Germ Cell Tumors in Gonads: Navigating Traditional Pathways, Venturing into Uncharted Territories, Pushing the Frontiers.

Alice, Ellen, Jasleen, Rakshitha

Pediatric Cancer Research Writers Program

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Discussion

Exploring the study of gonadal germ cell tumors was an fascinating experience allowing our team to discover new insights on an obscure subject. This study led to the introduction of the complexity and consequences of gonadal germ cell tumors. A prominent aspect was the intricacy of their development and differentiation between genders and various factors that are unanticipated. This analysis stretched our insight and awareness on GCTs and triggered curiosity of the connection between medical professions, developmental aspects and the complexity of GCTs. 

Abstract

Gonadal germ cell tumors (GCTs) present significant diagnostic and therapeutic challenges due to their diverse histological types and biological behaviors. This study reviews the various types of GCTs, focusing on the differences between seminomas and non-seminomatous germ cell tumors (NSGCTs), and their occurrence in the testes and ovaries. Seminomas, including testicular seminomas and ovarian dysgerminomas, are characterized by uniform cells and generally have a favorable prognosis with radiation and chemotherapy. NSGCTs, comprising embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratomas, are more aggressive and often require complex treatment strategies. Teratomas are particularly notable for their histological diversity, with mature teratomas being benign in children and women but potentially malignant in postpubertal males. The study also highlights mixed germ cell tumors, which combine various GCT components, complicating diagnosis and treatment.

This review underscores the importance of immunohistochemical markers such as PLAP, CD117, and OCT3/4 in differentiating GCT types and guiding treatment. Additionally, the unique features of spermatocytic seminomas and the phenomenon of 'burnt-out' germ cell tumors are discussed, emphasizing the distinct pathophysiological mechanisms in the testes. The findings suggest that understanding the histopathological and molecular characteristics of GCTs is crucial for accurate diagnosis, prognosis, and personalized therapeutic approaches.

Keywords: Gonadal germ cell tumors, seminomas, non-seminomatous germ cell tumors, teratomas, immunohistochemical markers, testicular cancer, ovarian cancer, embryonal carcinoma, yolk sac tumor, choriocarcinoma.

Introduction

Gonadal germ cell tumors (GCTs) are a diverse group of neoplasms that arise from germ cells within the gonads, namely the testes in males and the ovaries in females. These tumors encompass a broad spectrum of histological types, each exhibiting unique biological behaviors and clinical outcomes. GCTs are particularly intriguing from an academic and clinical perspective due to their varied presentation in the two gonads and the significant differences in frequency and nature of specific neoplasms within each.

The classification of GCTs broadly divides them into seminomas and non-seminomatous germ cell tumors (NSGCTs). Seminomas, including testicular seminomas and ovarian dysgerminomas, are characterized by relatively uniform cells and generally present with a favorable prognosis when treated with radiation and chemotherapy. In contrast, NSGCTs, which include embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratomas, are typically more aggressive and often necessitate a combination of surgical intervention and multi-agent chemotherapy.

Diagnostic challenges in GCTs are compounded by their ability to mimic other neoplasms, necessitating the use of specific immunohistochemical markers such as placental alkaline phosphatase (PLAP), CD117, and OCT3/4 to accurately differentiate between tumor types. Unique variants, such as spermatocytic seminomas which occur exclusively in the testes, and the phenomenon of 'burnt-out' germ cell tumors, add to the complexity of diagnosis and highlight the distinctive pathophysiological mechanisms at play within the testes.

Therefore, this article provides a detailed and updated overview of the literature regarding the occurrence of germ cell tumors in patients and outlines the major recent progress that has been made in our understanding of the pathogenesis of germ cell tumors and the early recognition of (pre-)neoplastic changes. 

Classification of Testicular GCTs:

The types of testicular GCTs are divided into two main categories. The Type I and III testicular GCTs are together referred to as non-GCNIS-related GCTs. The Type II testicular GCTs are referred to as GCNIS-related GCTs. This is simply based on the recognition of the different cells of origin and related pathogenesis, in which the knowledge on the origin of the Type II tumors (i.e., GCNIS, see below), is the dominant player in the classification because of its well-recognized status. This distinction between the GCNIS-related and non-GCNIS-related testicular GCTs is of relevance because of their different clinical behavior, i.e., malignant versus (predominantly) benign. As such, they will be discussed separately. Of special notion is the fact that, so far, morphology, mRNA, microRNA, and protein profiles of (Type I and II) teratoma and yolk sac tumor elements are similar; therefore, noninformative to make a differential diagnosis. However, this is consistently the case regarding their molecular genetic make-up, being therefore of diagnostic value. In addition, various animal models have been reported to be informative for GCT, which will be summarized hereunder because of their potential impact in understanding the pathogenesis of this type of cancer.

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Figure 1. Schematic representation of the various entities of testicular germ cell tumors (GCTs). The timeline is indicated on the left side and the proposed animal models on the right. The GCTs include the non-GCNIS (germ cell neoplasia in situ) related GCTs (left panel) and GCNIS-related GCTs (right panel). The non-GCNIS related GCTs are subcategorized into the prepubertal teratomas (TE) and yolk sac tumors (YST) as well as the spermatocytic tumors. These are also referred to as Type I and III, respectively. The GCNIS-related GCTs are histologically (and clinically) subdivided into the seminomas (SE) and the various elements of nonseminomatous GCTs, being embryonal carcinoma (EC), YST, choriocarcinoma, and TE. Note the overlapping histology between the prepubertal TE/YST and the TE and YST elements in the GCNIS-related nonseminomas. 

However, they have a separate (and independent) pathogenesis. The presumed cells of origin are indicated in green, reflecting a (partially and fully erased) primordial germ cell (Type I and II), to partially paternal imprinted spermatogonium/spermatocyte (Type III). The precursors are indicated when known (preinvasive), while specifically the benign and malignant behavior of the pediatric TE and YST is highlighted. In addition, the most prominent and recurrent molecular genetic changes are indicated, of putative interest to be used for molecular pathological approaches. These include total genomic anomalies, like polyploid/aneuploid, specific chromosomal imbalances like losses (-) and gains (+), as well as recurrent mutations (italics). In addition, the methylation status is indicated as well as the possible use of miR-371a-3p as a liquid biopsy molecular biomarker (underlined). All malignant histological elements, independent of age, are identified by this biomarker (except TE). The WNT pathway is specifically involved in the YST components, independent of age and also of pathogenesis.

Arrested germ cell development is an important step in the development of TGCTs. Because the pathogenesis of GCNIS-related TGCTs starts before birth, understanding normal germ cell development is imperative to comprehending the pathogenesis of TGCTs. The gonocytes or primitive germ cells with stem cell–like markers such as receptor tyrosine kinase (c-KIT )and octamer binding transcription factors 3 and 4 (OCT3/4) may be identified at the bilaminar disk stage of the embryo at approximately 2 weeks of gestation. Primitive germ cells colonize the testicular parenchyma after extensive migration and, by puberty, lose the primitive markers to transform into mature sex cell progenitors. During migration, there is a hypothetical risk of gonocytes being deposited along the pathway, leading to the development of extragonadal GCTs. Because of activation of the hypothalamic-pituitary-gonadal axis at puberty, the gonocytes enter meiosis, triggered by the loss of expression of DMRT1 (sex-determining transcription factor), and obtain a haploid genotype.

Classification of Ovarian GCTs:

Ovarian germ cell tumors are basically equivalent to those originating from male germ cells. Yet there are some important biological and clinical differences between these two groups of tumors . For example, in contrast to the malignant nature of the vast majority of testicular tumors, most ovarian tumors are benign, presenting clinically as mature teratomas.Experimental data obtained in mice indicate that ovarian teratomas are formed from parthenogenetically activated ovarian germ cells. Human parthenotes isolated from the ovaries can rise to embryonic stem cells, and thus by extrapolation, one can assume that these cells could give rise to teratomas and other germ cell tumors as well.

The histogenesis of teratoma can be readily explained by parthenogenetic activation of ovarian germ cells. The histogenesis of malignant ovarian germ cell tumors is a bit more complicated, and several histogenetic schemes have been proposed, as reviewed by J. Prat in the monograph which he has edited with G. Mutter . Despite many attempts to modify our understanding of malignant ovarian germ cell, histogenesis is still incomplete. The panel of experts of WHO has thus decided to base the latest WHO classification of malignant germ cell tumors on the most popular model of histogenesis of these tumors dating back to the work of Teilum. According to this scheme, the malignant germ cell can form either dysgerminoma or embryonal carcinomas, which in turn could give rise to choriocarcinoma, yolk sac carcinoma, or teratoid tumors.

Figure 2. Schematic representation of the various entities of ovarian germ cell tumors (GCTs). Ovarian germ cell tumors are classified into several subtypes, each with distinct characteristics: Dysgerminomas are the most common malignant type, typically found in younger women and highly responsive to treatment. Yolk sac tumors are aggressive malignancies that secrete alpha-fetoprotein (AFP) and require prompt chemotherapy. Teratomas can be benign (mature teratomas) or malignant (immature teratomas), with the benign form being the most common ovarian germ cell tumor overall. Choriocarcinomas are rare, highly malignant tumors associated with elevated human chorionic gonadotropin (hCG) levels. Embryonal carcinomas are rare, aggressive tumors that often coexist with other germ cell tumor types.

In the expanded histogenetic algorithm presented above, we propose that the tumor formation depends in all cases on parthenogenetic activation of the ovarian germ cells [ova], which may give rise as such to benign tumors, i.e., teratomas. Alternatively, if the germ cells undergo malignant transformation, they may give rise to dysgerminoma or form embryonal carcinoma cells. EC cells may form either a monotypic tumor-embryonal carcinoma or by differentiating into somatic and extrasomatic cells and tissues form the malignant stem cells of a malignant mixed germ cell tumor. Even monotypic EC tumors contain syncytiotrophoblastic cells, which may be present in most of such tumors. EC cells can sometimes differentiate into yolk sac or choriocarcinoma cells, which as such may form tumors of the same name, overgrowing the EC component, which may be hard to find. Alternatively, EC cells may remain part of the mixed germ cell tumors which in such cases will contain several other distinct components: EC cells, teratomatous tissues, yolk sac tumor, and choriocarcinoma, or various combinations of these elements. There is also some evidence that dysgerminomas may give rise to embryonal carcinoma, but there is no doubt that they can be part of mixed germ cell tumors.

Diagnosis

Diagnosis of GCTs requires numerous complex steps to accurately discern the subtype and stage of the tumors. The multimodal approach ensures a comprehensive assessment of the nature of the tumor, guiding both the diagnosis and subsequent treatment of GCTs. 

First, clinical presentation of symptoms similar to those produced by gonadal germ cell tumors is required to consider a potential diagnosis of GCTs. Common GCT symptoms include painful or painless testicular masses, a solid ovarian mass, and a mass visible in the lower back near the anus, often in an infant. Development of pubic hair, breast enlargement, or vaginal bleeding at a very young age may also be a sign of GCTs. Extragonadal germ cell tumors, a rarer type of GCTs, exhibit symptoms that vary widely depending on the location. These symptoms may include chest pain, cough, dyspnea (in cases of mediastinal tumors), or abdominal pain (in cases of retroperitoneal tumors). In advanced cases, both GCT and extragonadal GCT symptoms may include abdominal or back pain, gynecomastia, or respiratory distress associated with a mass inside the chest if metastasis has occurred.

If there is an adequate clinical presentation of GCT symptoms, medical professionals will perform a careful history examination of the patient. Health history can sometimes indicate a higher risk for GCTs; for example, those born with abnormal ovaries or testes due to genetic conditions such as Turner’s or Klinefelter’s are more susceptible to GCT growth. A thorough physical examination is performed after, either in the testicular area for males or the pelvic area for females. If the medical professional suspects the presence of an extragonadal GCT, a thorough palpation of the abdomen, supraclavicular regions, and chest is warranted.

Oftentimes, these examinations reveal firm, non-tender masses or an adnexal mass. After physical examinations, a complete diagnostic evaluation is obtained through various imaging modalities, laboratory studies, and surgical resections. Imaging modalities include an ultrasound of the testes and the ovaries as well as any possible masses, which provides detailed information on the potential GCTs; computed tomography (CT) scan of chest, abdomen, and pelvis, typically employed to assess the extent of GCTs and detect metastasis; and an X-Ray to form an image of the abdomen or the chest, where extragonadal tumors tend to grow. Medical professionals then perform blood tests to measure blood counts and liver and kidney function, properly assessing the health of the patient. Additional blood tests to monitor serum tumor marker levels may also be ordered. Serum tumor markers, such as Alpha-fetoprotein (AFP) and Human Chorionic Gonadotropin (hCG),  play a critical role in the diagnosis, prognosis, and monitoring of GCTs because their levels are elevated in some types. 

Finally, definitive diagnosis requires histological examination of tumor tissue. This is achieved through surgical resections and biopsies. The type of biopsy performed depends on the location and size of the tumor; with fine-needle aspiration, tissue is removed with a thin needle, while the entire tumor is removed in surgical biopsies. Usually, ovarian or testicular GCTs are removed along with the involved testes or ovary. Abdominal lymph nodes and extragonadal GCTs tumors arising in the lower back, the chest, or elsewhere will be removed surgically, if possible, or biopsied. The tissue is then analyzed carefully.

Depending on the pathology, GCTs are sorted into different subtypes. A GCT can be classified as a benign teratoma, malignant teratoma, yolk sac tumor (high AFP test), choriocarcinoma (high bHCG test), embryonal carcinoma, and germinoma. GCTs are then staged based on the tumor's size, presence of metastasis, and serum tumor marker levels. The stages, ranging from Stage I to Stage IV, determine the condition of the GCT and the treatment plan necessary for the patient. Stage I refers to a tumor that was completely resected. Stage II tumors are resected but leave a few cells behind. Stage III tumors have spread to the lymph nodes, while Stage IV tumors have spread to the lung, liver, or other locations. After diagnosis and staging, patients with GCTs undergo treatment immediately. 

Imaging

In-Situ GCT’S:

GCNIS is found in the testicular parenchyma adjacent to TGCTs in 90% of TGCTs and in the contralateral testis in 4%–8% of TGCTs. Patients with cryptorchidism or atrophic testis are at higher risk for GCNIS and TGCTs. Approximately 70% of GCNIS-positive men may develop TGCT within the next 7 years. Lenz et al (37) showed that an irregular or coarse echogenic appearance of the testicular parenchyma at US may suggest the possibility of GCNIS. However, this finding has not been confirmed in larger studies. The positive predictive value is low (22%). Currently, US has no role in screening for GCNIS.

1. Seminomas:

Pure seminomas, which account for up to 50% of TGCTs, commonly occur in men aged 30–40 years (38,39). Serum lactate dehydrogenase levels are elevated in patients with seminomas, and approximately 15% of patients may have a mildly elevated β-hCG level because of the presence of syncytiotrophoblastic cells. At pathologic examination, seminomas are usually solid tumors with a pale tan slightly lobulated cut surface. At histologic examination, a diffuse arrangement of large polygonal cells that are divided into large lobules by fibrous bands is a typical finding. In immunohistochemical analysis, seminoma cells stain positive for c-KIT, placental alkaline phosphatase, and OCT3/4 .

The imaging appearance reflects the uniform cellular composition of seminomas. At US, seminomas typically are homogeneous, hypoechoic, and solid appearing, with well-circumscribed or lobulated margins, and they show increased vascularity along the fibrovascular septa at Doppler US. At MRI, seminomas are homogeneously T1 hypointense and T2 hypointense, with well-circumscribed or lobulated margins. At diffusion-weighted MRI, marked restricted diffusion secondary to increased cellularity and underlying inflammation can be seen; bandlike hyperenhancement of fibrovascular septa is characteristic of GCNIS

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Figure 3. Pure seminoma in a 35-year-old man. (A) Photograph of the sectioned gross specimen demonstrates a testicular mass with a pale tan lobulated cut surface (arrows). (B) Photomicrograph shows nests of large polygonal cells with moderate eosinophilic cytoplasms and prominent nucleoli (arrows) that are separated by fibrous bands containing a lymphocytic infiltrate (arrowheads), which are consistent with a pure seminoma. (Hematoxylin-eosin stain; original magnification, ×20.) (C, D) Gray-scale (C) and color Doppler (D)US images of the scrotum show a well-circumscribed lobulated homogeneously hypoechoic testicular mass (arrow) with increased vascularity.

2. Non-Seminomatous germ cell tumors: 

NSGCTs comprise 30%–40% of all TGCTs and may be pure or mixed tumors. Mixed tumors show variable proportions of embryonal carcinoma, yolk sac tumors, postpubertal teratomas, and choriocarcinomas. NSGCTs are diagnosed in men during the 3rd decade of life. Unlike seminomas, NSGCTs manifest with advanced disease in 60% of patients. The prognosis is unfavorable for tumors with a higher clinical stage. Imaging findings of NSGCTs reflect their variegated nature and the proportion of specific histologic types. At US, NSGCTs are typically heterogeneous; have ill-defined margins; and contain cystic areas and echogenic foci that correspond to necrosis, hemorrhage, and calcifications. Cysts within NSGCTs correspond to epithelium-lined true cysts in teratomas and dilated rete testis or necrosis in other tumors. The presence of solid hypoechoic areas in NSGCTs commonly corresponds to embryonal carcinoma and yolk sac tumor components, whereas hemorrhagic areas or metastases with hemorrhage indicate choriocarcinoma . NSGCTs show heterogeneous signal intensity at T1- and T2-weighted MRI, with hemorrhage and necrosis. NSGCTs also show heterogeneous contrast enhancement and frequent invasion of adjacent structures.

Figure 4. NSGCTs in three patients. (A–C) Pathologic findings of an NSGCT with a predominant yolk sac tumor and embryonal carcinoma in a 26-year-old man. Photograph of the sectioned gross specimen (A) shows a discrete solid-cystic mass with areas of hemorrhage and necrosis (arrow in A). Photomicrograph of the yolk sac tumor component (B) shows tumor cells palisading around a central capillary, known as a Schiller-Duval body (arrow in B). (Hematoxylin-eosin stain; original magnification, ×40.) Photomicrograph of the embryonal carcinoma component (C) shows a tubulopapillary appearance of cytologically anaplastic-appearing cells (arrows in C). (Hematoxylin-eosin stain; original magnification, ×40.) (D) Gray-scale US image of the right testicle in a 22-year-old man with a pathologically proven NSGCT (mostly a mixture of embryonal carcinoma and postpubertal teratoma) shows an ill-defined heterogeneously hypoechoic mass (arrow) replacing the entire testicular parenchyma. (E) Gray-scale US image of the left testicle in a 24-year-old man with a pathologically proven NSGCT (99% teratoma) shows a cystic mass (arrow) with thickened septa.

3. Embryonal carcinomas:

Aggressive features such as extratesticular extension and metastatic disease are common in TGCTs that show embryonal carcinoma. At histopathologic examination, anaplastic-appearing cells with diverse architectural patterns are seen.

At US, embryonal carcinoma is a solid predominantly hypoechoic heterogeneous mass with ill-defined margins, contour abnormality of the testicle, and invasion of the tunica albuginea. Ill-defined hypoechoic areas and echogenic foci represent hemorrhage, necrosis, and calcifications. At MRI, the tumor shows heterogeneous signal intensity, with areas of necrosis and hemorrhage.

Figure 5. NSGCT with a predominant embryonal carcinoma component in a 24-year-old man. Gray-scale US image of the scrotum shows a lobulated heterogeneously hypoechoic testicular mass (arrow) with invasion of the adjacent tunica albuginea (arrowhead). This mass was proved to be an NSGCT with 95% embryonal carcinoma and 5% postpubertal teratoma at pathologic examination.

4. Post Pubertal Yolk-Sac Tumor:

A pure postpubertal yolk sac tumor in adults is rare and is almost always part of an NSGCT. The tumor demonstrates extraembryonic differentiation into yolk sac elements and is commonly associated with marked elevation of serum α-fetoprotein levels. At pathologic examination of gross specimens, the yolk sac tumor component in an NSGCT appears as a solid to cystic area with a gray to tan myxoid cut surface and foci of necrosis and hemorrhage. Tumor cells are positive for glypican-3 and α-fetoprotein at immunohistochemical analysis.

At imaging, NSGCTs with a predominant yolk sac tumor component may manifest as ill-defined masses with varying amounts of cystic change, indicating necrosis and echogenic foci that correspond to hemorrhage. The tumor usually demonstrates variable signal intensity at T1- and T2-weighted MRI because of hemorrhage and cystic degeneration.

Figure 6. NSGCT with a predominant yolk sac tumor component in a 19-year-old man. (A) Gray-scale US image of the scrotum shows a well-circumscribed hypoechoic testicular mass with scattered cystic areas (arrow) and TM in the remaining testicle (arrowhead). (B) Axial contrast-enhanced CT image of the scrotum shows a well-circumscribed heterogeneously enhancing mass in the right testicle (arrow). This mass was proved to be an NSGCT with 99% postpubertal yolk sac tumor.

5. Choriocarcinoma:

Up to 16% of NSGCTs show choriocarcinoma, which is the most aggressive TGCT. The pure form of this tumor is rare. Choriocarcinoma is associated with microscopic vascular invasion, resulting in early widespread hematogenous dissemination. Serum β-hCG levels are markedly elevated. The presence of hemorrhagic nodules is typical at pathologic examination of gross specimens. Extensive areas of hemorrhage that are surrounded by a mixture of trophoblasts with vascular invasion are seen at histopathologic examination. Tumor cells are positive for β-hCG and GATA binding protein 3 (GATA3) at immunohistochemical analysis.

Figure 7. (A, B) Testicular choriocarcinoma in a 29-year-old man. (A) Photograph of pathologic specimens shows a hemorrhagic tumor rimmed by a gray-tan area (arrows). (B) Photomicrograph shows large multinucleated syncytiotrophoblasts and intermediate-sized cytotrophoblasts (arrows), with areas of hemorrhage (arrowheads). (Hematoxylin-eosin stain; original magnification, ×20.) (C, D) Choriocarcinoma in a 39-year-old man. Gray-scale US image of the scrotum (C) shows an ill-defined heterogeneously hypoechoic mass with cystic areas (arrows in C) that represent hemorrhage and necrosis. 

6. Postpubertal Teratoma:

A pure teratoma is uncommon in postpubertal male patients, and most tumors manifest as a component of an NSGCT. Serum tumor marker levels are normal. One-third of patients present with advanced disease, including mediastinal or intracranial masses, which are associated with a higher incidence of recurrence. At pathologic examination of gross specimens, tumors are often solid to cystic masses, with histologic features that vary depending on the tissue types present.

Imaging shows predominantly cystic lesions with macroscopic fat, calcifications, and solid components, depending on their immaturity. At US, these masses are markedly heterogeneous and predominantly cystic. Echogenic areas may correspond to calcification, cartilage, immature bone, or macroscopic fat. At MRI, teratomas are well-circumscribed complex cystic masses with signal intensity that varies according to the contents of the tumor (eg, serum, mucin, or keratin). Somatic-type malignancies that arise in the teratoma (ie, previously called teratocarcinomas) are seen in approximately 3%–6% of teratomas. They may arise in the testes or retroperitoneal lymph nodes and are associated with a poor prognosis. Sarcoma is the most common somatic-type malignancy, the majority of which are rhabdomyosarcomas.

Figure 8. Pure postpubertal teratoma in a 42-year-old man. (A) Gray-scale US image of the scrotum shows a mixed solid and cystic testicular mass with a few punctate echogenic foci (arrow). (B) Axial contrast-enhanced CT image of the abdomen shows a retroperitoneal lymph node with multiple calcifications (arrowhead). Postpubertal teratoma was diagnosed on the basis of pathologic examination.

7. Burned-Out TGCTs: 

A burned-out TGCT is a metastatic TGCT in which the primary tumor has completely or partially regressed, forming a fibrotic scar-like area. Burned-out TGCTs manifest exclusively by means of metastasis, most commonly in the retroperitoneum. Proposed mechanisms include ischemic regression from rapid tumor growth that exceeds perfusion and immune-mediated regression . The most frequent subtypes that regress are NSGCTs that predominantly contain teratomas or choriocarcinomas. At pathologic examination, the regressed areas show dense fibrosis with scar formation, with or without tubular lithiasis, and lymphoplasmacytic inflammation.

Figure 9. Burned-out TGCT in three patients. (A) Photograph of the sectioned gross specimen in a young man (in his 20s) shows the testicular parenchyma with a fibrotic scar like area (arrow) and central calcification (arrowhead). (B) Gray-scale US image of the scrotum in a 26-year-old man shows a focus of hyperechoic calcification (arrow) and an ill-defined hypoechoic area (arrowhead) with predominant choriocarcinoma components. (C) Gray-scale US image of the right inguinal canal in a 17-year-old adolescent boy shows an atrophic and undescended testicle with multiple hyperechoic calcifications (arrows).

Ex-Situ GCT’s:

1. Prepubertal Teratoma and Associated Tumors:

Prepubertal teratomas and associated tumors account for 65% of testicular tumors in prepubertal children. They have an excellent prognosis compared with that of postpubertal teratomas. Dermoid cysts, epidermoid cysts, and well-differentiated neuroendocrine tumors are distinct types of prepubertal teratomas. These tumors are also seen in adults, especially epidermoid cysts. A prepubertal teratoma can be mature or immature. Younger patients and those with larger tumors and elevated α-fetoprotein levels are more likely to have immature teratomas. At US, mature teratomas commonly manifest as cystic lesions that contain sebaceous material that contributes to a heterogeneously echogenic appearance. Immature teratomas are typically larger and solid from neuroectodermal components. Imaging features may also change over time. CT and MRI can show fat, calcification, and cystic components in mature teratomas.

2. Prepubertal Yolk Sac Tumors: 

A pure form of prepubertal yolk sac tumor is the most common testicular malignancy in children younger than 2 years. Elevated serum α-fetoprotein levels are seen and used for diagnosis and surveillance. Tumors are histologically similar to the postpubertal type, except for a lack of GCNIS and the absence of regression.

At US, the prepubertal yolk sac tumor manifests as either a homogeneous solid hypoechoic mass that can involve the entire testicular parenchyma or as a heterogeneous mass with solid and cystic areas. At MRI, the mass is T2 hyperintense and T1 hypointense, with restricted diffusion and heterogeneous contrast enhancement.

3. Spermatocytic Tumors:

A spermatocytic tumor is a rare TGCT (ie, it represents only 1% of testicular cancers) that is derived from mature germ cells such as a spermatogonium or an early spermatocyte. These tumors rarely metastasize, and patients with them have normal serum tumor marker levels. In contradistinction to a seminoma, this tumor manifests in men during the 6th decade of life. At imaging, a spermatocytic tumor appears as a large (>5 cm) well-defined multinodular heterogeneous mass with cystic foci. It has an excellent prognosis, without recurrence or metastasis.

Medical Professions

The management of gonadal germ cell tumors (GCTs), which develop in the testes or ovaries, necessitates the involvement of a specialized team of healthcare professionals responsible for diagnosis, treatment, and ongoing care. This team typically includes a diverse range of medical experts with distinct roles and responsibilities in addressing the complexities of these types of cancers.

1.Medical Oncologist:

These dedicated professionals coordinate all aspects of a patient's cancer treatment plan. Their job involves diagnosing various cancers, discussing treatment options with patients, arranging and supervising drug treatments, and drafting chemotherapy regimens tailored for GCTs. They also expertly manage any treatment-related complications and provide unwavering patient support while overseeing their care. Their extensive training involves four years of medical school, three years in an internal medicine residency, and a two-year medical oncology fellowship, totaling nine years after completing a four-year undergraduate program, also known as pre-med. Salaries vary widely based on location, experience, and employer. The average salary for medical oncologists in the United States is $457,516 per year, with an average additional cash compensation for a Medical Oncologist in the United States is $216,441, with a range from $162,331 - $303,017.

2.Surgical Oncologist: 

Surgical oncologists are central in managing gonadal germ cell tumors (GCTs). They perform surgeries that provide tissue for initial diagnosis and staging but aim for a complete cure for early-stage disease. In advanced cases, surgery can debulk tumors before other treatments or assess response to chemotherapy. They are skilled in conducting critical procedures such as orchidectomy (testicle removal) or hysterectomy (uterus removal), depending on the patient's gender. To become a surgical oncologist, one must complete four years in medical school, a 5-year general surgery residency, and 2-3 years of surgical oncology fellowship, totaling 11-12 years after completing a 4-year undergraduate program, also known as pre-med. The average surgical oncologist salary in the United States is $284,293. Surgical oncologist salaries typically range between $146,000 and $552,000 yearly.

3.Urologists:

They are the primary specialists in managing gonadal germ cell cancer (GCTs) due to their expertise in the male reproductive system. They diagnose the cancer through physical exams, imaging studies, and biopsies, and perform surgeries like orchidectomy and lymph node dissection. Urologists also collaborate with medical oncologists for chemotherapy and other treatments, monitor patients for recurrence, and provide long-term care, including fertility management. To be a urologist, you will need four years of medical school, 4-5 years of urology residency, and an extra 1 or 2 years of fellowship if going into more specialized areas, totaling 9-11 years of schooling after receiving a college degree. The average Urologist salary in the United States is $423,360, but the range typically falls between $371,530 and $493,760. Salary ranges can vary widely depending on many important factors, including education, certifications, additional skills, and the years you have spent in your profession.

4.Gynecologists: 

In women, a collaborative approach involving gynecologists, medical oncologists, and surgical oncologists is common. Gynecologists play a big part in diagnosing and treating ovarian germ cell tumors (GCTs), preserving fertility, and managing hormone imbalances associated with these cancers. Future gynecologists will have to go through 4 years of medical school, followed by four years of obstetric gynecology residency and an extra three years if going into any specialty, for example, maternal-fetal medicine or gynecologic oncology. In the United States, the average salary for a Gynecologist is $320,000, with a typical range between $277,600 and $385,000. The salary range can vary widely based on education, certifications, additional skills, and years of experience.

5.Radiology oncologist: 

A radiation oncologist specializes in treating cancer with radiation therapy. These specialists use radiation therapy to treat specific types of germ cell tumors (GCTs), especially those resistant to chemotherapy. Radiation oncologists have experience in treating all types of cancer using various forms of radiation. ]They must complete four years of medical school, one year of clinical training in internal medicine or surgery, and four years of residency in radiation oncology. In the United States, the average annual salary for a Radiation Oncologist is $460,200. However, the salary range can vary widely, falling between $396,560 and $528,400. This wide range is influenced by education, certifications, additional skills, and years of experience.

6.Pathologists:

These doctors play a critical role in confirming the diagnosis by carefully examining tissue samples, identifying the specific type of germ cell tumor (GCT), and accurately staging the cancer. To be a pathologist, you will need to complete four years of medical school, 3-4 years of pathology residency, and an optional two years of fellowship if you want to go into a specialty under pathology, totaling to 9-10 years of schooling after finishing a pre-med program (undergraduate degree). The average annual pay for a Pathologist in the United States is $337,500. The majority of pathologist salaries currently range between $285,000 to $378,500 across the United States. 

7.Pediatric oncologists: 

They are vital in treating germ cell tumors (GCTs) in children and adolescents. They provide essential support to both young patients and their families throughout their cancer treatment. Pediatric oncologists are responsible for administering chemotherapy, which can be delivered through an IV infusion, in a pill or liquid, or via injection. Their years of schooling include four years of medical school, three years of pediatric residency, and three years of pediatric oncologist fellowship, totaling ten years of education after receiving an undergraduate degree, also known as the pre-med. The average annual salary for a Pediatric Oncologist in the United States is $175,055, with the current salary range falling between $170,000 and $217,500.Although many other specialists work with germ cell tumors (GCTs), these are the main professionals involved. An endocrinologist or radiologist may be added depending on the patient's case.

Treatments

GCTs are generally treated with chemotherapy, a drug therapy that uses chemicals to kill fast-growing cells in the body. However, specific treatment plans depend on the tumor’s stage and location. For Stage 1 GCTs located in the testes or ovaries, no chemotherapy is required unless another GCT forms. For Stage II-IV GCTs in the testes, Stage II-III GCTs in the ovary, and Stage I-II non-testes or ovary GCTs, patients are treated with cisplatin, etoposide, and bleomycin (anti-cancer drugs) intravenously every 3 weeks for 3 cycles. For Stage IV tumors in the ovary and Stage III-IV non-testes or ovary GCTs, cisplatin, etoposide, and bleomycin are administered intravenously every 3 weeks for 4 cycles. In some instances, radiation therapy is used instead of chemotherapy for germinoma. If there is a residual tumor present after initial treatment, additional surgical resection and chemotherapy may be necessary. 

Sometimes, patients experience relapses of GCTs. Stage I patients who relapse after surgical resection alone are treated with 3-4 cycles of cisplatin, etoposide, and bleomycin chemotherapy. Patients suffering with other staged tumors who relapse after receiving chemotherapy are treated with additional chemotherapeutic drugs such as Paclitaxel, Ifosfamide and Carboplatin as well as autologous stem cell transportation. Autologous stem cell transplantation describes the process of harvesting the patient’s blood or marrow stem cells, treating the patient with very high doses of carboplatin and etoposide, and re-infusing the patient’s own stem cells. “Autologous” refers to the use of the patient’s own stem cells to avoid immune rejections and other risks of receiving stem cells from donors. This transplantation is used to mitigate the negative effects of intense chemotherapy; the high doses of carboplatin and etoposide not only destroy cancer cells but also the bone marrow, where blood cells are produced. Therefore, the patient’s stem cells need to be collected before chemotherapy treatment and reinfused back into the bloodstream afterwards. These stem cells travel to the bone marrow, where they begin to produce new and healthy blood cells. Tandem transplantation, which refers to when this procedure is done twice, is used in more severe cases of GCTs. 

Late relapses (GCTs that occur more than 2 years after initial chemotherapy) in seminomas are given the same treatment as early relapses in seminomas (chemotherapy alone). However, for late relapses in nonseminomatous GCTs, chemotherapy alone is rarely curative and the prognosis for such patients is much worse. As a result, a combination of surgery and chemotherapy is used to improve cure rates. 

Once treatment is complete, patients are followed for recurrence through physical examinations, blood tests for AFP or bHCG (if they were abnormal initially), CT scans of the chest and abdomen, and chest X-rays after several years. While most patients have few long-term side effects from chemotherapy, their blood counts, kidney function, hearing, and lung function are routinely monitored for signs of chemotherapy toxicities. 

Statistics

Germ cell tumors (GCTs) are a category of cancers originating from primordial germ cells, the cells destined to become sperm or eggs. These tumors can manifest in the testes as testicular germ cell tumors (TGCTs) or in the ovaries as ovarian germ cell tumors (OGCTs). TGCTs hold the distinction of being the most prevalent cancer among young men, affecting individuals primarily between the ages of 15 and 35. Despite representing a relatively small proportion of all cancers, approximately 0.5%, TGCTs have garnered significant medical attention due to their impact on a young demographic. Remarkably, advancements in treatment modalities have led to a substantial increase in cure rates, from around 25% in the 1970s to nearly 80% in contemporary practice. The highest incidence of TGCTs is observed in regions such as Scandinavia, Germany, and New Zealand.

Figure 10.  This table shows the estimated cases for TGCTs in 2024 and the % of all new cancer cases, including estimated deaths and 5-year relative survival. SEER Cancer Statistics Factsheets: Testicular Cancer. National Cancer Institute.

In contrast to TGCTs, ovarian germ cell tumors (OGCTs) are less commonly diagnosed but carry a more severe prognosis. While ovarian cancer overall is the fifth leading cause of cancer-related death among women, contributing to 2.5% of all female cancers, it is essential to note that the majority of ovarian cancers are not of germ cell origin. However, OGCTs constitute a significant proportion of ovarian tumors in young women. The peak incidence of OGCTs occurs in women during their twenties and thirties.

Figure 11.  This table shows the estimated cases for OGCTs in 2024 and the % of all new cancer cases, including estimated deaths and 5-year relative survival. SEER Cancer Statistics Factsheets: Ovarian Cancer. National Cancer Institute.

The pediatric population is also susceptible to GCTs. These tumors represent a substantial portion of cancers affecting adolescents, comprising approximately 17% of all cancers in this age group. Age-specific incidence rates follow a bimodal distribution, with an initial peak in early childhood and a subsequent peak in adolescence (Figure 12).

Figure 12. Age-specific incidence of germ cell tumors in males and females ages 0−19 years in the United States, 2015−2019. Source: National Childhood Cancer Registry.

With an estimated 15,780 cases in the Americas and 69,600 globally, the impact of GCTs on children and adolescents is evident. Geographic disparities in the incidence of pediatric GCTs are pronounced, with countries like Japan, Denmark, and Singapore reporting higher rates.

The global burden of germ cell tumors, particularly in young populations, underscores the importance of ongoing research, early detection, and improved treatment strategies. While significant progress has been made in managing these cancers, there remains a need for continued efforts to enhance patient outcomes and reduce the impact of GCTs on individuals and communities worldwide.

Impacts and complications

Gonadal germ cell tumors (GCTs) are a significant concern in the field of oncology, affecting both males and females, predominantly in the testes and ovaries. GCTs have profound impacts on the physical, emotional, and psychological well-being of affected individuals. Physically, these tumors can lead to significant health challenges, including the potential loss of reproductive organs, which directly affects fertility. The aggressive nature of some GCTs may necessitate intensive treatments like chemotherapy, surgery, and radiation, resulting in long-term side effects such as fatigue, pain, and secondary health issues. Emotionally, the diagnosis of a GCT can cause significant distress, leading to anxiety, depression, and concerns about recurrence, impacting the overall quality of life.

Gonadal germ cell tumors (GCTs) are significantly influenced by a combination of genetic, environmental, and physiological risk factors. Cryptorchidism (undescended testis), atrophic testis, hypospadias, and testicular dysgenesis syndrome are prominent conditions linked to an elevated risk of developing these tumors. Additionally, a family history of testicular germ cell tumors (TGCT), hereditary syndromes like Cowden syndrome, and low sperm count are crucial genetic factors that increase susceptibility.

Exogenous exposure to estrogen, particularly during fetal development, has also been identified as a significant environmental risk factor. These risk factors collectively contribute to the complexity of diagnosing and treating GCTs, making it essential for healthcare providers to consider them when developing early detection strategies and personalized treatment plans. Understanding these risk factors aids in improving patient outcomes and overall quality of life post-treatment.

Conclusion

Raising awareness about Germ Cell Tumors (GCTs) is critically important for patients, families, healthcare providers, and the public at large. Numerous methods exist to enhance awareness and safety regarding this disease, including the use of social media platforms, fundraising activities, public events, and educational campaigns. These strategies are highly effective in preventing the spread of GCTs, and regardless of the outcomes, societal support is advantageous for everyone. As a community, we have the opportunity to utilize these methods for the greater good, aiding not just acquaintances and friends but also family members.

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