Non-Seminomatous: Epidemiology, Etiology, Pathogenesis, Classification, Pathology, Symptoms, Diagnosis, Staging, Treatment and Prevention

Non-Seminomatous Germ Cell Tumors (NSGCT)

~Introduction

Non-seminomatous germ cell tumors (NSGCTs) are a group of malignant testicular tumors derived from primitive germ cells, distinct from seminoma in their histology, biological behavior, tumor marker profile, and response to therapy. They are generally more aggressive, occur at a younger age, and frequently present with early metastasis. Despite this aggressive nature, advances in platinum-based chemotherapy have made NSGCTs among the most curable solid malignancies.

Testicular germ cell tumors account for about 95% of all testicular cancers, of which 40–50% are non-seminomatous. NSGCTs include embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, and mixed germ cell tumors.

~Definition

Non-seminomatous germ cell tumors are malignant tumors of the testis composed of one or more histological subtypes other than seminoma, characterized by rapid growth, early hematogenous spread, and elevated serum tumor markers such as AFP and β-hCG.

~Epidemiology

• Constitute 40–50% of testicular germ cell tumors

• Common age group: 15–30 years

• Rare after 40 years

• Higher incidence in Caucasian males

• Mixed germ cell tumors are most common

~Etiology and Risk Factors

1. Cryptorchidism

• Major risk factor

• Risk increases even after orchiopexy

2. Genetic Abnormalities

• Isochromosome i(12p) (characteristic finding)

• KIT and KRAS mutations

3. Testicular Dysgenesis

• Klinefelter syndrome

• Gonadal dysgenesis

4. Environmental Factors

• Prenatal estrogen exposure

• Endocrine disruptors

5. Previous Testicular Cancer

• Increased risk of contralateral tumor

~Pathogenesis

NSGCTs arise from germ cell neoplasia in situ (GCNIS). Under genetic and hormonal influences, these precursor cells differentiate into various malignant germ cell lineages.

Key molecular features:

• Gain of chromosome 12p

• Overexpression of OCT3/4

• Deregulated pluripotency pathways

~Classification of NSGCT

1. Embryonal Carcinoma

• Most aggressive component

• Poorly differentiated cells

• Frequently part of mixed tumors

2. Yolk Sac Tumor (Endodermal Sinus Tumor)

• Most common in children

• Produces alpha-fetoprotein (AFP)

• Schiller-Duval bodies seen histologically

3. Choriocarcinoma

• Highly malignant

• Produces very high β-hCG

• Early hematogenous spread

4. Teratoma

• Contains tissues from all three germ layers

• Chemotherapy-resistant

• Malignant potential in adults

5. Mixed Germ Cell Tumors

• Most common NSGCT

• Combination of two or more components

~Gross Pathology

• Testis enlarged and irregular

• Tumor is heterogeneous

• Areas of:

  • Hemorrhage

  • Necrosis

  • Cystic degeneration

• Poorly circumscribed

~Microscopic Features

Embryonal Carcinoma

• Sheets of pleomorphic cells

• High mitotic activity

• Gland-like structures

Yolk Sac Tumor

• Reticular or microcystic pattern

• Schiller-Duval bodies

• Hyaline globules (AFP positive)

Choriocarcinoma

• Cytotrophoblasts and syncytiotrophoblasts

• Extensive hemorrhage

Teratoma

• Mature or immature tissues

• Cartilage, neural tissue, epithelium

~Tumor Markers

Tumor markers are crucial for diagnosis and management.

Marker	Associated Tumor
AFP	Yolk sac tumor, embryonal carcinoma
β-hCG	Choriocarcinoma, embryonal carcinoma
LDH	Tumor burden

*AFP elevation excludes pure seminoma

~Clinical Features

Primary Presentation

• Painless testicular mass

• Rapid increase in size

Local Symptoms

• Scrotal heaviness

• Pain due to hemorrhage

Metastatic Symptoms

• Back pain (retroperitoneal nodes)

• Hemoptysis (lung metastasis)

• Gynecomastia (hCG secretion)

• Neurological symptoms (brain metastasis)

~Diagnosis

1. Clinical Examination

• Firm, irregular testicular mass

2. Scrotal Ultrasound

• Heterogeneous hypoechoic lesion

3. Serum Tumor Markers

• AFP, β-hCG, LDH

4. Radical Inguinal Orchiectomy

• Diagnostic and therapeutic

• Avoid scrotal biopsy

5. Imaging for Staging

• CT abdomen and pelvis

• CT chest

~Staging (TNM Classification)

Stage I

• Confined to testis

Stage II

• Retroperitoneal lymph node involvement

Stage III

• Distant metastasis (lungs, liver, brain)

~Treatment of NSGCT

NSGCTs are less radiosensitive but highly chemosensitive.

1. Radical Inguinal Orchiectomy

• First step in all cases

2. Chemotherapy

Standard regimen: BEP

• Bleomycin

• Etoposide

• Cisplatin

Used in:

• Stage II and III disease

• High-risk Stage I

3. Retroperitoneal Lymph Node Dissection (RPLND)

• Indicated in:

  • Residual masses

  • Teratoma

• Prevents relapse

4. Surveillance

• Selected Stage I patients

• Strict follow-up required

~Prognosis

Prognosis depends on stage and tumor markers.

Risk Group	5-Year Survival
Good	>90%
Intermediate	80–90%
Poor	50–70%

~Complications

Disease-Related

• Early metastasis

• Tumor hemorrhage

• Infertility

Treatment-Related

• Nephrotoxicity

• Ototoxicity

• Pulmonary fibrosis

• Secondary malignancies

~Follow-Up

• Tumor markers

• Imaging studies

• Long-term surveillance

• Fertility counseling

~Prevention and Awareness

• Testicular self-examination

• Early orchiopexy

• Regular follow-up for high-risk patients

~Comparison: Seminoma vs Non-Seminoma

Feature	Seminoma	NSGCT
Age	30–45 yrs	15–30 yrs
Growth	Slow	Rapid
Metastasis	Late	Early
AFP	Normal	Elevated
Radiosensitivity	High	Low

~Conclusion

Non-seminomatous germ cell tumors are aggressive but highly curable malignancies of young men. Early diagnosis, appropriate staging, and timely platinum-based chemotherapy have dramatically improved survival. Understanding the histological subtypes, tumor marker patterns, and treatment strategies is essential for effective management and excellent outcomes.