Bernard Czernobilsky

Endometrial biopsy-induced gene modulation: first evidence for the expression of bladder-transmembranal uroplakin Ib in human endometrium

OBJECTIVE To explore the possibility that endometrial injury modulates the expression of specific genes that may increase uterine receptivity. DESIGN Controlled clinical study. SETTING Clinical IVF unit and academic research center. PATIENT(S) IVF patients with 28- to 30-day menstrual cycles. INTERVENTION(S) Endometrial biopsies from two groups of patients were collected on days 20-21 of their spontaneous menstrual cycle. The experimental, but not the control, group underwent biopsies on days 11-13 and 21-24 of their preceding cycle. MAIN OUTCOME MEASURE(S) Global endometrial gene expression and specific analysis of uroplakin Ib (UPIb) mRNA level throughout the menstrual cycle. RESULT(S) Local injury modulated the expression of a wide variety of genes. One of the prominently up-regulated genes was the bladder transmembranal protein, UPIb, whose expression by the endometrium is shown here for the first time. Endometrial UPIb mRNA increases after biopsy in the same cycle wct 2with an additional elevation in the following cycle. Immunohistochemical analysis localized the UPIb protein to the glandular-epithelial cells. Genes encoding other membrane proteins such as adipose differentiation-related protein and mucin 1, transmembrane, were also up-regulated. CONCLUSION(S) The biopsy-induced increase in the expression of UPIb and other genes encoding membrane proteins supports the possible importance of the membrane structure and stability during implantation. The specific role of UPIb in uterine receptivity should be elucidated.

Alpha smooth muscle actin (α-SM actin) in normal human ovaries, in ovarian stromal hyperplasia and in ovarian neoplasms

SummaryAn immunohistochemical investigation of alpha-smooth muscle actin (α-SM actin) using the monoclonal anti-α-SM-1 antibody was carried out in 15 normal ovaries, in three ovaries with stromal hyperplasia and in 27 neoplastic ovaries. In selected cases the pattern of actin isoforms was examined by means of 2 D-gel electrophoresis. In addition, the tissues were stained for vimentin and desmin. In normal ovaries α-SM actin was found in the inner cortex and in the theca externa. In ovarian stromal hyperplasia expression of α-SM actin was minimal or absent. In primary and metastatic epithelial tumors there was positive stromal staining for α-SM actin, especially in the vicinity of epithelial elements. This tended to be more widespread in malignant neoplasms. Thecomas did not express α-SM-actin and could thus be differentiated from leiomyomas which stained intensely for α-SM actin. Only focal stromal staining of α-SM actin was observed in granulosa and germ cell tumors. In all the tissues studied blood vessels were strongly positive for α-SM actin. Desmin, although present in the stroma of most of the specimens, was less abundant than α-SM actin. We concluded that α-SM actin is a component of the normal human ovary where it may contribute to the contractility of its stroma. Its absence in the normal outer cortex and theca interna, and in stromal hyperplasia and thecoma implies that sex hormones do not constitute a stimulus for α-SM actin production in the ovary. Among neoplasms it is most widely represented in the stroma of epithelial tumors in which it may reflect stromal stimulation mediated by neoplastic epithelium.

A familial syndrome of central nervous system and ocular malformations

A family is reported in which three of seven siblings were affected with an association of severe cerebral, cerebellar and ocular malformations. Brain malformations consisted of lissencephaly and the Dandy‐Walker anomaly; congenital cataracts, retinal dysgenesis and coloboma of the choroid were found in the eyes. The pathogenesis of these developmental anomalies is probably related to abnormal neuron migration and abnormal closure of fetal fissures, occurring at an early stage of embryonic development. The association of these malformations is unique, and may point to a new malformation syndrome, inherited as an autosomal recessive trait.

Ovarian clear cell adenofibromatous tumors. Benign, of low malignant potential, and associated with invasive clear cell carcinoma

The authors have studied 17 cases of ovarian clear cell tumors having an adenofibromatous pattern and classified them on a histologic basis into three categories: benign, of low malignant potential, and associated with invasive clear cell carcinoma. Clear cell adenofibroma is characterized by orderly tubules and glands lined by uniform epithelium with little or no nuclear atypia set in an abundant stroma with an interlacing pattern resembling ovarian stroma. Clear cell adenofibromatous tumors of low malignant potential had a similar stroma, but exhibited moderate to marked degrees of epithelial proliferation and atypia. In the third category there were cases of invasive clear cell carcinoma in which a distinct portion of the tumor met the criteria for clear cell adenofibroma, or clear cell adenofibromatous tumor of low malignant potential. Cases of invasive clear cell carcinoma exhibiting a desmoplastic reaction or a diffuse fibrous stroma, but lacking typical adenofibromatous areas, were not included in this study. The benign and low malignant potential tumors showed no clinical evidence of aggressive behavior, whereas those associated with invasive clear cell carcinoma often did. Although there have been no recurrences in our small group of patients with tumors of low malignant potential, the histologic similarity of the epithelium in these tumors to that seen in invasive carcinomas justifies such a categorization. Further studies of larger series using the proposed classification should yield more information concerning the biologic behavior of these types of clear cell adenofibromatous tumors. Cancer 53:1156‐1163, 1984.

Cystadenofibroma of the ovary: A clinicopathologic study of 34 cases and comparison with serous cystadenoma

The clinicopathologic features of 34 cystadenofibromas were analyzed and compared to those of 39 serous cystadenomas. The clinical features of the patients with cystadenofibromas were similar to those of the patients with cystadenoma. Pathologic features showed the following differences: Papillary projections of cystadenofibromas consisted of short, broad, firm structures which were frequently hyalinized. Those of cystadenomas were slender, delicate and friable showing less frequent hyalinization. Epithelial elements in both tumors were similar to those seen in a variety of neoplasms of müllerian derivation. However, while all the cystadenofibromas were histologically unequivocally benign, 6 cystadenomas showed epithelial tufting, 5 mitoses and atypia each, and 3 of these were diagnosed as borderline malignant. Characteristic histologic findings in the cystadenofibromas established beyond doubt their origin from germinal epithelium and underlying stroma, whereas in some of the other ovarian tumors of müllerian derivation, the cellular origin often remains conjectural at best. We concluded that ovarian cystadenofibroma is more common than generally believed and that is of an entirely benign nature, necessitating only conservative surgical therapy. The characteristic pathologic features of this neoplasm justify its separate listing in the group of müllerian ovarian tumors of surface epithelial and ovarian stromal origin.

Expression of the adherens junction protein vinculin in human basal and squamous cell tumors: Relationship to invasiveness and metastatic potential

The acquisition of an invasive or metastatic phenotype in malignant neoplasms is often correlated with reduced cellular adhesiveness. We investigated the expression of the adhesion-associated cytoplasmic protein, vinculin, in normal and neoplastic human squamous epithelia, as well as in metastases of squamous cell carcinomas, and correlated the results with invasiveness and metastatic potential. Tissue samples from various tumors were examined, including basal cell carcinomas (BCC), keratoacanthomas, and squamous cell carcinomas (SCC). In addition, lymph node metastases from nine of the SCC were tested in this study. Our results indicate that most BCC, keratoacanthomas, and in situ SCC display strong positive staining for vinculin. The level of immunolabeling for vinculin and its pattern of distribution in the low malignant, nonmetastasizing lesions was similar to those observed in normal squamous epithelia. In contrast, in SCC, which are invasive and possess metastatic potential, as well as in their metastases, vinculin labeling was negative or poor, irrespective of their degree of differentiation. In conclusion, poor vinculin labeling in tumors of squamous epithelial origin examined here appears to be related to the metastatic potential of the tumor. Vinculin immunostaining of primary tumors originating in stratified squamous epithelia may thus be of value in helping to determine the metastatic potential of these neoplasms.

Immunocytochemical study of an endometrial diffuse clear cell stromal sarcoma and other endometrial stromal sarcomas

Intermediate filament composition was studied in the following endometrial stromal tumors: low‐grade stromal sarcoma (endolymphatic stromal myosis), high‐grade stromal sarcoma with an associated adenocarcinoma (collision tumor), diffuse clear cell stromal sarcoma and a mesodermal mixed tumor (carcinosarcoma). The tumor cells of the stromal tumors as well as the mesenchymal elements of the mixed mesodermal tumor were decorated exclusively with antibodies to vimentin. Desmin was not demonstrated in these tumor cells. A biochemical study of the cytoskeletal filaments present in the low‐grade stromal sarcoma revealed, in addition to vimentin, β and γ actin as seen in normal endometrial stroma. Cytokeratins were only identified in epithelial components which were present in some of these tumors. Intermediate filament typing in these endometrial neoplasms contributes to the elucidation of histogenetic problems, may delineate mesenchymal from epithelial elements, may separate muscle from stromal lesions and in one instance helped to define a hitherto unreported diffuse clear cell stromal sarcoma.

Ovarian Brenner tumors. II: Malignant

In this study, nine malignant Brenner tumors were reviewed and divided into well and poorly differentiated types. To meet the criteria for malignancy, stromal invasion must be observed. A component of typical benign, metaplastic, and/or proliferating Brenner tumor should be identified. The presence of these latter elements is necessary because the malignant component is often too poorly differentiated to be identified as a Brenner tumor, and a metastatic lesion cannot otherwise be ruled out on pathologic grounds. Well‐differentiated tumors often occurred in close relationship to proliferating and occasionally to metaplastic areas, and poorly differentiated ones in relationship to low malignant potential areas. The malignant component may consist of transitional cell, squamous, or undifferentiated carcinoma or an admixture of these. A component of adenocarcinoma may be associated with other malignant elements, but pure mucinous or serous adenocarcinomas would be regarded as separate neoplasms. Although the number of cases is small, the well‐differentiated tumors appear to have a better prognosis than the poorly differentiated ones.

Vaginal adenosis in women born prior to the diethylstilbestrol era

Vaginal adenosis was evaluated in 41 women, all of whom had been born prior to the diethylstilbestrol (DES) era, and compared with the adenosis commonly encountered in DES-exposed progeny. The patients were 24 to 88 years of age (median, 44 years). Six of the women were symptomatic, and in four of these six the glands were enmeshed in a marked inflammatory infiltrate. In an additional 26 women the adenosis was discovered as incidental, nonsymptomatic macroscopic nodules or cysts. The remaining nine cases of adenosis were discovered by pathologists. Three types of epithelia characterized the glands: mucinous, tuboendometrial, and embryonic. Mucinous columnar cells resembling the lining of the normal endocervix and tuboendometrial cells resembling the lining of the normal fallopian tube or endometrium constituted the glands exclusively in 22 and eight specimens, respectively, and as a mixture in seven. The glands lined by mucinous cells most often presented clinically as cysts or nodules. The specimens composed of tuboendometrial cells were most often discovered on microscopic examination. The third type of epithelium, composed of embryonic columnar cells, was encountered in four specimens. These glands, less than 30 micron in greatest diameter, were located at the junction between the lamina propria and the squamous epithelium, and were incidental microscopic findings. It is concluded that the microscopic appearances of adenosis in women born prior to the DES era are identical to those encountered in young women exposed in utero to DES.

Uterine Tumors Resembling Ovarian Sex Cord Tumors : An Update

Summary: Tumors of the uterus resembling ovarian sex cord tumors were reported by Clement and Scully in 1976 and were divided in 2 groups: group 1, endometrial stromal tumors, and group 2, mural uterine tumors-both with elements resembling ovarian sex cord tumors. In the former, the sex cord component constitutes a minor portion of an endometrial stromal neoplasm, whereas in the latter, it is the predominant or exclusive component of a uterine wall lesion composed of a variety of mesenchymal elements. An origin from endometrial stromal cells, adenomyosis, stromal myosis, endometriosis, or multipotential cells within the myometrium was postulated in both groups of tumors. In group 1 tumors, the prognosis depends on the type, grade, and stage of the underlying stromal neoplasm. Group 2 tumors seemed to be benign, although because of the occasional recurrence of these tumors, they should be considered of low-grade malignant potential. In recent years, the histological features in group 2 were found to be much more varied than those in group 1 and consisted among others of retiform areas, glomeruloid structures, and Leydig-like cells. In group 1 tumors, the sex cord elements remained limited to cords, trabeculae, nests, and tubules. Eventually, the abbreviation ESTSCLE, or endometrial stromal tumors with sex cord-like elements, was given to group 1 tumors, whereas UTROSCT, or uterine tumor resembling ovarian sex cord tumor, was used for group 2 tumors. The most significant information in recently conducted studies concerns the immunophenotype of these lesions especially of UTROSCT. Out of the plethora of the immunohistochemical stains, a panel of 4 including calretinin, inhibin, CD99, and Melan A has emerged which seemed to be the most characteristic sex cord markers. Positivity for calretinin and at least for 1 of the other above-mentioned markers may thus confirm the diagnosis of UTROSCT. Endometrial stromal tumors with sex cord-like elements, on the other hand, usually express only 1 sex cord marker, mostly calretinin. However, additional studies are necessary to confirm these observations. In conclusion, UTROSCT and, to a lesser degree, ESTSCLE, are polyphenotypic neoplasms, which, according to the evidence available at present, most likely arise from pluripotential uterine mesenchymal cells. In UTROSCT, the differentiation into sex cord components is predominant or exclusive, whereas in ESTSCLE, it is minor.