Contributed by John M. Skaugen, M.D. and Rajiv Dhir, M.D.FINAL DIAGNOSIS
Mixed germ cell tumor (embryonal carcinoma; yolk sac tumor, post-pubertal type; teratoma, post-pubertal type) with invasion of the rete testis, lymphovascular invasion and germ cell neoplasia in-situ (GCNIS). Pathologic stage pT2 NX MX.
Follow-up:
A CT scan of the chest, abdomen and pelvis prior to surgery demonstrated no evidence of metastasis. He is currently undergoing surveillance. Postoperative tumor markers showed a sustained decrease into the normal range.
DISCUSSION
Testicular Germ Cell Tumors (GCTs) (1, 2):
Germ cell tumors arise from the primitive germ cells (spermatogonia, oogonia) in both men and women. They are most commonly seen in the testes and less commonly in the ovaries, but can also arise in the mediastinum, pineal or pituitary gland or retroperitoneum.
In adult men, most of these tumors arise from a precursor lesion, germ cell neoplasia in-situ (GCNIS), which will be the focus of discussion here. The majority of primary testicular tumors are malignant GCTs. In the United States, the incidence is up to approximately 6 per 100,000 in whites and 1 per 100,000 in blacks. Approximately 25% of cases can be attributed to genetic susceptibility. Risk factors include cryptorchidism, subfertility, a family history of germ cell tumor, and some disorders of sex development (ex. 45, X/46, XY mosaicism, AR or SRY mutations). Of interest, many of the tumors demonstrate isochromosome 12p as a potentially distinctive chromosomal abnormality. This finding can be useful when assessing metastatic disease.
Germ Cell Neoplasia In-Situ (GCNIS):
This precursor lesion is confined to the seminiferous tubules and consists of scattered cells which are enlarged and atypical, often resembling the cells of seminoma (Figure 4). The majority of GCTs discussed here will show GCNIS in the residual affected testis. Specific variants include intratubular seminoma and intratubular embryonal carcinoma, which have cell characteristic of these two tumors filling the tubules. The malignant cells can be highlighted with several immunohistochemical stains, such as PLAP, OCT3/4 and CKIT (Figure 4).
Seminoma:
This tumor is the most common testicular GCT, comprising just over 50% of all tumors in pure form. Of the remaining non-seminomatous tumors, approximately 1/3 will have a component of seminoma (mixed GCTs with seminoma are still considered non-seminomatous). The median age is approximately 35 years (range: 30-49 years). Most patients present with a testicular mass, and many will have testicular and/or low back pain. These tumors tend to first metastasize to retroperitoneal lymph nodes, though the majority are locally confined at presentation. Elevation of serum β-hCG may be seen in 10-20% of cases, and LDH may also be elevated in some cases.
Grossly, the tumors tend to be fleshy, tan to pink and lobulated to multinodular. There may be foci of necrosis and hemorrhage. Extratesticular extension is seen in less than 10% of cases. Microscopically, they typically consist of sheets of large, clear cells with prominent nucleoli, distinct cell borders and fibrovascular septa with variable amounts of lymphocytic infiltrate (Figure 5). Variable cytological features may be seen in a minority of cases, such as plasmacytoid or signet ring areas. Immunohistochemically, the tumor cells are typically positive for PLAP, OCT3/4, CKIT (CD117) and SOX17.
Embryonal Carcinoma:
This tumor comprises somewhere between 5-15% of all GCTs in pure form. Overall, it is a component of 40% of all GCTs, and a component of 87% of non-seminomatous GCTs. The typical age range is 25-32 years, approximately 10 years younger than seminoma. Patients may present with a testicular mass or symptoms related to metastatic disease (ex. back pain, dyspnea, neurological symptoms, etc.). Patients with this tumor are more likely to have metastatic disease at the time of diagnosis, most commonly in the retroperitoneal lymph nodes. Serum β-hCG, LDH and PLAP may be elevated.
Grossly, the tumors are typically pale-gray and irregular with hemorrhage and necrosis. Extratesticular extension is seen in approximately 20% of cases. Microscopically, they consist of large, amphophilic cells with enlarged, irregular nuclei that display vesicular to clumped chromatin and prominent nucleoli. There are often areas of coagulative necrosis and a high mitotic rate. The most common architectural patterns are solid, glandular and papillary (Figure 6). Immunohistochemically, the tumor cells are typically positive for cytokeratins, PLAP, OCT3/4, CD30 and SOX2.
Yolk Sac Tumor (post-pubertal):
This tumor is rare in pure form, comprising slightly less than 1% of all GCTs. However, it is a component of 44% of non-seminomatous GCTs. The typical age range is 15-40 years. Patients typically present with a testicular mass, or less commonly with symptoms related to metastatic disease. Nearly all patients will have elevated serum AFP.
Grossly, the tumors may be grey to tan to yellow with variable cystic and myxoid areas. There is often hemorrhage and necrosis. The microscopic appearance is highly variable, with 11 possible patterns described: reticular/microcystic, myxomatous, macrocystic, solid, glandular/alveolar, endodermal sinus, papillary, hepatoid, sarcomatoid, parietal, polyvesicular vitelline. The most common patterns are reticular/microcystic and solid (Figure 7). There may be areas of basement membrane deposition or hyaline globules. Immunohistochemically, the tumor cells are typically positive for cytokeratins, SALL4, AFP and glypican 3. Glandular areas may be positive for CEA, and hepatoid areas are usually positive for HepPar1.
Teratoma (post-pubertal):
This tumor comprises approximately 5% of all GCTs in pure form. It is present as a component of approximately 50% of all mixed GCTs. The typical age range is similar to the other non-seminomatous GCTs. Patients may present with a testicular mass or symptoms related to metastatic disease. Up to 1/3 of patients can have metastasis at the time of diagnosis, mostly commonly to the retroperitoneal lymph nodes. Serum tumor markers are usually negative.
Grossly, the tumors may be multinodular with solid and cystic areas. Cartilage, mucus or keratin may be seen, as well as fleshy areas. Microscopically, essentially any tissue type can theoretically be identified, often with atypia. The most common components identified are cartilage, gastrointestinal or respiratory glands, squamous epithelium, urothelium, neuroglia and fibrous stroma. Somatic-type malignancy can arise in any of these tissue types within the tumor, though this is uncommon. Immunohistochemically, glandular components may be positive for PLAP or SALL4 in a minority of cases. Individual tissue types often retain their typical staining patterns.
Choriocarcinoma:
This tumor is also rare in pure form, comprising approximately 0.3% of all GCTs. It is present as a component of approximately 15% of all mixed GCTs. The typical age range is 25-35 years. Patients often present with symptoms of metastatic disease (ex. lower back pain, hemoptysis, GI bleeding, neurological changes) rather than a testicular mass. Patients may also have gynecomastia or thyrotoxicosis as a result of significantly elevated β-hCG. Serum β-hCG is typically significantly elevated (> 50,000 IU/L).
Grossly, the tumors are often small and may be non-apparent. They may be grey, often with central hemorrhage and necrosis. Microscopically, these tumors classically consistent of clusters of clear to pale mononucleated cells with mild to moderate nuclear pleomorphism capped by or intermixed with large multinucleated cell with intracytoplasmic lacunae and smudged chromatin (Figure 8). The mononuclear cells represent cytotrophoblasts and intermediate trophoblasts, which the multinucleated cells represent syncytiotrophoblasts. The cells are typically seen at the periphery of areas of hemorrhage and necrosis. Immunohistochemically, the syncytiotrophoblasts are positive for hCG and inhibin, while mononuclear trophoblasts may be positive for SALL4, with intermediate trophoblasts also being positive for hPL. Tumor cells may also be positive for PLAP, cytokeratins or EMA in some cases.
Mixed Germ Cell Tumors:
The majority of non-seminomatous GCTs are mixed GCTs (approximately 70%), making them the second most common testicular GCT overall. Patients will present similarly to the above pure tumors. The typical age range is between those of seminomatous and non-seminomatous GCTs (median age approximately 30 years). Serum tumor markers may be elevated depending on the specific components.
Grossly, the tumors are often variegated with areas of hemorrhage and necrosis. They may have the gross features described above for their specific components. Microscopically, the tumors consist of various components of any of the above described pure tumors. A majority of tumors have a component of embryonal carcinoma, and many also have a component of teratoma or seminoma. Yolk sac tumor components may be overlooked, particularly in a background of embryonal carcinoma. Immunohistochemical stains can be helpful to identify all components. Two specific types of mixed GCT exist - polyembryoma and diffuse embryoma (Figure 9). Polyembryoma forms embryo-like bodies which consist of an amniotic-like cavity, core of embryonal carcinoma and component of yolk sac tumor. Diffuse embryoma also consists of embryonal carcinoma and yolk sac tumor components in relatively equal amounts forming a double layer - an inner, necklace-like layer of embryonal carcinoma with a thin outer layer of yolk sac tumor.
Trophoblastic Differentiation in Germ Cell Neoplasia:
Elevated serum β-hCG may be seen in up to 10-20% of non-choriocarcinoma GCTs, which correlates with focal trophoblastic differentiation microscopically (Figure 10). This is seen as scattered syncytiotrophoblasts and large mononuclear trophoblasts in a haphazard arrangement. The typical pattern of choriocarcinoma is not seen (syncytiotrophoblasts surrounding/capping mononuclear trophoblasts). These cells are often seen adjacent to blood vessels. Immunohistochemically, these cells have the same staining patterns as choriocarcinoma. Additionally, the serum β-hCG levels are typically less than 1,000 IU/mL, much less than those seen in choriocarcinoma.
Staging (3):
For staging testicular tumors, it is important to document the size and gross extension. Involvement of structures outside the testis and/or extension through the tunica albuginea should be documented. The size of involved lymph nodes, if applicable, should also be documented.
For pure seminomas, pT1 is subdivided into two categories (T1a, T1b) based on a size cutoff of ? 3.0 cm. This subdivision does not apply to non-seminomatous GCTs. Involvement of the rete testis is also still considered pT1. There are several scenarios which qualify as pT2: invasion of the hilar soft tissue, invasion of the epididymis, extension through the surface of the tunica albuginea (penetrating the visceral mesothelial layer). Additionally, tumors that do not meet any of these criteria, but have definitive lymphovascular invasion qualify as pT2. Invasion of the spermatic cord, including involvement surrounding the vas deferens, would be considered pT3. Of note, this must be direct extension. Invasion of the scrotum would be considered pT4.
Lymph node staging involves the number of involved lymph nodes and the size of the metastases. Distant metastasis staging depends on the site (non-regional lymph nodes/pulmonary versus non-pulmonary).
Staging of these tumors also involves a serum tumor marker component, so obtaining these values is important to appropriately determine the stage group.
REFERENCES
Contributed by John M. Skaugen, M.D. and Rajiv Dhir, M.D.
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