Breast hamartoma: reassessment of an under-recognised breast lesion.

AIMS: Breast hamartomas are an under-recognised lesion because they lack a distinctive microscopic appearance. Microscopic diagnosis can often conclude 'no significant lesion' or 'normal breast tissue', leading to repeated biopsies and diagnostic delay. We describe the histological, immunohistochemical and radiological features of breast hamartomas with the aim of identifying specific signs to facilitate their diagnosis and to differentiate them from normal breast and fibroepithelial lesions. METHODS AND RESULTS: Forty-seven breast hamartomas were reassessed (histological diagnosis and imaging features). An immunohistochemical study [oestrogen receptor (ER), progesterone receptor (PR), CD34, high-mobility group A2 (HMGA2)] was performed. On breast imaging, hamartomas most often presented as probably benign solid masses with circumscribed margins and variable densities. Histologically, breast hamartomas resembled normal breast, although their stromal component was predominant, separating randomly scattered epithelial elements with areas of pure collagenous stroma. Pseudoangiomatous stromal hyperplasia (PASH) was present in 93.6% of cases and CD34 antibody highlighted intralobular, perilobular and interlobular distribution of CD34-positive fibroblasts. By comparison, CD34 was mainly expressed in the intralobular normal breast tissue stroma. Hamartoma stromal cells expressed HMGA2, ER and PR in 79%, 66% and 76.3% of our cases, respectively, compared to 7.7%, 23% and 19% in normal breast tissue, respectively (P < 0.0001; P = 0.0005; P < 0.0001). CONCLUSIONS: After ascertaining that core needle biopsy is effectively intralesional, breast hamartomas can be diagnosed with confidence by taking into account the presence of stromal changes, PASH, interlobular distribution of CD34-positive fibroblasts, HMGA2 and hormonal receptor stromal expression.

Factors predicting the spontaneous regression of cervical high-grade squamous intraepithelial lesions (HSIL/CIN2).

PURPOSE: To determine clinical, pathological and virological factors predicting the spontaneous regression of HSIL/CIN2. METHODS: This retrospective study included 73 patients with HSIL/CIN2 diagnosed by biopsy between 2012 and 2016 and followed-up without treatment in the department of gynecology at Bordeaux University Hospital. All biopsies sampled inside or outside our department were reviewed and immunolabelled for p16 and Ki67. The response rate was the regression or the disappearance of HSIL/CIN2 as defined by the regression or the disappearance of initial colposcopic findings, cytological and/or histological results. RESULTS: The diagnosis of CIN2 was confirmed in 63 of 70 biopsies available for review. The Cohen's kappa coefficient was κ = 90%, indicating almost perfect inter-observer agreement. The lesion spontaneously regressed or disappeared in 36 of 60 patients (60%) with confirmed CIN2 during a median follow-up of 20 months (range 6-55). Baseline factors influencing the response rate were colposcopic findings (69% with minor change vs 31% with major change, p = 0.033), cytological results (72% with ASCUS/LSIL vs 28% with ASC-H/HSIL, p = 0.018), and HPV genotyping (71% with HPV not 16 vs 42% with HPV-16, p = 0.027). The other factors (age, smoking, surface area of the lesion, p16 and Ki67 expressions) did not significantly influence the outcome. CONCLUSION: Colposcopic findings, cytological results, and HPV genotyping were baseline factors predicting spontaneous regression of HSIL/CIN2.

Intraductal papillary mucinous neoplasms of the pancreas and European guidelines: importance of the surgery type in the decision-making process.

BACKGROUND: The European Consensus 2018 established a new algorithm with absolute and relative criteria for intraductal papillary mucinous neoplasms of the pancreas (IPMN) management. The aim of this study was to validate these criteria and analyse the outcomes in function of the surgical procedure and IPMN subtype. METHODS: Clinical, radiological and surgical data (procedure, morbidity/mortality rates) of patients who underwent surgery for IPMN between 2007 and 2017. The predictive value of the different criteria was analysed. RESULTS: 124 patients (men 67%; mean age 65 years) underwent surgery for IPMN (n = 62 malignant tumours; 50%). Jaundice, cyst ≥4 cm and Wirsung duct size 5-9.9 mm or ≥ 10 mm were significantly associated with malignancy (4.77 < OR < 11.85 p < 0.0001). The positive predictive value of any isolated criterion ranged from 71 to 87%, whereas that of three relative criteria together reached 100%. The mortality and morbidity (grade III-IV complications according to the Dindo-Clavien classification) rates were 3 and 8%, respectively. Morbidity/mortality after duodenopancreatectomy and total pancreatectomy were significantly higher for benign IPMN (p = 0.01). CONCLUSION: Considering the morbidity associated with extended surgery, particularly for benign IPMN, the results of the present study suggest that high-risk surgery should be considered only in the presence of three relative criteria and including the surgery type in the decision-making algorithm.

Syndecan-1 regulates adipogenesis: new insights in dedifferentiated liposarcoma tumorigenesis.

Syndecan-1 (SDC1/CD138) is one of the main cell surface proteoglycans and is involved in crucial biological processes. Only a few studies have analyzed the role of SDC1 in mesenchymal tumor pathogenesis. In particular, its involvement in adipose tissue tumors has never been investigated. Dedifferentiated liposarcoma, one of the most frequent types of malignant adipose tumors, has a high potential of recurrence and metastastic evolution. Classical chemotherapy is inefficient in metastatic dedifferentiated liposarcoma and novel biological markers are needed for improving its treatment. In this study, we have analyzed the expression of SDC1 in well-differentiated/dedifferentiated liposarcomas and showed that SDC1 is highly overexpressed in dedifferentiated liposarcoma compared with normal adipose tissue and lipomas. Silencing of SDC1 in liposarcoma cells impaired cell viability and proliferation. Using the human multipotent adipose-derived stem cell model of human adipogenesis, we showed that SDC1 promotes proliferation of undifferentiated adipocyte progenitors and inhibits their adipogenic differentiation. Altogether, our results support the hypothesis that SDC1 might be involved in liposarcomagenesis. It might play a prominent role in the dedifferentiation process occurring when well-differentiated liposarcoma progress to dedifferentiated liposarcoma. Targeting SDC1 in these tumors might provide a novel therapeutic strategy.

Pulmonary artery pseudoaneurysm after radiofrequency ablation: report of two cases.

We report two cases of pulmonary arterial pseudoaneurysms (PAs) following percutaneous radiofrequency ablation (PRFA). The first patient was a 74-year-old Caucasian man who was treated for a secondary location of an advanced melanoma. A computed tomography scan at 72 h after the procedure, performed for basithoracic pain, hyperthermia and haemoptysis, revealed a 17-mm PA within the ablative zone. A lobectomy was performed. The second patient was an 80-year-old white man followed up for a right apical lung adenocarcinoma. Massive haemoptysis occurred 24 h after PRFA; emergent contrast-enhanced CT and pulmonary arteriography revealed a pulmonary artery PA (20 mm diameter), which was embolised with coils. The initial clinical course was satisfactory; however, 15 days after the procedure, the patient unfortunately presented a new massive haemoptysis and died a few hours later. The long ablation duration and the multiple repositioning of the electrodes might have been risk factors for this rare and potentially lethal complication.

[Prevention and screening of cervical cancer]. / Prévention et dépistage des cancers du col de l'utérus.

Cervical cancer may be prevented by human papillomavirus (HPV) vaccination and the treatment of intraepithelial lesions diagnosed using cervical pap smears. HPV vaccines are effective for the prevention of CIN2/3 related to HPV 16, 18 and some other oncogenic HPV subtypes in HPV-naïve women. They are very well tolerated and to date, no increase in the incidence of auto-immune diseases has been reported. HPV vaccines primarily target girls aged 11-14 years old and catch-up programs include girls aged 15-19 years old. Vaccination coverage is below 40% in France, which is insufficient to induce herd immunity. Screening via pap smears is performed every three years in women between 25 and 65 years old, after two normal annual smears. However, screening is an individualised decision and is only performed in 57% of women. Abnormal smears require subsequent diagnostic investigations. Apart from high grade intra-epithelial lesions which generally require treatment, these abnormalities may be observed as they often undergo spontaneous regression due to viral clearance.

Reducing reflex first-line prescriptions in a surgical pathology laboratory: toward sustainable practice with positive economic and clinical effects.

In surgical pathology departments, reflex first-line techniques (RFLTs) are aimed at reducing workloads and addressing recent shortages of medical personnel. However, the impacts thereof on economic and diagnostic factors have been poorly addressed. Also, in the era of global warming, environmental considerations are crucial. This study assessed the economic and diagnostic efficacies of routine pathological RFLT and the quality of care and sustainability. Ten RFLTs of the Bordeaux University Hospital pathology department (six special stains, one cytology technique, and three immunohistochemical tests) were studied. First, a retrospective economic analysis evaluated the average cost of these RFLTs per slide and per year. Second, diagnostic relevance was prospectively surveyed. Third, the effects of changes made were analyzed over 2 years. The ten RFLTs were associated with average annual costs of €46,708. Diagnostic relevance analysis indicated that most stains were unnecessary; only 17% were requested as second-line techniques. Elimination of 7/10 tests afforded annual cost savings of €22,522 and reduced the workload by 5568 tests/year, without compromising the workflow or diagnostic quality. Seven of ten RFLTs could be eliminated without compromising diagnostic quality or the workflow. This afforded not only financial benefits but also positive social and environmental impacts. We offer valuable insights into appropriate practices in surgical pathology laboratories. Collaboration between the medical and technical teams was crucial; other healthcare sectors would also benefit from our approach.

Droplet digital polymerase chain reaction detection of KRAS mutations in pancreatic FNA samples: Technical and practical aspects for routine clinical implementation.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) is associated with a 5-year survival rate of less than 6%, and current treatments have limited efficacy. The diagnosis of PDAC is mainly based on a cytologic analysis of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples. However, the collected specimens may prove noncontributory in a significant number of cases, delaying patient management and treatment. The combination of EUS-FNA sample examination and KRAS mutation detection can improve the sensitivity for diagnosis. In this context, the material used for molecular analysis may condition performance. METHODS: The authors prospectively compared the performance of cytologic analysis combined with a KRAS droplet digital polymerase chain reaction (ddPCR) assay for PDAC diagnosis using either conventional formalin-fixed, paraffin-embedded cytologic samples or needle-rinsing fluids. RESULTS: Molecular testing of formalin-fixed, paraffin-embedded cytologic samples was easier to set up, but the authors observed that the treatment of preanalytic samples, in particular the fixation process, drastically reduced ddPCR sensitivity, increasing the risk of false-negative results. Conversely, the analysis of dedicated, fresh needle-rinsing fluid samples appeared to be ideal for ddPCR analysis; it had greater sensitivity and was easily to implement in clinical use. In particular, fluid collection by the endoscopist, transportation to the laboratory, and subsequent freezing did not affect DNA quantity or quality. Moreover, the addition of KRAS mutation detection to cytologic examination improved diagnosis performance, regardless of the source of the sample. CONCLUSIONS: Considering all of these aspects, the authors propose the use of an integrated flowchart for the KRAS molecular testing of EUS-FNA samples in clinical routine.

Let-7 microRNA and HMGA2 levels of expression are not inversely linked in adipocytic tumors: analysis of 56 lipomas and liposarcomas with molecular cytogenetic data.

The aim of our study was first to assess the role of HMGA2 expression in the pathogenesis of adipocytic tumors (AT) and, second, to seek a potential correlation between overexpression of HMGA2 and let-7 expression inhibition by analyzing a series of 56 benign and malignant AT with molecular cytogenetic data. We measured the levels of expression of HMGA2 mRNA and of eight members of the let-7 microRNA family using quantitative RT-PCR and expression of HMGA2 protein using immunohistochemistry. HMGA2 was highly overexpressed in 100% of well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS), all with HMGA2 amplification, and 100% of lipomas with HMGA2 rearrangement. Overexpression of HMGA2 mRNA was detected in 76% of lipomas without HMGA2 rearrangement. HMGA2 protein expression was detected in 100% of lipomas with HMGA2 rearrangement and 48% of lipomas without HMGA2 rearrangement. We detected decreased expression levels of some let-7 members in a significant proportion of AT. Notably, let-7b and let-7g were inhibited in 61% of WDLPS/DDLPS. In lipomas, each type of let-7 was inhibited in approximately one-third of the cases. Although overexpression of both HMGA2 mRNA and protein in a majority of ordinary lipomas without HMGA2 structural rearrangement may have suggested a potential role for let-7 microRNAs, we did not observe a significant link with let-7 inhibition in such cases. Our results indicate that inhibition of let-7 microRNA expression may participate in the deregulation of HMGA2 in AT but that this inhibition is neither a prominent stimulator for HMGA2 overexpression nor a surrogate to genomic HMGA2 rearrangements.

Regression of cervical high-grade squamous intraepithelial lesions (HSIL/CIN2) managed expectantly.

OBJECTIVES: Many women with cervical high-grade squamous intraepithelial lesions (HSIL/CIN2) are managed expectantly, because about half of them will regress spontaneously, thus avoiding systematic loop electrosurgical excision procedure and related adverse effects. However, most of the guidelines have restricted this strategy to the youngest women. The objectives of our study were to determine the rate and the predictors of regression of HSIL/CIN2 managed expectantly. STUDY DESIGN: This retrospective study included 128 patients under 40 years of age (median 29, range 21-39), and HSIL/CIN2 diagnosed by biopsy between 2012 and 2019. They were followed-up without treatment in the department of gynecology at Bordeaux University Hospital, France. The regression of HSIL/CIN2 was defined by the regression or the disappearance of initial colposcopic findings, cytological and/or histological results. RESULTS: The lesion spontaneously regressed or disappeared in 76 (59%) patients during a median follow-up of 25 months (range, 7-86). In the multivariable analysis, minor change at colposcopy (odds ratio OR = 2.8 (CI95% 1.2-6.9), P = 0.02), low grade lesions (ASC-US/LSIL) by cytology (OR = 4.1 (CI95% 1.7-10.1), P < 0.001), and infection by HPV other than HPV-16 (OR = 5.4 (CI95% 2.3-13.9), P < 0.001) predicted the spontaneous regression of HSIL/CIN2. CONCLUSIONS: Colposcopic findings, cytological results, and HPV genotyping, but not the age, were baseline factors predicting the evolution of HSIL/CIN2 in patients under 40.

KRAS gene mutation quantification in the resection or venous margins of pancreatic ductal adenocarcinoma is not predictive of disease recurrence.

Pancreatic ductal adenocarcinoma (PDAC) patients eligible for curative surgery undergo unpredictable disease relapse. Even patients with a good pathological response after neoadjuvant treatment (NAT) remain susceptible to recurrent PDAC. Molecular analysis of R0 margins may identify patients with a worse prognosis. The molecular status of mutant KRAS (exon 2, codon 12/13) was analysed retrospectively by digital droplet PCR in tumour areas, venous and resection margins of resected tumours, either undergoing up-front surgery (UFS) or after NAT with a good pathological response. Expectedly, tumour tissues or remnants from patients who underwent NAT presented lower KRAS mutant allele frequencies (MAF) than patients eligible for UFS. Similarly, ypT1 tumour MAFs were greater than the ypT0 tumour remnant MAFs in the NAT group. Mutant KRAS status in margins did not distinguish NAT subgroups. It was not predictive of shorter recurrence-free or overall survival within or between groups. KRAS-double negativity in both venous and resection margins did not identify patients with a better prognosis, regardless of the groups. The cohorts 'sizes were small due to limited numbers of patients meeting the inclusion criteria, but KRAS-positivity or MAFs in resection and venous margins did not carry prognostic value. Comparison of margins from good versus bad responders receiving NAT may provide better clinical value.

Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases.

The high mobility group A (HMGA2) gene encodes a protein that alters chromatin structure and regulates the transcription of many genes; it is implicated in both benign and malignant neoplasias, but its rearrangements are a feature of development of several mesenchymal tumors. Given its implication in these tumors and particularly adipocytic tumors, and the availability of antibodies usable on paraffin-embedded tissues, we evaluated the immunohistochemical expression of this gene in a series of 1052 mesenchymal tumors. The objective was to define the value and limitations of HMGA2 immunohistochemical expression for histotyping, and compare with molecular data reported in the literature. We thus analyzed 880 cases on tissue microarray and 182 cases on whole sections (211 adipocytic tumors, 628 sarcomas, 213 benign mesenchymal tumors, and 10 normal adipose tissues). A nuclear immunostaining was detected in 86% of conventional and intramuscular lipomas, in 86% of well-differentiated liposarcomas and in 67% of dedifferentiated liposarcomas, as opposed to 16% of other benign adipose tumors and to 15% of non-well-differentiated liposarcoma/dedifferentiated liposarcoma sarcomas. Among benign mesenchymal tumors and lesions, it was detected in 90% of nodular fasciitis and in 88% of benign fibrous histiocytomas with respective specificities of 85 and 100%, and in 90% of aggressive angiomyxoma, contrary to other vulvovaginal tumor types, which expressed HMGA2 only rarely. The normal adipose tissue was always negative for HMGA2. Although not specific, immunohistochemical detection of the HMGA2 protein is helpful for the distinction of normal adipose tissue from well-differentiated lesions, particularly on biopsy or on re-excision. It is less sensitive than MDM2/CDK4 for dedifferentiated liposarcomas diagnosis, but it appears more specific to distinguish dedifferentiated liposarcomas from other poorly differentiated sarcomas. Finally, and may be more importantly, HMGA2 is useful for the diagnosis of benign fibrous histiocytoma, nodular fasciitis and vulvovaginal benign mesenchymal tumors.

[Adenoid cystic carcinoma of the breast: clinical, histological and immunohistochemical characterization]. / Le carcinome adénoïde kystique du sein: étude clinique, histologique, immunohistochimique et revue de la littérature.

BACKGROUND: Adenoid cystic carcinoma (ACC) of the Breast is a rare tumour (less than 1 % of all breast carcinomas). The aim of this study was to determine the clinical, histological and immunohistochemical characteristics of these tumours. METHODS: From the database of the Bergonié Institute of Bordeaux, 30 cases of ACC were identified. The clinical and histological features of these carcinomas were characterized. An immunohistochemical study was performed with the following antibodies: ER, PR, HER-2-neu, Vimentin, EGFR, P63, SMA, CK5/6, CK8/18, CK14, cKIT, MIB1, CD44 and CD24. RESULTS: Thirty patients were included (median age 60.7 years). The 10 axillary lymph node dissections and two sentinel lymph procedures were negative. The architecture was frequently of a mixed type (26/30) and less often solid (4/30). Among the 23 patients for whom follow up was available (median follow-up: 84 months [2-288]), there were three local recurrences and three metastatic events. The tumors with recurrence and metastasis showed more necrosis, a mitotic count greater than 4/10hpf, and in one case perineural infiltration. All the tumours were ER, PR and Her-2-neu negative. Morphological and immunophenotypical analysis disclosed in each tumor, a basaloid and a luminal cell population with divergent immunophenotypical patterns. CONCLUSIONS: The mammary ACC is made of two cell types and is of good prognosis despite its triple negative phenotype, similar to the basal-like infiltrating carcinoma NOS. Axillary lymph node dissection is not recommended. Good local control by at least large lumpectomy with long-term follow-up is necessary.

FOLFIRINOX-based neoadjuvant chemoradiotherapy for borderline and locally advanced pancreatic cancer: A pilot study from a tertiary centre.

BACKGROUND: Neoadjuvant chemoradiotherapy, potentially relevant to increase resection rate in pancreatic cancer, is still debated. AIMS: To assess tolerance, resection rate and outcomes of patients with non-metastatic pancreatic ductal adenocarcinoma treated by concomitant chemoradiotherapy. METHODS: This monocentric study included all consecutive patients treated from 2010 to 2014 for non-metastatic pancreatic adenocarcinoma. Chemotherapy was followed by chemoradiotherapy in operable patients, surgical resectability being assessed by CT-scan. RESULTS: Seventy-nine patients were included: 41 patients had borderline and 38 locally advanced tumours. All patients were treated by chemotherapy (FOLFIRINOX), followed by chemoradiotherapy (median dose: 59 Gy, range 45-66 Gy) for 94% of patients. Thirty-seven patients (47%) could subsequently benefit from surgery with a complete R0 resection in 94% of cases, with a postoperative mortality of 5%. Median overall survival was 21.5 months (median follow-up: 48.8 months). Local control, overall and disease-free survival were significantly higher for patients who underwent resection compared to others, with 89.2% vs 59.5% (p = 0.01), 49.7 vs 17.4 months (p < 0.01) and 25.5 vs 9.2 months (p < 0.01), respectively. CONCLUSION: Neoadjuvant treatment consisting of FOLFIRINOX chemotherapy followed by chemoradiotherapy is an efficient strategy for patients with borderline and locally advanced pancreatic cancer, resulting in a 43% rate of secondary complete surgical resection associated with high local control, overall and disease-free survival.

High Clinical Value of Liquid Biopsy to Detect Circulating Tumor Cells and Tumor Exosomes in Pancreatic Ductal Adenocarcinoma Patients Eligible for Up-Front Surgery.

PURPOSE: Expediting the diagnosis of pancreatic ductal adenocarcinoma (PDAC) would benefit care management, especially for the start of treatments requiring histological evidence. This study evaluated the combined diagnostic performance of circulating biomarkers obtained by peripheral and portal blood liquid biopsy in patients with resectable PDAC. EXPERIMENTAL DESIGN: Liquid biopsies were performed in a prospective translational clinical trial (PANC-CTC #NCT03032913) including 22 patients with resectable PDAC and 28 noncancer controls from February to November 2017. Circulating tumor cells (CTCs) were detected using the CellSearch® method or after RosetteSep® enrichment combined with CRISPR/Cas9-improved KRAS mutant alleles quantification by droplet digital PCR. CD63 bead-coupled Glypican-1 (GPC1)-positive exosomes were quantified by flow cytometry. RESULTS: Liquid biopsies were positive in 7/22 (32%), 13/22 (59%), and 14/22 (64%) patients with CellSearch® or RosetteSep®-based CTC detection or GPC1-positive exosomes, respectively, in peripheral and/or portal blood. Liquid biopsy performance was improved in portal blood only with CellSearch®, reaching 45% of PDAC identification (5/11) versus 10% (2/22) in peripheral blood. Importantly, combining CTC and GPC1-positive-exosome detection displayed 100% of sensitivity and 80% of specificity, with a negative predictive value of 100%. High levels of GPC1+-exosomes and/or CTC presence were significantly correlated with progression-free survival and with overall survival when CTC clusters were found. CONCLUSION: This study is the first to evaluate combined CTC and exosome detection to diagnose resectable pancreatic cancers. Liquid biopsy combining several biomarkers could provide a rapid, reliable, noninvasive decision-making tool in early, potentially curable pancreatic cancer. Moreover, the prognostic value could select patients eligible for neoadjuvant treatment before surgery. This exploratory study deserves further validation.

CD63-GPC1-Positive Exosomes Coupled with CA19-9 Offer Good Diagnostic Potential for Resectable Pancreatic Ductal Adenocarcinoma.

Tumor-released extracellular vesicles (EVs) contain tumor-specific cargo distinguishing them from healthy EVs, and making them eligible as circulating biomarkers. Glypican 1 (GPC1)-positive exosome relevance as liquid biopsy elements is still debated. We carried out a prospective study to quantify GPC1-positive exosomes in sera from pancreatic ductal adenocarcinoma (PDAC) patients undergoing up-front surgery, as compared to controls including patients without cancer history and patients displaying pancreatic preneoplasic lesions. Sera were enriched in EVs, and exosomes were pulled down with anti-CD63 coupled magnetic beads. GPC1-positive bead percentages determined by flow cytometry were significantly higher in PDAC than in the control group. Diagnosis accuracy reached 78% (sensitivity 64% and specificity 90%), when results from peripheral and portal blood were combined. In association with echo-guided-ultrasound-fine-needle-aspiration (EUS-FNA) negative predictive value was 80% as compared to 33% for EUS-FNA only. This approach is clinically relevant as a companion test to the already available diagnostic tools, since patients with GPC1-positive exosomes in peripheral blood showed decreased tumor free survival.

Pathologic complete response to trastuzumab-based neoadjuvant therapy is related to the level of HER-2 amplification.

PURPOSE: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are used to determine human epidermal growth factor receptor-2 (HER-2) status and patient eligibility for trastuzumab therapy. Using FISH and IHC, we analyzed the relationship between pathologic complete response to trastuzumab-based neoadjuvant therapy and level of HER-2 amplification in locally advanced breast cancer. EXPERIMENTAL DESIGN: Breast biopsies from 93 HER-2-positive patients treated with trastuzumab-based neoadjuvant therapy were centrally collected and analyzed retrospectively for HER-2 amplification using FISH and HER-2 overexpression using IHC. Tumors were classified by FISH as no, low, or high amplification. Biopsies were reassessed centrally by IHC and graded 0, 1+, 2+, or 3+. RESULTS: HER-2 status of tumor samples as assessed by FISH and IHC correlated: 16 no amplification (11 IHC 1+ and 5 IHC 2+), 27 low amplification (26 IHC 3+ and 1 IHC 2+), and 50 high amplification (all IHC 3+). Trastuzumab-based neoadjuvant therapy achieved pathologic complete response in 35 of 93 (37.6%) tumors. Pathologic complete response rate in low- and high-amplification tumors was significantly higher than in no-amplification tumors (44% versus 6%; P < 0.004). Pathologic complete response rate in high-amplification tumors was significantly higher compared with low-amplification tumors (56% versus 22%; P < 0.005). In the subgroup of low- plus high-amplification tumors, no correlation was found between pathologic complete response rate and IHC score, treatment regimen, T or N stage, tumor grade, or hormonal receptors. CONCLUSIONS: This is the first study to show positive correlation between level of HER-2 amplification assessed by FISH and rate of pathologic complete response to trastuzumab-based neoadjuvant treatment.

Histologic analysis has a prognostical value in colorectal biopsies assessed for suspicion of graft-versus-host disease.

Gastrointestinal (GI) graft-versus-host-disease (GVHD) is a common and severe complication of allogeneic hematopoietic stem cell transplantation, but clinical and histological features are unspecific. The aim of this study was to correlate the histological GI GVHD grade with the clinical outcomes. In a retrospective study of 112 patients with clinically suspected GI GVHD, colonic biopsies were reviewed by three pathologists without knowledge of the corresponding clinical data and classified in four scores, according to the NIH Consensus Project recommendations: no GVHD, possible, probable, and unequivocal GVHD. At the end of the study, the histological and clinical data were confronted with the following results: clinical diagnosis of GI GVHD was established for 70 patients (62.5%) and histological scores correlated well with the clinical diagnosis (p < 0.001) and particularly with the prognosis (p < 0.05).When severe lesions were observed, the 1 year overall survival declined to 9%. None of the features reported in the literature to support GVHD diagnosis, eosinophil count, endocrine cells aggregate, immunohistochemical analysis (cytomegalovirus, CD123, chromogranin), did not help us for diagnosis. So routine histopathology alone without immunohistochemistry is a strong and reproducible tool to diagnose GI GVHD with the help of clinical and biological information, and most importantly, histological grading proved to be a powerful prognostic value.