Available online 7 July 2022

Abstract

Germ cell neoplasia in situ (GCNIS) is the precursor of both seminomatous and non-seminomatous germ cell tumors. It consists of distended tubules that may have either intratubular seminoma or intratubular embryonal carcinoma cells. Many invasive non-seminomatous tumors contain a mixture of tumor types, which are reviewed here. Morphology, aided by a panel of immunostains, can determine the presence and percent of embryonal carcinoma, yolk sac tumor, choriocarcinoma, or teratoma in such tumors. Use of immunostains, required for diagnosis in perhaps 25% of testicular neoplasms, is reviewed. Changes of classification in the AJCC (8th edition) in 2016 are discussed, including the partitioning of two tumor types: the central role of chromosome 12p amplification allows both teratoma and yolk sac tumor to be divided into prepubertal types (lacking amplification) and post-pubertal types. Occasionally, sex cord-stromal tumors, hematolymphoid tumors, or epididymal adenomatoid tumors enter the differential diagnosis of germ cell neoplasms.

Section snippetsGross Processing of the Orchiectomy Specimen

All diagnoses start with proper gross processing. Because the testicular tunica albuginea is impermeable to fixative, placing it directly into fixative will cause autolysis. Instead, the testis should be at least bisected prior to fixation. Even in normal testis, fixation artifact can create areas that resemble tumor (Fig. 1). A margin section of spermatic cord should be sampled first before the tumor is sampled to avoid contamination of tumor on the knife blade. About one block should be

Non-Invasive Precursor

The precursor of invasive germ cell tumors, currently accepted by ISUP, is germ cell neoplasia in situ (GCNIS), formerly designated intratubular germ cell neoplasia, unclassified type (IGCNU). Differentiated forms of intratubular germ cell tumors are also seen, most commonly intratubular seminoma or intratubular embryonal carcinoma (in 24% of cases with embryonal carcinoma)4.

GCNIS almost always accompanies invasive germ cell tumors. Most patients (>70%) with GCNIS develop an invasive germ cell

Invasive neoplasms of the testis

Germ cell tumors comprise 95% of testicular tumors. Extragonadal locations include pineal, mediastinum, and retroperitoneum. Certain conditions increase the risk of germ cell tumors, namely: cryptorchidism (about 4 ×), history of a prior testicular tumor, first degree relative with a germ cell tumor, gonadal dysgenesis, and androgen insensitivity syndrome. Orchidopexy does not decrease the risk of a germ cell tumor, but allows for regular testicular exam. Patients with history of cryptorchidism

Seminoma

Clinically, seminoma is the most common germ cell tumor, present in 50% of all germ cell tumors. It is most common in middle-aged men (mean age at diagnosis, 40 years) and rare in children and the elderly. Patients present with a painless testicular mass, but up to 15% may have a normal exam.

30% of patients have metastases at presentation, but only 3% have symptoms related to metastases. The serum α-fetoprotein is normal. In 10% of patients with Stage I seminoma, β-human chorionic gonadotropin

Spermatocytic Tumor

Formerly designated spermatocytic seminoma, spermatocytic tumor has been proven to be quite different from seminoma, with contrasting morphologic, cytogenetic, and clinical features. It occurs only in the testis and represents up to 2% of germ cell tumors. 9% are bilateral. There is a right-side predilection.

It very rarely metastasizes and therefore is almost always cured by orchiectomy. Patients' average age is in the 50s and they present with a testicular mass.

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Unusual cases may be associated

Embryonal Carcinoma

Embryonal carcinoma is a frequent component of mixed germ cell tumor but considerably less common as a pure tumor. Most men present in their 20–30s with a testicular mass and it is very rare in children and older men. 40% of patients have metastasis at presentation but only 10% of patients have symptoms related to metastases. Serum AFP is normal, and β-hCG is elevated in 60% of cases.

Grossly one expects a fleshy gray-white tumor, often with prominent necrosis and hemorrhage. Microscopically (

Yolk Sac Tumor (Endodermal Sinus Tumor)

The AJCC (8th edition) in 2016 now divides yolk sac tumor into a prepubertal and a post-pubertal type. In children (and rarely occurring in adults) prepubertal yolk sac tumor is the most common germ cell tumor (and most common testicular tumor), where it occurs in pure form. The majority of cases are diagnosed before 24 months with a mean age of 18 months. There is neither chromosome 12p amplification nor GCNIS.

In adults, postpubertal yolk sac tumor is histologically identical to the

Teratoma

The AJCC 8th edition now recognizes two types of teratoma. An mRNA-binding protein called IMP3 is a marker for both types, as well as occurring in most testicular germ cell tumors19.

Prepubertal teratoma, or type I, is the second most common germ cell tumor in children. It occurs in its pure form with a mean age at diagnosis of 13 months. It arises from a non-transformed germ cell with no GCNIS, and possesses diploid DNA and a 46, XY karyotype, without chromosome 12p abnormalities. Metastases do

Monodermal forms of teratoma

These include carcinoid tumor and embryonic type neuroectodermal tumor: Carcinoid tumors can be associated with other teratomatous elements (15% of cases). They have a good prognosis, with 10–14% developing metastases. Carcinoid syndrome occurs rarely. They usually are not associated with GCNIS.

One type of teratoma overgrowth of immature neural elements resembles primitive neuroectodermal tumor (PNET) (Fig. 26). Adult cases are associated with GCNIS and i12p. Pediatric cases are not, and a

Dermoid Cyst

A variant of prepubertal teratoma, dermoid cyst has a consistent benign outcome after orchiectomy. This places it into a separate category from mature teratoma23,24. Benign teratomas lacking the cutaneous-type adnexal structures of dermoid cysts have been described.

Dermoid cyst is composed of mature skin with adnexal structures and smooth muscle bundles in the wall (like arrector pili) and hair; may have ciliated epithelium, intestinal mucosa, or bone. Unlike in mature teratoma, they lack

Epidermoid Cyst

As another variant of prepubertal teratoma, epidermoid cyst has a benign after orchiectomy. It still may have loss of heterozygosity on some of the same chromosomes as in malignant germ cell tumors25. Microscopically, epidermoid cyst has a keratin-filled squamous lining. Like dermoid cyst, there is no cytologic atypia or associated GCNIS. Unlike dermoid cyst, it lacks adnexal structures or heterologous elements.

Choriocarcinoma

In its pure form it is very unusual (<1% of germ cell tumors) but it is a component of 10% of mixed germ cell tumors. Many patients present with symptoms related to metastases to the brain or lungs. The serum β-hCG is elevated, and the cross-reactivity of this with other hormones may lead to gynecomastia and thyrotoxicosis. Patients have a poorer prognosis than with other germ cell tumors, but the tumor is sensitive to chemotherapy. Children do not develop choriocarcinoma.

Grossly the tumor is

Mixed Germ Cell Tumor

Comprising about 33% of all germ cell tumors, mixed tumors are composed of two or more germ cell tumor types, often seminoma and nonseminomatous components. Notably, the latter disparate types tend to have the same allelic loss profiles26. Embryonal carcinoma with yolk sac tumor is common. If β-hCG is elevated, presence of a minute choriocarcinoma component should be sought.

Regressed Tumor

Germ cell tumors may regress. Microscopically, replacement of the testis by viable and necrotic fibrovascular tissue can preclude typing of preexisting tumor (Fig. 29), although sometimes immunostains of any remnant of necrotic tumor may permit a precise diagnosis27. Scar tissue is nodular or stellate with chronic inflammation, prominent vessels, and ghost outlines of tubules. Only a cystic trophoblastic lesion may be present after chemotherapy28. The differential diagnosis is a scar due to

Germ cell tumor staging

We conclude by discussing the TNM staging system for testicular germ cell tumors (Table 3). AJCC 8th edition modifications1 are italicized. Notably, vascular invasion or tunica albuginea perforation into tunica vaginalis (Fig. 31) are required to raise the stage from pT1 to pT2. An important point to emphasize is to caution against misrecognizing vascular invasion, which accounted for the majority of the 7% of second-opinion diagnoses that had clinically-significant alterations29. The

Treatment

With seminoma, clinical stage I tumors and non-bulky stage II tumors are usually treated by radical orchiectomy and radiation to ipsilateral para-aortic and pelvic lymph nodes. Some patients with a stage I tumor may be treated by radical orchiectomy alone, with careful follow-up. The cure rate is 95% for stage I tumors and nearly 90% for stage II tumors. In patients with bulky stage II seminoma and more advanced stages, orchiectomy and chemotherapy are performed, with survival rates of 80%.

In nonseminomatous Germ Cell Tumors, for Stage I-

Treatment option A is radical orchiectomy and retroperitoneal lymph node dissection. The cure rate is 90–95% and the relapse rate is 5–10%. Treatment option B is radical orchiectomy and surveillance with a cure rate of 60–70% and a relapse rate of 30–40%. Chemotherapy, however, salvages almost all of these relapses

For Stage II, if non-bulky, orchiectomy, lymph node dissection, and chemotherapy are used with a cure rate of 90%. If tumor is bulky, orchiectomy, chemotherapy, and resection of

Therapy effect

The most common finding after chemotherapy in the retroperitoneal lymph nodes is necrotic tissue with surrounding fibrosis and inflammation. Often, minimal or no viable tumor is left. The variety of findings has been reviewed38. The use of immunostains to highlight dead cells, or “paleoimmunohistochemistry,” is useful in such instances. In teratoma, the stromal cells after chemotherapy are derived from the same cells as the tumor38.

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