Cristiano Lanza

Role of acid and bile reflux in development of specialised intestinal metaplasia in distal oesophagus

BACKGROUND Barretts oesophagus is defined as specialised intestinal metaplasia in the distal oesophagus, regardless of extension. AIM To study distal oesophagus function, and acid and bile exposure in patients with Long Segment (>3 cm), Short Segment (1 to 2 cm) and Ultra-short Segment (<1 cm) Barretts Oesophagus, and in patients with gastro-oesophageal reflux disease without intestinal metaplasia. PATIENTS Study population comprised 17 patients with Long, 8 with Short, 9 with Ultra-Short Segment Barretts oesophagus, 32 with reflux disease and 12 healthy volunteers. METHODS Patients were evaluated by manometry and by 24-hour pH and bile monitoring. RESULTS Patients with intestinal metaplasia had greater acid exposure of the distal oesophagus than healthy volunteers. Patients with Long Segment Barretts oesophagus had a longer history of symptoms, worse lower oesophageal sphincter pressures and longer bile and acid exposure than the other patients. Long Segment Barretts oesophagus was predicted by low oesophageal pressure and increased bile exposure, age and male sex. CONCLUSION Acid exposure in the distal oesophagus is probably the aetiological factor behind intestinal metaplasia, but a severely damaged antireflux barrier and bile in the refluxate are necessary for Long Segment Barretts Oesophagus to develop.

Fine needle aspiration of non-small cell lung cancer: current state and future perspective.

A. Fassina, R. Cappellesso, F. Simonato, C. Lanza, A. Marzari and M. Fassan

Early signet ring cell carcinoma arising from colonic adenoma: The molecular profiling supports the adenoma-carcinoma sequence

Among colorectal cancers, the prevalence of signet ring cell carcinoma (SRCC) is lower than 1%; to date, only 6 cases of early SRCCs arising in colonic adenoma have been reported. In spite of the well-established understanding of the phenotypic and genetic changes occurring in conventional colonic carcinogenesis, the molecular landscape of colon SRCC is still far to be elucidated. We describe the histologic and immunohistochemical phenotype and the molecular profile of a case of intramucosal SRCC developed within a 4.5-cm large sigmoid adenoma. The DNA sequencing of the 2 microdissected neoplastic components (adenomatous and SRCC) showed the same G12V KRAS mutation. Interestingly, although the adenomatous epithelium showed unequivocal p53 overexpression, no signet ring cancer cells featured p53 nuclear immunostain. This molecular pattern supports the unique histogenesis of the 2 coexisting neoplastic oncotypes, also suggesting that the signet ring cell component is derived from the molecular de-differentiation (p53 loss) of the preexisting adenomatous lesion.

The original sin of oesophageal mucosa

During embryogenesis, the gastro-oesophageal junction (GEJ)evolves through different mucosal phenotypes [1]. The histologyof the GEJ (Plate-A) of a 20-week fetus (intrauterine death, with-outmalformations)demonstratesahybridmultilayeredjunctionalepithelium. A double histochemical/immunohistochemical stainshows co-expression of markers of divergent cell-commitments(basal squamous cells: p63 immunostain [brown nuclei]; super-ficial mucosecreting cells: PAS after diastase digestion [purplecells]; Plate-B). This feature, which strictly recalls the Mul-tilayered Epithelium (MLE) of adult oesophagus, raises the

PD-L1 overexpression in ampulla of Vater carcinoma and its pre-invasive lesions

PD‐1/PD‐L1 checkpoint immunotherapy has been proposed recently as a promising treatment in relapsed/refractory disease, used eventually in combination with traditional chemotherapy in different cancer settings. To date, no data are available concerning PD‐L1 expression in ampulla of Vater carcinoma and its pre‐invasive lesions.

Adenosquamous gallbladder carcinoma: Multigene hotspot mutational profiling reveals a monoclonal origin of the two components

Adenosquamous carcinoma (ASC) of the gallbladder is a rare malignant tumor that is characterized by a coexisting of glandular and squamous components. In a case of ASC, we performed hotspot multigene mutational profiling of 164 hotspot regions of eleven cancer-associated genes (AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN and TP53) in the two microdissected components. Both tumor phenotypes resulted characterized by a p.E542K point mutation in the PIK3CA gene, whereas adenocarcinoma component revealed also a TP53 Q331* homozygous stop mutation. Of note, coexisting high-grade dysplastic epithelium was characterized by a mixed cell population, with an upper part featuring a glandular differentiation and a basal layer of p63 positive (squamous committed) cells. Overall these data provide evidence of an early squamous differentiation of the lesion with a common genetic landscape of the two components.

BRAF p.V600E-specific immunohistochemical assessment in colorectal cancer endoscopy biopsies is consistent with the mutational profiling

periportal histological signs of chronic cholestasis in chronic cholangiopathies is patchy, and that periportal regions are affected in a heterogeneous fashion, with approximately half of them showing no histological signs of chronic cholestasis in our series. The stains are not reciprocally linked, as all stains were positive in only a minority (9%) of periportal regions. Adding cytokeratin 7 to a routine set of histochemical stains, including orcein, should ensure that all signs of chronic cholestasis are detected in most biopsies from patients with chronic cholangiopathies. Owing to the patchy distribution of the stain positivity in our series, it is hard to conclude whether periportal K7 positivity precedes the accumulation of copper and copper-binding protein.

Assessment of intratumor immune-microenvironment in colorectal cancers with extranodal extension of nodal metastases

BackgroundNo data is available on the molecular background of the extra-nodal extension (ENE) of lymph node metastasis (LN) in colorectal cancer (CRC).MethodsA series of 22 ENE-positive CRCs was considered and three samples per case were selected (the primary CRC, an ENE-negative and an ENE-positive metastatic LN). Samples (n = 66) were analysed by immunohistochemistry for PD-L1, CD4, CD8, CD68 and CD80. Fifteen out of twenty-two cases were further profiled through a hotspot multigene mutational custom panel, including 164 hotspot regions of AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN and TP53 genes.ResultsA significantly higher percentage of CD4-, CD8- and CD68-positive cells was observed at the invasive front of both CRCs and in ENE in contrast with what observed at the core of both CRCs and their matched nodal metastases. ENE was also characterized by a significantly higher number of CD80-positive cells. No significant difference was observed in PD-L1 distribution among the different specimens. Fourteen out of 15 CRCs (93%) showed at least a driver mutation. The most frequently mutated gene was TP53 (n = 8 tumors), followed by APC (n = 6), BRAF (n = 4), KRAS, NRAS and PIK3CA (n = 2). In 11 out of 15 CRCs (73%) the mutational profiling of the primary tumor was consistent with what obtained from the two matched LNs.ConclusionsA heterogeneous intratumor immune-microenvironment has been observed in ENE-positive CRCs, which are characterized by an increased leukocytic infiltration at the ENE invasive front.

Abstract 3219: Isolated tumor cells (ITC) in regional lymph nodes predict colorectal cancer (CRC) relapse

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Involvement of the lymph nodes (LN) is the most important prognostic factor in CRC and pN+ve status identifies patients requiring adjuvant chemotherapy. Among pN0-patients, 20-30% develop recurrent disease. ITC+ve LNs in such patients (as assessed by immunohistochemistry) may potentially predict cancer recurrence. No prospective long-term follow-up trial has consistently validated the prognostic meaning of ITCs. ITCs in regional LNs were prospectively assessed in a cohort of 361 consecutive pN0-CRC patients. From each gross surgical specimen, LNs were microdissected according to a standardized protocol (mean LNs per patient=16.4; range 5-107). In all, 5,920 pN0-ve LNs were collected and immunohistochemically assessed (MNF116 staining was performed in 2 serial histology sections of each LN [11,840 histology specimens in all]). Overall cancer death and recurrence rates were calculated. The prognostic impact of ITC was also tested by multivariate statistics. ITCs were documented in 200 of 361 patients (55.5%). No relationship was documented between ITC+ve status and overall survival. CRC recurred in 36/361 (9%) cases and 29/36 (80%) recurrences were documented among ITC+ve patients. The prevalence of recurrent CRC among ITC+ve and ITC-ve patients was 14.5% and 4.3%, respectively. ITC+ status significantly correlated with cancer recurrence (p = 0.002, OR = 3.57; 95% CI=1.46-9.95; case-control Pearsons chi-squared) and disease-free interval (p=0.0005). In multivariate analysis, ITC-status was the only variable significantly associated with cancer recurrence. These results suggest considering ITC+ve status a reliable marker of cancer recurrence, and that pN0 ITC+ve cancer patients form a subgroup of candidates for adjuvant chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3219. doi:10.1158/1538-7445.AM2011-3219