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The filamentous bacterium actinomyces can cause serious gynaecological tract infections, including pelvic inflammatory disease (PID) and tubo-ovarian abscess. Thus, definitive diagnosis of actinomycotic granules (AMGs) in gynaecological specimens is clinically important. Non-infectious pseudoactinomycotic radiate granules (PAMRAGs) can mimic the microscopic appearance of AMGs. PAMRAGs may be more common than actinomycotic infections in specimens from patients using intrauterine devices and may be seen in patients with PID. Although the composition and aetiology of PAMRAGs is unclear and variable, a panel of histochemical stains can aid in diagnosis. On haematoxylin and eosin (H&E) stained sections, AMGs show as distinct granules with basophilic peripheral radiating filaments and a dense central eosinophilic core, whereas H&E stained sections of PAMRAGs feature refractile granules with irregular club-like peripheral projections and no central dense core. The filaments of AMGs are Gram positive on Brown and Brenn (B&B) stain and are highlighted with Gomori methenamine silver stain (GMS). They stain negatively with a modified acid fast bacillus (AFB) stain, aiding in the distinction of actinomyces from nocardia. PAMRAGs show negative or non-specific staining with B&B, GMS, and AFB stains. Therefore, knowledge of these staining properties and the distinguishing characteristics of PAMRAGs and AMGs enables recognition of this important diagnostic pitfall.

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PURPOSE OF INVESTIGATION: The aim of this study was to examine whether HPV testing specificity for cervical intraepithelial neoplasia (CIN) grades 2 or 3 could be improved by restricting the range of HPV types classified as 'high-risk'. METHODS: DNA was extracted from 28 CIN I, nine CIN II and 13 CIN III formalin-fixed, paraffin-embedded biopsies. HPV type was determined by General Primer mediated 5+/6+ PCR assay. RESULTS: The prevalence of specific HPV types among the different grades of CIN and the relationship to the referral smear diagnosis was examined. HPV type-16 alone was more highly associated with CIN grade (p < 0.0001; Specificity = 0.93; Sensitivity = 0.68) than was the group of HPV types collectively classed as high-risk (p = 0.025; Specificity = 0.23; Sensitivity = 1.00). CONCLUSIONS: These data suggest HPV testing specificity could be improved simply by including a separate test for HPV-16. In conjunction with previous studies, the data also suggests redefinition of the high-risk HPV category to take into account the differing degrees of oncogenicity of high-risk HPV types.

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OBJECTIVE: The best treatment modality and factors affecting recurrence among women with vaginal intraepithelial neoplasia (VAIN) are yet to be determined. The aims of the current study were to describe the clinical features, results of treatment, and factors affecting recurrence among patients with VAIN. METHODS: We conducted a retrospective review of 121 women with VAIN after confirming the histologic diagnosis. Patient demographics, clinical features, and results of therapy were recorded. Factors affecting recurrence were assessed using the odds ratio and the 95% confidence intervals among patients who were followed up for 7 months or more and had at least one posttreatment Papanicolaou smear. Significant univariate odds ratios were assessed jointly in a multivariate model with a stratified analysis. RESULTS: The mean age of the patients was 35.0 (+/-17), 41% of the patients smoked, 39% had a history of human papillomavirus infection, 27% had history of sexually transmitted diseases, 22% had history of surgery for cervical intraepithelial neoplasia (CIN), and 23% had total hysterectomy. The upper third of the vagina was the most common site of VAIN and 61% of the lesions were multifocal. Associated cervical and vulvar intraepithelial neoplasia (VIN) were present in 65 and 10%, respectively. Recurrences of VAIN and progression to invasive vaginal cancer occurred in 33 and 2%, respectively. Recurrences following partial vaginectomy, laser, and 5-fluorouracil were 0, 38, and 59%, respectively (P = 0.0001). Multifocality and method of treatment were significant independent predictors of VAIN recurrences (odds ratio 3.3, 95% CI 1.2, 9.2, P = 0.02, and 22.4, 95% CI 1.3, 393.6, P = 0.001, respectively), with no interaction, based on a stratified analysis. CONCLUSIONS: VAIN occurs most often among women with CIN or VIN, commonly involves the upper third of the vagina, and is often multifocal. Partial vaginectomy provides the highest cure rate and multifocality is a risk factor for recurrence.

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The use of tamoxifen among women with breast cancer or at high risk of the disease has greatly expanded over the past several decades. Tamoxifen has a complex effect on the female reproductive tract and several tamoxifen-associated changes have been described among tamoxifen users. These include endometrial thickening, cervical and endometrial polyps, endometrial hyperplasia, endometrial adenocarcinoma, uterine sarcoma, increase in the size of uterine leiomyomata, exacerbation of endometriosis and ovarian cysts. The most common uterine change associated with tamoxifen is endometrial polyps. The annual incidence of endometrial cancer among women on tamoxifen is 2 per 1000 and seems to be related to the cumulative tamoxifen dose. It is not clear whether endometrial cancer occurring among women on tamoxifen is of worse prognosis than endometrial cancer occurring among women not receiving tamoxifen. Tamoxifen is associated with several sonographic changes which make the use of ultrasound in surveillance of these patients difficult. There is no indication to implement routine screening for endometrial cancer among all women on tamoxifen. However, endometrial biopsy, preferably via hysteroscopy, should be considered in women with uterine bleeding.

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Background. Reports of supradiaphragmatic involvement of lymph nodes by serous borderline ovarian tumors are rare. Case. We describe the finding of metastatic tumor involving an internal mammary lymph node in a 74-year-old patient with serous borderline ovarian tumor. The positive lymph node was found incidentally during cardiac surgery 7 years after excision of the patient's serous borderline ovarian tumor. The incidence and significance of pelvic, paraaortic, and supradiaphragmatic lymph node involvement among women with borderline ovarian tumors is discussed. Conclusion. Supradiaphragmatic lymph node involvement can occur among women with serous borderline ovarian tumors. Borderline ovarian tumors should be included in the differential diagnosis of metastatic adenocarcinoma involving the supradiaphragmatic lymph nodes.

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OBJECTIVE: The best technique for obtaining cytologic specimens necessary for evaluation of diaphragmatic spread among women undergoing surgical staging for ovarian cancer has yet to be determined. The aim of the current study was to compare two methods for obtaining diaphragmatic cytology-wash and scrape-in accuracy, correlation to clinical findings, and smear quality. METHODS: We conducted a prospective study among women undergoing surgical staging for ovarian cancer. In each patient diaphragmatic scrape and wash specimens were obtained, then the undersurface of the diaphragm was inspected and palpated. The smears were examined for presence of cancer cells, correlated to clinical findings, and scored for quality (cellularity, preservation, and background). RESULTS: In 46 consecutive patients with stage I-III ovarian cancer, the diaphragm was clinically involved in 12 (26.1%). Malignant cells were demonstrated in 21 (45.7%) of wash and scrape specimens. There was perfect agreement between washes and scrapes and good agreement between clinical evaluation and scrapes or washes (kappa = 1.0 and 0.592, respectively). Wash specimens had significantly higher overall smear quality and cellularity scores (6.26 +/- 1.26 vs 6.11 +/- 1.06, P < 0.02, and 2.20 +/- 0.81 vs 1.85 +/- 0.76, P < 0.05, respectively). CONCLUSION: Although diaphragmatic wash specimens provide better-quality smears than scrape specimens, both techniques are equally diagnostic of diaphragmatic involvement in women undergoing surgical staging for ovarian cancer.

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BACKGROUND: Hemangioma of the cervix and focal nodular hyperplasia of the liver are both thought to be congenital vascular anomalies that could be associated with exogenous hormone use. CASE: A 34-year-old woman taking oral contraceptives developed hemangioma of the cervix and focal nodular hyperplasia of the liver. CONCLUSION: Cervical hemangioma can occur with focal nodular hyperplasia, and both could be related to oral contraceptives.

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OBJECTIVE: The aim of this study was to assess the prevalence and risk factors predictive of dysplasia among women seen in a gynecologic oncology service with the cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS) on Papanicolaou smears obtained by the ThinPrep method. METHODS: Patients with ASCUS ThinPrep Papanicolaou smears seen at the Division of Gynecologic Oncology, University of Vermont, between 1997 and 1999 were identified. The cytologic smears were reviewed and subtyped into reactive or suggestive of squamous intraepithelial lesion (SIL). The charts of these patients were reviewed and the following information was abstracted: age, gravidity, parity, menopausal status, use of hormonal replacement therapy, smoking, history of pelvic cancer, history of radiation therapy, history of abnormal Papanicolaou smear and its treatment, history of human papillomavirus (HPV) infection, and follow-up information including results of repeat Papanicolaou smears, colposcopy, and biopsies. The prevalence of dysplasia was calculated. The demographic features of women with ASCUS, reactive, were compared with those with ASCUS, SIL, using a two-sample t test, chi(2), and Fisher's exact test. Risk factors predictive of dysplasia were calculated using the odds ratio and the 95% confidence interval. P < 0.05 was considered significant. RESULTS: One hundred twenty-six patients with ASCUS on ThinPrep Papanicolaou smear were identified; 63 patients had ASCUS, reactive, and 63 patients had ASCUS, SIL. The demographic features of both groups were similar. The overall prevalence of dysplasia was 15.9% and was significantly higher among women with ASCUS, SIL, than among women with ASCUS, reactive (25.4% versus 6.4%, P = 0.003). The type of ASCUS cytology (reactive versus SIL), smoking, and history of HPV were significant risk factors for dysplasia (P = 0.003, 0.037, and 0. 042, respectively). CONCLUSIONS: The prevalence of dysplasia among women seen in a gynecologic oncology service with ASCUS cytology on ThinPrep Papanicolaou smears is 15.9%. Women with ASCUS favor SIL, those who smoke, and those with a history of HPV are at higher risk for dysplasia and should be offered colposcopy.

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OBJECTIVE: The aim of this study was to assess the incidence and risk factors predictive of significant histopathologic findings among women with atypical glandular cells of undetermined significance (AGCUS) on ThinPrep Papanicolaou smears. METHODS: ThinPrep smears with AGCUS obtained between 1997 and 1999 were reviewed. Patients' charts were reviewed and patients' characteristics, follow-up information, and colposcopy and biopsy results were recorded. Pathologic slides were reviewed. The demographic features of women with favor reactive smears were compared with those with favor neoplasia and risk factors predictive of significant histopathologic findings (high-grade squamous intraepithelial lesion, endometrial hyperplasia, and cervical or endometrial cancers) were calculated. RESULTS: The rate of diagnosis of AGCUS was 0.65%. Eighty-four patients with follow-up information were identified. The demographic features of women with smears favor neoplasia (n = 43) were similar to those with smears favor reactive (n = 41). The rates of incidence of any dysplasia or cancer and significant histopathologic findings were 32.1 and 22.6%, respectively, and were higher among women with smears favor neoplasia than among women with smears favor reactive (41.9% versus 22.0%, P = 0.051, and 34.9% versus 9.8%, P = 0.006, respectively). The subtype of cytology was the only factor that predicted significant histopathologic findings (odds ratio = 5.0, 95% confidence interval 1.6, 15.6, P < 0.010). CONCLUSIONS: In women with AGCUS on ThinPrep smears, significant histopathologic findings were found in 34.9% versus 9.8%, depending on the subtype of the smear (favor neoplasia vs reactive). Further studies are needed to validate the cytologic criteria for subtyping AGCUS smears and base management of women with AGCUS cytology on the subtype of the smear.

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OBJECTIVE: This study analyzes pediatric and adolescent Papanicolaou (Pap) smear diagnoses to determine the prevalence rates of squamous intraepithelial lesion (SIL) as well as infectious and reactive processes in this age group. DESIGN: A total of 10 296 Pap smear diagnoses from patients 10 to 19 years of age collected over a 1-year period and classified according to the Bethesda system were reviewed. This population was almost exclusively white, the majority residing in rural or suburban areas of Maine, New Hampshire, and Vermont. The percentage of abnormal smear results was then compared with data generated for older age subsets. RESULTS: The following diagnoses were made on 10 296 Pap smears from patients 10 to 19 years of age: 7208 (70.01%) normal; 1689 (16.4%) benign cellular change; 1004 (9.75%) atypical squamous cells of undetermined significance; 388 (3.77%) squamous intraepithelial lesion (SIL); and 7 (0.06%) atypical glandular cells of undetermined significance. A total of 1503 (14.6%) of smears showed infectious processes. Compared with the results of adult Pap smears collected over the same time period, the age 20 to 29 subset with 27 067 Pap smears and the age 30+ subset with 42 617 Pap smears showed 11.79% and 8.43% infectious processes and 3.49% and 1.27% SIL, respectively. Therefore, the highest rate of infectious processes and SIL was found in the subset of patients age 10 to 19 years. CONCLUSIONS: Because the development of SIL and hence cervical cancer is causally related to sexually transmitted human papilloma virus (HPV) infection, this high rate of abnormal Pap smear results of both an infectious and precancerous nature in this population may reflect a high level of sexual activity among adolescent girls. These data reinforce the importance of implementing early cervical Pap smear screening in the sexually active pediatric and adolescent population.

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Desmoplastic small round cell tumour (DSRCT) is an extremely aggressive neoplasm belonging to the family of "small round blue cell tumours", which includes primitive neuroectodermal tumour (PNET), Wilms' tumour and Ewing's sarcoma. DSRCT is considered to be a neoplasm derived from a primitive cell. It is immunohistochemically reactive with epithelial, neuronal and mesenchymal cell markers, demonstrating divergent differentiation along three cell lines. Originally thought to arise from serosal surfaces, the tumour has recently been reported in the central nervous system and ovary. The tumour in this case is a neoplasm that meets the histological, immunohistochemical, cytological and cytogenetic criteria of DSRCT; it is not associated with serosal membranes, and it has supraclavicular and axillary lymph node deposits and multiple pulmonary and brain metastases. Tumour cells from our case show cytogenetic similarities with Ewing's sarcoma and PNET. Electron microscopic findings suggest similarities between DSRCT and Wilms' tumour. Cloning and sequencing of PCR products showed in-frame fusion of EWS exon 7 to WT1 exon 8.

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Accuracy of diagnoses rendered using a live video telepathology network was assessed for permanent sections of surgical pathology specimens. To determine accuracy, telepathology diagnoses were compared with those obtained by directly viewing the glass slide using a standard microscope. A total of 294 cases were read via both telepathology and glass slide by attending pathologists at a tertiary care medical center. Overall accuracy was defined as exact concordance between diagnoses. Clinically insignificant differences in diagnoses were excluded to determine clinically significant accuracy. For the 285 cases with complete data, the overall accuracy for telepathology was 0.912 (95% confidence interval [CI], 0.872-0.941), whereas the overall accuracy for glass slide readings was 0.968 (95% CI, 0.939-0.985). This difference is statistically significant (p = 0.009). When focusing on clinically significant discrepancies, where the difference in diagnosis might affect therapeutic decisions, the video accuracy was only slightly less than the glass slide accuracy (0.965 [95% CI, 0.934-0.982] vs. 0.982 [95% CI, 0.957-0.994], respectively), but this difference is not statistically significant (p = 0.302). Most of the cases with clinically significant differences involved lesions with inherently high interobserver variation. Certainty of diagnosis did not differ between video and glass slide readings (p = 0.911), but there was an association between certainty of diagnosis and diagnostic accuracy for video (p = 0.003 for clinically significant accuracies). Based on these findings, we recommend when using this telepathology system that only preliminary diagnoses should be given in the following situations: for diagnostic areas with known high interobserver variability; when the consultant has any degree of uncertainty about the presence or absence of the lesion in question; and when there is insufficient experience using telepathology as a diagnostic medium.

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Prolonged storage of Karnovsky's fixative, at both 4 and -20 degrees C, is possible in the diagnostic electron microscopy setting. Ultrastructural detail was not compromised in specimens processed in fixative that had been stored for 6 months. Evidence of smooth muscle and neuroendocrine differentiation was present in the form of actin filaments/dense bodies and neurosecretory granules, respectively. No difference in preservation was detected between specimens fixed in freshly prepared Karnovsky's fixative and fixative that had been stored at either 4 or -20 degrees C for up to 6 months. Thus, community hospitals can be provided with Karnovsky's fixative on a semiannual basis for surgical pathology specimens that may require electron microscopy for diagnosis.

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In immunoelectron microscopic investigations, retention of antigenic sites is crucial. Methods for preparing samples for conventional electron microscopy involve chemical fixatives followed by dehydration in organic solvents and embedding in plastic resins, all procedures potentially detrimental to antigenicity. Cryomethods provide a physical fixation alternative for the preparation of biological samples for ultrastructural, immunocytochemical, and microanalysis studies without the use of any chemicals. This can be particularly useful in diagnostic pathology, providing an alternative to conventional fixation methods which sometimes destroy the antigen in question. The recent development of a portable cryofixation device, the PS1000 Portable Metal Mirror Ultra-Rapid Cryofixation Unit (Delaware Diamond Knives, Inc., Wilmington, DE, USA), provides an opportunity to freeze tissue immediately after procurement for use in diagnostic immunocytochemistry studies. This feasibility study examined the quality of tissue preservation with this device, in terms of both preservation of cellular ultrastructure and immunolabeling. Human tonsil and thymus tissue was slam frozen and, after cryosubstitution in Lowicryl K11M, was examined by immunoelectron microscopy. Good ultrastructural preservation was obtained and reasonable immunolabeling with antibodies to AE1/AE3 keratin filaments was also observed.

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Wilms' tumor is the most common malignancy of the genitourinary tract in children but the occurrence of extrarenal Wilms' tumor is extremely rare. Extrarenal Wilms' tumor, which by definition excludes a primary tumor in the kidney, has been reported less than fifty times. The ultrastructural appearance of renal Wilms' tumor has been well documented, but the present report is believed to be the first description of the ultrastructural appearance of extrarenal Wilms' tumor. The authors report, for the first time, localization of intermediate filament proteins (vimentin and cytokeratin) and epithelial membrane antigen (EMA) by immunoelectron microscopy in this neoplasm. Demonstration of the coexpression of vimentin and cytokeratin within the same blastemal cell, as well as the identification of desmosomes in a cell with vimentin intermediate filaments, suggests a relationship between stroma, blastema, and epithelia similar to that proposed in renal Wilms' tumor.

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The mouse monoclonal antibody anti-Leu-M1 (CD15) recognizes the carbohydrate determinant lacto-N-fucopentaose III, an oligosaccharide believed to be involved in cell-cell interactions. Anti-Leu-M1 is used in surgical pathology as an aid in the diagnosis of Hodgkin's disease. Additionally, adenocarcinomas derived from various organs stained positively with anti-Leu-M1 at the light microscopic level. Since mesotheliomas do not display positive reactivity to this antibody, Leu-M1 is clinically useful as part of a panel of antibodies in distinguishing adenocarcinomas from mesotheliomas. Previous work was carried out using post-embedding protein A-gold immunocytochemistry on thin sections embedded in Lowicryl K4M from a patient with Hodgkin's disease of the nodular sclerosing type; intense and precise labeling by gold particles was revealed in cytoplasmic granules, which were often clustered in a perinuclear location, in the Golgi apparatus, and focally along the plasma membrane of Reed-Sternberg cells. Moreover, polymorphonuclear leukocytes demonstrated similar labelling along the plasma membrane and over cytoplasmic granules. To define precisely the intracellular localization of Leu-M1 in human adenocarcinomas, we have performed post-embedding immunoelectron microscopy with the protein A-gold technique on sections embedded in Lowicryl K4M from neoplasms of the lung, stomach, colon, and breast. The pattern of labeling by gold particles indicative of Leu-M1 binding varied in adenocarcinomas of the different organs.

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A case of uterine carcinosarcoma (malignant mixed müllerian tumor) of the uterus containing a rhabdoid tumor element is described. In addition to a malignant glandular component and anaplastic sarcomatous areas, this tumor had multiple foci with histologic and ultrastructural features of malignant rhabdoid tumor. Vimentin positivity by immunohistochemistry was confirmed by immunoelectron microscopy. Although three malignant rhabdoid tumors of the uterus have been previously described, in addition to rhabdoid differentiation in an endometrial stromal sarcoma, to our knowledge this is the first report of rhabdoid tumor differentiation occurring within a uterine carcinosarcoma.

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A 21-year-old woman with a family history of von Hippel-Lindau disease presented with a mass in the head of the pancreas. Light microscopic features of the tumour suggested neuroendocrine differentiation and although it displayed positive immunostaining for the antigens expected in a neuroendocrine neoplasm, S-100 staining was also present. This unusual feature prompted further evaluation by routine and post-embedding protein-A gold immunoelectron microscopy, which demonstrated the presence of neuroendocrine granules. Tumour cell DNA content was normal by flow cytometry. Although this patient exhibited no other signs of von Hippel-Lindau disease, the presence of a pancreatic tumour with neuroendocrine differentiation demonstrated that she was affected. Future surveillance and genetic counselling will be influenced by this diagnosis.

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Anti-Leu-M1 (CD15) is a monoclonal antibody used in surgical pathology to diagnoses Hodgkin's disease. By light microscopic immunohistochemistry, anti-Leu-M1 reacts with Reed-Sternberg cells and their variants, notably lacunar cells in nodular sclerosing Hodgkin's disease, as well as granulocytes in Hodgkin's disease. The immunostaining of Reed-Sternberg cells has been characteristically described as a diffuse cytoplasmic pattern with a prominent perinuclear globular component. In addition, irregular plasma membrane reactivity has been observed. To define the intracellular localization of Leu-M1 precisely, the authors performed postembedding immunoelectron microscopy with the protein A-gold technique on sections embedded in Lowicryl K4M from a patient with nodular-sclerosing-type Hodgkin's disease. At the electron microscopic level, gold particle staining indicative of Leu-M1 binding was found within cytoplasmic granules and the Golgi apparatus, as well as focally at the plasma membrane. The cytoplasmic granules were located in a perinuclear region and in the cell periphery. Although the morphology of the granules was suggested of lysosomal structures, immunolabel was not detected on serial sections of these granules with three different antibodies directed against lysosomal antigens.

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