Introduction:
People with Inflammatory Bowel Disease (IBD) face an elevated risk of colorectal cancers, mainly adenocarcinomas. In addition to these, rarer tumors like lymphomas and sarcomas, including Neuroendocrine Neoplasms (NENs), are reported, though the link needs more exploration. We present two cases of NENs in mild left-sided UC, aggressive and have poor prognosis compared to regular colorectal cancers. Despite regular check-ups, both cases were advanced at detection, emphasizing the aggressive nature of NENs. While carcinoids might be coincidental, NENs could develop due to long-term inflammation affecting various cell types.
What Is the Role of Chronic Inflammation in Colon Carcinogenesis?
Inflammation Triggers Colon Cancer Pathways:
Chronic inflammation in the colon is closely linked to the development of colon cancer.
Three main pathways APC (Argon Plasma Coagulation) or Tumor Suppressor Gene or CIN (Cervical Intraepithelial Neoplasia), MSI (Microsatellite Instability), CIMP (CpG island Methylator Phenotype)) can be activated early in chronic inflammatory conditions, such as Ulcerative Colitis (UC).
Genetic and Inflammatory Factors:
In UC patients, genes associated with inflammation (e.g., COX-2, NOS-2) are elevated in inflamed colon areas.
Increased turnover of epithelial cells during inflammation contributes to cancer development.
Oxidative Stress and DNA Damage:
Chronic inflammation leads to oxidative stress, causing DNA damage and mutations.
Oxidative stress results from an imbalance of free radicals produced by inflammatory cells.
Role of Reactive Oxygen and Nitrogen Species (RONS):
Inflamed tissues show increased expression of NOS and other RONS.
Animal studies suggest that reducing oxidative stress can decrease inflammation and cancer risk.
Genetic Targets and Mutations:
Mutation of the p53 tumor suppressor gene is associated with oxidative stress in inflamed colonic mucosa.
Oxidative stress can lead to Microsatellite Instability (MSI), contributing to cancer development.
Chromosomal Instability (CIN):
Genomic instability occurs in cancerous and non-dysplastic mucosa of UC patients, suggesting it may be a marker for cancer risk.
Telomere shortening is proposed as a mechanism for CIN associated with UC.
Epigenetic Changes and DNA Methylation:
Oxidants can alter DNA methylation patterns, potentially affecting genes involved in colorectal cancer (CAC).
The role of hypermethylation in CAC is still under investigation.
Activation of Inflammatory Genes:
Oxyradicals can induce key genes like NF-κB, stimulating pro-inflammatory and carcinogenic effects.
TNF-α and PPARγ influence NF-κB activity, but their specific roles in carcinogenesis are not fully understood.
COX-2 and Chemoprevention:
COX-2, important in sporadic carcinogenesis, is induced in UC, especially in dysplastic and cancerous lesions.
COX-2 inhibitors in animal models and humans show protective effects against colon cancer, but their role in UC-associated cancer is uncertain.
How Are Neuroendocrine Tumors (NETS) Classified According to the World Health Organization?
Rare cancers originate from the endocrine and nervous systems, often in the gastrointestinal system. Classified by the World Health Organization based on grade:
Grade 1: well-differentiated, low grade.
Grade 2: well-differentiated, intermediate grade.
Grade 3: poorly differentiated, high grade.
Prognosis and Comparison to Colorectal Adenocarcinoma:
Generally, NETs have a less favorable prognosis than more common colorectal adenocarcinoma.
Classified into three grades based on tumor characteristics, G3 being poorly differentiated and high grade.
Association with Ulcerative Colitis (UC):
Often a documented association between UC and NETs, particularly with carcinoids.
Varying study conclusions about a possible link between UC and NETs with non-carcinoid neuroendocrine differentiation.
Metastatic Neuroendocrine Tumors:
Evidence of metastatic neuroendocrine tumors found in mesenteric lymph nodes in a specific case.
Literature suggests relatively positive outcomes for patients with these tumors despite their rarity.
Colonic Microbiota and Neuroendocrine Tumors:
Research explores a potential connection between colonic microbiota in neuroendocrine tumors and Crohn’s disease.
Suggests a shared biological origin for neuroendocrine differentiation and the development of Inflammatory Bowel Disease (IBD).
What Are the Clinical Distinctions Between CRC in IBD and Sporadic CRC?
Differences in Colorectal Cancer (CRC) in Inflammatory Bowel Disease (IBD) vs. Sporadic CRC:
Age and Histological Difference:
CAC affects younger individuals.
More mucinous or signet ring cell histology was observed.
Genetic Factors:
No clear genetic cause for CAC.
hMSH2 gene mutation linked to UC patients with HGD and cancer, but findings not universally supported.
Family History:
A positive family history increases CRC risk in IBD.
Similar risk increases in the general population.
Role of Chronic Inflammation in CRC Development in IBD:
Duration and Extent of Colitis:
Longer colitis duration increases CRC risk.
Extensive colitis involvement raises the risk.
Primary Sclerosing Cholangitis (PSC):
Higher CRC risk in IBD patients with PSC.
PSC also predisposes to biliary tract cancer.
Medication Impact:
Anti-inflammatory drugs like 5-aminosalicylates may reduce CRC risk.
Similar preventive effects seen with aspirin in healthy individuals.
Inflammation Correlation:
Little direct research on inflammation's correlation with CRC risk.
Histologically active inflammation associated with increased CRC risk.
Clinical vs. Histological Activity:
Clinical symptoms don't always correlate with CRC risk.
CRC can develop in areas with histologically active inflammation, even without visible symptoms.
Quiescent Inflammation Paradox:
Patients with quiescent inflammation may still develop CRC.
The severity of inflammation doesn't always align with CRC risk.
Immune Cells' Role:
Further insights into CAC pathogenesis from studying immune cells and their products.
What Challenges Are There in Understanding the Link Between IBD and Aggressive Forms of NENS?
Neuroendocrine Tumors (NENs):
Represent 0.1% to 3.9% of all colorectal malignancies.
Subdivided into Small-Cell Neuroendocrine Carcinoma (SCNC) and Large-cell Neuroendocrine Carcinoma (LCNC) based on cell characteristics.
Diagnosis of NENs:
Diagnosis involves cytological-histological features and immunohistochemical findings.
SCNC and LCNC have distinct cell characteristics and criteria for classification.
LCNC diagnosis requires positive immunohistochemical staining for specific neuroendocrine markers.
Incidence and Prognosis:
Reported incidence ranges from 0.1% to 3.9%, with a study reporting 0.6% in colon and rectal cancers.
NENs have a particularly poor prognosis compared to common colorectal adenocarcinoma.
High rate of liver metastasis (50%) and a reported 1-year survival rate of about 40%.
Association with IBD:
Reports of neuroendocrine tumors associated with IBD, but many are less aggressive carcinoids found incidentally.
Unclear if there is a real association between IBD and more aggressive NENs.
Some suggest that NENs in IBD may evolve from dysplastic cells in inflamed areas.
Studies and Findings:
Studies show that NENs in IBD patients tend to be aggressive with poor response to chemotherapy.
Limited understanding of the link between IBD and aggressive NENs.
Lack of clear identification of a subgroup of IBD patients at risk for these tumors.
Research Gaps:
Uncertain if the association between IBD and NENs is incidental or indicative of a real connection.
Need for further research to explore the relationship and identify potential risk factors.
Existing hypotheses like pancellular dysplasia need more confirmation from published case reports.
Conclusion:
In the past decade, there have been gained insights into colorectal cancer in Inflammatory Bowel Disease (IBD). Identifying and managing cancer risk factors is crucial. Targeted surveillance, advanced colon checks, and timely abnormal growth removal enhance outcomes. Ongoing research aims to understand IBD-cancer links, develop new prevention methods, and discover early detection tools. Continuous efforts seek to improve outcomes for IBD patients and lessen the impact of colorectal cancer on public health.
