Polyps and Polyposis Syndromes in Children: Novel Endoscopic Considerations.

Polypectomy is the most common therapeutic endoscopic intervention in children. Management of sporadic juvenile polyps is limited to polypectomy to resolve symptoms, whereas polyposis syndromes pose a multidisciplinary challenge with broader ramifications. In preparation for polypectomy, there are key patient, polyp, endoscopy unit, and provider characteristics that factor into the likelihood of success. Younger age and multiple medical comorbidities increase the risk of adverse outcomes, classified as intraoperative, immediate postoperative, and delayed postoperative complications. Novel techniques, including cold snare polypectomy, can significantly decrease adverse events but a more structured training process for polypectomy in pediatric gastroenterology is needed.

Colorectal polyposis as a clue to the diagnosis of Cowden syndrome: Report of two cases and literature review.

Cowden Syndrome (CS) is an autosomal dominant disorder characterized by hamartomatous growth in several organs and by an increased risk of malignancies, which makes its recognition essential to undertake risk reduction measures. Although the involvement of gastrointestinal tract is extremely common, awareness of this entity among gastroenterologists appears limited. We report on two unrelated patients: a 46-year-old male and a 38-year-old woman, who were referred to the Genetic Clinic because of the endoscopic finding of multiple colorectal polyps. Despite both displayed striking clinical (and, in the first case, familial) manifestations of Cowden Syndrome (PTEN Hamartoma Tumor Syndrome-PHTS), they had not been recognized before. Diagnosis of PHTS was confirmed by the detection of causative PTEN variants. Pathological examination of the polyps showed multiple histology types: hyperplastic, juvenile, serrated and lymphoid. Hyperplastic polyps analyzed from both patients failed to show BRAF V600E and KRAS codon 12/13 mutations, which provides evidence against their potential to evolve to colorectal cancer through the serrated pathway. We then reviewed the literature on gastrointestinal polyps detected in patients with Cowden Syndrome, in order to provide a comprehensive scenario of presentations: among a total of 568 patients reported in the literature, 91.7 % presented with colon polyps, with 63.0 % having two or more different histological types of polyps; besides, 58.5 % had extra-colonic polyps (located either in stomach and/or in small intestine). Finding multiple polyps with mixed and/or unusual histology should alert gastroenterologists and pathologists about the possible diagnosis of Cowden Syndrome and prompt the search for other manifestations of this condition in the patient.

Successful surgical treatment of Cronkhite-Canada Syndrome with bilateral flail chest: a case report.

BACKGROUND: Development of multiple rib fractures leading to bilateral flail chest in Cronkhite-Canada Syndrome (CCS) has not been reported. CASE PRESENTATION: A 59-year-old man presented with complaints of fatigue, chest pain, respiratory distress and orthopnea requiring ventilatory support to maintain oxygenation. CCS with bilateral anterior and posterior flail chest due to multiple rib fractures (2nd-10th on the right side and 2nd-11th on the left side). He underwent open reduction and anterior and posterior internal fixation using a titanium alloy fixator and a nickel-titanium memory alloy embracing fixator for chest wall reconstruction. He recovered gradually from the ventilator and showed improvement in his symptoms. He gained about 20 kg of weight in the follow up period (6 months after discharge from the hospital). CONCLUSION: CCS is a rare, complex disease that increases the risk of developing multiple rib fractures, which can be successfully treated with open reduction and internal fixation.

Successful Treatment of Juvenile Polyposis of Infancy With Sirolimus.

Juvenile polyposis syndrome is a rare autosomal dominant condition characterized by multiple hamartomatous polyps throughout the gastrointestinal tract. Juvenile polyposis of infancy is a generalized severe form of juvenile polyposis syndrome associated with a poor prognosis. A 47-month-old female infant presented initially with gastrointestinal bleeding and protein-losing enteropathy at 4 months of age. At the age of 12 months, the condition worsened, requiring albumin infusions every 24 to 48 hours and red blood cell transfusions every 15 days. Upper gastrointestinal endoscopy, colonoscopy, and small-bowel enteroscopy revealed diffuse polyposis that was treated with multiple endoscopic polypectomies. Despite subtotal colectomy with ileorectal anastomosis, protein-losing enteropathy and bleeding persisted, requiring continued blood transfusions and albumin infusions. A chromosomal microarray revealed a single allele deletion in chromosome 10q23, involving both the PTEN and BMPR1A genes. Loss of PTEN function is associated with an increased activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway involved in cell proliferation. Treatment with sirolimus, an mTOR inhibitor, was initiated with the aim of inhibiting polyp growth. Soon after initiation of treatment with sirolimus, blood and albumin infusions were no longer needed and resulted in improved patient growth and quality of life. This case represents the first detailed report of successful drug therapy for life-threatening juvenile polyposis of infancy.

Clinical and Histologic Overlap and Distinction Among Various Hamartomatous Polyposis Syndromes.

INTRODUCTION: Hamartomatous polyposis syndromes (HPS) are rare autosomal-dominant inherited disorders associated with gastrointestinal (GI) tract and other cancers. HPS include Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and phosphatase and tensin homolog hamartomatous tumor syndromes (PHTS). Diagnosis, management, and outcome prediction of HPS pose a clinical challenge. To characterize genotype, phenotype, histology and outcomes of individuals with HPS. METHODS: A retrospective cohort study (2004-2017) of consecutive patients that were clinically diagnosed with HPS that visited a specialized GI oncology clinic. Demographic, clinicopathological, and genetic data were obtained from medical records. RESULTS: Fifty-two individuals from 34 families were included. Common clinical manifestations were GI bleeding (40% JPS, 23% PJS, and 25% PHTS) and bowel obstruction (46.15% PJS and 11.4% JPS). Twenty patients (38.4%) underwent surgery, 5 of whom required multiple procedures. Higher polyp burden was associated with the need for surgery (P = 0.007). Polyp histology varied widely with 69.2% of patients exhibiting histology different from the syndrome hallmark. GI cancer history was positive in 65%, 40%, and 50% of JPS, PJS, and PHTS families, respectively. Five (9.6%) patients developed cancers (one patient each had small bowel-1, colon-1, and thyroid-1, one patient had both small bowel adenocarcinoma and breast cancer, and one had both breast cancer and liposarcoma). Twenty (38.4%) patients tested positive for STK11, PTEN, SMAD4, BMPR1A, or AKT1 mutations: Sanger sequencing and multi-gene next generation sequencing panels detected mutations in 40.9% and 100% of tested cases, respectively. DISCUSSION: HPS patients present versatile phenotypes with overlapping clinical and histological characteristics. Polyp burden is associated with the need for surgery. Next-generation sequencing increases mutation detection.

Massive juvenile polyposis of the stomach in a family with SMAD4 gene mutation.

Relatively little is known on the genotype-phenotype correlations between SMAD4 gene mutations, juvenile polyposis of the intestine and Hereditary Hemorrhagic Teleangectasia. We describe a family in which the proband (a 46-year old woman) had massive polyposis of the stomach-leading to surgery-with high-grade dysplasia at histology. Molecular analysis was carried out using Next Generation sequencing techniques with Miseq Illumina Platforms and a minimal coverage of 40 reads. In the proband, the analysis showed the presence of a truncating mutation in the SMAD4 gene (c.1213dupC, a variant previously associated with juvenile polyposis and Hereditary Hemorrhagic Teleangectasia). The same mutation was detected in two other members of the family (father and brother of the proband), who showed massive polypoid involvement of the stomach at gastroscopy. By taking the family history, subtle evidence of Hereditary Teleangectasia was found (nasal bleeding and arterovenous malformations) in the three gene carriers. Colonoscopy showed polyp occurrence in all three affected members with SMAD4 mutation, with prevalence of adenomatous lesions in one (father), of hamartomas in the brother, and of a mix of histological types in the proband. The main features of the family can be summarized as follows: (A) In hereditary juvenile polyposis, lesions of different histology can be detected at colonoscopy; (B) In the gene carriers of SMAD4 mutations, lesions of the stomach require careful surveillance and, when necessary, surgical interventions; (C) Signs and symptoms of Hereditary Hemorrhagic Teleangectasia should be suspected (and searched) in individuals with SMAD4 constitutional mutations.

The Role of the Surgical Pathologist in the Diagnosis of Gastrointestinal Polyposis Syndromes.

Polyps of the gastrointestinal tract are very common lesions and most frequently sporadic in nature. Some polyp subtypes are associated with rare hereditary polyposis syndromes, including juvenile polyposis syndrome, Peutz-Jeghers syndrome, and Cowden syndrome. However, many sporadic benign lesions of the gastrointestinal tract can mimic some of these syndromic hamartomatous polyps. The role of the surgical pathologist is to raise the possibility of a hereditary condition in case of suggestive polyp histology and to look for clinical information to support the suspected diagnosis. In this review, the clinical presentation and the pathology associated with these rare hamartomatous polyposis syndromes are discussed in an attempt to provide pathologists clues in suggesting one such syndrome on the basis of histologic findings and clinical context. Identification of affected individuals is important because of the increased gastrointestinal and other malignancies. Recently, new adenomatous polyposis syndromes have been discovered, expanding the genetic causes of patient diagnosed with multiple colonic adenomas. By being aware of the clinical phenotype and the tumor spectrum associated with gastrointestinal polyposis syndromes, surgical pathologists can play a critical role in recommending genetic counseling when suspicious of such a diagnosis. This may lead to the identification of a genetic cause and appropriate surveillance of affected family members to screen for associated malignancies.

A Case with Serrated Polyposis Syndrome Controlled by Multiple Applications of Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection.

BACKGROUND Serrated polyposis syndrome (SPS) is characterized by numerous hyperplastic polyps and sessile serrated adenoma/polyp (SSA/P) in the large intestine. SSA/P is known to transform into malignant lesions through the serrated pathway instead of the adenoma-carcinoma sequence. Early diagnosis with lower gastrointestinal endoscopy and early treatment are now considered to be essential. CASE REPORT We had an experience with a case of SPS to which endoscopic treatment was applied in multiple sessions. Endoscopic treatment was performed for 16 lesions in total, and the pathological findings were SSA/P for 15 and adenoma for the other lesion. We intend to continue performing endoscopic surveillance for any newly developing lesions. CONCLUSIONS SPS has a potential for malignant transformation, and issues, such as long-term prognosis and optimal therapeutic strategies, await resolution. However, multiple endoscopic treatments are useful for cases with lesions that are controllable employing this modality.

Sequential Crohn's Ileitis, Ileosigmoidal Fistula, Segmental Sigmoid Polyposis, and Sigmoid Stricture: The Natural History.

BACKGROUND: We have previously recognized segmental sigmoid polyps as an indicator of a fistula from Crohn's ileitis to the sigmoid or the proximal rectum. In the course of this study, we realized that many patients with this fistula had no sigmoid polyps, but the sigmoid was the site of marked inflammation and early or late stricture formation. Furthermore, in some patients with a stricture, the fistula was not recognized until the surgeon (or the pathologist) dissected an inflammatory peri-ileal and/or a perisigmoidal mass.In this study, we have sought to clarify the sequence of events by focusing on the segmental inflammation and the stricturing of the sigmoid so that its significance can be recognized as a local complication of the ileitis and the progression of its severity as opposed to arising sui generis. MATERIALS AND METHODS: From our database of >3000 patients with inflammatory bowel disease at Lenox Hill Hospital, we identified 45 patients with Crohn's ileitis and ileosigmoid fistula (ISF): 24 had segmental sigmoid polyps and 18 had segmental inflammatory sigmoid strictures. The fistula was first seen by imaging in 36 patients, but not until resection by the surgeon or dissection by the pathologist in 7 patients. RESULTS: The method of diagnosis for the initial recognition of the ISF and the sigmoid stricture is presented in Table 1. In 36 of the 45 cases, the ISF was recognized by radiologic imaging. In total, 31 of the 36 cases required surgical intervention, not because of the fistula, but because of small-bowel obstruction due to the ileitis. In 7 of the 31 (22%) cases, the fistula was recognized only by dissection of the inflammatory ileosigmoid mass by the surgeon or examination of the surgical specimen by the pathologist. The sequence of events from the originating ileitis to the ISF to the segmental sigmoid polyposis and stricture, with the resulting sigmoid obstruction, is shown in Figures 1A-E. CONCLUSIONS: We emphasize the natural history of the ISF so that its recognition will lead to earlier medical management of the originating ileitis. Furthermore, it adds evidence of the recognition that the causative agent of Crohn's disease is carried by the fecal stream.

An unusual case of hamartomatous polyposis with malignancy complication in a patient with ulcerative colitis treated with golimumab.

We report an unusual case of hamartomatous polyposis with malignant complications in a patient with ulcerative colitis on golimumab and previous thiopurine therapy. This patient was evaluated for iron deficiency anemia and underwent hemicolectomy for extensive right-side predominant inflammatory pseudopolyps. Anemia persisted post-colectomy and subsequent gastroscopy showed a fungating polypoid lesion along with numerous carpet-like strawberry appearing polyps in the stomach extending from the gastro-esophageal junction to the distal part of the antrum, necessitating a gastrectomy. Histology showed extensive hamartomatous-like polyps with adenocarcinoma and nodal metastases. Presence of alopecia totalis and hamartomas in this patient raise the possibility of Cronkhite-Canada Syndrome although this may also represent an undescribed hamartomatous polyposis associated with ulcerative colitis. Even though thiopurine analogue and anti-tumor necrosis factor agents have not been associated with increased risk of solid tumors, immunosuppression in patients with extensive polyposis should be cautiously used due to the potential accelerated malignancy risk. This case also highlights the importance of performing additional imaging of the gastrointestinal tract, in inflammatory bowel disease patients with anemia, particularly if the severity is incongruent with disease activity.

Juvenile polyposis syndrome: An unusual case report of anemia and gastrointestinal bleeding in young infant.

BACKGROUND: Juvenile polyposis syndrome, a rare disorder in children, is characterized with multiple hamartomatous polyps in alimentary tract. A variety of manifestations include bleeding, intussusception, or polyp prolapse. In this study, we present an 8-month-old male infant of juvenile polyposis syndrome initially presenting with chronic anemia. To the best of our knowledge, this is the youngest case reported in the literature. METHODS: We report a rare case of an 8-month-old male infant who presented with chronic anemia and gastrointestinal bleeding initially. Panendoscopy and abdominal computed tomography showed multiple polyposis throughout the entire alimentary tract leading to intussusception. Technetium-99m-labeled red blood cell (RBC) bleeding scan revealed the possibility of gastrointestinal tract bleeding in the jejunum. Histopathological examination on biopsy samples showed Peutz-Jeghers syndrome was excluded, whereas the diagnosis of juvenile polyposis syndrome was established. RESULTS: Enteroscopic polypectomy is the mainstay of the treatment. However, polyps recurred and occupied the majority of the gastrointestinal tract in 6 months. Supportive management was given. The patient expired for severe sepsis at the age of 18 months. CONCLUSION: Juvenile polyposis syndrome is an inherited disease, so it is not possible to prevent it. Concerning of its poor outcome and high mortality rate, it is important that we should increase awareness and education of the parents at its earliest stages.

Cronkhite-Canada syndrome - A Case report.

BACKGROUND/AIM: Cronkhite-Canada syndrome (CCS) is a non-inherited, sporadic disorder characterized by generalized gastrointestinal polyps (hamartomas), cutaneous pigmentation, alopecia and onychodystrophy. More than 500 CCS patients have been reported, mostly from Asian countries. Patients with CCS have a propensity to develop colonic traditional serrated adenomas (TSA). Some authors found increased frequency of colonic carcinomas in CCS patients. In the present communication, we report a patient with CCS in whom a colonoscopic examination failed to disclose a coexistent TSA. CASE REPORT: A 73-year-old female had a history of alopecia and nail atrophy. Because of iron deficiency anemia and occult gastrointestinal bleeding, she underwent a colonoscopic examination. RESULTS: Colonoscopy revealed multiple broad-based polyps. Due to continuous bleedings, a coloproctectomy was performed four months after colonoscopy. Pathology disclosed 50 hamartomas and, unexpectedly, a TSA with high-grade dysplasia in the cecum. CONCLUSION: The TSA was either overlooked at colonoscopy or not interpreted as different from the other colonic polyps by the endoscopist. CCS cases are very rare in Western countries. Given this circumstance, it is suggested that, when confronting the next CCS case, endoscopists should perform a comprehensive colonoscopic examination, including chromoscopy and directed biopsies from irregular polyps, to rule out a TSA, an adenoma prone to evolve into invasive carcinoma.

Serrated lesions of the appendix in serrated polyposis patients.

Patients with serrated polyposis develop multiple serrated polyps throughout the large bowel: hyperplastic polyps (HP), sessile serrated adenomas (SSA) and traditional serrated adenomas (TSA). The frequency and the characteristics of serrated lesions of the appendix have not been reported in serrated polyposis patients. We conducted a retrospective study of 34 serrated polyposis patients who underwent a total or right hemicolectomy for adenocarcinoma or polyp burden. An appendiceal serrated lesion was identified in 23 (68%): 13 SSAs, three SSAs with dysplasia, four HPs and three TSAs. The BRAF(V600E) mutation was present in four polyps, all of SSA subtype (one with dysplasia). KRAS mutations were identified in 11 polyps (48%), in more than half of SSAs and of TSAs, and in none of the four HPs. None of the polyps displayed high levels of CpG island methylator phenotype (CIMP). There was no methylation in the promoter of the MLH1, p16 or MGMT gene. Serrated lesions of the appendix are frequently found in serrated polyposis patients and are most commonly of SSA-type morphology, frequently associated with KRAS mutation. It is unclear if appendiceal serrated polyps are a feature of serrated polyposis or a lesion frequently identified in association with a proximal colonic adenocarcinoma.

JP-HHT phenotype in Danish patients with SMAD4 mutations.

Patients with germline mutations in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT): the JP-HHT syndrome. The complete phenotypic picture of this syndrome is only just emerging. We describe the clinical characteristics of 14 patients with SMAD4-mutations. The study was a retrospective, register-based study. SMAD4 mutations carriers were identified through the Danish HHT-registry, the genetic laboratories - and the genetic departments in Denmark. The medical files from relevant departments were reviewed and symptoms of HHT, JPS, aortopathy and family history were noted. We detected 14 patients with SMAD4 mutations. All patients had polyps removed and 11 of 14 fulfilled the diagnostic criteria for JPS. Eight patients were screened for HHT-symptoms and seven of these fulfilled the Curaçao criteria. One patient had aortic root dilation. Our findings support that SMAD4 mutations carriers have symptoms of both HHT and JPS and that the frequency of PAVM and gastric involvement with polyps is higher than in patients with HHT or JPS not caused by a SMAD4 mutation. Out of eight patients screened for aortopathy, one had aortic root dilatation, highlighting the need for additional screening for aortopathy.