Hyperplastic Polyposis Research Articles

Hereditary Colorectal Cancer and Polyposis Syndromes

The majority of cases of inherited colorectal cancer (CRC) are accounted for by two syndromes: Lynch syndrome and familial adenomatous polyposis (FAP). In the management of FAP, the role of prophylactic surgery is clearly defined, although the optimal procedure for an individual patient depends on a number of factors. In the management of Lynch syndrome, the indications for prophylactic procedures are emerging. The authors address the clinical evaluation, investigation findings, medical and surgical therapy, and extracolonic diseases of FAP, attenuated form of FAP (AFAP), MYH-associated polyposis, Lynch syndrome, familial colorectal cancer type X (FCCTX), hyperplastic polyposis syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. AFAP has been described that is associated with fewer adenomas and later development of CRC compared with classic FAP. The AFAP phenotype occurs in less than 10% of FAP patients. The clinical criteria for AFAP are no family members with more than 100 adenomas before the age of 30 years and (1) at least two patients with 10 to 99 adenomas at age over 30 years or (2) one patient with 10 to 99 adenomas at age over 30 years and a first-degree relative with CRC with few adenomas. Given that polyposis has a later onset and the risk of CRC is less well established in AFAP, some authors question whether prophylactic colectomy is necessary in all AFAP patients. This review contains 26 tables and 173 references Keywords: Colorectal cancer, Lynch syndrome, hyperplastic polyp, Peutz-Jeghers syndrome, juvenile polyposis syndrome, familial adenomatous polyposis

Hereditary Colorectal Cancer and Polyposis Syndromes

The majority of cases of inherited colorectal cancer (CRC) are accounted for by two syndromes: Lynch syndrome and familial adenomatous polyposis (FAP). In the management of FAP, the role of prophylactic surgery is clearly defined, although the optimal procedure for an individual patient depends on a number of factors. In the management of Lynch syndrome, the indications for prophylactic procedures are emerging. The authors address the clinical evaluation, investigation findings, medical and surgical therapy, and extracolonic diseases of FAP, attenuated form of FAP (AFAP), MYH-associated polyposis, Lynch syndrome, familial colorectal cancer type X (FCCTX), hyperplastic polyposis syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. AFAP has been described that is associated with fewer adenomas and later development of CRC compared with classic FAP. The AFAP phenotype occurs in less than 10% of FAP patients. The clinical criteria for AFAP are no family members with more than 100 adenomas before the age of 30 years and (1) at least two patients with 10 to 99 adenomas at age over 30 years or (2) one patient with 10 to 99 adenomas at age over 30 years and a first-degree relative with CRC with few adenomas. Given that polyposis has a later onset and the risk of CRC is less well established in AFAP, some authors question whether prophylactic colectomy is necessary in all AFAP patients. This review contains 26 tables and 173 references Keywords: Colorectal cancer, Lynch syndrome, hyperplastic polyp, Peutz-Jeghers syndrome, juvenile polyposis syndrome, familial adenomatous polyposis

Delayed diagnosis of Peutz\u2013Jeghers syndrome due to pathological information loss or mistake in family/personal history

ObjectiveTo report Peutz–Jeghers syndrome (PJS) cases with non-definitive clues in the family or personal history and finally diagnosed through pathological examination and STK11 gene mutation test.Clinical presentation and interventionPJS was suspected in 3 families with tortuous medical courses. Two of them had relatives departed due to polyposis or colon cancer without pathological results, and the other one had been diagnosed as hyperplastic polyposis before. Diagnosis of PJS was confirmed by endoscopy and repeated pathological examinations, and the STK11 mutation test finally confirmed the diagnosis at genetic level, during which 3 novel mutation were detected (536C > A, 373_374insA, 454_455insGGAGAAGCGTTTCCCAGTGTGCC).ConclusionEarly diagnosis of PJS is important and may be based on a family history with selective features among family members, and the pathological information is the key. The novel mutations also expand the STK11 variant spectrum.

Induction of the endogenous sialoglycan ligand for eosinophil death receptor Siglec-8 in chronic rhinosinusitis with hyperplastic nasal polyposis.

Siglec-8, an immune-inhibitory sialoglycan binding lectin (S8), is expressed on the surface of eosinophils and mast cells, which are potent mediators of allergic inflammation. When S8 engages endogenous sialoglycan ligands, eosinophils undergo apoptosis and mast cell mediator release is inhibited. In the human airway, Siglec-8 ligands (S8L) are sialylated keratan sulfate chains carried on isoforms of the protein Deleted in Malignant Brain Tumors-1 (DMBT1), an immunoregulatory protein that we recently identified as the endogenous ligand for S8, DMBT1S8. We herein report that S8L is overexpressed in chronic rhinosinusitis with nasal polyposis (CRSwNP), a prevalent eosinophilic laden airway disease. Quantification and comparison of the degree to which DMBT1 carries the S8L by immunoblot analysis and lectin blot overlay, respectively, from nasal lavage showed that the S8L/DMBT1 ratio was significantly increased in CRSwNP vs. control or CRS patients. We identified the histological sites of S8L and DMBT1 expression in fresh surgically resected human nasal polyps. Histochemistry of diseased polyps and adjacent nondiseased middle turbinate (MT) tissue from CRSwNP demonstrated colocalization of S8L and DMBT1 with highest staining in submucosal glands >> epithelium > stoma. S8L expression was specifically elevated in the submucosal glands and epithelium of polyp tissue compared to MT. We hypothesize that expression of the isoform of DMBT1 carrying the Siglec-8 binding sialoglycan, DMBT1S8, is induced in polyps of CRSwNP specifically at the site of disease, is produced in the submucosal glands of polyps and secreted into the lumen of the sinonasal cavity as a host response to mitigate eosinophil-mediated inflammation.

Abstract C131: Patient compliance with professional society guidelines for surveillance and re-screening following initial screening colonoscopy

Abstract Background: Screening colonoscopy followed by timely surveillance and rescreening colonoscopy can prevent most colorectal cancers (CRC) by enabling removal of pre-cancerous polyps. Surveillance compliance with professional society guidelines is unknown. We examined compliance patterns of a community-based cohort screened at an endoscopy center in South Carolina with documented 83% and 89% CRC incidence and mortality reductions, respectively, validating very high polyp clearance, which supports using these data to study surveillance timing compliance relative to recommendations. Historically, data sources to study surveillance compliance have been limited because no colonoscopy series is documented with evidence of high polyp clearance at screening. Methods: Patients provided screening colonoscopy from September 4, 2001 to December 31, 2015 followed through July 31, 2016 were studied for surveillance and rescreening colonoscopy timing classified by risk status at screening and to study the impact of the 2006 surveillance guidelines - 1-year surveillance for sessile adenoma removed piecemeal, hyperplastic polyposis syndrome or > 10 adenomas; 3 years for 3-10 adenomas, ≥1cm adenoma, villous features or high-grade dysplasia; 5 years for 1-2 small adenomas; 10 years for no adenoma or < 3 small hyperplastic polyps in left colon). Surveillance was classified as appropriate, overuse and underuse within each risk category. We used Kaplan-Meier analysis with the log-rank test, and logistic regression to identify the factors associated. Findings: Of 14,048 study-eligible patients (after excluding patients aged <40/≥75 years, CRC at screening, 2nd colonoscopy not due during study period, attained 75 years, and missing pathology), majority were female (51.0%), aged 50-59 years (55.1%), black (51.9%), and had Medicare/private insurance (87.9%). Of 6,817 surveillance-eligible, 52.6% completed it, 17% at the appropriate time. Among 3-year- and 5-year-eligibles, overuse (39% and 36%, respectively) and underuse (48.4% and 55.8%, respectively) were widespread. Among the 10-year rescreening-eligible, 45% completed it (mean 5.08 years since screening), 39.9% too early, 5.1% timely or late. Compared to pre-guideline period, overuse decreased among the 5-year category (25.5% vs. 48.6%), and increased among the 3-year category (41.5% vs. 35.4%). Among the 10-year rescreening group, overuse increased (60.4% vs. 31.6%). Overuse more likely among the 5-year group vs. ≤3-year (OR:2.7; 95%CI: 2.1- 3.4). Other overuse predictors were: adenoma ≥1cm (OR:1.9; 95%CI: 1.3-2.7) and multiple advanced adenoma features (OR:2.1; 95%CI: 1.4-3.2). For underuse, right-sided adenoma (OR:1.6; 95%CI: 1.2-2.1) and Medicaid (OR: 3.4; 95%CI: 1.4-8.1) were significant. Conclusions: Surveillance compliance improved following the 2006 guidelines. Underuse by patients with right-sided adenoma and Medicaid insurance needs research and policy attention, as also premature rescreening among low-risk population. Citation Format: Meng-Han Tsai, Sudha Xirasagar, JiaJia Zhang. Patient compliance with professional society guidelines for surveillance and re-screening following initial screening colonoscopy [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C131.

Birt-Hogg-Dub\xe9 syndrome with simultaneous hyperplastic polyposis of the gastrointestinal tract: case report and review of the literature

BackgroundBirt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant genodermatosis characterized by benign growth of the hair follicles, the presence of pulmonary cysts, spontaneous pneumothorax, and bilateral renal tumors that are usually hybrid oncocytic or multifocal chromophobe renal cell carcinoma. The diagnosis is confirmed by the presence of a pathogenic variant in the tumor suppressor folliculin (FLCN) gene mapped at 17p11.2. Although the dermatological lesions typical of BHDS are benign and only cause aesthetic concerns, and the pulmonary manifestations are controllable, the greater tendency of patients with this syndrome to present benign or malignant renal tumors, often bilateral and multifocal, makes the diagnosis of this syndrome important for the prognosis of the patients. The objective was to report the case of a patient with BHDS, without pulmonary manifestations and with hyperplastic polyposis of the gastrointestinal tract, and to perform a literature review.Case presentationA 60-year-old man complained of abdominal pain and diarrhoea for 2 months. Physical examination was normal except for the presence of normochromic papules in the frontal region of the face associated with hyperkeratotic and hyperchromic papules in the dorsal region. The excisional biopsies of the skin lesions indicated trichodiscomas. Esophagogastroduodenoscopy, enteroscopy, and colonoscopy showed the presence of hyperplastic polyps in the stomach, duodenum, jejunum, colon, and rectum. Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen revealed multiple expansive solid lesions in both kidneys, with necrotic and calcified areas. Renal magnetic resonance angiography also showed a solid lesion in the right kidney measuring 5 cm in diameter and another solid lesion in the left kidney measuring 8 cm in diameter, both suggestive of renal angiomyolipoma. CT scans of the skull, chest, and temporal bones were normal. The genetic study revealed the presence of a variant of FLCN in the intron 13.ConclusionsTo the best of our knowledge, this is the first reported case of BHDS with the simultaneous finding of gastrointestinal hyperplastic polyposis, which may represent a possible phenotypic expression of this syndrome that has not yet been described.

MUTYH-associated colon disease: adenomatous polyposis is only one of the possible phenotypes. A family report and literature review.

The MutY human homologue gene (MUTYH) is responsible for about a quarter of attenuated familial adenomatous polyposis. Occasionally, it has been associated with hyperplastic polyps and serrated adenoma. We report a family where the same MUTYH mutation determined four different phenotypes, including a case of hyperplastic polyposis syndrome. A family with a history of right-sided colon cancer and multiple colonic polyposis was investigated. Genetic tests were correlated with clinical findings to define phenotypic manifestations of MUTYH mutations. The pertinent English-language literature was reviewed to evaluate the risk of malignancy of MUTYH and the role of prophylactic surgery. Three male siblings carried a biallelic MUTYH mutation (G382D-exon13), while the fourth was heterozygote. One developed an isolated cecal cancer at the age of 48. Another, aged 38, was diagnosed with numerous minute colonic and rectal polyps and underwent a proctocolectomy, with final pathology showing a picture of hyperplastic and lymphoid polyposis. The third biallelic brother, 46 years old, developed four hyperplastic lesions, while the heterozygote brother had a large flat serrated adenoma of the right colon removed at the age of 50. Many aspects of MUTYH mutation still need to be clarified and one of them regards the different phenotypic expressions. Although the majority of reported cases manifested attenuated adenomatous polyposis, hyperplastic polyps and serrated adenomas appear to be more common than expected. Presenting hyperplastic polyposis syndrome is very unusual and may represent a clinical dilemma for correct management. Current evidence suggests to handle MUTYH-associated polyposis as typical FAP.

Exome sequencing characterizes the somatic mutation spectrum of early serrated lesions in a patient with serrated polyposis syndrome (SPS)

BackgroundSerrated or Hyperplastic Polyposis Syndrome (SPS, HPS) is a yet poorly defined colorectal cancer (CRC) predisposition characterised by the occurrence of multiple and/or large serrated polyps throughout the colon. A serrated polyp-CRC sequence (serrated pathway) of CRC formation has been postulated, however, to date only few molecular signatures of serrated neoplasia (BRAF, KRAS, RNF43 mutations, CpG Island Methylation, MSI) have been described in a subset of SPS patients and neither the etiology of the syndrome nor the distinct genetic alterations during tumorigenesis have been identified.MethodsTo identify somatic point mutations in potential novel candidate genes of SPS-associated lesions and the involved pathways we performed exome sequencing of eleven early serrated polyps obtained from a 41 year-old female patient with clinically confirmed SPS. For data filtering and analysis, standard pipelines were used. Somatic mutations were identified by comparison with leukocyte DNA and were validated by Sanger sequencing.ResultsThe BRAF p.V600E or KRAS p.G12D mutation was identified in six polyps (~50%) and not found in polyps from the distal colon. In addition, we found seven unique rare somatic alterations of seven different genes in four serrated tumours, all of which are missense variants. The variant in ABI3BP and CATSPERB are predicted to be deleterious. No established cancer gene or candidate genes related to serrated tumorigenesis were affected.ConclusionsSomatic mutations seem to be rare events in early hyperplastic and serrated lesions of SPS patients. Neither frequently affected genes nor enrichment of specific pathways were observed. Thus, other alterations such as non-coding variants or epigenetic changes might be the major driving force of tumour progression in SPS.

A Rare Case of Familial Hyperplastic Polyposis Syndrome

Introduction: Hyperplastic polyposis syndrome (HPS) is defined as a presence of multiple hyperplastic polyps (HP), serrated adenomas (SA) and/or tubular adenomas (TA) in the colon. The familial association and genetic basis of this condition has not been clearly defined and is rarely reported in previous literature. We report a case of hyperplastic polyposis syndrome affecting 2 members of the same family (Mother and Daughter). Case Report: A 60 year old Hispanic female presented to our hospital for her routine screening colonoscopy. Multiple polyps (24) were observed and biopsies were taken. The polyp histology revealed multiple TA, HP and SA. Due to a concern for risk of colorectal cancer (CRC) and risk of other family members being affected, a repeat colonoscopy in 1 year as well as screening colonoscopy for patient's son and daughter was recommended. The patient's 40 year old daughter underwent colonoscopy and 3 polyps (2 HP, 1 SA) were found. Subsequently the patient has undergone 3 yearly colonoscopies which revealed 11, 4 and 10 polyps respectively. The patient will continue to have yearly surveillance colonoscopies. On the other hand, the patient's daughter had 2 repeat colonoscopies showing 7 and 20 polyps respectively. After risk assessment and discussion, she underwent a subtotal colectomy. The patient's son refused to undergo any screening colonoscopy. With no definitive genetic testing available for HPS, the patients insurance denied any genetic work up for other familial cancer syndromes as their criteria were not met. Discussion: HPS is a rare condition and data is mostly reported as case series and case reports. Risk of CRC in patients with HPS is now established with about 40% of them developing CRC, although, the familial nature of HPS is rarely reported. Therefore recommendations for screening of family members at a relatively younger age (40 years) can be accepted. As genetic testing is not available, the recommendation of proper screening intervals by the endoscopist (every 1-2 years) and the accurate identification of polyp lesions by pathologist hold prime importance. Subtotal colectomy can be recommended when large HP and SA cannot be adequately differentiated, as the serrated adenoma pathway for CRC is now well established. Considering the risk of CRC and tendency of familial inheritance timely screening of the family members is the main modality for management of HPS until conclusive genetic testing is available.

Methylated free-circulating HPP1 DNA is an early response marker in patients with metastatic colorectal cancer.

Detection of methylated free-circulating DNA (mfcDNA) for hyperplastic polyposis 1 (HPP1) in blood is correlated with a poor prognosis for patients with metastatic colorectal cancers (mCRC). Here, we analyzed the plasma levels of HPP1 mfcDNA in mCRC patients treated with a combination therapy containing a fluoropyrimidine, oxaliplatin and bevacizumab to test whether HPP1 mfcDNA is a suitable prognostic and response biomarker. From 467 patients of the prospective clinical study AIO-KRK-0207, mfcDNA was isolated from plasma samples at different time points and bisulfite-treated mfcDNA was quantified using methylation specific PCR. About 337 of 467 patients had detectable levels for HPP1 mfcDNA before start of treatment. The detection was significantly correlated with poorer overall survival (OS) (HR = 1.86; 95%CI 1.37-2.53). About 2-3 weeks after the first administration of combination chemotherapy, HPP1 mfcDNA was reduced to non-detectable levels in 167 of 337 patients. These patients showed a better OS compared with patients with continued detection of HPP1 mfcDNA (HR HPP1(sample 1: pos/ sample 2: neg) vs. HPP1(neg/neg) = 1.41; 95%CI 1.00-2.01, HPP1(neg,pos/pos) vs. HPP1(neg/neg) = 2.60; 95%CI 1.86-3.64). Receiver operating characteristic analysis demonstrated that HPP1 mfcDNA discriminates well between patients who do (not) respond to therapy according to the radiological staging after 12 or 24 weeks (AUC = 0.77 or 0.71, respectively). Detection of HPP1 mfcDNA can be used as a prognostic marker and an early marker for response (as early as 3-4 weeks after start of treatment compared with radiological staging after 12 or 24 weeks) to identify patients who will likely benefit from a combination chemotherapy with bevacizumab.

Gastric and Colonic Polyposis in a Patient Without Genetic or Hereditary Predisposition Presenting as Iron Deficiency Anemia

A 44 year-old female with no medical history presented with a 3-week history of melena. Labs revealed hemoglobin 8.5 g/dL, iron 16 ug/dL, and ferritin 5.3 ng/mL. Imaging noted large soft tissue densities of the stomach and multiple lesions in the right colon. EGD revealed a large (>15 cm), polypoid lesion extending from the fundus into the body and several large polyps in the cardia and antrum. Colonoscopy revealed large polyps at the cecum (5 cm), transverse (8 cm), and small (< 1 cm) polyps in the rectosigmoid. Gastric histology demonstrated hyperplastic polyps (HPP), and colonic biopsies revealed tubulovillous adenomas without dysplasia or malignancy. EUS of the gastric lesion showed areas of submucosal involvement without invasion of the muscularis propria, capsule endoscopy was negative for small bowel lesions. Genetic testing for polyposis syndromes was negative. Attempts at endoscopic debulking were unsuccessful, and a total gastrectomy and right hemicolectomy were performed. This case of diffuse gastric hyperplastic and colonic adenomatous polyposis represents a rare cause of iron deficiency anemia in a young patient. Few cases detailing both gastric and colonic polyposis in an individual with no hereditary predisposition are reported. HPP are the most common gastric polyps encountered. Reports demonstrate large HPP may have malignant potential similar to adenomas. HPP greater than 1 cm in size may indicate the presence of premalignant or neoplastic changes. In cases of diffuse gastric involvement, gastrectomy may be warranted as biopsies may be insufficient in detecting cancer. An association between gastric hyperplastic polyposis, carcinomas, and colonic neoplasms has been described. Hypergastrinemia has been postulated as a possible link between gastric polyposis and colorectal neoplasms due to the role of gastrin as a growth-promoting tumoral agent. Gastric adenomatous polyps increase the risk of colorectal neoplasia, however, information is limited regarding HPP and their risk. A recent study investigated the association of sporadic gastric HPP with colorectal neoplasia and found the risk of colorectal adenomas increased in patients with sporadic gastric hyperplastic polyposis. In our case, gastrectomy histology was consistent with hyperplastic polyps and colectomy histology showed foci of invasive adenocarcinoma. This case supports the notion for consideration of surveillance colonoscopy in patients with large or multiple gastric HPP.Figure 1Figure 2Figure 3

Colonic Hyperplastic Polyposis Syndrome: A Rare Hyperpolyposis Syndrome

Case: A sixty-five-year-old Thai female with history of diabetes, dyslipidemia, and uterine fibroids (for which she received a total abdominal hysterectomy) presented with post-prandial, gnawing epigastric abdominal pain and melena for four days prior to admission. She was presumably treated for H. pylori by her primary care physician with resulting resolution of pain until the most recent episode leading to her presentation. She denied any NSAID use and was not on any blood thinners or antiplatelet agents. Her hemoglobin at presentation was 9.0 g/dL (MCV 84, RDW 17.9) and ferritin of 9.0 mg/dL with the rest of her labs being unremarkable, including coagulation profile. She underwent upper endoscopy showing innumerable small, pale polyps in the fundus and body of the stomach (fundic gland polyps); a pedunculated polyp in the stomach (not removed); an antral ulcer (chronic gastritis, negative for H. pyloriby immunohistochemistry and urease testing); and multiple large, pedunculated polyps in the 2nd portion of the duodenum. Colonoscopy the following day demonstrated several polyps in the terminal ileum; innumerable sessile, broad-based, semi-pedunculated, and pedunculated polyps throughout the entire colon and rectum; as well as an ascending colonic mass. Pathology of the polyps demonstrated hyperplastic changes, and pathology of the mass demonstrated hyperplastic and serrated adenomatous changes. Discussion: Colonic Hyperplastic Polyposis Syndrome is a rare syndrome characterized by the development of multiple colorectal lesions, often a mixture of hyperplastic and flat serrated adenomas. The proposed molecular pathways involve 1) mutations of BRAF CIMP-H with subsequent loss of MLH1, p16, and MGMT and 2) mutation of KRAS with resulting stimulation of the Wnt/β-catenin pathway. Diagnosis can be made when 1) at least five serrated lesions occur in the colon with 2 or more polyps having a diameter of at least 10 mm or 2) when at least 30 serrated lesions of any size are distributed throughout the colon. Patients with this syndrome have a 50% lifetime risk for colorectal cancers. The practice is to perform biennial colonoscopic surveillance.

OC-049 Sessile Serrated Lesions: Easily Missed in a Heterogenous Cohort?: Abstract OC-049 Table 1

Introduction Colorectal cancer is now thought to arise from more than one molecular pathway. Lately, the serrated pathway has been placed in the limelight as it may account for 20–30% of colorectal cancers. However, sessile serrated lesions are easily missed on colonoscopy and in histopathological analysis despite their neoplastic potential. We conducted an observational study to understand the presentation, characteristics and significance of sessile serrated lesions detected in colonoscopies done for a variety of indications. Methods A retrospective analysis of all sessile serrated lesions identified through the colorectal histopathological database from January 2012 – March 2015 was performed in our tertiary centre. Histology was reported by specialist gastrointestinal pathologists as per national standards. Results 138 colonoscopies were performed in 118 patients who were found to have sessile serrated lesions. The table below shows the breadth of indications for colonoscopy in these cases. A total of 351 serrated lesions were noted, with just over half in the right colon (180/351, 51.3%). 67/351 polyps were >1 cm in size. 42/118 patients did have polyps noted on previous colonoscopies (19 had serrated lesions). The prevalence of co-existing adenomas in this cohort was 50% (59/118). A subgroup analysis identified 13 patients in the entire cohort who met the WHO criteria for serrated polyposis syndrome. 4 of these patients (4/13; 30.8%) had been diagnosed with colorectal cancer in the past compared with 16/105 (15.2%) in the non serrated polyposis syndrome group. Only 8/13 patients underwent genetic screening and of this, 2 had hyperplastic polyposis syndrome and 2 had MYH polyposis. Conclusion This large series of sessile serrated lesions has demonstrated the heterogeneity of circumstances in which they are detected during colonoscopy. Only 16% of patients were found to have serrated lesions on a previous colonoscopy. This may indicate that a large proportion of these polyps were missed or not recognised previously. A small proportion of these patients will have a serrated polyposis syndrome that increases their colorectal cancer risk even further and genetic screening is advocated in all these patients. Disclosure of Interest None Declared

Peripheral blood eosinophilia correlates with hyperplastic nasal polyp growth

Eosinophils are thought to play a significant role in nasal polyposis, but the exact mechanism by which they contribute to polyposis remains unclear. Therefore, we proposed to test the hypothesis that peripheral blood eosinophilia (PBE) is a surrogate and biomarker for polyp load. To do this, we examined whether PBE levels correlate with nasal polyp load in a longitudinal manner. We retrospectively analyzed the fluctuation of PBE and nasal polyp load in each patient (n = 61) assessed preoperatively, 1-2 months postoperatively, and 3-12 months postoperatively. Nasal polyp load was assessed using computed tomography (CT) scan preoperatively and nasal endoscopy postoperatively. Correlation coefficients were analyzed using parametric statistics. There was a positive correlation between initial preoperative baseline PBE and CT scan staging of polyp load (r = 0.35, p < 0.01). When patients were analyzed longitudinally, we found that the change in PBE correlated with the change in nasal endoscopy scores obtained at or near the same timepoint (r = 0.82, p < 2.0 × 10(-10) ). When nasal polyp load increased with time, we observed a stepwise increase in eosinophil counts (r = 0.37, p < 0.02). PBE correlates with nasal polyp load. PBE levels may be used along with nasal endoscopy to prospectively follow nasal polyp load postoperatively in chronic rhinosinusitis patients with hyperplastic nasal polyposis who have eosinophilia, asthma, and/or aspirin-exacerbated respiratory disease.

ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

Serrated polyposis syndrome

SUMMARY Serrated polyposis syndrome, also called hyperplastic polyposis, is a condition characterized by numerous neoplastic polyps throughout the colon and rectum. The polyps possess a distinct serrated morphology. The term serrated refers to the ‘saw-tooth’ pattern formed by epithelial cells in the colonic crypts on standard histologic preparations. Historically, serrated lesions have been lumped together under the term ‘hyperplastic polyps’, and were assumed to carry no malignant potential. Over the past decade, however, an increasing body of evidence suggests that serrated lesions exist along a spectrum and represent an alternative molecular pathway to the development of colorectal cancer in contrast to the traditional adenocarcinoma sequence. Although a hallmark genetic signature for serrated polyposis syndrome remains unidentified, this is an area of active investigation.

MONITORING OF CASES WITH A CHRONIC PERSISTENT INFECTION WITH HELICOBACTER PYLORI

Introduction: The patients with persistent forms of Helicobacter pylori (HP) infection are refractory to eradication treatment. They receive unsuccessful therapies, experience frequent recurrences and re-infections. One of the main reasons for the development of persistent forms is an inadequate and insufficient treatment. The persistent forms of HP infection create conditions for the maintenance of activity and for the progression of the induced chronic gastritis. In this aspect these cases will be at a higher risk for the development of gastric cancer. The aim of this study is: to monitor and analyze the cases with persistent HP infection and to establish an approach for their management. Clinical material and methods: The study includes 12 patients (8 female and 4 male) at a middle age of 63,7, with a persistent HP infection, who have been observed for a period of five years. Two methods for the detection of HP infection are used – one invasive and one non-invasive. Upper endoscopy with morphological examination was performed. Results: In 9/12 patients HP was unsuccessfully treated for three times, in 2 patients – four times, and in 1 patient – five times. In all patients the initial treatment consisted of a standard triple therapy (STT). In 5 of them STT was conducted twice, with the same regimen for a period of seven days. Two patients received three courses of STT. In four patients an antibiotic resistance was established by means of a cultured assessment. In three cases an HP resistance to Clarithromycine and Metronidazole was demonstrated. Significant gastro-duodenal pathology with atrophic gastritis, intestinal metaplasia, and hyperplastic polyposis was found in all patients. The persistent clinical symptoms had 9 patients. Conclusion: We believe that a devised and proposed step strategy which covers early detection of infection, reliable diagnosis, adequate and successful treatment, and dispensary monitoring, contributes to the prevention of gastric cancer.

The interplay between histone deacetylases and c-Myc in the transcriptional suppression of HPP1 in colon cancer

HPP1 (hyperplastic polyposis protein 1), a tumor suppressor gene, is downregulated by promoter hypermethylation in a number of tumor types including colon cancer. c-Myc is also known to play a role in the suppression of HPP1 expression via binding to a promoter region cognate E-box site. The contribution of histone deacetylation as an additional epigenetic mechanism and its potential interplay with c-Myc in the transcriptional regulation of HPP1 are unknown. We have shown that the treatment of the HPP1-non-expressing colon cancer cell lines, HCT116 and DLD-1 with HDAC inhibitors results in re-expression of HPP1. RNAi-mediated knockdown of c-Myc as well as of HDAC2 and HDAC3 in HCT116 and of HDAC1 and HDAC3 in DLD-1 also resulted in significant re-expression of HPP1. Co-immunoprecipitation (IP), chromatin IP (ChIP), and sequential ChIP experiments demonstrated binding of c-Myc to the HPP1 promoter with recruitment of and direct interaction with HDAC3. In summary, we have demonstrated that c-Myc contributes to the epigenetic regulation of HPP1 via the dominant recruitment of HDAC3. Our findings may lead to a greater biologic understanding for the application of targeted use of HDAC inhibitors for anti-cancer therapy.

The endoscopist's guide to serrated polyposis

Serrated polyposis is a condition of the colon characterized by multiple serrated polyps. This review aims to provide a practical guide to the day-to-day management of serrated polyposis, including diagnosis, endoscopic identification of serrated polyps, surveillance, the role of endoscopic and surgical management and the screening of family members. The literature was searched using PubMed and MEDLINE databases for the terms "serrated polyp", "serrated polyposis" and "hyperplastic polyposis". English-language abstracts were read and the full article was retrieved if relevant to the review. Expert opinion from the authors was also sought. Advances in our knowledge of the molecular pathways involved in serrated polyposis and an improved clinical picture of the disease from retrospective studies have led to better understanding of its pathogenesis and natural history. However, there are still areas not answered by the literature, and hence empirical management or expert opinion has to be followed. Improvements in our understanding of serrated polyposis, together with improvements in endoscopic equipment and technique, have enabled the endoscopist to be at the forefront of managing this condition from diagnosis to endoscopic surveillance and control of the polyps.

Circulating cell-free methylated DNA and lactate dehydrogenase release in colorectal cancer

BackgroundHypermethylation of DNA is an epigenetic alteration commonly found in colorectal cancer (CRC) and can also be detected in blood samples of cancer patients. Methylation of the genes helicase-like transcription factor (HLTF) and hyperplastic polyposis 1 (HPP1) have been proposed as prognostic, and neurogenin 1 (NEUROG1) as diagnostic biomarker. However the underlying mechanisms leading to the release of these genes are unclear. This study aimed at examining the possible correlation of the presence of methylated genes NEUROG1, HLTF and HPP1 in serum with tissue breakdown as a possible mechanism using serum lactate dehydrogenase (LDH) as a surrogate marker. Additionally the prognostic impact of these markers was examined.MethodsPretherapeutic serum samples from 259 patients from all cancer stages were analyzed. Presence of hypermethylation of the genes HLTF, HPP1, and NEUROG1 was examined using methylation-specific quantitative PCR (MethyLight). LDH was determined using an UV kinetic test.ResultsHypermethylation of HLTF and HPP1 was detected significantly more often in patients with elevated LDH levels (32% vs. 12% [p = 0.0005], and 68% vs. 11% [p < 0.0001], respectively). Also, higher LDH values correlated with a higher percentage of a fully methylated reference in a linear fashion (Spearman correlation coefficient 0.18 for HLTF [p = 0.004]; 0.49 [p < .0001] for HPP1). No correlation between methylation of NEUROG1 and LDH was found in this study. Concerning the clinical characteristics, high levels of LDH as well as methylation of HLTF and HPP1 were significantly associated with larger and more advanced stages of CRC. Accordingly, these three markers were correlated with significantly shorter survival in the overall population. Moreover, all three identified patients with a worse prognosis in the subgroup of stage IV patients.ConclusionsWe were able to provide evidence that methylation of HLTF and especially HPP1 detected in serum is strongly correlated with cell death in CRC using LDH as surrogate marker. Additionally, we found that prognostic information is given by both HLTF and HPP1 as well as LDH. In sum, determining the methylation of HLTF and HPP1 in serum might be useful in order to identify patients with more aggressive tumors.