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Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age 35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR)

Human papillomavirus (HPV) in oral carcinoma (OSCC) and potentially malignant disorders (OPMD) is controversial. The primary aim was to calculate pooled risk estimates for the association of HPV with OSCC and OPMD when compared with healthy oral mucosa as controls. We also examined the effects of sampling techniques on HPV detection rates. Methods: Systematic review was performed using PubMed (January 1966-September 2010) and EMBASE (January 1990-September 2010). Eligible studies included randomized controlled, cohort and cross-sectional studies. Pooled data were analysed by calculating odds ratios, using a random effects model. Risk of bias was based on characteristics of study group, appropriateness of the control group and prospective design. Results: Of the 1121 publications identified, 39 cross-sectional studies met the inclusion criteria. Collectively, 1885 cases and 2248 controls of OSCC and 956 cases and 675 controls of OPMD were available for analysis. Significant association was found between pooled HPV-DNA detection and OSCC (OR=3.98; 95% CI: 2.62-6.02) and even for HPV16 only (OR=3.86; 95% CI: 2.16-6.86). HPV was also associated with OPMD (OR=3.87; 95% CI: 2.87-5.21). In a subgroup analysis of OPMD, HPV was also associated with oral leukoplakia (OR=4.03; 95% CI: 2.34-6.92), oral lichen planus (OR=5.12; 95% CI: 2.40-10.93), and epithelial dysplasia (OR=5.10; 95% CI: 2.03-12.80). Conclusions: The results suggest a potentially important causal association between HPV and OSCC and OPMD. © 2011 John Wiley & Sons A/S.

Percutaneous core biopsy (CB) has been introduced to increase the ability of accurately diagnosing breast malignancies without the need of resorting to surgery. Compared to conventional automated 14 gauge needle core biopsy (NCB), vacuum-assisted needle core biopsy (VANCB) allows obtaining larger specimens and has recognized advantages particularly when the radiological pattern is represented by microcalcifications. Regardless of technical improvements, a small percentage of percutaneous CBs performed to detect breast lesions are still classified, according to European and UK guidelines, in the borderline B3 category, including a group of heterogeneous lesions with uncertain malignant potential. We aimed to assess the prevalence and positive predictive values (PPV) on surgical excision (SE) of B3 category (overall and by sub-categories) in a large series of non-palpable breast lesions assessed through VANCB, also comparison with published data on CB. Overall, 26,165 consecutive stereotactic VANCB were identified in 22 Italian centres: 3107 (11.9%) were classified as B3, of which 1644 (54.2%) proceeded to SE to establish a definitive histological diagnosis of breast pathology. Due to a high proportion of microcalcifications as main radiological pattern, the overall PPV was 21.2% (range 10.6%-27.3% for different B3 subtypes), somewhat lower than the average value (24.5%) from published studies (range 9.9%-35.1%). Our study, to date the largest series of B3 with definitive histological assessment on SE, suggests that B3 lesions should be referred for SE even if VANCB is more accurate than NCB in the diagnostic process of non-palpable, sonographically invisible breast lesions.

Light microscopic, ultrastructural and immunohistochemical features of a case of primary meningioma of the lung are described in this report. The lesion was incidentally discovered in the right lung of a 68-year-old man and treated by lobe resection. No evidence of recurrence or metastasis has been detected 2 years after surgery. The literature is reviewed and the differential diagnosis from other neoplasms presenting as coin lesions in the lung is stressed. Different histogenetical theories and the relation to so-called "minute pulmonary chemodectomas" are discussed.

This article describes the clinical aspects and the histologic features of three cases of gingival cyst of the adult. The diagnostic problems of this rare entity are discussed. Radiographic examination to determine the presence of bone loss must be undertaken to differentiate the gingival cyst of the adult from the more frequent lateral periodontal cyst.

We describe a case in which nodular macroglossia, a very rare type of tongue involvement, was associated with the co-deposition of lambda light chain and beta-2 microglobulin fibrils in the tongue. The combined presence of two different amyloid fibrils did not lead to a more unfavourable clinical outcome. We believe that both these features often remain underdiagnosed and are in fact more frequent than reported. A careful clinical examination of the tongue together with serum immunofixation should be routine in all patients with dialysis-related amyloidosis in order to investigate the prevalence and type of tongue involvement and to rule out other types of amyloidosis. In all cases of suspected mixed amyloidosis, immunohistochemical characterization of fibrils should be carried out by electron microscopy.

The aim of this study was to evaluate the prognostic impact of quantitative estrogen receptor (ER) expression at relapse for ER-positive breast cancer with ER-positive recurrence.A total of 81 patients with ER-positive primary breast cancer and ER-positive paired recurrence were included. ER expression was evaluated as the percentage of tumor cells staining for ER under immunohistochemistry. Samples were defined as ER-high (ER50%) or ER-low (ER≥10% and ≤50%).Quantitative ER expression on relapse biopsy was an independent prognostic factor for overall survival in multivariate analysis, both as a continuous (hazard ratio=0.8; 95% confidence interval=0.7-0.92, p=0.001) and as a categorical (ER-high vs. ER-low; hazard ratio=0.26; 95% confidence interval=0.11-0.59, p=0.001) variable. Patients whose status changed from ER-high (primary BC) to ER-low (relapse) had the poorest outcome, with a 10-year overall survival rate of 14%.Even in the case of maintenance of ER-positivity on primary and relapse of breast cancer, recurrence biopsy provides prognostic information.

PURPOSE: The aim was to evaluate the role of tumor-infiltrating lymphocytes (TIL) in predicting molecular response after preoperative endocrine or cytotoxic treatment for HR+/HER2- patients who do not achieve a pathological complete response. METHODS: Stromal (Str) TIL were centrally evaluated on samples from diagnostic core-biopsies of HR+/HER2- patients included in two prospective randomized trials: the LETLOB trial (neoadjuvant endocrine-based treatment) and the GIOB trial (neoadjuvant chemotherapy-based treatment). Pre- and post-treatment Ki67 was centrally assessed. RESULTS: StrTIL were evaluable in 111 cases (n = 73 from the LETLOB trial and n = 38 from the GIOB trial). Median StrTIL was 2%. Patients with high StrTIL (StrTIL ≥10%, n = 28) had more frequently breast cancer of ductal histology (p = 0.02), high grade (p = 0.049), and high Ki67 (p = 0.02). After neoadjuvant endocrine treatment (LETLOB cohort), a significant Ki67 suppression (p < 0.01) from pre- to post-treatment was observed in both the low and high StrTIL groups. High StrTIL patients achieve more frequently a relative Ki67 suppression ≥50% from baseline as compared to low StrTIL patients (55 vs. 35%, p non significant). After neoadjuvant chemotherapy (GIOB cohort), a significant Ki67 suppression was observed only for low StrTIL patients (Wilcoxon p = 0.001) and not in the high StrTIL group (p = 0.612). In this cohort, the rate of patients achieving a relative Ki67 suppression ≥50% from baseline was significantly higher in the low vs high StrTIL group (64% vs 10%, p = 0.003). Geometric mean Ki67 suppression was evaluated in each cohort according to StrTIL: the lowest value (-41%) was observed for high StrTIL cases treated with chemotherapy. CONCLUSIONS: This hypothesis-generating study suggests that in HR+/HER2- breast cancer StrTIL at baseline may influence the achievement of a molecular response after neoadjuvant treatment. Further evaluation in large studies is needed, and interaction with the type of treatment warrants to be explored.

// Giulia Orsi 1 , Monica Barbolini 1 , Guido Ficarra 2, 3 , Giovanni Tazzioli 1, 3 , Paola Manni 2 , Tiziana Petrachi 1 , Ilenia Mastrolia 1 , Enrico Orvieto 4 , Carlotta Spano 1 , Malvina Prapa 1 , Shaniko Kaleci 5 , Roberto D’Amico 5 , Valentina Guarneri 6 , Maria Vittoria Dieci 6 , Stefano Cascinu 1 , Pierfranco Conte 6 , Federico Piacentini 1, 3, * , Massimo Dominici 1, * 1 Department of Medical and Surgical Sciences for Children and Adults, University-Hospital of Modena and Reggio Emilia, 71-41124 Modena, Italy 2 Division of Pathology, University-Hospital of Modena and Reggio Emilia, 71-41124 Modena, Italy 3 Breast Unit, University-Hospital of Modena and Reggio Emilia, 71-41124 Modena, Italy 4 Department of Pathology, Padua University Hospital, 2-35128 Padua, Italy 5 Department of Diagnostic and Clinical Medicine and Public Health, Statistics Unit, University-Hospital of Modena and Reggio Emilia, 71-41124 Modena, Italy 6 Department of Surgery, Oncology and Gastroenterology, Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Via Gattamelata, 64-35128 Padua, Italy * These authors contributed equally to this work Correspondence to: Massimo Dominici, email: massimo.dominici@unimore.it Keywords: GD2, disialoganglioside, BC, TNBC, metaplastic Received: November 04, 2016 Accepted: March 09, 2017 Published: March 18, 2017 ABSTRACT Breast cancer (BC) is a heterogeneous disease, including different subtypes having diverse incidence, drug-sensitivity and survival rates. In particular, claudin-low and basal-like BC have mesenchymal features with a dismal prognosis. Disialoganglioside GD2 is a typical neuroectodermal antigen expressed in a variety of cancers. Despite its potential relevance in cancer diagnostics and therapeutics, the presence and role of GD2 require further investigation, especially in BC. Therefore, we evaluated GD2 expression in a cohort of BC patients and its correlation with clinical-pathological features. Sixty-three patients with BC who underwent surgery without prior chemo- and/or radiotherapy between 2001 and 2014 were considered. Cancer specimens were analyzed by immunohistochemistry and GD2-staining was expressed according to the percentage of positive cells and by a semi-quantitative scoring system. Patient characteristics were heterogeneous by age at diagnosis, histotype, grading, tumor size, Ki-67 and receptor-status. GD2 staining revealed positive cancer cells in 59% of patients. Among them, 26 cases (41%) were labeled with score 1+ and 11 (18%) with score 2+. Notably, the majority of metaplastic carcinoma specimens stained positive for GD2. The univariate regression logistic analysis revealed a significant association of GD2 with triple-receptor negative phenotype and older age (> 78) at diagnosis. We demonstrate for the first time that GD2 is highly prevalent in a cohort of BC patients clustering on very aggressive BC subtypes, such as triple-negative and metaplastic variants.

Pulse granuloma is a rare benign entity considered to be a foreign-body reaction to vegetables particles. It occurs most frequently in the oral cavity of edentulous patients wearing a complete mobile denture, associated with impacted lower third molar or in postextractive alveolar sockets. The authors analyzed 2 cases by both optical and confocal laser scanning microscopy, a research technique based on laser light microscopic analysis of biological samples stained for fluorescence observation. CLSM allowed improved tissue imaging, bidimensional pictures with better resolution at cellular level, and, in particular, the possibility of a three-dimensional image reconstruction. In conclusion, this study reports the fine definition of pulse granuloma at microscopic level by CLSM and the results warrant the use of this technique for further analyses.

Ameloblastomas are considered to be aggressive and locally invasive neoplasms derived from odontogenic epithelium with a tendency for recurrence and bone destruction. Although the relationship between nevoid basal cell carcinoma syndrome (NBCCS) and ameloblastoma is less frequent, it might constitute a peculiar stigmata of this hereditary disorder. The objective of the current study was to evaluate whether a combined clinical and biomolecular approach could be useful for the identification of NBCCS among patients with a diagnosis of ameloblastoma. The authors collected ameloblastoma tumors recorded in the databases of the Pathology Departments of the University of Modena during the period 1991–2011. Family trees were drawn for all 41 patients affected by these specific odontogenic tumors. Two patients with ameloblastoma were also affected by multiple basal cell carcinomas and odontogenic keratocysts tumors (OKCTs) achieving the requested clinical criteria for the diagnosis of NBCCS. The clinical diagnoses were confirmed by the identification of two different novel PTCH1 germline mutations (c.2186A > T [p.K729 M]; c.931insA) in those unrelated patients. Clinical ameloblastoma findings can be used as screening for the identification of families at risk of NBCCS. Ameloblastomas diagnosis warrants the search for associated cutaneous basal cell carcinomas and other benign and malignant tumors related to NBCCS. Thus, we propose the inclusion of ameloblasoma as criterion for the identification of NBCCS.

Objective: Orofacial granulomatosis (OFG) is a rare condition characterized by non-caseating granulomas in the orofacial region. Protease-Activated Receptors (PARs) play a role in inflammatory diseases in diverse human tissues. The aim of the study was to investigate the expression of PAR-1, PAR-2, MMP-2, MMP-9, COX-1, and COX-2 in tissues taken from OFG patients. Methods: PAR-1, PAR-2, MMP-2, MMP-9, COX-1, and COX-2 expression was evaluated by immunohistochemistry in biopsies taken from oral Crohn's disease (five cases), Melkersson–Rosenthal syndrome (MRS) (six cases), cheilitis granulomatosa (five cases) and normal oral mucosa (five cases). Results: PAR-1 was observed in mononuclear inflammatory cells in edematous/lichenoid lesions, whereas a strong PAR-2 immunostaining was detected in epithelioid histiocytes and giant cells in granulomatous lesions, irrespective of the clinical features (Crohn vs MRS). MMPs and COX-2 were expressed in the inflammatory component of edematous/lichenoid lesions and markedly overexpressed in granulomatous lesions. COX-1 was weakly and variably expressed in both edematous/lichenoid and granulomatous lesions. Conclusion: Thus, PAR-1 and PAR-2 expressions were related to the intensity and type of inflammatory response but not to the type of clinical lesion. Simultaneous overexpression of PARs, MMPs and COXs suggests synergism among these proinflammatory receptors and enzymes.

We report three cases of polymorphous adenocarcinoma (PLA) of the breast in 37-, 55- and 74-year-old women, respectively. The patients have no evidence of previous malignancy. The tumours consist of monotonous cells showing a wide spectrum of growth patterns: solid nests, trabeculae, tubules, cribriform structures, strands and fascicles reminiscent of polymorphous low-grade adenocarcinoma of salivary glands. To our knowledge, PLA has never been reported in the breast; therefore, this tumour should be added to the list of neoplastic lesions of the breasts that have the same features as those of the salivary glands.

Transthyretin (TTR) amyloidosis is a form of systemic amyloidosis caused by an amyloidogenetic TTR variant. The most common mutant forms of TTR are mainly produced by the liver and therefore orthotopic liver transplantation (OLT) is currently accepted as the only known curative treatment. We describe the clinical and pathological features of a patient with TTR variant (gly53glu) with TTR amyloid infiltration of the leptomeningeal vessels in whom fatal cerebral haemorrhage occurred two months after OLT, soon after severe viral pneumonia.