Clear cells of Toker in the developing anogenital region of male and female fetuses.

The clear cells of Toker are a mysterious population of intra-epidermal glandular cells. They were originally described in nipples, but were recently observed in the vulva as well. It was hypothesized that intra-epidermal embryonic remnants or underlying glands were a potential source. The embryological aspects were investigated by studying specimens of the anogenital region of 18 male and 15 female fetuses between 12 and 39 weeks gestation. The search for Toker cells was enhanced by cytokeratin (CK) 7 immunohistochemistry. The investigation showed that Toker cell elements are a normal, though highly variable constituent of the developing anogenital region. The study revealed the following: (1) single intra-epidermal glandular vesicles near follicular anlages in interlabial sulcuses of female fetuses of 15 and 16.5 weeks gestation; (2) CK7+ solitary cells, clusters, and vesicles which were related to developing intra-epidermal follicular canal tracks and tended to disperse inside the epidermis in fetuses of approximately 18 weeks gestation; (3) dispersed CK7+ cells in fetuses of 19-23 weeks gestation; (4) characteristic CK7+ Toker cell proliferations in fetuses more than 23 weeks gestation. These observations indicate that in the anogenital region, primordial follicular cells programmed to participate in the formation of apocrine and mammary-like glands, become displaced into the epidermis where they disperse, and proliferate into Toker cell populations. However, the proximity of Toker cells to CK7+ cells in excretory ducts of late fetal apocrine and mammary-like glands suggested a possible additional source. Consequences for Toker cells of the breast and primary Paget disease are discussed.

Development and structure of the glandopreputial sulcus of the human clitoris with a special reference to glandopreputial glands.

The structure and development of the sulcus between the glans and prepuce of the human clitoris have hardly been investigated. Interest in its structure was raised when in the female, in contrast to the male, glands were found to develop from the solid lamella-like precursor of the glandopreputial sulcus. It prompted a further histological analysis of the sulcus in female fetuses and newborn and an extension of that study to clitorises of adult women. The investigation showed that in the clitoris, in contrast to the penis, the transformation of the glandopreputial lamella into the open sulcus was mostly incomplete and apparently remained so throughout life. As a most striking and probably exclusively female feature, two to eight eccrine glands developed from the base of the lamella in fetuses older than 14.5 weeks gestation. These glands formed secretory coils near and occasionally inside the adjacent distal corpora cavernosa. Some glands showed atresia, cystic dilatation, and squamous metaplasia. A remarkably similar picture was observed in the adult clitorises, in which the secretory coils were often found between the large blood vessels and nerves to the glans and were connected to the sulcus by long excretory ducts. All glands revealed unmistakably eccrine features. It is suggested that their secretion moistens the female glandopreputial sulcus, which is not lubricated by urethral secretion as in the male. The findings may explain the rare clitoral phimosis, cysts, and some pilonidal sinuses.

Penislike clitorises with megalourethras in nonvirilized female fetuses and a newborn. A histopathologic study and its bearing on their pathogenesis.

PURPOSE: The aim of the study was to analyze the microstructure of penislike clitorises in female pseudohermaphroditism in relation to their pathogenesis. METHODS: Penislike clitorises from 2 fetuses and 1 newborn with anorectal malformations and multiple other caudal anomalies and 1 fetus with phallic urethra duplication were histologically examined in toto. RESULTS: The penislike clitorises revealed basically female features in the histogenesis of the corpora cavernosa and glans and in the absence of penile raphe, septum, fasciae, and periurethral glands. In 2 cases, the "phallic urethra" was completely surrounded by a single corpus cavernosum and in 3 cases by a circular glans. Labia minora and vestibular bulbs had not developed in 3 cases. The urethras had transformed into fusiform or scaphoid megalourethras with stenotic meatuses in 3 specimens and an extra orifice in the fourth specimen. CONCLUSIONS: Penislike clitorises in female pseudohermaphroditism show a fundamental dysgenesis of major structural elements. The pattern favors the hypothesis of an early error in the formation of the cloacal membrane and adjacent cloaca in embryos between 26 and 29 days postovulation that may lead to dysregulation of molecular developmental interactions during the following formation of the genital tubercle.

Mammary-like gland adenoma of the vulva: review of 46 cases.

AIMS: Hidradenoma papilliferum (HP) of the anogenital region, which was previously thought to be an apocrine tumour, is now believed to be derived from anogenital mammary-like glands (MLG) and is more accurately termed MLG adenoma. We sought to explore any ramifications that may have resulted from the perceived change in histogenesis of this tumour. METHODS: We performed a clinicopathological audit of 46 cases. RESULTS: The mean age was 52 years and the range 31-90 years. Symptoms occurred in 23%, comprising nodules of increasing size 9%, pruritus 9% and bleeding 6%. Tumours occurred in the known distribution of mammary-like glands. The labia minora accounted for 50%, labia majora 40%, fourchette 7% and clitoris 3%. Tumours were described clinically as cystic in 42%, ulcerated 33% and solid 25%. Histologically, adjacent normal MLG were often present. There was striking diversity in histology. Tubular, papillary, cystic and solid areas were seen in various combinations. Two cell types, epithelial and myoepithelial, were present. The most common epithelial cell, the ductal cell, was seen alone in 43% or associated with apocrine metaplasia (57%) and/or foam cells (13%) and/or squamous cells (13%). Myoepithelial cells were usually flattened, but were prominent and clear cell in type in 11%. Stroma was variable in amount and either desmoplastic or sclerotic. Inflammatory cells were particularly associated with tumours involving the surface. Unusual architectural patterns resembled breast lesions such as erosive adenomatosis, sclerosing adenosis and ductal adenoma. No recurrence or association with malignancy was recorded. CONCLUSIONS: MLG adenomas demonstrate a marked diversity in histological pattern and cell morphology. The ductal cell and a site compatible with and/or the presence of adjacent normal MLG are the most characteristic features. Unusual vulvar tumours, which have been previously reported as erosive adenomatosis, sclerosing adenosis, papillary adenofibroma, syringocystadenoma papilliferans, etc., are variants of MLG adenomas.

Müllerian serous cystadenoma of the scrotum following orchiopexy.

A 24-year-old man presented himself with a nodular lesion of about 1 cm diameter at the site of a previous orchiopexy associated with surgery for cryptorchism. Histopathology revealed the lesion to be adenomatous and confined to the scrotum. Histological and immunohistological features were not consistent neither with median raphe cysts or cutaneous adenomas nor with the intrascrotal adenomas of the rete testis, epididymis, nor with (malignant) mesotheliomas. However, the lesion did compare well with serous (papillary) cystadenomas of the testis or paratestis. These adenomas are thought to originate in remnants of the Müllerian system or of peritoneal lining altered by Müllerian metaplasia. This implies that the scrotal adenoma may have developed from an implant of such elements during orchiopexy 14 years ago. Complete excision of the lesion appears to be an adequate therapy.

Duplication of accessory phallic urethra (urethra triplication) in the female, signaling mesenchymal interruptions of the cloacal membrane as a cause for sagittal urethral duplications.

A specimen of accessory phallic urethra duplication (triplication) in a 32.5-week gestation female was studied histologically. The specimen demonstrated an anterior "phallic urethra" ending inside a penoclitoral organ in a megalourethra-like dilatation with a narrow epispadiac meatus and "anterior urethrocutaneous fistula" and a posterior canal opening with the anal canal. With histology suggestive of a split persistent urogenital sinus, correlation to normal development strongly suggests an error in the formation of the cloacal membrane and developing superficial cloaca at 26 to 29 days' ovulation age (2 to 4 mm), causing an isolated interruption of the membrane by mesenchyme, which by participating in the growth of the early cloaca may extend as far as the vaginal orifice later. Differences in number, position, and size of such mesenchymal interruptions can explain other duplications and triplications and offer a single alternative for the many current theories of pathogenesis, none of which are compatible with new insights in normal development.