Although most mesotheliomas present with pleural effusions, it is controversial whether mesothelioma can be diagnosed with confidence in effusion cytology. Therefore, an ancillary marker of malignant ...mesothelial cells applicable in effusions would be clinically valuable. BRCA-1-associated protein (BAP1) is a tumor suppressor gene, which shows biallelic inactivation in approximately half of all mesotheliomas. We investigated whether loss of BAP1 expression by immunohistochemistry can be used to support a diagnosis of mesothelioma in effusion cytology. Immunohistochemistry for BAP1 was performed on cell blocks and interpreted blinded. 43 of 75 (57%) effusions associated with confirmed mesothelioma showed negative staining with positive internal controls. Of 57 effusions considered to have atypical mesothelial cells in the absence of a definitive diagnosis of mesothelioma, 8 cases demonstrated negative staining for BAP1. On follow-up six of these patients received a definitive diagnosis of mesothelioma in the subsequent 14 months (two were lost to follow-up immediately, and mesothelioma could not be excluded). Only 5 of 100 consecutive benign effusions were interpreted as BAP1 negative. One of these patients died soon after and mesothelioma could not be excluded. On unblinded review the four other patients with apparently negative BAP1 staining but no malignancy lacked convincing positive staining in non-neoplastic cells suggesting that BAP1 immunohistochemistry may have initially been misinterpreted. 47 effusions with adenocarcinoma were BAP1 positive. We conclude that loss of BAP1 expression, while not definitive, can be used to support the diagnosis of mesothelioma in effusion cytology. We caution that interpretation of BAP1 immunohistochemistry on cell block may be difficult and that convincing positive staining in non-neoplastic cells is required before atypical cells are considered negative. We also note that BAP1 loss is not a sensitive test as it occurs in only half of all mesotheliomas and cannot be used to exclude the diagnosis.
BRCA1-associated protein 1 (BAP1) is a tumour suppressor gene frequently inactivated in mesothelioma, rarely also in association with germline mutation. BAP1 mutations have been associated with ...improved prognosis and distinct clin-icopathological features. We sought to determine the clin-icopathological significance of BAP1 immunohistochemistry (IHC) in mesothelioma. We performed IHC on a tissue microarray (TMA) cohort comprising all available thoracic mesotheliomas encountered during the period 1991-2014 at our institution (n=229). All cases were independently reviewed to confirm the diagnosis and subclassify as epithe-lioid, sarcomatoid or biphasic. The median age at diagnosis was 72 years; 188 (82.1%) were male; 120 (52.4%) were epithelioid (median survival 13.0 months), 67 (29.3%) sar-comatoid (median survival 5.6 months) and 42 (18.3%) biphasic (median survival 10.6 months). Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in non-neoplastic cells) occurred in 106 (46.3%) mesotheliomas. There was complete interobserver concordance for BAP1 IHC status. BAP1 loss was strongly associated with younger age at onset (p<0.01) and epithelioid differentiation (p<0.01). BAP1 loss predicted an improved median survival of 16.11 months (95% CI 12.16–20.06) versus 6.34 months (95% CI 5.34–7.34), p<0.01. In a multivariate model including age, gender and histological type, BAP1 loss, younger age and epithelioid differentiation remained protective (all p<0.01). If our results are confirmed by others, BAP1 IHC may have a role to predict prolonged survival or triage formal genetic testing for germline BAP1 mutation in patients presenting with mesothelioma.
Inflammatory myofibroblastic tumor (IMT) of the female genital tract is under-recognized. We investigated the prevalence of ALK-positive IMT in lesions previously diagnosed as gynecologic smooth ...muscle tumors. Immunohistochemistry (IHC) for ALK was performed on tissue microarrays of unselected tumors resected from 2009 to 2013. Three of 1176 (0.26%) “leiomyomas” and 1 of 44 (2.3%) “leiomyosarcomas” were ALK IHC positive, confirmed translocated by fluorescence in situ hybridization (FISH) and therefore more appropriately classified as IMT. On review significant areas of all 4 tumors closely mimicked smooth muscle tumors morphologically, but all showed at least subtle/focal features suggesting IMT. Recognizing that the distinction between IMT and leiomyoma/leiomyosarcoma can be subtle, we then reviewed 1 hematoxylin and eosin slide from each patient undergoing surgery for “leiomyoma” from 2014 to 2017 and selected cases for ALK IHC with a low threshold. Of these, 30 of 571 (5.3%) underwent IHC. Two were confirmed to be IHC positive and FISH rearranged. Of the 6 IMTs, only 1 tumor with a previous diagnosis of leiomyosarcoma, an infiltrative margin and equivocal necrosis, metastasized. Of note it demonstrated a less aggressive clinical course compared with most metastatic leiomyosarcomas (alive with disease at 6 y). The patient was subsequently offered crizotinib to which she responded rapidly. In conclusion, IMTs may closely mimic gynecologic smooth muscle tumors. IMTs account for at least 5 of 1747 (0.3%) tumors previously diagnosed as leiomyoma and 1 of 44 (2.3%) as leiomyosarcoma. These tumors may be recognized prospectively with awareness of subtle/focal histologic clues, coupled with a low threshold for ALK IHC.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/
Background and Aim
There is conflicting evidence on the association between folate intake and the risk of upper gastrointestinal tract cancers. In order to further elucidate this relationship, we ...performed a systematic review and quantitative meta‐analysis of folate intake and the risk of esophageal, gastric, and pancreatic cancer.
Methods
Four electronic databases (Medline, PubMed, Embase, and Current Contents Connect) were searched to July 26, 2013, with no language restrictions for observational studies that measured folate intake and the risk of esophageal cancer, gastric cancer, or pancreatic cancer. Pooled odds ratios and 95% confidence intervals were calculated using a random effects model.
Results
The meta‐analysis of dietary folate and esophageal cancer risk comprising of nine retrospective studies showed a decreased risk of esophageal cancer (odds ratio OR 0.59; 95% confidence interval 95% CI 0.51–0.69). The meta‐analysis of dietary folate and gastric cancer risk comprising of 16 studies showed no association (OR 0.94; 95% CI 0.78–1.14). The meta‐analysis of dietary folate and pancreatic cancer risk comprising of eight studies showed a decreased risk of pancreatic cancer (OR 0.66; 95% CI 0.49–0.89).
Conclusion
Dietary folate intake is associated with a decreased risk of esophageal and pancreatic cancer, but not gastric cancer. Interpretation of these relationships is complicated by significant heterogeneity between studies when pooled, and by small numbers of studies available to analyze when stratification is performed to reduce heterogeneity.
There is some uncertainty about pathological grading of mucinous colorectal adenocarcinoma, defined as colorectal cancer demonstrating at least 50% mucinous differentiation. Under the WHO 2000 ...classification mucinous colorectal cancer was considered high grade. However under the current WHO 2010 classification microsatellite unstable/mismatch repair-deficient (MSI/MMRd) mucinous colorectal cancer is considered low grade, whereas microsatellite stable/mismatch repair proficient (MSS/MMRp) tumours are high grade. However there is little empirical evidence for this approach. We therefore compared the long term survival of patients with MSI/MMRd vs MSS/MMRp mucinous colorectal cancer in a large unselected cohort of patients undergoing surgery at our institution from 1998 to 2011. There were 2608 patients in the cohort, of which 264 (10.1%) were mucinous. 95 (36%) of the mucinous tumours were microsatellite unstable. The all-cause 5-year survival of mucinous MSI/MMRd colorectal cancer was similar to that of non-mucinous low-grade colorectal cancer (73 vs 67%, P=0.368), and significantly better than that of both non-mucinous high-grade (73 vs 53%, P<0.001) and mucinous MSS/MMRp colorectal cancer (73 vs 57%, P=0.023). The 5-year survival of mucinous MSS/MMRp colorectal cancer was slightly better than that of non-mucinous high-grade patients (57 vs 53%, P=0.027), but significantly worse than that of non-mucinous low-grade colorectal cancer (57 vs 67%, P=0.018). In multivariate Cox regression analysis, conventional histological grade based on glandular differentiation maintained prognostic significance (P=0.003) whereas MSI/MMRd status just failed to be statistically significant (P=0.062). Our findings support the WHO 2010 approach that as a group mucinous MSS/MMRp colorectal cancers are biologically aggressive. However, grading based exclusively on MSI/MMR status may be overly simplistic as conventional grading based on the degree of glandular differentiation still holds greater prognostic significance in multivariate analysis.
Background and Aim: Barrett's esophagus has been associated with the presence of hiatal hernia; however, to date no meta‐analysis of the relationship has been performed. We aimed to conduct a ...systematic review and meta‐analysis, providing a quantitative estimate of the increased risk of Barrett's esophagus associated with hiatal hernia.
Methods: A search was conducted through four electronic databases (Medline, PubMed, Embase, and Current Contents Connect) to 4 April 2012, for observational studies of Barrett's esophagus patients. We calculated pooled odds ratios and 95% confidence intervals using a random effects model for the association of hiatal hernia with any length Barrett's esophagus, as well as with short segment Barrett's esophagus and long segment Barrett's esophagus. 33 studies comprising 4390 Barrett's esophagus patients were eligible for the meta‐analysis.
Results: Hiatal hernia was associated with an increased risk of Barrett's esophagus of any length (odds ratio 3.94; 95% confidence interval 3.02–5.13). Heterogeneity was present (I2 = 82.03%, P < 0.001), and the Egger test for publication bias was significant (P = 0.0005). The short segment Barrett's esophagus subgroup analysis likewise showed an increased risk (odds ratio 2.87; 95% confidence interval 1.75–4.70). The strongest association was between hiatal hernia and long segment Barrett's esophagus (odds ratio 12.67; 95% confidence interval 8.33–19.25). The increased risk was present even after adjusting for reflux and body mass index.
Conclusions: The presence of hiatal hernia was associated with an increased risk of Barrett's esophagus, even after adjusting for clinically significant confounders. The strongest association was found between hiatal hernia and long segment Barrett's esophagus.
Somatostatin receptors (SSTR) are commonly expressed by neuroendocrine tumors. Expression of SSTR-2a and SSTR-5 may impact symptomatic management; however, the impact on survival is unclear. The aim ...of this study is to correlate SSTR-2a and SSTR-5 expression in pancreatic neuroendocrine tumors (PNETs) with survival. This study is designed to determine the prognostic significance of somatostatin receptors SSTR-2a and SSTR-5 in PNETs. This retrospective cohort study included cases of resected PNETs between 1992 and 2014. Clinical data, histopathology, expression of SSTR and Ki-67 by immunohistochemistry, and long-term survival were analyzed. A total of 99 cases were included in this study. The mean age was 57.8 years (18-87 years) and median tumor size was 25 mm (range 8-160 mm). SSTR-2a and SSTR-5 expression was scored as negative (n = 19, 19.2%; n = 75, 75.8%, respectively) and positive (n = 80, 80.1%; n = 24, 24.2%). The median follow-up was 49 months. SSTR-2a expression was associated with improved overall survival, with cumulative survival rates at 1, 3, and 5 years being 97.5%, 91.5%, and 82.9%, respectively. Univariate analysis demonstrated better survival in SSTR-2a positive patients (log rank P = 0.04). SSTR-5 expression was not associated with survival outcomes (log rank P = 0.94). Multivariate analysis showed that positive SSTR-2a expression is a stronger prognostic indicator for overall survival Hazard Ratio (HR): 0.2, 95% Confidence interval (CI): 0.1-0.8 compared to high Ki-67 (HR: 0.8, 95% CI: 0.1-5.7). Expression of SSTR-2a is an independent positive prognostic factor for survival in PNETs.
Summary Gynecologic and primary peritoneal serous carcinoma may be difficult to distinguish from abdominal mesotheliomas clinically, morphologically, and immunohistochemically. BAP1 double-hit ...inactivation and subsequent loss of protein expression have been reported in more than half of all abdominal mesotheliomas. We therefore sought to investigate the expression of BAP1 in serous carcinoma and explore its potential utility as a marker in the differential diagnosis with mesothelioma. We searched the computerized database of the Department of Anatomical Pathology, Royal North Shore Hospital, Australia, for all cases of gynecologic and peritoneal serous carcinomas and mesotheliomas diagnosed between 1998 and 2014. Immunohistochemistry for BAP1 was then performed on tissue microarray sections. Cases with completely absent nuclear staining in the presence of a positive internal control in nonneoplastic cells were considered negative. If staining was equivocal (eg, absent nuclear staining but no internal control), staining was repeated on whole sections. Loss of BAP1 expression was found in only 1 of 395 (0.3%) serous carcinomas but in 6 of 9 (67%) abdominal mesotheliomas ( P < .001) and 131 of 277 (47%) thoracic mesotheliomas ( P < .001). We conclude that BAP1 loss occurs extremely infrequently in gynecologic and peritoneal serous adenocarcinomas, whereas it is very common in mesotheliomas including abdominal mesothelioma. Therefore, although positive staining for BAP1 cannot be used to exclude a diagnosis of mesothelioma, loss of BAP1 expression can be used to very strongly support a pathological diagnosis of abdominal mesothelioma over serous carcinoma.
There is conflicting epidemiological evidence on the role of folate and breast cancer risk. We conducted a systematic review and quantitative meta-analysis of folate intake and folate blood levels ...and the risk of breast cancer. Four electronic databases (Medline, PubMed, Embase, and Current Contents Connect) were searched to April 11, 2014, with no language restrictions for observational studies that measured folate intake or blood levels and the risk of breast cancer. The meta-analysis of dietary folate intake comprising 36 studies with 34,602 cases, and a total sample size of 608,265 showed a decreased risk of breast cancer, with an odds ratio (OR) of 0.84 95 % confidence interval (CI) 0.77–0.91. When stratified by menopausal status and by study design, none of the meta-analyses of prospective studies showed any statistically significant decrease in the risk of breast cancer. The meta-analysis of total folate showed no statistically significant association with breast cancer OR of 0.98 (95 % CI 0.91–1.07). There was no significant association between either dietary or total folate intake and breast cancer when stratified by hormonal receptor status. The meta-analysis of blood folate levels found no significant association with the risk of breast cancer, with an OR of 0.86 (95 % CI 0.60–1.25). Breast cancer does not appear to be associated with folate intake, and this did not vary by menopausal status or hormonal receptor status. Folate blood levels also do not appear to be associated with breast cancer risk.
Context Esophageal cancer is a neoplasm with a poor prognosis. Its two histologic subtypes, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), have been associated with ...different risk factors. The possibility of an association between the consumption of hot food and beverages and esophageal cancer, especially ESCC, has long been suspected, presenting a potentially modifiable risk factor. A meta-analysis of existing observational studies was performed to provide a quantitative estimate of the risk of esophageal cancer associated with the consumption of hot food and drink. Evidence acquisition A search was conducted through MEDLINE, PubMed, EMBASE, and Current Contents Connect to November 11, 2014. Pooled ORs and 95% CIs were calculated using a random effects model for the risk of esophageal cancer associated with the consumption of hot food and drink. Subgroup analyses were conducted for ESCC and EAC, as well as for studies that adjusted for tobacco smoking and alcohol consumption, two well-recognized risk factors for ESCC. Evidence synthesis Consumption of hot food and drink was associated with an increased risk of any esophageal cancer (OR=1.90, 95% CI=1.46, 2.48). Heterogeneity was observed. There was an increased risk of ESCC (OR=2.29, 95% CI=1.79, 2.93), which remained even after adjusting for significant confounding variables (OR=2.39, 95% CI=1.71, 3.33). The relationship was not significant for EAC. Conclusions The consumption of hot food and beverages was associated with an increased risk of esophageal cancer, particularly ESCC.
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