Multiparametric prognostic evaluation of biological factors in primary breast cancer.

BACKGROUND: An array of biological features related to tumor cell differentiation status, growth rate, and invasive potential have been identified as potential prognostic factors in breast cancer. We were interested in determining their relative importance in predicting patient survival. PURPOSE: We evaluated the relative weight of the following four biological factors in predicting survival of patients with breast cancer: tumor cell DNA content (determined by flow cytometry), tumor cell proliferation rate (determined by thymidine kinase activity), expression levels of cathepsin D and urokinase plasminogen activator, and several "classical" clinical and histological factors. METHODS: Selected from a prospectively updated database, the study population consisted of 319 primary breast cancer patients who received treatment and follow-up care (median, 6 years) in the Centre René Huguenin. To determine the profile of biological factors for each patient, we used frozen tumor specimens and (except for the flow cytometric DNA content assay) commercially available assay kits. We determined by Cox multivariate analysis the relationships of the biological factors to each other, to classical prognostic factors, and to disease-free and metastasis-free survival. RESULTS: In the overall population, disease-free survival was best predicted by node status (P = .004), clinical tumor size (P = .02), and cathepsin D expression (P = .01), whereas metastasis-free survival was best predicted by node status (P = .0004), clinical tumor size (P = .009), and urokinase plasminogen activator expression (P = .04). In node-negative patients, thymidine kinase activity was the only factor selected for disease-free (P = .04) and metastasis-free (P = .05) survival. In node-positive patients, the number of positive axillary lymph nodes was the only factor selected for disease-free (P = .0008) and metastasis-free (P = .00017) survival. CONCLUSIONS: Our retrospective analysis has identified protease expression and tumor cell proliferation rate as important biological prognostic factors in breast cancer. Prospective clinical trials should be undertaken to confirm these results.

Characterization and distribution in normal and tumoral human tissues of breast cancer-associated antigen defined by monoclonal antibody 7B10.

Monoclonal antibody 7B10, raised against the human breast cancer cell line T47D, identifies an antigen found in human breast carcinomas and in normal breast. Western blot and immunoprecipitation studies detected a Mr 76,000 antigen in cytosol, cell membrane, and cell culture supernatants of T47D cells. 7B10 binding to T47D cell extracts was affected by proteolytic digestion with protease type VI, trypsin, and subtilisin while it was not altered by neuraminidase digestion. Adsorption of breast cancer cell line extracts with concanavalin A reduced 7B10 immunoreactivity more than 70%. These results suggest that the antigen is a glycoprotein and that the epitope does not contain sialic acid. 7B10 was reactive with neither human milk fat globule membrane, nor skimmed milk, nor the milk-derived HBL 100 cell line. Conversely binding was detected in more than 50% of normal breast epithelial cells in culture. 7B10 immunostaining was positive on frozen sections of normal breast and nonmalignant mastopathies in 30 to 90% cells. In frozen sections of other normal tissues, 7B10 immunoreactivity was detected only in colon, apocrine glands of skin, parotid ducts, and luteal phase endometrium, confirming previous data on paraffin sections. Strong, homogeneous immunostaining was observed on frozen sections of intraductal and invasive lobular breast carcinomas (100% of cases), while more heterogeneous staining was found on invasive ductal carcinomas. Colon and rectal carcinomas, one carcinoma of the esophagus, and some cells in serous ovarian carcinomas also showed 7B10 reactivity. Immunoblotting of the 7B10-immunoreactive fraction isolated by Sepharose CL-6B chromatography of a breast carcinoma tissue sample extract identified the Mr 76,000 antigen, which was also detected in several breast cancer specimens, in colon adenocarcinomas, and in serous ovarian carcinoma fresh tumor extracts. The Mr 76,000 glycoprotein described here represents a breast cancer-associated antigen previously undescribed, mainly expressed in normal breast and breast tumors.

Prognostic index for clinical Stage I cutaneous malignant melanoma.

Thirteen variables were evaluated for their significance in predicting the survival of 148 patients in a retrospective study with clinical Stage I cutaneous malignant melanoma. The variables studied were histological type, tumor thickness, level of invasion, mitotic activity, pigmentation type, existence of ulceration, presence of lymphocytic infiltration, cell type, sex and age of the patient, site of melanoma, and wide local excision preceded or not by contact radiotherapy and associated or not with lymphadenectomy. When these variables were individualized, only seven were significantly related to survival: histological type; tumor thickness; level of invasion; mitotic activity; pigmentation type; existence of ulceration; and sex of the patient. Multivariate analysis based on Breslow's version of the Cox proportional-hazards model was performed on a group of 110 patients. This analysis demonstrated that 5 of the original 13 variables (i.e., mitotic activity, tumor thickness, sex, lymphadenectomy, and site of primary melanoma) could be used to develop a prognostic model. A Gompertz distribution which provided for an appropriate smoothing of the Breslow model estimates was used to derive a simple prognostic index and to predict the survival of individual patients. Fifty-four patients in a prospective study were subsequently evaluated with the Gompertz model in order to test the prognostic accuracy of the model for the five variables.

Identification of CGA as a novel estrogen receptor-responsive gene in breast cancer: an outstanding candidate marker to predict the response to endocrine therapy.

The estrogen receptor (ER) status of breast tumors is used to identify patients who may respond to endocrine agents such as tamoxifen. However, ER status alone is not perfectly predictive, and there is a pressing need for more reliable markers of endocrine responsiveness. Here, we identified the well-known CGA gene (coding for the alpha subunit of glycoprotein hormones) as a new ERalpha-responsive gene in human breast cancer cells. We used a real-time quantitative reverse transcription-PCR assay to quantify CGA mRNA copy numbers in a large series of breast tumors. CGA overexpression (> 10 SD above the mean for normal breast tissues) was observed in 44 of 131 (33.6%) breast tumor RNAs, ranging from 20 to 16,500 times the level in normal breast tissues; the highest levels of CGA gene expression were close to those observed in placenta. Significant links were observed between CGA gene overexpression and Scarff-Bloom-Richardson histopathological grade I+II (P = 0.015), and progesterone (P = 0.0009) and estrogen (P < 10(-7)) receptor positivity, which suggested that CGA is a marker of low tumor aggressiveness. We observed CGA mRNA overexpression in 44 of 90 (48.9%) ERalpha-positive tumors and in none of the 41 ERalpha-negative tumors. Immunohistochemical studies demonstrated that human chorionic gonadotropin alpha protein was strictly limited to ERalpha-positive tumor cells. Overexpression of the CGA gene was not accompanied by overexpression of the CGB gene. Our results also suggest that CGA could be a more reliable marker than PS2 and PR for ERalpha functionality and, thus, for endocrine responsiveness. Moreover, the CGA marker has the added value of dichotomizing ERalpha-positive patients into two subgroups of similar size. Specific antibodies directed to secreted human chorionic gonadotropin alpha protein are commercially available, thus facilitating the future application of this marker to the clinical management of breast cancer.

Prognostic value of c-myc proto-oncogene overexpression in early invasive carcinoma of the cervix.

The prognostic effect of c-myc oncogene overexpression was assessed in a multivariate analysis of 93 patients with invasive carcinoma of the cervix, stage Ib, IIa, and IIb proximal. The treatment was based on the association of brachytherapy-colpohysterectomy and lymphadenectomy. Analysis of c-myc gene expression was done using Northern and slot blot hybridization techniques. Overexpression of c-myc (ie, levels at least three times the mean observed in normal tissues) was present in 33% of the tumors. The proportion of carcinomas with c-myc overexpression significantly increased with the size of the primary tumor (P = .04). No relationship was found between c-myc overexpression and the other clinical and histologic parameters, including the nodal status. The relative risk of relapse (overall, pelvic failure, distant metastases) was analyzed in a Cox's proportional hazards model. Three factors were significantly related to the risk of overall relapse when the multivariate analysis was performed, namely, the tumor size, the nodal status, and c-myc expression. A combination of c-myc expression and the nodal status provided a very accurate indication of the risk of relapse. Indeed, patients with negative nodes had a 3-year disease-free survival rate of 93% (95% confidence interval [Cl], 79% to 98%) when c-myc was expressed at a normal level, whereas this rate was only 51% (95% Cl, 26% to 63%) when c-myc was overexpressed (log-rank test, P = .02). In addition, in the subgroup of patients with positive nodes, this rate was 44% (95% Cl, 25% to 77%) and 15% (95% Cl, 4% to 49%) when c-myc gene was expressed at normal level, or overexpressed, respectively. Finally, c-myc gene overexpression was, in the multivariate analysis, the first factor selected by the model regarding the risk of distant metastases.

Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma.

PURPOSE: Several histologic grading systems have been validated in soft tissue sarcomas (STS), but no system is currently accepted worldwide. The National Cancer Institute (NCI) and French Federation of Cancer Centers Sarcoma Group (FNCLCC) systems were examined comparatively in the same population of patients with STS to determine which system is the best prognosticator with regard to metastasis development and tumor mortality. PATIENTS AND METHODS: Four hundred ten adult patients with nonmetastatic STS were examined. Histologic grade was established according to the NCI and FNCLCC systems in each case. The prognostic value of both systems was examined using univariate and multivariate (Cox's model) analyses, and special attention was devoted to tumors with discordant grades. RESULTS: In univariate analysis, both the NCI and FNCLCC systems were of prognostic value to predict metastasis development and tumor mortality. In multivariate analysis, high-grade tumors, irrespective of the system used, size > or = 10 cm, and deep location were found to be independent prognostic factors for the advent of metastases. Tumor grade had a higher predictive value than size or depth, and higher prognostic weight was assigned to the FNCLCC grading system in Cox models. Grade discrepancies were observed in 34.6% of the cases. An increased number of grade 3 STS, a reduced number of grade 2 STS, and a better correlation with overall and metastasis-free survival within subpopulations with discordant grades were observed in favor of the FNCLCC system. CONCLUSION: The FNCLCC system showed slightly increased ability to predict distant metastasis development and tumor mortality. The use of this system to evaluate STS aggressiveness might be favored.

Prognostic factors in localized primary synovial sarcoma: a multicenter study of 128 adult patients.

PURPOSE: To identify most significant and therapeutically relevant prognostic factors in adults with localized primary synovial sarcomas (SS) and to confirm the usefulness of the French Federation of Cancer Centers (FNCLCC) grading system, the prognostic impact of which has been already proven in soft tissue sarcomas. PATIENTS AND METHODS: Data on 128 patients with nonmetastatic SS collected from a cooperative database by the FNCLCC Sarcoma Group between 1980 and 1994 were studied retrospectively. Immunohistochemistry was performed at diagnosis in 77 cases (61%). The tumors were classified as biphasic (n = 45), monophasic fibrous (n = 72), and poorly differentiated (n = 10) subtypes. Histologic grade was determined according to the FNCLCC method, and vascular invasion was assessed in every case. RESULTS: The 5-year disease-specific survival (DSS) rate for this series of patients with localized SS was 62.9% (+/- 9.6% [SD]) with a median follow-up time of 37 months (range, 8 to 141 months). In multivariate analysis, the adverse risk factors associated with decreased DSS were International Union Against Cancer/American Joint Committee on Cancer stage III/IVA disease, male sex, and truncal tumor locations. For metastasis-free survival (MFS), disease stage III/IVA, tumor necrosis, and monophasic subtypes were the major factors associated with a less favorable prognosis. Separately, when not using disease stage, tumor necrosis, and mitotic activity, histologic grade became the most significant prognostic factor for both DSS and MFS. In addition, larger tumors and older patients become associated with a significantly worse prognosis. Independent adverse risk factors for local recurrence-free survival included histologic grade 3 and truncal tumor location. CONCLUSION: These data confirm that not all SS present the same severe outcome. High-risk patients identified on the basis of these parameters may qualify for an aggressive treatment approach.

Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group.

PURPOSE: To define the prognostic factors in adult patients with locally controlled soft tissue sarcoma (STS) and to determine which patients should be considered for adjuvant treatment. PATIENTS AND METHODS: Five hundred forty-six patients with a nonmetastatic and locally controlled STS, collected in a cooperative data base by the French Federation of Cancer Centers (FNCLCC) Sarcoma Group from 1980 and 1989, were studied. Histologic slides of all patients were collegially reviewed. Initial treatment consisted of complete tumor resection with amputation in only 4% of the patients. Adjuvant radiotherapy was administered to 57.9% and adjuvant chemotherapy to 31%. Relationships between tumor characteristics were analyzed, and univariate and multivariate analyses were performed using Cox models for the hazards rate of tumor mortality, development of distant metastasis, and strictly local recurrence. RESULTS: Unfavorable characteristics with an independent prognostic value for tumor mortality were: grade 3 (P = 3 x 10(-10)), male sex (P = 1.5 x 10(-5)), no adjuvant chemotherapy (P = 5.4 x 10(-5)), tumor size > or = 5 cm (P = 3.8 x 10(-3)), and deep location (P = 4.6 x 10(-3)). Unfavorable characteristics for the development of distant metastasis were: grade 3 (P = 4 x 10(-12)), no adjuvant chemotherapy (P = 6.4 x 10(-4)), tumor size > or = 10 cm (P = 9.8 x 10(-4)), and deep location (P = 1.3 x 10(-3)). For the development of local recurrence, the unfavorable characteristics were: no adjuvant radiotherapy (P = 3.6 x 10(-6)), poor surgery (local excision) (P = 2 x 10(-4)), grade 3 (P = 7.6 x 10(-4)), and deep location (P = 10(-2)). Grade, depth, and tumor size were used to define groups of patients according to the metastatic risk. Adjuvant chemotherapy was beneficial in terms of overall survival and metastasis-free survival in grade 3 tumor patients only. Despite worse characteristics concerning tumor depth, tumor-node-metastasis (TNM) and American Joint Committee (AJC)/International Union Against Cancer (UICC) classifications and grade in patients with adjuvant radiotherapy, the latter experienced significantly fewer local recurrences than patients with no radiotherapy. CONCLUSION: Grade, tumor depth, and tumor size could be used to select patients with a high metastatic risk, for which adjuvant chemotherapy could be beneficial.

Relationship between c-erbB-2 and other tumor characteristics in breast cancer prognosis.

The aim of this study was to evaluate c-erbB-2 overexpression by means of a quantitative biochemical technique in 488 primary breast cancer patients with long-term follow-up (median, 10 years) and its relation to other biochemical prognostic factors (uPA, p53, and epidermal growth factor receptor) and adjuvant therapy. High levels of c-erbB-2 (>500 IU/mg protein) were associated with estrogen receptor (ER) and progesterone receptor negativity, high histoprognostic SBR grade and high levels of uPA and p53. Univariate analyses showed shorter metastasis-free survival (MFS) and overall survival (OS) in patients whose tumors overexpressed c-erbB-2 in the overall population, in subgroups defined by ER and uPA status, and in patients with positive pathological nodal status, SBR grade II, progesterone receptor, and p53-negative tumors. Patients with ER-positive, c-erbB-2-positive tumors had a shorter MFS and OS than those patients with c-erbB-2-negative tumors. No difference was observed between adjuvant-treated and untreated patients (chemotherapy and/or hormone therapy) in the c-erbB-2-negative subgroup. There was a trend toward a longer short-term MFS in c-erbB-2-positive patients treated with chemotherapy, whereas an opposite effect was observed with hormone therapy. Cox multivariate analyses showed that high levels of c-erbB-2 negatively influenced MFS in the overall population as well as in node-positive patients and in tamoxifen-treated patients, along with pN and uPA. Results for OS were comparable with those obtained for MFS. These results suggest that c-erbB-2 overexpression in breast cancer may be a better predictor of the response to tamoxifen than is ER status alone.

Angiosarcoma arising in a solitary schwannoma (neurilemoma) of the sciatic nerve.

Angiosarcomas rarely develop within a peripheral nerve or a peripheral nerve sheath tumor. We describe an epithelioid angiosarcoma that arose in a benign schwannoma (neurilemoma) of the right thigh in a 65-year-old man who did not have von Recklinghausen's disease. Histologically, the resected tumor was a high-grade undifferentiated sarcoma that was predominantly arranged in solid sheets or nests and composed of epithelioid cells. The endothelial origin of the tumor was suggested by Factor VIII R-ag, Ulex europaeus-I, CD34, CD31, BNH9, and vimentin immunoreactivity, along with the ultrastructural evidence of occasional Weibel-Palade bodies. In this location, epithelioid angiosarcoma should be distinguished from malignant transformation of a schwannoma with epithelioid changes. This observation stresses the importance of immunohistochemical and ultrastructural analysis in the differential diagnosis of vascular tumors with features of epithelioid sarcoma.

Detection of the synovial sarcoma translocation t(X;18) (SYT;SSX) in paraffin-embedded tissues using reverse transcriptase-polymerase chain reaction: a reliable and powerful diagnostic tool for pathologists. A molecular analysis of 221 mesenchymal tumors fixed in different fixatives.

Synovial sarcoma (SS) is a relatively rare sarcoma, which may be confused with several other mesenchymal and nonmesenchymal lesions. It bears the t(X;18) (SYT;SSX) translocation, which seems to be specific for this tumor type and can be detected in paraffin-embedded tissue, using reverse transcriptase-polymerase chain reaction (RT-PCR). However, the specificity and sensitivity of this detection method have rarely been examined in a large series. Using RT-PCR, we examined 250 mesenchymal and nonmesenchymal, benign and malignant, paraffin-embedded lesions for the SS t(X;18) (SYT-SSX) translocation. PCR products were obtained from 221 tumors (88.5%). There were 135 non-SS tumors, 22 biphasic, and 64 monophasic spindle/round cell SS, of which 10 were cytogenetically confirmed as t(X;18)-positive. SYT-SSX gene fusion transcripts were detected in the SS tumor category only (100% specificity), including 100% of the biphasic SS and 86% of monophasic spindle/round cell SS. Nine tumors originally diagnosed as SS were t(X;18) (SYT-SSX)-negative. Following reassessment, only 3 of these tumors showed clinicopathologic, immunohistochemical, and/or ultrastructural features consistent with that diagnosis, thus raising the overall detection sensitivity to 96%. With regard to the potential adverse effect of the fixatives used, PCR products were obtained in 100%, 91.5%, 90.5%, and 0% of tumors fixed with AFA, buffered formalin, Holland Bouin, and conventional Bouin's fluid, respectively. This study shows that the detection of the SS t(X;18) (SYT-SSX) in paraffin-embedded tissue is feasible with a 100% specificity and an overall 96% sensitivity, provided non-Bouin's fluid fixation is used.

Breast cyst fluid proteins and breast cancer.

A specific breast cyst fluid protein was purified by the following steps: ultracentrifugation, gel filtration, DEAE and Con A chromatography, and gel filtration with guanidine, 6 M. The protein was pure, having a molecular weight of 17,800 daltons on SDS-PAGE and 68,000 daltons on gel filtration. The GCDFP 17,800 is immunologically distinct from other breast cyst fluid components and known milk and plasma proteins. A specific radioimmunoassay was developed and used to determine GCDFP 17,800 in 158 samples of breast cancer cytosol. The GCDFP 17,800 levels were significantly different between grade I tumors (mean of 813 ng protein per mg +/- 430 SEM) and grade III tumors (mean 184 ng protein per mg +/- 59 SEM) and were correlated with progesterone receptor values in postmenopausal women (Spearman's correlation, p = 0.03) but not in premenopausal women. The value of GCDFP 17,800 did not differ between the pre- and the postmenopausal women. By immunocytochemistry the intracellular localization of the GCDFP 17,800 was also found in relation to tumor grading and in correlation with PR values. GCDFP 17,800 appears as a hormone-induced protein of the breast cells. Its intracellular detection by means of radiolabeling allows a more sensitive and precise evaluation of the hormone-dependence of the breast cancer cells and emphasizes the heterogeneity of the tumor cell population.

Comparison of enzyme immunoassay and immunohistochemical measurements of estrogen and progesterone receptors in breast cancer patients.

Before replacing enzyme immunoassay of estrogen and progesterone receptors by immunohistochemistry, results of both methods were compared on 437 samples obtained from breast cancer patients (342 primary breast carcinomas, 16 local recurrences, 49 biopsies, and 30 tumor specimens obtained after neoadjuvant treatment). Immunohistochemistry (IHC) results were first assessed semiquantitatively on the basis of the estimated proportion of positive tumor cells, and then quantitatively using the "quick score." Semiquantitative IHC hormone receptors results (positive > or = 10%) correlated well with enzyme immunoassay status (positive >15 fmol/mg protein) in 358 surgical samples (342 primary tumors and 16 recurrences), with overall concordance rates of 89.9% and 82.1%, respectively. Among the 100 discordant cases, a large intraductal carcinoma component was observed in 7 of 36 cases for estrogen receptor (ER) and 15 of 64 for progesterone receptor (PR). Thirty-five discordant cases also were observed near the cut-off values. Hormone receptor levels by enzyme immunoassay correlated strongly with the quantitative IHC "quick score." Whatever the method, hormone receptor status was associated with histologic grade (SBR) and tumor size, whereas age correlated strongly with ER positivity. Similar results were obtained for biopsy specimens and posttreatment samples. This comparison improved the reliability of the IHC technique, which is currently routinely used for ER and PR determination in the authors' institution.

[Human papillomaviruses in uterine cervix pathology: clinical implications, detection and type]. / Les papillomavirus humains (HPV) en pathologie cervicale utérine: implications cliniques, indications du typage.

Recently, intense interest has been focused on the relation between HPV infection and the precancerous and cancerous lesions of the uterine cervix, as documented in numerous publications on the subject. We carried out a prospective anatomoclinical study on 224 women (HPV positive) in the René Huguenin Centre, from April 1984 to December 1988. Among these patients, cytology, colposcopy and biopsy, where necessary, were performed, concurrently with the detection of HPV on cervical smears using a molecular hybridization method (G Orth). We analysed the anatomo-clinical results and propose practical implications, in taking the evolution of the patients into account. These patients were followed up and treated when necessary for cervical intra-epithelial neoplasia (CIN) or carcinoma, associated or unassociated with HPVs (oncogene in 70% of cases). 24% of the patients where infected by an HPV, without any lesion. This virus disappeared spontaneously during the follow-up period. It can be concluded therefore that HPV infection, even oncogene, does not necessarily carry on CIN. Among CIN 1-2, associated or unassociated with HPV, the adequate treatment cured the patients and the virus disappeared. In some cases, a simple follow-up showed spontaneous regression of the lesion and the virus--CIN 3 was removed when necessary with a systematic pathological examination of the endocervix and the surgical sample limits. In a few cases, the virus persisted without lesion. HPV infection did not modify our protocol in the invasive carcinoma. These observations are available in a Centre with a well-trained anatomo-clinical team. In our opinion, the major priority involved in the recognition of cervical HPV infection is to perform a more systematic colposcopy (even for normal smears with subtle atypia), allowing the detection of early precancerous lesion, clinically occult. On the other hand, the oncogene HPV notion has caused us to take more aggressive action regarding treatment of some CIN 1-2, but may not be of benefit to the patient. We remain convinced that the CIN, with or without HPV, or not oncogene with HPV, must only be treated based on the clinical extension and the pathological gravity of the lesions.

[Immunohistochemical determination of hormonal receptors on cell-blocks from fine-needle cytopunctures of breast carcinoma]. / Détermination des récepteurs hormonaux par immunohistochimie sur vytoblocs de cytoponctions des cancers du sein.

We assessed the reliability of hormonal receptors (HR) by means of immunohistochemisty (IHC) on cell blocks obtained from diagnostic fine-needle cytopunctures in a group of 142 primary breast carcinoma. The results were compared to biochemical assessment (EIA) on their corresponding tissue samples (118 surgical specimens and 24 core needle biopsies). Percentage of stained nuclei and a score incorporating the proportion and the intensity of positive nuclei were evaluated. A two-group classification (cutoff 10% of stained nuclei) was used to define HR status. Highly positive tumors (>= 50% of stained nuclei) were also individualized. Regarding HR status, concordance rate between immunostaining and biochemical assessment was 86.6% for ER and 76.8% for PR. Major discrepancies were found in 6.3% and 15.5% of cases for ER and PR, respectively. A good correlation was also observed between quantitative values obtained by the two methods (r = 0.69 for ER and 0.60 for PR). Discrepancies were mainly related to weak positive staining, values close to the respective cutoffs and when biochemical evaluation was performed on core needle biopsies. We conclude that IHC on cell blocks prepared from fine-needle cytopuncture specimens of breast carcinomas is useful as a routine procedure for hormonal receptor determination especially when planning neoadjuvant treatment.

[c-myc and c-Ha-ras proto-oncogenes in cervical cancer: prognostic value]. / Les proto-oncogènes c-myc et c-Ha-ras dans les cancers du col de l'utérus: intérêt pronostique.

The biological behaviour of invasive carcinoma of the uterine cervix is not always predictable. It is therefore important to establish new biological markers which could be useful in determining a more reliable prognosis. We have analyzed the c-Ha-ras and c-myc proto-oncogenes in a large series (154 cases) of cervical cancers at various clinical stages. Alterations of c-Ha-ras (deletion, mutation) and c-myc (amplification) were frequently observed in cervical cancers and were shown to be associated with tumor progression. Furthermore, c-myc overexpression, when detected in early cervical cancers, provides a means of identifying patients at high risk of early recurrence.

[Case report forum: the example of French sarcoma group multidisciplinary discussion tools. Sarcomes de la FNCLCC]. / Forum de discussion de cas clinique: exemple de la concertation pluridisciplinaire web du groupe Sarcomes de la FNCLCC.

Within the Rubis 4th framework of European project is led a pilot experiment of tools and services for health professionals in prospect for the Aquitanian healthcare network. The sarcoma group of the FNCLCC (47 people) uses on its web site a multidisciplinary dialogue with a specific discussion forum. This service allows the anonymous publication of a imaging clinical case and to start a take care discussion. 87 cases were published in 13 months involving 261 answers from February 1999 to February 2000. A case is published every 4 days on average and the deadlines for replies regularly drop (15 days in February 1999 down 1.1 day in February 2000). The cases are published either for a diagnosis or treatment request (30%) or for the physical preparation of meeting or for the continuous medical training (70%). There are many advantages in comparison with the other possibilities of discussion: availability, autonomy of publication, cost, number of experts participating. These NTIC services will be developing within the regional healthcare oncology networks and are already tested by other regional groups (Lymphoma) considering the simplicity of use, management and training of the functionality.

[Standards, Options and Recommendations (SOR) for drafting of anatomic and surgical pathology reports or cytopathology reports in oncology]. / Standards, Options et Recommandations (SOR) pour la rédaction d'un compte rendu d'anatomie et de cytologie pathologiques en cancérologie.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop practice guidelines according to the definitions of the Standards, Options and Recommendations project for the content of the anatomic and surgical pathology or cytopathology reports in field of oncology. METHODS: Data were identified either by searching on Medline or via members of the expert groups personal references lists. When the guidelines were defined, the document was submitted to 49 independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the drafting of the anatomic and surgical pathology or cytopathology reports in oncology are: 1) The reports must contain the identification of the pathologist, of the patient and of the specimen, a gross description for the surgical specimen, eventually a microscopic description, the diagnosis, all the elements essential for establishing the prognosis and for the clinical care, and a conclusion. 2) The reports could contain some comments. 3) The reports must be brief, precise, clear, homogeneous and ideally standardised, in order to be comprehensible for all the clinicians and the pathologists.

[Standards, options and recommendations: practice guidelines for difficult diagnosis in surgical pathology or cytopathology in cancer patients]. / Standards, options et recommandations: conduite a tenir devant une lésion de diagnostic anatomo-cyto-pathologique difficile en cancérologie.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993 is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for difficult diagnoses in surgical pathology or cytopathology in cancer patients. METHODS: Data were identified by searching Medline and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 71 independent reviewers. RESULTS: The main recommendations to prevent and reduce the number of difficult diagnoses in surgical pathology or cytopathology are: 1) The development of quality insurance programs with use of written procedures in each pathology laboratory (standard). 2) The knowledge of clinical data in order to explain surgical pathology or cytopathology results (standard). 3) The availability of complementary patient informations (radiologic data . . .) can be useful to explain surgical pathology or cytopathology results (option). The main recommendations to detect lesions associated with difficult diagnosis in surgical pathology or cytopathology are: 1) Tumor types known as potential difficult diagnosis in surgical pathology or cytopathology should be reviewed by a second pathologist. 2) The systematic second reviewing for every case is expensive but has to be done when the difficulty is know (sarcoma, lymphoma . . .) by experienced pathologists. The main recommendations to solve difficult diagnosis in surgical pathology or cytopathology are: 1) Block recuts, use of special techniques (immunocytohistochemistry and molecular biology), additional data from clinicians, second opinion by a local pathologist, or new specimen can be required for establishing the diagnosis (options). 2) Outside second opinion by expert pathologist has to be considered once the other steps did not allow to establish surgical or cytopathology diagnosis (recommendations, expert agreement).

Analysis of alterations adjacent to invasive vulvar carcinoma and their relationship with the associated carcinoma: a study of 67 cases.

A retrospective analysis of histological lesions adjacent to 67 invasive vulvar squamous cell carcinomas (SCC) was undertaken to analyse their nature, as well as their relationship to SCC. Patient age, clinical presentation and histological type of carcinoma, ISSVD classification of its adjacent lesions, disease-free and overall survival were reviewed. Severe undifferentiated vulvar intra-epithelial neoplasia (VIN3) was found in 19.4% of cases and vulvar lichen sclerosus (VLS) in 76.1% of cases. All VLS, except 2 cases, were associated with squamous cell hyperplasia (SCH), and a concomitant differentiated VIN was found in 76.6% of cases. Undifferentiated VIN3 was never associated with VLS. VLS was significantly associated with a keratinizing, well-differentiated SCC (98% of cases), while undifferentiated VIN3, was linked preferentially to 2 other types of SCC: in 77% of cases, a moderately-differentiated SCC with the same histological features as the so-called basaloid carcinoma and, in 23% of cases, a well-differentiated SCC with a variable extent of koilocytic atypia, similar to the so-called warty carcinoma. Carcinoma of the fourchette was more often associated with undifferentiated VIN3. Disease-free and overall survival were significantly better for carcinoma associated with undifferentiated VIN3 (p < 0.01 and p < 0.05, respectively). These findings suggest invasive vulvar SCC occurs on 2 distinct types of vulvar lesions: differentiated VIN and/or SCH associated with VLS and undifferentiated VIN3. Furthermore, the histological type of the carcinoma seems to differ according to adjacent lesions.