1.7 per 100,000 to 2.7 per 100,000 amongst males, from 15-39 years of age. The incidence is increasing according to many reports worldwide [1]. European Cancer Registry-Based Study on Survival and Care of Cancer Patients (EUROCARE) reports markedly distinct age-adjusted incidence rates of GCTs in Europe for males and females 64 per 1,000,000 versus 4 per 1,000,000, respectively. There is lack of Indian data. In general, 80% of GCT are benign, 20% are malignant. In the pediatric age group, 2.5% of malignant germ cell tumors are found [2]. Germ cell tumors usually occur in the second or third decade of life. Fertility sparing surgery is offered to all patients. Chemotherapy with platinum-based combinations has extended 5-year survival rates from 100 % in stage I to approximately 75% in higher stages. Despite good clinical outcome, in developing countries such as ours there are many challenges we come across while treating patients especially since they present with advanced stage, heavy nodal burden and poor risk factors. In this study, we report our experience of extracranial germ cell tumors at a tertiary referral center, focussing on demography, histopathology, management, outcome and prognosis.

Aim
Aim of study was to evaluate the extracranial germ cell tumors presenting at our institute with regards to gender, age, clinical presentation, pathology, management, acute toxicity and survival.
A written informed consent was obtained prior to chemotherapy and surgery. Surgical procedures were evaluated. It was either biopsy initially to unilateral oophorectomy (fertility sparing surgery) or total abdominal hysterectomy and bilateral salpingo-oophorectomy in females. In males, biopsy for upfront inoperable disease or high inguinal unilateral orchidectomy was the procedure performed. The tissues were evaluated primarily with hematoxylin and eosin stain; however, IHC was evaluated wherever needed. Patients were treated with the standard chemotherapy protocols. Patients warranting chemotherapy were put on BEP regimen (Bleomycin 30 units day 1, day 8, day 15, Etoposide 100 mg/m 2 and Cisplatin 20 mg/m 2 on day 1 to 5 every three weeks). Chemotherapy regimen was changed to EP (Etoposide 100 mg/m 2 and Cisplatin 20 mg/m 2 on days 1 to 5 every three weeks) after 4 cycles of BEP in patients who had indications for more than four cycles of chemotherapy. Bleomycin was omitted in patients with abnormal pulmonary function test. Chemotherapy was administered for 4-6 cycles in majority of the patients. Patients were reviewed for toxicities before every cycle of chemotherapy. Toxicity was evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 5.0) [5]. Response evaluation was done in all patients after three chemotherapy cycles and after completion of all defined cycles as per stage with tumor markers (AFP, βHCG and LDH), ultrasonography or CECT of the abdomen and pelvis.

II Follow Up
All patients were advised three monthly follow up during the first 2 years followed by six monthly thereafter. Physical examination, marker evaluation as well as chest radiograph and CT scan of abdomen and pelvis were performed.

III Evaluation
Complete remission was taken as normalisation of tumor markers and resolution of tumor mass on CT scan. Progressive disease were defined as rising markers post treatment normalisation, new lesion on radiological examination, and pathologically proven new lesion.

IV Statistical Analysis
The Statistical Package for the Social Sciences (IBM SPSS version 25 for Windows) was used for statistical analysis. The descriptive statistics were used to characterize the patient population. Chi-square test and Kaplan Meier survival curves were plotted for disease-free survival (DFS) and overall survival (OS). Cox regression model was used for univariate analysis and multivariate analysis of prognostic factors. The prognostic factors having statistically significant p-value in univariate analysis were included in multivariate analysis. A p-value of < 0.05 considered statistically significant in all performed analysis. Diseasefree survival was defined as time from diagnosis until recurrence (local or systemic) whereas overall survival was defined as time from diagnosis to death or last follow-up.
15.8% (6) of males and 19% (7) of females were considered for neoadjuvant chemotherapy (NACT) followed by surgical intervention. At presentation 81.5% (31) of male patients underwent high inguinal orchidectomy, debulking surgery in 2.6% (one patient with sacrococcygeal mass), whereas biopsy was performed in 15.8% (6). Surgical intervention in females included biopsy in 10.8% (4), cytoreductive surgery in 8.1% (3), fertility sparing surgery in 64.8% (24), total abdominal hysterectomy and bilateral salpingo-oophorectomy in 16.2% (6) patients. Postoperative staging revealed that 13.2%, 36.8%, and 50% were in stage I, stage II, and stage III respectively in males. In females 35.1%, 21.6%, 29.7%, and 13.5% were stage I, stage II, stage III, and stage IV respectively. Postoperatively 94.7% of male patients had chemotherapy whereas 94.6% of female patients had adjuvant chemotherapy. Pre-chemotherapy pulmonary function test (PFT) was done in 65.8%, not done in 10.5% while the status not known in 23.7% of male patients. In females 62.2% of patients underwent PFT, 18.9% did not undergo PFT while the status is not known of 18.9% of patients.
The median numbers of chemotherapy cycles were 4 (range 1-6) in both male and females. In all patients who received more than 4 cycles of chemotherapy, their chemotherapy regimen was changed to EP after four cycles of BEP. Post-chemotherapy toxicity analysis in males revealed that 42.1% developed mild grade I complications. Grade III toxicities including diarrhoea, mucositis, neutropenia, anaemia and febrile neutropenia was seen in 18.4%, 7.9%, 7.9%, 10.5% and 13.2% respectively.

III Analysis of Prognostic Factors
Univariate analysis using Cox-regression showed that histopathological subtypes, metastatic status at diagnosis, risk group, upfront surgery, stage were affecting the DFS and OS (p < 0.05) in addition to that OS is also influenced by ECOG PS at diagnosis (p = 0.044). Multivariate analysis showed that the histological subtypes (p = 0.001) and risk groups (p = 0.029) are the independent prognostic factors for DFS, while metastatic status at presentation (p = 0.037), upfront surgical intervention (p = 0.039), and histopathological subtypes (p = 0.009) were the independent prognostic factor for OS details depicted in (Table 3).

Discussion
GCTs are uncommon tumor. The incidence of GCT is increasing. There is a lack of recent data from India on epidemiology of GCT. The male and female distribution was equal in our study. In this study, the median age at diagnosis was 31 years and 15 years in males and females. The findings from other Indian study by Joshi A et al. reported that the median age for seminomatous and nonseminomatous GCT were 28 years and 39 years respectively in males [6]. Mustafa SA et al. in their study reported that the median age was 37 years for males [7]. Lakshman M et al. in their study reported the median age of female GCT as 22 years [8].
In our study, we noted that the most commonly affected age group were 31-40 years in males and 11-20 years in females. This distribution was similar to study by SS Chavan et al. [9]. However, some studies reported the bimodal distribution of age [10]. Testicular mass and abdominal pain was the most common presenting symptoms in males and females respectively in our study. 47.3% and 16.7% were metastatic disease at presentation for males and females respectively. The most common metastatic site was lungs; other studies also reported findings to consistent with our study [6,8].
Western literature reported the similar epidemiological findings to that of our study especially considering male patients with median age at diagnosis of 28 years, 56% of the male GCT patients were in metastatic stage [11]. In our study male patient were in good, intermediate, and poor risk as 44.7%, 34.2%, and 21.1% respectively and female patients on risk group stratification were in 48.6%, 35.1%, and 16.2% respectively. Vasconcellos et al reported similar risk group distribution of patients for male GCT. The most common histological subtype was seminoma in males and dysgerminoma in females similar to other studies [6,7,10]. In this study seminoma and dysgerminoma was associated with raised AFP and LDH, nonseminoma and non-dysgerminoma was associated with raised AFP, βHCG, and LDH, which was consistent with other aforementioned studies. The median number of chemotherapy cycles were 6 in both male and female patients. The median size of the tumor was 6 cm in males and 9 cm in females, which were consistent with other studies [6,9]. The incidence of febrile neutropenia was less in this study, compared to study by Joshi et al. This may be due to prophylactic use of GCSF in our study. The median delay due to chemotherapy toxicities between the cycles were 11 days in males and 8 days in females. In this study, the recurrence was 32% during the median follow-up of 34 months. Other studies reported recurrence rate from 12-30% [8,11,12].
We observed in this study that the median DFS and OS were 57 and 71 months respectively. Five years DFS and OS were 42.8% and 67% respectively. This survival data was not in concordance with the other studies probably because most of our patients were in advanced stage, poor risk groups, and of unfavourable histology. If alone the 5-year survival was seen for all stages excluding stage IV, the survival was good and comparable to other studies indicating the effectiveness of platinum based systemic chemotherapy that was given to all patients. This study highlights that most of the patients presenting to a tertiary care center are in advanced stage with high nodal burden disease. All this ultimately leads to the suboptimal response and suboptimal survival in patients of GCT. However, those who presented in early stage, with favourable histology and underwent multidisciplinary cancer care enjoyed a good long survival.

Conclusion
GCTs are most frequently diagnosed in adolescence and young patients. If diagnosed earlier, a well-orchestrated multidisciplinary management approach improves the outcome and survival. In developing countries most of the cases of GCT presents at advanced stage with high nodal burden. It must be emphasised that the GCT is primarily a disease of young and adolescents, therefore these groups of patients should undergo proper investigations and referral, if any suspicion of malignancy is encountered.

Ethical Approval
The Institutional Research Committee (IRC) at the All India Institute of Medical Sciences, Patna has approved the study (Ref No. AIIMS/Pat/IRC/2020/591, dated 3/11/2020).