Morphological and Immunohistochemical Differences between Gonadal Maturation Delay and Early Germ Cell Neoplasia in Patients with Undervirilization Syndromes

Cools, Martine; Aerde, Koen van; Kersemaekers, Anne-Marie F.; Boter, Marjan; Drop, Stenvert L. S.; Wolffenbuttel, Katja P.; Steyerberg, Ewout W.; Oosterhuis, J. Wolter; Looijenga, Leendert H. J.

doi:10.1210/jc.2005-0139

Cited by 179 publications

(161 citation statements)

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“…Whereas older reports included many adult patients and mainly reported the presence of invasive germ cell tumors, 6,28,29 more recent studies on pediatric patients refer to pre-invasive lesions, ie, intratubular germ cell neoplasia, of the testis. 2,8 Intratubular germ cell neoplasia is encountered mostly in pubertal or adolescent patients; 2,8 however, the risk is calculated for entire patient groups that often include very young individuals in whom intratubular germ cell neoplasia has not had time to develop. Moreover, an intermediate stage between delayed maturation and adult type of intratubular germ cell neoplasia exists.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, an intermediate stage between delayed maturation and adult type of intratubular germ cell neoplasia exists. 8 Whether this lesion is predetermined to evolve into invasive cancer in all cases is unknown. In the general population, fully developed intratubular germ cell neoplasia is estimated to progress to an invasive tumor in 50% of cases during 5 years, and its prevalence is similar to that of germ cell tumors, suggesting a 100% progression to invasiveness over time.…”

Section: Discussionmentioning

confidence: 99%

“…KITLG is not expressed in gonads with delayed maturation germ cells. 8,14 For the diagnosis of intratubular germ cell neoplasia, the presence of at least one cross-section of a seminiferous tubule containing a homogeneous population of atypical germ cells with angulated nuclei is required. These cells must show either homogeneous double expression of POU5F1 (nuclear) and TSPY1 (cytoplasmic and membranous) or homogenous expression of POU5F1 (nuclear) in the absence of TSPY1.…”

Section: Gonadal Histology Assessmentmentioning

confidence: 99%

“…5 Germ cell cancer is very rare in childhood and adolescence; 7 however, non-invasive precursor lesions characterized as intratubular germ cell neoplasia, also termed as carcinoma in situ of the testis, have been repeatedly described in this age group. 2,8 Interestingly, the occurrence of intratubular germ cell neoplasia in pediatric patients, which is at a maximum of 6% of cases, does not reach the frequency of germ cell cancer in adulthood reported in most literature. 2,[8][9][10][11] The prevalence of intratubular germ cell neoplasia appears to be remarkably higher (15%) in pediatric patients with partial androgen insensitivity than in patients with complete androgen insensitivity.…”

mentioning

confidence: 98%

“…2,8 Interestingly, the occurrence of intratubular germ cell neoplasia in pediatric patients, which is at a maximum of 6% of cases, does not reach the frequency of germ cell cancer in adulthood reported in most literature. 2,[8][9][10][11] The prevalence of intratubular germ cell neoplasia appears to be remarkably higher (15%) in pediatric patients with partial androgen insensitivity than in patients with complete androgen insensitivity. 4 Hannema et al described that residual activity of AR has a positive effect on the development of Wolffian structures and the enlargement of seminiferous tubules during puberty in patients with complete androgen insensitivity syndrome.…”

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confidence: 98%

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Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology

et al. 2014

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Patients with complete androgen insensitivity syndrome are at an increased risk for the development of gonadal germ cell cancer. Residual androgen receptor (AR) activity and abnormal gonadal location may influence the survival of atypical germ cells and the development of other histopathological features. To assess this, we evaluated 37 gonads from 19 patients with complete androgen insensitivity (ranging in age from 3 months to 18 years). Histological abnormalities were examined using hematoxylin and eosin-stained sections and sections stained for POU5F1 and KITLG, markers of early changes in germ cells at risk for malignant transformation. Hamartomatous nodules (HNs), Leydig cell hyperplasia (LCH), decreased germ cells, tubular atrophy and stromal fibrosis were more pronounced as age increased (Po0.001). Expected residual AR activity acted as a positive predictor only for non-malignant germ cell survival in (post)pubertal patients (Po0.05). Immunohistochemical studies indicated that delayed maturation of germ cells was present in three patients, whereas intermediate changes that occurred between delayed maturation and intratubular germ cell neoplasia, designated pre-intratubular germ cell neoplasia, were identified in four cases. Intratubular germ cell neoplasia was observed in one patient. Neither POU5F1 nor KITLG expression was dependent on expected residual AR activity. An independent effect of inguinal versus abdominal position of the gonads was difficult to assess because inguinal gonads were present primarily in the youngest individuals. In conclusion, many histological changes occur increasingly with age. Expected residual AR activity contributes to better survival of the general germ cell population in (post)pubertal age; however, it did not seem to have an important role in the survival of the germ cells at risk for malignant transformation (defined by POU5F1 positivity and KITLG overexpression) in complete androgen insensitivity. Comparison of the high percentage of patients in our study that were carrying germ cells with delayed maturation or pre-intratubular germ cell neoplasia with previously reported cumulative risk of tumor development in adult patients indicates that not all such precursor lesions in complete androgen insensitivity will progress to invasive germ cell cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Gonadal Histology Assessmentmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 98%

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Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology

et al. 2014

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Recent developments in testicular germ cell tumor research

Geijn

Hersmus

Looijenga

2009

Birth Defects Research Pt C

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Testicular germ cell tumors of adolescents and adults (TGCTs; the so-called type II variant) are the most frequent malignancies found in Caucasian males between 20 and 40 years of age. The incidence has increased over the last decades. TGCTs are divided into seminomas and nonseminomas, the latter consisting of the subgroups embryonal carcinoma, yolk-sac tumor, teratoma, and choriocarcinoma. The pathogenesis starts in utero, involving primordial germ cells/gonocytes that are blocked in their differentiation, and develops via the precursor lesion carcinoma in situ toward invasiveness. TGCTs are totipotent and can be considered as stem cell tumors. The developmental capacity of their cell of origin, the primordial germ cells/gonocyte, is demonstrated by the different tumor histologies of the invasive TGCTs. Seminoma represents the germ cell lineage, and embryonal carcinoma is the undifferentiated component, being the stem cell population of the nonseminomas. Somatic differentiation is seen in the teratomas (all lineages), whereas yolk-sac tumors and choriocarcinoma represent extra-embryonal differentiation. Seminomas are highly sensitive to irradiation and (DNA damaging) chemotherapy, whereas most nonseminomatous elements are less susceptible to radiation, although still sensitive to chemotherapy, with the exception of teratoma. To allow early diagnosis and follow up, appropriate markers are mandatory to discriminate between the different subgroups. In this review, a summary will be given related to several recent developments in TGCT research, especially selected because of their putative clinical impact.

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Gonadoblastoma locus and the TSPY gene on the human Y chromosome

Lau

Kido

2009

Birth Defects Research Pt C

101

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The gonadoblastoma (GBY) locus is the only oncogenic locus on the human Y chromosome. It is postulated to serve a normal function in the testis, but could exert oncogenic effects in dysgenetic gonads of individuals with intersex and/or dysfunctional testicular phenotypes. Recent studies establish the testis-specific protein Y-encoded (TSPY) gene to be the putative gene for GBY. TSPY serves normal functions in male stem germ cell proliferation and differentiation, but is ectopically expressed in early and late stages of gonadoblastomas, testicular carcinoma in situ (the premalignant precursor for all testicular germ cell tumors), seminomas, and selected nonseminomas. Aberrant TSPY expression stimulates protein synthetic activities, accelerates cell proliferation, and promotes tumorigenicity in athymic mice. TSPY binds to type B cyclins, enhances an activated cyclin B-CDK1 kinase activity, and propels a rapid G(2)/M transition in the cell cycle. TSPY also counteracts the normal functions of its X-homologue, TSPX, which also binds to cyclin B and modulates the cyclin B-CDK1 activity to insure a proper G(2)/M transition in the cell cycle. Hence, ectopic expression and actions of the Y-located TSPY gene in incompatible germ cells, such as those in dysgenetic or ovarian environments and dysfunctional testis, disrupt the normal cell cycle regulation and predispose the host cells to tumorigenesis. The contrasting properties of TSPY and TSPX suggest that somatic cancers, such as intracranial germ cell tumors, melanoma, and hepatocellular carcinoma, with detectable TSPY expression could exhibit sexual dimorphisms in the initiation and/or progression of the respective oncogenesis.

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Morphological and Immunohistochemical Differences between Gonadal Maturation Delay and Early Germ Cell Neoplasia in Patients with Undervirilization Syndromes

Abstract: The dimorphic expression of OCT3/4 allows distinction between maturation delay and CIS. Studies in larger patient series are essential before a biopsy to evaluate the neoplastic risk can eventually be proposed as an alternative for gonadectomy.

Cited by 179 publications

References 31 publications

Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology

Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology

Recent developments in testicular germ cell tumor research

Gonadoblastoma locus and the TSPY gene on the human Y chromosome

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