Yolk Sac Tumor (Endodermal Sinus Tumor)
~Introduction
Yolk sac tumor (YST), also known as endodermal sinus tumor, is a highly malignant germ cell tumor that resembles the primitive yolk sac structures of early embryonic development. It is one of the most aggressive malignant germ cell tumors and occurs predominantly in children and young adults. Yolk sac tumors can arise in the gonads (testis and ovary) or at extragonadal sites, such as the sacrococcygeal region, mediastinum, and retroperitoneum.
YSTs are characterized by rapid growth, early metastasis, and the production of alpha-fetoprotein (AFP), which serves as an important diagnostic and prognostic tumor marker. Despite their aggressive nature, advances in chemotherapy have significantly improved survival rates, especially when diagnosed early.
~Historical Background
The term endodermal sinus tumor was first introduced by Teilum in 1959, who recognized the resemblance of these tumors to the endodermal sinus (yolk sac) of the rat placenta. Later, the term yolk sac tumor became widely accepted as it better reflected the embryological origin of the tumor.
~Epidemiology
Yolk sac tumors show a distinct age and sex distribution:
Children: Most common malignant germ cell tumor in infants and young children
Males: Frequently occurs in the testis, especially under 3 years of age
Females: Second most common malignant ovarian germ cell tumor (after dysgerminoma)
Extragonadal sites: More common in children than adults
Incidence
Accounts for 1–2% of all ovarian cancers
Represents up to 80% of testicular germ cell tumors in children
Rare in adults but often appears as a component of mixed germ cell tumors
~Etiology and Pathogenesis
Yolk sac tumors arise from primitive germ cells that fail to differentiate normally. These cells undergo malignant transformation and differentiate along extra-embryonic yolk sac lines.
Proposed Mechanisms
Abnormal migration of primordial germ cells during embryogenesis
Genetic instability leading to malignant transformation
Association with chromosomal abnormalities, especially isochromosome 12p (i12p) in adult cases
Risk Factors
Cryptorchidism (undescended testis)
Gonadal dysgenesis
Klinefelter syndrome (in mediastinal YSTs)
Prior germ cell tumors
~Sites of Occurrence
1. Gonadal Yolk Sac Tumor
Testis: Most common site in infants and children
Ovary: Typically affects adolescents and young women
2. Extragonadal Yolk Sac Tumor
Sacrococcygeal region
Mediastinum
Retroperitoneum
Pineal gland
Vagina (rare, seen in infants)
~Clinical Features
Testicular Yolk Sac Tumor
Painless testicular swelling
Rapid increase in testicular size
Firm, non-tender mass
Ovarian Yolk Sac Tumor
Abdominal pain and distension
Pelvic mass
Menstrual irregularities
Acute abdomen due to tumor rupture (rare)
Extragonadal Tumors
Symptoms depend on location
Mediastinal tumors may cause cough, chest pain, or dyspnea
Sacrococcygeal tumors present as a mass at birth or early infancy
~Gross Pathology
Large, soft to firm mass
Poorly circumscribed
Cut surface shows:
Yellowish-white appearance
Areas of hemorrhage and necrosis
Ovarian tumors are often unilateral and rapidly enlarging
~Microscopic Pathology
YSTs display marked histological diversity, often showing multiple growth patterns within the same tumor.
Characteristic Histological Patterns
1. Reticular (Microcystic) Pattern
Most common pattern
Network of spaces lined by tumor cells
Resembles lace-like structures
2. Schiller-Duval Bodies (Pathognomonic)
Central blood vessel surrounded by tumor cells
Enclosed within a cystic space
Resembles a glomerulus
Highly characteristic but not always present
3. Solid Pattern
Sheets of poorly differentiated cells
4. Papillary Pattern
Papillary projections with fibrovascular cores
5. Hepatoid Pattern
Tumor cells resemble hepatocytes
Associated with high AFP production
~Cytological Features
Large polygonal cells
Clear to eosinophilic cytoplasm
Prominent nucleoli
Frequent mitotic figures
Presence of hyaline globules (PAS-positive, AFP-positive)
~Immunohistochemistry
Immunohistochemistry is crucial for diagnosis.
Positive Markers
Alpha-fetoprotein (AFP) – most important marker
Glypican-3
SALL4
Cytokeratin
PLAP (variable)
Negative Markers
OCT3/4 (helps differentiate from embryonal carcinoma)
CD30
~Tumor Markers
Alpha-Fetoprotein (AFP)
Elevated in nearly all yolk sac tumors
Useful for:
Diagnosis
Monitoring treatment response
Detecting recurrence
Other markers:
LDH (non-specific)
Beta-hCG (usually normal unless mixed tumor)
~Differential Diagnosis
Embryonal carcinoma
Clear cell carcinoma (ovary)
Hepatocellular carcinoma (hepatoid variant)
Teratoma
Dysgerminoma / Seminoma
Immunohistochemistry and AFP levels are key in differentiation.
~Staging
Testicular YST
Uses TNM staging system
Ovarian YST
Uses FIGO staging
Early-stage tumors have a significantly better prognosis.
~Treatment
1. Surgery
Primary treatment modality
Testicular YST: Radical inguinal orchiectomy
Ovarian YST: Unilateral salpingo-oophorectomy (fertility-sparing)
2. Chemotherapy
YSTs are highly chemosensitive.
Standard Regimen:
BEP regimen
Bleomycin
Etoposide
Cisplatin
Chemotherapy has dramatically improved survival rates.
3. Radiotherapy
Limited role
Generally not effective
~Prognosis
Before the advent of chemotherapy, YSTs had a poor prognosis. Today, outcomes are significantly improved.
Survival Rates
Children: >90% long-term survival
Early-stage ovarian YST: 80–90% survival
Advanced disease: Lower but improving with treatment
Prognostic Factors
Stage at diagnosis
AFP levels before and after treatment
Response to chemotherapy
Presence of metastasis
~Complications
Tumor rupture
Metastasis (lungs, liver, lymph nodes)
Chemotherapy-related toxicity
Fertility issues
~Follow-Up and Monitoring
Regular AFP monitoring
Imaging studies
Long-term surveillance due to risk of recurrence
~Prevention
There are no known preventive measures due to the embryonic origin of the tumor. However:
Early detection
Awareness of testicular masses
Regular follow-up in high-risk patients
~Recent Advances
Improved chemotherapy protocols
Fertility-preserving surgical techniques
Molecular studies for targeted therapy
Better risk stratification using AFP kinetics
~Conclusion
Yolk sac tumor is a highly malignant but highly treatable germ cell tumor, particularly when diagnosed early. It predominantly affects children and young adults and is marked by elevated alpha-fetoprotein levels and distinctive histopathological features such as Schiller-Duval bodies. Advances in chemotherapy have transformed this once-fatal disease into one with excellent survival outcomes. Early diagnosis, accurate pathological identification, and aggressive multimodal treatment are essential for optimal prognosis.
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