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Germ Cell Tumors

In the developing embryo germ cells migrate to the ovaries or testicles and form the ova (egg cells) or sperm cells. Germ cell tumors occur where these cells start to grow in abnormal or uncontrolled way. These tumors typically produce high levels of alphafetoprotein (AFP), which helps with diagnosis. Germ cell tumors are most common in children and young adults. There are different sub-types: which can be devided into seminoma (in young men, or refered to as germinoma in females), or non-seminomas, which include (embryonal carcinoma, immature teratoma, endodermal sinus tumor (sometimes called 'yolk sac tumors'), choriocarcinoma, and 'mixed germ cell tumors').

Most germ cell tumours occur in the testicals (male gonads) or in the ovaries (female gonads). However, they can also develop in other parts of the body such as the sacrococcygeal region, brain, abdomen and other sites - this may occur when some of the germ cells in the embryo did not migrate properly. These are referred to as Extragonadal Germ Cell Tumors - meaning that they started outside of the gonads and there is no evidence of cancer in the testes/ovaries.

The remaider of this page focuses on Extragonadal germ cell tumors (EGCT) in adults. See separate pages on testicular cancer, ovarian cancer and childhood germ cell tumors (which tend to be quite different to those in adults). For information on germ cell tumours of the brain see also the section on brain tumors.

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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications (Extragonadal Germ Cell Tumors)
Childhood Germ Cell Tumors
Testicular Cancer (in adults)
Ovarian Cancer (in adults)
Brain Tumors

Information Patients and the Public (3 links)

Information for Health Professionals / Researchers (5 links)

Latest Research Publications (Extragonadal Germ Cell Tumors)

Sun H, Ding H, Wang J, et al.
The differences between gonadal and extra-gonadal malignant teratomas in both genders and the effects of chemotherapy.
BMC Cancer. 2019; 19(1):408 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A tumor comprising of different types of tissues (such as hair, muscle, bone, etc.) is known as a teratoma. It is a type of germ cell (cells that make sperm or eggs) tumor. When these germ cells have rapid cancerous growth, then such a teratoma is called a malignant teratoma. We have studied the differences between gonadal and extra-gonadal malignant teratomas and the effects of chemotherapy in both genders.
METHODS: The samples of 3799 male and 1832 female patients with malignant teratoma samples, between the ages of 1 and 85+ years, were selected from the years 1973 to 2014. Trends in incidence, estimated prevalence, incidence rates, and frequency were calculated in gonadal and extra-gonadal tumors with age adjustment. The five-year observed, expected, and relative survival rates were analyzed to study the prognosis.
RESULTS: The gonadal took over a majority percentage of malignant teratomas compared with the extra-gonadal (90% vs. 10% in male; 83% vs. 17% in female). For the male, the total of the gonadal and the extra-gonadal were all significantly decreased from 1973 to 2014 (p < 0.05). For the female, there were no significant trends. As for prevalence, incidence, and frequency, there were two separate peaks of malignant teratomas. One peak was at under 1 year old, which was composed of the extra-gonadal tumor; the other peak was at 20-24 for male and 10-34 for female, which was composed of the gonadal tumor. This separation of the gonadal and extra-gonadal showed a significant difference (p < 0.05). As for the prognosis, the extra-gonadal tumor showed significantly lower survival rates than the gonadal (p < 0.05). In the short term, the survival rate of the chemotherapy group was higher than the supportive care group. However, in the long term, the survival rate of the chemotherapy group was lower than the supportive care group.
CONCLUSION: The gonadal and extra-gonadal malignant teratomas show lots of differences. Chemotherapy might not help improve survival rates.

Li R, Li H
Poor prognosis of retroperitoneal mixed extragonadal germ cell tumors in an HIV-infected man with severe immunosuppression and bilateral cryptorchidism: a case report.
BMC Cancer. 2019; 19(1):244 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Nonseminomatous germ cell tumors (NSGCTs) represent one of the main groups of germ cell tumors (GCTs), and they have a more invasive course than seminomatous GCTs. Human immunodeficiency virus (HIV) positivity is considered to be a risk factor for testicular seminoma patients, but reports about HIV-infected individuals with NSGCTs are rare.
CASE PRESENTATION: We report a case of a retroperitoneal mixed extragonadal germ cell tumor in an HIV-infected man who has been diagnosed with bilateral cryptorchidism since birth. A 30-year-old man presented with a large heterogeneously mixed echo mass located in the right lower abdomen according to an abdominal ultrasound; he was HIV-positive and had a low CD4 count of 70 cells/ml in the followed test, which suggested severe immunosuppression, and ultrasound-guided biopsy histology revealed a malignant yolk sac tumor of the testis. First, the patient received combination antiretroviral therapy; then, to relieve his symptoms, an exploratory laparotomy and retroperitoneal neoplasm resection under general anesthesia were performed for subsequent treatment. The postoperative histopathological examination indicated that the patient exhibited malignant mixed GCTs of the undescended testis that were composed predominantly of yolk sac tumors with foci of embryonal cell carcinoma and seminoma; It is a rare type in various GCTs, especially in HIV-infected patients. After the operation, the patient underwent computed tomography follow-up scans at 1 week and 2 weeks, and the results showed that the size of the right inguinal mass gradually increased, which suggested a poor outcome. To limit the growth of the tumors, right inguinal mass resection under local anesthesia was performed 17 days after the initial operation, and pathological examination revealed mixed GCT metastasis. Subsequently, the patient received salvage chemotherapy with a regimen of cisplatin, etoposide, and ifosfamide. Unfortunately, the patient died 1 week after the first cycle of chemotherapy because of severe immunosuppression, a low platelet count and cancer cachexia.
CONCLUSIONS: Because of severe immunosuppression, the treatment of advanced extragonadal NSGCTs in an HIV-infected patient resulted in a poor prognosis. This outcome should be considered in further research, and appropriate management for achieving long-term survival needs to be established.

Lee T, Seo Y, Han J, Kwon GY
Analysis of chromosome 12p over-representation and clinicopathological features in mediastinal teratomas.
Pathology. 2019; 51(1):62-66 [PubMed] Related Publications
Teratomas show diverse biologic behaviour and prognosis as well as variable histological features. Importantly, post-pubertal testicular teratomas composed of mature components have a potential for malignant behaviour, in contrast to ovarian dermoid cysts and pre-pubertal testicular teratomas which are considered almost always benign. On the other hand, the biological behaviour and histogenesis of extragonadal teratomas are still not fully elucidated. In this study of mediastinal mature teratoma (MT), we investigated clinicopathological features and chromosome 12 short arm (12p) status which constitutes a major genetic aberration in the germ cell tumours (GCT) and is indicative of malignant potential. A total of 123 cases of primary mediastinal MT were included, and clinical data were retrieved regarding demographic information, adjuvant treatment, post-operative clinical course, and level of serum tumour markers. Histopathological features were evaluated in 123 cases and 12p status was studied by FISH in 25 cases. Female predilection was identified in the post-pubertal group (38 males vs 77 females), and paediatric teratoma cases had longer follow-up (mean 62.2 months vs 26.5 months). All patients had excellent prognosis with no tumour-associated death, regardless of age and sex. None of the MT cases had cytological atypia and all 21 cases finally evaluated by fluorescence in situ hybridisation were negative for 12p over-representation. Our results support the benign nature of mediastinal MT and suggest the possibility that it may share a common histogenesis with pre-pubertal type GCTs.

Antunes HP, Almeida R, Sousa V, Figueiredo A
Mixed extragonadal germ cell tumour of the prostate.
BMJ Case Rep. 2018; 2018 [PubMed] Related Publications
Extragonadal germ cell tumours (EGGCTs) originated in prostate are extremely rare, with <20 cases described in the literature. We report a case of a patient with a primary prostatic mixed EGGCT. A 47-year-old man presenting severe low urinary tract symptoms and signs of prostatic enlargement, with no malignancy suspicion, underwent transurethral resection of the prostate. The histopathological evaluation suggested the diagnosis of a retroperitoneal sarcoma. The patient underwent neoadjuvant chemotherapy and then was submitted to radical cystoprostatectomy. Histology revealed a mixed EGGCT of the prostate with yolk sac tumour and seminoma components. No testicular abnormalities were identified on the postoperative scrotal ultrasound. The patient went through four cycles of chemotherapy with bleomycin, etoposide and cisplatin. After 12 months of follow-up, the patient is alive and free of recurrence.

Joshi S, Sivarajah V
Retroperitoneal seminoma, a rare cause of testicular pain.
BMJ Case Rep. 2018; 2018 [PubMed] Related Publications
Extragonadal retroperitoneal seminomas are a rare cause of testicular pain in males. We report the case of a 46-year-old man, who presented with right-sided testicular pain, clinically mimicking testicular torsion. The patient underwent a scrotal exploration, which revealed normal testes. He went on to have a contrast-enhanced CT abdomen and pelvis, which revealed a 55 mm para-aortic mass, displacing the duodenum and inferior vena cava, with an adjacent 22 mm lymph node. Histological analysis revealed that it was a seminoma.

O'Mara N, Cheung C, McManus R, Cross KS
Devil within: an incidental and rare finding of an extragonandal retroperitoneal germ cell teratoma carcinoid tumour.
BMJ Case Rep. 2018; 2018 [PubMed] Related Publications
Extragonadal germ cell tumours (GCTs) are uncommon neoplasms comprising approximately 2%-5% of all GCTs. Of these, approximately 30%-40% occurs as primary retroperitoneal GCTs. This case report details the presentation, diagnosis and management of a 53-year-old man presenting with an incidental finding of a primary extragonadal retroperitoneal teratoma with carcinoid transformation.

Inoue Y, Nakamura T, Nakanishi H, et al.
Therapy-related acute myeloid leukemia and myelodysplastic syndrome among refractory germ cell tumor patients.
Int J Urol. 2018; 25(7):678-683 [PubMed] Related Publications
OBJECTIVES: To analyze cases of therapy-related acute myeloid leukemia and myelodysplastic syndrome diagnosed after chemotherapy for refractory testicular and extragonadal germ cell tumor in our experience.
METHODS: A total of 171 consecutive patients who were diagnosed and treated as refractory germ cell tumor and had records of detailed chemotherapy doses between April 1998 and December 2015 were retrospectively reviewed.
RESULTS: Four testicular tumor patients (4/171, 2.3%) developed therapy-related acute myeloid leukemia and myelodysplastic syndrome. Three of them were affected after complete remission of the primary testicular tumor. A median time interval from a start of chemotherapy to a secondary tumor development was 6.8 years (range 3.7-11.5 years). The median total dose of etoposide, ifosfamide, cisplatin and nedaplatin were 3640 mg/m
CONCLUSIONS: The present findings show that refractory germ cell tumor patients have an increased risk of therapy-related acute myeloid leukemia and myelodysplastic syndrome. A cumulative dose of etoposide is a significant risk of leukemogenesis. As therapy-related acute myeloid leukemia and myelodysplastic syndrome has a poor prognosis, close follow up is required for refractory germ cell tumor patients.

Gell JJ, Zhao J, Chen D, et al.
PRDM14 is expressed in germ cell tumors with constitutive overexpression altering human germline differentiation and proliferation.
Stem Cell Res. 2018; 27:46-56 [PubMed] Free Access to Full Article Related Publications
Germ cell tumors (GCTs) are a heterogeneous group of tumors occurring in gonadal and extragonadal locations. GCTs are hypothesized to arise from primordial germ cells (PGCs), which fail to differentiate. One recently identified susceptibility loci for human GCT is PR (PRDI-BF1 and RIZ) domain proteins 14 (PRDM14). PRDM14 is expressed in early primate PGCs and is repressed as PGCs differentiate. To examine PRDM14 in human GCTs we profiled human GCT cell lines and patient samples and discovered that PRDM14 is expressed in embryonal carcinoma cell lines, embryonal carcinomas, seminomas, intracranial germinomas and yolk sac tumors, but is not expressed in teratomas. To model constitutive overexpression in human PGCs, we generated PGC-like cells (PGCLCs) from human pluripotent stem cells (PSCs) and discovered that elevated expression of PRDM14 does not block early PGC formation. Instead, we show that elevated PRDM14 in PGCLCs causes proliferation and differentiation defects in the germline.

Lee B, Chan M, Goh R
An Unusual Cause of Headache and Sudden Death of a Young Sailor-Postmortem Computed Tomography and Histological Findings of a Fatal Retroperitoneal Malignant Mixed Germ Cell Tumor.
J Forensic Sci. 2018; 63(5):1568-1572 [PubMed] Related Publications
A 26-year-old Caucasian sailor, with no past medical history aside from headache for the last 1 week, was found dead in his cabin. The body was stored in a refrigerator on board and disembarked for autopsy 3 days later. Autopsy showed a large, nodular, necrotic and hemorrhagic retroperitoneal mass, and smaller hemorrhagic nodules in the brain, lungs, liver, and left kidney, with the brain being markedly edematous. Both testes were descended and normal. Histologically, the retroperitoneal mass showed a malignant mixed germ cell tumor comprising choriocarcinoma, embryonal carcinoma, and teratoma components. Retroperitoneal extragonadal germ cell tumors are uncommon, and this case of a young male who presented with headache and sudden death due to metastases is extremely rare.

Silva LLCD, Vergilio FS, Yamaguti DCC, et al.
Yolk sac primary tumor of mediastino: a rare case in a young adult.
Einstein (Sao Paulo). 2017 Oct-Dec; 15(4):496-499 [PubMed] Free Access to Full Article Related Publications
Germ cell tumors are rare neoplasms that mostly occur in the gonads, although they can also affect other body sites, especially the anterior mediastinum (50 to 70% of all extragonadal germ cell tumors). We report a case of a primary mediastinal yolk sac tumor, a rare and aggressive germ cell tumors subtype. This was a 38-year-old man who was admitted to Hospital do Servidor Público Estadual "Francisco Morato de Oliveira", complaining about dyspnea and dry cough for 1 year. The computed tomography scan of his chest revealed a large mass in the anterior mediastinum with heterogeneous enhancement to the contrast associated with pleural effusion. There were also high serum levels of alpha-fetoprotein. After neoadjuvant chemotherapy, the patient underwent surgical resection of the mass, followed by pathological examination, which confirmed a primary mediastinal yolk sac tumor, a nonseminomatous subtype of germ cell tumors. Primary mediastinal yolk sac tumors have poor prognosis, despite advances in therapy with surgical resection and cisplatin-based chemotherapy. This poor prognosis is due to the degree of invasion and unresectability in most patients by the time of the diagnosis.

Rampinelli F, Donarini P, Visenzi C, et al.
The Rare Extragonadal Omental Teratoma: A Case Report.
J Minim Invasive Gynecol. 2017 Sep - Oct; 24(6):1046-1048 [PubMed] Related Publications
Teratomas of extragonadal origin are extremely rare, and the most common extragonadal site to find teratomas is the omentum. Teratomas are typically found in women of reproductive age, but they are also seen in young girls and postmenopausal women. Generally, teratomas arise from germ cells that may induce different cells to originate from the 3 primitive embryonic layers. Three main theories have been proposed to explain their location. The present report summarizes these theories as well as describes a case of a mature cystic teratoma of the omentum that was managed by laparoscopic resection.

Wanous A, McPhail IR, Quevedo JF, Sandhu NP
Mediastinal seminoma presenting with superior vena cava syndrome.
BMJ Case Rep. 2017; 2017 [PubMed] Free Access to Full Article Related Publications
We present a rare cause of superior vena cava syndrome (SVC) in a previously healthy male aged 31 years. Malignancy was suspected due to unintentional weight loss and childhood exposure to radioactive fallout from a nuclear facility accident. A very large anterior mediastinal mass was identified and demonstrated to be an extragonadal seminoma. Extragonadal germ cell tumours are rare tumours with a high potential for cardiovascular, pulmonary and vascular sequelae. Studies have documented an increased risk of developing seminoma in patients with radioactive exposure. Chemotherapy was initiated, during which the patient experienced progressive and new symptoms, found to be due to extensive thromboembolic disease, which responded well to anticoagulation. Seventy-two months after completing chemotherapy, without need for surgical management, he remains free of the disease.

Xiao GQ, Priemer DS, Wei C, et al.
ZBTB16 is a sensitive and specific marker in detection of metastatic and extragonadal yolk sac tumour.
Histopathology. 2017; 71(4):562-569 [PubMed] Related Publications
AIMS: Accurate histological diagnosis and classification of germ cell tumours (GCTs) is key to informing successful therapeutic and surveillance strategy. The modern therapeutic approach for yolk sac tumour (YST) is highly curative. Because YST takes on a large morphological spectrum, it can be confused for other GCT subtypes as well as somatic carcinomas, particularly when YST presents in an extragonadal or a metastatic setting. Currently available immunohistochemical markers are limited by suboptimal sensitivity and specificity. We reported recently that ZBTB16 is a sensitive and specific marker for testicular YST. ZBTB16 is absent in other GCTs and in most common somatic carcinomas, including those of gastrointestinal, pancreatobillary, respiratory, genitourinary and gynaecological tracts. The purpose of this study is to investigate the diagnostic utility of ZBTB16 in the settings of metastatic and extragonadal YST.
METHODS AND RESULTS: We studied 32 archived metastatic and four extragonadal primary YSTs as well as 51 somatic malignancies for their immunohistochemical expression of ZBTB16. For comparison, α-fetoprotein (AFP) and glypican-3 were also studied in parallel. Our results demonstrated an overall sensitivity of 91.6% for ZBTB16 in detecting metastatic and extragonadal YSTs. The non-YST elements (teratoma and embryonal carcinoma) in 15 YST-containing metastatic mixed GCTs were non-reactive. With the exception of occasional myoepithelial cells of salivary gland carcinoma, all the 51 somatic malignancies were negative for ZBTB16.
CONCLUSIONS: ZBTB16 is a sensitive and specific marker for YST and is diagnostically superior to AFP and glypican-3 in metastatic and extragonadal settings.

Tampakis A, Tampaki EC, Damaskos C, et al.
Orchitis reveals an extragonadal primary mediastinal thymic seminoma: a coincidence or not?
World J Surg Oncol. 2017; 15(1):85 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mediastinal thymic seminomas are rare male germ cell tumors with extragonadal origin that appear predominately with a cystic appearance.
CASE PRESENTATION: A 22-year-old male was referred to our department for further investigation of a mediastinal mass discovered incidentally during routine chest X-ray. The patient has denied any symptoms including dyspnea, chest pain, cough, fever, dysphagia, hemoptysis, weight loss, and weakness. His past medical history was remarkable for orchitis, for which he had undergone a bilateral testicular biopsy, without the latter however, indicating the presence of a germ cell tumor or a premalignant lesion. Contrast-enhanced chest computed tomography revealed a lobulated and well-marginated cystic lesion in the anterior mediastinum. Differential diagnosis included mostly a multilocular thymic cyst, a lymphoma, a seminoma, or a soft tissue tumor. Resection of the mass revealed a primary thymic seminoma.
CONCLUSIONS: A surgical approach for the management of these tumors might be reasonable considering that an extensive sampling is mandatory to gain an appropriate biopsy preoperatively in order to securely confirm or refute the presence of a mediastinal extragonadal tumor. Orchitis might be a sign of a general disorder of the germ cells which might transform in time.

Larish A, Kumar A, Kerr S, Langstraat C
Primary Gastric Choriocarcinoma Presenting as a Pregnancy of Unknown Location.
Obstet Gynecol. 2017; 129(2):281-284 [PubMed] Related Publications
BACKGROUND: Pregnancy of unknown location presents a diagnostic challenge, in rare occasions leading to the diagnosis of malignancy. We describe a case of β-hCG-secreting nongestational primary gastric choriocarcinoma presenting as a pregnancy of unknown location.
CASE: A 37-year-old woman, gravida 4 para 3013, presented with several days of vaginal bleeding and rising β-hCG level without ultrasound localization of pregnancy. The diagnosis of pregnancy of unknown location was made and methotrexate administered at a β-hCG level of 7,779 milli-international units/mL. A 40% decrease in β-hCG level was noted between days 4 and 7. One week later, an inappropriate β-hCG level rise to 10,937 milli-international units/mL was noted, prompting a second dose of methotrexate and computed tomography imaging, leading to the discovery of gastric and liver lesions. Pathology from gastric biopsies revealed nongestational choriocarcinoma. The patient was treated with chemotherapy, with death from cardiac arrest 7 months after diagnosis.
CONCLUSION: Malignancies that can secrete β-hCG include gestational trophoblastic disease, gonadal and extragonadal germ cell tumors, and malignancies with choriocarcinoma differentiation. Although ectopic pregnancy compromises approximately 2% of first-trimester pregnancy, gestational trophoblastic neoplasia and gestational choriocarcinoma can be seen in 1 of 1,500 and 1 of 20,000 pregnancies, respectively. When β-hCG levels do not fall appropriately in women undergoing medical management for pregnancy of unknown location, ectopic β-hCG secretion by a malignancy must be considered.

Harada Y, Koyama T, Takeuchi K, et al.
NUT midline carcinoma mimicking a germ cell tumor: a case report.
BMC Cancer. 2016; 16(1):895 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: NUT midline carcinoma (NMC) is a rare and highly aggressive malignancy. Although more information on NMC has been recently accumulating in the literature, most oncologists and pathologists remain unfamiliar with the clinical and pathologic features of this disease. The clinical features of NMC sometimes mimic those of other malignancies, and NMC can therefore be overlooked if the diagnosis is not suspected. We present the case of a young male with NMC arising in the mediastinum with elevated serum alpha-fetoprotein levels suggestive of an extragonadal nonseminomatous germ-cell tumor.
CASE PRESENTATION: A 28-year-old Japanese male presented with cough and left-sided chest pain for 6 weeks. The patient had a mediastinal tumor with metastases to the right lung, lymph nodes, and bones at initial presentation. Nonseminomatous germ cell tumor was suspected due to the young age, location of the tumors, and elevated serum alpha-fetoprotein. However, biopsy confirmed the diagnosis of NMC with immunohistochemistry. The tumor briefly responded to cytotoxic chemotherapy but subsequently progressed and became refractory to the chemotherapy regimen. External beam radiotherapy was administered with dramatic shrinkage of the tumor and a metabolic response on 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography (
CONCLUSIONS: Serum levels of alpha-fetoprotein may be elevated in patients with NMC. Regardless of the level of tumor markers, immunohistochemistry for NUT should be performed in cases of poorly differentiated carcinomas without glandular differentiation arising in the midline structures.

Monn MF, Jaqua KR, Bihrle R, Cheng L
Primary Choriocarcinoma of the Bladder: A Case Report and Review of Literature.
Clin Genitourin Cancer. 2017; 15(2):188-191 [PubMed] Related Publications
Primary choriocarcinoma of the urinary bladder is a rare entity, and should be distinguished from urothelial carcinoma with trophoblastic differentiation. The leading treatment modalities include surgical extirpation, chemotherapy, and radiation; however, survival remains poor. Herein we describe a rare case of choriocarcinoma of the bladder in a man who presented for evaluation with hematuria and subsequently underwent radical cystectomy with urinary diversion. Diagnosis of extragonadal germ cell tumor was confirmed using fluorescence in situ hybridization identification of isochromosome 12p.

Stolnicu S, Szekely E, Molnar C, et al.
Mature and Immature Solid Teratomas Involving Uterine Corpus, Cervix, and Ovary.
Int J Gynecol Pathol. 2017; 36(3):222-227 [PubMed] Free Access to Full Article Related Publications
Extragonadal teratomas are rare, and localization in the endometrium and cervix is exceptional, with fewer than 10 case reports documented so far in the English literature. We report here the case of a 46-year-old patient who presented with simultaneous immature teratoma in the endometrium and mature teratomas in the ovary in association with gliomatosis peritonei but with no evidence of gestational origin; she subsequently developed multiple solid mature teratomas in the cervix and parauterine tissue. No other similar cases have been previously reported to our knowledge. There are many similarities between the patient's pattern of recurrence and "growing teratoma syndrome (GTS)". Although the patient was not treated with chemotherapy after her first presentation and this case does not meet formal criteria for GTS, we believe that the pattern and histology of recurrences in this case represent a variant of GTS. Considering that the initial presentation in this case was endometrial and ovarian makes the occurrence of GTS-like syndrome even more unique.

Ravishankar S, Malpica A, Ramalingam P, Euscher ED
Yolk Sac Tumor in Extragonadal Pelvic Sites: Still a Diagnostic Challenge.
Am J Surg Pathol. 2017; 41(1):1-11 [PubMed] Related Publications
We present the clinicopathologic features of 15 cases of extragonadal yolk sac tumor (EGYST) detected in female patients and reviewed at our institution from 1988 to 2016. We recorded: patient age, clinical presentation, tumor location, FIGO stage (where applicable), histologic patterns including presence/absence of Schiller-Duval bodies, other germ cell or somatic components, immunoperoxidase results, treatment, and outcome. Patients' ages ranged from 17 to 87 (median, 62) years and presentation included: abnormal uterine bleeding, 12; hematuria, 1; labial mass, 1; abdominal pain, 1. Primary sites were as follows: uterus (11), vagina (1), vulva (1), bladder (1), and peritoneum (1). Seven patients presented at FIGO stage III or IV. The following histologic patterns were observed: microcystic/reticular (7), glandular (8), solid (8), papillary (5), and hepatoid (1). An admixture of histologic patterns was present in 10 cases. Schiller-Duval bodies were seen in only 3 (23%) cases. Eight cases (46%), all uterine primaries, had associated somatic components, and 2 (15%) had a second germ cell component. In 13/14 (93%) cases, the yolk sac tumor component was either missed or misclassified as adenocarcinoma. Immunoperoxidase studies facilitated the diagnosis in all cases as follows: SALL4, 12/12; CDX2, 10/12; α fetoprotein, 7/14; glypican-3, 9/10; cytokeratin 20, 5/9 (rare cells); cytokeratin 7, 3/12 (nondiffuse); PAX8, 2/9 (variable expression). All patients received chemotherapy and all except 1 underwent surgical resection. Follow-up from 5 to 86 months was available for 13 patients: 5 died of disease, 6 are alive with disease, and 2 have no evidence of disease. EGYST arising in the female pelvis of peri/postmenopausal patients may be associated with a somatic component and represent either somatically derived YST or YST differentiation within a somatic carcinoma. EGYST in younger patients is likely a true germ cell neoplasm, and may respond to germ cell appropriate chemotherapy. The benefit of germ cell appropriate chemotherapy in somatically derived EGYST is less clear. Awareness that the presence of glandular or microcystic patterns may lead to under-recognition or misdiagnosis of EGYST in combination with immunomarkers for germ cell and yolk sac differentiation will facilitate the diagnosis.

Thompson JP, Jean-Gilles J, Dogra V
Testicular Microlithiasis in the Setting of Primary Extragonadal Germ Cell Tumor: A Case Series.
Ultrasound Q. 2017; 33(1):41-45 [PubMed] Related Publications
The clinical significance of testicular microlithiasis (TM) in patients with primary extragonadal germ cell tumor (EGCT) is not well understood. When EGCT is suspected, sonographic and physical examination of the testicles should be performed to evaluate for testicular lesion or atrophy; negative testicular ultrasound with current technology virtually excludes the possibility of occult primary lesion. Although EGCTs are known to be associated with elevated level of serum tumor markers, the utility of tumor markers in the presence of TM is not well understood. Current guidelines for TM follow-up and management do not include any potential correlation between TM and primary EGCT, an association that should be addressed on future updates.

Vekić B, Živić R, Kalezić M, Matić P
Benign cystic teratoma of the mesosigmoid – Report of a case.
Srp Arh Celok Lek. 2016 Sep-Oct; 144(9-10):550-2 [PubMed] Related Publications
Introduction: Extragonadal intraperitoneal teratomas are very rare, especially those arising from mesentery and mesocolon. In the contemporary literature only 22 cases of such tumors have been published and described.
Case Outline: We report a case of a 52-year-old woman with a benign cystic teratoma of the mesosigmoid. The patient presented with mild clinical signs of intestinal obstruction. Computerized tomography of the pelvis and abdomen showed a large 9.7 × 8.9 × 9.4 cm calcified tumor in the lower part of the left hemiabdomen. Extraluminal obstruction was verified by colonoscopy at 35 cm from the anal verge. Intraoperatively, a cystic calcified tumor of the mesosigmoid was found causing extraluminal obstruction of the left colon. The tumor was extirpated and a partial resection of the adherent great omentum was performed. The histopathological examination revealed a benign cystic teratoma.
Conclusion: Considering the fact that mesenteric teratomas are extremely rare tumors, it is difficult to designate a general conclusion for an adequate treatment of patients suffering from them. Complete surgical excision is indicated in order to establish a correct histopathological diagnosis and to relieve the patients of symptoms.

Willems E, Martens S, Beelen R
Robotically enhanced mediastinal teratoma resection: a case report and review of the literature.
Acta Chir Belg. 2016; 116(5):309-312 [PubMed] Related Publications
Mediastinal teratomata are rare, extragonadal germ cell tumors, which can occur at any age and are often asymptomatic. We present the case of a 57-year-old female with chronic cough diagnosed with a mass in the anterior mediastinum. The mass was successfully resected using the Intuitive Da Vinci® robotic system. The patient had an uneventful recovery. Review of the literature demonstrates that robotic surgery of the mediastinum is a safe and feasible alternative in selected cases.

Choi JE, Choe AR, Yoon SE, et al.
Germ Cell Tumor Targeting Chemotherapy in Gastric Adenocarcinoma with an Endodermal Sinus Tumor Component: A Case Report.
Chemotherapy. 2017; 62(1):54-57 [PubMed] Related Publications
The most common sites for extragonadal germ cell tumors are the midline mediastinum, retroperitoneum and, much less frequently, the stomach. The stomach-originated primary germ cell tumor carries a poor prognosis, especially when metastasis occurs to the liver, with a mean survival time of 1 month. We describe the case of a 77-year-old male who presented with usual symptoms of gastric malignancy. Gastrectomy was performed. Histopathology of surgically resected tissue revealed a mixture of adenocarcinoma and endodermal sinus tumor components with α-fetoprotein production. After liver metastasis was identified, oxaliplatin and capecitabine were administered as palliative chemotherapy. The response was poor. For the second-line therapy, bleomycin, etoposide, and cisplatin (BEP) therapy was initiated. The overall response to these drugs was a partial response and the residual liver lesion was considered to be resectable. The patient died of pneumonia 11 months following the BEP session, representing an overall survival time of 22 months. Gastric adenocarcinoma with a germ cell tumor component is uncommon and an effective combination of chemotherapeutic agents is not yet clear. In this case, the patient received germ cell tumor-targeting chemotherapy and showed a durable response. Hence, germ cell-targeting cytotoxic agents have potential as the 'front-line regimen'.

Shaikh F, Murray MJ, Amatruda JF, et al.
Paediatric extracranial germ-cell tumours.
Lancet Oncol. 2016; 17(4):e149-e162 [PubMed] Related Publications
Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups.

van Leeuwen MT, Gurney H, Turner JJ, et al.
Patterns and trends in the incidence of paediatric and adult germ cell tumours in Australia, 1982-2011.
Cancer Epidemiol. 2016; 43:15-21 [PubMed] Related Publications
PURPOSE: Germ cell tumour (GCT) aetiology is uncertain and comprehensive epidemiological studies of GCT incidence are few.
METHODS: Nationwide data on all malignant GCTs notified to Australian population-based cancer registries during 1982-2011 were obtained. Age- and sex-specific, and World age-standardised incidence rates were calculated for paediatric (0-14) and adult (15+) cases using the latest WHO subtype classification scheme. Temporal trends were examined using Joinpoint regression.
RESULTS: There were 17,279 GCTs (552 paediatric, 16,727 adult). Age-specific incidence in males (all histologies combined) was bimodal, with peaks during infancy for most sites, and second, larger, peaks during young adulthood. Incidence of ovarian tumours peaked at age 15-19. Around half of paediatric tumours were extragonadal, whereas adult tumours were mostly gonadal. Yolk sac tumours and teratomas predominated in infants, whereas germinomas became more frequent towards adulthood. Increasing incidence trends for some adult gonadal tumours have stabilised; the trend for male extragonadal tumours is also declining.
CONCLUSION: Broad similarities in the shape of age-specific incidence curves, particularly for gonadal, central nervous system, and mediastinal tumours provide epidemiological support for commonalities in aetiology among clinically disparate GCT subtypes. Differences in peak ages reflect underlying subtype-specific biological differences. Declining incidence trends for some adult gonadal tumours accords with the global transition in GCT incidence, and supports the possibility of a reduction in prevalence of shared aetiological exposures.

Jovanović M, Janjusević N, Mirković D, et al.
Giant primary retroperitoneal seminoma: A case report.
Vojnosanit Pregl. 2016; 73(2):205-7 [PubMed] Related Publications
INTRODUCTION: Primary extragonadal seminomas are rare tumors. There have been only a few cases of the primary retroperitoneal seminomas reported in the literature up to date.
CASE REPORT: We reported a 56-year-old man with giant primary retroperitoneal seminoma presented with the enlargement of the left side of the abdomen and deep venous thrombosis of the left leg. Computed tomography of the abdomen showed a large tumor occupying the left part of the retroperitoneal space with 23 x 13 cm in diameter. Firm tumor mass having 25 x 15 cm in diameter was surgically removed from the left retroperitoneum. The tumor adhered the tunica adventitia of the aorta and it was carefully resected from the aortic wall. The diagnosis of seminoma was made during histopathological examination. The patient underwent chemotherapy. Two years after finished chemotherapy the patient accepted left orchiectomy with the aim of eliminating the possibility of the occult malignancy of the testicle. Histopathological analysis of the testicular tissue was normal and the diagnosis of primary retroperitoneal seminoma was confirmed. CONCLUSION. Despite its small incidence in general population, the diagnosis of retroperitoneal seminoma should be considered in male patients with nonspecific symptoms and with retroperitoneal tumor mass.

Busch J, Seidel C, Zengerling F
Male Extragonadal Germ Cell Tumors of the Adult.
Oncol Res Treat. 2016; 39(3):140-4 [PubMed] Related Publications
Male extragonadal germ cell tumors (EGCTs) are characterized by a malignant transformation of germ cells without the presence of a gonadal primary tumor. EGCTs represent up to 5% of all germ cell tumors (GCTs) with an incidence around 1/1,000,000. It is assumed that EGCTs either derive from a malignant transformation of germ cells that were misdirected during embryogenesis, or from germ cells that have spread throughout the body during embryogenesis to fulfil different roles in immunological processes or distinct organ functions. EGCTs are mainly localized along the median axis, especially in the mediastinum and in the retroperitoneum. Regarding histology, they have the same subtypes as gonadal GCTs (seminomas and non-seminomas). EGCTs are normally diagnosed in advanced stages due to tumor-associated symptoms or as incidental finding during routine diagnostic or therapeutic procedures. An integral part of EGCT treatment is cisplatinum-based chemotherapy: residual tumor resection is only indicated for non-seminomatous EGCTs. The prognosis of malignant retroperitoneal EGCTs depends on tumor localization and histology. The 5-year overall survival ranges from 40% to 90% and is more favorable for retroperitoneal or seminomatous tumors than for mediastinal non-seminomatous tumors. Mature teratomas of mediastinal EGCTs are benign and are only treated by surgical resection.

Makino T, Konaka H, Namiki M
Clinical Features and Treatment Outcomes in Patients with Extragonadal Germ Cell Tumors: A Single-center Experience.
Anticancer Res. 2016; 36(1):313-7 [PubMed] Related Publications
BACKGROUND: The prognosis for non-seminomatous extragonadal germ cell tumors (EGCTs), especially mediastinal, has been shown to be worse than for seminomatous EGCTs.
PATIENTS AND METHODS: Fourteen patients with EGCT (seven pure seminomas and seven non-seminomas) were treated at the Kanazawa University Hospital between 1992 and 2014; the primary tumor sites were mediastinum in nine patients and retroperitoneum in five patients. All patients were treated with cisplatin-based combination chemotherapeutic regimens followed by a multimodal strategy that included high-dose chemotherapy (HDCT), aggressive surgery, and early salvage chemotherapy.
RESULTS: Although all patients with seminomatous EGCT achieved long-term survival, almost all patients with non-seminomatous EGCT had elevated serum tumor markers and high mortality rates. However, we experienced that patients with mediastinal non-seminomatous EGCT achieved long-term cancer-free survival with HDCT. The 5-year overall survival of patients with seminomatous and non-seminomatous EGCT was 100% and 44%, respectively.
CONCLUSION: Herein we describe the treatment outcomes of patients with EGCT at our Institute and propose HDCT reconsideration for poor-risk patients.

Gilligan T
Decision Making in a Data-Poor Environment: Management of Brain Metastases From Testicular and Extragonadal Germ Cell Tumors.
J Clin Oncol. 2016; 34(4):303-6 [PubMed] Related Publications
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.A 32-year-old man with a history of a mixed germ cell tumor of the testis presented with acute-onset, right-sided weakness and numbness. His previous treatment included orchiectomy, which revealed a 5-cm tumor that was 95% yolk sac tumor and 5% embryonal carcinoma, and retroperitoneal lymph node dissection for clinical stage I disease in January 2010, which revealed no nodal metastases. Starting in June 2010, he was treated with four cycles of etoposide and cisplatin for pulmonary and thoracic lymph node metastases and a rising serum alpha-fetoprotein (AFP) level. He subsequently received four cycles of paclitaxel, ifosfamide, and cisplatin for relapse in the lungs and mediastinal nodes with a rising AFP level starting in January 2011. He reported having a 2-week history of intermittent headaches in December 2011, when he presented with acute-onset, right-sided weakness and numbness. Computed tomographs of the head was obtained and demonstrated a left parietal intracranial hemorrhage without midline shift or hydrocephalus. Brain magnetic resonance imaging (MRI) showed a complex, 4.5-cm mass consistent with a hemorrhagic metastasis. His serum AFP level was elevated at 47 ng/mL. The patient became progressively obtunded and underwent emergency surgical decompression and resection of the tumor. Histopathologic evaluation of the resected tissue showed metastatic germ cell tumor predominantly consisting of a yolk sac element (Fig 1). His AFP level declined rapidly after resection, and computed tomography of the chest, abdomen, and pelvis showed no evidence of metastatic disease. However, 2 weeks later, his AFP level rose again, and repeat MRI of the brain showed a 3-cm mass in the left mesial parietal lobe adjacent to the resection site. He started treatment with filgrastim to facilitate collection of circulating hematopoietic stem cells. Several days later, after apheresis, he received his first of two cycles of high-dose carboplatin 700 mg/m(2) on days -5, -4, and -3 and etoposide 750 mg/m(2) on days -5, -4, and -3. The patient had a complete response to high-dose chemotherapy and no major acute complications. His cancer remains in complete remission 3 years later without additional treatment. His three lines of chemotherapy left him with chronic peripheral neuropathy.

Cierna Z, Mego M, Miskovska V, et al.
Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors.
Ann Oncol. 2016; 27(2):300-5 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Testicular germ cell tumors (TGCTs) belong to the most chemosensitive solid tumors; however, a small proportion of patients fail to be cured with cisplatin-based chemotherapy. Inhibitors of PD-1/PD-L1 pathways represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate expression and prognostic value of PD-1 and PD-L1 in TGCTs.
PATIENTS AND METHODS: Surgical specimens from 140 patients with TGCTs (131 with primary testicular tumor and 9 with extragonadal GCTs) were included into the translational study. PD-1 and PD-L1 expression was detected in the tumor tissue by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method, compared with their expression in normal testicular tissue and correlated with clinicopathological characteristics and clinical outcome.
RESULTS: None of the GCTs exhibited PD-1 protein, although expression of PD-L1 was significantly higher in GCTs in comparison with normal testicular tissue (mean QS = 5.29 versus 0.32, P < 0.0001). Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor prognostic features, including ≥3 metastatic sites, increased serum tumor markers and/or non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly better progression-free survival [hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.16-1.01, P = 0.008] and overall survival (HR = 0.43, 95% CI 0.15-1.23, P = 0.040) compared with patients with high PD-L1 expression.
CONCLUSIONS: In this translational study, we showed, for the first time, the prognostic value of PD-L1 expression in TGCTs and our data imply that the PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs.

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