p53 protein accumulation and response to adjuvant chemotherapy in premenopausal women with node-negative early breast cancer.

PURPOSE: Thirty percent of women with node-negative breast cancer will have a recurrence within 10 years after diagnosis. Molecular markers may identify those patients and predict whether they benefit from adjuvant therapy. The European Organization for Research and Treatment of Cancer (EORTC) conducted a randomized trial (EORTC 10854) to compare perioperative treatment with one course of fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus no further therapy. We studied tumors from premenopausal patients with node-negative breast cancer randomized in this trial to determine whether p53 accumulation, c-erbB-2 expression, percentage of Ki-67-positive cells, estrogen receptor (ER-immunoassay [IA]), progesterone receptor (PR-IA), and angiogenesis could be used as prognostic factors and predictors of responsiveness to adjuvant chemotherapy. PATIENTS AND METHODS: Paraffin-embedded tumor specimens from 441 premenopausal women with node-negative breast cancer were collected from the larger EORTC trial. Paraffin sections from the tumors were analyzed for immunohistochemical expression of p53, c-erbB-2, Ki-67, ER, PR, and angiogenesis. RESULTS: Patients with p53-negative tumors showed a significant benefit from perioperative chemotherapy (P < .01), whereas patients who had p53-positive tumors did not (P = .80). At a median follow-up time of 49 months, univariate analyses for disease-free survival (DFS) failed to show prognostic value for p53, c-erbB-2 and angiogenesis. Both univariate and multivariate results showed Ki-67 positivity, ER-IA negativity, and a younger age to be associated with a worse prognosis. CONCLUSION: p53 accumulation was associated with a poor response to one perioperative course of FAC chemotherapy. Ki-67, ER-IA, and age are important prognostic factors in premenopausal women with node-negative breast cancer.

Demonstration of in vivo mammogenic and lactogenic effects of recombinant ovine placental lactogen and mammogenic effect of recombinant ovine GH in ewes during artificial induction of lactation.

The present study demonstrates that ovine placental lactogen (oPL) (ovine chorionic somatotrophin) may have an important role in the mammogenesis and/or lactogenesis of the ewe. Its effects were compared with that already described for ovine growth hormone (oGH). In the first experiment, 40 nulliparous ewes were induced to lactate by means of a 7 day (days 1-7) oestro-progestative treatment (E2+P4). The ewes from Group 1 (n=12) received no further treatment, while those of the other groups received either recombinant oGH (roGH, 28 micrograms/kg, i.m., twice daily, Group 2, n=12) or recombinant oPL (roPL, 79 micrograms/kg, i.m., twice daily, Group 3, n=12) from day 11 to 20. All ewes received 25 mg hydrocortisone acetate (HC) twice daily on days 18-20. Control Group 00 (n=2) received no steroid treatment at all, and the control Group 0 (n=2) received only the E2+P4 treatment. Thirteen ewes (three from each experimental group and the two of each control group) were slaughtered at the end of hormone treatments (day 21) before any milking stimulus. The 27 remaining ewes from Groups 1-3 were machine-milked and milk yields recorded daily from day 21 to 76. The E2+P4 treatment enhanced the plasma levels of oPRL, oGH and IGF-I between days 1 and 7 by 1.5, 2. 3 and 2.6 times respectively (P=0.002); roGH treatment induced a highly significant enhancement of IGF-I plasma levels from day 11 to 20, whereas a similar effect appeared for roPL-treated ewes only from day 17 to 20 (P<0.01). Eight weeks after the last exogenous hormone injections, milk yields of both roGH- and roPL-treated groups progressively rose to twice that of unsupplemented groups (P<0.001). The mammary DNA content on day 21 was higher for animals which received either oGH or oPL but, due to individual variations in so few samples (n=3), this difference was not significant. No beta-casein was measured in mammary tissue from control ewes, whereas steroid-treated ewes (E2+P4+HC) had higher casein concentrations regardless of subsequent hormonal treatment on days 11-20 (P<0.001). beta-Casein concentrations in mammary parenchyma of roGH-treated ewes did not differ from that of ewes which received only E2+P4+HC; roPL supplementation clearly enhanced expression of beta-casein (P<0.001). IGF-I stimulation by either roGH or roPL was more precisely examined during a second experiment, in which two twice-daily i.m. doses (58 or 116 micrograms/kg) of either roGH or roPL were administered to four groups of six ewes that were E2+P4 treated as those of Experiment 1. A control group (n=6) received no exogenous hormone from day 11 to 13. On day 13, hourly blood samples were taken from all ewes over 11 h. Both doses of roGH significantly stimulated IGF-I in a dose-dependent manner. The 58 micrograms/kg dose of roPL did not significantly stimulate IGF-I, but although being somewhat less efficient than the 58 micrograms/kg dose of roGH, the 116 micrograms/kg dose of roPL significantly stimulated IGF-I secretion (P<0. 001). These results suggest that mammogenesis and/or lactogenesis in the ewe is in part controlled by somatotrophic hormones such as oGH and oPL and that IGF-I could be one of the mediators of these hormones.

Establishment and characterization of a new cell line (VHB-1) derived from a primary breast carcinoma.

A continuous line of human breast carcinoma cells, VHB-1, was established in culture following collagenase treatment of an infiltrating duct cell carcinoma. The cells displayed an epithelial pattern and multiplied rapidly. Maintained in monolayer culture, the VHB-1 cells exhibited a 30-h doubling time and a plating efficiency of 20%. The cells possessed an abnormal karyotype with a mode of 70-74 chromosomes per cell. The karyotype was heavily rearranged and numerous marker chromosomes were found. Transplantation of the cells into nude mice produced tumors bearing histological resemblance to the original material. The VHB-1 cells contained significant levels of prolactin receptors, were steroid hormone (estrogen, progesterone, androgen, glucocorticoid) receptor positive, and were capable of functional differentiation in vitro. These characteristics make the VHB-1 cell line a suitable model for studying the biological properties of human breast tumors.

Lymph node invasion in hypopharynx and lateral epilarynx carcinoma: a prognostic factor.

Hypopharynx (HC: pyriform fossa, postcricoïd area, and posterior wall) and lateral epilarynx carcinomas (LEC: aryepiglottic fold, pharyngoepiglottic fold, and arytenoïd) have a high tendency to cervical lymph node invasion. Such nodal extension is a well-known prognostic factor. This study is based on a retrospective review of 884 clinical records of previously untreated HC or LEC. Seventy percent of patients revealed palpable nodes at their first examination, with a higher percentage for HC (73%) than LEC (62%). The 5-year survival rate was divided by three in the presence of contralateral, bilateral, or fixed nodes, or in cases of nodes exceeding 3 cm. Multiple positive nodes, extracapsular spread, or lower-neck positive nodes significantly decreased survival, doubled the number of neck recurrences, and tripled the number of distant metastases while control at the primary site remained unvaried.

The utility of mitotic index, oestrogen receptor and Ki-67 measurements in the creation of novel prognostic indices for node-negative breast cancer.

INTRODUCTION: Prognostic factors can be useful to identify node-negative patients at increased risk of relapse who should receive adjuvant treatment. In the past, oestrogen receptor status and mitotic index have been shown to be significant predictors of prognosis. Different techniques for the measurement of these prognostic factors are available. METHODS: Paraffin-embedded tumour specimens from 441 pre-menopausal patients with node-negative breast cancer who were previously randomized onto a trial comparing peri-operative chemotherapy with no further therapy were studied. Oestrogen receptor status was determined by the classical biochemical assay and by immunohistochemistry (ER-IA). Mitotic index was assessed by counting the number of mitoses and by calculating the percentage of tumour cells positively staining for the antibody Ki-67. RESULTS: There was a good correlation between ER-IA and the biochemical ER-assay (P<0.01), and the percentage of Ki-67 positive tumour cells and mitotic counts (P<0.01) respectively. However, ER-IA significantly predicted disease-free survival (RR=2.67, 95% CI: 1.60-4.44, P<0.01) whereas the biochemical assay was only borderline significant (RR=1.54, 95% CI: 1.00-2.36, P=0.05). Similarly, Ki-67 was a stronger indicator of prognosis (RR=2.84, 95% CI: 1.80-4.48, P<0.01) than mitotic counts (RR=1.56, 95% CI: 1.22-2. 00, P<0.01). CONCLUSIONS: We conclude that ER-IA performs better in predicting prognosis than the classical biochemical oestrogen receptor assay. Ki-67 is a more accurate marker for tumour cell proliferation and predicts prognosis of patients with breast cancer better than do mitotic counts.

Discordant malignant lymphoma synchronous or successive high-grade B lymphoma associated with Hodgkin's disease. A clinico pathologic and immunophenotypic study of 4 cases.

We report in 4 patients the rare association of Hodgkin's disease and high grade B malignant lymphoma. In 2 cases, both tumours were disclosed at the same time but in different tissues from the same region. In the 2 other patients, the second tumour was found 11 months and 12 months after the first respectively. In all cases Hodgkin's disease was of the nodular sclerosing type, the tumour cells expressing CD 30 and CD 15. The high grade lymphomas were of the polymorphic centroblastic (large non cleaved) type and expressed the B markers. One (case 4) was secondary to a follicular lymphoma. In 2 cases (2 and 4) the search for a latent EBV infection was negative in both tumours. In case 1, only the Reed-Sternberg cells were positive with both techniques. Such an association is different from so-called composite lymphomas, and can be called "discordant lymphoma". Different related conditions are discussed. This association is distinct from lymphomas or Hodgkin's disease complicating the treatment of Hodgkin's disease or malignant lymphomas.

[Non-Hodgkin's malignant lymphoma with primary gastro-intestinal localisation. Therapeutic aspects]. / Lymphomes malins non hodgkiniens à localisation primitive gastro-intestinale. Aspects thérapeutiques.

A retrospective analysis of 38 patients with primary gastrointestinal non Hodgkin's lymphoma (PGINHL) referred to "Center Oscar Lambret, Lille, France", from January 1964 to December 1986 has been carried out. Kiel classification and the working formulation for clinical usage were used for histologic diagnosis and Ann Arbor classification modified by Musshoff for clinical staging. The patients, 29 males and 9 females, ranged in age from 7 to 71 years with a mean of 45.5 years for men and 45.1 years for women. Seventeen patients were classified as presenting with low-grade malignancy lymphomas and 21 as high-grade malignancy lymphomas. Nineteen patients presented with early clinical forms and 19 with advanced ones. Laparotomy was performed on all patients but one. Treatment modalities included: surgical resection, chemotherapy and radiotherapy in various combinations. There were 21 patients with recurrence, 6 of them responding to retreatment. The complete population survival curve reached a plateau at 48% after a 41-month follow-up. Five-year survival was 16% for early clinical forms and 80% for advanced ones (P less than 0.001) and 24% for high-grade malignancy lymphomas versus 75% for low-grade malignancy lymphomas (P less than 0.01). Moreover, the 5-year survival rate was 82% for patients with complete surgical resection of primary lesions versus 16% for those with incomplete resections (P less than 0.001). Laparotomy seems to play a major role in diagnostic accuracy, although the role of surgery in therapeutic management remains controversial. However our findings show that surgical resection is important to achieve local control of PGINHL. According to our results the only prognostic determinant that keeps its prognostic value is the extent of surgical resection (complete or incomplete) (P less than 0.05).

[Immunohistochemical demonstration of ceruloplasmin and lactoferrin in a series of 59 thyroid tumors]. / Détection immunohistochimique de la céruloplasmine et de la lactoferrine sur une série de 59 tumeurs thyroïdiennes.

Fifty-nine thyroid tumors were re-examined and studied using immunohistochemistry to detect the presence of ceruloplasmin (CP), lactoferrin (LF), thyroglobulin, thyrocalcitonin, carcinoembryonic antigen and ferritin. In an attempt to study the contribution of the immunodetection of CP and LF in the diagnosis of malignant versus benign tumors, specially in follicular tumors, we compared our results of immunodetection with those of Tuccari and Barresi, and carried out our own studies on the usefulness of these immunolabelling. Concerning CP and LF staining, we have found the following data: 1) little (in contrast to Tuccari and Barresi) or no staining in normal thyroid and benign adenomas; 2) diffuse and intense staining in papillary and follicular carcinomas (as noted by the previous authors); 3) diffuse and weak staining for medullary carcinomas (in contrast to Tuccari and Barresi who found none). Our findings suggest that a diffuse and intense cytoplasmic staining with CP and LF concerning more than one third of all cells is a criterion of malignancy, whereas a weak paranuclear staining of a few cells is more in favor of a benign process.

[Lymphatic metastasis revealing a calcitonin-secreting extrathyroid carcinoma]. / Métastases ganglionnaires révélatrices d'un carcinome extra-thyroïdien à calcitonine.

We report a case of right sus-clavicular lymph nodes metastasis which revealed a calcitonin secreting carcinoma in a 36 years old woman. Any tumor has been noted in the completely included thyroid gland. There was many lymph nodes metastasis in the right mediastinal removal. A pulmonary origin neuroendocrine carcinoma hyposthesis has been evoked. The outcome proved to be quickly fatal with cerebral metastasis occurrence. Extrathyroid calcitonin secreting carcinomas are rare. Then the discussion was founded on the diagnosis process in the face of hypercalcitoninemia, and on the calcitonin secretion by neuroendocrine cells and neoplasms of the lung.

[Stromal luteoma of the ovary. Differential diagnosis of steroid cell tumors]. / Le lutéome du stroma ovarien. Diagnostic différentiel des tumeurs à cellules stéroïdes.

An observation of a stromal luteoma of the ovary is reported. It is a rare tumor (only about thirty cases of it have been published yet), occurring mostly in post menopausal women. Endocrine symptoms and sometimes virilizing signs may be observed. Abnormal vaginal bleeding is the most frequent clinical manifestation. This macroscopically observed tumor is surrounded by ovarian stroma and entirely composed of luteinized cells devoid of crystals of Reinke. Hyperthecosis of ovarian stroma is often observed. Its evolution is always benign. The authors recalled the place of stromal luteoma of the ovary among steroid (lipid) cell tumors and the elements of a differential diagnosis. These tumor might derive from ovarian stromal cells.

[Pseudomyxoma peritonei secondary to a teratoma of the omentum with a mucinous component of borderline malignancy]. / Pseudomyxome péritonéal secondaire à un tératome épiploïque à composante mucineuse de malignité frontière.

A mature cystic teratoma of the omentum occurred in a 37 years old woman who had an appendicectomy at the age of 8. This extragonadal teratoma contained a predominant mucinous glandular pattern of borderline malignancy, responsible for pseudomyxoma peritonei. Ovarian biopsies had only shown surface mucinous deposits at the time of the first laparotomy but two years later ovarian mucinous cystadenomas of borderline malignancy appeared. The patient developed intestinal obstruction, surround by mucinous retractile material and died four years and an half after initial diagnosis. This case is, to our knowledge, the first pseudomyxoma peritonei occurring from an extragonadal teratoma, the events chronology suggesting the secondary nature of the ovarian tumors.

[Uterine hemangiopericytomas. Two case reports]. / Hémangiopéricytomes utérins. A propos de deux observations.

The diagnosis of uterine haemangiopericytoma is still a matter of debate. The existence of haemangiopericytoma must be proven on the basis of classical histology, ultrastructure histology and immunohistochemical analyses. The diagnosis, even when apparently sure, must nevertheless be proven. We described two cases emphasizing the clinical and laboratory features of uterine haemangiopericytoma. Progress in nuclear magnetic resonance imaging, ultrastructural analysis and immunohistochemistry should help in confirming the diagnosis of haemangiopericytoma. Highly vascular leiomyoma or low malignity grade leiomyosarcoma have been mistakenly identified as haemangiopericytoma.

[Primary lymphomas of the breast. 9 case reports]. / Les lymphomes primitifs du sein. A propos de 9 observations.

Between the 1st of January 1974 and the 30th of June 1989, we saw 9 cases of primary lymphoma of the breast at the Oscar Lambret Centre, all occurring in women. This comprised 0.27% of the malignant tumours of the breast and 3.2% of all non-Hodgkin lymphomas. 8 occurred on the right side and 1 on the left. There were multiple tumours in 5 cases. The clinical findings were always suggestive of a malignant condition and so were the mammography findings in 6 cases. Two patients had total mastectomy. In the other cases, the diagnosis was made (twice) by biopsy or by lumpectomy (5 cases). Using Kiel-Lennert's classification: 5 were highly malignant and 4 of low grade malignancy (using the Working Formulation, three were moderate and 4 were intermediate; 1 was very high grade and 1 intermediate or high). Treatment changed a lot during the period under consideration. Five patients are still alive without any recurrence. One died of lymphoma and two died of intercurrent causes and one died of unknown causes.

[Mobile tongue cancer. Prognostic value of lymph node invasiveness. Apropos of 744 cases]. / Les cancers linguaux et pelvi-linguaux. Valeur pronostique de l'envahissement ganglionnaire. A propos de 744 cas.

Between 1974 and 1983, 744 carcinomas of the mobile tongue were treated at Centre Oscar Lambret. 54% of the tumours were T1 T2 and 66% N0 (84% for T1 T2 - 46% for T3 T4) (UICC, 1979). The 3 and 5 year survival rates were 47% and 35% for N0 patients versus 17% and 11% for patients with palpable cervical node. In 598 patients without a previous history of neoplasm, this cancer was isolated at first examination. The pronostic study was carried out only on this group. Palpable lymph node reduced the 5 year survival to one third by affecting the local and neck control and risk of distant metastases. 311 patients underwent at least an unilaterale neck dissection. The 5 years survival rate for N- group (68%) was double that of the N+ R- group (32%) which in turn was double that of the N+ R- group (14%). The presence of 3 or more positive nodes or one infra-omohyoid node divided the survival by 3 (22 and 20% respectively versus 68% for N- patients).

[Phyllodes tumors]. / Les tumeurs phyllodes.

A review of mammary phyllodes tumors is presented. Clinical, radiological and cytological features are treated, with special emphasis on the histopathological grading system and prognostic indicators. Other analytical methods are described: immunohistochemistry, hormonal receptors study, flow cytometry and electron microscopy. A large place is also given to differential diagnosis, clinical course, histogenesis and originality of some phyllodes tumors. The authors stress the importance of wide excision and the contribution of frozen sections in surgical treatment.

Accuracy and safety of laparoscopic lymphadenectomy: an experimental prospective randomized study.

INTRODUCTION: The goal of this study was to investigate the accuracy and safety of bilateral pelvic and paraaortic lymphadenectomy performed via transperitoneal laparoscopy (LS) compared to laparotomy (LT) in a porcine model. MATERIALS AND METHODS: Fifteen adult, female hogs underwent LS and 15 underwent LT. A complete pelvic and paraaortic lymphadenectomy was performed in each animal by an experienced surgeon. Lymph nodes were counted by a pathologist in each case. Operative times were reviewed and included all procedures performed. The intraoperative complications were noted. Four weeks after the lymphadenectomy, the animals underwent exploratory laparotomy, and intraperitoneal adhesions were quantified. RESULTS: Thirty animals were evaluable. The average total number of lymph nodes retrieved by LS was 16.9 +/- 3.8, which was not statistically (P = 0.77) different from 16.5 +/- 4.9 nodes in LT. The average operating time in LT was 60 +/- 16 min compared with 128 +/- 24 min in LS. Twenty-eight animals were evaluable for adhesion formation. The average adhesion scores observed in anterior abdominal wall (P = 0.0006), paraaortic (P = 0.0005), right (P = 0.015), and left (P = 0.0324) iliac areas after LS were uniformly lower than after LT. DISCUSSION: This study indicates that laparoscopic pelvic and paraaortic lymphadenectomy is a safe and effective procedure. The node yield is similar for both approaches. The transperitoneal laparoscopy pelvic and paraaortic lymphadenectomy may not induce the degree of adhesion formation associated with laparotomy.

Expression of Bcl-2 in node-negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy.

The aim of this study was to assess relationships between Bcl-2 expression, response to chemotherapy and a number of pathological and biological tumour parameters in premenopausal, lymph node-negative breast cancer patients. Expression of Bcl-2 was determined using immunohistochemistry on paraffin-embedded sections in a series of 441 premenopausal, lymph node-negative breast cancers of patients randomised to receive perioperative chemotherapy (5-fluorouracil, doxorubicin, cyclophosphamide) or no perioperative chemotherapy. Immunohistochemistry of Bcl-2 was evaluated by scoring both staining intensity (0-3) and number of positive cells (0-2). Using these scores tumours were grouped into categories 0-6. It was found that 9.2% of the tumours were completely negative (0), 17.2% weakly (1 + 2), 41.6% moderately (3 + 4) and 31.9% strongly positive (5 + 6) for Bcl-2. A positive correlation was found between high Bcl-2 expression and oestrogen (P < 0.001) and progesterone receptor positivity (P < 0.001) and low tumour grade (P < 0.001), whereas high Bcl-2 expression was negatively correlated with p53 (P < 0.001) and c-erb-B-2 positively (P < 0.001), high Ki-67 index (P < 0.001), mitotic index (P < 0.001) and large tumour size (P = 0.006). Patients with tumours expressing high levels of Bcl-2 (overall score 3-6) had a significantly better disease-free (P = 0.004) and overall (P = 0.009) survival. However, in a multivariate model this association no longer remained significant. There was a trend for an effect of adjuvant chemotherapy on disease-free survival both for patients with Bcl-2-positive (HR-0.61, 95% CI 0.35-1.06, P = 0.07) and negative (HR = 0.55, 95% CI 0.27-1.12, P = 0.09) breast tumours at a median follow-up of 49 months. The level of Bcl-2 expression does not seem to predict response to perioperative chemotherapy in premenopausal, lymph node-negative breast cancer patients. High levels of Bcl-2 are preferentially expressed in well-differentiated tumours and are associated with favourable prognosis. However, Bcl-2 expression is not an independent prognostic factor in this patient series.