Abnormal sexual differentiation and neoplasia

doi:10.1016/0165-4608(87)90180-4

Cancer Genetics and Cytogenetics

Volume 25, Issue 2, April 1987, Pages 191-218

https://doi.org/10.1016/0165-4608(87)90180-4 Get rights and content

Abstract

The prevalence of neoplasia is increased in individuals with certain disorders of sexual differentiation. Etiology and frequency of neoplasia vary with the particular disorder.

In uncomplicated cryptorchidism, the testis is at least 10 times more likely to undergo neoplastic transformation than a normal scrotal testis. Neoplasia probably is a function of both testicular location (intraabdominal) and underlying dysgenetic structure. If cryptorchidism is unilateral, and if orchiopexy has not been performed prior to age 6–10 years, orchiectomy should be encouraged.

In those forms of gonadal dysgenesis not associated with a Y chromosome (e.g., 45,X; 45,X/46,XX; 46,XX) there is no definite increase in neoplasia, suggesting that elevated gonadotropin levels per se are not carcinogenic. Gonadal tumors are found in at least 30% of individuals with XY gonadal dysgenesis and are particularly frequent (55%) in H-Y antigen-positive patients. These tumors are almost always gonadoblastomas or dysgerminomas. Similar tumors are found in 15%–20% of 45,X/46,XY individuals. In either situation the neoplastic transformation could be a) secondary to the existence of XY gonadal tissue in an inhospitable environment, or b) integrally related to that process—genetic or cytogenetic—producing the dysgenetic gonads. The risk of neoplasia is sufficiently high that most of these patients should be offered early gonadal extirpation.

The prevalence of gonadal tumors is not increased in Klinefelter's syndrome, further indicating that gonadotropins are not carcinogenic per se. However, Klinefelter patients are 20 times more likely to develop a carcinoma of the breast than are 46,XY males. Extragonadal germ cell tumors also are more common.

In female pseudohermaphrodites there is probably no increased risk of neoplasia, whereas, in true hermaphrodites neoplasia is unusual but does occur. Neoplasia occurs in patients with complete testicular feminization (complete androgen insensitivity) but rarely in those with incomplete testicular feminization/Reifenstein's syndrome, 5α-reductase deficiency, anorchia, agonadia, or testosterone biosynthetic defects. In complete testicular feminization the risk of malignant tumors is small prior to age 25. After age 25, it is about 2%–5%. Orchiectomy is recommended after pubertal feminization.

References (222)

A Pouplard et al.
Antigonadotropic cell antibodies in the serum of cryptorchid children and infants and of their mothers
J Pediatr
(1985)
A Czeizel et al.
Genetics of undescended testis
J Urol
(1981)
G.G Gehring et al.
Malignant degeneration of cryptorchid testes following orchiopexy
J Urol
(1974)
D.C Martin
Malignancy in the cryptorchid testis
Urol Clin North Am
(1982)
A.R Sohval
Testicular dysgenesis as an etiologic factor in cryptorchidism
J Urol
(1954)
M Nistal et al.
Histological classification of undescended testes
Hum Pathol
(1980)
A.R Sohval
Testicular dysgenesis in relation to neoplasm of the testicle
J Urol
(1956)
R.B Greenblatt et al.
The spectrum of gonadal dysgenesis. A clinical, cytogenetic, and pathologic study
Am J Obstet Gynecol
(1967)
H Rehder et al.
Dysgerminoma in Turner's syndrome
Beitr Path Bd
(1976)
J.C Warren et al.
Hilus-cell adenoma in a dysgenetic gonad with XX/XO mosaicism
Lancet
(1964)

R.S.K Chaganti et al.

Chronic myelogenous leukemia in the monosomic cell line of a fertile Turner syndrome mosaic (45,X/46,XX)

Cancer Genet Cytogenet

(1982)

E.K Muechler et al.

Hormonal and cytogenetic studies in phenotypically female patients with gonadal dysgenesis

Int J Gynaecol Obstet

(1981)

M.H Louka et al.

Endometrial carcinoma in Turner's syndrome

Gynecol Oncol

(1978)

M Maeyama et al.

Case report of dysgerminoma in a patient with 46,XX pure gonadal dysgenesis

Gynecol Oncol

(1983)

H.W Jones et al.

The pathology and cytogenetics of gonadal agenesis

Am J Obstet Gynecol

(1963)

A Talerman et al.

Gonadoblastoma and dysgerminoma in a true hermaphrodite with a 46,XX karyotype

Am J Obstet Gynecol

(1981)

M Manuel et al.

The age of occurrence of gonadal tumors in intersex patients with a Y chromosome

Am J Obstet Gynecol

(1976)

S.D Frasier et al.

Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins

J Pediatr

(1964)

K Boczkowski et al.

Sibship occurrence of XY gonadal dysgenesis with dysgerminoma

Am J Obstet Gynecol

(1972)

P.R Fleishman et al.

Gonadal dysgenesis in two siblings

Am J Obstet Gynecol

(1976)

S.A Phansey et al.

XY gonadal dysgenesis in three siblings

Am J Obstet Gynecol

(1980)

D.W Bruneteau et al.

Pure gonadal dysgenesis with an XY chromosomal constitution (Swyer's syndrome): Report of two cases

Am J Obstet Gynecol

(1976)

A Psaroudakis et al.

Cytogenetic studies in gonadal dysgenesis with dysgerminoma

Am J Obstet Gynecol

(1976)

P Blanchet et al.

XY gonadal dysgenesis with gonadoblastoma discovered after kidney transplantation

Am J Obstet Gynecol

(1977)

R.E Magenis et al.

Turner syndrome resulting from partial deletion of Y chromosome short arm: Localization of male determinants

J Pediatr

(1984)

J.L Simpson et al.

The relationship of neoplasia to disorders of abnormal sexual differentiation

Birth Defects: Original Article Series

(1976)

C.G Scorer

The descent of the testis

Arch Dis Child

(1964)

A Levin et al.

The undescended testis

Surg Gynecol Obstet

(1973)

C.G Scorer et al.

Congenital Deformities of the Testis and Epididymis

N.L Vandemark et al.

Temperature effects

F.K Mostofi

Testicular tumors: Epidemiologic, etiologic, and pathologic features

Cancer

(1973)

M Westenfelder

Maldescensus testis, risk for malignant degeneration

J Muller et al.

Cryptorchidism and testis cancer: Atypical infantile germ cells followed by carcinoma in situ and invasive carcinoma in adulthood

Cancer

(1984)

J.A Dow et al.

Testicular tumors following orchiopexy

South Med J

(1967)

D.E Johnson et al.

Cryptorchism and testicular tumorigenesis

Surgery

(1968)

P.M Atkinson

The effects of early experimental cryptorchidism and subsequent orchidopexy on the maturation of the guinea-pig testicle

Br J Surg

(1974)

W Mengel et al.

Comparison of the morphology of normal and cryptorchid testes

J.L Simpson et al.

Gonadal dysgenesis in individuals with apparently normal chromosomal complements

Birth Defects: original Article Series

(1971)

J.L Simpson et al.

XY gonadal dysgenesis: Genetic heterogeneity based upon clinical observations, H-Y antigen status and segregation analysis

Hum Genet

(1981)

J.L Simpson

Gonadal dysgenesis and abnormalities of the human sex chromosomes: Current status of phenotypic-karyotypic correlations

Birth Defects: Original Article Series

(1975)

F.G Murphy et al.

Brenner tumor and mucinous cystadenoma of borderline malignancy in a patient with Turner's syndrome

Obstet Gynecol

(1979)

M.I Bonakdar et al.

Gonadoblastoma with a 45,XO karyotype

Obstet Gynecol

(1980)

N.F Lyons et al.

A virilizing hilus-cell tumour in an African patient with Turner's syndrome

Br J Obstet Gynecol

(1980)

A.N Lindsay et al.

Dysgerminoma in a patient with the syndrome of gonadal dysgenesis with a 45,X karyotype

Am J Med Genet

(1981)

M.B Goldberg et al.

Gonadal malignancy in gonadal dysgenesis: Papillary pseudomucinous cystadenocarcinoma in a patient with Turner's syndrome

J Clin Endocrinol Metab

(1967)

S.K Patel et al.

Gonadoblastoma. Distinctive ovarian tumor

Arch Pathol

(1972)

H.R Pratt-Thomas et al.

Gonadoblastoma with tubal pregnancy

Am J Clin Pathol

(1976)

M.J Piazza et al.

Bilateral gonadoblastoma with chromosomal aberration

Obstet Gynecol

(1977)

J Dewhurst et al.

Gonadoblastoma in a patient with gonadal dysgenesis without a Y chromosome

Obstet Gynecol

(1982)

D Muhlenstedt et al.

Gonadoblastoma mit uberwucherndem Dysgerminom bei Turner-Mosaik [ $45, XO 46, X,i(Xq)$ ]

Arch Gynecol

(1979)

Cited by (332)

Diuron-induced fetal Leydig cell dysfunction in in vitro organ cultured fetal testes
2024, Reproductive Toxicology
Diuron is a phenylurea herbicide widely used in the agricultural industry. In recent years, the risk of infertility and developmental defects has increased due to exposure to environmental pollutants. In this study, we investigated the toxicity of diuron in fetal mouse testes using three-dimensional organ cultures. Fetal testes derived from embryonic day (E) 14.5 were cultured with 200 µM diuron for 5 days. The results revealed that diuron did not impair fetal germ cell proliferation or the expression levels of germ cell markers such as Ddx4, Dazl, Oct 4, Nanog, Plzf, and TRA 98. Similarly, the gene or protein expression of the Sertoli cell markers Sox9 and Wt1 in diuron-exposed fetal testes did not change after 5 days of culture. In contrast, diuron increased fetal Leydig cell markers (FLC), Cyp11a1, Cyp17a1, Thbs2, and Pdgf α, and decreased adult Leydig cell (ALC) markers, Sult1e1, Hsd173, Ptgds, and Vcam1. However, 3-βHSD, an FLC and ALC marker, was consistently maintained upon exposure to diuron in fetal testes compared to non-treated groups. In conclusion, our study demonstrates that diuron negatively impacts Fetal Leydig cell development, although it does not affect germ and Sertoli cells.
Disorders of Sex Development for Neonatologists
2023, Principles of Neonatology
Disorders of sex development (DSD) are a group of conditions that arise from atypical establishment of the chromosomal complement, development of the gonads, or formation of the genitalia. At about 5 weeks of gestation, the undifferentiated embryonic gonadal ridge begins to form, which may develop into an ovary or a testis, depending initially on the presence of the SRY gene and subsequent activation of different regulatory genetic cascades leading to different hormonal milieus. Estimates of the prevalence of DSD range widely; a reasonable estimate is 1 in 5000 to 6000, although some have placed the number as high as 2%. The current nomenclature for DSDs is mechanistically based and includes three broad groups: the 46,XX DSDs, the 46,XY DSDs, and sex chromosomal DSDs. Within each of these three categories, disorders have been described based on genetic, enzymatic, or receptor defects. The most common DSD is congenital adrenal hyperplasia due to 21-hydroxylase deficiency. In this chapter, we discuss the characteristics and the approach to management of these disorders.
Pediatric germ cell tumors
2023, Seminars in Diagnostic Pathology
Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report
2021, Gynecologic Oncology Reports
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
Variation of Gonadal Dysgenesis and Tumor Risk in Patients With 45,X/46,XY Mosaicism
2020, Urology
To describe the gonadal features of patients with 45,X/46,XY mosaicism, and to evaluate the prevalence of gonadal tumor in different phenotypes.
The medical records of consecutive patients with 45,X/46,XY karyotype or its variants who had undergone gonadal biopsy or gonadectomy at a single institute between 1996 and 2017 were retrospectively reviewed.
Of 34 patients with 45,X/46,XY mosaicism, a unilateral dysgenetic testis and a contralateral streak gonad was detected in 20 patients (59%), bilateral streak gonads in 9 (26%), and bilateral dysgenetic testes in 5 (15%). A gonad composed of both streak and dysgenetic testicular portions was observed in 7 gonads of 6 patients. All streak gonads were removed, and bilateral gonadectomy was performed in 15 patients raised as girls. Pathologic examination revealed gonadal tumors in 6 of the 34 (18%) patients, including a gonadoblastoma in 7 gonads among 5 patients and an association of dysgerminoma with gonadoblastoma in 1 gonad. All 6 patients who developed gonadal tumor had female genitalia. Postoperative course was uneventful except 1 boy. A seminoma was developed in his soritaly scrotal testis at the age of 16 years.
The prevalence of gonadal tumor in patients with 45,X/46,XY mosaicism may vary according to the phenotype, and high in patients with female phenotype. Considering the increased risk of gonadal tumors in such patients, early investigation and individual management, including prophylactic gonadectomy, are recommended. In male patients, a close follow-up of the preserved testes is mandatory until adulthood.
Nonneoplastic Diseases of the Testis
2020, Urologic Surgical Pathology
Changes in our understanding of pathology have accelerated in recent years. The ability to approach a diagnostic problem from different points of view—clinical, morphologic, and molecular genetic—has led to an integrative approach to pathology. Nontumoral pathology of the testis has not been an exception. In this chapter, we start from a histophysiologic base that includes the development of the testicle, the descent of the prepubertal testis, and the adult testicle. The chapter continues with congenital anomalies of the testis and the alterations in sexual development, the classifications for which have not been uniformly accepted by those who study these matters. We focus on the undescended testis, a source of controversy regarding its best treatment—surgical versus hormonal. The problem of the infertile patient is addressed, bearing in mind not only the primary alterations, be these chromosomal or molecular, but also considering that efficient testicular function is only acquired when there is a harmonious interaction between different glands and organs. Vascular pathology of the testis is always interesting, whether focusing on a dramatic situation such as testicular torsion, or considering the relationship between varicocele and infertility. In the section on Inflammation and Infection, besides the classical processes, other lesser known processes are included in the section Other Testicular and Epidydima Lesions. Compared with the previous edition, this chapter incorporates a significant number of figures that properly document the text.

View all citing articles on Scopus

^☆: Supported in part by Grants 02840, 19866, and 52903 from the National Institutes of Health, the March of Dimes, and the Mother's Aid Research Fund of the Chicago Lying-In Hospital.

¹: Dr. Verp is a fellow of the Andrew W. Mellon Foundation

View full text

ReviewAbnormal sexual differentiation and neoplasia☆

Abstract

J Pediatr

J Urol

J Urol

Urol Clin North Am

J Urol

Hum Pathol

J Urol

Am J Obstet Gynecol

Beitr Path Bd

Lancet

Cancer Genet Cytogenet

Int J Gynaecol Obstet

Gynecol Oncol

Gynecol Oncol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

J Pediatr

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

J Pediatr

The relationship of neoplasia to disorders of abnormal sexual differentiation

Birth Defects: Original Article Series

The descent of the testis

Arch Dis Child

The undescended testis

Surg Gynecol Obstet

Congenital Deformities of the Testis and Epididymis

Temperature effects

Testicular tumors: Epidemiologic, etiologic, and pathologic features

Cancer

Maldescensus testis, risk for malignant degeneration

Cryptorchidism and testis cancer: Atypical infantile germ cells followed by carcinoma in situ and invasive carcinoma in adulthood

Cancer

Testicular tumors following orchiopexy

South Med J

Cryptorchism and testicular tumorigenesis

Surgery

The effects of early experimental cryptorchidism and subsequent orchidopexy on the maturation of the guinea-pig testicle

Br J Surg

Comparison of the morphology of normal and cryptorchid testes

Gonadal dysgenesis in individuals with apparently normal chromosomal complements

Birth Defects: original Article Series

XY gonadal dysgenesis: Genetic heterogeneity based upon clinical observations, H-Y antigen status and segregation analysis

Hum Genet

Gonadal dysgenesis and abnormalities of the human sex chromosomes: Current status of phenotypic-karyotypic correlations

Birth Defects: Original Article Series

Brenner tumor and mucinous cystadenoma of borderline malignancy in a patient with Turner's syndrome

Obstet Gynecol

Gonadoblastoma with a 45,XO karyotype

Obstet Gynecol

A virilizing hilus-cell tumour in an African patient with Turner's syndrome

Br J Obstet Gynecol

Dysgerminoma in a patient with the syndrome of gonadal dysgenesis with a 45,X karyotype

Am J Med Genet

Gonadal malignancy in gonadal dysgenesis: Papillary pseudomucinous cystadenocarcinoma in a patient with Turner's syndrome

J Clin Endocrinol Metab

Gonadoblastoma. Distinctive ovarian tumor

Arch Pathol

Gonadoblastoma with tubal pregnancy

Am J Clin Pathol

Bilateral gonadoblastoma with chromosomal aberration

Obstet Gynecol

Gonadoblastoma in a patient with gonadal dysgenesis without a Y chromosome

Obstet Gynecol

Gonadoblastoma mit uberwucherndem Dysgerminom bei Turner-Mosaik [45,XO46,X,i(Xq)]

Arch Gynecol

Review
Abnormal sexual differentiation and neoplasia☆

Gonadoblastoma mit uberwucherndem Dysgerminom bei Turner-Mosaik [ $45, XO 46, X,i(Xq)$ ]