Human mammary tumor virus (HMTV) in endometrial carcinoma.

OBJECTIVE: Human mammary tumor virus (HMTV) is 90% to 98% homologous to mouse mammary tumor virus, the etiological agent of mammary tumors in mice. Human mammary tumor virus sequences were found in 40% of the breast cancers studied in both American and Australian women. In addition, 10% of endometrial carcinomas studied in Australian women also contained HMTV sequences. We have explored the possibility that endometrial cancer of American women may also contain HMTV. METHODS/MATERIALS: Nested polymerase chain reactions, radioactive internal probing, and sequencing were used to establish the presence of unique nucleotide sequences of HMTV in human genomic DNA. The genomic DNAs were tested to guarantee that they were free of murine DNA. Immunohistochemistry with a monoclonal antibody specific for HMTV envelope protein demonstrated that HMTV sequences were translated. RESULTS: Thirteen (23.2%) of 56 of the endometrial cancers studied contained HMTV sequences and proteins. Human mammary tumor virus sequences and protein were not detected in the 33 normal endometria studied. CONCLUSION: Human mammary tumor virus, an agent with high homology to mouse mammary tumor virus, was found in 23.2% of the endometrial cancers studied, thus opening the possibility of a pathogenic role.

Loss of p16INK4A expression in low-grade ovarian serous carcinomas.

According to a tumor progression model, low-grade ovarian serous carcinomas may evolve from serous borderline tumors or micropapillary tumors. We sought to investigate the role of and associations between BRAF mutational status, extracellular signal regulated kinase activation, and p16(INK4A) expression in various types of ovarian serous tumors. We analyzed 29 typical ovarian serous borderline tumors, 8 micropapillary tumors, 4 low-grade invasive ovarian serous carcinomas, and 24 high-grade invasive ovarian serous carcinomas for the BRAF mutational status at codon 600; in addition, expression levels of the downstream signaling protein extracellular signal regulated kinase and the p16(INK4A) tumor suppressor protein were assessed by immunohistochemistry. There was a decline in p16(INK4A) expression from serous borderline tumors to micropapillary tumors with almost complete loss in low-grade invasive carcinomas. High-grade carcinomas had a variable p16(INK4A) expression pattern. We found a T1799A BRAF mutation in 12 typical serous borderline tumors (41%) and 1 micropapillary tumor (12.5%). No mutations were found in the low-grade and high-grade invasive carcinomas (0%). Among the typical borderline tumors, cases with BRAF mutations tended to have stronger p16(INK4A) expression compared with cases with wild-type BRAF. No other correlations were identified between the BRAF mutational status and expression levels of the analyzed proteins. Loss of p16(INK4A) expression may be a pathogenetic factor in the progression from serous borderline tumors to low-grade invasive carcinomas. The divergent molecular profiles support the theory that high-grade carcinomas are unrelated to serous borderline tumors or low-grade carcinomas.

[Optical biopsy in gynecology]. / Biopsie optique en gynécologie: l'aspect pathologie anatomique.

Optical biopsy allows living tissues to be visualized in situ and in real time. Confocal endomicroscopy is already used to detect neoplastic and pre-neoplastic gastrointestinal lesions, with a precision comparable to that of conventional biopsy. Likewise, precancerous cervical lesions can be identified with fluorescence endomicroscopy. More recently, confocal microlaparoscopy using fluorescent contrast agents has been used, both in vivo and in vitro, to identify healthy and cancerous ovaries. This technique could serve for early diagnosis of ovarian cancer and preinvasive ovarian dysplasia that has already been described by histology automated image analysis (morphometry) and immunohistochemistry, particularly in women with an elevated risk of ovarian cancer. Real-time diagnosis by optical biopsy would allow the surgeon to take appropriate action in case of positive findings, and would also help to avoid unnecessary surgery. This would particularly benefit younger women wishing to preserve their fertility.

Laparoscopic morcellation of didelphic uterus with cervical and renal aplasia.

This is a case report (and review of the literature) of a 12-year and 10-month-old girl with a rare congenital anomaly of uterus didelphys, unilateral cervix aplasia, and ipsilateral renal aplasia. She had severe dysmenorrhea from the first menses. In an effort to preserve fertility, a cervical fistula was made that closed over. A laparoscopic hemi-hysterectomy was done successfully and rapidly with laparoscopic morcellation. Because no ureter was present, it was not necessary to trace it. For this congenital anomaly, laparoscopic morcellation of the obstructed hemiuterus is the preferred treatment either as a primary procedure or as a secondary procedure following failure of a surgical cervical fistula for the young patient.

Prepubertal unilateral fibrous hyperplasia of the labium majus: report of eight cases and review of the literature.

OBJECTIVE: To report and propose a consensus term for eight cases of a newly recognized, asymptomatic, rapidly growing unilateral labium majus mass without palpable borders in prepubertal girls, appearing to be temporally associated with the physiologic increase of adrenal hormones. METHODS: Histologic examination, special stains, and immunohistochemistry were performed on all cases. In our personal cases, electron microscopy and chromosomal analysis were also performed, together with pelvic magnetic resonance imaging (MRI), inguinal exploration, vaginoscopy with biopsies, and adrenal hormone levels. RESULTS: Of the eight cases, seven were Ashkenazi Jewish girls from the same area in New York City. The unilateral masses were asymptomatic, soft, without palpable borders. The overlying skin had a slightly tan peau d'orange surface. The masses could not be completely excised because they extended into the contiguous pelvic floor. Histologically, the masses were composed of bland hypocellular fibrous tissue extending into the deep subcutaneous tissue. The masses blended into the surrounding tissue and adjacent pelvic floor as shown by MRI preoperatively and postoperatively. Residual tissue did not progress after incomplete resection. CONCLUSION: These fibrous lesions develop in months at the time of physiologic increase in adrenal hormone secretion just before puberty and subsequently appear to stop growing. The surgeon should not attempt a complete removal but simply excise sufficient tissue for a reasonable cosmetic result and to confirm the diagnosis. The lesions reflect fibroblastic hyperplasia, which is possibly hormone-driven. The ethnic and geographic clustering of cases raises consideration of environmental exposures or genetic predisposition.

[Stage I ovarian carcinoma: two distinct malignancies?]. / Cancers ovariens au stade I: deux carcinogenèses différentes?

Ovarian cancers are the most lethal gynecologic malignancies and are rarely diagnosed in their early stages. The most common of these tumors--serous papillary carcinoma--is generally asymptomatic in the early stages. Non serous carcinomas (endometrioid and clear-cell carcinomas) have a higher chance of early diagnosis, as the associated endometriosis can cause pelvic pain, while endometrial hyperplasia/neoplasia can lead to vaginal bleeding. In addition, serous papillary carcinomas tend to be bilateral with peritoneal involvement, while non serous papillary carcinomas are often unilateral. Non serous papillary carcinomas tend to occur in younger, hyperestrogenic, often infertile patients. Serous papillary carcinomas potentially arise from dysplastic epithelial cells lining the ovarian surface and inclusion cysts, while the substrate of non serous papillary tumors is atypical endometriotic tissue. Tumor markers also tend to differ between the two forms of ovarian cancer. Pelvic laparoscopy and prophylactic oophorectomy have offered new insights into the mechanisms and early stages of ovarian malignancies.

Systemic Inflammation and Autoimmunity in Women with Chronic Endometritis.

PROBLEM: To determine in women with recurrent pregnancy loss (RPL) and/or implantation failure (RIF) the prevalence of chronic endometritis (CE), systemic inflammation and autoimmunity, and whether they relate. METHOD OF STUDY: This retrospective study examined inflammatory (adiponectin, CRP, leptin, and IL6) and autoimmune (total immunoglobulins, ANA, thyroid antibodies, antiphospholipid antibodies) markers in a group of 55 women with RPL/RIF. A diagnosis of CE was reached by endometrial biopsy, demonstrating CD138-positive plasma cells on histology. The prevalence of markers of systemic inflammation and autoimmunity was compared between women with and without CE. RESULTS: Among all RPL/RIF patients, 32.7% demonstrated at least one positive inflammatory marker, 61.8% at least one autoimmune marker, and 45.5% CE. Moreover, CE patients did not differ in systematic inflammatory or autoimmune profiles from those without CE. CONCLUSIONS: Endometritis and elevated inflammatory and autoimmune markers are common in women with RPL/RIF, but endometritis cannot be predicted based on either peripheral inflammatory or autoimmune markers.

[Prophylactic salpingectomy or salpingo-oophorectomy as an ovarian cancer prevention?]. / Salpingectomie prophylactique ou annexectomie prophylactique dans la prévention du cancer de l'ovaire ?

A recent hypothesis has stated that many ovarian cancers (especially high-grade serous histotype) could arise from the distal part of the fallopian tube. On one hand we know that risk-reducing salpingo-oophorectomy is the most effective prevention for ovarian cancer among BRCA mutation carriers. On the other, oophorectomy increases the relative risk for cardiovascular, osteoporotic psychosexual and cognitive dysfunctions in premenopausal women. This raises the question whether bilateral salpingectomy could be an effective strategy in the prevention of ovarian cancer in case of hereditary predisposition and in the general population. Here we discuss origin of ovarian cancer in the light of the latest molecular studies and the relative risks and benefits of a strategy of exclusive salpingectomy in comparison with the classical adnexectomy.

Characterization of ovarian nuclei with the parameter of power ratio.

The nucleoli and chromatin clumps of ovarian cells contain important features in discriminating malignant cells from normal ones. In geometric properties, the ovarian nucleoli and chromatin clumps appear as irregularly shaped dark spots in the nuclear images from specimens immunohistochemically stained with antibody to Mib-1. Malignant cells often have more active and larger nucleoli and chromatin clumps. However, estimating the size of the nucleoli or chromatin clumps is a difficult task since it is not easy to recognize and accurately separate the regions of nucleoli and chromatin clumps from the rest of the nuclei that are highly irregular and variant in contents and intensities. In this paper, we develop a method to derive a parameter called power ratio that is proportionally related to the size of nucleoli and chromatin clumps based on an ideal nuclear model without the region segmentation of nucleoli or chromatin clumps. Results of characterization of the parameter and comparison between malignant and normal cells are provided.

Cultured bilayered skin allograft for vaginal construction.

OBJECTIVE: This is the first report of live human cultured bilayered skin allograft (taken from another person) (LHCBSA) to line a dissected space to create a vagina. CASE: A 19-year-old with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome) of vaginal and uterine agenesis had a space dissected and lined with LHCBSA. Although the lining devitalized within 2 weeks, there was a rapid ingrowth of vaginal mucosal cells from the vaginal dimple with an excellent long-term result. CONCLUSION: This is the first report that LHCBSA is able to stimulate vaginal mucosal cell growth for a neovagina. It is possible that it might stimulate other surface tissue lining to cover adjacent raw areas such as bladder or esophagus.

Squamous papilloma with hyperpigmentation in the skin graft of the neovagina in Rokitansky syndrome: literature review of benign and malignant lesions of the neovagina.

BACKGROUND: It is rare for a benign or malignant neoplasm to develop in a neovagina. CASE: This is the first report of a squamous papilloma with hyperpigmentation which developed in the neovagina 12 years after a McIndoe procedure was done with a split-thickness skin graft from the patient's buttock. The patient had congenital absence of the vagina and uterus (Rokitansky syndrome, Mayer-Rokitansky-Küster-Hauser syndrome, MRKH syndrome). It presented as post-coital blood spotting for 3 months. CONCLUSION: As a routine, all cases of vaginal construction regardless of the reason for the surgery or the lining of the neovagina should have a continuous annual examination and careful inspection of the entire vagina. Biopsy of any unusual finding should be done. Despite the dark color of the vaginal lesion, bleeding and rapid appearance our patient had a benign tumor. Radiation therapy to the neovagina and prolonged treatment with podophyllin and cauterization should be avoided.

Prepubertal distal longitudinal vaginal folds.

OBJECTIVE: The purpose of this paper is to further describe prepubertal distal longitudinal vaginal folds and its natural history. DESIGN: Biopsy of the folds and follow-up through puberty. RESULTS: Histology of the folds shows normal vaginal mucosa over loose fibrous connective tissue without a firm fibrous core. The folds disappear in puberty. CONCLUSIONS: Prepubertal distal longitudinal folds are common, and disappear probably by spreading out during puberty with the physiologic estrogenic widening and lengthening of the vagina. This can occur because the folds do not have a dense fibrous core. The folds may be confused with the vaginal rhabdomyosarcoma or sexual molestation if the fold reaches the hymen, and forms a "bump". The folds are benign.

The spectrum of endometrial pathology induced by progesterone receptor modulators.

Progesterone receptor modulators (PRM) are hormonally active drugs effective in the management of endometriosis and uterine leiomyomata. The endometrial effects of progestin blockade by PRMs in premenopausal women are currently being evaluated in several clinical trials, but few pathologists have had access to these materials and published information of the histological changes is scanty. Eighty-four endometrial specimens from women receiving one of four different PRMs were reviewed by a panel of seven experienced gynecologic pathologists to develop consensus observations and interpretive recommendations as part of an NIH-sponsored workshop. Although the pathologists were blinded to agent, dose, and exposure interval, the review was intended to provide an overview of the breadth of possible findings, and a venue to describe unique features. Endometrial histology included inactive and normal-appearing cycling endometrium. Overtly premalignant lesions (atypical hyperplasia or EIN) were not seen. In a subset of cases, asymmetry of stromal and epithelial growth resulted in prominent cystically dilated glands with admixed estrogen (mitotic) and progestin (secretory) epithelial effects of a type not encountered in contemporary clinical practice. The variety of endometrial appearances suggested that findings might differ by agent and dose over time according to relationships that must be specified for each agent. The constellation of changes seen in those endometria with cystically dilated glands is so novel that new terminology and diagnostic criteria are required for pathologists to recognize them. The panel has designated these changes as PRM-associated endometrial changes (PAEC). Additional follow-up studies will be needed to fully define their natural history and relationship to specific agents and administration regimens.

Stage I ovarian carcinoma: different clinical pathologic patterns.

OBJECTIVE: To analyze clinicopathologic patterns of early ovarian carcinoma. DESIGN: Retrospective chart and histopathology review. SETTING: Mount Sinai School of Medicine, New York and the Centre Jean Perrin, Clermont Ferrand, France. PATIENT(S): Seventy-six consecutive cases of Fédération Internationale de Gynécologie et d'Obstétrique stage I ovarian carcinoma. INTERVENTION(S): Surgical staging. MAIN OUTCOME MEASURE(S): Symptomatology, pathology, and histology analysis. RESULT(S): Twenty-two cases (29%) were serous papillary carcinomas and 54 were nonserous carcinomas (71%) (40 endometrioid, 10 clear cell, and 4 mixed endometrioid and clear cell carcinomas). Ninety-eight percent of ovarian endometriosis, 95% of endometrial carcinomas, and 83% of endometrial polyps and hyperplasias were associated with nonserous carcinomas. Most patients with serous papillary carcinoma presented with asymptomatic pelvic masses; patients with nonserous carcinomas presented with pelvic pain or abnormal vaginal bleeding with or without pelvic mass. CONCLUSION(S): Over two thirds of stage I ovarian carcinomas were nonserous, and were diagnosed because of associated symptoms: pelvic pain with endometriosis and/or adnexal masses, or vaginal bleeding from endometrial pathology. Serous papillary carcinomas were often asymptomatic and diagnosed during follow-up evaluations in breast cancer patients. Stage I ovarian carcinoma has different clinical and pathologic patterns than advanced ovarian carcinoma. The risk of ovarian and endometrial malignancy should be taken into consideration during evaluation of patients with endometriosis and breast cancer histories.

Mesenteric fibromatosis masquerading as an ovarian neoplasm twenty years after Chernobyl radiation exposure.

BACKGROUND: Since their initial description in 1832, desmoid tumors have been reported to occur in virtually every part of the body. Intra-abdominal desmoid tumors, or mesenteric fibromatosis, are often associated with Familial Adenomatous Polyposis mutation in a syndrome known as Gardner's Syndrome. Although sporadic cases of desmoid tumors do occur, unlike Gardner's Syndrome, they predominantly occur extra-abdominally. CASE: Case report of a 61-year-old female who presented with two months of abdominal pain, progressive lower abdominal distension and a 10-15 pound weight gain accompanied by one week of urinary hesitancy and frequency. Patient underwent a diagnostic workup for an ovarian neoplasm, but was found at surgery to have mesentric fibromatosis. CONCLUSION: Although uncommon, mesentric fibromatosis must be considered in the differential diagnosis when evaluating a patient with an abdominal mass of unknown origin.

Human papillomavirus-related cervical lesions in adolescents: a histologic and morphometric study.

OBJECTIVE: To evaluate the cytopathic effect of human papillomavirus (HPV) infection in adolescents. METHODS: Cervical biopsies from 100 patients, 50 from adolescents age 14 to 20 and 50 from mature women age 35 to 64, all diagnosed with HPV-related lesions (condylomas), were studied histologically and morphometrically. Fifty were associated with low-grade squamous intraepithelial lesions and 50 with high-grade squamous intraepithelial lesions. RESULTS: Epithelial cells with large hyperchromatic, often bizarre-shaped, nuclei, staining positive for HPV-16, were identified in most samples from adolescents. These nuclei were, on average, almost twice as large as those seen in biopsies from older women (P = 0.003), and they mostly occupied the lower half of the epithelium (P = 0.0008). These large cells were further analyzed for texture by a novel image-analysis approach, the autocorrelation factor beta, that revealed a markedly different, smoother nuclear structure, suggestive of a large viral load, different from the irregular chromatin pattern seen in dysplastic nuclei. CONCLUSIONS: These peculiar nuclei were ubiquitous in the adolescent cervical biopsies and probably represent a primary abundant productive viral infection. They should not necessarily be interpreted as dysplastic.

Prophylactic oophorectomy: a morphologic and immunohistochemical study.

BACKGROUND: The tumorigenesis of ovarian carcinoma is poorly understood. The authors studied morphologic features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries, normal ovaries, and papillary serous ovarian carcinomas to identify possible preneoplastic changes in ovarian surface epithelium. METHODS: Morphologic features and immunohistochemical expression patterns of CA-125, Ki-67, p53, E-cadherin, and Bcl-2 were evaluated in 21 normal ovaries, 31 ovaries that were removed prophylactically for increased carcinoma risk, and 7 ovarian papillary serous carcinomas. Representative slides from formalin-fixed, paraffin-embedded tissue blocks were submitted to immunohistochemical staining and were evaluated independently by three gynecologic pathologists. For statistical analyses, Fisher exact tests, multivariate analyses, Spearman rank correlation coefficients, Wald statistics, Kruskal-Wallis tests, and Mann-Whitney tests were used. Immunohistochemical staining results were correlated with morphologic findings. RESULTS: The authors found progressive increases in reactivity with the lowest expression in normal ovarian epithelium, stronger expression in epithelium from prophylactically removed ovaries, and the highest expression in carcinomas for Ki-67 and p53. A similar trend was observed for CA-125. Positivity for Ki-67 and p53 was seen predominantly in the epithelium of inclusion cysts and deep invaginations, including those areas that had been identified as hyperplastic or dysplastic on routine hematoxylin and eosin-stained sections. CONCLUSIONS: The current results suggest biologic/molecular evidence for the existence of preneoplastic changes in ovarian surface epithelium and support the previously proposed concept of ovarian dysplasia. Subtle morphologic alterations of the ovarian epithelium may be biologically significant.

Caracterizaçäo morfométrica das lesöes do colo uterino relacionadas ao vírus da papilomatose humana / Morphometric characterization of cervix uteri lesions related to human papillomatosis virus

Este estudo é voltado para os seguintes aspectos ligados às lesSes cervicais relacionadas ao Vírus da Papilomatose Humana (VPH): 1) identificaçäo do vírus em tecido histologicamente normal; 2) diferenciaçäo morfométrica das alteraçSes induzidas pelo subtipo do VPH em condilomas, e 3) as diferenças morfométricas entre condiloma puro e Neoplasia Cervical Intraeptelial do Grau I (NIC I). Usamos o índice morfométrico núcleo/citoplasmático para as medidas da área, perímetro e máximo diâmetro, da célula e do núcleo celular. Quarenta e oito lâminas de biópsias cervicais foram estudadas e os achados, classificados dentro de três grupos: normal (22 casos), condiloma (20 casos) e NIC I (6 casos). A presença do DNA do VPH, detectada usando-se a metodologia da hibridizaçäo in situ, foi usada para estudar se o tecido histologicamente normal seria reconhecido como sendo infectado pelo VPH. Os casos de condiloma foram entäo comparados por meio de análise morfométrica para o subtipo do DNA do VPH por hibridizaçäo in situ, a fim de diferenciar os subtipos de VPH de baixo e alto risco. Os parâmetros foram avaliados por análise multivariada e demonstraram classificar corretamente todos os casos, exceto dois, com uma probabilidade posterior bastante elevada. Concluímos que os dados morfométricos foram úteis no diagnóstico diferencial entre as lesöes cervicais relacionadas ao VPH.

A classificaçäo de Bethesda: uma análise morfométrica das biópsias do colo uterino / The Bethesda system: a morphometric analysis of cervix uteri biopsies

Com a possibilidade de se estender a classificaçäo de Bethesda também para os laudos histológicos, consideramos neste trabalho alguns dos problemas mais importantes ligados às lesöes relacionadas ao vírus da Papilomatose Humana (VPH), em particular a possibilidade de se estabelecer critérios para a definiçäo diagnóstica entre lesSes de alto e baixo grau. Comparamos características citológicas e histológicas de condiçöes pré-cancerosas do colo uterino por meio de análise morfométrica. Cortes histológicos de 62 espécimes de biópsias cervicais guiadas por colposcópio foram estudadas. Os casos foram agrupados de acordo com o diagnóstico histopatológico em três grupos: normal (33 casos), Lesäo Intraeptelial de baixo grau (LIE-BG, 21 casos) e Lesäo Escamosa Intraepitelial de alto grau (LIE-AG, 8 casos). Foram criados dois programas DRAW e COUNT3, considerando os seguintes parâmetros: área, perímetro, diâmetro máximo e circularidade dos núcleos das células nas leöes, e a celularidade da camada superficial do epitélio cervical. Após as mediçSes das células de interesse, os resultados eram submetidos a análise estatística multivariada, e computada a probabilidade posterior para confirmar a homogeneidade dos casos dentro do grupo diagnóstico. rea e celularidade parecem ser os parâmetros mais confiáveis. Apenas seis casos apresentaram a probabilidade posterior abaixo de 0,975. Os procedimentos morfométricos deram pleno suportte à distinçäo entre tecido escamoso normal, LIE-BG e LIE-AG.