Belgian guidelines for pathology reporting of neuroendocrine neoplasms of the pancreaticobiliary and gastrointestinal tract.

Since neuroendocrine neoplasms are rare tumors, registration of patient data in national and multinational registries is recommended. Indeed, this will facilitate multicenter studies on the epidemiology, efficacy and safety of diagnostic and therapeutic strategies for well-differentiated neuroendocrine tumors as well as for neuroendocrine carcinomas. In Belgium, data on patient and tumor characteristics of all newly diagnosed malignancies have been collected in the Belgian Cancer Registry since 2004 including anonymized full pathological reports. The Digestive Neuroendocrine Tumor (DNET) registry collects information on classification, staging, diagnostic tools and treatment in a prospective national online database. However, the terminology, classification and staging systems of neuroendocrine neoplasms have changed repeatedly over the past 20 years as a result of a better understanding of these rare tumors, by joining forces internationally. These frequent changes make it very difficult to exchange data or perform retrospective analyses. For optimal decision making, for a clear understanding and to allow reclassification according to the latest staging system, several items need to be described in the pathology report. This paper provides an overview of the essential items in reporting neuroendocrine neoplasms of the pancreaticobiliary and gastrointestinal tract.

Immature squamous metaplasia of esophageal glands associated with squamous cell carcinoma.

Background: Esophageal immature squamous metaplasia is hardly reported in the literature. This entity can, however, be misinterpreted as high grade dysplasia or invasive squamous cell carcinoma and hence represent a potential pitfall. Case presentation: Histopathological examination of a superficial esophageal lesion removed by endoscopic submucosal dissection revealed a squamous cell carcinoma associated with immature squamous cell metaplasia arising from esophageal glands. Immunohistochemical stainings allowed to distinguish malignant from metaplastic cells. Conclusions: Immunohistochemistry for Ber-EP4 is helpful in making the distinction between esophageal squamous cell carcinoma and immature squamous metaplasia. This can avoid overstaging and overtreatment, especially in early esophageal cancer.

Polypoid colon mucosa in a leukemia patient.

A woman, followed for chronic myeloid leukaemia, presented for a routine examination. Her medical history was marked by recurrent Helicobacter pylori gastritis and polymyalgica rheumatica. She was under dasatinib and hormone replacement therapy. At clinical examination, she complained about digestive disorders with altered bowel habits. Biology, including leucocyte count, remained normal. A colonoscopy was performed. Endoscopic examination revealed a colonic mucosa covered by multiple tiny nodular lesions (<5mm) from the hepatic angle to the sigmoid and with an abnormal pattern of vascularisation (Fig. 1). Staged biopsies were taken. Microscopic examination revealed discrete achi-tectural distortions. The stroma contained a mixed inflammatory infiltrate composed of neutrophils, eosinophils and lymphocytes. Immunohistochemistry for CD3, CD5, CD20 and CD79 did not bring arguments for a lymphoma. There were no malignant or dysplastic cells. (Fig. 2). What is your diagnosis?

Isolated oesophageal Crohn's disease mimicking oesophageal carcinoma treated by Merendino procedure.

Oesophageal involvement is a very rare presentation of Crohn's disease. It can occur as an isolated mass causing dysphagia and can be mistaken for malignancy. Here, we report a case of a 75-year-old woman presenting with dysphagia and weight loss. Gastroscopy showed an ulcerating mass, and her barium swallow showed a bird beak appearance at the level of the gastro-oesophageal junction (GEJ). Repetitive biopsies were inconclusive. Fluorodeoxyglucose-positron emission tomography showed high glucose uptake (standardised uptake value: 10.2) at the level of the GEJ. Endoscopic ultrasound classified the lesion as uT3N1. Step-by-step surgical exploration revealed an oesophageal mass. A frozen section examination showed an absence of malignancy and the presence of inflammatory tissue. A partial oesophagogastrostomy was performed, and reconstruction was achieved by a Merendino procedure. Definitive histopathological examination revealed isolated oesophageal Crohn's disease.

Case report: Sclerosed hemangioma of the liver: A diagnostic challenge.

Hemangiomas are the most common noncystic benign hepatic tumors and are usually incidentally discovered during routine radiological examinations. The diagnosis of hepatic hemangiomas with a typical presentation is generally easy with plain and cross-sectional imaging; however, it can be complicated when hemangiomas undergo histological changes such as fibrosis. Sclerosed hepatic hemangioma (SHH) is the extreme presentation of this fibrotic process. These atypical lesions can be misdiagnosed as primary hepatic malignancies or metastasis. Their diagnosis is established by histological examination. We report the case of a patient with an SHH, which was misdiagnosed as an intrahepatic cholangiocarcinoma. This article's aim is to draw attention to this infrequent pathology and underline the features of this benign tumor that could suggest its diagnosis prior to surgery to avoid unnecessary hepatic resections.

Accuracy and other quality indicators of solid pancreatic mass endoscopic ultrasound-guided fine needle aspiration and biopsy in two academic endoscopy centers.

BACKGROUND AND AIMS: Endoscopic ultrasound fine-needle aspiration/biopsy (EUS-FNA/FNB) is highly accurate, but discrepancies between cytological and surgical diagnoses are still observed. We aimed to determine its accuracy and monitor quality indicators in our facilities. PATIENTS AND METHODS: We performed a retrospective review of all cases of pancreatic solid lesions evaluated by EUS-FNA/FNB, between July 2015 and June 2018, in two centers. Cytological and surgical findings were categorized into five groups: benign, malignant, suspect of malignancy, undetermined and insufficient for diagnosis. Final diagnosis was based on surgical diagnosis and, in patients who did not undergo surgery, on clinical outcome after 6 months follow-up. RESULTS: Altogether, 142 patients were included. FNA was the preferred tissue acquisition method (88%), with a predilection for the FNA 22G needle (57%). Cytology was insufficient for diagnosis in 2 cases, therefore a full diagnostic sample was available in 98.6% of the patients (>90%, ESGE target). Fifty-five (38.7%) patients underwent surgery. In term of cancer diagnosis, comparison with final surgical pathology (n=55) revealed 89% true positives, 5.5% true negatives, 3.6% false positives and 1.8% false negatives. When combining surgical diagnosis and clinical outcomes together, EUS-guided sampling sensitivity was 97.4% (92.5-99.5), specificity was 92.3% (74.9-99.1), positive predictive value was 98.2% (93.6- 99.5), negative predictive value was 88.9% (72.3-96.1) and accuracy was 96.4% (91.9-98.8). Post-procedural acute pancreatitis was reported in 2 patients (1.4%). CONCLUSIONS: These results reveal a performance for diagnostic tissue sampling well above the ESGE proposed target standard. Also, the uncommon high specificity illustrates the determining role of the pathologist's final interpretation and diagnosis.

Lessons learned about appendiceal neuroendocrine neoplasms from data analysis of the Belgian Cancer Registry 2010-2015.

BACKGROUND AND STUDY AIMS: Appendiceal neuroendocrine neo-plasms (aNENs) are a diverse group of malignant neoplasms of varying biological behavior for which information about manage-ment and outcome is sparse, with the majority of available studies being retrospective, including only a limited number of patients, and therefore not necessarily reflecting the reality in the community. In the present study clinical, epidemiological and pathological data of appendiceal neuroendocrine neoplasms in Belgium is provided and compared with current literature. METHODS: A population-based study was conducted by linking data of the Belgian Cancer Registry with medical procedures in the Belgian Health Insurance database for patients diagnosed with aNEN between 2010 and 2015. RESULTS: We found an aNEN incidence of 0.97/100.000 person years in Belgium. Neuroendocrine carcinoma of the appendix are rare. Most appendiceal neuroendocrine tumors (aNETs) are small G1 tumors. Positive lymph nodes are often found in tumors larger than 2cm, especially aNET G2. CONCLUSION: A rapid uptake of changing classifications was seen in the community. However, systematic reporting of risk factors for small aNEN can still be improved and should be stimulated. In 9% of cases, reclassifications had to be made, pointing out that in a retrospective analysis, original pathological reports should be checked for specific parameters, before reliable conclusions can be drawn.

Mantle cell lymphoma simulating inflammatory bowel disease.

We report a case of colorectal involvement by a mantle cell lymphoma (MCL) that had been considered before as inflammatory bowel disease. Diagnosis of low-grade MCL can be difficult, and here we highlight the importance of thorough histopathological examination in case of supposed inflammatory bowel disease that does not react to therapy.

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.

Inflammatory hepatocellular adenoma, focal nodular hyperplasia and hepatic granulomas in one single patient : possible physiopathologic explanations.

We report the case of a hepatocellular adenoma associated with focal nodular hyperplasia and hepatic granulomas in a 30-yearsold woman. This association has rarely been described before but might be explained by underlying common pathophysiologic mechanisms. In this manuscript possible links between the three entities are discussed.

A rare presentation of small diaphragmatic epidermoid cyst with extremely elevated serum CA19-9 level.

Epidermoid cysts are rare lesions that can occur anywhere in the body. They are associated with elevated serum levels of CA 19-9. The spleen represents the most common site of intra-abdominal localisation. Only two cases of diaphragmatic epidermoid cyst are reported in the literature. We present the case of a 61-year-old woman with a small suprasplenic subdiaphragmatic cyst discovered during the investigation of left flank pain. The establishment of an adequate diagnosis was challenging due to the difficulty in specifying the exact localisation of the cyst, the extremely elevated CA 19-9 level of 19,000 and the high uptake on 18-fluoro-2-deoxy-D-glucose positron emission tomography. The definitive diagnosis followed complete surgical excision. Intra-abdominal epidermoid cysts are usually discovered incidentally on imaging for another reason. The cyst is lined by squamous epithelium responsible for the secretion of CA 19-9. The elevation of serum CA 19-9 is due to small rupture or increased intraluminal pressure followed by diffusion to the bloodstream. Surgery with en-bloc resection represents the optimal treatment to avoid any risk of recurrence. The definitive diagnosis is established by demonstrating positive immunohistopathological staining of epithelial cell to CA 19.9.

Benign, premalignant and malignant pancreatic cystic lesions: the pathology landscape.

Pancreatic cystic lesions are being increasingly detected in last years. Pancreatic cysts can be classified grossly into pseudocysts and true cysts. In the true cysts group, it is important to distinguish mucinous from non-mucinous cysts because the former are considered being premalignant lesions. In this article the major types of pancreatic cysts are reviewed, with emphasis on the histopathological aspects. Molecular markers in the cyst fluid are being increasingly studied in recent years ; the clinical utility of such biomarkers should be addressed in future studies.

DLL4 expression is a prognostic marker and may predict gemcitabine benefit in resected pancreatic cancer.

BACKGROUND: There is an increasing interest for Notch signalling pathway and particularly Delta-like ligand 4 (DLL4) as potential therapeutic target to improve outcome for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Using immunohistochemistry (IHC) and tissue microarray (TMA), we assessed the expression patterns of DLL4, Notch1 and Notch3 in 151 patients from two independent cohorts of resected PDAC. We investigated the prognostic and the predictive significance of these proteins. RESULTS: High IHC DLL4 expression in cancer cells was associated with worse overall survival (OS) and disease-free survival (DFS) than low DLL4 expression (median OS: 12.9 vs 30.4 months, P=0.004 and median DFS: 8.8 vs 17.4 months, P=0.02). High DLL4 expression remained a significant negative prognostic factor in multivariate analysis (HR for OS: 2.1, P=0.02 and HR for DFS: 2.0, P=0.02). Low DLL4 abundance was associated with a longer OS-only for patients who received an adjuvant gemcitabine-based chemotherapy (P<0.001) but not for patients who did not receive gemcitabine (P=0.72). Furthermore, the interaction test for adjuvant gemcitabine therapy was statistically significant (P<0.001). The validating cohort recapitulated the findings of the training cohort. CONCLUSIONS: Low DLL4 abundance in tumour cells may predict the benefit from adjuvant gemcitabine therapy after PDAC resection.

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.

IGF-IR: a new prognostic biomarker for human glioblastoma.

BACKGROUND: Glioblastomas (GBMs) are the most common malignant primary brain tumours in adults and are refractory to conventional therapy, including surgical resection, radiotherapy and chemotherapy. The insulin-like growth factor (IGF) system is a complex network that includes ligands (IGFI and IGFII), receptors (IGF-IR and IGF-IIR) and high-affinity binding proteins (IGFBP-1 to IGFBP-6). Many studies have reported a role for the IGF system in the regulation of tumour cell biology. However, the role of this system remains unclear in GBMs. METHODS: We investigate the prognostic value of both the IGF ligands' and receptors' expression in a cohort of human GBMs. Tissue microarray and image analysis were conducted to quantitatively analyse the immunohistochemical expression of these proteins in 218 human GBMs. RESULTS: Both IGF-IR and IGF-IIR were overexpressed in GBMs compared with normal brain (P<10(-4) and P=0.002, respectively). Moreover, with regard to standard clinical factors, IGF-IR positivity was identified as an independent prognostic factor associated with shorter survival (P=0.016) and was associated with a less favourable response to temozolomide. CONCLUSIONS: This study suggests that IGF-IR could be an interesting target for GBM therapy.

Microsatellite instable vs stable colon carcinomas: analysis of tumour heterogeneity, inflammation and angiogenesis.

BACKGROUND: Microsatellite instability (MSI) accounts for 15% of all colorectal tumours. Several specific clinicopathologicals (e.g., preference for the proximal colon over the distal colon, improved prognosis and altered response to chemotherapeutics) are described for this subset of tumours. This study aimed to analyse morphological, inflammatory and angiogenic features of MSI vs microsatellite stable (MSS) tumours. METHODS: Twenty-seven MSS and 29 MSI, TNM stage matched, colorectal tumours were selected from the archive of the Department of Pathology, UZ Leuven. Morphology was analysed on haematoxylin-eosin sections. Immunohistochemistry for CD3, CD4, CD8, CD20 and CD68 was used to map tumour infiltration in both a digital and traditional microscope-based manner for all distinct morphological components of the tumour. CD31 immunostains were performed to assess angiogenesis. RESULTS: Morphological tumour heterogeneity was a marked feature of MSI tumours, occurring in 53% of the cases as compared with 11% of the MSS tumours (P<0.001). Digital immune quantification showed an increased number of tumour-infiltrating cytotoxic T-lymphocytes (CD8+) in MSI compared with MSS tumours for both the tumour (P=0.02) and peritumoural area (P=0.03). Traditional microscope-based quantification confirmed these results (P<0.001 for both) and, in addition, revealed large numbers of CD68+ macrophages in the peritumoural area of MSI cancers (P=0.001). Moreover, traditional microscope-based analysis was able to distinguish between lymphocytes directly infiltrating the tumoural glands (intra-epithelial) and those infiltrating only the neoplastic stroma around the glands (intratumoural). Quantification showed high numbers of intra-epithelial CD3+, CD4+, CD8+, CD20+ and CD68+ cells in MSI compared with MSS cancers (P<0.001, P=0.01, P<0.001, P<0.001 and P=0.006, respectively). Higher microvessel density (MVD) was observed in MSI tumours compared with their MSS counterpart. CONCLUSIONS: Mixed morphology, reflecting tumour heterogeneity, is an important feature of MSI tumours and may have both diagnostic and therapeutic impact. The inflammatory reaction also presented with significant differences in MSI vs MSS colorectal tumours. MSI cancers showed mainly infiltration by cytotoxic T-cells in both the tumour and the close border around the tumour, as well as increased intra-epithelial infiltration in contrast to MSS tumours. The type of immune cell and the compartment it resides in (intratumoural or intra-epithelial) depend both on MSI status and morphology. Finally, MSI tumours showed a higher angiogenic capacity represented by an increased MVD, hinting for possible therapeutic consequences.

Pooled analysis of the surgical treatment for colorectal cancer liver metastases.

Liver metastases in colorectal cancer patients decreases the expected 5 year survival rates by a factor close to nine. It is generally accepted that resection of liver metastases should be attempted whenever feasible. This manuscript addresses the optimal therapeutic plan regarding timing of resection of synchronous liver metastases and the use of chemotherapy in combination with resection of synchronous metachronous liver metastases. The aim is to pool all published results in order to attribute a level of evidence to outcomes and identify lacking evidence areas. A systematic search of guidelines, reviews, randomised controlled, observational studies and updating a meta-analysis was performed. Data were extracted and analysed. Data failed to demonstrate an effect of timing of surgery or use of chemotherapy on overall survival. Concomitant resection of liver metastases and the primary tumour may result in lower postoperative morbidity. Systemic peri-operative chemotherapy may improve progression free survival compared to surgery alone.

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.