Hereditary polyposis syndromes remain a challenging disease entity:Old dilemmas and new insights

In this editorial we present an overview and insights of the management of hereditary polyposis syndromes.The primary focus was on familial adenomatous polyposis,juvenile polyposis syndrome and Peutz-Jegher syndrome.Genetic testing has become increasingly available and is easier than ever to integrate into clinical practice.Furthermore,several genes have been added to the expanding list of genes associated with hereditary polyposis syndromes,allowing for precise diagnostics and tailored follow-up.Endoscopic evaluation of patients with hereditary polyposis syndromes is paramount in the surveillance strategies.Current endoscopic procedures include both diagnostic procedures and surveillance as well as therapeutic interventions.Recommendations for endoscopic procedures in the upper and lower gastrointestinal canal were described.Surgery is still a key component in the management of patients with hereditary polyposis syndromes.The increased cancer risk in these patients often render prophylactic procedures or intended curative procedures in the case of cancer development.Surgical interventions in the upper and lower gastrointestinal canal were described with relevant considerations.Development of chemopreventive medications is ongoing.Few drugs have been investigated,including nonsteroidal anti-inflammatory drugs.It has been demonstrated that cyclooxygenase-2 inhibitors may lower the number of polyps.Other medications are currently under investigation,but none have,to date,consistently been able to prevent development of disease.

Polyposis found on index colonoscopy in a 56-year-old female-BMPR1A variant in juvenile polyposis syndrome:A case report

BACKGROUND Juvenile polyposis syndrome(JPS)is a rare hereditary polyposis disease frequently associated with an autosomal-dominant variant of the SMAD4 or BMPR1A gene.It often manifests with symptoms in children and adolescents and is infrequently diagnosed in asymptomatic adults.Establishing the diagnosis is important as patients with JPS have a high risk of developing gastrointestinal cancer and require genetic counselling and close routine follow-up.CASE SUMMARY We report on the case of a 56-year-old female diagnosed with JPS after genetic testing revealed a rare variant of the BMPR1A gene BMPR1A c.1409T>C(p.Met470Thr).She was initially referred for colonoscopy by her general practitioner after testing positive on a screening faecal immunochemical test and subsequently found to have polyposis throughout the entire colorectum on her index screening colonoscopy.The patient was asymptomatic with a normal physical examination and no related medical or family history.Blood tests revealed only mild iron deficiency without anemia.To date,there has only been one other reported case of JPS with the same genetic variant.Subsequent colonoscopies were organised for complete polyp clearance and the patient was returned for surveillance follow-up.CONCLUSION JPS patients can present with no prior symptoms or family history.Genetic testing plays an important diagnostic role guiding management.

Juvenile polyposis syndrome

Juvenile polyposis syndrome is a rare autosomal dominant syndrome characterized by multiple distinct juvenile polyps in the gastrointestinal tract and an increased risk of colorectal cancer.The cumulative life-time risk of colorectal cancer is 39% and the relative risk is 34.Juvenile polyps have a distinctive histology characterized by an abundance of edematous lamina propria with inflammatory cells and cystically dilated glands lined by cuboidal to columnar epithelium with reactive changes.Clinically,juvenile polyposis syndrome is defined by the presence of 5 or more juvenile polyps in the colorectum,juvenile polyps throughout the gastrointestinal tract or any number of juvenile polyps and a positive family history of juvenile polyposis.In about 50%-60% of patients diagnosed with juvenile polyposis syndrome a germline mutation in the SMAD4 or BMPR1A gene is found.Both genes play a role in the BMP/TGF-beta signalling pathway.It has been suggested that cancer in juvenile polyposis may develop through the socalled "landscaper mechanism" where an abnormal stromal environment leads to neoplastic transformation of the adjacent epithelium and in the end invasive carcinoma.Recognition of this rare disorder is important for patients and their families with regard to treatment,follow-up and screening of at risk individuals.Each clinician confronted with the diagnosis of a juvenile polyp should therefore consider the possibility of juvenile polyposis syndrome.In addition,juvenile polyposis syndrome provides a unique model to study colorectal cancer pathogenesis in general and gives insight in the molecular genetic basis of cancer.This review discusses clinical manifestations,genetics,pathogenesis and management of juvenile polyposis syndrome.

Synchronized early gastric cancer occurred in a patient with serrated polyposis syndrome:A case report

BACKGROUND Serrated polyposis syndrome(SPS)is a relatively rare disease that is characterized by multiple serrated lesions/polyps.Very little is known regarding the extracolonic cancers associated with SPS.The genetic basis of the process remains unknown.CASE SUMMARY A 67-year-old male patient initially presented with belching and abdominal distension for a year as well as diarrhea for over 2 mo.The patient underwent colonoscopy and was diagnosed with serrated polyposis syndrome.Half a year later,a gastroscopy was performed during the postoperative re-examination to screen for other lesions of the upper gastrointestinal tract.An elevated lesion was detected in the anterior wall of the gastric antrum.Curative en bloc resection of the lesion was achieved via endoscopic submucosal dissection.The pathological result was high-grade dysplasia with focal intramucosal carcinoma.Exome sequencing was performed for the patient and five gastric cancer-associated variants(methylenetetrahydrofolate reductase,metaxin 1,coiled-coil domain containing 6,glutamate ionotropic receptor delta type subunit 1,and aldehyde dehydrogenase 1)were identified.CONCLUSION This paper reports a case that presented with both SPS and early gastric cancer.Genetic mutations that were potentially responsible for this condition were sought by exome sequencing.

Clinical predictors for sessile serrated polyposis syndrome:A case control study

AIM To compared individuals with serrated polyposis syndrome (SPS) to those with sessile serrated adenoma (SSA) and adenomas in the setting of endoscopists with high adenoma detection rates at a secondary and tertiary academic centre.METHODS Retrospectively we collated the clinical,endoscopic and histological features of all patients with SPS at St Vincent's public and private hospital in the last 3 years.Patients were identified by searching through 2 pathology databases.Variables explored included smoking status,symptoms,and family history of concurrent colorectal cancer,number and location of polyps.Patients with SPS were matched to two cohorts (1) patients with SSA not meeting World Health Organization (WHO) criteria for SPS over 3 years; and (2) patients with exclusively adenomas.The control cases were also matched according to gender and endoscopist.Adenoma detection rates ranged from 25% to 40%.RESULTS Forty patients with SPS were identified and matched with 40 patients in each control group.In total 15452 colonoscopies were performed over the study period which amounts to a prevalence of 1: 384 patients (0.26%) with SPS.Fourteen patients (35%) required more than 1 year to accumulate enough polyps to reach WHO criteria for SPS.The diagnosis of SPS was largely incidental and 5% SPS patients were diagnosed with colorectal cancer over 3 years.The chance of detecting a meta-synchronous adenoma was similar in those with SPS(42%) and those with SSA(55%),P = 0.49.The majority of patients(75%) meeting criteria for SPS were women.The mean age of those with SPS (45 years) was significantly lower than both cohorts with SSA(57 years) and adenomas(63 years),P = 0.01.On univariate analysis cigarette exposure,firstdegree family history of colorectal cancer and a high BMI weren't significantly more associated with SPS compared to patients with SSA or patients with adenomas.However,patients with SPS (97%) and patients with SSAs not meeting SPS criteria(98%) were significantly more likely to be Caucasian compared to patients with adenomas (79%),P = 0.01.CONCLUSION The prevalence of SPS in our study was 0.26%.The vast majority of patients diagnosed with SPS were women.As a group,they were significantly younger compared to patients with SSA not meeting WHO criteria and patients with adenomatous polyps by more than a decade.Patients with SPS were no more likely to have a first degree relative with colorectal cancer or smoking history than the other two groups.Patients with serrated polyps were more likely to be Caucasian than patients with adenomas.

Re-recognition of BMPR1A-related polyposis:beyond juvenile polyposis and hereditary mixed polyposis syndrome

Background Bone morphogenetic protein receptor type 1A(BMPR1A)is responsible for two individual Mendelian diseases:juvenile polyposis syndrome and hereditary mixed polyposis syndrome 2,which have overlapping phenotypes.This study aimed to elucidate whether these two syndromes are just two subtypes of a single syndrome rather than two isolated syndromes.Methods We sequenced the BMPR1A gene in 186 patients with polyposis and colorectal cancer,and evaluated the clinicopathological features and phenotypes of the probands and their available relatives with BMPR1A mutations.Results BMPR1A germline mutations were found in six probands and their three available relatives.The numbers of frameshift,nonsense,splice-site,andmissensemutations were one,one,two,and two,respectively;two of the sixmutations were novel.Typical juvenile polyps were found in only three patients.Two patients had colorectal cancer rather than any polyps.Conclusions Diseases in BMPR1A germline mutation carriers vary from mixed polyposis to sole colorectal cancer,and typical juvenile polyps do not always occur in these carriers.The variety of phenotypes reflected the features of BMPR1Amutation carriers,which should be recognized as a spectrum of one syndrome.Genetic testing may be a good approach to identifying BMPR1A-related syndromes.

Dual primary gastric and colorectal cancer:The known hereditary causes and underlying mechanisms

In this editorial,I commented on the paper by Lin et al,published in this issue of the World Journal of Gastrointestinal Oncology.The work aimed at analysing the clinicopathologic characteristics and prognosis of synchronous and metachronous cancers in patients with dual primary gastric and colorectal cancer(CRC).The authors concluded the necessity for regular surveillance for metachronous cancer during postoperative follow-up and reported the prognosis is influenced by the gastric cancer(GC)stage rather than the CRC stage.Although surveillance was recommended in the conclusion,the authors did not explore this area in their study and did not include tests used for such surveillance.This editorial focuses on the most characterized gastrointestinal cancer susceptibility syndromes concerning dual gastric and CRCs.These include hereditary diffuse GC,familial adenomatous polyposis,hereditary nonpolyposis colon cancer,Lynch syndrome,and three major hamartomatous polyposis syndromes associated with CRC and GC,namely Peutz-Jeghers syndrome,juvenile polyposis syndrome,and PTEN hamartoma syndrome.Careful assessment of these syndromes/conditions,including inheritance,risk of gastric and colorectal or other cancer development,genetic mutations and recommended genetic investigations,is crucial for optimum management of these patients.

Management of pouch related symptoms in patients who underwent ileal pouch anal anastomosis surgery for adenomatous polyposis

BACKGROUND Adenomatous polyposis syndromes(APS)patients with ileal pouch anal anastomosis(IPAA)suffer frequent symptoms with scarce signs of inflammation,distinct from ulcerative colitis patients.While the management of pouchitis in ulcerative colitis patients is well established,data regarding response to treatment modalities targeting pouch-related disorders in APS patient population is scarce.AIM To assess clinical,endoscopic and histologic response to various treatment modalities employed in the therapy of pouch related disorders.METHODS APS patients who underwent IPAA between 1987-2019 were followed every 6-12 mo and pouch-related symptoms were recorded at every visit.Lower endoscopy was performed annually,recording features of the pouch,cuff and terminal ileum.A dedicated gastrointestinal pathologist reviewed biopsies for signs and severity of inflammation.At current study,files were retrospectively reviewed for initiation and response to various treatment modalities between 2015-2019.Therapies included dietary modifications,probiotics,loperamide,antibiotics,bismuth subsalicylate,mebeverine hydrochloride,5-aminosalicylic acid compounds and topical rectal steroids.Symptoms and endoscopic and histologic signs of inflammation before and after treatment were assessed.Pouchitis disease activity index(PDAI)and its subscores was calculated.Change of variables before and after therapy was assessed using Wilcoxon signed rank test for continuous variables and using McNemar's test for categorical variables.RESULTS Thirty-three APS patients after IPAA were identified.Before treatment,16 patients(48.4%)suffered from abdominal pain and 3(9.1%)from bloody stools.Mean number of daily bowel movement was 10.3.Only 4 patients(12.1%)had a PDAI≥7.Mean baseline PDAI was 2.5±2.3.Overall,intervention was associated with symptomatic relief,mainly decreasing abdominal pain(from 48.4%to 27.2%of patients,P=0.016).Daily bowel movements decreased from a mean of 10.3 to 9.3(P=0.003).Mean overall and clinical PDAI scores decreased from 2.58 to 1.94(P=0.016)and from 1.3 to 0.87(P=0.004),respectively.Analyzing each treatment modality separately,we observed that dietary modifications decreased abdominal pain(from 41.9%of patients to 19.35%,P=0.016),daily bowel movements(from 10.5 to 9.3,P=0.003),overall PDAI(from 2.46 to 2.03,P=0.04)and clinical PDAI(1.33 to 0.86,P=0.004).Probiotics effectively decreased daily bowel movements(from 10.2 to 8.8,P=0.007),overall and clinical PDAI(from 2.9 to 2.1 and from 1.38 to 0.8,P=0.032 and 0.01,respectively).While other therapies had minimal or no effects.No significant changes in endoscopic or histologic scores were seen with any therapy.CONCLUSION APS patients benefit from dietary modifications and probiotics that improve their pouch-related symptoms but respond minimally to anti-inflammatory and antibiotic treatments.These results suggest a functional rather than inflammatory disorder.

Hamartomatous polyps:Diagnosis,surveillance,and management

Hereditary polyposis syndrome can be divided into three categories:Adenomatous,serrated,and hamartomatous polyps.Hamartomatous polyps,malformations of normal tissue presenting in a disorganized manner,are characterized by an autosomal dominant inheritance pattern.These syndromes exhibit hamartomatous gastrointestinal polyps in conjunction to extra-intestinal manifestations,which require conscientious and diligent monitoring.Peutz-Jeghers syndrome,Cowden syndrome,and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome(HPS).Diagnosis can be pursued with molecular testing and endoscopic sampling.Early identification of these autosomal dominant pathologies allows to optimize malignancy surveillance,which helps reduce morbidity and mortality in both the affected patient population as well as at-risk family members.Endoscopic surveillance is an important pillar of prognosis and monitoring,with many patients eventually requiring surgical intervention.In this review,we discuss the diagnosis,surveillance,and management of HPS.

Capsule endoscopy in neoplastic diseases

Until recently, diagnosis and management of small-bowel tumors were delayed by the diffi culty of access to the small bowel and the poor diagnostic capabilities of the available diagnostic techniques. An array of new methods has recently been developed, increasing the possibility of detecting these tumors at an earlier stage. Capsule endoscopy (CE) appears to be an ideal tool to recognize the presence of neoplastic lesions along this organ, since it is non-invasive and enables the entire small bowel to be visualized. High- quality images of the small-bowel mucosa may be captured and small and ? at lesions recognized, without exposure to radiation. Recent studies on a large population of patients undergoing CE have reported small-bowel tumor frequency only slightly above that reported in previous surgical series (range, 1.6%-2.4%) and have also confirmed that the main clinical indication to CE in patients with small-bowel tumors is obscure gastrointestinal (GI) bleeding. The majority of tumors identified by CE are malignant; many were unsuspected and not found by other methods. However, it remains difficult to identify pathology and tumor type based on the lesion’s endoscopic appearance. Despite its limitations, CE provides crucial information leading in most cases to changes in subsequent patient management. Whether the use of CE in combination with other new diagnostic (MRI or multidetector CT enterography) and therapeutic (Push- and-pull enteroscopy) techniques will lead to earlier diagnosis and treatment of these neoplasms, ultimately resulting in a survival advantage and in cost savings,remains to be determined through carefully-designed studies.

Wireless capsule endoscopy

Wireless capsule endoscopy is a new technique that allows complete exploration of the small bowel without exlemal wires. Its role has been analyzed in many small bowel diseases such as obscure gastrointestinal bleeding, Crohn＇s disease and gastrointestinal polyposis syndromes with promising results. Studies on other pathologies （i.e. small bowel tumour, celiac disease） are under evaluation to define the role of this technique.