[Comparison of the ThinPrep monolayer technique and conventional cervical Pap smears in a high-risk population using the Munich II nomenclature]. / Vergleich der ThinPrep-Dünnschichtzytologie mit der konventionellen zervikalen Exfoliativzytologie in einem Risikokollektiv unter Verwendung der Münchener Nomenklatur II.

OBJECTIVE: In this prospective study using the Munich II nomenclature for cervical cytology. Pap smear results obtained by the ThinPrep monolayer technique and those obtained by the conventional method were compared. METHODS: Pap smears were obtained from 1,000 women using an Ayre spatula/endocervical brush combination. Following transfer of the cell sample onto a slide, the same collection devices were rinsed in a liquid medium and processed using ThinPrep-2000 processor (split-sample technique). RESULTS: Specimen inadequacies due to drying artefacts, cell overlap or low number of epithelial cells were rare with both methods without any significant differences. However, ThinPrep slides were significantly less often compromised by red or white blood cells or by cytolysis. In contrast, endocervical cells were missing in 11.6% of slides compared to only 2.3% in conventional Pap smears. ThinPrep yielded results of unknown significance (Pap III) significantly less often (4.2 vs 6.3%). CONCLUSIONS: ThinPrep slides are less frequently compromised by blood components or cytolysis. Inconclusive results of Pap III are slightly less frequent when using ThinPrep. However, there is a significant percentage of slides lacking the endocervical component. Using a combination of spatula and cytobrush, this may not necessarily be due to non-representative cell sampling.

[Management of gynecological tumors associated with BRCA1 and BRCA2 germline mutations. Case report and literature review]. / Management dei tumori ginecologici associati a mutazioni germinali BRCA1 e BRCA2. Caso clinico e review della letteratura.

Genetic investigation of BRCA1 and BRCA2 germline mutations is, nowadays, a diagnostic procedure with practical clinical applications. The role of this genes in DNA repair and stability and in cancer development is now well recognised. Most involved are breast and ovarian cancers, but, less frequently, other gynecological cancers like cervical, corpus uteri and Fallopian tubes cancers and also other non gynecological malignancies. We report the case of a 67-year-old patient with strong familiarity for breast cancer, with a BRCA2 germline mutation, who developed in 30 months 4 primary malignancies: in chronological order, breast cancer, chronic lymphatic leukemia, and synchronous ovarian and endocervical adenocarcinoma. A better knowledge of the biological and clinical behaviour of BRCA related cancers is of strategical importance in the management of patients with strong familiar neoplastic history or with genetic test positivity. An adequate counselling can help in the management of these cancers in the prevention and early diagnosis taking also into consideration the possibility of a prophylactic surgery.

Determination of growth fractions in benign breast disease (BBD) with monoclonal antibody Ki-67.

Certain types of benign breast disease (BBD) carry an increased risk of malignancy. Several morphological criteria such as an atypia score are used to define this group, and the use of a kinetic parameter may provide additional information. Therefore, the growth fractions of 120 benign breast lesions were determined using the monoclonal antibody Ki-67. The values obtained range from 0.3% to 10.8% (average 3.1% +/- 2.2%) compared to breast carcinomas with an average of 15.3% +/- 10.1%, range 0.8% to 47.8%. All specimens were classified using the terminology of Azzopardi. The prevailing histological entities were cystic disease, fibroadenoma, and blunt duct adenosis. Between these groups no differences in growth fractions were observed. Postmenopausal patients had slightly lower values than premenopausal women. Further prospective studies are needed to evaluate whether those cases of BBD with a high number of Ki-67 positive cells have an increased risk of breast cancer, independently from conventional histological classifications.

Growth fractions in breast cancers determined in situ with monoclonal antibody Ki-67.

The growth fractions of 160 mammary carcinomas and 30 benign mammary lesions were determined in situ by immunostaining with the monoclonal antibody Ki-67. Benign lesions had a mean value of 3% Ki-67 positive cells, whereas the mean value of mammary carcinomas was 16.6%. A comparison of the mean values of Ki-67 positive cells with the histological grade of the tumours showed a correlation between these two variables--that is, histological grade 1 showed 9%, grade 2 16%, and grade 3 26% proliferating cells. Considering the individual Ki-67 values in the different histological grades, it was evident that there was considerable scatter in the number of proliferating cells, so that the proliferation rates of grades 1, 2, and 3 overlapped each other. This indicates a dissociation between histological grade of malignancy and size of the growth fraction in most breast cancers. Follow up studies are needed to establish which of the two variables--that is, morphological degree of malignancy, or the proportion of Ki-67 positive cells--correlates better with response to treatment and survival in individual cases.

Blood-borne cancer cells--quo vadis?

The detection of blood-borne cancer cells may help in clinical staging and further understanding of cancer metastasis. We developed a cytokeratin-based immunomagnetic method to isolate epithelium-derived cells from the circulating blood of patients. The number of cell clusters positive for cytokeratin/prostate-specific antigen (PSA) from the peripheral blood of prostate cancer patients and cytokeratin/p185c-erbB-2 from the peripheral blood of breast cancer patients has been related to stage of the disease. Breast cancer patients who presented cytokeratin/p185c-erbB-2-positive cell clusters showed a decrease in such cells under adriamycin adjuvant therapy with Further molecular characterization by a highly sensitive microsatellite multiplex-PCR enabled reproducible detection of microsatellite alterations. The impact of these individually targeted results may contribute to an individual diagnostic and therapeutic strategy.

Adenoid cystic carcinoma of the Bartholin's gland: the University of Michigan experience.

Adenoid cystic carcinoma of the Bartholin's gland has been encountered in 11 patients at the University of Michigan Medical Center since 1936. At the time of presentation the average age was 48.9 years, the lesion size was between 0.5 to 4 cm. The presenting symptoms were pain and/or pruritis associated with a solitary mass. Early in this series, excisional biopsy was used to treat eight patients. The last three patients have been treated with a radical vulvectomy and unilateral or bilateral groin lymph node dissection. Local recurrence has occurred in five patients and distant recurrence in four patients. In spite of the high recurrence rate, 5- and 10-year survival has been high with all seven evaluable patients surviving 5 and 10 years. However, adenoid cystic carcinoma of the vulva is associated with late recurrences and metastases: three patients were dead of disease at 12, 15 and 31 years after initial diagnosis.

The role of vaginal hysterectomy in the treatment of endometrial carcinoma.

Between 1964 and 1991, vaginal hysterectomy was performed in 60 patients with clinical stage I endometrial carcinoma, who were not considered candidates for the conventional surgical approach. Of these patients, 66.7% were obese with a median weight of 235 pounds. Other risk factors included hypertension (63%), diabetes mellitus (34%), cardiac disease (28%) and pulmonary disease (12%). Operative mortality was 0%. The complication rate was 14%, with four patients requiring transfusions and four patients developing vaginal cuff cellulitis. Forty per cent of patients received adjuvant pre- or postoperative radiation therapy. Crude survival at 5 and 10 years was 91.1% and 87.1%, respectively. However, only one patient died from disease 6 years after primary treatment. Although we consider surgical staging as the standard of care for the treatment of endometrial cancer, vaginal hysterectomy has a definite place in the management of patients with good prognostic criteria who are at high operative risk for the standard surgical approach.

Clinical relevance of immunohistochemical expression of p53-targeted gene products mdm-2, p21 and bcl-2 in breast carcinoma.

The present study was designed to investigate the clinical/prognostic relevance of immunohistochemical expression of p53-targeted genes mdm-2, p21WAF1 and bcl-2 alone and in combination with p53 for the indirect assessment of p53 gene status in breast cancer. 141 archival breast carcinomas were immunostained, and the putative mutational status of the p53 gene was defined in 21 of them, as a control for immunohistochemistry, using the polymerase chain reaction single-strand conformational polymorphism (PCR-SSCP) analysis. Genetic changes of p53 correlated significantly with p53 protein overexpression (p = 0.01) but did not do so with any of the related molecules. Immunohistochemical p53 status was directly correlated with mdm-2 (p = 0.0001), p21 (p = 0.0004) and inversely with bcl-2 (p = 0.005) expression. bcl-2 proved to be an independent marker of prognosis, p53 only in the group of node-positive carcinomas, whereas bcl-2-/p53+ tumours revealed the worst prognosis. Mdm-2 and p21 expression was of prognostic significance neither alone nor in combination. We conclude that the detection of down-stream regulators of p53 does not increase the efficacy of immunohistochemistry in assessing the functional status of p53 in breast cancer; however, their combined analysis may help to select subgroups of patients at the extremes of risk for recurrence, or those with greater chances for survival.

Neovaginal cytology after total pelvic exenteration for gynecological malignancies.

Vaginal reconstruction has become an established method to restore sexual function in women who have undergone ultraradical surgery and/or irradiation for the treatment of gynecologic malignancies. Cytologic evaluation of the neovagina serves a major role in the detection of recurrent disease. The purpose of this retrospective 6-yr study (January 1987-December 1993) was to evaluate the cytologic features of vaginal smear specimens from neovaginas constructed utilizing split-thickness skin grafts. Thirty-four vaginal smears were obtained at regular intervals from nine women (mean age: 51 yr) who underwent total pelvic exenteration with vaginal reconstruction for recurrent malignancies of the vagina and the cervix. Anucleated, keratinizing squames were a constant finding in each smear. Over a 4-mo-6-yr postoperative period, superficial and intermediate squamous cells were present in the majority of the smears and the maturation index showed a shift to the right. In two cases, a squamous cell carcinoma of the cervix recurred within the neovagina. Knowledge of the cytologic features associated with neovaginas is important in order to distinguish normal changes from neoplastic lesions.

Benign granular cell tumor mimicking carcinoma of the breast. Report of a case.

A case of granular cell tumor of the breast in a 59 year-old woman is presented. Clinical evaluation suggested carcinoma with infiltration of the skin. The granular cell tumor was diagnosed on frozen section and the lesion was treated by wide local excision including the overlying skin. Granular cell tumors of the breast, which are usually benign, may closely mimic breast carcinoma, both clinically and on frozen section. The possibility of granular cell tumor of the breast with its potential for a false-positive diagnosis on frozen section supports a two-step procedure for the treatment of breast cancer, especially in young women, to prevent inappropriate radical surgery.

Cyclophosphamide, methotrexate, 5-fluorouracil, and folinic acid (CMFF) as first line chemotherapy for treatment of advanced breast cancer. A pilot study.

In order to evaluate the maximum tolerable dose of a combination chemotherapy consisting of cyclophosphamide, methotrexate, 5-fluorouracil, and folinate (CMFF), 30 female patients with histopathologically confirmed, previously untreated advanced breast cancer were entered into this pilot study. Chemotherapy consisted of fixed doses for methotrexate (40 mg/m2 i.v. on day 1), 5-fluorouracil (500 mg/m2 i.v. on day 2 to 4) and folinic acid (2 x 200 mg/m2 i.v., 0 + 2 h on day 2 to 4). The dose of cyclophosphamide was escalated stepwise, starting with 200 mg/m2 i.v. on day 2 to 4, to 240 mg/m2, 290 mg/m2, 360 mg/m2 and 400 mg/m2, respectively, for each subsequent five patients. Treatment was repeated every four weeks. A total of 92 treatment cycles was given. Myelosuppression was the dose-limiting toxicity: leukopenia WHO grade III or IV was observed after a total of 28 cycles and anemia of equal intensity after 1 cycle. No thrombocytopenia WHO grade III or IV was recorded. Myelotoxicity increased with higher doses of cyclophosphamide. Among non-hematologic toxicities, alopecia was reported in two-thirds of the patients. Nausea and vomiting was noted in 25% of treatment cycles, but in one cycle only WHO grade III was recorded. No other toxicities exceeding WHO grade II occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

[Determination of the growth fraction using monoclonal antibody Ki-67 in breast cancers]. / Détermination de la fraction de croissance à l'aide de l'anticorps monoclonal Ki-67 dans les cancers du sein.

In 329 breast tissues (120 benign lesions and 209 invasive breast carcinomas) the growth fraction was determined using the monoclonal antibody Ki-67. The percentage of Ki-67 positive cells or the Ki-67 growth fraction was determined on histologic and cytologic specimens after immunoperoxidase staining. In benign breast lesions, the Ki-67 growth fraction never exceeded 11%, whereas in breast cancer 14.4 +/- 9.9% of cells were Ki-67 positive ranging from 1 to 48%. Breast carcinomas were classified according to the histologic grading system of Bloom and Richardson (G1-G3). Poorly differentiated carcinomas. (G3) had significantly higher Ki-67 growth fractions than well differentiated tumors (G1). Ki-67 was also correlated with axillary lymph node status. Growth fractions of N+ carcinomas were significantly higher than those of N0 tumors (16.4 +/- 10.4% versus 12.4 +/- 9.4%; p = 0.006). Thus, this new method yields similar results to those obtained by other researchers through the use of flow cytometry and thymidine labelling. As determination of Ki-67 growth fractions is an easy and rapid technique, it is ideal for routine clinical use. Ki-67 may be useful in prognosis and in the selection of patients for various treatment modalities such as adjuvant therapy. A wide-spread use of Ki-67 would be helpful to gain further experience.

[Paget disease of the vulva: resolution after local treatment with imiquimod--report of a case and review of the literature]. / Morbus Paget der Vulva: Remission durch Lokalbehandlung mit Imiquimod--Fallbericht und Literaturübersicht.

Paget disease is a rare disorder of the skin of the vulva, comprising less than 1% of vulvar neoplasms. Surgical excision is considered the standard of care. While the invasive variant of Paget disease is rare, frequent local recurrences from non-invasive disease, which are inoperable, constitute a major clinical problem. In this article we report on a 71-year-old patient with recurrent disease treated successfully with imiquimod cream. Symptoms such as local itching subsided shortly after initiation of treatment. Four weeks later, first signs of resolution could be demonstrated colposcopically. Within 8 weeks, complete clinical remission was achieved. Thus, topical imiquimod is not only effective as treatment of vulvar intraepithelial neoplasia, but may also be used for selected patients with recurrent Paget disease as an alternative to repeat surgical interventions.

Prevalence of human papilloma virus infection in women in rural Ethiopia.

In Ethiopia cervical carcinoma is the most frequent cancer in women. HPV infection is a prerequisite for this disease. However, to date there have been no data on human papilloma virus (HPV) prevalence in Ethiopia. Outpatients attending Attat hospital in rural Ethiopia were examined for the presence of HPV DNA using the Digene HPV test. 15.9% of patients were found to be HPV positive. The proportion of HPV high risk types was 13.2% [age-standardised rates: HPV: 14.4% (95% CI: 8.5-20.2); HPV high risk: 11.6% (95% CI: 6.3-16.9)]. Compared to other countries HPV prevalence is high, especially of high risk types. Until vaccination programmes take effect, screening programmes should not be based on HPV testing alone as this will lead to significant overtreatment of healthy women.

[In situ determination of the Ki-67 growth fraction (Ki-67 GF) in human tumors (studies in breast cancer)]. / In-situ-Bestimmung der Ki-67-Wachstumsfraktion (Ki-67-WF) an menschlichen Tumoren (Ergebnisse beim Mammakarzinom).

The monoclonal antibody Ki-67 has been described in 1983 by Gerdes. Lymphocytes stimulated with PHA as well as a number of human tissues have been studied using the antibody. The results have shown, that the Ki-67 antigen is expressed by all cells in the active phases of the cell cycle not, however, by resting cells or the starting sequences of the cell cycle. Although the nature of the Ki-67 antigen ist not yet known, several studies have demonstrated that the Ki-67 growth fraction is a valuable parameter for characterization of malignant tumors. So far, the so-called "Ki-67 growth fraction" (Ki-67 GF) has been determined on non-Hodgkin-lymphomas and on malignant tumors of the bone, kidney and lung. The most extensive data are available on breast cancer. In the author's studies the APAAP-method (APAAP = "alkaline phosphatase-anti-alkaline phosphatase") is preferred as an immunohistochemical staining method. The median Ki-67 growth fraction of 261 breast carcinomas was 12.5% (range 1 to 65%), being five times higher than in benign breast tissue (n = 126). The Ki-67 GF of breast cancer was correlated to different parameters known to be related to prognosis. Thus, a correlation was found with the age of patients, tumor stage, histological grading and hormone receptor status. These results are similar to those obtained by autoradiography and flow cytometry. Of 141 patients the clinical outcome of disease is known (median follow-up 22 months): 25 patients have developed local recurrence of the chest wall. This group of patients showed no significant correlation to the Ki-67 growth fractions of the primary tumors. However, the Ki-67 GF was significantly higher in 20 patients with early systemic disease and in 19 patients who died from breast cancer. Based on these results a clinical trial on adjuvant chemotherapy of lymphnode-negative patients should be taken into consideration. Thus, the prognosis for early stage breast cancer might be improved.

[T-cell classification of the peripheral venous blood of patients with breast cancer]. / T-Zell-Klassifizierung im peripheren Venenblut bei Patientinnen mit Mammakarzinomen.

Using monoclonal antibodies the total number of T-lymphocytes, as well as of helper and suppressor T-cells, was measured in peripheral venous blood of 78 women with carcinoma of the breast and 68 women without malignant disease (control group). There was no significant difference between the two groups as regards pre-operative values. The same was true with regard to different carcinoma stages. Serial tests on 15 patients who had received adjuvant chemotherapy revealed a reduction in the absolute number of all lymphoid cells except monocytes. Helper T-cells were more strongly affected than suppressor T-cells. By determining lymphocyte subpopulations in women with leukopenia caused by cytostatics one will probably be able to identify those patients particularly susceptible to infection. Determining T-cells may also make it possible to deduce a special recurrence risk.

[The internet--new information sources on reproductive medicine?]. / Das Internet--Neue Informationensquellen zur Reproduktionsmedizin?

Within the last two years Internet pages have become a highly interesting source of up-to-date information. The scientific value of those homepages for reproductive medicine differ in a wide range. The Internet still remains a very interesting source for up-to-date information covering the field of infertility treatment with a growing influence on patient decisions and with increasing economical impact.