Common ("classical") and covered cloacal exstrophy: a histopathological study and a reconstruction of the pathogenesis.

Current opinion about structure and pathogenesis of cloacal exstrophy was challenged by histopathological findings and new insights into the normal development. Autopsy specimens of common (n = 3) and covered cloacal exstrophy (n = 4) with single intraexstrophic and -perineal phallic structures and perineo-exstrophic canals have been analyzed histopathologically. The findings were correlated to normal development to reconstruct the pathogenesis. By identifying a specific cloaca-derived urethra field as distinct from allantois-derived bladder fields, the exstrophic area is found to reflect the original hindgut configuration in embryos of approximately 26-29 postovulatory days gestational age (2-4 mm). Correlation to normal development suggests malfunctioning of the primitive streak/caudal eminence as a primary fault that leads to a defective cloacal region in the hindgut disturbing cloacal-intestinal-allantoic dissociation and also causes lengthening of the intestinal region into a blind-ending colon, teratoma-like lesions, and vertebral and muscular anomalies. The current idea that membranes in "covered cloacal exstrophy" represent persisting cloacal membranes is dismissed by finding an amnion-like structure, which suggests dysfunction of an umbilical ring placode as a simultaneous 2nd fault. This malfunctioning may cause omphalocele by defective demarcation of the umbilical cord and may replace midline stroma of the infraumbilical abdominal wall by extraembryonic tissue that stretches into a weak temporary membrane, may leave a perineo-extrophic canal, and may allow the formation of a single perineal or intraexstrophic phallus. Malfunctioning without replacement may result in a purely epithelial "allantoic" membrane, which by disintegrating in combination with the cloacal membrane will expose common cloacal exstrophy.

Hypospadias and associated penile anomalies: a histopathological study and a reconstruction of the pathogenesis.

Hypospadias is considered to be the result of inadequate fusion of urethral folds and, possibly, of canalization of a glandar epithelial cord during the formation of the spongy urethra. This theory had to be reconsidered because a recent study in normal human embryos has exposed such fusion and invagination as misconceptions. Autopsy specimens of five penises with hypospadias from foetuses and neonates were studied histologically. The findings complemented with data from the literature were correlated to the normal developmental process to reconstruct the pathogenesis of the disorder. Histopathological analysis revealed that the hypospadic orifice was the proximal part of a mucosal delta which revealed the structure of the roof and meatus of a flattened distal urethra. Branches of the raphe bordering the delta and terminating in prominent 'dog ears' had the characteristics of the transient urethral labia (folds). Associated curvature and torsion could be related to structural abnormalities of vascular structures, notably the distal corpus spongiosum, and fasciae predominantly proximal to the hypospadic orifice. Correlation with normal development indicated that hypospadias and associated anomalies are not caused by disturbed fusion or glandar invagination but by maldevelopment of a complex of primordial fascial and vascular tissue proximal to the urethral orifice which normally form the venter side of the penis by disproportionately strong proliferation and make the urethral orifice shift distalward. Insufficient growth may disturb that shift with the degree of deficiency determining the precise position of the urethral orifice, size of the urethral delta and defect of the prepuce. Shortage and/or poor organisation of these tissues explain curvature and, if asymmetrical, torsion, both of which can occur also with minimal urethral deformity or as congenital ventral curvature and torsion without hypospadias.

Anal and ano-urogenital malformations: a histopathological study of "imperforate anus" with a reconstruction of the pathogenesis.

Histopathological information about "anorectal malformations" is scarce and the pathogenesis still controversial. Autopsy specimens of 20 human fetuses and newborns with "main" types of the disorder were studied histologically. Supplemented with surgical-anatomical data from the literature and with information from our own and earlier embryological research in animal models as well as from recent observations on the normal development of the human perineum, the study allowed for a new reconstruction of the pathogenesis of the disorder. The histological analysis of the malformations in human fetuses and newborns showed a ventralward deviation of the anal canal as the principal deformity. Ano-urogenital communications and differently structured ectopic anocutaneous canals issued from anywhere between the bladder and the vestibular/urethral orifice (female urethra excluded) and between the orifice and the usual site of the anus, respectively, or they ended blindly, but with a suggestion of lost communication. They occurred isolated or in association with other primary or secondary regional anomalies. Patho-embryological data from animal models revealed that the deviation was caused by defective development of the dorsal cloaca and not by disturbances in a series of fusion processes inside and outside the cloaca, as is currently believed. This mechanism fits well into recent adjustments of ideas about the normal development of the perineum. The cause of the defect is still obscure, but a malfunctioning of cells ingressing from an end-stage primitive streak that affects the dorsal side of the prospective cloaca appears most likely. The data collected permit a new reconstruction of the pathogenesis of anal and ano-urogenital malformations.

Sézary syndrome in a young man with severe atopic dermatitis.

Sézary syndrome (SS) is a rare cutaneous T-cell lymphoma. SS usually develops de novo. We describe a 23-year-old man with a proven history of severe atopic dermatitis since childhood, who developed SS. This case contributes to the discussion about the possibility of a relationship between inflammatory dermatitis, atopy and subsequent SS. We provide criteria that should be fulfilled to define such an association.

The small-cell variant of mycosis fungoides. A clinicopathological and quantitative electron microscopic study on 14 patients.

Small-cell variants of Sézary syndrome and mycosis fungoides (MF) have been described. However, in these studies the nuclear area of the small-cell variant of MF (SC-MF) as compared to histological classical MF (CL-MF) was not characterized objectively by quantitative electron microscopy. In a 14-year follow-up period, of a total of 76 patch/plaque stage MF patients seen in the Department of Dermatology of the University Hospital Utrecht, 14 (18%) had an infiltrate composed of atypical lymphocytes characterized by a distinctly smaller cell diameter and smaller, hyperchromatic, deeply indented nuclei as compared to the usual cell type of MF. The aim of the investigation was to confirm this observation objectively using quantitative electron microscopy (morphometry) and to define SC-MF as compared to CL-MF. The study was performed on the 14 patients with SC-MF, and 10 patients with clinical and histological CL-MF and 4 patients with chronic eczema. Electron micrographs of sections obtained from each biopsy were analysed by computer to produce the following data: a nuclear contour index (NCI), the mean nuclear area (MNA), the mean nuclear area of the cells above the 75th percentile (P75NA) and the percentage of cells larger than 30 microm2. The values of MNA differed significantly between patients with SC-MF and those with CL-MF (17.6 vs 23.2 microm2; P = 0.02), as did the values of P75NA (20.7 vs 27.9 microm2; P = 0.01). The NCI of the SC-MF and CL-MF patients were similar. These results are consistent with our observations that SC-MF does indeed exist.

bcl-2 protein expression in primary cutaneous large B-cell lymphoma is site-related.

PURPOSE: Primary cutaneous large B-cell lymphoma (PCLBCL) that presents on the leg has recently been recognized as a distinct disease entity. These lymphomas have a reduced disease-free survival and a worse prognosis as compared with the more common, morphologically similar PCLBCL that present on the head or trunk. Studies in noncutaneous diffuse large B-cell lymphomas suggest a relationship between the expression of bcl-2 protein and clinical behavior. In the present study, we investigated whether these two groups of PCLBCL differ in the expression of bcl-2 protein and the presence of t(4;18), known as one of the causes of bcl-2 overexpression. PATIENTS AND METHODS: Paraffin sections from pretreatment biopsies of 14 PCLBCLs of the head or trunk and nine PCLBCLs of the legs were investigated for expression of bcl-2 protein using immunohistochemistry, and for the presence of the 14;18 translocation using polymerase chain reaction (PCR) amplification with primers against both the major breakpoint region (mbr) and the minor cluster region (mcr) of bcl-2. For reasons of comparison, nine secondary cutaneous large B-cell lymphomas (SCLBCLs) were also studied. RESULTS: Expression of bcl-2 protein was found in all nine PCLBCLs of the leg and in all nine SCLBCLs, but not in any of the 14 PCLBCLs on the head and trunk. The t(14;18) was only detected in two of seven SCLBCLs, but not in the five PCLBCLs of the leg or the eight PCLBCLs on the head or trunk studied. CONCLUSION: The striking differences in bcl-2 expression between PCLBCL of the head or trunk and PCLBCL on the leg suggest that bcl-2 expression is site-related and may contribute to the different clinical behavior between these two groups of lymphomas. In addition, they underscore that PCLBCL on the head and trunk and PCLBCL on the leg are distinct disease entities, as recently recognized in the European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas.

p53 and bcl-2 expression do not correlate with prognosis in primary cutaneous large T-cell lymphomas.

Overexpression of p53 protein in cutaneous T-cell lymphoma (CTCL) has been reported in primary cutaneous large T-cell lymphomas (PCLTCL) and has been associated with tumor progression and transformation in mycosis fungoides. However, the prognostic significance of p53 expression has not been studied thus far. In the present study we investigated the expression of p53 as well as bcl-2 protein in 27 PCLTCL, including 19 CD30-positive and 8 CD30-negative lymphomas, retrieved from the registry of the Dutch Cutaneous Lymphoma Working Group. The results were correlated with follow-up data and proliferative activity, as assessed by the percentage of MIB-1 positive tumor cells. Overexpression of p53 protein, defined as nuclear staining of more than 5% of the tumor cells, was found in 10 of 27 cases (37%), including 6 of 19 (32%) CD30+lymphomas and 4 of 8 (50%) CD30-PCLTCL. bcl-2 protein was expressed in 6 of 19 (32%) CD30+lymphomas and in only 1 of 8 (12%) CD30-PCLTCL. However, no significant correlation between p53 or bcl-2 expression and prognosis was found, neither in the whole group, nor within the CD30+ or CD30- group. In addition, no relationship between p53 expression and proliferative activity was found. The results confirm that p53 expression is more common in PCLTCL than in mycosis fungoides and Sézary syndrome. However, neither p53 nor bcl-2 expression correlated with survival or proliferative activity.

Immunophenotyping and gene rearrangement analysis provide additional criteria to differentiate between cutaneous T-cell lymphomas and pseudo-T-cell lymphomas.

Differentiation between cutaneous pseudo-T-cell lymphomas and cutaneous T-cell lymphomas (CTCLs) may be extremely difficult. In this study, it was investigated whether demonstration of an aberrant phenotype and detection of clonal T-cell receptor gamma (TCR gamma) gene rearrangements can be used as additional differential diagnostic criteria. Immunohistochemical studies and TCR gamma gene rearrangement analysis using a polymerase chain reaction with primers specific for V gamma 1-8 and V gamma 9 gene segments in combination with denaturing gradient gel electrophoresis (PCR/ DGGE) were performed on frozen material of 11 pseudo-T-cell lymphomas and 17 CTCLs, including 9 cases of mycosis fungoides (MF) and 8 pleomorphic CTCLs. Clonal TCR gamma gene rearrangements were found in 66% of patch/plaque-stage MF and 100% of tumor-stage MF and pleomorphic CTCL, but not in any of 10 pseudo-T-cell lymphomas studied. Aberrant expression of CD2, CD3, and/or CD5 antigens was noted in 3 of 6 (50%) cases of patch/plaque-stage MF, all three cases of tumor-stage MF, and 5 of 8 (62%) pleomorphic CTCLs, but not in any of the 11 pseudo-T-cell lymphomas. Moreover, in pseudo-T-cell lymphomas exhibiting a nodular or diffuse growth pattern, a considerable admixture with reactive CD8+ T cells (15 to 60%), B cells (up to 20%), and macrophages was a characteristic finding. In conclusion, the results of this study suggest that demonstration of clonal TCR gene rearrangements and an aberrant phenotype, as well as demonstration of many admixed CD8+ T cells and B cells can be considered as useful additional criteria in the differentiation between pseudo-T-cell lymphomas and CTCLs.

The diagnostic value of morphometry on blood lymphocytes in erythrodermic actinic reticuloid.

BACKGROUND: As the differential diagnosis of erythrodermic actinic reticuloid vs Sézary syndrome (SS) can be very difficult, we examined the value of the nuclear contour index (NCI) on blood lymphocytes as the criterion for differential diagnoses. The NCI is defined as the nuclear parameter divided by the square root of the nuclear area. Three different parameters were studied: mean NCI, percentage of cells with an NCI of 6.5 or greater, and the highest NCI. These indexes were studied on blood lymphocyte samples obtained from 10 patients with erythrodermic actinic reticuloid and were compared with the findings in 10 patients with other benign forms of erythroderma and in seven patients suffering from SS. RESULTS: The patients with erythrodermic actinic reticuloid differed significantly from the group with SS regarding the percentage of cells with an NCI of 6.5 or greater and the highest NCI, but not when the mean NCI was considered. All three parameters revealed nonsignificant results for erythrodermic actinic reticuloid compared with other benign forms of erythroderma. The group with SS differed significantly from the patients with other benign forms of erythroderma regarding all three parameters. By combining three morphometric criteria (mean NCI, > or = 5.5; > 30% lymphoid cells with an NCI of > or = 6.5; and highest NCI, > or = 11.5), all patients with erythrodermic actinic reticuloid or other benign forms of erythroderma and six of the seven patients with SS were correctly classified. CONCLUSION: Our data indicate that assessment of the NCI on peripheral blood lymphocytes is of value in the differential diagnosis of erythrodermic actinic reticuloid vs SS.

Mammary Paget's disease confined to the areola and associated with multifocal Toker cell hyperplasia.

A hitherto unreported variant of mammary Paget's disease (MPD) limited to the areola, leaving the nipple unaffected, has been analyzed by serial sectioning of the whole areola and nipple. This otherwise characteristic MPD proved to be confined to the epidermis. There was no underlying carcinoma. This MPD was associated with a multifocal presence of monomorphic but otherwise similar cells in small collections surrounding the ostia of areolar mammary glands in the clinically unaffected area. This condition was interpreted as hyperplasia of mammary gland-related cells also found in normal nipples (so-called Toker cells). The observations hint at a possible derivation of some cases of mammary and extramammary Paget's disease from such Toker cells.

The pathogenesis of familial multiple cylindromas, trichoepitheliomas, milia, and spiradenomas.

Early stages in the development of hereditary cylindromas associated with trichoepitheliomas, milia, and spiradenomas revealed that (a) trichoepitheliomas were derived from the bulges of hair follicles and probably represented an abnormal histogenesis from which rarely poorly differentiated trichoepitheliomas developed; (b) milia were the result of cystic alteration of the trichoepitheliomatous bulge proliferations; and (c) cylindromas and spiradenomas were different appearances of the same tumor and developed from two separate sources, follicular bulge proliferations and eccrine glands. From the bulge proliferations multiple cylindromatous buds developed that, by increasing in number, formed the classical cylindroma and, by increasing in size rather than in number, gave the spiradenomatous variant. Eccrine glands transformed into cylindromas by cylindromatous growth from the basal cell layer. Connections between the original structures and the tumors were mostly lost. Tumors from both sources revealed the same morphology, which was most indicative of eccrine differentiation including secretory and excretory elements. Apocrine differentiation was a rare and possibly secondary event. The multiplicity in derivation and differentiation suggest an adnexal progenitor cell as the most likely source.

Cysts of mammarylike glands in the vulva.

A hidrocystoma which originated in a mammarylike gland (MLG) of the vulva is described. It involved the main collecting duct and was characterized by a peripheral basal layer of myoepithelium and a luminal layer of cuboidal to columnar cells with discrete cytoplasmic snouts and by lobules opening into the cavity. Adhering to it were cutaneous glands, including MLGs, and dartos muscle. These features distinguish it from the other cysts of the vulva, including vestibular, urogenital sinus, and keratinous cysts. Another cystic lesion of the MLGs was evidenced only microscopically and involved multiple whole glands. It resembled similar alterations in eccrine, apocrine, and mammary glands, and most likely represented involution cysts of MLGs.

Mammary-like glands of the vulva and their disorders.

Supernumerary mammary glands derived from rudiments of the embryonic milk lines or mammary ridges in the vulva are considered a source of a series of unusual tumors resembling lesions of the breasts. This phenomenon was reevaluated in light of recent observations of mammary-like anogenital glands (MLG), which are a normal constituent of the vulva and appear to be closely related to eccrine glands. An analysis of the literature reveals that the concept of "milk lines" originated in a mixture of phylogenetic and ontogenetic theories at the beginning of this century and was not supported by observations in human embryos, which show that primordia of the mammary glands do not extend beyond the axillary-pectoral area. The breasts and the vulva are so widely separated by time and space that the vulvar MLG can not be derived from the mammary ridges or milk lines. The profile of the MLG, which can also reveal some eccrine or apocrine features, makes these glands the most likely source of a series of lesions occurring in the anogenital region and comprising lactating glands, lactating adenoma, fibroadenoma, hidrocystoma, hidradenoma papilliferum, and most cases of extramammary Paget's disease and invasive adenocarcinoma.

Adenocarcinoma of the mammary-like glands of the vulva: a concept unifying sweat gland carcinoma of the vulva, carcinoma of supernumerary mammary glands and extramammary Paget's disease.

An unusual case of primary adenocarcinoma of the vulva is described. It combined features of the three different types of adenocarcinoma of the skin of the vulva which are currently recognized, i.e. sweat gland carcinoma, adenocarcinoma derived from supernumerary mammary glands, and extramammary Paget's disease (EMPD). Central in this tumor was a recently recognized type of cutaneous gland which appeared special for the anogenital region and was distinguished because it combined morphological features of eccrine, apocrine and mammary glands. As it most resembles mammary glands, it is named "mammary-like gland". On the basis of the case presented and of a critical review of the literature, it was concluded that, with the exception of a few sweat gland carcinomas similar to those elsewhere in the skin, adenocarcinomas of the skin of the vulva form a single category of neoplasms with a variable expression of features reminiscent of eccrine, apocrine and mammary gland carcinomas. The data strongly suggested a common derivation from the mammary-like gland or, in cases of EMPD, its related germinative cells in the epidermis.

Apoeccrine glands in nevus sebaceus.

Apoeccrine glands were found in 13 of 57 specimens of nevus sebaceus. The glands showed the basic structure of eccrine glands, but differed in that a part of the secretory duct was lined by characteristic apocrine epithelium. The apocrine alteration varied from slight apocrine changes in a few secretory cells to an almost complete alteration of the secretory epithelium in other glands. The association with changes in the excretory ducts of rare glands suggested a transformation of eccrine into apocrine glands. It was nevertheless considered as most likely that a majority of the apocrine glands in nevus sebaceus had developed in the "classic" way in association with pilosebaceus structures. In nevus sebaceus, apoeccrine glands appeared to represent eccrine glands with a variable degree of apocrine metaplasia that could result in complete transformation rather than the formation of a separate category of specialized sweat glands. The capacity of eccrine epithelium to transform into apocrine epithelium is why difficulties are experienced in the precise categorization of sweat gland neoplasms into eccrine and apocrine tumors.

Primary cutaneous T-cell lymphoma: clinicopathological features and prognostic parameters of 35 cases other than mycosis fungoides and CD30-positive large cell lymphoma.

Within the group of primary cutaneous T-cell lymphomas (CTCLs), mycosis fungoides (MF), Sézary's syndrome (SS), and CD30-positive lymphomas have been delineated as clinicopathological entities. Primary CTCLs that do not belong to one of these entities represent a heterogeneous and ill-defined group of neoplasms. This paper describes the clinical and histological features of 35 of such cases. The object of this study was to define prognostic parameters for this group of primary CTCLs. Using a slightly modified version of the updated Kiel classification, a subdivision was made into CTCL, pleomorphic, small cell type (n = 3); pleomorphic, medium-sized cell type (n = 6); pleomorphic, large cell type (n = 18); and immunoblastic lymphomas (n = 8). Altogether, these lymphomas had a poor prognosis with estimated 2- and 4-year survival rates of 53 and 22 percent, respectively. Patients with pleomorphic, small and medium-sized cell lymphomas (n = 9) proved to have a significantly better survival than those with pleomorphic, large cell lymphomas (P = 0.032) and immunoblastic lymphomas (P = 0.008). Primary cutaneous immunoblastic lymphomas had the worst prognosis with an estimated 2-year survival rate of 14 percent. Other parameters including age (P = 0.345), sex (P = 0.662), extent of skin lesions at presentation (P = 0.0854), and mode of initial treatment (P = 0.609) had no significant effect on the survival time. The results of this study suggest that primary CTCLs other than classical MF, SS, and CD30-positive lymphomas have a poor prognosis in most cases, and that the current classification may be a useful means of predicting the clinical behaviour in these lymphomas.