Histopathology Of Testicular Germ Cell Tumors

Testicular GCTs account for less than 1% of all internal organ malignancies in adult males.25 Nevertheless, these tumors are important because they typically affect young adult males and men in their most productive years. Furthermore, testicular GCTs are readily curable if diagnosed on time and treated appropriately.

GCTs account for more than 90% of all testicu-lar tumors. These tumors have many features in common. Thus, they have a peak incidence in the 25- to 40-year age group. All GCTs of adult testes, with the exception of spermatocytic seminoma, originate from intratubular CIS. All testicular tumors tend to metastasize first to the periaortic lymph nodes but can disseminate later hematoge-nously to other major organs as well. Currently, over 90% of all testicular GCTs are curable by modern therapeutic approaches.26

For clinical purposes, adult testicular GCTs should be separated from the testicular tumors of infancy and childhood. In the adult testes, two types of GCT predominate: seminomas, which account for 40% of all GCTs, and NSGCTs, which account for 35%. If one adds to them the third entity—NSGCT combined with seminoma (accounting for about 15% of all GCTs)—it becomes evident that seminomas and NSGCTs form the vast majority of all tumors of the adult testis. Spermatocytic seminomas, pure yolk sac tumors, pure choriocarcinomas, and teratomas of postpubertal or adult testes are rare. The same holds true for sex cord tumors such as Sertoli cell tumors and Leydig cell tumors. Most of the testicular tumors of infancy and childhood are classified as yolk sac tumors and teratomas.

Seminoma

Seminoma is the most common GCT of the testis.6 This tumor is composed of a single cell type. The neoplastic cells resemble spermatogonia and have vesicular nuclei and well-developed cytoplasm filled with glycogen. The cells are arranged into nests surrounded by fibrous septa infiltrated with lymphocytes (Figure 4-2).Tumor cells may grow in the form of cords, solid sheets, or distinct nodules or may present in a tubular, reticular, cystic, or cribriform pattern.6 Tumors invade or replace the adjacent testicular tissue, but occasionally the cells grow between the seminiferous tubules. Intratubular spread is found in one-third of all tumors. Invasion of the rete testis, often in a pagetoid manner, is seen in 40% of cases and may be accompanied by intratubular extension into the epididymis. Most seminomas show brisk mitotic activity, but there is no evidence that counting mitoses has any prognostic significance.6

Immunohistochemistry is useful in distinguishing seminomas from embryonal carcinoma. Typi

Mitotic Seminoma
Figure 4-2. Seminoma. The tumor cells are arranged in solid nests surrounded by lymphocyte-rich fibrous septa (hematoxylin and eosin; x160 original magnification).

cally, most seminomas express PLAP and do not stain with antibodies to keratin (AE1/AE3) whereas embryonal carcinoma cells are PLAP negative and keratin positive.614 Furthermore, most seminomas express CD117 and do not express CD30 whereas most embryonal carcinomas are CD117 negative and CD30 positive.27

Human chorionic gonadotropin-positive multi-nucleated syncytiotrophoblastic cells are present in appoximately 25% of all seminomas.6 Cytogenetic studies show a marker chromosome, i(12p), in the majority of cases.

Nonseminomatous Germ Cell Tumors

NSGCTs comprise a group of neoplasms that may present in the following several histologic forms: (1) pure embryonal carcinoma; (2) mixed germ cell tumors (also known as teratocarcinomas), composed of embryonal carcinoma, somatic tissues, and extraembryonic tissues equivalent to yolk sac carcinoma and choriocarcinoma; (3) pure yolk sac tumor; (4) pure choriocarcinoma; (5) NSGCT combined with seminoma; and (6) teratoma of postpubertal testes.

Embryonal Carcinoma

The term "embryonal carcinoma" is used for a cell type as well as for a subtype of NSGCT. Embryonal carcinoma (EC) cells are undifferentiated malignant cells resembling the developmentally pluripotential and uncommitted cells from early stages of embryogenesis. Embryonal carcinoma cells that have lost their capacity to differentiate form monomorphic tumors composed of single cell type. Such pure embryonal carcinomas, account for 2 to 3% of all GCTs. Developmentally pluripotent EC cells form the stem cells of mixed GCTs (teratocarcinomas), which account for 30 to 35% of all testicular GCTs. In British classification systems, teratocarcinoma is also known as malignant teratoma [immature].

EC cells are usually polygonal, columnar, or cuboidal and have indistinct borders, contributing to the crowding of nuclei in histologic sections. Because the cytoplasm is scant, the nuclei appear as overlapping one another. These tumor cells may be arranged into solid sheets or into papillary, glandlike, or tubular structures (Figure 4-3). The mitotic rate is high, and the tumor cells often undergo apop-tosis. Broad areas of necrosis, intratubular invasion, vascular invasion, and distant metastases (found in 60% of cases) are common.

Immunohistochemically, ECs are positive for keratin, CD30, and (quite often) PLAP. They are negative for CD117 and epithelial membrane antigen (EMA).6,27Cytogenetic study will usually reveal an isochromosome, i(12p). Syncytiotrophoblastic cells positive for chorionic gonadotropin are commonly found adjacent to EC cells, but the finding of such cells is still compatible with the diagnosis of EC.

Mixed Germ Cell Tumor (Teratocarcinoma)

Mixed GCTs are NSGCTs that are composed of (1) malignant stem cells equivalent to EC, (2) a ter-atomatous portion composed of somatic tissues, and (3) extraembryonic tissues such as choriocarcinoma and yolk sac carcinoma. Apparently, these EC cells have retained their capacity to differentiate, like their equivalent embryonic cells in the pre-implantation embryos. EC differentiating into somatic tissues such as neural tissue, cartilage, bone, and glands gives rise to the teratomatous part of such tumors. EC cells differentiating into extraembryonic tissues form the parts of the tumor composed of yolk sac and choriocarcinoma components.

For clinical purposes, there are no significant differences between EC cells that form monomorphous

Embryonal Carcinoma
Figure 4-3. Embryonal carcinoma. Tumor cells form solid sheets and papillary structures (hematoxylin and eosin; x180 original magnification).

tumors and those that have retained their capacity to differentiate into other tissues. The EC cells that are developmentally "nullipotent" are cytologically indistinguishable from those found in mixed GCTs considered to be pluripotent. The only significant difference is that mixed GCTs containing yolk sac carcinoma elements usually secrete a-fetoprotein (AFP), and those containing trophoblastic elements secrete human chorionic gonadotropin (hCG) into the blood. On the other hand, patients harboring pure EC may be sero-logically negative for AFP and hCG.

Yolk Sac Tumor

The cells that form the yolk sac tumor (also known as endodermal sinus tumor or "Teilum tumor") resemble the cells found in the extraembryonic structures corresponding to visceral embryonic endoderm of the peri-implantation-stage germinal disc, extraembryonic yolk sac, allantois, and related extraembryonic mesenchyme (magma reticulare). Yolk sac components are typically found in about 65% of all mixed GCTs,6 but they may exceptionally be the only element of adult NSGCTs.28 29 Pure yolk sac tumor is the most common testicular tumor of infancy and early childhood.6 Infantile yolk sac tumors appear to be biologically distinct from yolk sac tumors of adults29,30 and should not be included among the NSGCTs.

Yolk sac tumor components of NSGCTs in adults have the same histologic features as the pure infan tile yolk sac tumors. Ulbright and colleagues6 list 11 different patterns: (1) a reticular pattern, composed of a network of interlacing elongated cells, micro-cystic clear spaces, and vacuolated cells resembling fat cells; (2) a macrocystic pattern, in which larger empty spaces are lined by flattened cells; (3) an endodermal sinus pattern, in which cuboidal or columnar cells are attached to vascular papillary cores (often described as "festooned") or line tissue spaces in a labyrinthine pattern (resembling the endodermal sinus of the murine placenta) and/or form glomeruloid bodies (Schiller-Duval bodies); (4) a papillary pattern resembling mesothelioma or other micropapillary tumors; (5) a solid pattern composed of solid sheets of epithelial cells; (6) a glandular/alveolar pattern, in which cuboidal or columnar cells form structures resembling intestinal or endometrioid glands or line acinar and cystic spaces; (7) a polyvesicular vitelline pattern composed of cuboidal or flat epithelium-lined cysts surrounded by generally loose mesenchyme; (8) a myx-omatous pattern composed of spindle-shaped or stellate cells lying in a loose myxomatous stroma containing prominent thin-walled blood vessels; (9) a sarcomatoid pattern composed of anaplastic spindle cells; (10) a hepatoid pattern resembling fetal liver; and (11) a parietal yolk sac pattern, in which the extracellular basement membrane material predominates. The reticular pattern is most commonly seen, followed by the solid and endodermal sinus patterns (Figure 4-4).

Immunohistochemically, most yolk sac tumors stain with antibodies to AFP. Epithelial cells are positive for keratins. Staining for CD34 is often positive, allowing one to distinguish yolk sac tumors from seminomas and EC, which are negative. Staining for PLAP may give positive or negative results and is of limited value. EMA is typically negative and is helpful in distinguishing yolk sac tumors from adenocarcinomas. Other immunohistochemical stains are of lesser diagnostic value.

Choriocarcinoma

Choriocarcinomas are composed of cells resembling syncytiotrophoblastic and cytotrophoblastic cells that line the chorionic villi. Pure testicular chorio-

Medical Images Testicular Growths
Figure 4-4. Yolk sac tumor. The tumor consists of inter-anastomosing strands. Focally, the tumor cells form glomeruloid structures (Schiller-Duval bodies) (hematoxylin and eosin; x120 original magnification).

carcinomas are extremely rare, accounting for 0.3% of all testicular tumors.6 Focal choriocarcinoma cells can be found in 8% of all NSGCTs.30

Choriocarcinoma cells tend to destroy tissue and invade blood vessels, causing necrosis and hemorrhage. Such foci typically contain (1) mononuclear cytotrophoblastic cells with clear cytoplasm and (2) multinucleated syncytiotro-phoblastic cells (Figure 4-5).

Combined Seminoma and NSGCT

The combined seminoma and NSGCT is included under the heading of mixed GCTs in some texts6

Where Are Germ Cells Found
Figure 4-5. Choriocarcinoma. The tumor consists of mononuclear cytotrophoblastic and multinucleated syncytiotrophoblastic cells (hematoxylin and eosin; x180 original magnification).

whereas other texts place them in a separate category.31 Such combined tumors provide an interesting insight into the histogenesis of GCTs, indicating that some NSGCTs arise from preexisting seminomas.32 However, another published interpretation is that seminoma and NSGCT both arise from a common precursor germ cell (see Chapter 1).

Combined tumors account for 15% of testicular GCTs. Most often these tumors consist of seminoma admixed with embryonal carcinoma cells. However, seminoma may be admixed with other NSGCT components, such as teratoma, yolk sac, and choriocar-cinoma, which may be present in varying proportions. For practical purposes, these combined tumors are treated as NSGCTs. By convention, pure semi-nomas containing syncytiotrophoblastic cells are not included in this category.

Teratoma of Postpubertal Testis

Teratomas of the postpubertal testis, also known as mature teratomas, are composed of somatic tissues. In contrast to mixed NSGCTs (teratocarcinomas), these teratomas do not contain EC cells.

Even though these tumors do not contain EC cells, they occasionally produce metastases that may be composed of somatic tissues (mature metastasizing teratoma) or that consist of EC cells.6,33 It seems that most of these metastases are derived from small foci of EC that have not been recognized in the primary testicular tumor. These teratomas are thus best considered fully differentiated forms of mixed NSGCTs (teratocarcinoma) in which almost all EC cells have differentiated into somatic tissue. Since one cannot be entirely sure that a large tumor does not contain EC cells in a part that was not examined histologically, or that some EC cells have already metastasized before the tumor was resected, all ter-atomas of postpubertal testes should be considered as being potentially malignant.

In the seminiferous tubules adjacent to these teratomas, there are atypical germ cells corresponding to CIS or ITGCN. Such intratubular neo-plastic cells are not found in the seminiferous tubules adjacent to testicular teratomas of infancy or in the testes adjacent to dermoid cysts of post-pubertal testes.34 These findings indicate that the teratomas of adult testes are histogenetically more akin to NSGCTs and seminomas than to teratomas of prepubertal testes and dermoid cysts, which are benign tumors that are unrelated to intratubular malignant germ cells.

Spermatocyte Seminoma

Spermatocytic seminoma is a tumor composed of cells that show signs of spermatogenic differentiation. This tumor accounts for 2% of all testicular GCTs. In contrast to other GCTs, it has a peak incidence in the sixth decade.35 Most tumors are benign, but some may undergo secondary malignant transformation and give rise to sarcoma.

The tumors are composed of polymorphous neo-plastic cells arranged into solid sheets interrupted by broad acellular fibrous strands. Three cell types can be recognized: small cells with round nuclei superficially resembling lymphocytes, intermediate cells with large vesicular nuclei and well-developed eosinophilic or basophilic cytoplasm, and large cells with loosely structured chromatin resembling spireme chromatin in primary spermatocytes in mei-otic prophase.6 Intratubular CIS is not present in adjacent seminiferous tubules, suggesting that the histogenesis of these tumors is different from that of seminomas and NSGCTs. In contrast to classic seminomas that are associated with EC and other NSGCT elements in 15% of cases, spermatocytic seminomas never progress into other NSGCTs.

Testicular Tumors of Infancy and Childhood

Most testicular tumors of infancy and childhood are classified as yolk sac tumors or teratomas.36-38 His-tologically, these tumors have the same features as the equivalent tumors in adult testes. In contrast to seminomas, NSGCTs, and teratomas of postpubertal or adult testes, prepubertal testicular tumors usually are not associated with atypical germ cells in the adjacent seminiferous tubules. These findings suggest that the histogenesis of prepubertal GCTs is different from that of postpubertal tumors.

Teratomas arising in prepubertal testes are invariably benign. Yolk sac tumors removed in the early stages of development have an excellent prognosis, but even tumors that have metastasized are curable with proper treatment.39 In the series analyzed by Grady and colleagues,39 which contained 212 prepubertal yolk sac tumors, 33 tumors had metastasized. The metastases were into the abdominal lymph nodes in 9 cases, were hematogenous in 13 cases, and were combined lymphogenous and hematoge-nous in 6 cases. The pattern of metastasis of prepubertal yolk sac tumors differs thus from the usual route of spread of postpubertal GCTs.

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