A novel Fc-engineered cathepsin D-targeting antibody enhances ADCC, triggers tumor-infiltrating NK cell recruitment, and improves treatment with paclitaxel and enzalutamide in triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) prognosis is poor. Immunotherapies to enhance the antibody-induced natural killer (NK) cell antitumor activity are emerging for TNBC that is frequently immunogenic. The aspartic protease cathepsin D (cath-D), a tumor cell-associated extracellular protein with protumor activity and a poor prognosis marker in TNBC, is a prime target for antibody-based therapy to induce NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). This study investigated whether Fc-engineered anti-cath-D antibodies trigger ADCC, their impact on antitumor efficacy and tumor-infiltrating NK cells, and their relevance for combinatory therapy in TNBC. METHODS: Cath-D expression and localization in TNBC samples were evaluated by western blotting, immunofluorescence, and immunohistochemistry. The binding of human anti-cath-D F1M1 and Fc-engineered antibody variants, which enhance (F1M1-Fc+) or prevent (F1M1-Fc-) affinity for CD16a, to secreted human and murine cath-D was analyzed by ELISA, and to CD16a by surface plasmon resonance and flow cytometry. NK cell activation was investigated by flow cytometry, and ADCC by lactate dehydrogenase release. The antitumor efficacy of F1M1 Fc-variants was investigated using TNBC cell xenografts in nude mice. NK cell recruitment, activation, and cytotoxic activity were analyzed in MDA-MB-231 cell xenografts by immunophenotyping and RT-qPCR. NK cells were depleted using an anti-asialo GM1 antibody. F1M1-Fc+ antitumor effect was assessed in TNBC patient-derived xenografts (PDXs) and TNBC SUM159 cell xenografts, and in combination with paclitaxel or enzalutamide. RESULTS: Cath-D expression on the TNBC cell surface could be exploited to induce ADCC. F1M1 Fc-variants recognized human and mouse cath-D. F1M1-Fc+ activated NK cells in vitro and induced ADCC against TNBC cells and cancer-associated fibroblasts more efficiently than F1M1. F1M1-Fc- was ineffective. In the MDA-MB-231 cell xenograft model, F1M1-Fc+ displayed higher antitumor activity than F1M1, whereas F1M1-Fc- was less effective, reflecting the importance of Fc-dependent mechanisms in vivo. F1M1-Fc+ triggered tumor-infiltrating NK cell recruitment, activation and cytotoxic activity in MDA-MB-231 cell xenografts. NK cell depletion impaired F1M1-Fc+ antitumor activity, demonstrating their key role. F1M1-Fc+ inhibited growth of SUM159 cell xenografts and two TNBC PDXs. In combination therapy, F1M1-Fc+ improved paclitaxel and enzalutamide therapeutic efficacy without toxicity. CONCLUSIONS: F1M1-Fc+ is a promising immunotherapy for TNBC that could be combined with conventional regimens, including chemotherapy or antiandrogens.

Prognostic Relevance of Tumor-Infiltrating Immune Cells in Cervix Squamous Cell Carcinoma.

There exists a variety of studies about tumor-infiltrating immune cells (TIICs) in cervical cancer, but their prognostic value in correlation with the histopathological subtype has never been investigated. Therefore, the aim of this study was to quantify TIICs in a panel of 238 sporadic cervical cancers and investigate the correlation with cervical cancer subtype and patient survival. TIICs levels were significantly increased in the subgroup of CSCC (191 samples) in comparison to CAC (47 samples). In CSCC, TIICs' infiltration showed a negative correlation with age, FIGO stage and with the histone protein modification H3K4me3. Moreover, in CAC, it was positively correlated with p16 and with the glucocorticoid receptor and inversely correlated with the MDM2 protein and with H3K4me3. Interestingly, immune infiltration was an independent positive prognosticator for disease-free survival (DFS) in patients with CSCC, those bearing tumors with the strongest TIICs infiltration showing the better DFS. Altogether, the present study provides a differentiated overview of the relations between TIIC levels and prognosis in patients with CSCC vs. patients with CAC.

Correlation of the TIGIT-PVR immune checkpoint axis with clinicopathological features in triple-negative breast cancer.

Background: T cell immunoreceptor with Ig and ITIM domains (TIGIT) interacts with poliovirus receptor (PVR) to contribute to cancer immune escape. Recently, TIGIT and PVR have been identified as promising immunotherapy targets. Their gene expression is upregulated in many solid tumors, but their protein expression level is not well documented, particularly in triple negative breast cancer (TNBC), the breast cancer subtype that most benefit from immunotherapy. Methods: TIGIT and PVR expression levels were assessed by immunohistochemistry in 243 surgically resected localized TNBC and then their relationship with clinical-pathological features and clinical outcome was analyzed. Results: TIGIT expression was observed in immune cells from the tumor microenvironment, whereas PVR was mainly expressed by tumor cells. High TIGIT expression was significantly associated with age (p=0.010), histological grade (p=0.014), non-lobular histology (p=0.024), adjuvant chemotherapy (p=0.006), and various immune cell populations (tumor infiltrating lymphocytes (TILs), CD3+, CD8+, PD-1+ cells; all p<0.0001), PD-L1+ tumor cells (p<0.0001), and PD-L1+ stromal cells (p=0.003). Infiltration by TIGIT+ cells tended to be higher in non-molecular apocrine tumors (p=0.088). PVR was significantly associated with histological grade (p<0.0001), the basal-like (p=0.003) and non-molecular apocrine phenotypes (p=0.039), high TILs infiltration (p=0.011), CD3+ (p=0.002), CD8+ (p=0.024) T cells, and PD-L1 expression in tumor (p=0.003) and stromal cells (p=0.001). In univariate analysis, only known prognostic factors (age, tumor size, lymph node status, adjuvant chemotherapy, TILs and CD3+ T-cell infiltrate) were significantly associated with relapse-free survival (RFS) and overall survival. High TIGIT and PVR expression levels tended to be associated with longer RFS (p=0.079 and 0.045, respectively). The analysis that included only non-molecular apocrine TNBC revealed longer RFS for tumors that strongly expressed TIGIT or PVR (p=0.025 for TIGIT and 0.032 for PVR). Conclusions: These results indicated that in TNBC, TIGIT+ cells can easily interact with PVR to exert their inhibitory effects. Their wide expression in TNBC and their association with other immune checkpoint components suggest the therapeutic interest of the TIGIT-PVR axis.

Prognostic Relevance of Nuclear Receptors in Relation to Peritumoral Inflammation and Tumor Infiltration by Lymphocytes in Breast Cancer.

The prognostic impact of tumor-infiltrating lymphocytes (TILs) is intensively investigated in breast cancer (BC). It is already known that triple-negative breast cancer (TNBC), the most aggressive type of BC, has the highest percentage of TILs. In addition, there is an influence of steroid hormone receptor expression (type I nuclear receptors) on TIL subpopulations in breast cancer tissue. The link between type II nuclear receptors and the level of TILs is unclear. Therefore, the aim of this study was to quantify TILs in a panel of 264 sporadic breast cancers and investigate the correlation of TIL levels with type I and II nuclear receptors expression. TIL levels were significantly increased in the subgroup of TNBC. By contrast, they decreased in estrogen (ER)- or progesterone receptor (PR)-positive cases. Moreover, TIL levels were correlated with type II nuclear receptors, including PPARγ, with a significant inverse correlation of the nuclear form (r = −0.727, p < 0.001) and a weak positive correlation of the cytoplasmic form (r = 0.202, p < 0.002). Surprisingly, BC cases with a TIL Salgado score of >15% showed a significantly decreased overall survival. In addition, peritumoral inflammation was also quantified in BC tissue samples. In our cohort, although the level of peritumoral inflammation was not correlated with OS, it determined the prognostic value of ER, PR, and PPARγ in BC. Altogether, the present study provides a differentiated overview of the relations between nuclear receptor expression, TIL levels, peritumoral inflammation, and prognosis in BC.

Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network.

BACKGROUND: Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France. METHODS: The nationwide incidence of sarcoma or TIM (2013-2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed. RESULTS: Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1-0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p<10-6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per. CONCLUSIONS: This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (1<106/year) are less likely to be included in clinical trials.

Targeting MDM2-dependent serine metabolism as a therapeutic strategy for liposarcoma.

Well-differentiated and dedifferentiated liposarcomas (LPSs) are characterized by a systematic amplification of the MDM2 oncogene, which encodes a key negative regulator of the p53 pathway. The molecular mechanisms underlying MDM2 overexpression while sparing wild-type p53 in LPS remain poorly understood. Here, we show that the p53-independent metabolic functions of chromatin-bound MDM2 are exacerbated in LPS and mediate an addiction to serine metabolism that sustains nucleotide synthesis and tumor growth. Treatment of LPS cells with Nutlin-3A, a pharmacological inhibitor of the MDM2-p53 interaction, stabilized p53 but unexpectedly enhanced MDM2-mediated control of serine metabolism by increasing its recruitment to chromatin, likely explaining the poor clinical efficacy of this class of MDM2 inhibitors. In contrast, genetic or pharmacological inhibition of chromatin-bound MDM2 by SP141, a distinct MDM2 inhibitor triggering its degradation, or interfering with de novo serine synthesis, impaired LPS growth both in vitro and in clinically relevant patient-derived xenograft models. Our data indicate that targeting MDM2 functions in serine metabolism represents a potential therapeutic strategy for LPS.

Prognostic value of HMGA2, CDK4, and JUN amplification in well-differentiated and dedifferentiated liposarcomas.

HMGA2, CDK4, and JUN genes have been described as frequently coamplified with MDM2 in atypical lipomatous tumor, well-differentiated liposarcoma, and dedifferentiated liposarcoma. We studied the frequency of amplification of these genes in a series of 48 dedifferentiated liposarcomas and 68 atypical lipomatous tumors/well-differentiated liposarcomas. We correlated their amplification status with clinicopathological features and outcomes. Histologically, both CDK4 (P=0.007) and JUN (P=0.005) amplifications were associated with dedifferentiated liposarcoma, whereas amplification of the proximal parts of HMGA2 (5'-untranslated region (UTR) and exons 1-3) was associated with atypical lipomatous tumor/well-differentiated liposarcoma (P=0.01). CDK4 amplification was associated with axial tumors. Amplification of 5'-UTR and exons 1-3 of HMGA2 was associated with primary status and grade 1. Shorter overall survival was correlated with: age >64 years (P=0.03), chemotherapy used in first intent (P<0.001), no surgery (P=0.003), grade 3 (P<0.001), distant metastasis (P<0.001), node involvement (P=0.006), and CDK4 amplification (P=0.07). In multivariate analysis, distant metastasis (HR=8.8) and grade 3 (HR=18.2) were associated with shorter overall survival. A shorter recurrence-free survival was associated with dedifferentiated liposarcoma (P<0.001), grade 3 (P<0.001), node involvement (P<0.001), distant metastasis (P=0.02), recurrent status (P=0.009), axial location (P=0.001), and with molecular features such as CDK4 (P=0.05) and JUN amplification (P=0.07). Amplification of 5'-UTR and exons 1-3 (P=0.08) and 3'-UTR (P=0.01) of HMGA2 were associated with longer recurrence-free survival. Distant metastasis was associated with shorter recurrence-free survival (HR=5.8) in multivariate analysis. Dedifferentiated liposarcoma type was associated with axial location, grade 3 and recurrent status. In conclusion, we showed that the amplification of HMGA2 was associated with the atypical lipomatous tumor/well-differentiated liposarcoma histological type and a good prognosis, whereas CDK4 and JUN amplifications were associated with dedifferentiated liposarcoma histology and a bad prognosis. In addition, we also provided the first description of the molecular evolution of a well-differentiated liposarcoma into four successive dedifferentiated liposarcoma relapses, which was consistent with our general observations.

[Breast surgeon role in the management of high-risk breast lesions]. / Quelle prise en charge chirurgicale pour "les lésions à haut risque" de cancer du sein?

Diagnostics of high-risk breast lesions have increased these last years with the augmentation of breast percutaneous biopsies. They are lesions that confer an enlarged risk of breast cancer, either because of an increased probability of finding cancer after open surgery, a possible evolution toward in situ or invasive cancer, or because of an increased probability of developing breast cancer over the long term. Much progress has been made these last years in their histological diagnostic, classification and pathogenesis. Nevertheless, no consensus exists to date on the management of these "high-risk" lesions. In particular, surgical indications and follow-up modalities remain controversial for each histological type. In this review, the principal factors that could impact surgical decision and long-term follow-up are discussed with areas of controversy highlighted.

Localised angiosarcomas: the identification of prognostic factors and analysis of treatment impact. A retrospective analysis from the French Sarcoma Group (GSF/GETO).

BACKGROUND: Angiosarcomas represent less than 2% of all adult soft tissue sarcomas. Prognostic factors and the role of (neo-) adjuvant treatments in the management of localised angiosarcomas require further investigation. METHODS: We have conducted a retrospective multicenter study (June 1980 to October 2009) of 107 patients with localised angiosarcomas. All of the cases were centrally reviewed by a certified pathologist. Univariate and multivariate analyses were conducted to identify independent poor prognostic factors (PF). Overall survival (OS) and Local Recurrence-Free Survival (LRFS) were estimated using the Kaplan-Meier method. The effect of treatments was explored using the Cox model after adjusting for the PF. RESULTS: The median age was 71 years. 22.4% and 62.6% developed an angiosarcoma in pre-existing lymphoedema and within irradiated tissue respectively. The median OS, LRFS and Disease Recurrence-Free Survival (DRFS) were 38.8, 27 and 36.1 months, respectively. In multivariate analysis, the following parameters influenced the OS: lymphoedema (Hazard ratio (HR)=2.0) and size >5cm (HR=1.5). After adjustment to these PF, R0 margins was the only treatment parameter that improving the OS (HR=0.2). In the multivariate analysis, the LRFS was influenced by an age >70 (HR=1.8) and pre-existing lymphoedema (HR=2.0). After adjustment for these PF, R0 margins (HR=0.5) and adjuvant radiotherapy (HR=0.3) improved the LRFS. CONCLUSIONS: Our results suggest the following points: (i) pre-existing lymphoedema, tumour size and age >70 are probably the major prognostic factors in patients with localised angiosarcomas; (ii) the achievement of R0 margins is probably of major importance for improving the patient outcome and (iii) adjuvant radiotherapy probably decreased the risk of local recurrence.

The non-crosslinking fixative RCL2®-CS100 is compatible with both pathology diagnosis and molecular analyses.

Formalin is the key agent for tissue fixation and pathological diagnosis. However, it poorly preserves nucleic acids and this can impair molecular studies. An alternative to formalin would be a fixative which can allow both morphologic and molecular analyses. To assess the suitability of such a fixative, breast (n = 11) and colon (n = 12) tumor samples were fixed in the non cross-linking RCL2®-CS100 fixative and compared to paired formalin-fixed and to frozen samples, the current standards for histology and molecular analyses, respectively. Sections from RCL2®-CS100-fixed samples showed good preservation of cellular and architectural morphology, suitable for routine diagnosis. Although some antibodies required change in the immunohistochemical procedures, quality of the immunohistochemical staining was comparable to that obtained after formalin fixation. HER2 chromogenic in situ hybridization was also successfully performed. High quality DNA could be isolated from RCL2®-CS100-fixed cancer tissues as evidenced by successful amplification of large DNA fragment, CGH array, KRAS and microsatellites genotyping. The quality of RNA from RCL2®-CS100-fixed samples was slightly decreased in comparison to that of RNA isolated from frozen samples, as evidenced by a decreased RNA integrity number but remained exploitable for molecular assays. Our results support the use of the RCL2®-CS100 fixative for histological diagnosis and recovery of high-quality nucleic acids for molecular applications. However, specific procedures for tissue handing and processing, essential to provide high-quality specimens, could limit its use to small target lesions which cannot be frozen without impairing their pathological evaluation.

[Neoadjuvant treatment of breast cancer: implications for the pathologist]. / Place du pathologiste dans la prise en charge néoadjuvante des cancers du sein.

These past few years, neoadjuvant strategy has taken an increasing place in the management of breast cancer patients. This strategy is mainly indicated to obtain a tumour bulk regression allowing a breast conserving surgery in patients that otherwise would have undergone mastectomy. Of note, development of new chemotherapy agents and targeted therapies has critically helped in the progress of neoadjuvant strategy as it is currently associated with better pathological response rates. In this context, the pathologist is at the crossroad of this multidisciplinary process. First, he provides on the initial core needle biopsy the tumour pathological characteristics that are critical for the choice of treatment strategy, i.e. histological type, histological grade, proliferative activity (mitotic count and Ki67/MIB1 index labeling), hormone receptor status (oestrogen receptor and progesterone receptor) and HER2 status. Secondly, the pathologist evaluates the pathological response and the status of surgical margins with regards to the residual tumour on the surgical specimen after neoadjuvant treatment. These parameters are important for the management of the patient, since it has been shown that complete pathological response is associated with improved disease free survival. Several grading systems are used to assess the pathological response in breast and axillary lymph nodes. The most frequently used in France are currently the systems described by Sataloff et al. and Chevallier et al. In this review, we detail the different steps involving the pathologist in neoadjuvant setting, with special regards to the quality process and future perspectives such as emerging predictive biomarkers.

[Hormone receptors and HER-2 changes during breast cancer progression: clinical implications]. / Variation d'expression des récepteurs hormonaux et d'HER-2 dans l'évolution du cancer du sein : quelles implications en pratique clinique ?

Breast cancer remains a major public health problem. Even if there is an increase in this cancer curability, metastatic breast cancer remains a lethal disease in the vast majority of cases. Therapeutic advances in the chemotherapeutic and targeted therapies fields induced an increase in survival, however the proportion of long survivors remains low. Phenotypic instability, an early process initiated during tumour progression, and continued on the metastatic stage of the disease, can be one of the putative hypotheses explaining these results. An increasing amount of scientific data are pledging for a reanalysis of the phenotypic profile regarding hormone receptors and HER-2 status of metastatic lesions in order to identify drugable targets and allow individualisation of the treatment of these metastatic breast cancer patients. Phenotypic changes between the primary tumour and the paired metastatic lymph nodes are a challenging pitfall, raising the question of which site has to be assessed in the adjuvant treatment decision process. This article presents a comprehensive analysis of the frequency of theses phenotypic changes altogether with new modalities to evaluate this phenotypic status.

Small cell carcinoma with concomitant adenocarcinoma arising in a Barrett's oesophagus: report of a case with a favourable behaviour.

Most Barrett's oesophagus-associated cancers are adenocarcinomas which occur in a pure form. They are rarely combined with another type of malignancy, such as endocrine tumours. Within the endocrine spectrum, small cell carcinomas (SmCC) usually have a highly aggressive behaviour with a poor prognosis. We report a case of composite SmCC and adenocarcinoma in the setting of a Barrett's oesophagus, in a 54-year-old man. This tumour was identified on a surgical specimen after neoadjuvant treatment with radiotherapy and 5-FU-Cis-platin based chemotherapy. The SmCC component was positive for chromogranin A, synaptophysin, neural cell adhesion molecule and neuron-specific enolase and negative for high molecular weight cytokeratin. The adenocarcinoma component showed a converse phenotype. In our case, the origin of the SmCC component could be explained by the numerous chromogranin A-positive cells observed in the Barrett's oesophagus or by the potential progenitor cells that may be located in the submucosal oesophageal gland ducts and the Barrett's metaplasia. Our report is thus indicative of the high and totipotential risk of Barrett's oesophagus. Moreover, it is particular because of its favourable behaviour, with a 6-year disease-free survival, after neoadjuvant chemoradiation, surgery and postoperative chemotherapy.

Dedifferentiated liposarcomas with divergent myosarcomatous differentiation developed in the internal trunk: a study of 27 cases and comparison to conventional dedifferentiated liposarcomas and leiomyosarcomas.

Dedifferentiated liposarcoma (DLPS) is one of the most frequent sarcomas of the retroperitoneum and represents most undifferentiated sarcomas of the internal trunk. In about 5% cases, the dedifferentiated component is an heterologous sarcoma such as leiomyosarcoma or rhabdomyosarcoma. We reviewed a series of 65 sarcomas with a myogenic differentiation developed in the internal trunk for which initial diagnoses were leiomyosarcoma (37), rhabdomyosarcoma (6), malignant mesenchymoma (6), and DLPS (16). Immunostainings for MDM2, CDK4, alpha smooth actin, desmin, caldesmon, myogenin, c-kit, and progesterone receptor were performed. In 48 cases, the amplification status of MDM2 and CDK4 could be evaluated with quantitative polymerase chain reaction on paraffin-embedded tissues extracted DNAs. After review of the cases, final diagnoses were leiomyosarcoma (35), rhabdomyosarcomatous (20) or leiomyosarcomatous (7) DLPS, probable DLPS (2), and malignant mesenchymoma (1). DLPS were bigger tumors (median: 18.2 cm) than leiomyosarcomas (median: 12 cm). They had a lower 5-year recurrence-free survival than leiomyosarcomas (45% vs. 71%) but a higher 5-year metastasis-free survival (73% vs. 39%). There was no significant difference in overall survival (57% vs. 34%). Outcome of patients with a DLPS with a myosarcomatous component did not differ from conventional DLPS. In conclusion, most sarcomas with a rhabdomyosarcomatous differentiation occurring in the internal trunk of adults are DLPS. Moreover, DLPS with a myogenic component have a low metastatic potential, similar to conventional DLPS and significantly lower to the metastatic potential of leiomyosarcomas.

[Positive sentinel node biopsy in breast cancer: is axillary surgery necessary in all cases?]. / Biopsie du ganglion sentinelle positive dans le cancer du sein: place du curage axillaire de complément?

Our retrospective study analyzes various factors to evaluate the risk of invasion of the not sentinel node when the sentinel node biopsy is positive in the infiltrated breast cancers. We compared in single varied then multivaried analysis, various parameters between two groups: positive not sentinel nodes and negative not sentinel nodes among 180 cases of positive sentinel node biopsy between 2001 and 2004. At the time of the single varied analysis, seem to be risk factors of non sentinel node involvement: the histopronostic SBRIII rank, positive a HER2neu status, the presence of extracapsulal node extension and infiltration of the sentinel node by a macrometastasis. The tumoral embol, the absence of hormonal receivers, a tumoral size > 10 mm and the number of sentinel node taken appear at the limit of the significativity. In multivaried analysis, SBRIII rank and the presence of an extracapsular node extension remain related to non sentinel node involvement. The histological type, association with a CIS, the size of the sentinel nodes, the number of positive sentinel nodes and the year of surgery are nonsignificant. Additional axillairy clearing out at the time of a positive node sentinel biopsy should be discussed according to different criteria determined by a precise histological analysis.

[Vascular hepatic injury following neoadjuvant treatment for a cardial adenocarcinoma]. / Altérations vasculaires hépatiques après traitement néoadjuvant d'un adénocarcinome du cardia.

We report a case of a locally advanced cardial adenocarcinoma, occurring in a 48-year-old woman, who underwent concomitant radiotherapy and 5 FU-cis-platin based chemotherapy. Surgical tumor resection was then performed, which incidentally revealed an isolated liver nodule measuring 12 mm. This nodule was histologically characterized by an intense sinusoidal dilatation and a central venular occlusion, similar to that seen in veno-occlusive disease. This lesion was not correlated to any clinical or biological dysfunction and was finally considered as a vascular injury linked to the additive effect of the combined chemotherapy and radiotherapy. This observation illustrates some iatrogenic hepatic side effects, that have been rarely described in digestive cancers and mainly in the case of colo-rectal metastases. Vascular damage may remain histological, as in our case. But one should be aware that vascular injuries could influence hepatic function and regeneration after wide hepatectomy as well as extensive fibrosis.

[Recent data on lobular neoplasia of the breast: the pathologist's opinion]. / Données récentes sur les néoplasies lobulaires du sein: le point de vue du pathologiste.

Lobular neoplasia is the new WHO terminology that encompasses the so-called lobular carcinoma in situ and atypical lobular hyperplasia. Besides the classical forms, particular variants have been described, which are mammographically detectable with distinct histologic patterns and behaviour. These variants are characterized by pleomorphic cells, necrosis with calcifications and may be associated to an invasive lobular carcinoma. Their clinical issue looks more like a preinvasive lesion than a marker of increased risk. Thus, their identification on biopsy requires a surgical reexcision. Hybrid forms, sharing a mixed lobular and ductal morphology and phenotype, have also been mentionned. Despite a lack of prognostic evaluation, it seems logical to recommend a subsequent surgical investigation when they are observed. Classical forms are usually managed by simple follow-up, although this attitude does not make a consensus among pathologists. Lobular neoplasia are not all indolent lesions and belong to an heterogeneous group that percutaneous guided biopsies have emphasized. They should be managed in a pluridisciplinar way and correctly diagnosed on percutaneous biopsies as well as surgical specimens.

[Management of non-palpable breast lesions with vacuum-assisted large core needle biopsies (Mammotome). Experience with 560 procedures at the Val d'Aurelle Center]. / Prise en charge des lésions mammaires infra-cliniques par macrobiopsies assistées par le vide (procédure Mammotome). Expérience du Centre Val d'Aurelle à propos d'une série de 560 procédures.

Percutaneous vacuum-assisted large core needle biopsy of breast microcalcifications is now commonly performed as the initial approach to nonpalpable breast lesions. It can obviate the need for surgery in women with benign lesions and often lead to a one-stage surgical procedure when malignant lesions are diagnosed. To illustrate this strategy, we describe our experience based on 560 procedures performed within a 36 Month-period. Sixty percent of the lesions were benign, mostly fibrocystic changes. Thirty percent of the specimens were malignant, almost exclusively intraductal carcinomas, sometimes associated with an invasive component. This component must be identified by the pathologist in order to avoid incomplete treatment and to plan lymph node excision. Finally, 10% of the specimens were boderline including lobular neoplasia, atypical ductal hyperplasia and columnar cell lesions with atypia. Surgical excision is recommended for atypical ductal hyperplasia, columnar cell lesions with atypia and lobular neoplasia with particular features, pleomorphic or comedo-like, to avoid missing more aggressive associated lesions. A strict procedure is required for the analysis of needle core biopsies and the subsequent surgical specimens, to accurately classify breast lesions provided by a mammographic screening program. This procedure should be based on a multidisciplinary approach and dialog.

Pleomorphic liposarcoma: clinicopathologic, immunohistochemical, and follow-up analysis of 63 cases: a study from the French Federation of Cancer Centers Sarcoma Group.

The clinicopathologic and immunohistochemical features of 63 pleomorphic liposarcomas are presented. There were 35 men and 28 women (median age 63 years; range 18-93 years). Tumor size ranged from 2 to 23 cm (median 10 cm). Tumor locations included lower extremity (36.5%), especially the thigh (28.5%), limb girdles (17.5%), upper extremity (16%), thoracoabdominal wall (9.5%), and internal trunk (20.5%). A total of 75% were deep seated and/or extracompartmental. Histologically, lesions show a varying combination of lipogenic and nonlipogenic areas characterized by malignant fibrous histiocytoma-like, round cell liposarcoma-like, and/or epithelioid/carcinoma-like features. A pericytic pattern was focally present in 15 (24%) tumors. Eighteen (29%) lesions were grade 2, and 45 (71%) were grade 3 sarcomas. Tumor necrosis was observed in 51 (81%) cases, vascular invasion in three, and mitotic counts ranged from 3 to 124 per 10 high power fields (median 25). Lipogenic areas were S-100 protein immunoreactive, at least focally, in 20 of 42 (48%) cases. Nonlipogenic areas showed focal reactivity for smooth muscle actin (24 of 49; 49%), desmin (9 of 48; 19%), CD34 (18 of 45; 40%), S-100 protein (5 of 49, 10%), CD68 (6 of 46, 13%), and epithelial membrane antigen (13 of 49, 26.5%). Epithelioid areas showed epithelial membrane antigen (4 of 11; 36%) but not cytokeratin (0 of 11) reactivity. Treatment procedures in 51 patients consisted of simple tumorectomy (16) and wide excision (33). Five and 31 patients received neoadjuvant and adjuvant chemotherapy and/or radiation therapy, respectively. Follow-up (48 patients, range 7-276 months; median 38 months) showed a 45% local recurrence rate and a 42.5% metastasis rate, metastases occurring mostly in lungs and pleura. Seventeen patients (35%) died of disease, of whom none was metastatic at diagnosis. Five-year overall, metastasis-free, and local recurrence-free survivals were 57%, 50%, and 48%, respectively. Patient age > or =60 years, truncal tumor location, deep situation, tumor size >5 cm, vascular invasion, and incomplete tumor excision were significant adverse prognostic factors. Tumor grade and histology did not affect patient outcome. In conclusion, pleomorphic liposarcoma is a rare, often deep-seated and limb-based aggressive and metastasizing neoplasm of late adulthood. It shows a wide range of morphologic appearances, but tumor grade and histology have no effect on patient outcome.