Pathology > Study Images > Male Genitals > Testis > Neoplasms
Objectives Anat & Hist Congenital Vascular Neoplasms

IV.Neoplasms

Objectives:

  1. Germ Cell Tumors

After completing this section you will:

  • know the classification of testicular germ cell tumors and how they originate
  • know the commonest type
  • be able to describe clinical and histologic features
  • know which tumor produces which marker
  • predict possible clinical outcomes and response to treatment
  1. Sex Cord-Stromal Tumors

After completing this section you will:

  • know the sex cord-stromal tumors of the testis
  • know their hormonal effects
  • describe clinical features
  • describe their biologic behavior

  1. Germ cell tumors

    Epidemiology

Germ cell tumors (GCTs) are more common in whites than blacks, both African and North American, and Asians. The peak incidence is between 20 and 34 years when it is the most common malignancy in males. Germ cell tumors are uncommon after 50 years of age. The mean age of seminoma is about 40 years and that for teratoma is about 30 years.

Question: What is the commonest malignant testicular tumor after 50 years of age?

The cause of germ cell tumors is unknown. Cryptorchidism significantly increases the risk, 4 to 10 fold, of subsequent development of germ cell tumors. Development of a germ cell tumor in one testis increases the risk of developing a tumor in the contralateral testis.

Histogenesis and Classification

There are several classification systems of testicular germ cell tumors. All of these derive from the concept that testicular GCTs originate from germ cells, which may develop along two unrelated pathways. Seminomas (germinomas) recapitulate some aspects of spermatogenesis and are distinct from other tumors, called non-seminomatous germ cell tumors (NSGCTs). Non-seminomatous germ cell tumors represent progeny of pluripotent embryonic cells formed from germ cells through the process of parthenogenesis.

All testicular GCTs originate from intratubular germ cells that pass through a pre-invasive carcinoma-in-situ stage. There are many GCTs that contain both seminoma and NSGTs and whether these tumors derive clonally from a single transformed cell or from multifocal carinogenesis is not known. The transition from carcinoma-in-situ to invasive carcinoma is marked by a long latency period. It is not known whether the intratubular cells have the potential to grow invasively from the beginning or additional steps are required for acquisition of invasiveness.

Question: Germ cell tumors may also arise in extra-gonadal sites. What are these sites?

Seminoma

This is the commonest single type of primary testicular tumor. It occurs in two forms: Classic (or conventional) and spermatocytic seminomas. Seminoma accounts for 35 to 70% of testicular neoplasms and does not develop before puberty.

Classic seminoma

Classic seminoma usually forms a mass situated anywhere in the testis and produces a moderate smooth or bosselated enlargement of the organ. Typically the cut surface is uniform yellow or tan. Hemorrhage and necrosis are uncommon.


Classic seminoma. The cut surface is tan and bosselated.


Classic seminoma. A nodular tumor completely replaces the testis.

Microscopically, the tumor is composed of sheets of uniform undifferentiated germ cells with clear or fine granular cytoplasm, well-defined cell border and round nuclei, frequently with prominent nucleoli. The sheets of tumor cells are separated by slender fibrous septa. Diffuse or focal intense lymphoid infiltrate is seen in most tumors. Glycogen may be demonstrated in the cytoplasm of the tumor cells.


Classic seminoma. Sheets of tumor cells separated by thin fibrous septa heavily infiltrated by lymphocytes.


High magnification showing uniform tumor cells.

Mitotic figures are usually infrequent. In about a third of cases, noncaseating granulomatous areas containing small giant cells are found. Tumor giant cells that mimic syncytiotrophoblasts in appearance and which may contain intracytoplasmic ß-hCG are present in some tumors. This may lead to a mild increase in serum ß-hCG. In some seminomas, the neoplastic cells are more pleomorphic and have more mitotic figures than in typical seminoma. These tumors have been called anaplastic seminomas. Although these tumors tend to occur at higher stages than classical seminoma, stage for stage this subgroup has the same prognosis as the classical type.


Classic seminoma. Left panel shows multinucleate giant cells of foreign body type. Right panel shows syncytiotrophoblast-like tumor giant cell.

When metastases occur, they tend to involve regional lymph nodes initially, followed by systemic spread. Classic seminoma is highly sensitive to radiation therapy, and the overall 5-year survival is in the order of 90-95%. Seminomas containing syncytiotrophoblastic giant cells should not be considered as mixed germ cell tumors.

Spermatocytic seminoma

This is a rare but distinct clinicopathologic variant of seminoma that occurs only in the descended testes of elderly men and forming about 5% of seminomas. The tumor is bilateral in about 6% of cases compared to about 2% in classic seminoma.

The tumor tends to be poorly demarcated, usually soft with a gelatinous or mucoid appearance. Cystic areas, especially in the center, are common but hemorrhage or necrosis is almost always absent.

Spermatocytic seminomas form solid sheets of cells without the nesting pattern of classical seminoma. The overall pattern has some superficial resemblance to the early stage germ cells of the testis. Three populations of tumor cells, separated according to size, are seen: 1) small cells that superficially resemble lymphocytes, 2) intermediate or medium-sized cells, the commonest cell type, have round nuclei and finely granular chromatic pattern, and 3) large or giant cells. Mitotic figures are usually abundant and the lymphocytic infiltrate and granulomas seen in classic seminoma are absent.

Spermatocytic seminoma is an extremely indolent tumor with rather limited malignant potential and rarely if ever metastasizes.

Embryonal carcinoma

This subtype of GCTs represents the most primitive form of the NSGCTs. It accounts for about 15 to 35% of testicular GCTs.

Grossly, the tumors are large, often hemorrhagic and necrotic producing a variegated cut surface.


Embryonal carcinoma. Tumor replaces the whole testis.

Histologically, they are extremely pleomorphic and show a variety of patterns forming glands, tubules, and even primitive embryo-like structures. Many mitotic figures are present.

Anaplastic and solid undifferentiated areas may present as sheets of cells with large, hyperchromatic nuclei, prominent nucleoli and poorly-defines cell borders.


Poorly differentiated area in embryonal carcinoma.

When large numbers of the embryo-like structures are present the tumor is referred to as a polyembryoma. These structures contain a disc and two cavities surrounded by loose mesenchyme simulating a 2 week embryo.


Left panel shows an embryo; right panel shows embryo-like structure in polyembryoma.

Embryonal carcinoma metastasizes early and widely via both lymphatic and hematogenous routes. Radiation is not as effective as with seminoma, but newer chemotherapeutic agents have greatly improved prognosis. Tumors confined to the testis now have a prognosis essentially identical to that of seminoma (95% 5-year survival). Unlike seminoma, however, many embryonal carcinomas are high stage tumors at the time of presentation. These more widely disseminated tumors still have "a cure rate greater than 50%".

Yolk Sac Tumor (Endodermal Sinus Tumor)

Yolk sac tumor (YST), also known as endodermal sinus tumor, is a distinct entity from embryonal carcinoma of which it was considered a variant in the past. It is noted for its resemblance to rat fetal yolk sac and the presence of microscopically distinctive structures known as Schiller-Duval bodies. Testicular yolk sac tumors occur in two forms: either as a pure form in young children or as a focal differentiation within other NSGCTs, mainly embryonal carcinoma, in adults. Pure YST of the adult testis is rare. In this form, it presents as a fairly rapid testicular enlargement. The cut surface is gray-white and may be cystic.


Yolk sac tumor.

Microscopically, the tumor shows a variety of patterns, the commonest of which is a loose meshwork of small spaces and cysts (producing a sieve-like appearance) lined by either flattened cells or vacuolated cells with nuclei that protrude in a "hobnail" fashion.


Yolk sac tumor showing tubules and cysts lined by flattened cells producing a sieve-like appearance.

A solid pattern that resembles embryonal carcinoma is also seen. In some tumors, Schiller-Duval bodies (endodermal sinus) are seen. These are glomerulus-like structures with a central core of blood vessel surrounded by an inner layer of epithelial-like cells, a space and an outer layer of similar cells. Varying numbers of eosinophilic globules may be seen.

YST is almost invariably associated with production of large amounts of alpha-fetoprotein (AFP) and also alpha-1 antitrypsin (a -1AT). AFP may be followed as a marker of disease progression in the patient's serum. Antibodies directed against AFP may also be used to stain the tumors and aid in their diagnosis.


Yolk sac tumor stained with antibodies against AFP. Note the brown staining of the epithelium indicating the presence of AFP.

The biologic behavior of YST is similar to that of embryonal carcinoma.

Teratoma

It is in this group that confusion over terminology and subgrouping exist between the various classification schemes. In the British Testicular Tumor Panel classification (used widely in Europe), all testicular GCTs excluding classic seminoma, spermatocytic seminoma, and YST in children are called teratomas. In the WHO classification (used in the US) the term is restricted to a tumor typically composed of several tissues representing two or more germinal layers. In the latter classification, teratomas are further subdivided into mature, immature and teratoma with malignant transformation. However, all three are included under teratoma differentiated in the BTTP scheme while teratoma undifferentiated refers to embryonal carcinoma.

Mature Teratoma

The tumor is composed exclusively of well-differentiated tissues and by definition, contains no malignant-looking tissue. Some may consist of nests of mature cartilage, smooth muscle and squamous or mucous epithelial-lined cysts. In others, more complex and organoid arrangement is seen and abortive gastrointestinal tract, brain, eye, pancreas, salivary gland, and other organs can easily be recognized.


Mature teratoma showing cysts lined by mucous epithelium (left) and keratinizing squamous epithelium (right).


Mature teratoma. Mature cartilage (left) and spaces lined by mucus secreting glandular epithelium (right) are present.


Another example of a mature teratoma.

Although the tumor has a benign histologic appearance, its clinical course in the adult is unpredictable and it can metastasize. The metastases show the same well-differentiated picture as the primary tumor. In children, teratomas whatever their histological appearances behave in a benign fashion.

Immature Teratoma

In this type of teratoma there are incompletely differentiated, fetal-appearing tissues, often of neural differentiation.


Immature teratoma with primitive brain tissue (upper left corner) and well-differentiated glands (lower half).

Teratoma with Malignant Transformation

This is a rare type of teratoma in which the malignant component is a typical malignant tumor seen in other organs and may be epithelial, squamous cell or adenocarcinoma, or a sarcoma.

AFP may be present in any teratoma that contains gastrointestinal mucosa or clusters of liver-like cells.

Choriocarcinoma

This is a highly malignant neoplasm that is usually widely disseminated and frequently fatal. In this form of testicular GST the cells differentiate in the direction of trophoblastic (placental) tissue and both cytotrophoblast and syncitiotrophoblast must be present for the diagnosis to be made. Pure choriocarcinoma of the testis is extremely rare, and the tumor is much more common as a component of mixed GCTs.

The tumor typically presets in adolescent or young adults with widespread disease, and an often small, painless primary lesion in the testis. It is extensively hemorrhagic and necrotic and, sometimes, may be reduced to a fibrous scar, leaving widespread metastases with no apparent testicular mass. On occasion, the tumor may be large and bulky. Hemoptysis due to pulmonary involvement is common.


Choriocarcinoma: large, hemorrhagic, necrotic tumor.

Microscopically, the tumor is composed of two types of cells: syncytiotrophoblasts, large multinucleate cells with abundant vacuolated cytoplasm containing hCG and cytotrophoblasts, polygonal cells with distinct cell borders and single nuclei, which grow in clusters and are surrounded by the syncytiotrophoblasts.


Choriocarcinoma, left panel, and placenta, right panel. Note similarity in histologic appearances.


Choriocarcinoma. Sheet of cytotrophoblasts surrounded by syncytiotrophoblasts.

Choriocarcinoma often responds well to chemotherapy but the advanced destructive nature of the tumor still results in a high mortality rate.

Question: Choriocarcinoma is one of the very few carcinomas that metastasize more frequently via bloodstream than lymphatics. What are the others?

Mixed Germ Cell Tumors

All germ cell tumors presumably arise from primordial germ cells and so it is not surprising that mixed forms are quite common. Up to half of primary testicular GSTs contain mixtures of two or more of the pure forms described above, while apparently pure primary tumors may give rise to metastases containing mixtures of pure forms or pure metastases of another type. Most of the patients with seminoma initially who die of the disease have another, more aggressive form of GST in their metastases.

When mixed germ cell tumors occur, the prognosis is usually that of the worst component. However, choriocarcinoma is an exception to this rule. Mixed tumors containing choriocarcinoma tend to be less advanced at diagnosis than pure choriocarcinoma and their prognoses are correspondingly better.

  1. Sex Cord/Gonadal Stromal Tumors

Sex cord/gonadal stromal tumors are rare and constitute about 5% of testicular tumors.

Leydig/Interstitial Cell Tumor

These tumors are functionally active, secreting androgens, estrogens or both. They occur at any age but are most common between 20 and 60 years. In pre-pubertal boys, hormonal effects dominate the clinical picture and manifest primarily as sexual precocity. In some adults, feminization and gynecomastia are observed.

Most are benign with about 10% in adults giving rise to metaststases. It is difficult to predict biological behavior on histological grounds.

Sertoli Cell Tumor

These tumors are more rare than Leydig cell tumors. They elaborate androgens or estrogens. Occasionally, they cause gynecomastia but sexual precocity is infrequent.

Most are benign but a few, about 10%, behave in a malignant fashion.

Objectives Anat & Hist Congenital Vascular Neoplasms