Testicular Tumours: Germ Cell Tumours

Germ Cell Tumours:
Germ cell tumour gives rise to either a seminoma (an undifferentiated germ cell tumour) or an embryonal carcinoma (a tumour of totipotent cells).
Embryonal carcinoma may undergo somatic differentiation and become a teratoma. Alternatively, extra-embryonic differentiation results in a yolk sac tumor (endodermal sinus tumour) or a choriocarcinoma.
Metastases of germ cell tumours may show a form of differentiation not present in the primary tumour.
Infants and children are most commonly afflicted with yolk sac tumours and teratomas. Choriocarcinomas are more frequent in the second or third decades, embryonal carcinoma in the third decade, and seminoma in the fourth decade.
Identification of tumour marker includes:
1. Chorionic gonadotropin : Typically found in patients with choriocarcinoma.
2. Alpha-fetoprotein: Found in patients with yolk sac tumour or embryonal carcinoma with yolk sac elements.
Pathogenesis:
Important risk factors are the following:
1. Cryptorchidism: Associated with 10% of testicular tumours.
2. Genetic factors: Higher risk of testicular neoplasia among siblings of patients with testicular tumours ; some familial clustering reported. Significant racial differences also exist (rare in African blacks).
3. Testicular dysgenesis: Includes testicular feminization and Klinefelter syndrome.
Cytogenetic abnormalities involving chromosome 12 are common; i(12p) is present in 90% of testicular germ cell tumors. In the remaining cases, extra genetic material derived from 12p is found in other chromosomes, thus implicating genes located on the short arm of chromosome 12.
Incidence:
Incidence of germ cell tumours is approximately 6: 100,000 men annually, with peak incidence between ages 15 to 34 years.
Germ cell tumours account for 10% of cancer deaths in this age group. Incidence is higher in whites than in blacks in all geographic locations.
Classification and histogenesis:
Diverse classification schemes are based on different morphologic patterns and variable concepts of histogenesis. Testicular germ cell tumours may contain a single histological pattern (40% of cases) or a mixture of patterns (60% of cases).
Most tumours arise from a focus of intratubular carcinoma in situ.
The neoplastic germ cells may give rise to seminoma or transform into a totipotential neoplastic cell (embryonal carcinoma) capable of further differentiation.
Germ cell neoplasms accordingly may be divided into seminomas and non-seminomatous tumours.
General characters of Germ cell Tumors:
Clinically, most cases present with painless enlargement of the testis.
Neoplasia should be considered in the differential diagnosis of all testicular masses, even those that are painful. Clinical evaluation, however, does not reliably distinguish between the various types of germ cell tumours.
Clinical staging is accomplished via physical examination, radiographic imaging of the retroperitoneum and chest, and assay of various tumour marker.
Clinical stages are as follows:
Stage I: Tumour confined to the testis
Stage II: Metastases limited to retroperitoneal nodes below the diaphragm.
Stage III: Metastases outside the retroperitoneal nodes or above the diaphragm.
Metastases: Lymphatic metastases are most common in retroperitoneal para-aortic nodes but may occur in more distant sites (Example: mediastinal and supraclavicular nodes).
The lungs are the most common site for hematogenous metastases, followed by liver, brain, and bone.
Biological behaviour: Biological behaviour of nonseminomatous germ cell tumours (NSGCTs) is in general, more aggressive than that of seminomas. Roughly 70% of seminomas present with localized (clinical stage I) disease, in contrast, 60% of NSGCTs present with advanced stage (stage II or III) disease. Extensive metastases may be present even with small primary lesions, particularly in the case of choriocarcinoma.
Immunology: Several peptides may be produced by germ cell tumours and can be detected in body fluids by sensitive assays. AFP and HCG are the most commonly assayed. Lactate dehydrogenase although not specific for testicular tumours, is produced by the tumour cells, and the degree of elevation provides a rough measure of tumour burden.

Serum markers are of value to:
i) Evaluate testicular masses
ii) Stage germ cell tumours
iii) Assess tumour burden
iv) Monitor the response of a germ cell tumour to therapy.

Treatment includes radiation and chemotherapy, depending on the histologic type of the tumour (seminoma versus NSGCT) and the stage of the disease, chemotherapy, in particular, has dramatically improved the prognosis of patients with NSGCT.

Abstracts: Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues.Mod Pathol. 2005 Feb;18 Suppl 2:S61-79.
Gonadal germ cell tumors continue to be the cause of diverse, diagnostically challenging issues for the pathologist, and their correct resolution often has major important therapeutic and prognostic implications. They are academically interesting because of the biological diversity exhibited in the two gonads and variation in frequency of certain neoplasms. The most dramatic examples of the latter are the frequency of dermoid cyst in the ovary compared to the testis and the reverse pertaining to embryonal carcinoma. Within the teratoma group, there is strong evidence that ovarian and prepubertal testicular teratomas are derived from benign germ cells, a pathogenesis that likely applies also to the rare dermoid cysts and uncommon epidermoid cysts of the testis. In contrast, postpubertal testicular teratomas derive from malignant germ cells, specifically representing differentiation within a preexistent nonteratomatous cancer. As expected, given the foregoing, teratomas in boys are clinically benign, whereas in postpubertal males they are malignant, independent of their degree of immaturity. On the other hand, immaturity is an important finding in ovarian teratomas, irrespective of age, although its significance in children has recently been challenged. It is usually recognized on the basis of embryonic-appearing neuroepithelium, which shows mitotic activity and apoptosis in contrast to differentiated neuroepithelial tissues, which may occur in mature ovarian teratomas. Rarely it is based on the presence of cellular, mitotically active glial tissue. Fetal-type tissues alone are not sufficient for a diagnosis of immature teratoma. Further differences between the teratomatous tumors in the two gonads are the relative frequency of monodermal teratomas in the ovary in contrast to the testis, where only one subset, carcinoids, is seen with any frequency. When uncommon somatic-type malignancies (usually squamous cell carcinoma) occur in mature cystic teratomas of the ovary, this is a de novo form of malignant transformation; similar tumors in the testis, a very rare event, represent overgrowth of teratomatous elements that originated from malignant, nonteratomatous germ cell tumors and, therefore, had previously undergone malignant transformation. Germinomas may have several unusual features in each gonad; these include microcystic arrangements that suggest yolk sac tumor, tubular patterns that mimic Sertoli cell tumor, apparent increased cytological atypia that causes concern for embryonal carcinoma, and prominent syncytiotrophoblast giant cells that suggest choriocarcinoma. Awareness of these variants, good technical preparations, the retained typical cytological features of germinoma cells, and the judicious use of tailored panels of immunohistochemical stains resolve these dilemmas in virtually all instances. Two aspects of germinomas are unique to the testis. Firstly, intertubular growth of small seminomas may cause them to be overlooked. Secondly, the distinctive spermatocytic seminoma occurs only in the testis. A newly recognized aspect of this tumor is the propensity for some to be relatively monomorphic, making them apt to be mistaken for usual seminoma or embryonal carcinoma, although the characteristic polymorphic appearance in some foci, absence of intratubular germ cell neoplasia, unclassified type, and immunohistochemical stains should prevent this error. Cytoplasmic membrane immunoreactivity for placental alkaline phosphatase and CD117, with usual negativity for AE1/AE3 cytokeratins, is helpful in the diagnosis of germinoma. The recently described marker, OCT3/4, a nuclear transcription factor, is especially helpful in the differential of germinoma and embryonal carcinoma with other neoplasms. Yolk sac tumor continues to be confused occasionally with clear cell carcinoma of the ovary. Glandular ('endometrioid-like') yolk sac tumors mimic endometrioid carcinomas; predominant or pure hepatoid yolk sac tumors cause concern for metastatic hepatocellular carcinoma or, in the ovary, primary hepatoid carcinoma, and solid patterns, especially in limited samplings, may be misinterpreted as germinoma. The usually younger age of patients with yolk sac tumors helps with the differential considerations with the nongerm cell tumors, as do other clinical and microscopic features and selected immunohistochemical stains. Choriocarcinoma is rare in both gonads, and those in the ovary must be distinguished from metastatic tumors of placental origin. Syncytiotrophoblast cells alone, admixed with other forms of germ cell tumor, still are confused with choriocarcinoma, but this phenomenon, which is much more frequent than choriocarcinoma, lacks the plexiform arrangement of different trophoblast cell types that typifies the latter. Mixed germ cell tumors (which may show almost any combination of components) are common in the testis but rare in the ovary. A separately categorized, rare form of mixed germ cell tumor seen in both gonads is the polyembryoma. It is perhaps the most photogenic of all gonadal germ cell tumors and is also intriguing because of its distinctive, organized arrangement of yolk sac tumor and embryonal carcinoma elements and recapitulation of very early embryonic development, even to the extent of having in its fundamental unit, the embryoid body, a miniature yolk sac, and amniotic cavity. These tumors, which are constituted by innumerable embryoid bodies, almost always contain teratomatous glands in minor amounts, and one way of viewing the polyembryoma is to consider it the most immature form of teratoma. Embryoid bodies are also common as a minor component of many mixed germ cell tumors, particularly in the testis, and the diffuse embryoma is another variant that has a particular arrangement of yolk sac tumor and embryonal carcinoma elements. Regression of gonadal germ cell tumors is a phenomenon restricted to the testis, for unknown reasons. These so-called 'burnt-out' germ cell tumors can be recognized by a distinctive constellation of findings, including sometimes minor foci of residual recognizable germ cell neoplasia, a well-defined zone of scarring (often having residual ghost tubules), associated lymphoplasmacytic infiltrate, intratubular calcification and, in about 50%, of in situ germ cell neoplasia.