[Vulvar lichen sclerosus. The importance of early clinical and histological diagnosis]. / Lichen sclerosus vulvae. Die besondere Bedeutung der klinischen und histopathologischen Früherkennung.

Vulvar lichen sclerosus (LS) is a chronic progressive skin disease of unclear etiology. It is often overlooked in early stages, but progresses to destructive atrophy and is associated with an increased risk of vulvar squamous cell carcinoma. The classical symptoms are pruritus and pain, but they are often not distinctive, so that unclear vulvar problems often lead to a biopsy. The histological picture of early LS is quite different from that of late LS with an atrophic epidermis, markedly sclerotic dermis and stiff dilated vessels. The epidermis in early LS is usually normal with only minor irregularities in the rete pattern. The basement membrane is normal or focally widened, while the edematous dermis has only scattered ectatic vessels. The often dense lichenoid and intraepidermal infiltrate explains the spongiosis and vacuolization of the basal layer keratinocytes. Very early cases may only have a sparse lymphocytic infiltrate and hyper-/parakeratosis of the follicular ostia. Early topical therapy can dampen the progression to atrophic, irreversible LS.

Palliative cytostatic treatment of cervical carcinoma.

UNLABELLED: PURPOSE OF THE ARTICLE: In patients recurring after primary therapy for cervical cancer, treatment remains palliative. In the present article we focus on treatment results with single cytostatic drugs or combinations in randomized trials in squamous cell cervical cancer. RESULTS: In one randomized trial, monotherapy with platinum analogues lead to overall remission rates between 11% and 15% only. The median overall survival ranged between 5.6 and 6.5 months. Various combinations lead to overall remission rates between 21% and 31% and the median overall survival ranged between 7.3 and 14.3 months. The most active combinations were cisplatin/bleomycin/mitomycin C/vindesine, cisplatin/paclitaxel, and cisplatin/irinotecan. There are several smaller studies with cystostatic therapy in cervical adenocarcinoma. However, using 5-fluoruracil, ifosfamide, paclitaxel, or cisplatinum, only response rates between 15 and 30% can be achieved. Predictors of a favorable chemotherapy response include a higher performance status, higher age, extrapelvic recurrence sites (especially lung metastases), a recurrence-free interval > 1 year, and no previous radiotherapy and chemotherapy. CONCLUSION: In conclusion, palliative cytostatic therapy with single agents has moderate activity. Combinations are more active but also more toxic. In general, chemotherapy needs to be used earlier in the course of disease when tissue vascularization is preserved.

Are endometrial carcinoma cells disseminated at hysteroscopy functionally viable?

OBJECTIVE: The aim of this study was to evaluate the rate of transtubal dissemination of endometrial carcinoma cells by hysteroscopy and the functional viability of disseminated tumor cells by assessing cell adhesion in an in vitro model. METHODS: We studied 24 uteri obtained at TAH+BSO in patients with endometrial carcinoma. Further inclusion criteria were negative peritoneal cytology, no involvement of the uterine serosa or extrauterine disease, and endometrial surface involvement >1 cm in diameter. In vitro fluid hysteroscopy was performed with a 5-mm single-flow rigid hysteroscope. A maximum of 150 ml saline was infused at a maximum pressure of 100 mm Hg for a maximum of 3 min. Fluid running off through the tubes was collected. The cell suspension was enriched by a density gradient centrifugation. The isolated cells had a mean viability of 90% as judged by trypan blue exclusion. Viable cells (5 x 10(4) per 2-cm(2) polyvinyl chloride well plate) were cultured with equal parts of Dulbecco's modified Eagle's minimal essential medium and Ham's F-12 for 24 h. The endpoint of the analysis was the adherence of tumor cells to the polyvinyl chloride well plate, which was taken as a proxy for functional cell viability. Cytological evaluation was performed separately by two cytologists blinded to the source and date of the smears. RESULTS: Transtubal fluid dissemination was seen in 20 of 24 (83%) uteri. Tumor cells were found in 17 specimens (71%). In 10 (42%) specimens the disseminated tumor cells were functionally viable. CONCLUSIONS: Our model suggests that hysteroscopy can cause dissemination of malignant cells into the abdominal cavity from uteri containing endometrial carcinoma and that these cells can be functionally viable and adhere to a matrix.

Microinvasive carcinoma of the cervix: site of first focus of invasion.

OBJECTIVE: To evaluate the topography of the first invasive focus in microinvasive squamous cell carcinoma of the uterine cervix. METHODS: We studied 120 formalin-fixed and paraffin-embedded cold-knife conization specimens processed as step-serial sections. Four types of microinvasion were distinguished according to site: type I (ectocervical outside the last cervical gland), type II (ectocervical between the external os and the last gland and in connection with the surface epithelium), type III (ectocervical between the external os and the last gland but deep in cervical glands), and type IV (intracervical and in connection with the surface epithelium). RESULTS: A total of 142 early invasive foci were seen in the 120 cones. A single focus was seen in 106 (88%) specimens, whereas 14 (12%) had more than one focus. The foci were classified as type I in 16 (11%), type II in 31 (22%), type III in 70 (49%), and type IV in 25 (18%) cases. CONCLUSION: One half of the early invasive foci originated at the surface epithelium (types I, II, IV), either at the ectocervix (types I, II) or in the endocervix (type IV).

Prognostic factors in surgically treated stage ib-iib cervical carcinomas with special emphasis on the importance of tumor volume.

OBJECTIVE: The aim of the study was to analyze the importance of tumor volume as a prognostic factor for overall survival (OS) in surgically treated stage Ib-IIb cervical carcinoma. METHODS: One hundred thirteen of one hundred sixty-five patients with histopathological stage Ib-IIb cervical carcinoma (44 Ib1, 24 Ib2, 10 IIa, 35 IIb) treated by radical abdominal hysterectomy between 1989 and 1999, for whom tumor volume could be assessed, were included in this study. Of the 113 patients, 90 (79.6%) received postoperative radiotherapy. Measurement of tumor volume was performed on giant histological sections using a semiautomatic image analyzer. The prognostic significance of tumor volume was analyzed and compared with that of various clinicopathological parameters using uni- and multivariate statistics. RESULTS: The 5-year disease-free survival was 71.4%. Increasing tumor volume was associated with more frequent lymph node metastases and a significant decrease in OS (P = 0.0112). The Median tumor volume was smaller in stage IIa tumors than in stage Ib2 tumors, and histopathological stage did not correlate linearly with lymph node metastases as well as OS. Stage Ib2 tumors were associated with worse overall survival than stage IIa tumors. In univariate analysis, lymph node metastases, histopathological stage, lymph vascular space involvement, tumor volume, parametrial spread, and tumor involvement of resection margins were significant parameters for OS. In multivariate statistical analysis, only lymph node metastases and histopathological staging remained independent prognostic factors for OS. CONCLUSIONS: Tumor volume does not seem to confer additional prognostic information if histopathological stage and lymph node status are known. However, it may provide important prognostic information if lymph node status is not known or histopathological stage cannot be assessed.

[Colposcopy of CIN and microinvasive cervical carcinoma]. / Kolposkopie der CIN und des mikroinvasiven Zervixkarzinoms.

The colposcopist must distinguish between two patterns: nonsuspicious findings and suspicious findings. With experience, the colposcopist will succeed more and more in distinguishing between the two, thereby markedly reducing the number of biopsies. Suspicious findings are not synonymous with abnormal findings because the latter are not always due to premalignant lesions. A number of features are of value in the different diagnosis of colposcopic findings: sharp borders, response to acetic acid (white epithelium), surface contour, appearance of blood vessels, surface extent (size), combinations of abnormalities, iodine uptake, and keratinization. The diagnostic features described above can be expressed to varying degrees, and can be found singly or in combination. The more distinct a feature is and the greater the variety of features seen in combination, the higher the index of suspicion. Attempting to differentiate between the various grades of CIN (SIL) colposcopically is more questionable, as these lesions are regarded now as forming a spectrum of the same biologic process.

Cervical intraepithelial neoplasia III: long-term outcome after cold-knife conization with clear margins.

OBJECTIVE: To evaluate the long-term outcome of patients with severe cervical intraepithelial neoplasia or squamous cell carcinoma in situ (CIN III) after cold-knife conization with clear margins. METHODS: A total of 4417 women (mean age 36, range 18-72 years) with histologically confirmed CIN III had cold-knife conization with clear margins at our institution between 1970 and 1994. All patients were followed up with colposcopy, cytology, and pelvic examination for a mean of 18 years (range 5-30years). RESULTS: New high-grade squamous intraepithelial lesions (SILs) (CIN II and III) developed in 15 (0.35%) patients (mean age 35, range 25-65 years) after a median of 107 (range 40-201) months. A total of 4402 (99.65%) patients (mean age 36, range 18-72 years) were free of high-grade SILs after a mean follow-up of 18 (range 5-30) years. High-grade glandular intraepithelial lesions developed in two (0.05%) patients 14 and 17 years after conization. Twelve (0.3%) patients had metachronous vulvar intraepithelial neoplasia (VIN) grade III or vaginal intraepithelial neoplasia (VAIN) grade III, and one (0.02%) patient had invasive vaginal carcinoma 10 years after conization. CONCLUSION: Cold-knife conization with clear margins was an adequate method to definitively treat CIN III.

Clear cell carcinoma of the uterine cervix: pathology and prognosis in surgically treated stage IB-IIB disease in women not exposed in utero to diethylstilbestrol.

OBJECTIVE: The purpose of this research was to compare the clinical behavior, pathology findings, and prognosis of surgically treated FIGO stage IB-IIB clear cell carcinomas of the cervix with those of squamous cell carcinomas and non-clear cell adenocarcinomas. METHODS: Fifteen patients with clear cell adenocarcinomas of the cervix (8 FIGO stage IB, 7 FIGO stage IIB) were reviewed. The control group consisted of 444 squamous cell carcinomas and 59 non-clear cell adenocarcinomas. None of the patients had a history of in utero exposure to diethylstilbestrol. All patients underwent radical abdominal hysterectomy with systematic pelvic lymphadenectomy. All specimens were processed as serial giant frontal sections. The mean follow-up in the clear cell group was 83 (13-182) months. Statistical analysis was done with contingency tables, chi(2) tests, and Fisher's exact test. RESULTS: Twelve of the fifteen clear cell carcinomas (80%) were endophytic and tended toward deep cervical infiltration. Clear cell carcinomas extended to the uterine corpus significantly more often than squamous cell and non-clear cell adenocarcarcinomas (P < 0.001). The rates of parametrial involvement and pelvic lymph node involvement were 40 and 47%, respectively. Four patients (27%), all with positive pelvic nodes, developed recurrences an average of 14 (4-48) months after initial therapy. The extrapelvic sites of relapse were the lung, liver, and bone. Clear cell carcinomas had a worse 5-year survival rate (67%) than squamous cell carcinomas (80%) and non-clear cell adenocarcinomas (77%) but this was not statistically significant (P = 0.6). No significant differences were seen for age, growth pattern, parametrial and vaginal involvement, parametrial and pelvic lymph node metastases, frequency of recurrent disease, and time to first recurrence. CONCLUSION: The clinicopathologic findings and prognosis of surgically treated patients with stage IB-IIB clear cell carcinomas without exposure to diethylstilbestrol in utero are similar to those of patients with squamous cell carcinomas and non-clear cell adenocarcinomas.

Numerical chromosomal aberrations of chromosome 1 and 7 in dysplastic cervical smears.

Cervical smears with Papanicolaou's staining (PAP) reveal only morphological characteristics of epithelial cells of the cervix uteri. Since chromosomal aberrations are known to play a role in malignant transition, we analyzed cervical smears for numerical changes of the chromosomes 1 and 7 with fluorescence in-situ hybridization to probe for a diagnostic value of these chromosomes in the characterization of cervical dysplasia. Cervical smears were collected from 21 patients with suspect histology of curettage or biopsy specimen, 14 of them having been subsequently graded as cervical intraepithelial neoplasia (CIN) III and 5 as CIN II. Nineteen normal cervical smears (PAP I-II) served as controls. Smears were hybridized with chromosomal enumeration probes for chromosome 1 and 7. Disomic cells (2 copies of chromosome 1 and 7) were decreased in the CIN II (63%) and CIN III group (57%) with respect to the control group (77%). Cells with 3 signals for chromosome 7 were significantly more frequent in the CIN III and the CIN II group than in the control group (6.7, 6.4 and 0.7%, respectively). Only the CIN II group (10%), but not CIN II (6%), showed a significant trisomy for chromosome 1 as compared with the controls (3.8%). A close correlation between the incidence of trisomy 1 or 7 and PAP grading was observed. PAP III-IIID smears with high trisomy 1 counts corresponded to CIN III histology, while all CIN II patients were PAP III-IIID with low incidence of trisomy 1. We conclude that trisomy of chromosome 7 is a feature of cervical dysplasia and seems to be an early event in dysplastic transition. In contrast, trisomy of chromosome 1 is observed only in high grade dysplasia and may be a marker for pre-malignant lesions.

The prognostic significance of peritoneal seeding and size of postsurgical residual in patients with stage III epithelial ovarian cancer treated with surgery, chemotherapy, and high-dose radiotherapy.

OBJECTIVE: The aim of this study was to retrospectively analyze the prognostic importance of age, histologic type and grade, ascites, lymph node status, size and type of postoperative residual disease, and radiation dose on disease-specific (DSS) and progression-free survival (PFS) in stage III epithelial ovarian cancer patients who had been treated with radical surgery, postoperative chemotherapy, and high-dose radiotherapy. METHODS: Consolidation radiotherapy including whole abdominal radiation, pelvic, and upper abdominal boosts was employed in 46 patients who showed no evidence of residual or progressive disease after completion of multiagent chemotherapy. The median follow-up for all patients was 36 months and 103 months for patients at risk. The prognostic impact of pretreatment and treatment parameters on DSS and PFS was tested in univariate and multivariate analyses. RESULTS: The 5-year DSS and PFS rates for all patients were 38 and 33%, and for patients with 0-< or =2 cm residual tumor 65 and 61%, respectively. In univariate analysis, initial peritoneal seeding (both: P = 0.02), ascites (P = 0.03; 0.01), size of residual (0-< or =2 cm vs >2 cm), and residual miliary subdiaphragmatic (MDS) and localized peritoneal seeding (LPS) in the upper abdomen (P = 0.0002; 0.0003) were significantly correlated with DSS and PFS. Dose of radiation (< or =30 vs >30 Gy) correlated with DSS only (P = 0.02). In multivariate analysis size of residual disease (0-< or =2 cm vs >2 cm and/or MDS or LPS) remained the only independent prognostic factor for DSS and PFS (both; P = 0. 001). CONCLUSION: Patients with localized peritoneal seeding who were rendered free of disease elsewhere had an outcome equally poor as that of patients with gross residuals (>2 cm) in the upper abdomen. If our findings can be confirmed, attempted resection of all localized seeding in patients who are otherwise cytoreducible to no or minimal residual disease may be considered in combination with Taxol-containing regimens as are now being utilized for patients with gross disease.

Colposcopic diagnosis: clinical aspects and experiences.

Colposcopy can be applied as an integral part of every gynecologic examination in concert with cytology; to identify and localize lesions suspected on the basis of abnormal cytology findings; and to clarify the nature of clinically suspicious lesions. This implies using colposcopy to clarify the nature of cervical changes seen with the naked eye. This practice is superior to colposcopy which is restricted to evaluating abnormal smears because it can pick up some lesions missed by cytology. But it is not as effective as routine colposcopy because it can miss lesions not picked up by gross inspection of the cervix and because there is no opportunity to inspect the lower tract of the cervical canal. Considering that only 15-20% of lesions are purely endocervical, not too much time is wasted by examining these cases. If colposcopy is limited to evaluating grossly suspicious lesions, then its role is merely to avoid unnecessary biopsies.

Life-threatening tracheal metastasis complicating ovarian cancer--a case report.

BACKGROUND: Tracheal metastasis is a rare manifestation of recurrent ovarian cancer. CASE: We describe tracheal metastasis causing increasing respiratory distress in a patient with progressive stage IIIc undifferentiated serous-papillary cancer involving the peritoneum and pleura and the retroperitoneal, diaphragmatic, parahilar, mediastinal, pretracheal, paratracheal, and supraclavicular lymph nodes. The situation necessitated rapid endoscopic laser ablation. CONCLUSION: Malignant tracheal obstruction should be considered in the differential diagnosis of patients with advanced ovarian cancer and respiratory distress.

Chemotherapy versus radiotherapy versus observation for high-risk cervical carcinoma after radical hysterectomy: A randomized, prospective, multicenter trial.

BACKGROUND: Adjuvant treatment modalities after radical hysterectomy have long been used in an attempt to eradicate microscopic tumor residuals in patients at high risk for recurrence. However, it has not been clearly demonstrated that adjuvant radiation, adjuvant chemotherapy, or both improve the outcome. To evaluate the effect of adjuvant treatment in patients with high-risk cervical cancer after radical hysterectomy, the Austrian Gynecologic Oncology Group conducted a prospective, randomized, multicenter clinical trial between 1989 and 1995. MATERIAL AND METHODS: Seventy-six patients with stage IB-IIB cervical cancer treated with radical hysterectomy with pelvic lymph node metastases and/or vascular invasion randomly received adjuvant chemotherapy (400 mg/m2 carboplatin, and 30 mg bleomycin), standardized external pelvic radiation therapy, or no further treatment. RESULTS: After a median follow-up of 4.1 years (range, 2-7) there were no statistically significant differences (P = 0.9530) in disease-free survival among the three treatment arms. CONCLUSION: The data suggest that adjuvant chemotherapy or radiation do not improve survival or recurrence rates in high-risk cervical cancer patients after radical hysterectomy. The most important treatment for these patients seems to be radical abdominal hysterectomy with systematic pelvic lymphadenectomy.

Exfoliative cytology of a lymphoepithelioma-like carcinoma in a cervical smear. A case report.

BACKGROUND: Lymphoepithelioma-like carcinoma of the cervix (LELC) is cytologically identical to its counterparts at other sites, such as the nasopharynx. LELC can be suspected on a cervical cytologic smear. The differential diagnosis includes nonkeratinizing squamous cell carcinoma with prominent stromal inflammation, carcinoma with intense stromal eosinophilia, glassy cell carcinoma, malignant lymphoma (especially lymphoepitheloid-Lennerts lymphoma) and metastatic Schmincke-Regaud tumor. CASE: A 55-year-old female presented with an ulcerated endophytic tumor in the cervix. Exfoliative cytology showed uniform, large tumor cells, often associated with inflammatory cells, with round or oval nuclei and one or more prominent nucleoli. The cytoplasm was finely granular to flocculent, and the nuclei were uniformly vesicular. The chromatin was peripherally marginated. The cell borders were indistinct. There was no evidence of dyskeratotic or keratinized cells, koilocytes or glandlike formations. These findings were highly suspicious for LELC and were confirmed by biopsy. Flow cytometry showed DNA aneuploidy, with a DNA index of 1.08. In situ hybridization was negative for human papillomavirus 16 and 18. CONCLUSION: LELC of the uterine cervix has cytologic features that are sufficiently characteristic for a specific cytologic diagnosis. The diagnosis, nevertheless, has to be proven by histology.

Consolidation radiotherapy after carboplatin-based chemotherapy in radically operated advanced ovarian cancer.

OBJECTIVE: The aim of the study was to evaluate the effect of additional radiotherapy after chemotherapy on the relapse-free and overall survival rates of patients with advanced ovarian cancer. METHODS: Between 1985 and 1992 64 patients with radically operated ovarian cancers (4 stage IC, 2 stage II, 54 stage III, and 4 stage IV) were enrolled in a randomized study. Radical surgery comprised total abdominal hysterectomy and bilateral salpingo-oophorectomy, omentectomy, and pelvic and paraaortic lymphadenectomy. All patients received adjuvant chemotherapy with carboplatin IV 400 mg/m2, epirubicin IV 70 mg/m2 on day 1 and prednimustine orally 100 mg/m2 on days 3 to 7 at 1-month intervals. Thirty-two patients without residual disease were randomized to whole abdominal radiation (30 Gy, administered over 4 weeks). An additional 21.6 Gy were delivered to the pelvis and 12 Gy to the paraaortic region up to the diaphragm for total doses of 51.6 and 42 Gy, respectively. Cancer-related survival was calculated with the Kaplan-Meier and Cox proportional hazards methods. RESULTS: The relapse-free and overall survival rates of patients who received adjuvant chemoradiotherapy were significantly higher than those of patients who received adjuvant chemotherapy only (68% vs 56% at 2 years and 49% vs 26% at 5 years, P = 0.013, and 87% vs 61% at 2 years and 59% vs 33% at 5 years, P = 0.029). The differences were most pronounced in patients with stage III disease (77% vs 54% at 2 years and 45% vs 19% at 5 years, P = 0. 0061, and 88% vs 58% at 2 years and 59% vs 26% at 5 years, P = 0. 012). Toxicities were acceptable. CONCLUSION: Sequential combination of platinum-based chemotherapy with open-field abdominal radiotherapy is a promising adjuvant regimen for patients with advanced ovarian cancer.

Prognostic factors in patients with carcinoma of the uterine cervix treated with external beam irradiation and IR-192 high-dose-rate brachytherapy.

PURPOSE: Prognostic factors in cancer of the cervix for patients treated with external beam irradiation (EBR) and low-dose-rate (LDR) brachytherapy have been characterized. However, despite the increasing use of high-dose-rate (HDR) intracavitary placements (ICP), few studies with adequate follow-up have analyzed prognostic factors. This study investigates pretreatment and treatment factors for their correlation with treatment outcome after EBR and HDR-ICP. METHODS AND MATERIALS: Between September 1985 and December 1994, 181 patients with carcinoma of the cervix FIGO stages IB-IV received EBR and HDR brachytherapy. Hemoglobin (Hb) levels were maintained above a level of 11 g/dl during the treatment by transfusion. Patient age ranged from 34 to 84 years (median: 66). The median follow-up time for patients at risk is 69 months (range: 23-140). Pretreatment and treatment parameters analyzed to determine their prognostic value included age, FIGO stage, tumor size, tumor type and grade, pretreatment Hb level, number of HDR-ICP, total dose from HDR-ICP, overall dose to point A, and overall treatment time. Also evaluated was the prognostic value of enlarged lymph nodes noted on pretreatment CAT scan of the abdomen and pelvis. Endpoints studied in uni- and multivariate analyses were disease-specific survival (DSS), freedom from disease (FFD), pelvic control (PC), and probability of distant metastases (DM). RESULTS: At 5 years the DSS, FFD, and PC rates for all patients were 60%, 58%, and 67%, respectively. The 5-year FFD by stage was: IB: 94%; II: 63%; IIIB: 43%; and IV: 0%. The PC rates were 94%, 66%, 59%, and 0%, respectively. In univariate analysis the prognostic factors identified for FFD were FIGO stage, tumor size, initial Hb level, and enlarged pelvic and/or paraaortic nodes (all: p < 0.0001). Age was inversely correlated with outcome (p = 0.0081). The 5-year FFD rates for tumors (< 3, > or = 3 < 6, > or = 6 cm) were 97%, 65%, and 24%; patients with initial Hb levels < or = 11g/dl had a FFD of 26% versus 69% for patients with levels > 11g/dl; and those with pelvic and/or paraaortal nodes > or = 1 cm had a survival of 32% versus 68% in patients with negative readings. The same factors were also prognostically significant for DSS, PC, and DM. Patients with persistent disease or pelvic failures had a significantly higher incidence of DM than patients in whom pelvic disease was controlled (p < 0.0001).Histological and treatment parameters including overall treatment time were not of prognostic significance for any of the endpoints studied. In multivariate analysis tumor size was the most powerful parameter for DSS, FFD, PC (p < 0.0001) and DM (p = 0.0001), followed by low initial Hb level (DSS: p = 0.0004, FFD: p = 0.0009, PC: p = 0.0012, DM: p = 0.0265), and enlarged pelvic and/or paraaortic nodes which were predictive for DSS (p = 0.0210) and DM (p = 0.0011). CONCLUSION: This study confirms that prognostic factors for patients treated with HDR brachytherapy are similar to those reported in previous series that employed LDR brachytherapy. The significance of tumor size, pretreatment Hb level, and enlarged pelvic and/or paraaortic lymph nodes on CAT scan over FIGO stage of disease were demonstrated. Future prospective trials should be undertaken to confirm the validity of these factors and to elucidate their therapeutic implications.