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gonadal teratoma

Monday 21 February 2011

Digital cases (Digital slides)

- HPC:387 : Necrotic ovarian cyst. Necrotic mature ovarian teratoma ?

Gonadal teratoma

The relative proportion of teratoma among the germ cell tumors is quite different in the two gonads, with about 95% of ovarian germ cell tumors represented by pure ovarian teratoma, but only about 4% of testicular teratoma among testicular germ cell tumors.

Most teratomatous elements in the testis occur as a component of mixed germ cell tumors, which represent about one-third of all testicular germ cell tumors and contain teratoma in about 50% of the cases.

On the other hand, ovarian mixed germ cell tumors of the ovary are uncommon, representing less than 1% of ovarian germ cell tumors.

In comparing gonadal teratomas, the behavior in the testis, but less so in the ovary, depends to a great extent on whether the patient is prepubertal or postpubertal.

Prepubertal testicular teratomas are benign, yet their morphologically similar counterparts in the postpubertal testis are malignant, whether mature or immature.

There are benign gonadal teratomas that are derived from nontransformed germ cells; these include the usual mature ovarian teratoma, prepubertal testicular teratoma, and dermoid and epidermoid cysts of the testis.

There are malignant gonadal teratomas that are malignant because of their derivation from a malignant germ cell through the intermediary forms of an invasive germ cell tumor, such as yolk sac tumor or embryonal carcinoma (’preteratomatous’ malignant transformation).

This applies to most postpubertal testicular teratomas (with the exceptions of dermoid and epidermoid cyst and possibly carcinoid tumor), and it seems likely also to explain the rare teratomatous elements that develop in the uncommon mixed germ cell tumors of the ovary.

Additionally, some gonadal teratomas are malignant because of ’post-teratomatous’ malignant transformation; such tumors usually occur in the ovary and exhibit a spectrum of biologic behavior, with low-grade examples including grades 1 and 2 immature teratoma, differentiated neuroectodermal tumors (eg, ependymoma), malignant struma (papillary carcinoma in struma ovarii), carcinoid and strumal carcinoid.

High-grade examples include dermoid cysts with squamous cell carcinoma or various sarcomas or melanoma, primitive neuroectodermal tumor, and ovarian glioblastoma.

Localization

- ovarian teratoma
- testicular teratoma

Mature postpubertal gonadal teratomas

Teratomas in the ovary occur over a broad age range, albeit with a proclivity for the reproductive years,6 whereas those in the postpubertal testis are almost always restricted to patients between 20 and 40 years of age.

DNA quantification shows that mature ovarian teratomas are diploid, and cytogenetic study demonstrates that they almost always have a normal 46,XX karyotype, whereas mature teratomas of the postpubertal testis are hyperdiploid to hypotriploid with complex cytogenetic abnormalities including invariable 12p amplification, often in the form of an isochromosome [i (12p)].

Molecular genetic analysis has also shown that mature ovarian teratomas are usually homozygous for polymorphic markers, indicating that they derive most often from a germ cell that has completed meiosis I but not meiosis II, a conclusion supported by cytogenetic analysis.

When heterozygosity does occur, it predictably is in loci that tend to be located distant from the centromere—that is, in genes most susceptible to crossing over at the metaphase plate of meiosis I.

On the other hand, genetic analysis has also shown that the teratomatous elements in postpubertal mixed germ cell tumors of the testis have strikingly parallel allelic losses compared to the nonteratomatous components of the same tumor, supporting the concept that postpubertal teratoma of the testis usually derives from other forms of germ cell tumor.

The most important contrasting feature, however, between mature ovarian and postpubertal testicular teratomas is that the former have a uniformly benign clinical course, whereas metastases, often of nonteratomatous germ cell tumor types, occur in 20–40% of the latter.

There are also differences in the gross and light microscopic features of mature ovarian and postpubertal testicular teratomas, with the ovarian tumors usually being predominantly cystic (the familiar dermoid cyst) in contrast to the predominant solid appearance of the testicular tumors.

On microscopic examination, the mature ovarian teratomas have a well-organized, arrangement of tissues that often duplicates the relationships seen in normal organs, for instance pilosebaceous structures and sweat glands within squamous epithelial-lined ’dermis’ or respiratory epithelium encircled by smooth muscle and cartilage.

The elements within these ’organoid’ tissues, furthermore, lack cytological atypia and have scant mitotic activity that is mostly confined to the normal proliferative zones of the organs they replicate.

On the other hand, postpubertal testicular teratomas have a more disordered arrangement, frequently show significant cytological atypia, and may have widespread mitotic activity.

Additionally, the seminiferous tubules adjacent to these tumors show IGCNU in approximately 90% of the cases, and there is often widespread testicular atrophy with impaired to absent spermatogenesis.

A spectrum of different types of tissues may be identified in mature teratomas of both the ovary and testis, although there are some notable differences in their frequency in the two gonads.

For instance, choroid plexus and thyroid tissue are common in ovarian teratomas, and pituitary tissue may also be seen on occasion, rarely giving rise to functioning prolactinomas. These tissue types are infrequent (choroid plexus) to rare (thyroid) to virtually nonexistent (pituitary) in testicular teratomas. Paradoxically, prostatic tissue infrequently occurs in ovarian teratomas but is even rarer in the testis. Meninges are a described but rare finding in testicular teratomas, with one reported case of a microcystic meningioma of teratomatous origin.

Mature prepubertal gonadal teratomas

A comparison of mature prepubertal gonadal teratomas, in contrast to the situation with the postpubertal examples, shows striking similarities between those in the ovary and the testis.

Prepubertal testicular teratomas represent approximately 30% of testicular germ cell tumors in children, are typically pure, have a diploid DNA content and normal 46,XY karyotype, show normal findings by comparative genomic hybridization studies, often have organoid tissue arrangements, lack cytological atypia and widespread mitotic activity, are not associated with IGCNU, and are clinically benign.

These features are all similar to those mentioned above for mature ovarian teratomas.

Germ cells in the seminiferous tubules adjacent to pediatric teratomas may appear somewhat atypical, with occasional cells showing nuclear enlargement or multinucleation, but these features are different from the seminoma-like cells of IGCNU and have been interpreted as a reactive phenomenon based on similar changes in germ cells adjacent to sex cord-stromal tumors in the pediatric testis.

There are occasional exceptions, with prepubertal testicular teratomas exhibiting adjacent IGCNU, similar to the situation with gonadal dysgenesis in children, but these remain outliers.

Dermoid and epidermoid cysts of the testis

Two examples of postpubertal testicular teratomas that are analogous to mature ovarian teratomas and prepubertal testicular teratomas are dermoid and epidermoid cysts, although the pathogenesis of the latter, whether a neoplasm or not, is controversial.

The loss of heterozygosity in some epidermoid cysts, however, provides support for its teratomatous nature.

The rare testicular dermoid cyst shares with the common ovarian dermoid the usual presence of grossly identifiable hair within a cystic tumor and, on microscopic examination, the organoid replication of skin and absence of cytological atypia or widespread mitotic activity.

It also lacks adjacent IGCNU and the association with testicular atrophy, instead usually occurring in a testis with normal spermatogenesis.

The typical arrangement of pilosebaceous units to an epidermal surface is a necessary feature for the diagnosis of testicular dermoid cyst.

The presence of a lipogranulomatous reaction in the testicular parenchyma is characteristic, helpful in diagnosis and is due to the leakage of oily, sebaceous gland secretion from the cyst into the adjacent testis.

Other, noncutaneous elements may be present in testicular dermoids, as in the ovary.

Sometimes these elements also have an organoid arrangement, for instance showing a reiteration of small bowel mucosa and submucosa. Epidermoid cyst represents about 1% of testicular tumors and is rare in the ovary.

Whether these lesions are neoplasms or not remains a topic of debate, although some show loss of heterozygosity for certain chromosomal loci, supporting a neoplastic pathogenesis.

Epidermoid cysts lack atypia and mitotic activity, and the testicular cases, like dermoid cyst, are not associated with IGCNU.

Dermoid and epidermoid cysts are benign.

Histogenesis

These differences in gonadal teratomas can be explained by a pathogenetic model wherein ovarian teratomas, prepubertal testicular teratomas, and dermoid/epidermoid cysts are derived from benign germ cells.

The generally homozygous nature of ovarian teratomas further supports a parthenogenetic-like pathogenesis.

On the other hand, the usual postpubertal testicular teratoma is derived from a malignant germ cell (IGCNU) that gives rise to a nonteratomatous form of germ cell tumor, which, in turn, differentiates to form teratomatous elements.

This pathogenesis is supported by the strikingly parallel patterns of allelic loss in teratomas of the postpubertal testis and the other germ cell tumor types that accompany them.

This explains the association of pure testicular teratoma in postpubertal patients with IGCNU and metastases of nonteratomatous type and the uncommon occurrence of postpubertal testicular teratoma without other germ cell tumor types.

In this model, therefore, malignant transformation in the example of postpubertal testicular teratomas occurs prior to teratomatous differentiation (’preteratomatous’ malignant transformation).

On the other hand, for those rare ovarian teratomas with malignant elements, malignant transformation occurs after the development of the teratoma (’post-teratomatous’ malignant transformation).

This applies to those dermoid cysts that develop malignant somatic neoplasms, most commonly squamous cell carcinoma but rarely other types such as malignant melanoma, adenocarcinoma and various forms of sarcoma, a phenomenon seen in 0.2–1.4% of mature ovarian teratomas.

The homozygous nature of the malignant elements in these cases, which is similar to the benign elements, supports derivation of the former from the latter, as do similar cytogenetic changes in the two components.

Additionally, immaturity in ovarian teratomas can be seen in a similar light as representing clones of malignant neuroepithelium that develop within a pre-existing teratoma.

Immature gonadal teratoma

Immaturity, usually manifest as immature neuroepithelium but sometimes additionally or rarely solely as cellular, mitotically active glia, is important to assess in ovarian teratomas.

Semiquantification of the amount of neuroepithelium correlates with survival in ovarian immature teratoma, at least in adult patients, and is the basis for grading of these tumors.

Those with less than one lower power field (times 4) of immature neuroepithelium on the slide with the greatest amount of such tissue (grade 1) have a survival of at least 95%, whereas greater amounts of immature neuroepithelium (grades 2 and 3), with modern treatment, have a lower overall survival (approximately 85%).

These correlations may not apply, however, to immature teratomas of the ovary in children since recent work has shown a good outcome with surgery alone, regardless of the degree of immaturity, in these cases.

Immature ovarian teratomas are associated with gliomatosis peritonei, a favorable prognostic finding if composed of completely mature tissues, with the seemingly unexpected recent discovery, using molecular methods, that these glial ’implants’ are not tumor derived but represent teratoma-induced metaplasia of submesothelial cells.

On the other hand, immaturity in postpubertal testicular teratomas has no established significance. The different importance of immature elements in these two forms of teratoma can also be rationalized by the pathogenetic model discussed previously.

Since ovarian teratomas are derived from benign germ cells, immature elements represent the evolution of a malignant clone, and it is therefore logical that the prognosis relates to the amount of this component.

This clonal concept is supported by the demonstration of small foci of immature neuroepithelium, of no apparent clinical significance, in otherwise typical ovarian dermoid cysts, as well as occasional cases of immature teratoma that develop subsequent to excision of an ovarian dermoid.

The lack of 12p amplification in immature ovarian teratomas, in contrast to its presence in other types of malignant ovarian germ cell tumor, is also in keeping with this hypothesis by supporting a fundamentally different pathogenesis for immature ovarian teratoma compared to other malignant ovarian germ cell tumors.

In fact, immature ovarian teratoma usually shows only relatively minor cytogenetic abnormalities, in contrast to the other forms of malignant ovarian germ cell tumor, with increasing abnormalities as the grade of the immaturity becomes higher.

On the other hand, since testicular teratomas in postpubertal patients represent the end stage of a differentiation process from other types of malignant germ cell tumor, it is immaterial if ’immaturity’ is present.

Immaturity, in a sense, is ’trumped’ by the invasive malignant germ cell tumor from which the teratoma derived in the postpubertal testis.

When considering possible immaturity in ovarian teratomas, it is important not to mistake cellular but differentiated neural elements, such as those resembling cerebellar granular cells, for immature elements.

Immature neural elements should have a somewhat vesicular chromatin and show apoptosis and mitotic activity, in contrast to end stage differentiated neural elements.

Such fully differentiated neural cells have a uniformly dense chromatin without mitotic activity or apoptosis. It is also important not to consider fetal-type tissue, such as cartilage, evidence of immaturity. The diagnosis of immaturity requires tissue with an embryonal appearance, almost always neuroepithelium, as noted earlier.

Overgrowth of immature neural elements in either ovarian or testicular teratomas is the basis for the diagnosis of primitive neuroectodermal tumor (PNET).

Ovarian PNETs have an aggressive clinical course and poor prognosis;58, 59 on the other hand, the prognosis of PNET in postpubertal testicular teratoma is less clear, since, as discussed, these tumors are malignant in the absence of overgrowth of immature neuroepithelium.

Nonetheless, since such elements seem to be chemoresistant, their overgrowth probably does have an ultimately negative prognostic impact.

It is well established that the identification of PNET in post-chemotherapy resections of patients with testicular germ cell tumors does have a seriously negative prognostic significance.

Overgrowth of other types of neural elements has also been described in ovarian teratomas, resulting in different forms of ’monodermal’ neuroectodermal tumors, including ovarian ependymoma (differentiated neuroectodermal tumor) and glioblastoma (anaplastic neuroectodermal tumor).

Ovarian ependymomas have a low-grade malignant course, and ovarian glioblastoma, like PNET, pursues an aggressive course.

Overgrowth of immature tubules, blastema, and stroma may result in nephroblastoma-like tumors.

These are uncommon and seen most frequently in the postchemotherapy setting of patients with metastatic testicular germ cell tumors.

Although experience is limited, they do not appear to have the same ominous prognostic significance in this setting as do PNETs.

Monodermal gonadal teratomas

The most common monodermal teratoma is struma ovarii, but, enigmatically, struma testis is so rare that no appreciable experience exists to merit comment.

Struma ovarii may be either solid or cystic, with the solid examples usually being glistening, tan-brown, or beefy red nodules.

While the diagnosis of struma ovarii is usually straightforward, certain variants may pose diagnostic difficulties.

Cellular examples may lack conspicuous follicles and have a solid appearance or grow as hollow to solid tubules of clear cells that mimic metastatic renal clear cell carcinoma, primary clear cell carcinoma of mullerian-type, or Sertoli cell tumor.

Tumors with oxyphilic cells may simulate steroid cell tumor or diverse other oxyphilic neoplasms. The key to the correct interpretation is extensive sampling to detect characteristic foci of follicles with intraluminal colloid. Appropriate immunostains, including thyroid transcription factor-1 and thyroglobulin, can also be used.

Cystic examples of struma ovarii may have extensive areas of nondescript pale cuboidal epithelium lining cystic spaces, sometimes with small papillae having hyalinized fibrous cores.

These are prone to misinterpretation as cystadenomas of surface epithelial origin, usually serous cystadenoma.

In some cases of cystic struma, the follicles lack colloid and are lined by cells with pale cytoplasm, causing possible confusion with mucinous cystadenoma.

A frequently helpful feature is the brown to green color of the cystic tumor, and extensive sampling will often identify well-formed, though dispersed, thyroid follicles in the fibrous septa between cysts.

The cellular examples just noted should not be misinterpreted as follicular carcinoma, which is rare in struma ovarii and requires the identification of clear-cut invasive growth (capsular penetration) or vascular invasion.

When ’malignant struma’ does occur, it is almost always in the form of papillary carcinoma, with the same histologic features as in the thyroid gland and an excellent prognosis.

As in the thyroid gland, degenerative-based pseudopapillae on the background of adenomatous changes should be distinguished from papillary carcinoma using conventional thyroid criteria.

Another relatively common monodermal teratoma is gonadal carcinoid tumor. These lesions are generally similar in the ovary and testis (except for the restriction to date of strumal carcinoid to the ovary), typically have a solid, tan to yellow gross appearance, and usually show an insular or ’mid-gut’ type of pattern and less commonly trabecular growth.

In many cases, there is retraction artifact between the islands of carcinoid tumor and the surrounding fibrous stroma.

They may be admixed with other teratomatous elements, but do not occur with nonteratomatous germ cell tumor components in the testis and rarely do in the ovary.

This observation, plus the absence of IGCNU in the testicular cases suggest that the testicular carcinoids have a pathogenesis similar to ovarian or prepubertal testicular teratoma. Gonadal carcinoids usually pursue a clinically benign course.

They must be distinguished from gonadal metastasis of carcinoid tumor, with prominent lymphovascular invasion and bilateral involvement favoring metastasis and associated teratomatous elements indicating a primary lesion.

Strumal carcinoid is a unique tumor with thyroid follicles admixed with carcinoid. Like ovarian carcinoid, it rarely metastasizes.

Mucinous carcinoid is the rarest form of primary gonadal carcinoid and, thus far, only documented in the ovary.

It shows a spectrum of appearances, from well-differentiated examples consisting of glands lined by goblet and neuroendocrine cells, lacking atypia and ’floating’ within mucin pools, to atypical examples having cribriform and fused glands lined by stratified cells with mucinous and neuroendocrine features, to those with a frankly carcinomatous component.

Many cases are associated with either a teratomatous or mucinous tumor of surface epithelial type.

As with the distinction of primary from metastatic carcinoid tumor of any type in the gonads, the presence of those associated elements may be important in distinguishing a primary mucinous carcinoid of the ovary from a metastasis of appendiceal origin.