Study of the expression of Tn antigen in different types of human breast cancer cells using VVA-B4 lectin.

VVA-B4 lectin was used to investigate the differences in Tn antigen expression in tissues of different types of human breast cancer (benign lesions, carcinoma in situ, invasive carcinoma) and in normal tissues neighboring lobular carcinoma. Locations in which Tn antigen was expressed were identified using the avidin-biotin-peroxidase labeling system. Tissues collected during cosmetic procedures and classified as normal were completely negative, except for one case. Benign proliferative changes including fibroadenoma, apocrine and cylindrical metaplasia showed a very weak positive reaction, although strongly positive cells were also observed. The reaction in non-invasive cases of atypical hyperplasia was diversified depending on site. Intralobular hyperplasia was characterized by a particularly high percentage of labeled cells. A majority (up to 80%) of ductal and lobular carcinoma in situ showed very strong or moderate staining. In invasive cancers, there were conspicuous differences between stage of cancer development and tendency towards a decrease in intensely labeled cell count in the most advanced stages. In normal tissues in the direct neighborhood of carcinoma in situ, the cytoplasm of 40% of cells was strongly labeled. However, the findings for normal tissues in the close vicinity of invasive cancer were the most surprising, since there was either no or only very weak positive reaction. It can be concluded that glycosylation modifications during carcinogenesis, as demonstrated by the presence of Tn epitope, develop very early, before any destructive changes in proliferation/apoptosis or cell differentiation become discernible.

Leptin: a proliferative factor for breast cancer? Study on human ductal carcinoma.

Mammary adipose tissue is an important source of paracrine mitogens and anti-mitogens, including insulin-like growth factor, transforming growth factors, and cytokines (especially, TNFalpha and IL-1beta). Nevertheless, it is also an important source of the adipocytokine, leptin. Recently, leptin was reported to stimulate the proliferation of various cell types (pancreatic beta cells, prostate, colorectal, lung, etc.) as a new growth factor. It was also shown to stimulate the proliferation of breast cancer cell lines. In this study, we conducted an immunohistochemical analysis of leptin expression in normal tissue and benign and malignant ductal breast cell, representing the different states of the invasion process. We determined for the first time that leptin is expressed both by ductal breast tumors and by benign lesions as atypical hyperplasia. This suggests that leptin may be taken up or synthesized by all modified ductal breast cells, and may prove a proliferative factor. Moreover, leptin is unexpressed by normal tissue in the healthy breast but is exhibited by the normal tissue in near vicinity of the malignant ductal breast lesions. We also postulated that leptin may be a prognostic or diagnostic factor for ductal breast cancer. These putative hypotheses require further study.

The meaning and predictivity of Hürthle cells in fine needle aspiration cytology for thyroid nodular disease.

AIMS: The significance of Hürthle cells in thyroid nodule fine needle aspiration cytology (FNAC) samples remains uncertain. This study aims to clarify the meaning and the predictivity of this kind of cells. METHODS: One hundred and ten patients with Hürthle cells in FNAC of thyroid nodules were reviewed. Histopathology was correlated with cytological findings. RESULTS: The density of Hürthle cells in FNACs ranged from 20 to 100%. Eighty-nine patients had benign nodular disease (Hürthle cell or follicular adenoma), and 21 patients had malignant tumours. The presence of more than 50% Hürthle cells in FNAC correlated with benign or malignant Hürthle cell neoplasm. Hürthle cell carcinomas displayed more than 90% Hürthle cells in FNAC. CONCLUSIONS: Surgery is indicated for all nodular lesions with more than 50% Hürthle cells in FNAC.

Is Nottingham prognostic index useful after induction chemotherapy in operable breast cancer?

The Nottingham prognostic index (NPI), based on tumour size in breast, node involvement and Scarff-Bloom-Richardson (SBR) grading, has been shown to constitute a definitive prognostic factor of primary operable breast cancer in the adjuvant setting. We performed a retrospective study to evaluate the prognostic value of this index in 163 patients after neoadjuvant chemotherapy. Secondly, we examined the influence on survival of a revised NPI, only based on residual tumour size in breast and SBR grading in 228 patients, and consequently called breast grading index (BGI). The prognostic value of these two indices was also evaluated by replacing the SBR grade with the MSBR grade, a French modified SBR grading; the modified NPI (MNPI) and modified BGI (MBGI) were, respectively, obtained in 153 and 222 patients. At a median follow-up of 9.3 years, survival was significantly related to these four indices (P<0.001). Multivariate analysis revealed that MBGI was the only one which retained a prognostic influence on disease-free survival (P<0.02). In conclusion, the 'amount' of residual tumour in breast and/or nodes, as defined by NPI and revised indices, confers a determinant prognosis after neoadjuvant chemotherapy, inviting an alternative postsurgical treatment for a subgroup of patients with a decreased survival.

[Mixed müllerian tumours of the endometrium. About four cases developed on tamoxifen treatment]. / Tumeurs mixtes müllériennes de l'endomètre. A propos de quatre cas développés sous tamoxifène.

We report four cases of mixed müllerian tumors of the endometrium arising in postmenopausal women taking tamoxifen for breast carcinoma. Various histopathologic features were encountered: one müllerian adenosarcoma and three malignant mixed müllerian tumors so called carcinosarcomas (in one case the sarcomatous component was homologous composed of tissues normally found in the uterus, while the others were heterologous because they were containing some elements normally not found in the uterus). Concern has been raised about prolonged tamoxifen treatment and subsequent occurrence of endometrial adenocarcinoma. Then, attention has been drawn through high-risk histologic subtypes including poorly differentiated patterns, uterine sarcomas and such mixed müllerian tumors. There is no consensus regarding internal surveillance of women receiving tamoxifen. The usefulness of pelvic sonography has not been demonstrated.

Prognostic significance of a complete pathological response after induction chemotherapy in operable breast cancer.

Only a few papers have been published concerning the incidence and outcome of patients with a pathological complete response after cytotoxic treatment in breast cancer. The purpose of this retrospective study was to assess the outcome of patients found to have a pathological complete response in both the breast and axillary lymph nodes after neoadjuvant chemotherapy for operable breast cancer. Our goal was also to determine whether the residual pathological size of the tumour in breast could be correlated with pathological node status. Between 1982 and 2000, 451 consecutive patients were registered into five prospective phase II trials. After six cycles, 396 patients underwent surgery with axillary dissection for 277 patients (69.9%). Pathological response was evaluated according to the Chevallier's classification. At a median follow-up of 8 years, survival was analysed as a function of pathological response. A pathological complete response rate was obtained in 60 patients (15.2%) after induction chemotherapy. Breast tumour persistence was significantly related to positive axillary nodes (P=5.10(-6)). At 15 years, overall survival and disease-free survival rates were significantly higher in the group who had a pathological complete response than in the group who had less than a pathological complete response (P=0.047 and P=0.024, respectively). In the absence of pathological complete response and furthermore when there is a notable remaining pathological disease, axillary dissection is still important to determine a major prognostic factor and subsequently, a second non cross resistant adjuvant regimen or high dose chemotherapy could lead to a survival benefit.

[Uterine sarcoma in patients receiving tamoxifen therapy. Apropos of 2 cases]. / Sarcome utérin survenant au cours d'une hormonothérapie par tamoxifène. A propos de deux cas.

INTRODUCTION: Tamoxifen--a non steroidal triphenylethyl compound--in addition to having antiestrogenic properties may provoke weak estrogenic effects, the well known "paradoxical effects" on the female genital tractus. Concern has been raised about prolonged tamoxifen treatment and subsequent occurrence of endometrial adenocarcinoma; subsequent attention has been drawn through high risk histologic subtypes including poorly differentiated patterns and uterine sarcomas. EXEGESIS: We report two cases of uterine sarcoma arising in postmenopausal women taking tamoxifen, 20 mg daily during 38 and 42 months, for breast carcinoma: one leiomyosarcoma and one endometrial stromal sarcoma; both cases were asymptomatic and detected by pelvic sonography. CONCLUSION: Further studies will be required to establish if there is a relationship between long term tamoxifen exposure and highly aggressive types of cancer of the uterine corpus exhibiting adverse histologic features such as uterine sarcomas. There is no consensus regarding uterine surveillance of women receiving tamoxifen. We advocate an annual gynecologic examination plus imaging by means of transvaginal ultrasonography.

[Stewart-Treves syndrome following mastectomy for breast cancer: a case report]. / Le syndrome de Stewart-Treves après mammectomie pour cancer du sein: un cas.

INTRODUCTION: Stewart-Treves syndrome has been defined by the eponymous authors as a lymphangiosarcoma in a setting of postmastectomy upper extremity lymphoedema. EXEGESIS: The clinical record of one patient with Stewart-Treves syndrome is analyzed. The primary angiosarcoma of the skin represented by a purple nodule occurred on a chronic lymphoedematous arm following radical mastectomy and axillary lymph node dissection for breast carcinoma performed 9 years earlier. Immunohistochemistry tests formally eliminated epithelial cutaneous metastasis and produced evidence in favour of conjunctive vascular tissue origin of the tumor. CONCLUSION: Conservative surgery for breast cancer, application of axillary sentinel node biopsy in the lymphatic staging and prevention of arm lymphoedema should reduce the incidence of this syndrome.

Localization of human BRCA1 and BRCA2 in non-inherited colorectal carcinomas and matched normal mucosas.

We characterized the expression of BRCA1 and BRCA2 in 38 sporadic colorectal carcinomas and matched normal mucosas with 9 anti-BRCA1 antibodies and 4 anti-BRCA2 antibodies, raised against several different epitopes, using immunohistochemical technique. We demonstrated an increased BRCA1 and BRCA2 staining in the apical cell pole of epithelial malignant cells and we also revealed a significant increase in BRCA1 and BRCA2 nuclear foci in tumor colorectal specimens in comparison with corresponding normal tissues. These increases in BRCA1 and BRCA2 expression may be explained by the fact that colorectal tissue is subject to very active proliferation and differentiation.

Cystemustine induces redifferentiation of primary tumors and confers protection against secondary tumor growth in a melanoma murine model.

N'-(2-Chloroethyl)-N-(2-(methylsulfonyl)-ethyl)-N'-nitrosourea (cystemustine) is a chloroethylnitrosourea that has been used in the treatment of human melanoma. Its main antitumor effect is DNA damage to malignant melanocytes. Although unreported at present, other effects may also account for its cytotoxicity, some of them could be more or less delayed with respect to its administration. In this report, we have developed a model of secondary tumor with B16 melanoma in syngeneic C57B16 recipients to investigate the impact of cystemustine treatment of primary B16 melanoma tumors on the fate of secondary implanted untreated tumors. The data presented in this report indicate that cystemustine-treated cells or the administration of cystemustine provoke an important growth delay of primary melanoma tumors, together with an increase in cell pigmentation and cell morphology changes. Data also show that prime treatment induces a dramatic decrease in tumor weight of secondary untreated tumors accompanied by an increase in melanin content and an alteration of cell morphology. Finally, 1H-NMR spectroscopy was performed on treated B16 cells, showing an alteration in the phospholipid derivatives of melanocytes, suggesting subsequent modifications of membrane phospholipid composition. In conclusion, the data highlight two important findings: (a) cystemustine produces modifications other than DNA damage, i.e., cell morphology changes, pigmentation, and phospholipid metabolism alterations, indicating an interference with cell cycle, cell redifferentiation, and proliferation programs; and (b) cystemustine-treated tumors appear to confer a protective effect against the development of secondary untreated tumors that may be mediated by cytokines or an immune response.

Joint scintigraphy in rabbits with 99mtc-N-[3-(triethylammonio)propyl]-15ane-N5, a new radiodiagnostic agent for articular cartilage imaging.

UNLABELLED: The aim of this study was to investigate joint scintigraphy in rabbits with 99mTc-N-[3-(triethylammonio)propyl]-15ane-N5 (NTP 15-5), a new radiopharmaceutical that specifically localizes in cartilaginous tissues. METHODS: Scans obtained after intravenous injection of the 99mTc-labeled compound in normal and arthropathy-induced rabbits were compared with those of the bone-imaging agent 99mTc-methylene diphosphonate (99mTc-MDP). RESULTS: The radioactive uptake of 99mTc-NTP 15-5 was detected in cartilaginous tissues 5 min after injection and was stable for 2 h. The uptake intensity was related to age and joint disease severity, and cartilage alterations not revealed by radiography induced a significant decrease of radiotracer uptake. On the other hand, imaging performed with 99mTc-MDP did not reveal the early changes in arthrosis but was more specific for bone remodeling in advanced stages of diseases or in inflammatory processes. CONCLUSION: Our results indicate that 99mTc-NTP 15-5 could be a good tracer for human arthrosic and arthritic cartilage detection, especially for the early diagnosis of joint diseases.

Brca1 and Brca2 protein expression patterns in different tissues of murine origin.

We have analyzed by immunohistochemistry Brca1 and Brca2 protein expression in mouse during embryonic development, in adult tissues, and during postnatal mammary gland development. Our observations confirm previous localization of Brca1 and Brca2 mRNA on frozen sections by in situ hybridization, and demonstrate that Brca1 and Brca2 proteins are expressed in rapidly proliferating cell types undergoing differentiation. These results imply that Brca1 and Brca2 proteins are involved in the process of proliferation and differentiation in multiple tissues, notably in the mammary gland during pregnancy and lactation.

[Breast cancer detected by a stellar opacity. Histologic characteristics: 155 cases]. / Cancers du sein révélés par une opacité stellaire. Caractéristiques histologiques: 155 cas.

UNLABELLED: Retrospective study (1985-1998) concerning surgical and histopathological features of 155 subclinical breast cancers revealed by spiculated opacity on screening mammograms. MATERIALS AND METHODS: The patients were 44-78 years old (mean age, 58.5 years), 129 were postmenopausal. Preoperative localization was stereotactic in 57 instances (36.5%), sonographic in 98 instances (63.5%). Maximum tumor diameter varied from four to 25 millimeters (mean diameter 11 mm), below 10 min in 97 cases, below 5 mm in 15 cases. Axillary lymph node dissection was performed immediately (95%) or secondarily (5%). RESULTS: Subclinical breast tumors exhibiting spiculated picture were infiltrating carcinomas: Infiltrating ductal carcinoma (IDC) in 130 cases (84%), infiltrating lobular carcinoma (ILC) in 25 cases (16%). Not any ductal carcinoma in situ (DCIS) was detected by such an irregular opacity. The grading according to Scarff-Bloom-Richardson was used in IDC: 95 grade I (73%), 31 grade II (24%), four grade III (3%). Hormone receptor status was obtained upon 145 tumors: both estrogen receptors were present in 125 cases (86%). Axillary lymph node involvement (N+) was found in ten cases (6%), always concerning IDC > 5 mm. Conservative surgery was achieved in mort cases (97%). DISCUSSION: Subclinical breast cancers revealed by spiculated opacity were predominantly corresponding to infiltrating process IDC or ILC, in contrast with breast cancers revealed by microcalcifications, mainly meaning DCIS. In our experience mammographically-detected spiculated malignant tumors were not bearing unfavourable pathological or biological features: they appeared commonly well differentiated and hormonosensitive, furthermore axillary lymph nodes were rarely involved.

[Assessment of different histoprognosis grading systems for primary ovarian cancer: 100 patients given the same treatment for primary ovarian adenocarcinoma]. / Travail original présenté lors de la Société Française d'oncologie gynécologique des 5 et 6 novembre 1999. Evaluation de différents systèmes de grade histopronostique des cancers ovariens primitifs. Série de cent patientes traitées de façon homogène pour un adénocarcinome ovarien primitif.

BACKGROUND: Numerous grading systems have been proposed for invasive ovarian epithelial carcinoma. But, conflicting reports have been published addressing the value of grade as an independent prognostic factor. DESIGN: The present study investigated the consistency, reproducibility and prognostic value of four different grading systems in a series of 100 homogeneously treated (cytoreductive surgery & platinum based chemotherapy) patient. All the slides were reviewed in a double-blind manner by 3 pathologists, typed according to the WHO and graded. Multivariate assessment of survival time was performed with the Cox model. RESULTS: Population parameters - mean age: 60 years, - stage (FIGO) III & IV 85% - survival: 5 years OS: stage III & IV=22,5%. No significant difference for survival was observed when the patients were classified with any of the 4 grades evaluated. Prognostic factors: age<60 (p<0,001), optimal surgery (p<0,01), n+(p<0,02), necrosis>50% (p<0,04), mitotic count<15MF/10HPF (p<0,03) and vascular invasion (p<0,03). Those 3 parameters were assigned to a new highly relevant grade. At multivariate analysis, it was significantly associated with DFS and OS (p<0,01). CONCLUSION: Our grade is simple, useful for all histologic types, non subjective and reproducible. Further studies are warranted to confirm its clinical utility.

Structural and numerical aberrations of chromosome 22 in a case of follicular variant of papillary thyroid carcinoma revealed by conventional and molecular cytogenetics.

This study reports a case of papillary carcinoma with vesicular components showing multiclonal aberrations of chromosome 22 as revealed by RHG-banding cytogenetics and by fluorescence in situ hybridization (FISH; whole chromosome 22 and BCR-ABL-specific locus probes, multi-FISH). Four clones with chromosome 22 changes as the sole abnormality were seen. The main abnormal clone lacked the whole chromosome 22. A del(22)(q11) was observed in a second group of cells. The third clone had an idic(22). Finally, FISH revealed a fourth abnormal cell population with a der(17)t(?17;22). Some of these chromosome 22 alterations have been described in other solid tumors such as meningiomas and neurinomas, suggesting a common genetic pathway of tumor progression occurring in a multistep process. Chromosome 22 changes do not seem to be involved in pure papillary thyroid tumors and therefore could be related to the maintenance of a follicular-type histological pattern.

Endometrial histopathology in 700 patients treated with tamoxifen for breast cancer.

OBJECTIVE: The aim of this study was the evaluation of endometrial histopathologic findings from 700 patients treated with tamoxifen (Tx) for breast cancer from two medical centers (United States and France). METHODS: A retrospective review of data including histologic slides from 134 hysterectomies and 566 endometrial biopsies from Tx-treated patients who presented with abnormal vaginal bleeding and/or abnormal sonograms was performed. Analysis of histologic characteristics included inactive/atrophic and functional endometria, endometrial polyps, hyperplasia and metaplasia, and endometrial cancer. Duration of Tx therapy was recorded when available, and its correlation with endometrial pathology was assessed. RESULTS: The only statistically significant difference between the data from the United States and France was the number of hysterectomies, which was almost double in France (27% vs 13.7%). Nonpathologic endometria made up 61.14% (inactive/atrophic 46%, functional 15.14%). Pathologic changes were found in 39.86% cases, of which polyps were 23.14%, glandular hyperplasia 8%, and metaplasia 3%; endometrial cancer made up 4.71% (33 cases). Nine cancers were well-differentiated endometrioid adenocarcinomas, and 24 were moderately or poorly differentiated, of which 13 had nonendometrioid components (serous, clear cell, MMMT). Fifteen cancers were found in endometrial polyps; 12 were invasive to the myometrium and 4 to blood vessels. The weight of the uteri exceeded 300 g in 15 cases, with 4 exceeding 900 g. The average age of all patients was 60.91 years and of the cancer patients alone it was 69.26 years. The shortest average duration of Tx therapy (2.5 years) was found in patients with inactive/atrophic endometria and the longest (6.8 years) in patients with endometrial cancer. Patients with endometrial polyps and cancer presented more often with abnormal vaginal bleeding than those with inactive/atrophic endometrium. CONCLUSIONS: Most Tx-treated patients had no pathologic endometrial changes. Endometrial polyps, hyperplasia, and metaplasia, consistent with an estrogen-agonist effect of Tx, were found in roughly one-third of all patients. The endometrial cancers were often high-grade and invasive tumors. Patients with endometrial pathology were more often symptomatic than patients with inactive/atrophic endometria.

BRCA2 protein expression in sporadic breast carcinoma with or without allelic loss of BRCA2.

To elucidate the cellular role of BRCA2 in sporadic breast tumors, we studied the cellular localization and the expression of BRCA2 in carcinomas presenting or not allelic loss of BRCA2. The breast tumors were first classified with or without allelic loss of BRCA2 and then immunohistochemical staining was performed on tumors and matched normal tissues using antibodies raised against BRCA2. We showed that BRCA2 is found either in the nucleus or in perinuclear compartments such as the endoplasmic reticulum and the Golgi vesicles. We have earlier demonstrated the presence of BRCA1 as an exocrine secretion in the lumen of ductules in the normal mammary gland, as well as BRCA1 and BRCA2 in milk-fat globules inside mammary-gland ductules during lactation. Here we show that BRCA2 is present within the lumina of breast ductules, indicating that BRCA2 protein may also be secreted in the mammary gland. No correlation was found in breast tumors between the expression of BRCA2 protein and allelic loss of BRCA2.

[Microinvasive ductal carcinoma of the breast. Role of axillary lymph node dissection]. / Carcinome canalaire micro-invasif du sein. Place du curage ganglionnaire axillaire.

The role of axillary lymph node dissection for microinvasive ductal carcinoma in situ of the breast was analyzed in a series of 60 consecutive cases. Forty-four cases were subclinical mammographically-detected carcinomas revealed by the clusters of microcalcifications. Although pathologists differ in their criteria for microinvasion, the maximal size considered in this retrospective study was 2 mm. Axillary lymph node involvement was found in 3 cases (i.e. 5%) which harbored poor histologic features: comedocarcinoma subtype, high nuclear grade, and size of the ductal carcinoma in situ greater than 3 cm, requiring total mastectomy. While there is no need for axillary dissection in women with pure ductal carcinoma in situ, the management is quite different in proven microinvasion. Owing to the weakness of prognostic information given by cellular, biochemical and molecular features, instead of lymph node status, axillary dissection is still recommended in microinvasive ductal carcinoma in situ.

Quantification of BRCA1 protein in sporadic breast carcinoma with or without loss of heterozygosity of the BRCA1 gene.

In sporadic breast cancer, no mutations of the BRCA1 gene have been reported so far, whereas BRCA1 mRNA is markedly decreased in invasive breast cancer. To elucidate the contribution of the BRCA1 gene in sporadic breast cancer, we quantified the BRCA1 protein, using [125I] labeling of whole-cell proteins, lentil-lectin affinity chromatography, immunoprecipitation by anti-BRCA1 antibodies (C-20, D-20, I-20 and K-18), purification of the immune complex by protein A affinity chromatography and chromato-focusing. As loss of 1 allele may lead to a decreased expression of the gene, 10 tumors were previously checked for loss of heterozygosity (LOH) of the BRCA1 gene, using 3 intragenic microsatellite markers. Our results indicated that the BRCA1 gene product was decreased in the 4 tumors with LOH compared with matched normal breast tissues. Reduced amounts of BRCA1 protein were also detected in 3 of 6 tumors without LOH. Our quantitative method allowed us to demonstrate that the BRCA1 protein level was decreased in sporadic invasive breast carcinomas with or without LOH of the BRCA1 gene, implying multiple mechanisms of BRCA1 expression down-regulation in these tumors. Our data suggest that the amount of BRCA1 protein present may play an important role in human sporadic breast carcinoma.

Subcellular localization of BRCA1 protein in sporadic breast carcinoma with or without allelic loss of BRCA1 gene.

The localization of BRCA1 protein was studied in 49 sporadic breast carcinomas for which allelic losses of BRCA1 have been investigated. One group consisted of 15 breast carcinomas having one allelic loss of BRCA1 and the other group of 34 breast carcinomas with no allelic loss of BRCA1. The localization of BRCA1 in the 2 groups was performed using polyclonal antibodies (K-18; C-20; D-20; I-20) raised against BRCA1 and by comparing frozen and paraffin-embedded tissues. We show that no correlation was found between the expression of BRCA1 protein and allelic loss of BRCA1. But, the nuclear detection of BRCA1 in frozen samples was improved when compared to paraffinized ones.