The risk of lymph node metastasis in T1 colorectal cancer: new parameters to assess the degree of submucosal invasion.

PURPOSE: In T1 colorectal cancer, the depth is the main factor assessing the degree of submucosal invasion (DSI) to predict the risk of lymph node metastasis (LNM). The width (WSI) and the area of submucosal invasion (ASI) have been suggested as additional parameters to assess the risk of LNM. A review of the literature was undertaken on the correlation between WSI and ASI parameters and the incidence of LNM. METHODS: A Medline, PubMed, and Cochrane Library search was performed to retrieve all studies reporting correlation between WSI/ASI and risk of LNM in T1 colorectal cancer. RESULTS: Eight studies including 1727 patients were identified. All considered the degree of WSI and its influence on LNM: seven assessed different width cut-off of submucosal invasion, and one study the mean width of submucosal invasion in patients having or not involved lymph nodes. The WSI was significantly a prognostic factor for LNM (p < 0.05) in four studies. Both 2 and 3 mm seem to be the most discriminatory cut-off values of submucosal width invasion in defining the risk difference of LNM above and below the cut-off (2 mm, OR = infinite; 3 mm, OR = 6.9). Patients having a cut-off ≤ 5 mm of WSI showed a low risk (5.6%) of LNM rendering radical surgery unnecessary. Four studies assessed the risk of LNM according to the involved submucosal area (width × depth). In two of these, the ASI was a significant prognostic factor for LNM (p < 0.05). CONCLUSION: The WSI and ASI seem to be reliable prognostic factors for LNM in T1 colorectal cancer. There is no agreement on ideal cut-off value.

Potential pitfalls in reporting non-neoplastic gastrointestinal mucosal biopsies.

Biopsies taken from the gastrointestinal tract (GIT) comprise a significant percentage of the pathologists' routine work. The variable histology and normal components of each organ along the GIT, as well as the different ways of responding to injury among these organs, can cause morphological changes that could result in potential diagnostic pitfalls. Herein, we review the pathological conditions of the GIT that could cause these diagnostic pitfalls. Our aim was to increase awareness among pathologists and trainees regarding these conditions and provide a pragmatic approach to prevent them and achieve a correct diagnosis.

Pitfalls in the reporting of neoplastic and pseudo neoplastic lesions in the colon and rectum.

INTRODUCTION: Colonic biopsies comprise large portion of pathologists' daily work. Within various pathological entities, there are histological ranges and variations. Unawareness of all of these variabilities might lead to misdiagnosis by an inexperienced pathologist and, accordingly, to mismanagement.

Portal hypertension in primary biliary cholangitis: prevalence, natural history and histological correlates.

OBJECTIVES: The histopathological mechanisms underlying portal hypertension in primary biliary cholangitis (PBC) are poorly understood, as is its natural history. We have therefore determined the prevalence, severity and progression of portal hypertension in PBC and investigated whether its presence is related to specific histological lesions. METHODS: Hepatic venous pressure gradient (HVPG) was measured in 86 patients, with 186 assessments over up to 7 years of follow-up and the results correlated with a semiquantitative grading of 8 histological features and nodular regenerative hyperplasia (NRH). RESULTS: Portal hypertension (HVPG >5 mmHg) was present in 88% of all assessments (86% at baseline), and in 45% of patients at baseline was >12 mmHg (high-risk portal hypertension). The rise in portal pressure occurs early in the disease, since 45% of patients with normal serum bilirubin had a raised HVPG, as did 72% of patients with early (Ludwig stages 1 and 2) disease. After baseline, there was a small increase in HVPG over the next 5 years in most patients. In patients with precirrhotic PBC, 82% had portal hypertension and in 34% this was >12 mmHg. Portal pressure correlated significantly with a semiquantitative grading of cholestasis, interface hepatitis and portal tract and sinusoidal fibrosis. NRH was present in only 20% of wedge biopsies. CONCLUSIONS: Portal hypertension commences in the early stages of PBC, long preceding both rises in serum bilirubin and the development of cirrhosis. Around 34% of precirrhotic PBC patients have 'high-risk' portal hypertension, which is associated with lesions in the portal tracts and sinusoids rather than with NRH.

Histopathological Mimics of Inflammatory Bowel Disease.

This review article discusses the challenges of making a firm histopathological diagnosis of inflammatory bowel disease (IBD) on biopsy and resection material and the importance of its distinction from a range of other inflammatory and infective conditions that may closely mimic IBD. In many cases, the diagnosis of ulcerative colitis or Crohn's disease is straightforward, especially when patients have a typical presentation and characteristic histopathological features. Knowledge of the full clinical history is very important, particularly past and recent medical history, drug history, foreign travel, or known contact with individuals with specific infection. Discussion of all cases of suspected IBD within a multidisciplinary team meeting is required to ensure that clinical, radiological, and pathological features can be correlated. Mimics of IBD can be divided into 4 categories: 1) those due to specific infection, 2) those due to a specific localized inflammatory process, 3) those due to iatrogenic causes, and 4) other rarer causes. Accurate diagnosis of IBD and exclusion of these mimics are crucial for patient management. Once a diagnosis of IBD has been proffered by a pathologist, it is very difficult to "undiagnose" the condition when an alternative diagnosis or "mimic" has been subsequently identified. The histological diagnosis of each of these IBD mimics is discussed in detail, with guidance on how to avoid the pitfall of missing these sometimes very subtle and "difficult to diagnose" conditions.

The effect of radiotherapy on rectal cancer: a histopathological appraisal and prognostic indicators.

The management of rectal cancer is a major undertaking. There are currently multiple treatment modalities with variable degrees of complications. Radiotherapy (RT) is one of the more frequently used modalities either on its own or more frequently with chemotherapy mostly before the definitive surgery. The outcome of RT is unpredictable. RT has its serious side effects and there are no guarantees of its usefulness in all patients. This article outlines the effect of RT on the tumor, reviews the various staging systems of responses to RT and present recent evidence of which case is less responsive to such treatments to avoid unnecessary complications.

Reporting Colonic Biopsies in Patients With Inflammatory Bowel Disease; a Practical Approach.

Crohn's disease (CD) and ulcerative colitis (UC) are common diseases; for convenience, we lump them together as inflammatory bowel disease (IBD). Colonic biopsies are essential for establishing a diagnosis, monitoring treatment, and/or identifying complications. This article attempts to detail the histological criteria of UC and CD and also informs on a lifelong approach of reporting colonic biopsies from patients with IBD. Often the clinical information on the accompanying request form is not available to the pathologist. In these cases, the author has initiated a reproducible system of pattern-based reporting with a differential diagnosis. This type of report offers a working diagnosis for the clinician before the final diagnosis, which is recommended to be undertaken in a setting of combined clinico-pathological conference (CPC). This system carries objective parameters and standardizes reporting to significantly minimize the interobserver variations among reporting pathologists. If a CPC facility is not available, we offer an alternative evidence-based arrangement. We discourage the use the term "nonspecific colitis" as we have shown that it has no clinical value or agreed-upon and recognized histopathological features. As the paper addresses mucosal biopsies, the entity of indeterminate colitis will not be included in this article as this diagnosis is strictly based on colonic resectate. 10.1093/ibd/izy288_video1 izy288.video1 5839278247001.

Liver biopsy in primary biliary cholangitis: is sinusoidal fibrosis the missing key?

AIMS: The role of liver biopsy in primary biliary cholangitis (PBC) is controversial, as is the optimal method of histological assessment. We compared the Ludwig and Ishak systems and three components of the Japanese (Nakanuma) staging system to evaluate their clinical and biochemical correlations and prognostic value. METHODS: We reviewed biopsies from 106 patients with PBC, derived from a previous trial of colchicine therapy with 24-34 years' follow-up, following which five clinical outcomes were evaluated: hepatic decompensation, cholestatic PBC death/liver transplant, portal hypertensive PBC death, all PBC deaths and overall survival. RESULTS: Ludwig and Ishak stages correlated well with prognostically significant parameters, including serum bilirubin, and both Mayo and Child Scores. Serum aspartate aminotransferase correlated with interface hepatitis (IFH), and alkaline phosphatase with orcein deposition, bile duct (BD) loss and cholestasis. Ludwig correlated with all five clinical outcomes, while Ishak stage was only significantly correlated with two. While sinusoidal fibrosis, orcein deposition, BD loss and cholestasis all predicted hepatic death/transplant, after correction for Mayo Score, the only histological parameters predictive of clinical outcomes were IFH (associated with two) and sinusoidal fibrosis (associated with all five). CONCLUSION: Liver biopsy is required in the diagnosis of around 20% of patients with PBC. The Ludwig system is of more prognostic value than both Ishak and any of the three individual components of the Nakanuma staging system, but the major histological parameter providing independent prognostic value beyond the Mayo Score is sinusoidal fibrosis.

Early molecular and functional changes in colonic epithelium that precede increased gut permeability during colitis development in mdr1a(-/-) mice.

BACKGROUND: The early molecular changes preceding the onset of mucosal inflammation in colitis and their temporal relationship with gut permeability remain poorly defined. This study investigated functional and transcriptomic changes in mdr1a(-/-) mice lacking the intestinal transporter P-glycoprotein, which develop colitis spontaneously when exposed to normal enteric flora. METHODS: Mdr1a(-/-) mice were housed in specific pathogen-free conditions to slow colitis development and compared to congenic controls. Mucosal permeability and cytokine secretion were analyzed in ex vivo colon. Gene expression in colonic mucosal and epithelial preparations was analyzed by microarray and qPCR. Colonocyte responsiveness to bacterial antigens was measured in short-term culture. RESULTS: Colon from 4-5-week-old, disease-free mdr1a(-/-) mice was histologically normal with no evidence of increased permeability compared to controls. However, these tissues display a distinctive pattern of gene expression involving significant changes in a small number of genes. The majority of upregulated genes were associated with bacterial recognition and the ubiquitin-proteasome system and were gamma-interferon (IFN-gamma) responsive. Expression of the antiinflammatory factor pancreatitis-associated protein (PAP) and the related gene RegIIIgamma were markedly reduced. Colonocytes from 4-5-week mdr1a(-/-) exhibit similar transcriptomic changes, accompanied by higher basal chemokine secretion and increased responsiveness to LPS. Significant increases in colonic permeability were associated with older (12-16-week) mdr1a(-/-) mice displaying molecular and functional evidence of active inflammation. CONCLUSIONS: These studies show that early epithelial changes associated with altered responsiveness to bacteria precede increased permeability and mucosal inflammation in this model of colitis, highlighting the importance of P-glycoprotein in regulating interactions with the commensal microflora.

The malignant adenoma: when to operate and when to watch.

BACKGROUND: Adenomas are the precursors to colorectal cancer. Malignant adenomas represent an early form of colorectal cancer, in which cancer has invaded by direct continuity through the muscularis mucosa into the submucosa. The management of these malignant adenomas depends upon their histological risk factors and the patient's general condition. METHODS: A literature review of publications regarding the malignant adenoma/polyp using Medline was performed. RESULTS: The three main histological characteristics associated with an increased risk of residual disease and the potential for metastases are completeness and margin of excision, degree of differentiation and Haggitt level of invasion. CONCLUSION: The dilemma as to which course of action is in the best interest of the patient with high-risk adenoma, be it either therapeutic polypectomy alone or surgical resection, is best resolved by a multidisciplinary team involving the surgeon, pathologist and endoscopist, taking the patient's condition and wishes into account.

Physical activity before and after diagnosis of colorectal cancer: disease risk, clinical outcomes, response pathways and biomarkers.

Physical inactivity may be responsible for 13-14% of colon cancer, an attributable risk greater than family history. Epidemiological evidence shows an association between occupational and recreational physical activity and colon cancer, but has not established whether physical activity is protective against low-risk or more advanced adenomas. The evidence is inconclusive as to whether physical activity protects against rectal cancer and is conflicting with respect to whether physical activity has equal effects on male and female risk of colorectal cancer. The effect of exercise 'interventions' on the risk of colorectal cancer is currently not known. Also, although inferences can be made from epidemiological studies, no optimal exercise regimen can be confidently prescribed for protection against colorectal cancer. There is little available evidence for the benefits of physical activity before diagnosis of colorectal cancer for disease-specific survival and prognosis, and the clinical effects of an exercise intervention after diagnosis have not been investigated. There is some evidence that improvements in cardiorespiratory fitness reduce adverse effects from cancer treatment when physical activity is undertaken following diagnosis of colorectal cancer. Markers/mechanisms by which physical activity may protect against colorectal cancer and/or improve disease prognosis include gastrointestinal transit-time, chronic inflammation, immune function, insulin levels, insulin-like growth factors, genetics and obesity. Research evidence is, however, limited as to whether these markers are beneficially affected by physical activity, either before or after diagnosis of colorectal cancer.

Vascular endothelial growth factors and receptors in colorectal cancer: implications for anti-angiogenic therapy.

There are conflicting associations between growth factor expression and clinicopathological variables in colorectal cancer. This study aimed to define the expression of members of the VEGF family and the receptor, VEGFR2, in primary and metastatic sites of colorectal cancer and their relationship to metastatic potential. Thirty colorectal cancers, 12 lymph node metastases and 9 liver metastases were immunostained for VEGF-A, VEGF-C, VEGF-D and VEGFR2. VEGFR2 was expressed by endothelial cells and by the malignant epithelium. VEGF-C and VEGFR2 were co-expressed in the same territory and correlated throughout the primary tumour and in metastatic lymph nodes, but not in liver metastases. Their expression at the invasive tumour edge correlated with expression in metastatic nodes. The benefit of anti-VEGF antibodies might be increased by directing additional therapies against VEGF-C or against the kinase receptors to target redundancy in the system. A component of the therapeutic benefit might be due to a direct anti-tumour effect as well as an anti-angiogenic effect.

Pseudohepatic tumour associated with secondary syphilis in an HIV-positive male.

Inflammatory pseudohepatic tumours are unusual tumour-like conditions which can easily be mistaken for malignant lesions or liver abscesses. Patients usually present with fever, abdominal pain and loss of weight. The aetiology is unclear but the predominant inflammatory pattern of pathology and the associated systemic reactions suggest an underlying infectious agent. In the majority, microorganisms are not detected. As even routine imaging procedures usually fail to distinguish hepatic pseudotumours from liver neoplasms, biopsy is the definitive means of diagnosis. Until now, no case of pseudohepatic tumour has been reported as being associated with secondary syphilis. We believe secondary syphilis is the cause of this pseudohepatic tumour in our HIV-positive male.