Virilizing ovarian tumor of low malignant potential associated with antecedent tamoxifen use for breast cancer.

A patient is described who was treated with tamoxifen for breast cancer and developed an androgen-producing ovarian tumor of low malignant potential, which itself is a rare condition. Clinically overt virilism was leading to the diagnosis and promptly improved after surgical removal of the tumor. A causal relationship between tamoxifen use and the tumor is discussed on the basis of the known tumor-inducing potential of tamoxifen.

Angiogenesis in cervical neoplasia: microvessel quantitation in precancerous lesions and invasive carcinomas with clinicopathological correlations.

Recently, angiogenic properties have been shown in preinvasive cervical lesions. Our goal was to determine the angiogenesis in cervical intraepithelial neoplasia (CIN) and the relationship between microvessel counts, histopathological parameters, and clinical outcome in invasive cervical carcinoma. One hundred thirty-eight cervical specimens were evaluated; among these 20 were designated normal epithelium, 20 low-grade CIN, 40 high-grade CIN, and 58 invasive carcinoma. Histological sections immunostained for CD31 were quantitatively evaluated for microvessel density. The tumor proliferation rate was determined by the Ki-67 Labeling Index. Comparison of microvessel counts from normal epithelium with those from CIN and invasive carcinoma showed significant increases in precancerous lesions and invasive cancer (P < 0.0001). Microvessel density was found to be associated with the overall survival in women with invasive carcinoma (P < 0.01). There was a significant correlation of microvessel density (P < 0.05) with relapse-free survival in patients with regional lymph node metastasis. A Cox stepwise regression analysis revealed microvessel density, together with depth of invasion, regional lymph node status, and vascular invasion, to be a strong independent prognostic indicator for overall survival in patients with clinical stage IB cervical carcinoma.

Altered expression of mdm-2 and its association with p53 protein status, tumor-cell-proliferation rate and prognosis in cervical neoplasia.

Recent results suggest that p53 inactivation is required for cervical-carcinoma development. The mdm-2 oncogene, which forms an auto-regulatory feedback loop with the normal p53 protein, has been found amplified in human carcinomas, thus abolishing the anti-proliferative function of p53. To investigate whether the mdm-2/p53 interaction plays a role in cervical neoplasms, we performed an immunohistochemical study in archival fixed, embedded specimens that included 178 pre-cancerous lesions (CIN) and invasive squamous-cell carcinomas of clinical stage IB. In addition to p53, we assessed the p53-associated protein, mdm-2, and the Ki-67 labelling index (LI). The presence of HPV was assessed by in situ DNA hybridization. Tumor expression of all nuclear proteins was scored as fraction of positive CIN or cancer nuclei. The analysis demonstrated a significant association of the Ki-67 LI with grade of atypia in cervical neoplasms. p53 accumulation and mdm-2 expression are higher in invasive carcinomas than in pre-cancerous lesions. No correlation was observed with HPV status. An inverse correlation was found between increased tumor-cell proliferation and mdm-2 expression in invasive carcinomas (p < 0.0001). mdm-2 expression was significantly associated with p53 accumulation (p < 0.02). However, the investigated nuclear proteins were not associated with overall survival in patients with invasive carcinomas. Cox stepwise-regression analysis revealed regional lymph node status and depth of invasion to be independent parameters.

[Fetal fibronectin as a marker of prematurity in a high risk patient sample]. / Fetales Fibronectin als Marker der Frühgeburtlichkeit im Risikokollektiv.

The accuracy of cervicovaginal fetal fibronectin as a predictor of preterm birth was studied in patients with increased risk for preterm delivery (according to the Creasy-score). In a prospective blind observational study the smear from the posterior fornix vaginae of 56 pregnant patients without PROM was examined using a quantitative immunoassay for the detection of fetal fibronectin. The patients who tested positively for fetal fibronectin had significantly more preterm deliveries than those with a negative result (CHI square-test, p < 0.01, RR 5.1). Overall, sensitivity, specificity, positive and negative predictive values were 56%, 87%, 45% and 91%, respectively. In patients with preterm labor these values were 75%, 87%, 60%, and 93%, respectively. No patient with a negative result delivered preterm during the following two weeks. It is concluded that performing the fetal fibronectin test in patients with preterm labor is useful for the prediction of preterm birth. Routine testing in patients at increased risk (asymptomatic patients) is not recommended for lack of effectiveness.

[Breast preserving therapy of breast carcinoma: analysis of over 1,300 patients treated in the Basel region]. / Brusterhaltende Therapie beim Mamma-Karzinom: Analyse bei über 1300 in der Region Basel behandelten Patientinnen.

From 1977 to 1994 a total of 1329 breast cancer patients have been treated with breast conserving surgery in the region of Basel. This analysis is based on 832 patients treated from 1977 to 1990 according to a prospective treatment protocol, which was adjusted only once (1985). In comparison with the most known international publications this analysis represents one of the greatest homogeneous series of breast conserving treatment. We observe an overall 5-year survival of 91% and a 10-year survival rate of 77%. 94% of the women remain locally recurrence free at 5 years and 86% at 10 years respectively. At 5 years, freedom of local recurrence totals to 97% in patients without (pN0) and to 89% in patients with tumor involvement of the axillary lymph nodes (pN+) (p = 0.00008), as well as to 96% for pT1 and 91% for pT2-tumors (p = 0.08328). In our analysis the R0-resection significantly influences local recurrence free survival.

Expression of CD44 and variant isoforms in cervical intraepithelial neoplasia.

The cell adhesion molecule CD44 and its variant isoforms have been found to be related to invasive and metastatic character of cancer cells. Their expression in gynecologic precancerous lesions has not yet been reported. Mouse monoclonal antibodies directed against a common epitope (CD44s) and exons 4v, 6v, and 9v were used to study the expression of CD44 and variant isoforms by immunohistochemistry in cervical intraepithelial neoplasia (CIN). Twenty tissue samples with normal cervical epithelium and 57 samples with CIN of different histological grades and different HPV status were included in this study. The standard CD44, CD44-4v, CD44-6v, and CD44-9v were expressed in normal cervical epithelium and in precancerous lesions. In distinct contrast to the normal epithelium, however, the standard CD44, CD44-4v, and 6v showed a reduced expression in precancerous lesions, whereas CD44-9v was significantly overexpressed. Expression of CD44 standard and CD44-4v was correlated with the histological grade but not with the HPV status. Compared with mild and moderate dysplasia, severe dysplasia and carcinoma in situ are associated with low expression of CD44s (P = 0.007) and of CD44-4v (P = 0.03). These observations reveal dynamic changes in CD44 expression during neoplastic cell transformation in cervical intraepithelial neoplasia.

Assessment of EGFR and TGF-alpha expression in relationship to HPV status and Ki-67 distribution in cervical intraepithelial neoplasms.

Expression of epidermal-growth-factor receptor (EGFR), transforming growth factor alpha (TGF-alpha) and Ki-67 proliferation antigen in cervical intra-epithelial neoplasms were analyzed. To examine the interrelationship of TGF-alpha, EGFR, Ki-67 and HPV status in dysplasia and carcinoma in situ, formalin-fixed tissue sections of 92 women were immunostained with monoclonal antibodies to EGFR, TGF-alpha and Ki-67. The presence of HPV was assessed by in situ DNA hybridization. The highest positive TGF-alpha expression was seen in the group of mild dysplasia. The difference was significant between the relatively high expression in mild dysplasia and the low occurrence in severe dysplasia and carcinoma in situ as well. The same relation could be found between TGF-alpha expression in papilloma-virus-negative dysplasia and those with the presence of HPV 16/18. In contrast to these findings, the Ki-67 proliferation marker was intensely detectable in severe dysplasia and carcinoma in situ. Ki-67-stained neoplastic cell nuclei were found in a significantly higher percentage of HPV-positive than in HPV-negative lesions. TGF-alpha over-expression is obviously combined with low proliferating activity and vice versa. Irrespective of the grade of dysplasia or HPV status, EGFR was expressed abnormally as compared with normal squamous epithelium. Over-expression of TGF-alpha in mild dysplasia could be associated with the autocrine pathway of cell-growth regulation. In the presence of HPV 16/18 the EGFR/TGF-alpha pathway for growth stimulation is probably not involved.

[Surgical treatment of vaginal prolapse after hysterectomy]. / Zur operativen Behandlung des Scheidenvorfalls nach Hysterektomie.

Forty-five women were treated with a sacrospinous ligament fixation of the vaginal apex between 1979 and 1993. The patients had a complete vaginal prolapse following abdominal or vaginal hysterectomy or in three cases a combined uterine and vaginal prolapse. The sacrospinous ligament fixation was carried out as described by Amreich, Sederl and Richter. The fixation of the vagina was successful performed in 43 women. These results were obtained using absorbable suture material. A sciatic nerve damage was observed in two patients for a short time with spontaneous recovery, coincident with suture absorption and nerve regeneration. We consider and recommend fixation of the vaginal apex to the sacrospinous ligament as the technique preferred for the operative treatment of a vaginal prolapse and for the rare cases of uterine prolapse, which cannot be corrected otherwise.

No tumor-specific expression levels of protein kinase C isoenzymes and of c-fos in human breast cancer cell cultures.

Epithelial cells derived from 46 human breast tissue samples of patients suffering from breast cancer have been cultivated. Twenty-five of these cell cultures stemmed from normal and 21 from tumor tissues. Moderate to large variations of protein levels of three protein kinase C (PKC) isoenzymes (alpha, delta and epsilon) were found among the various cell cultures. The cell cultures also exhibited very heterogeneous basal as well as inducible levels of c-fos mRNA. However, none of these variations could be correlated with the character of the original tissue nor with any clinical parameter of the respective patient. Our results suggest that altered levels of PKC isoenzymes or of the protooncogene c-fos per se cannot serve as an indication for a transformed behavior of the epithelial cell fraction of human breast tissue.

[Clinical diagnosis: open surgical biopsies]. / Klinische Diagnostik: die offenen chirurgischen Biopsien.

The main goal of an open biopsy in the breast is directed towards confirmation or exclusion of suspected cancer. The curved incision parallel to the areolar line must allow excision of the tumor completely. Persisting isolated lumps should be extirpated even if by all other diagnostic means they seem to be benign. Cases of pathologic secretion (tumors, suspicious cytology, significant galactography, abundant secretion) need surgical intervention as well. The clinical value of homologue biopsies taken from the contralateral breast in cases of breast cancer on one side is questionable.

Therapy of vulvar carcinoma.

83 vulvar carcinoma patients were originally treated in the period between 1970 and 1990. 82 patients presented with squamous cell carcinoma. 70% of the patients were in Stage I or II. It was originally possible to operate on 74 of the 83 patients. A simple or partial vulvectomy was applied 17 times. A bilateral inguinal lymph node excision additionally took place in 6 cases. 51 patients were subjected to radical vulvectomy with inguinofemoral lymph node excision. In 13 cases, pelvic lymph node extirpation was also performed. A posterior pelvic exenteration was performed in 6 cases presenting extensive carcinoma involvement of the vulva. In the remaining 9 patients, either it was not possible to operate, or a nonradical operation could be performed. The primary morbidity, consisting of wound healing disturbances and infections, amounted to 50% in our group. We observed lymphedema in 47% of the cases, although it was clinically important in only 10%. We did not have any primary surgical mortality. The 5-year survival rate was 82% in our patients without inguinofemoral lymph node involvement and only 40% in lymph node metastatic cases. The absolute 5-year cure rate was 66%, or 69% corrected. To be able to give increased preference to less invasive methods an improved prevention and clarification procedure for physicians and patients is necessary.

[Diagnostic problems in local recurrence after breast saving treatment]. / Diagnostische Probleme beim Lokalrezidiv nach brusterhaltender Behandlung.

353 patients with stages pTis, pT1-2, pN0-1, cM0 breast cancer have been treated consecutively by breast conserving therapy in a prospective, nonrandomized study at the University Hospital Basel and the Women's Clinic Rheinfelden/Baden/Germany. The median age was 47 years, the median follow-up time 67 months, and 4% only of this collective were lost to follow-up after a median time of 42 months. In 79% of the cases the tumor was excised totally, while in 19% the resection margins were positive and in 2% only the margins were not available for histological judgement. The rate of local failure reached 8% with a median time interval of 53 months. 116 patients showed postactinic induration in the primary tumor region. 73 of these were given additional diagnostic examination: The postactinic induration was judget clinically suspicious in 51 cases and clinically nonsuspicious of local failure in 22 cases. All 73 patients received additional examination by mammography and biopsy. By comparison with the histological results the clinical results were correct in 59% and false in 41%, while the mammographic results were correct in 82% and false in 18% of the cases.

[1989 Basel Mammography Action]. / Mammographie-Aktion Basel 1989.

To evaluate the compliance for a breast cancer screening program in the region of Basel, a mammography and a clinical examination has been offered free of charge to women between 40 and 60 years of age, especially to women with familial breast cancer. From September to November 1989, 602 women participated. Results were obtained from an epidemiologic questionnaire and a two-view mammography. The median age was 55.1 years. 70.2% of the women never had a mammography before. 28.8% indicated a history of familial breast cancer. So far 444 women have been evaluated. No pathological results were obtained in 84.8% In 10.7% a second examination has been recommended in the near future. In 4.5% the mammography led to an aspiration biopsy or surgical lumpectomy where 5 (1.2%) neoplasms have been detected. Due to the limited duration of the campaign and the invitation especially addressed to women at risk, our results are not comparable with large-scale screening campaigns known from the literature. Nevertheless, we succeeded to sensitize the female population for this kind of breast care. The overwhelming success shows that the basis for a large-scale screening program may exist.

[Sarcoma of the breast]. / Sarkome der Mamma.

Sarcoma of the breast represents only 0.2-1% of all mammary malignancies. This study reports 5 such cases, including 2 osteosarcomas, 1 fibro-, 1 lipo-, and 1 malignant fibrous sarcoma. The treatment used was mastectomy in 3 cases with excision of axillary lymph nodes. The remaining 2 patients were treated by simple mastectomy whereby 1 of these received a immediate reconstruction with a prosthesis. 1 patient demonstrated local recurrence and died. The remaining 4 patients did not develop neither metastases nor local recurrence and are still alive after an observing period between 12 months up to 17 years. Today, first-line treatment is wide local excision or simple mastectomy. Excision of the axillary lymphatics, adjuvant radiotherapy, and chemotherapy have been disappointing in the treatment of breast sarcoma.

[Breast saving therapy: diagnostic problems in after care]. / Brusterhaltende Therapie: diagnostische Probleme in der Nachsorge.

From 1.1.1977 through 31.12.1985 two hundred seventy-five patients with stages pTis, pT1-2, pN0-1, cM0 breast cancer were treated by breast-conserving therapy. Six patients (2%) were lost to follow-up. Fifty-four patients developed significant subcutaneous or parenchymal induration in the treated breast. The induration was considered clinically suspicious for recurrence in 30/54 and non-suspicious in 24/54. Of the 30 suspicious indurations mammography was diagnostic or suggestive of recurrence in 12 (40%), and the diagnosis of recurrence could be confirmed microscopically in 16 (53%). Mammography showed no pathologic findings in 14/30 (42%) patients with suspicious indurations, and in 12/30 (40%) the impression of benignity was also confirmed microscopically. In patients whose mammograms were diagnostic or suggestive of tumor, malignancy was demonstrated by pathologic examination in all cases. In 21/24 (87.5%) clinically benign indurations no tumor could be found on microscopic examination. Twenty of these patients had a normal mammogram, and in only 1 of these was a recurrence discovered incidentally during a cosmetic operation. Four of the 24 patients with clinically benign indurations had pathologic mammograms, and in 2 of these the diagnosis of recurrence was established histologically. - The rate of agreement between suspicious clinical and mammographic or microscopic findings was about 50%, whereas the correlation for clinically benign indurations was greater than 80%.