[Changes in the TNM classification of gynecological tumors]. / Anderungen der TNM-Klassifikation gynäkologischer Tumoren.

Based on the results of clinical and histomorphological studies in recent years, a revision of the TNM classification of malignant tumours of the female genital organs became necessary. Vulvar cancer saw the most significant changes. In the T1 category the new system recognises tumour size and its relation to the infiltration of adjacent structures by the tumour. The number of positive regional lymph nodes has also been included in the new staging system. For cervical cancer, there is a new subdivision of the category T2a depending on tumour size with a breakpoint of ≤ 4 cm versus > 4 cm and a subdivision into T2a1 und T2a2. In endometrial cancer, the previous pT1a and pT1b were merged to pT1a. The former category T1c has changed into T1b. The category pT1c is no longer used. For the first time, there is a TNM classification system for uterine sarcomas.

[Pathoanatomical preparation and reporting of specimens from precancerous lesions and carcinomas of the vulva]. / Pathologisch-anatomische Aufarbeitung und Befundung von Präparaten bei Präkanzerosen und Karzinomen der Vulva.

On the basis of varying morphology and pathogenesis, two types of vulvar intraepithelial neoplasias (VIN) have been defined: the common type (approximately 98%), classic VIN, is characterised by strong association to high-risk HPV infection (up to 90%), occurrence at younger age (median age 30-40 years) and multifocality. The differentiated (or simplex) type is rare (1%-2%) and is associated with older age (median age 65 years) and p53 alterations. It is usually diagnosed in combination with vulvar (keratinizing) squamous cell carcinoma. The classification currently preferred by the WHO in which VIN are classified into VIN 1-3 is to be replaced due to new data and according to a proposal by the International Society for the Study of Vulvovaginal Diseases (ISSVD) which eliminates VIN 1 and combines VIN 2 and 3 to VIN of common or, depending on histopathology, differentiated type. Prognostically relevant factors in vulvar cancer include stage of disease, inguinal lymph node involvement, size of metastatic deposits and presence of extracapsular extension, depth of invasion and distance of the tumor from resection margins. Tumor grade and the presence of lymphovascular space involvement are controversially discussed.

Validation of the accuracy of the sentinel lymph node procedure in patients with vulvar cancer: results of a multicenter study in Germany.

OBJECTIVE: To investigate the diagnostic accuracy of the sentinel node procedure in patients with vulvar cancer, a multicenter study was launched in Germany in 2003 involving 7 oncology centers. PATIENTS AND METHODS: Between 2003 and 2006, 127 women with primary T1-T3 vulvar cancer were entered in the study and treated with sentinel node removal after application of (99m)Technetium labeled nanocolloid and/or blue dye. Subsequently, in all women a complete inguinofemoral lymphadenectomy and the adequate vulvar operation were performed. Sentinel lymph nodes were examined by routine pathologic examination (H&E), followed by step-sectioning and immunhistochemistry if negative. RESULTS: The sentinel node procedure was successful in 125 out of 127 cases, in 2 cases no sentinel nodes were detected. 21 patients received unilateral lymphadenectomy, 103 women were operated on both groins. In 39 women out of 127, positive lymph nodes in one or both groins were identified (30.7%). In 36 women, the sentinel nodes were also positive (sensitivity 92.3%). We had three cases with a false negative sentinel node (false negative rate: 7.7%), all of these women presenting with tumors in midline position. One tumor was a T1 tumor (10 mm), 2 tumors being classified as T2 (40 and 56 mm, respectively). In one additional case (18 mm T1 tumor, midline position), the sentinel was positive in the right groin, but false negative on the left side. CONCLUSIONS: This study shows that identification of SLN in squamous cell cancer of the vulva is feasible, however not highly accurate depending on tumor localization and size. The false negative rate seems to be acceptable if the procedure is restricted to stage 1 tumors with clinically negative lymph node status. Tumors situated in or close to the midline seem to be less suitable for this procedure. Implementation of SLNB into clinical practice should be performed with care and only by experienced teams as to avoid preventable groin relapses.

Diagnosis, Therapy and Follow-up Care of Vulvar Cancer and its Precursors. Guideline of the DGGG and DKG (S2k-Level, AWMF Registry Number 015/059, November 2015.

Purpose: This is an official guideline, published and coordinated by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO, Study Group for Gynecologic Oncology) of the Deutsche Krebsgesellschaft (DKG, German Cancer Society) and the Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG, German Society for Gynecology and Obstetrics). The number of cases with vulvar cancer is on the rise, but because of the former rarity of this condition and the resulting lack of literature with a high level of evidence, in many areas knowledge of the optimal clinical management still lags behind what would be required. This updated guideline aims to disseminate the most recent recommendations, which are much clearer and more individualized, and is intended to create a basis for the assessment and improvement of quality care in hospitals. Methods: This S2k guideline was drafted by members of the AGO Committee on Vulvar and Vaginal Tumors; it was developed and formally completed in accordance with the structured consensus process of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). Recommendations: 1. The incidence of disease must be taken into consideration. 2. The diagnostic pathway, which is determined by the initial findings, must be followed. 3. The clinical and therapeutic management of vulvar cancer must be done on an individual basis and depends on the stage of disease. 4. The indications for sentinel lymph node biopsy must be evaluated very carefully. 5. Follow-up and treatment for recurrence must be adapted to the individual case.

Loss of heterozygosity of BRCA1, TP53 and TCRD markers analysed in sporadic endometrial cancer.

Genetic alterations of tumour suppressor genes, for which loss of heterozygosity (LOH) is one mechanism of gene inactivation, are important steps in the development of endometrial cancer. To investigate the clinical relevance of LOH of BRCA1 (17q21), TP53 (17p13) and TCRD (14q11) in endometrial cancer, polymerase chain reaction (PCR)-based fluorescent DNA technology for the detection of microsatellite polymorphisms was applied. One hundred and thirteen archival endometrial cancer samples with matched normal tissues were examined. Allele loss at three loci were correlated with age, tumour size, lymph node status, metastases, stage, histological types, grade, expression of oestrogen receptor (ER) and progesterone receptor (PgR), family history of cancer, previous history of cancer or precursor lesions, and previous history of hormone replacement therapy (HRT). LOH for BRCA1 was detected in 18.1%, of TP53 in 26.9%, and of TCRD in 26.3% of informative cases. LOH of BRCA1 correlated with medium grade, positive ER status, and family history of cancer; LOH of TP53 correlated with younger age, high grade, positive PgR status, and with tumours from patients without HRT; LOH of TCRD correlated only with family history of cancer. LOH at all three loci correlated only with grade and positive family history. Allele loss of one of the three tumour suppressor loci did not correlate with disease-free survival (DFS), but LOH of BRCA1 correlated significantly with decreased overall survival (OS). The latter, together with the correlation of LOH of BRCA1 locus with steroid hormone receptor expression, might give a hint to the potential involvement of the co-localised 17 beta-hydroxysteroid dehydrogenase (HSD) gene in the development of endometrial cancer.

Immunohistological characterization of the cellular immune response against Yersinia enterocolitica in mice: evidence for the involvement of T lymphocytes.

Previous work from this laboratory has demonstrated that cloned T lymphocytes from spleens of Yersinia-infected mice can transfer immunity against Y. enterocolitica into naive animals. In this study, we investigated the cellular immune response to parenteral infection of Yersinia-resistant C57 BL/6 mice with the highly virulent Y. enterocolitica strain WA of serotype O:8 employing immunohistological methods. In the course of the infection the spleen and the liver were the organs most extensively affected. Histologically, three different patterns of inflammatory reactions could be observed: (i) small non-pyogenic granuloma-like lesions (in the liver only), (ii) microabscesses lacking a sharp outline, and (iii) larger abscesses disclosing a distinct cellular border (spleen and liver). Immunohistologically, Y. enterocolitica was detectable within abscesses but not in the small granuloma-like lesions present in the liver. CD11b/18 positive cells (= Mac-1-antigen expressed on macrophages, monocytes, granulocytes and NK-cells) could be shown in Yersinia-induced lesions. The number of these cells correlated with the extent of tissue alterations induced by Y. enterocolitica. More strikingly, we were able to demonstrate for the first time that both CD4 (helper) and CD8 (cytotoxic) T lymphocytes are present in Yersinia-induced lesions. In summary, we could demonstrate for the first time that granuloma-like lesions can be induced by Y. enterocolitica. Moreover, we supported our recent study suggesting that T lymphocytes are probably involved in the immune response against Y. enterocolitica in mice.

Regulation of apoptosis in squamous cell carcinoma of the vulva.

OBJECTIVE: To analyze the expression of Bcl-2, Bax and ICH-1-L in squamous cell cancer of the vulva. STUDY DESIGN: Slides of 72 vulvar squamous cell carcinomas were stained immunohistologically for Bcl-2, Bax and ICH-1-L. They were analyzed for the percentage of positive tumor cells, staining intensity and pattern, and amount of Bcl-2-positive lymphocytes around the tumor. Results were analyzed for correlations with clinical and histologic characteristics. Disease-free and overall survival were evaluated by Kaplan-Meier curves with the log-rank test. RESULTS: Strong expression of Bcl-2 was present in 15% of tumors. Carcinomas with high Bcl-2 expression more frequently had lymph node metastasis (P = .03), without significant differences in other clinical or histologic parameters, disease-free and overall survival. Strong Bax expression was observed in 57%, without prognostic significance. Carcinomas showed high ICH-1-L expression in 35%. These tumors seemed to have longer disease-free survival, while overall survival was significantly longer (P = .02). A strong Bcl-2-positive inflammatory infiltrate was highly predictive of lymph node metastasis (P = .02) and disease-free survival (P = .03). CONCLUSION: In squamous cell carcinoma of the vulva, inhibition of apoptosis is associated with a more-aggressive phenotype, and a Bcl-2-positive inflammatory infiltrate is predictive of prognosis. A study with more patients should confirm the importance of apoptosis in vulvar carcinoma.

Squamous cell carcinoma of the vulva. Expression of tumor proteases cathepsin-D and pro-cathepsin-L.

OBJECTIVE: To analyze the expression of cathepsin (cath)-D and pro-cath-L in squamous cell carcinoma of the vulva and to determine whether those proteases have prognostic significance. STUDY DESIGN: Seventy-eight carcinomas were evaluated for tumor type, grade, inflammation and vascular space involvement. Formalin-fixed, paraffin-embedded tissue was stained for cath-D and pro-cath-L. Distribution, intensity and number of stained cells were examined and analyzed by the chi 2 test and receiver operator characteristic curves. RESULTS: Cath-D and pro-cath-L staining showed different distribution patterns. Cath-D expression at the tumor border was associated with development of recurrence (P = .018). Lymph node involvement was dependent on the staining patterns of cath-D and pro-cath-L. The number of pro-cath-L-positive cells correlated with the development of recurrence (P < .01). CONCLUSION: Protease expression of cath-D and pro-cath-L is localized in different tumor areas. The different staining patterns are associated with lymph node involvement and development of recurrence. The number of pro-cath-L-positive cells may be useful for predicting tumor recurrence.

[Vaginal bleeding and premature contractions during pregnancy in uterus bicornis with expulsion of a decidual polyp]. / Ausstossung eines Deziduapolypen aus dem nichtgraviden Uterushorn bei einer Schwangerschaft mit Uterus bicornis.

Diagnosis and clinical course of a rare case are described, and the importance of prenatal ultrasound diagnostic is discussed.

Prognostic impact of KI67, p53, human epithelial growth factor receptor 2, topoisomerase IIalpha, epidermal growth factor receptor, and nm23 expression of ovarian carcinomas and disseminated tumor cells in the bone marrow.

Examination of tumor biological factors for prognostic and predictive indicators is not part of routine testing in ovarian cancer. As in other tumors, the detection of hematogenous tumor spread could help to estimate the risk of metastatic disease. We examined the expression of p53, KI67, topoisomerase IIalpha (Top IIa), epidermal growth factor receptor (EGFR), human epithelial growth factor receptor 2 (HER2) and nm23 in tumor tissues from 90 patients with ovarian cancer. All underwent bone marrow (BM) aspiration and screening for disseminated tumor cells in the bone marrow (DTC-BM) at primary diagnosis. BM aspiration, cytospin preparation, and immunocytochemical staining with the anticytokeratin antibody (A45-B/B3) were done following a standardized protocol. The expression of p53, KI67, Top IIa, EGFR, HER2, and nm23 was evaluated by immunohistochemistry on paraffin-embedded tissue samples and classified by percentage of stained cells or immunoreactive score (IRS). The prognostic impact of the individual factors together with standard histologic parameters was calculated by univariate and multivariate analyses. Expression rates for HER2 (2+/3+: 34.5%), KI67 (median 30%), p53 (median IRS 5), and Top IIa (median IRS 4) were relatively high, whereas nm23 (median IRS 2) and EGFR (IRS 0: 61%) showed weak staining. In 21/90 patients (23.3%), DTC-BM (>/=1/2 x 10(6) cells) could be detected. The presence of DTC-BM was inversely related to nodal status (P = .015) but not to the other factors examined. Tumor stage (P = .02), lymph node involvement (P = .003), grade (P = .046), postoperative tumor residue (P < .001), peritoneal seeding (P = .02), and KI67 (P = .046) significantly correlated with overall survival (OS) after a median observation time of 28 months (2-105). The finding of ascites was borderline significant (P = .050). The presence of DTC-BM (P = .04) and KI67 positivity (P = .02) predicted reduced distant disease-free survival. By multivariate analysis, postoperative tumor residue remained an independent factor for OS (P = .02, relative risk = 4.6). As a primarily locoregional disease, tumor stage and postoperative tumor residue are the main determinants of prognosis in patients with ovarian cancer. However, even in advanced stages, examination of tumor biological factors could help to stratify subgroups of patients and establish targeted therapies.

[Minimizing operative morbidity. Sentinel-lymphonodectomy in vulvar cancer -- quo vadis?]. / Minimierung der Operationsmorbidität. Die Sentinel-Lymphonodektomie beim Vulvakarzinom -- Quo vadis?

Complete groin dissection is established in the operative standard procedure in treatment of vulvar carcinoma. For lateral localized carcinomas without node metastases only ipsilateral dissection is necessary. But in early tumor stages most of the patients are node negative and no oncologic benefit can be postulated although operative morbidity is high. Only for carcinomas with depth of infiltration less than 1 mm it is possible to avoid groin dissection. Studies demonstrate that clinical and apparative diagnostic procedures do not predict lymph node involvement accurately. Thus the concept of sentinel-lymphonodectomy has been evaluated in the last years in vulvar carcinoma. With > 95 % detection rate was very high and false negative cases have been reported only very rarely. Because results with the first patients in Germany showed similar results the AGO developed a concept for an observational study which will avoid complete groin dissection in sentinel node negative T1-T2N0 vulvar carcinoma. Before participation is possible e learning phase has to be completed. Exact control of the patients should look for reduction of operative morbidity with equivalent oncologic effectiveness.

Prognostic factors that predict pelvic lymph node metastasis from endometrial carcinoma.

BACKGROUND: Recent reports indicate that certain pre- and intraoperatively determined risk factors are predictive of pelvic lymph node metastases from endometrial cancer, allowing selective pelvic lymph node dissection. The objective of this study was to evaluate the accuracy of pre-, pre-/intra- and postoperatively determined tumor characteristics. METHODS: The study is based on 100 patients treated from 1987-1991 with total abdominal hysterectomy and bilateral salpingo-oophorectomy. In all patients thorough pelvic lymphadenectomies were performed (no sampling). These patients were evaluated according to different macroscopic and histologic tumor characteristics retrospectively in a blind fashion (the lymph node status was later determined separately). Multivariate analysis was applied and the results were compared using receiver operator characteristic curves. In 15 of 100 patients, pelvic lymph node metastases could be histologically demonstrated. RESULTS: Multivariate analysis of 22 tumor characteristics identified the following as being independent in relation to pelvic lymph node metastases: preoperatively determined characteristics: serous papillary tumor type, invasion of myometrium, and histologic grade (Christopherson); pre-/intraoperatively: serous papillary type, histologic grade (Christopherson), and cervical involvement; and postoperatively: lymphangiosis carcinomatosa and hemangiosis carcinomatosa. Receiver operator characteristic curves show that for pelvic node metastases the postoperatively determined histologic findings are more predictive than all other factors that can be evaluated pre- and/or intraoperatively. CONCLUSION: Pre- and intraoperative tumor characteristics can determine the individual risk for pelvic lymph node involvement, but additional studies addressing the therapeutic value of pelvic lymphadenectomy would be necessary to define a probability threshold for lymphadenectomy in a decision analysis.

Reliability of tumor typing of endometrial carcinoma in prehysterectomy curettage.

The aim of this study was to determine the sensitivity and the specificity of tumor typing in the prehysterectomy curettage in order to assess the diagnostic accuracy in patients with endometrial cancer. Tumor typing was performed on complete prehysterectomy curettages of 154 patients with endometrial cancer treated during 1987-1991. The results were compared with the histologic findings of the hysterectomy specimen as the gold standard. Patients with no carcinoma demonstrable postoperatively in the removed uterus were excluded from the study. Tumor typing on prehysterectomy curettage revealed only a moderate sensitivity of 46-64%. In contrast, the specificity was > 90% for all histologic subtypes with the exception of the endometrioid tumor type (68%). The histologic subtypes (papillary, adenocarcinoma with squamous differentiation, mucinous, serous papillary, clear cell) achieved similar high predictive values despite a much lower prevalence due to the high values of specificity. Tumor typing of endometrial carcinoma based upon the findings of the prehysterectomy curettage reveals different reliabilities depending on the tumor type.

Prognostic relevance of immunohistology, tumor size and vascular space involvement in axillary node negative breast cancer.

OBJECTIVE: Adjuvant treatment for patients with axillary node negative (ANN) breast cancer is controversial because operation alone gives a 70% cure rate. Features which predict recurrence are needed and we therefore evaluated the predictive value of tumor diameter and vascular involvement as well as of estrogen receptors (ER), progesterone receptors (PR), p53, MIB-1, c-erb and PCNA demonstrated by immunohistological staining in 178 patients with ANN breast cancer. Although ER status, tumor diameter and vascular space involvement were significantly correlated to the development of recurrence, their sensitivity, specificity and predictive value were too low to give them clinical value.

Tumor proliferation in squamous cell carcinoma of the vulva.

Tumor proliferation is of important prognostic significance for several neoplasms. The very few previous studies on this parameter in vulvar carcinoma have shown contradictory results. The aim of this study was to determine the prognostic significance of tumor proliferation in vulvar carcinoma. Paraffin-embedded tissue of 74 squamous cell carcinomas of the vulva was immunostained for MIB-1, detecting Ki-67, and analyzed for staining patterns and the percentage of positive cells. There were three general staining patterns: a diffuse distribution (diffuse type), a localized staining at the infiltrating tumor border (infiltrating type), and a localized staining in basal parts of infiltrating tumor cell aggregates (basal type). The percentage of positive cells was not correlated with morphologic or clinical parameters, nor was it correlated with disease-free and overall survival. MIB-1 staining types were correlated with tumor type and grading. Tumors of diffuse and infiltrating type seemed to have more frequent lymph node metastasis (p = 0.053) and shorter disease-free survival (p = 0.076). In these tumors, overall survival time was reduced significantly (p = 0.02). In multivariate analysis, MIB-1 staining types were the most important factor for overall survival with an odds ratio of 4.73. In conclusion, distribution and not the percentage of proliferating cells is of prognostic significance in squamous cell carcinoma of the vulva.

Successful treatment of malignant placental site trophoblastic tumor with combined cytostatic-surgical approach: case report and review of literature.

OBJECTIVE: Although rare among gestational trophoblastic diseases, the clinical relevance of malignant placental site trophoblastic tumor (PSTT) derives from its potential malignancy associated with early systemic tumor cell dissemination and manifestation of fatal metastases. Because of the low number of cases reported so far worldwide, several treatment strategies have been under consideration, which will be debated following this case report. METHOD: We present the case of a 33-year-old female with PSTT and metastases to the vagina and lung. A 9-month delay in accurate diagnosis was caused by a misinterpretation of her symptoms as signs of a spontaneous abortion. Specialized pathological examination finally led to the diagnosis of PSTT. Primary surgical treatment consisting of abdominal hysterectomy and unilateral salpingo-oophorectomy was followed by multiple resections of recurrent vaginal disease. After the completion of six cycles of EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) chemotherapy, hCG titers stayed within the normal range. The patient is without evidence of disease 39 months after primary diagnosis. RESULT: This is the third case of documented long-term remission (>1 year) in metastatic PSTT after combined cryostatic-surgical treatment. CONCLUSION: Since the few previously reported cases with prolonged remission have been treated with the described combined cytostatic-surgical approach consisting of cytoreductive surgery and adjuvant chemotherapy, this approach may be recommended for metastatic PSTT.

The cellular immune response against Yersinia enterocolitica in different inbred strains of mice: evidence for an important role of T lymphocytes.

Resistance of mice against infection with Yersinia enterocolitica has been shown to be related neither to the Ity locus coding for resistance against infection with Salmonella typhimurium and other pathogens nor to the H-2 locus. From other mouse infection models, e.g., murine leishmaniasis, there is evidence that a different T cell-dependent regulation of the host immune response in various inbred strains of mice determines the susceptibility to the infectious agent. However, until recently, little was known about the cellular immune response against Y. enterocolitica. Thus, in a first approach we used the highly virulent Y. enterocolitica strain WA of serotype O:8 and different inbred strains of mice (C57 BL/6, Balb/c and athymic T cell-deficient C57 BL/6 nude mice) to investigate the cell-mediated immunity against parenteral infection. Comparison of the median lethal dose and of the net-bacterial growth in the spleens of infected mice indicated that Balb/c mice could be considered as Yersinia-susceptible whereas C57 BL/6 mice were relatively resistant. However, in contrast to normal C57 BL/6, athymic T cell-deficient C57 BL/6 nude mice have proved to be highly susceptible to Yersinia infection suggesting that T cells are required for the elimination of the pathogen. This conclusion was supported by histomorphological and immunohistological results indicating that T lymphocytes were present in Yersinia-induced tissue lesions. Moreover, the adoptive transfer of Yersinia-specific T cell lines and clones into naive animals mediated significant protection against the pathogen in both Yersinia-resistant C57 BL/6 and in Yersinia-susceptible Balb/c mice. These findings emphasize an important role of T lymphocytes in the host response against Y. enterocolitica infection.

[Progress in the early diagnosis of breast carcinoma during the years 1981-1990. Results of a longitudinal study]. / Fortschritte in der Früherkennung des Mammakarzinoms in den Jahren 1981-1990. Ergebnisse einer Longitudinalstudie.

BACKGROUND AND OBJECTIVE: Current meta-analyses have left in doubt whether general breast screening increases survival rate. This study investigated whether efforts at early diagnosis of cancer in the 1980s have had an effect on average tumor size at first diagnosis and on survival rate. PATIENTS AND METHODS: From 1981 to 1990, 1656 consecutive patients (average age 56.6 years) at the I. Women's Clinic at the Ludwig-Maximilian University of Munich and the Women's Clinic Berlin-Charlottenburg were operated on for primary breast cancer. In a retrospective analysis, average tumor size at the primary operation and survival rate were determined for two periods: 1981-1985 (n=849) and 1986-1990. Mean follow-up time was 63 months. RESULTS: There was no difference between the two cohorts regarding age (p = 0.77) and axillary node status (p = 0.14). During the follow-up period there was a gradual decrease in the tumor size at first diagnosis. (Pearson's correlation coefficient: -0.79, p < 0.001). Average tumor size in those operated on was 25 mm up to 1985, and 21 mm after 1986 (p < 0.001). Until 1985, the initial reason for mammography was the planned subsequent operation in 19% of patients (n = 164), and in 27% (n = 215; p < 0.001) since 1986. But there was no statistically significant rise in disease-specific survival rate (log rank, p=0.48). Multivariate analysis confirmed the conventional prognostic parameters, such as tumor size (relative risk 2.21) and axillary lymph node metastases (relative risk 3.57), but not the period of follow-up (p=0.90). CONCLUSION: During the stated periods of follow-up there was a significant decrease in average tumor size at initial diagnosis. But this did not result in any demonstrably better disease-specific survival rate.

Mutations and amplification of oncogenes in endometrial cancer.

Alterations in oncogenes are critical steps in the development of endometrial cancer. To investigate the potential clinical relevance of the amplification of the oncogenes c-erbB2, c-myc, and int-2 and the mutation of K-ras in endometrial cancer, 112 tumors were examined using PCR-based fluorescent DNA technology. Amplification of the three oncogenes and the mutation of K-ras were correlated with age, tumor size, lymph node status, metastases, stage, histological types, grade, steroid hormone receptor expression (estrogen receptor, ER; progesterone receptor, PgR), family history of cancer, previous history of cancer or precursor lesions, and previous history of hormone replacement therapy. Oncogene amplification of c-erbB2 was detected in 18.9%, of c-myc in 2.7% and of int-2 in 4.2%, and K-ras mutation in 11.6%. No significant correlations could be detected between amplification of c-erbB2 and any of the other parameters. Mutation of K-ras is associated with positive expression of PgR. This might indicate that mutation and activation of K-ras are involved in the development of hormonal independence in endometrial cancer.

The fate and prognostic value of occult metastatic cells in the bone marrow of patients with breast carcinoma between primary treatment and recurrence.

BACKGROUND: The current study examines the fate of occult metastatic cells detected in bone marrow (BM) at primary diagnosis and evaluates whether persistently positive findings support the prognostic influence of these cells in patients with Stage I--III (International Union Against Cancer) breast carcinoma. METHODS: The authors analyzed BM aspirates, at the time of primary diagnosis and after a median interval of 19 months (range, 7--67 months), from 89 patients who were free of recurrence. The presence of cytokeratin (CK) positive cells was assessed with the monoclonal anti-CK antibody A45-B/B3. Patients were observed prospectively for a median of 41 (range, 12--78) months after the first aspiration. RESULTS: At the time of primary diagnosis, 24 of 89 patients (27%) presented with occult metastatic cells in the BM. Of the same 89 patients, 25 (28%) had a positive BM finding at the time of the second BM analysis. Among those patients with an initially negative BM finding, 15 patients (17%) had occult metastatic cells at time of the second BM aspiration, whereas 10 patients (11%) had a persistently positive BM finding. Patients with a persistently negative BM status (n = 50) had a significantly better overall survival than patients with a positive BM status at the time of the second BM aspiration (n = 25), both by univariate analysis (P = 0.045, log-rank) and multivariate analysis (P = 0.034, Cox regression). CONCLUSIONS: In many patients with primary breast carcinoma, minimal residual disease can be detected by follow-up examination of the BM. This finding is prognostically relevant and provides reason to include BM monitoring in future clinical trials.