Interobserver agreement of a gastric adenocarcinoma tumor regression grading system that incorporates assessment of lymph nodes.

Perioperative chemotherapy is increasingly used in combination with surgery for the treatment of patients with locally advanced, resectable gastric cancer. Histologic tumor regression grade (TRG) has emerged as an important prognostic factor; however, a common standard for its evaluation is lacking. Moreover, the clinical significance of regressive changes in metastatic lymph nodes (LNs) remains unclear. We conducted an international study to examine the interobserver agreement of a TRG system that is based on the Becker system for the primary tumors and additionally incorporates regression grading in LNs. Twenty observers at different levels of experience evaluated the TRG in 60 histologic slides (30 primary tumors and 30 LNs) based on the following criteria: for primary tumors, grade 1 represented complete response (no residual tumor), grade 2 represented <10%, grade 3 represented 10-50%, and grade 4 represented >50% residual tumor, as described by Becker et al. For LNs, grade "a" represented complete, grade "b" represented partial, and grade "c" represented no regression. The interobserver agreement was estimated using the Kendall's coefficient of concordance (W). Regarding primary tumors, agreement was good irrespective of the level of experience, reaching a W-value of 0.70 overall, 0.71 among subspecialized, and 0.71 among nonsubspecialized observers. Regarding LNs, interobserver agreement was moderate to good, with W-values of 0.52 overall, 0.64 among subspecialized, and 0.45 among nonsubspecialized observers. These findings indicate that the combination of the Becker TRG system with a three-tiered grading of regression in LNs generates a system that is reproducible. Future studies should investigate whether the additional information of TRG in LNs adds to the prognostic value of histologic regression grading in gastric cancer specimens.

Quantification of mucosal EEC in jejunum. A comparative study of IBS patients and healthy controls.

Background: Enteroendocrine cells (EEC) have been suggested to have a role in the pathogenesis of irritable bowel syndrome (IBS). Although many studies have analysed possible numeric changes of EEC in IBS, the results differ between different studies. One reason might be due to difficulties in standardising the morphometric method.Aim: The aim of this study was to compare two different methods for counting EEC in jejunum biopsies from patients with IBS and healthy controls.Method: Fifty-one patients with IBS and 35 healthy controls were included in the study. Jejunum mucosa was procured using a Watson capsule. Slides were immunostained for serotonin and chromogranin A and then scanned digitally. The morphometry was done by counting cells per high power field (hpf) and per mm2 after defining area of the mucosa. The two methods were compared using Bland Altman analysis.Results: There was no difference in the number of EEC in patients with IBS compared to healthy controls. The number of cells detected by per mm2 area of mucosa were higher than number of cells per hpf. Counting EEC per high power field systematically underestimated the number of cells in the mucosal area.Conclusions: Counting cells per mm2 mucosal area gives a better representation of the number of EEC in small bowel mucosa. The finding of no difference in EEC numbers does not imply an equal function and further studies are needed to evaluate the role, if any of EEC, in IBS.

Histopathologic tumor regression grading in patients with gastric carcinoma submitted to neoadjuvant treatment: results of a Delphi survey.

Studies investigating the histopathologic response of gastric carcinoma to neoadjuvant treatment have used a variety of different tumor regression grading systems. The aim of this Delphi survey was to review the available systems and reach consensus on a potential international standard. An international e-mail-based Delphi survey involving 6 expert pathologists was undertaken between January and October 2017. A questionnaire consisting of 72 items was formed after reviewing the 5 available systems. Rating of the items was done on a symmetric 4-point Likert-type scale, and feedback was provided between rounds. A total of 4 rounds were required to reach consensus on 97% of the items covering the topics: (1) specimen processing, (2) gross examination, (3) cross sectioning/method of sampling, (4) staining, (5) immunohistochemistry, (6) assessment of tumor regression in response to neoadjuvant therapy, (7) tumor regression grading, (8) assessment of regression of nodal metastases, and (9) role of histologic tumor type. Through the outcome of this comprehensive Delphi study, a group of experts is proposing a 4-tiered system for the grading of regression of the primary tumor, combined with a 3-tiered system for lymph node metastases. Grade 1 represents complete response, grade 2 contains less than 10% residual tumor (subtotal regression), grade 3 contains 10% to 50% residual tumor (partial regression), and grade 4 contains greater than 50% residual tumor (minimal/no regression). The addition of "a", "b", or "c" indicates complete, partial, or no response of lymph node metastases. It is recommended to use this grading system irrespective of histologic subtype.

Computed Tomography Follow-Up Assessment of Patients with Low-Grade Appendiceal Mucinous Neoplasms: Evaluation of Risk for Pseudomyxoma Peritonei.

BACKGROUND: Low-grade appendiceal mucinous neoplasms are rare. Both classification and management vary. This study aimed to follow up on patients with a diagnosis of LAMN after primary surgery with computer tomography (CT) scans to examine the risk for the development of pseudomyxoma peritonei (PMP). METHODS: This population-based prospective study investigated patients who underwent appendectomy between 2007 and 2013 and had histology results demonstrating the presence of LAMN. The patients were followed up with a CT scan every 6 months for 2 years, until December 2015. RESULTS: The study investigated 41 patients (20 females) with a median age of 65 years (range 20-87 years). The entire appendix was processed and examined, with results showing that 12 were perforated, and 3 had a positive margin. Extra-appendiceal mucin on the surface of the appendix was found in ten cases, and in two cases, extra-mucinous epithelial cells were detected. During a median follow-up period of 5.1 years (range 2-8.6 years), none of the patients experienced the development of PMP. CONCLUSIONS: These data suggest that for patients with LAMN confined to the appendix, involvement of the appendectomy margin or perforation with mucin locally, even with epithelial cells, did not predict the development of PMP, and a conservative approach seems justified. No reoperation was needed, and regular follow-up evaluation with CT scans was sufficient.

Detection of Free Cancer Cells in Pelvic Lavage with Double Immunocytochemistry at Rectal Cancer Surgery.

BACKGROUND/AIM: The aim of the present study was to describe a double immunocytochemical staining method for detecting free cancer cells after rectal cancer surgery and to evaluate their extent and prognostic role. MATERIALS AND METHODS: Immunocytochemistry was performed using antibodies against cytokeratin 20/caudal-typehomeobox transcription factor 2 (CDX2) and mucin glycoprotein-2 (MUC2)/p53 protein. The study included 29 patients with infraperitoneal rectal cancer who underwent bowel resection and four controls. The pelvic lavage was retrieved at the start of laparotomy, after total mesorectal excision and after abdominal lavage with sterile water. RESULTS: Free cancer cells were detected with the double immunocytochemical method in the two controls with carcinomatosis and one control with sigmoidal cancer. None of the patients with rectal tumours had presence of free cancer cells. CONCLUSION: Immunocytochemical analysis of peritoneal lavage was feasible and negative in patients with infraperitoneal rectal cancer. Further studies are encouraged to investigate the clinical relevance in cases with free cancer cells after incomplete total mesorectal excision.

Circumferential resection margin as a prognostic marker in the modern multidisciplinary management of rectal cancer.

BACKGROUND: A positive circumferential resection margin has been associated with a high risk of local recurrence and a decrease in survival in patients who have rectal cancer. OBJECTIVE: The purpose of this study was to analyze the involvement of circumferential resection margin in local recurrence and survival in a multidisciplinary population-based setting by using tailored oncological therapy and surgery with total mesorectal excision. DESIGN: Data were collected in a prospective database and retrospectively analyzed. Between 1996 and 2009, 448 patients with rectal cancer underwent a curative bowel resection. SETTINGS: Population-based data were collected at a single institution in the county of Västmanland, Sweden. RESULTS: Preoperative radiotherapy was delivered to 334 patients (74%); it was delivered to 35 patients (8%) concomitantly with preoperative chemotherapy. In 70 patients (16%), en bloc resections of the prostate and vagina were performed. Intraoperative perforations were seen in 7 patients (1.6%). The mesorectal fascia was assessed as complete in 117/118 cases. In 32 cases (7%), the circumferential resection margin was 1 mm or less. After a median follow-up of 68 months, 5 (1.1%) patients developed a local recurrence; one of them had circumferential resection margin involvement. The 5-year overall survival was 77%. In the multivariate analysis, the circumferential resection margin was not an independent factor for disease-free survival. LIMITATIONS: Mesorectal fascia was not assessed before 2007. The findings might be explained by a type II error but, from a clinical perspective, enough patients were included to motivate the conclusion of the study. CONCLUSIONS: Circumferential resection margin is an important measurement in rectal cancer pathology, but the correlation to local recurrence is much less than previously stated, probably because of oncological treatment and surgery that respects the mesorectal fascia and, when required, en bloc resections. Circumferential resection margin should not be used as a prognostic marker in the modern multidisciplinary management of rectal cancer.

p53 up-regulation during colorectal carcinogenesis.

BACKGROUND: We previously found foci of p53 up-regulation in dysplasia in colorectal adenomas (CRAs). The present study aimed at exploring the frequency of this phenomenon in CRAs with and without submucosal invasive carcinoma. MATERIALS AND METHODS: Sections from 568 polypectomies or surgical resections harbouring a CRA (without or with submucosal invasion) or overt colorectal carcinomas were challenged with p53 immunostaining. The largest section from single colorectal neoplasias was measured by the aid of a calibrated ocular scale in a conventional microscope. Lesions were divided into small adenomas (≤10 mm in size), large adenomas (≥11 mm in size), adenomas with submucosal invasion, and overt invasive carcinomas (without any recognizable adenoma remnant tissue). RESULTS: CRAs with three or more dysplastic foci of p53-up-regulation gradually increased from 8% in small adenomas (size: ≤10 mm) to 48% in large adenomas (size: ≥11 mm), and to 65% in the adenomatous tissue in adenomas displaying submucosal invasion), but plummeted to 13% in the submucosal carcinomatous tissue and to 11% in overt carcinomas. In contrast, extensive p53 up-regulation predominated in the submucosal carcinomatous tissue (87%) and in overt carcinomas (89%). CONCLUSION: The frequency of foci of dysplastic glands with up-regulation of p53 (hotspots) gradually increased from small to larger CRAs, being highest in the adenomatous tissue of CRAs with submucosal invasive carcinoma. The foci of p53 up-regulation became confluent (appreciated as extensive up-regulation) in the submucosal carcinomatous tissue and in overt carcinomas. It is concluded that a high number of foci with p53 up-regulation in adenomatous tissue might be required before submucosal invasive carcinoma ensues.

Spectrum of cytokeratin-positive cells in the bone marrows of colorectal carcinoma patients.

BACKGROUND: Bone marrow micrometastases (BMM) is considered to be of interest as a prognostic marker in solid tumors. The use of density-gradient separated bone marrow (BM) aspirates does not allow proper morphological characterization of the cells. An alternative approach, using routinely processed clots of BM aspirates, is presented. MATERIALS AND METHODS: BM clots from 56 colorectal carcinoma patients were stained for cytokeratin (CK), p53 and Ki67 by double immunohistochemistry. Cytokeratin-positive (CK+) cells were immunohistochemically divided into three groups, viz. Group A (CK+ probably malignant epithelial cells), Group B (CK+ morphologically non-epithelial cells) and Group C (CK+ contaminating cells). RESULTS: Thirty-three patients (59%) had CK+ cells, of which 19 (58%) had Group A cells and 14 (42%) had Group B cells. Fourteen of the 56 patients had reactive BM, eight of these had Group A cells and 3 had Group B cells. Group B cells and Group C cells did not express p53. Group A cells were noted in 35% of patients with carcinomas of Dukes' stage C and in 41% of patients with metastatic disease. CONCLUSION: Double immunohistochemical staining of routinely processed BM clot, for p53 and Ki67 along with CK allows the sub-classification of CK+ cells.