Germ cell tumors of the gonads: A selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues

Research output: Contribution to journalArticle

357 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalModern Pathology
Volume18
Issue numberSUPPL. 2
DOIs
StatePublished - Feb 2005

Fingerprint

Germ Cell and Embryonal Neoplasms
Gonads
Differential Diagnosis
Endodermal Sinus Tumor
Teratoma
Germinoma
Embryonal Carcinoma
Testis
Ovary
Neoplasms
Choriocarcinoma
Germ Cells
Embryoid Bodies
Seminoma
Trophoblasts
Dermoid Cyst
Coloring Agents
Sertoli Cell Tumor
Endometrioid Carcinoma
Carcinoma

Keywords

  • Germ cell tumors
  • Germinoma
  • Gonads
  • Ovary
  • Teratoma
  • Testis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

@article{afd5da5d3742424cbb432834f7bddd8e,
title = "Germ cell tumors of the gonads: A selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues",
abstract = "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.",
keywords = "Germ cell tumors, Germinoma, Gonads, Ovary, Teratoma, Testis",
author = "Thomas Ulbright",
year = "2005",
month = "2",
doi = "10.1038/modpathol.3800310",
language = "English",
volume = "18",
journal = "Modern Pathology",
issn = "0893-3952",
publisher = "Nature Publishing Group",
number = "SUPPL. 2",

}

TY - JOUR

T1 - Germ cell tumors of the gonads

T2 - A selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues

AU - Ulbright, Thomas

PY - 2005/2

Y1 - 2005/2

N2 - 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.

AB - 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.

KW - Germ cell tumors

KW - Germinoma

KW - Gonads

KW - Ovary

KW - Teratoma

KW - Testis

UR - http://www.scopus.com/inward/record.url?scp=13244279497&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=13244279497&partnerID=8YFLogxK

U2 - 10.1038/modpathol.3800310

DO - 10.1038/modpathol.3800310

M3 - Article

C2 - 15761467

AN - SCOPUS:13244279497

VL - 18

JO - Modern Pathology

JF - Modern Pathology

SN - 0893-3952

IS - SUPPL. 2

ER -