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Background/aim: Germline mutations in any of the succinate dehydrogenase (SDH) genes result in destabilization of the SDH protein complex and loss of SDHB expression at immunohistochemistry. SDHA is lost together with SDHB in SDHA-mutated tumours, but its expression is retained in tumours with other SDH mutations. We investigated whether SDHA/SDHB immunohistochemistry is able to identify SDH-related tumours in a retrospective case series of phaeochromocytomas (PCCs) and paragangliomas (PGLs)., Materials and Methods: SDHA and SDHB immunostaining was performed in 13 SDH gene-mutated tumours (SDHB: n=3; SDHC: n=1; SDHD: n=9) and 16 wild-type tumours. Protein expression by western blot analysis and enzymatic activity were also assessed., Results: Tumours harbouring SDH gene mutations demonstrated a significant reduction in enzymatic activity and protein expression when compared to wild-type tumours. SDHB immunostaining detected 76.9% of SDH mutated PCCs/PGLs (3/3 SDHB-mutated samples; 1/1 SDHC-mutated sample; 6/9 SDHD-mutated samples). In three SDHD-related tumours with the same mutation (p.Pro81Leu), positive (n=2) or weakly diffuse (n=1) SDHB staining was observed. All wild-type PCCs/PGLs exhibited SDHB immunoreactivity, while immunostaining for SDHA was positive in 93.8% cases and weakly diffuse in one (6.2%). SDHA protein expression was preserved in all tumours with mutations., Conclusion: SDHA and SDHB immunohistochemistry should be interpreted with caution, due to possible false-positive or false-negative results, and ideally in the setting of quality assurance provided by molecular testing. In SDHD mutation, weak non-specific cytoplasmic staining occurs commonly, and this pattern of staining can be difficult to interpret with certainty., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Screening gastroscopic examinations were performed in a cohort of individuals at high risk for developing gastric carcinoma (GC)., Patients and Methods: Five gastric biopsies were obtained following the Houston schema. Five histological parameters of gastritis were investigated: acute gastritis, chronic gastritis, and its sequelae; mucosal atrophy, intestinal metaplasia and pseudopyloric metaplasia., Results: Out of 134 patients, 50% (n=67) had Helicobacter pylori (HP) infection. The sum of scores for the first four parameters was significantly higher in HP-positive cases than in HP-negative ones (p<0.0001). The frequency of these histological parameters was similar to other series from Northern and Central Italy. Hence, none of the histological parameters of gastritis explain the high GC risk in this borough of Florence, considering that the incidence rate of GC is higher in Central than in Northern Italy., Conclusion: Similarities in the frequency of chronic gastritis and sequelae in Northern and Central Italy substantiate the conviction that the difference in GC risk in these regions might be the result of local environmental or lifestyle factors, rather than HP infection. This knowledge is crucial, considering that environmentally related diseases are theoretically preventable.

Background: Low serum levels of 1,25(OH)(2)D(3) (1,25D), have been associated with aggressive biologic behavior of prostate cancer (PCa). In the present study, we examined the effects of 1,25D and its novel, low-calcemic analog ZK191784 (ZK) on matrix metalloproteinases (MMPs), as well as on intercellular adhesion molecule-1 (ICAM-1) protein levels in human PCa cell lines LNCaP and DU-145., Materials and Methods: Cells were incubated with either vehicle (control), 1,25D or ZK. MMP-2 and MMP-9 activity was determined by gelatin zymography, while ICAM-1 levels were assessed by Western blot analysis and immunocytochemistry., Results: Compared to the controls, 1,25D and ZK caused a marked dose-dependent decrease in the gelatinolytic activity of the MMPs under study, particularly when ZK was used. Likewise, ICAM-1 was down-regulated in the cells incubated with 1,25D or ZK., Conclusion: Vitamin D analogs appear to be involved in the regulation of extracellular MMP activity and membrane adhesion molecule expression. Further studies, both in vitro and in vivo, are needed to define their role as potential therapeutic tools.

Background: Chewing of regurgitated food elicits in baboons life-long gastro-esophageal reflux (GER). The acid reflux transforms the multilayered squamous cell epithelium of the esophagus into columnar-lined mucosa with mucus-producing accessory glands. The function of this mucous gland metaplasia (MGM), which mimics Barrett's mucosa with MGM in humans, is to buffer the gastric acid entering the esophagus during regurgitation. In a previous study of entire esophagi, the majority of baboons showed MGM. The gastric mucosa was not investigated., Materials and Methods: Hematoxylin-eosin-stained sections from the esophagus, from the lesser gastric curvature and from the greater gastric curvature were collected separately from 50 adult baboons. The presence of MGM was assessed in each one of these locations., Results: MGM was demonstrated in 92% (46/50) of blocks from the esophagus, in 98% (49/50) of blocks from the lesser curvature and in 90% (45/50) of those of the greater curvature (fundus)., Conclusion: The majority of the animals had MGM, not only in the esophagus but also in the proximal gastric mucosa. Rationally, MGM in baboons starts in the distal esophagus and proceeds downwards, towards the proximal stomach. The histogenesis of the MGM in Barrett's mucosa in humans (that is Barrett's mucosa type 2) remains elusive. Therefore the baboon might be an important animal model for studying the histogenesis of Barrett's mucosa with MGM in humans, a recognized pre-cancerous lesion.

Background: Fundic gland polyps (FGPs) are common hamartomatous cystic lesions in the gastric mucosa. The aim was to assess the cellular components in sections stained with Giemsa or toluidine blue: two stains that easily differentiate parietal from chief cells., Materials and Methods: Sixty-eight consecutive gastric biopsies having well-oriented sections from the fundic mucosa were investigated: 34 had FGP, and 34 were control cases. Using an ocular microscale, the thickness of each FGP was divided into an upper and a lower compartment. The proportion of parietal and chief cells in each compartment was assessed in 3 consecutive high power fields (×40)., Results: In FGPs, parietal cells predominated in the upper compartment where the parietal chief cell ratio ≥60 was 59.8%, and in the lower compartment it was only 5.9% (p<0.05). Within cysts, cell exfoliation with secondary eosinophilic nuclear-free material was found. FGPs also displayed small glandular islands with an admixture of parietal and chief cells. The cytoplasm of parietal cells was often ballooned, vacuolated, with basophilic deposits or anucleated (ghost cells)., Conclusion: FGPs are composed of parietal cells predominantly in the upper half and with chief cells in the lower half, as well as with glandular islands showing cytological alterations in parietal cells. Intraluminal nuclear-free material seems to obstruct the outlets of the glands leading to cystic formation.

Unlabelled: The aim of this study was to verify and to compare in benign prostatic hyperplasia (BPH) patients, the effect of finasteride versus dutasteride therapy on chromogranin A (CgA) serum levels, as a marker of neuroendocrine (NE) differentiation., Patients and Methods: This was a prospective randomised study in which 60 consecutive men with clinical diagnosis of BPH were randomised to a 6-month period of finasteride 5 mg/day versus dutasteride 4 mg/day versus control (no therapy). Total prostate-specific antigen (PSA), testosterone and CgA were analysed at randomisation and thereafter at one-, three- and six-month intervals., Results: In both Group A (finasteride) and Group B (dutasteride), but not in Group C (no therapy), a statistically significant increase (p<0.05) in serum CgA levels was found at the three- and six-month intervals of therapy when compared with the start. Comparing the three groups, at three- and six-month intervals, serum CgA was significantly (p<0.05) higher in Group A and B than in Group C. At each interval, no significant (p>0.05) difference between Group A and B was found., Conclusion: In this population, 5-alpha reductase inhibitors, with no difference between finasteride and dutasteride, produced a significant increase in serum CgA levels, probably related to NE activation.

Background: It has been postulated that the occurrence of invasive carcinoma in a colon adenoma can be predicted by estimating the size of the resected polyp. Recently, significant intra- and inter-observer differences in size were found when 22 pathologists estimated the size of 12 polyp phantoms. In this work, the size of a large cohort of endoscopically-resected colon polyps was assessed with a novel method., Patients and Methods: Three pathologists measured photocopies of 148 resected polyps (adenomas at histology) in two independent trials., Results: The size recorded by the three participants was congruent in only 50% of the measurements in trial 1, and in 62% in trial 2. A significant difference in size assessment was found between the three investigators (p

We have previously recorded 6 cases of serrated adenoma in the cardia. Here we report a case, which differed cytologically from the 6 preceding cases in as much as the adenomatous cells had clear, micro-vacuolated cytoplasm and secreted neutral mucins. Similar cellular features found in gastric carcinomas were classified by Mulligan as of pylorocardiac gland cell type. Six of the 7 cases (including the one reported here) showed areas of invasive carcinoma. Because of its location, histological and histochemical features, the reported neoplasia was called serrated adenoma malignum of the cardia (Mulligan type). Serrated adenomas of the cardia seem to have a particular proclivity to evolve into invasive carcinomas.

Background: DNA ploidy and S-phase fraction (SPF) measured by DNA flow cytometry (FC) have been previously shown to correlate with several clinicopathological variables in several types of tumours., Patients and Methods: DNA FC was performed on multiple frozen tumour samples obtained from 115 patients undergoing curative surgery for gastric cancer (GC). The findings were prospectively tested for correlation with traditional clinicopathological indicators of prognosis., Results: Overall, 20 tumours (17.4%) were diploid, 46 (40.0%) monoclonal and 49 (42.6%) multiclonal. Excluding 4 patients who died within 1 month of surgery, high SPF (>9.6%) was detected in 55 patients (49.6%) and was found to be significantly associated with vascular invasion and multiclonality (p=0.02). An association of borderline statistical significance emerged with macroscopic type (p=0.06) and pN and pM status (p=0.07). Multivariate regression analysis did not show a significant effect of SPF (p=0.11) or DNA ploidy (p=0.28) on 7-year survival., Conclusion: Aneuploidy appears to be a prognostic factor of low penetrance, whereas SPF is a more promising parameter of tumour aggressiveness in patients with GC.

Colorectal adenomas from 1552 Italian patients were histologically classified into tubular (TAs), tubulo-villous (TVAs), villous (VAs), serrated (SAs) and microtubular (MTAs). The purpose was to compare the results to those in 3135 colorectal adenomas from Swedish patients. Of the 1552 adenomas, 827 (53%) were TAs, 352 (23%) TVAs, 196 (12%) VAs, 102 (7%), SAs and 14 (0.9%) MTAs. The remaining 61 (4%) were of combined phenotypes (COMBAs). The percentage of VA (considered as the most important dysplastic precursor of colorectal cancer) was higher in Florence than in Stockholm. Notably, the incidence of colorectal cancer in males was also higher in Florence (78.6/10(5)) than in Stockholm (57.2/10(5)). Notwithstanding, the highest rate of submucosal invasion (7%) was found among SAs. The diameter of the largest section was used to define the size of the largest adenoma in individual patients. Of the 1380 neoplasias measuring < or =12 mm, only 0.9% (n=13) had invasive carcinomas, but as many as 8.1% (n=14) of the 172 neoplasias measuring > or =13 mm. SAs and MTAs are special adenoma phenotypes with particular morphological and cell proliferative attributes at variance from those of TAs, VAs or TVAs. In the light of the present results, it is proposed that SAs and MTAs are included in future reports of colorectal adenomas in order to compare their frequency worldwide.

Colorectal adenomas are usually classified into two categories: tubular and villous adenomas. A mixed (tubulovillous) phenotype is also recognized. Two other histological phenotypes, namely serrated and microtubular adenomas, have been reported in the literature but neither have been included in large series. In this survey, all colorectal adenomas seen at this Department between 1993 and 2000 (n = 3135) were classified into the above 5 histological categories. The results showed that 66% (n = 2074) were tubular, 9% (n = 281) villous, 18% (n = 551) mixed, 6% (n = 202) serrated and the remaining 1% (n = 27) microtubular. More than 80% of the tubular, villous, serrated and microtubular adenomas were located in the colon. None of the microtubular adenomas were found in the rectum. The molecular signals whereby the colorectal mucosa in some patients "etch" serrated or microtubular neoplastic structures whereas in others tubular or villous neoplastic structures, have not been explored. One possible explanation might be that the pathway followed by the cascade of committed molecular events is less "accessible" for the "etching" of serrated and microtubular structures or that the process is less complex for the molecular design of tubular and villous configurations.

The nm23 gene is thought to play a role as an inhibitor of metastatic progression in several human cancers and its down-regulation has been associated with increased metastasis and reduced survival in some studies, though not in others. To better investigate the role of nm23 in gastric cancer (GC), the expression and prognostic impact of this gene was examined in 107 radically operated GC patients in a high risk area. The expression of nm23 was determined immunohistochemically by using the rabbit antibody anti-human nm23 protein. The expression of nm23 was detected in 40.2% (n = 43) of 107 gastric tumours and correlated with a poorer clinical outcome. In a survival analysis at 5 years, patients with nm23-positive tumours had significantly worse prognosis than patients (n = 64) with nm23-negative tumours (p < 0.05). The prognostic significance of nm23 expression was confirmed by multivariate analysis including terms for tumour stage and lymph node involvement. Our results suggest that the expression of the nm23 gene in gastric carcinoma is significantly related to tumour progression and poor prognosis at 5 years.

Population studies in the Pacific Basin showed that gastric carcinomas of intestinal type often concur with distant mucosal changes (DMCs). In the present work, the presence of DMCs was investigated in populations dwelling in the Atlantic Basin. A total of 1737 gastrectomy specimens were reviewed: 627 in New York, 435 in Reykjavik, 198 in Buenos Aires, 186 in Florence, 174 in London and the remaining 117 in Stockholm. A total of 17,282 sections were carefully scrutinized. The following DMCs were investigated: intramucosal glandular cysts, gastric cells with ciliated metaplasia, with large or small mucus negative vacuoles, and extensive intestinal metaplasia (IM). The highest frequencies of DMCs were found in Florence for specimens with intestinal type carcinoma: 41.3% had intramucosal cysts, 22.4% had cells with ciliated metaplasia, 12.9% cells with large vacuoles, and 50.9% had high IM. The highest frequency of gastric cells with small vacuoles was recorded in New York (9.1%), also in specimens with intestinal type carcinoma. Significantly lower DMCs percentages were found in specimens with carcinomas of diffuse type, and miscellaneous gastric diseases. The occurrence of DMCs was not influenced to a significant degree by the number of sections available per gastrectomy. Since environmental factors trigger the evolution of intestinal type carcinomas and as DMCs also occurred in specimens without carcinoma-although at a significantly lower rate--it is conceivable that DMCs are also evoked by environmental factors (before a gastric carcinoma ensues). DMCs were found in specimens having intestinal carcinomas either in the cardia, the corpus or the antrum. Thus, DMCs seem to provide the adequate "soil" for the development of gastric carcinomas of intestinal type, independently of the future localization of that tumor in the stomach.

The histologic phenotype of the dysplastic lesion juxtaposing colorectal carcinomas was assessed in 100 consecutive colectomy specimens: in 50 patients with inflammatory bowel disease (IBD) and in 50 controls (non-IBD patients). Adenomatous growths (AG) were regarded both Dysplasia Associated Lesion or Mass (DALM) and sporadic adenomas. AGs juxtaposing carcinomas were found in 76% (n = 38) of the IBD cases: 52.3% (20 out of 38) were villous, 28.9% (11 out of 38) serrated, 5.3% (2 out of 38) tubular and the remaining 13.2% (5 out of 38) were mixed AGs. Juxtaposing AGs (sporadic adenomas) were also found in 58% (n = 29) of the control cases: 51.7% (15 out of 29) were villous, 6.9% (2 out of 29) tubular, 3.4% (1 out of 9) serrated and the remaining 37.9% (11 out of 29) were mixed. The majority or 81.2% (31 out of 38) of the dysplastic lesions juxtaposing IBD carcinomas were villous or serrated AGs, but only 55.1% (16 out of 29) in control cases. Serrated AGs in particular accounted for nearly 29% of the non-invasive dysplastic lesions abutting IBD carcinomas but only for 3% in control specimens. It would appear that villous and serrated AGs are the most common non-invasive neoplastic lesions from which IBD carcinomas originate.