Diagnostic Pitfall of Gastric Signet-Ring Cells: How to Diagnose a Benign Signet-Ring Cell From a Malignant One.

Sometimes non-neoplastic changes of the gastric mucosa mimic diffuse-type gastric carcinoma, specifically signet-ring cell adenocarcinoma. In fact, gastric epithelial cells undergoing signet-ring cell change have a cellular morphology that is almost identical to signet-ring cell adenocarcinoma, often leading to misdiagnosis. Accurate recognition of signet-ring cell change is essential to avoid overdiagnosis and overtreatment of signet-ring cell adenocarcinoma. Research on this topic is limited and clinicians lack formal diagnostic tools when signet-ring cells are detected in biopsy specimens. The aims of this study are 3-fold. Firstly, to increase the awareness of both clinicians and pathologists of this rare but highly significant entity. Secondly, to report 4 additional examples of signet-ring cell change and analyze them alongside signet-ring cell adenocarcinoma to compare their morphological and phenotypic features and their evolution over time. Finally, to highlight the potential utility of endoscopic resection to confirm the diagnosis. Cells in signet-ring cell change strongly express E-cadherin, show a wild-type p53 expression, and have a low Ki67 index. In contrast, cells in signet-ring cell adenocarcinoma strongly express p53, have high proliferation rates, and show either no or weak E-cadherin staining. Genetic analysis may be useful in identifying patients at risk of hereditary early diffuse gastric adenocarcinoma, which can mimic signet-ring cell change.

Esophageal Melanocytosis: report of two cases and review of a rare and misunderstood entity.

Esophageal melanocytosis (EM) is a rare entity, which is characterized by a non-atypical melanocytic proliferation and melanin deposits in the esophageal mucosa. The confusion between the terms of melanosis and melanocytosis in the literature, the rarity of this lesion (less than 50 cases reported in the literature), its uncertain pathobiological course and the lack of experience of pathologists and gastroenterologists prompt us to draw the attention to this particular entity by reporting two cases and reviewing the literature. Magnifying endoscopy to observe intensive melanin accumulation followed by a biopsy are key for the diagnosis.

Guidelines for an optimal management of a malignant colorectal polyp. What is essential in a pathology report ?

Colorectal cancer (CRC) has become the most common malignancy in our country. Routine screening colonoscopy is on the rise. With the recent advances in endoscopic treatment, many T1 colorectal carcinomas are now found and their percentage amenable to endoscopic resection has increased. Endoscopists and pathologists dealing with the steadily increasing number of excised colorectal polyps have to collaborate closely to optimize patient care. Therapeutic management of patients after endoscopic resection is based on precise histological criteria that determine the risk of metastasis and the need for complementary surgery. This paper summarizes the procedures for the macroscopic management of endoscopic excisions and presents the identified risk factors which should be included in a standardized pathology report.

Mucin-producing hepatic cystic neoplasms: an uncommon but challenging disease often misdiagnosed and mismanaged.

Background: Mucin-producing hepatic cystic neoplasms (MHCN) are uncommon and potentially malignant.Methods: Nine MHCN were encountered in our centre for over 32 years. Patients' clinical, biological, radiological and pathological features were reviewed. Lesions were classified into Mucinous Cystic Neoplasms (MCN) and Intraductal Papillary Neoplasms of the Bile duct (IPNB) (WHO 2010 classification).Results: Five MCN and 4 IPNB were reviewed. Serum and intracystic tumour markers were insufficient to diagnose malignancy. Complications were encountered in five out of nine patients (56%), mean symptom duration was 26 months (range: 1-132). Three patients were mismanaged pre-referral. Radiological features enabled preoperative diagnosis in eight out of nine patients (89%). Greater tumour size, unilocular lesion and mural nodularity indicated malignancy. Radical tumour excision was achieved in eight patients. One IPNB patient was misdiagnosed and underwent unroofing. For 103 months median follow-up, five out of six patients with benign tumours were alive and disease-free, whereas the misdiagnosed IPNB recurred with fatal malignant transformation seven years later. Among the three patients with malignancies (median follow-up: 77 months), two IPNB died, one from cancer recurrence and one from unrelated causes, whereas the malignant MCN was alive and disease-free.Conclusions: Appropriate MHCN diagnosis is crucial, yet it is often misdiagnosed and mismanaged. The prognosis after complete excision is favourable.

The role of the pathologist and clinical implications in colorectal liver metastasis.

Colorectal liver metastases (CRLM) affect about 50% of colorectal cancer patients. With the improvement of neoadjuvant chemotherapy and the introduction of targeted therapy, resectability of CRLM and survival rates have improved over time. However, 60-70% of patients still recur. Several pathological and molecular parameters have been described as prognostic factors after CRLM resection. These parameters encompass not only tumoral features, but also non-tumoral ones, such as chemotherapy related liver injury, or factors related to tumour environment, namely Immunoscore. This review summarizes these prognostic indicators to clarify which patho-molecular parameters should be addressed in the pathological report.

A case of unusual histiocytic colitis in a chronic alcoholic obese patient with ankylosing spondylitis.

A 64 year-old Caucasian man was first investigated 21 years ago for persistent diarrhoea. A colonoscopy revealed an erosive pancolitis with unusual vacuolated macrophages. Characteristics of ulcerative colitis or Crohn's disease were absent. Similar findings were observed consistently over the following years. A treatment with Sulfasalazine, Methotrexate or Budesonide was efficient. Histiocytic colitis is rare, and the various causes and different diagnoses are reviewed. The cause for the chronic pancolitis in this obese chronic alcoholic remains unknown at the time of writing. Links to the dyslipidaemia and chronic ankylosing spondylitis presented by the patient are possible hypotheses worth investigating further.

Dysplasia in inflammatory bowel disease.

Ulcerative colitis and Crohn's diseases are relapsing longstanding inflammatory bowel diseases, associated with an increased risk of developing colorectal cancer. Continuous surveillance is necessary to detect the preneoplastic lesions in an early stage. New endoscopic techniques have improved the diagnostic accuracy and have resulted in a new and more simplified classification system of the dysplastic lesions in the bowel. Histopathologically these lesions are very heterogenous, consisting of adenomatous, villous and the more recently discovered serrated dysplasia. Its diagnosis may be hampered by the inflamed mucosa, resulting in a high interobserver variability in the categories of indefinite for dysplasia and low-grade dysplasia. Therefore the ECCO guidelines recommend to confirm the diagnosis of dysplasia by a pathologist with expertise in gastrointestinal pathology. In this article we give an overview of colitis-associated dysplasia from the point of view of the endoscopist and the pathologist.

Review of the quality of total mesorectal excision does not improve the prediction of outcome.

AIM: A fair to moderate concordance in grading of the total mesorectal excision (TME) surgical specimen by local pathologists and a central review panel has been observed in the PROCARE (Project on Cancer of the Rectum) project. The aim of the present study was to evaluate the difference, if any, in the accuracy of predicting the oncological outcome through TME grading by local pathologists or by the review panel. METHOD: The quality of the TME specimen was reviewed for 482 surgical specimens registered on a prospective database between 2006 and 2011. Patients with a Stage IV tumour, with unknown incidence date or without follow-up information were excluded, resulting in a study population of 383 patients. Quality assessment of the specimen was based on three grades including mesorectal resection (MRR), intramesorectal resection (IMR) and muscularis propria resection (MPR). Using univariable Cox regression models, local and review panel histopathological gradings of the quality of TME were assessed as predictors of local recurrence, distant metastasis and disease-free and overall survival. Differences in the predictions between local and review grading were determined. RESULTS: Resection planes were concordant in 215 (56.1%) specimens. Downgrading from MRR to MPR was noted in 23 (6.0%). There were no significant differences in the prediction error between the two models; local and central review TME grading predicted the outcome equally well. CONCLUSION: Any difference in grading of the TME specimen between local histopathologists and the review panel had no significant impact on the prediction of oncological outcome for this patient cohort. Grading of the quality of TME as reported by local histopathologists can therefore be used for outcome analysis. Quality control of TME grading is not warranted provided the histopathologist is adequately trained.

Lymph node ratio and surgical quality are strong prognostic factors of rectal cancer: results from a single referral centre.

AIM: Nodal stage is a strong prognostic factor of oncological outcome of rectal cancer. To compensate for the variation in total number of harvested nodes, calculation of the lymph node ratio (LNR) has been advocated. The aim of the study was to compare the impact, on the long-term oncological outcome, of the LNR with other predictive factors, including the quality of total mesorectal excision (TME) and the state of the circumferential resection margin. METHOD: Consecutive patients having elective surgery for nonmetastatic rectal cancer were extracted from a prospectively maintained database. Retrospective uni- and multivariate analyses were performed based on patient-, surgical- and tumour-related factors. The prognostic value of the LNR on overall survival (OS) and on overall recurrence-free survival (ORFS) was assessed and a cut-off value was determined. RESULTS: From 1998 to 2013, out of 456 patients, 357 with nonmetastatic disease were operated on for rectal cancer. Neoadjuvant radiochemotherapy was administered to 66.7% of the patients. The mean number of lymph nodes retrieved was 12.8 ± 8.78 per surgical specimen. A lower lymph node yield was obtained in patients who received neoadjuvant chemoradiotherapy (11.8 vs 14.2; P = 0.014). The 5-year ORFS was 71.8% and the 5-year OS was 80.1%. Multivariate analysis confirmed LNR, the quality of TME and age to be independent prognostic factors of OS. LNR, age and perineural infiltration were independently associated with ORFS. Low- and high-risk patients could be discriminated using an LNR cut-off value of 0.2. CONCLUSION: LNR is an independent prognostic factor of OS and ORFS. In line with the principles of optimal surgical management, the quality of TME and lymph node yield are essential technical requirements.

Pathological responses after angiogenesis or EGFR inhibitors in metastatic colorectal cancer depend on the chemotherapy backbone.

BACKGROUND: Optimal preoperative treatment before colorectal cancer metastases (CRCM) resection remains unclear. This study evaluated pathological responses (pR) in CRCM resected after chemotherapy alone or combined with angiogenesis or epidermal growth factor receptor (EGFR) inhibitors. METHODS: Pathological response was retrospectively evaluated on 264 resected metastases from 99 patients. The proportion of responding metastases after different preoperative treatments was reported and compared. Patient's progression-free survival (PFS) and overall survival (OS) were compared based on pR. RESULTS: The combination of anti-angiogenics with oxaliplatin-based chemotherapy resulted in more pR than when they were combined with irinotecan-based chemotherapy (80% vs 50%; P<0.001). Inversely, the combination of EGFR inhibitors with oxaliplatin-based chemotherapy seemed to induce fewer pR than when they were combined with irinotecan-based treatment (53% vs 72%; P=0.049). Overall survival at 5 years was improved for patients with a pR in all resected metastases compared with those who did not achieve a pR (68.5% vs 32.6%; P=0.023) and this response was the only factor predicting OS in a multivariate analysis. CONCLUSION: The chemotherapy partner combined with angiogenesis or EGFR inhibitors influenced pR in resected CRCM. In our exploratory analysis anti-angiogenic/oxaliplatin-based regimens and anti-EGFR/irinotecan-based regimens were associated with the highest pR. Prospective randomised trials should be performed to validate these observations.

Pancreatic neuroendocrine tumour grading on endoscopic ultrasound-guided fine needle aspiration: high reproducibility and inter-observer agreement of the Ki-67 labelling index.

OBJECTIVES: Assessment of proliferation by the Ki-67 labelling index (Ki67-LI) is an important parameter of pancreatic neuroendocrine tumour (pNET) prognosis on resection specimens. Ki67-LI values for grading are not fully established on endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). The aim of the study was to determine the accuracy of Ki67-LI on EUS-FNA to predict a final grade of pNET and to analyse the relationship between cytological grading and progression-free survival (PFS). METHODS: Between 1996 and 2010, 46 pNETs (33 were resected) from 45 patients were diagnosed by EUS-FNA. Ki67-LI was evaluated on cytological and histological material for each tumour and classified according to the 2010 WHO grading system. RESULTS: A very good inter-observer agreement for Ki67-LI on EUS-FNA and surgical specimens, respectively, were obtained. Discrepancies were observed between histology and cytology, especially in grade 2 (G2) tumours, where cytology underestimated grading owing to tumour heterogeneity. Still, EUS-FNA was able to distinguish a poor prognostic group, as the actuarial PFS of cytological (c) G3 tumours was 10 ± 4 months versus 29 ± 7 and 68 ± 10 for cG2 and cG1 tumours, respectively (P < 0.0001). CONCLUSION: This study attests the reproducibility of Ki67-LI of pNETs whether counted on cytology or histology with a very good inter-observer correlation. Determination of Ki67-LI on EUS-FNA of pNETs should be included systematically in their prognostic work-up.

Need for objective and reproducible criteria in histopathological assessment of total mesorectal excision specimens: lessons from a national improvement project.

AIM: Data on quality control of the pathologic evaluation of total mesorectal excision (TME) specimens are scarce. We aimed to assess differences between evaluation by local pathologists participating in PROject on CAncer of the REctum (PROCARE; a Belgian improvement project on rectal cancer) and by a review panel of experts. METHOD: Based on photographic material and histopathology slides, a Review Committee of gastrointestinal expert pathologists re-evaluated the mesorectal plane, the tumour differentiation grade, the (y)pT stage and the tumour regression grade in 444 patients previously routinely assessed by local pathologists. RESULTS: The surgical plane was reported in 89% of patients and the circumferential resection margin in 88% of patients by the local pathologist. The median number of lymph nodes harvested in patients undergoing neoadjuvant radiochemotherapy was 11 and 14 in the other patients. The Review Committee downgraded the surgical plane from (intra)mesorectal to intramuscular in 17% of patients, and upgraded it from intramuscular to (intra)mesorectal in 27%. Tumour differentiation grade, T stage and tumour regression grade differed between local pathologists and the Review Committee in 15%, 10% and 38%, respectively, of patients. T stage was upgraded, mainly from T2 to T3, in 8% of patients. Tumour regression was judged by the Review Committee to be less advanced in 15% of patients. CONCLUSION: Acknowledging some shortcomings, this study gives a realistic view of clinical practice. There are differences in interpretation with regard to both macroscopic and microscopic analysis of TME specimens. These findings indicate a need for more objective and reproducible criteria in histopathology. Being aware of this is a first step for improvement.

European consensus on the histopathology of inflammatory bowel disease.

The histologic examination of endoscopic biopsies or resection specimens remains a key step in the work-up of affected inflammatory bowel disease (IBD) patients and can be used for diagnosis and differential diagnosis, particularly in the differentiation of UC from CD and other non-IBD related colitides. The introduction of new treatment strategies in inflammatory bowel disease (IBD) interfering with the patients' immune system may result in mucosal healing, making the pathologists aware of the impact of treatment upon diagnostic features. The European Crohn's and Colitis Organisation (ECCO) and the European Society of Pathology (ESP) jointly elaborated a consensus to establish standards for histopathology diagnosis in IBD. The consensus endeavors to address: (i) procedures required for a proper diagnosis, (ii) features which can be used for the analysis of endoscopic biopsies, (iii) features which can be used for the analysis of surgical samples, (iv) criteria for diagnosis and differential diagnosis, and (v) special situations including those inherent to therapy. Questions that were addressed include: how many features should be present for a firm diagnosis? What is the role of histology in patient management, including search for dysplasia? Which features if any, can be used for assessment of disease activity? The statements and general recommendations of this consensus are based on the highest level of evidence available, but significant gaps remain in certain areas.

Histological and immunohistochemical revision of hepatocellular adenomas: a learning experience.

Light has been shed on the genotype/phenotype correlation in hepatocellular adenoma (HCA) recognizing HNF1 α -inactivated HCA (H-HCA), inflammatory HCA (IHCA), and ß -catenin-activated HCA (b-HCA). We reviewed retrospectively our surgical HCA series to learn how to recognize the different subtypes histopathologically and how to interpret adequately their immunohistochemical staining. From January 1992 to January 2012, 37 patients underwent surgical resection for HCA in our institution. Nine had H-HCA (25%) characterized by steatosis and loss of L-FABP expression; 20 had IHCA (55.5%) showing CRP and/or SAA expression, sinusoidal dilatation, and variable inflammation; and 1 patient had both H-HCA and IHCA. In 5 patients (14%), b-HCA with GS and ß -catenin nuclear positivity was diagnosed, two already with hepatocellular carcinoma. Two cases (5.5%) remained unclassified. One of the b-HCA showed also the H-HCA histological and immunohistochemical characteristics suggesting a subgroup of ß -catenin-activated/HNF1 α -inactivated HCA, another b-HCA exhibited the IHCA histological and immunohistochemical characteristics suggesting a subgroup of ß -catenin-activated/inflammatory HCA. Interestingly, three patients had underlying vascular abnormalities. Using the recently published criteria enabled us to classify histopathologically our retrospective HCA surgical series with accurate recognition of b-HCA for which we confirm the higher risk of malignant transformation. We also underlined the association between HCA and vascular abnormalities.

Serrated lesions of the colorectum, a new entity: what should a clinician/ endoscopist know about it ?

Serrated polyps of the colorectum have received much attention in recent literature. Several classifications have been proposed and created considerable confusion. Morphology and molecular biology have greatly contributed to the better identification of these entity. The recently published WHO classification, proposed using the term of "serrated polyp" as a generic term and defined sporadic serrated polyps as "a heterogeneous group" of lesions characterized morphologically by a serrated (sawtooth or stellate) architecture of the epithelial component which include hyperplastic polyps (HP), sessile serrated adenomas/polyps (SSA/P) and traditional serrated adenomas (TSA). With the development of molecular biology, it is now clear that the serrated pathway is one of the new carcinogenic pathways in the colon. There is now strong evidence that some serrated polyps correspond to precursors of some sporadic colorectal cancer (CRC). The aim of this article is to summarize the present data concerning the morphological and molecular characteristics of these serrated lesions and to give some recommendations for the management of such lesions.

Analysis of HER2 expression and gene amplification in adenocarcinoma of the stomach and the gastro-oesophageal junction: rationale for the Belgian way of working.

The Human Epidermal growth factor Receptor 2 (HER2) has been established as a key player in the development of certain human tumors. ToGA trial has demonstrated that the addition of the monoclonal antibody blocking HER2 receptor, trastuzumab (Herceptin®), to chemotherapy significantly improves overall survival of patients with HER2-positive advanced or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Therefore, it is essential that pathologists guarantee an accurate testing of HER2 status in these tumours. Following the international recommendations and the Belgian criteria for reimbursement of trastuzumab, a consortium of expert pathologists (Belgian Working Group Molecular Pathology) proposes an adaptation of the international guidelines in order to develop strategies for optimal performance, interpretation and reporting assays.

Quality of care indicators in rectal cancer.

Quality of health care is a hot topic, especially with regard to cancer. Although rectal cancer is, in many aspects, a model oncologic entity, there seem to be substantial differences in quality of care between countries, hospitals and physicians. PROCARE, a Belgian multidisciplinary national project to improve outcome in all patients with rectum cancer, identified a set of quality of care indicators covering all aspects of the management of rectal cancer. This set should permit national and international benchmarking, i.e. comparing results from individual hospitals or teams with national and international performances with feedback to participating teams. Such comparison could indicate whether further improvement is possible and/or warranted.