Germ cell tumor pathophysiology

Germ cells are the cells that develop in the embryo and they make up the reproductive system in males and females.
After the development of germ cells, they follow the body midline path and descend into the pelvis as ovarian cells or into the scrotal sac as testicular cells.
Th ovaries and testes are called gonads and many ovarian and testicular tumors have germ cell origin.
The pathophysiology of germ cell tumors is different based on the classification of germ cell tumors
Each of the distinct entities of germ cell tumor has a different pathogenesis

Dysgerminoma

It is understood that ovarian germ cell tumors are the result of the pathologic transformation of primordial germ cells during different stages of the development.
The pathophysiology of ovarian germ cell tumors depends on the histological subtype.
Their common origin is believed to be from the primordial germ cells that transformed pathologically in different stages of development.
Dysgerminoma arises from primordial germ cells, which are gonadal cells that are normally involved in the gametogenesis.
The majority of dysgerminomas in women present in the stage 1A.
Bilateral invovlement occurs in 10% to 15% of the cases.
In < 15% of the affected cases, elements of other germ cell tumors can also be found.
It is difficult to distinguish subtypes of ovarian germ cell tumor on gross pathology alone.
The majority of ovarian germ cell tumors have a solid and cysticappearance with areas of hemorrhage and necrosis
On microscopic pathology, ovarian germ cell tumors may be characterized by a uniform “fried egg” appearance (dysgerminoma), presence of Schiller-Duval bodies (yolk sac tumor), presence of embryonic-like neural, gastrointestinal, and/or cartilaginous tissue (teratoma), or mixed histopathological features (embryonal cell carcinoma).

Accounts for about a third of all testicular germ cell malignancies and is one of the most treatable cancers with a survival rate of 98% to 99% in early-stage disease
Originates in the germinal epithelium of the seminiferous tubules as a result from the proliferation of immature spermatogonia
On gross pathology, seminoma is characterized by pale gray to yellow nodules that are uniform or slightly lobulated and often bulge from the cut surface
Microscopic Pathology:
- On microscopic pathology, seminoma is characterized by
- Cells with fried egg appearance - key feature
Clear cytoplasm

Central nucleus, with prominent nucleolus. Nucleus may have "corners", i.e. it is not round.
- Lymphocytes - interspersed (common)
- Syncytiotrophoblasts, present in 10-20% of seminoma
Large, irregular, vesicular nuclei

Eosinophilic vacuolated cytoplasm (contains hCG)
- Florid granulomatous reaction
- Approximately 24% of Stage I seminomas have lymphovascular invasion for stage I (Tx, N0, M0)^[1]
- Intertubular seminoma may not form a discrete mass and mimic a benign testis^[1]

On microscopic histopathological analysis, uniform cells that resemble primordial germ cells, consisting of large, round cells with vesicular nuclei and clear or finely granular cytoplasm that is eosinophilic are characteristic findings of germinoma.
Pure germinomas are composed of large polygonal undifferentiated cells with abundant cytoplasm arranged in nests separated by bands of connective tissue
The histologic appearance of NGGCTs varies depending upon the specific cell types present^[2]

Infiltrating small lymphocytes are often present and can obscure the diagnosis, especially in small biopsy specimens^[2]
Genes involved in the pathogenesis of germinoma include gains of 1p, 8p, and 12q and losses of 13q and 18q, duplication of the short arm of chromosome 12, loss of 1p and 6q, alterations in sex chromosomes in children, alterations of the p14 gene, mutations of the c-kit gene, aberrations of CCND2 (12P13), and RB1, and gain-of-function mutations of KIT.
The progression to germinoma usually involves the mutations of the KIT/RAS signalling or AKT1/mtor pathways and cyclin/CDK-RB-E2F pathway if CCND2(12P13) and RB1 genes are aberrated

The hypermethylation of the RUNX3 gene promoter and overexpression of GATA-4, a transcription factor has been associated with the development of endodermal sinus tumor.
On gross pathology, solid gray-white with a gelatinous, myxoid, or mucoid appearance, necrosis, cystic changes, and hemorrhage are characteristic findings of endodermal sinus tumor.
On microscopic histopathological analysis, Schiller-Duval bodies is a characteristic finding of endodermal sinus tumor.

Pineal embryonal carcinoma is a relatively rare malignant neoplasm and accounts for a small proportion of all intracranial germ cell tumors.
It is an aggressive tumor and has a propensity to metastasize systemically
the most aggressive component has a component of embryonal carcinoma that is often found in mixed germ-cell tumors
On microscopic histopathological analysis, pineal embryonal carcinoma is characterized by:
- Poorly differentiated, pleomorphic cells in cords, sheets, or papillary formation
- Indistinct cell borders
- Nucleoli - key feature
- Vesicular nuclei (clear, empty appearing nuclei) - key feature
- Necrosis - common
- Mitoses - common
- Variable architecture:
- Solid (predominant in ~55% of cases)
- Glandular (predominant in ~17% of cases)
- Papillary (predominant in ~11% of cases)
- Nested
- Micropapillary
- Anastomosing glandular
- Sieve-like glandular
- Pseudopapillary
- Blastocyst-like
- Embryoid bodies - ball of cells in surrounded by empty space on three sides

Pineal teratoma:

Mature teratomas are benign, mature, well-differentiated cystic lesions; whereas immature teratomas are poorly differentiated lesions with solid components and malignant transformation
On other occasions, mature teratomas contain elements that undergo malignant transformation (most commonly squamous components).
Fat
Cystic spaces due to mucus production or other exocrine products
Soft-tissue from any part of the body Calcification, including teeth
On microscopic histopathological analysis, pineal teratoma is characterized by cells originating from at least two and usually all three embryonic layers (ectoderm, mesoderm, and endoderm).
The histological subtype may not necessarily determine the biological behavior

Sacrococcygeal teratoma

Microscopic Pathology of sacrococcygeal teratoma can be divided into following two types depending on the microscopic pathology:

Mature Teratoma

Immature Teratoma

Malignant
Consists of small fraction of incompletely differentiated tissue
They have elevated tumor markers including yolk sac component secreting alpha fetoprotein or primitive neuroectodermal tumor (PNET).

Polyembryoma is a rare, very aggressive, and usually found in the ovaries
It has features of both yolk sac tumor and undifferentiated teratoma/embryonal carcinoma
A characteristic finding of embryoid bodies lying in a loose mesenchymal stroma can be found
It can be seen in association with Klinefelter syndrome

Gonadoblastoma is a benign tumor that almost exclusively involves individuals suspected of intersex disorders. This tumor comprised of underdeveloped germ cells and sex-cord stromal cells which defines the term gonadoblastoma.
The exact pathogenesis of gonadoblastoma is not fully understood. Gonadal development starts at 5 weeks of gestation and continues according to sex chromosomes. Any defects in this complicated process lead to defective gonadal development and gonadal dysgenesis and subsequently, it may be converted to gonadoblastoma in 20% to 30% of the cases.