New Clinicopathologic Scenarios of EBV+ Inflammatory Follicular Dendritic Cell Sarcoma: Report of 9 Extrahepatosplenic Cases.

EBV+ inflammatory follicular dendritic cell (FDC) sarcoma is an indolent malignant neoplasm of spindled FDCs with a rich lymphoplasmacytic infiltrate and a consistent association with Epstein-Barr virus (EBV). It occurs exclusively in the liver and spleen, with the exception of a few colonic examples. In this study, we report 9 extrahepatosplenic cases, including 4 occurring in previously undescribed sites, but all apparently anatomically related to the aerodigestive tract. The cases included 5 gastrointestinal tumors all presenting as colonic pedunculated polyps, 2 presenting as mesocolon mass, and 2 involving the palatine or nasopharyngeal tonsils. One patient with a colonic tumor was complicated by paraneoplastic pemphigus. The patients had a median age of 58 years, with female predominance (female:male=7:2). A favorable outcome was observed in 7 patients. Histologically, EBV+ inflammatory FDC sarcomas arising from these anatomic sites were similar to their hepatosplenic counterparts. Spindled to oval neoplastic cells with ill-defined cell borders were dispersed or formed loose whorled fascicles in a dense lymphoplasmacytic background. They had vesicular nuclei with distinct nucleoli and typically exhibited a range of nuclear atypia in the same case. The neoplastic cells showed variable expression of FDC markers and were labeled for Epstein-Barr virus-encoded RNA on in situ hybridization. These 9 cases thus broaden the clinicopathologic scenarios of EBV+ inflammatory FDC sarcoma. Recognition of the potential existence of this tumor type in extrahepatosplenic sites permits a correct diagnosis to be made.

Traditional serrated adenoma-like lesions in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal carcinoma. The significance of serrated lesions resembling traditional serrated adenoma (TSA) in IBD patients is unclear. In this retrospective study, we analyzed 52 TSA-like lesions arising in 30 IBD patients and diagnosed in colectomy or endoscopic specimens. The 27 colectomy lesions presented predominantly as ill-defined areas with granular appearance, with a median size of 15 mm, located throughout the large bowel and associated with synchronous advanced colorectal lesions in 58%. Low-grade serrated dysplasia was present in 56%, high-grade serrated dysplasia in 37%, and TSA-type cytology in 7%. Increased Ki-67 immunostaining and abnormal p53 expression were identified in 96% and 48%, respectively; 74% had a KRAS mutation, and 4% had a BRAF mutation. Endoscopically resectable TSA-like lesions were all discrete polypoid lesions, smaller in size (median 9 mm), predominantly in the distal large bowel, with an adjacent precursor polyp in 24%, and associated with synchronous and metachronous advanced colorectal lesions in 6%. Most (92%) show TSA-type cytology. p53 overexpression was present in 4%, KRAS mutation in 41%, and BRAF mutation in 32%. None of the 52 TSA-like lesions demonstrated loss of MLH1 or SATB2 expression by immunohistochemistry. On follow-up, 4 patients were diagnosed with colorectal carcinoma or high-grade adenomatous IBD-associated dysplasia. None of the patients with lesions showing TSA-type cytology only developed an advanced lesion. Our findings suggest that some TSA-like lesions, essentially from colectomy, may represent a form of IBD-associated dysplasia associated with an increased risk of advanced neoplasia.

Intramucosal fat is uncommon in large bowel polyps but raises three differential diagnoses.

AIMS: This case series intends to expand currently limited knowledge regarding the existence and diagnostic significance of intramucosal fat in colorectal polyps. METHODS: Clinicopathological features of nine such polyps were reported following histopathological review, including S100 and EMA immunohistochemistry. RESULTS AND CONCLUSIONS: Such review subdivided seven polyps into three groups: (1) mucosal perineurioma/serrated polyps with fat among the perineurial stroma (three cases); (2) submucosal lipomas with adipose tissue extending into the overlying mucosa (two cases) and (3) polyps with intramucosal adipose tissue only, that is, the newly described but less-recognised entity known as intramucosal lipoma (two cases). The two remaining polyps of this series did not include submucosa but, from assessing their muscularis mucosae, were favoured to represent intramucosal lipomas. The first two phenomena are formally described for the first time by this case series. The last of these three diagnoses should prompt investigations for Cowden syndrome, but intramucosal lipomas are more often sporadic/non-syndromic.

An immunohistochemical approach to detect oncogenic CTNNB1 mutations in primary neoplastic tissues.

The Wnt/ß-catenin signaling pathway is dysregulated in different types of neoplasms including colorectal cancer (CRC). Aberrant activation of this signaling pathway is a key early event in the development of colorectal neoplasms, and is mainly caused by loss of function mutations in Adenomatous Polyposis Coli (APC), and less frequently by ß-catenin stabilization mutations via missense or interstitial genomic deletions in CTNNB1. In this study, we have defined an immunohistochemical algorithm to dissect Wnt pathway alterations in formalin-fixed and paraffin-embedded neoplastic tissues. Basically, consecutive sections of tumor specimens were stained by immunohistochemistry with two different monoclonal antibodies against ß-catenin: one (anti-active ß-catenin antibody) recognizes hypo-phosphorylated ß-catenin and the other recognizes the total pool of ß-catenin. We validated the strategy in the HCT116 CRC cell line which has an in-frame deletion of ß-catenin serine 45, and then studied human tumor microarrays containing colon adenomas, CRCs, solid pseudopapillary neoplasms of the pancreas as well as the whole tissue sections of CRCs, desmoid fibromatosis, and pilomatrixoma of the skin. In some tumors, we found strong ß-catenin cytoplasmic and/or nuclear staining with the total ß-catenin antibody but no staining with the anti-active ß-catenin antibody. This was inferred to be an altered/mutant ß-catenin staining pattern. All six colon adenomas of the 126 total adenomas studied for the altered/mutant ß-catenin staining pattern had presumptively pathogenic point mutations or deletions in CTNNB1. Four of 10 CRCs with the alterated/mutant ß-catenin staining pattern studied in depth, from 181 total CRCs from tissue microarray, had pathogenic CTNNB1 mutations. The frequencies of CTNNB1 alterations in non-colonic tumors with altered/mutant ß-catenin staining ranged between 46 and 100%. Our results demonstrate that the immunohistochemical approach described here can detect oncogenic forms of ß-catenin in primary tissue samples and can also highlight other tumors with presumptive novel defects activating the Wnt/ß-catenin pathway.

Molecular characterization of sessile serrated adenoma/polyps with dysplasia/carcinoma based on immunohistochemistry, next-generation sequencing, and microsatellite instability testing: a case series study.

BACKGROUND: Colorectal sessile serrated adenoma/polyps (SSA/Ps) are considered early precursor lesions in the serrated neoplasia pathway. Recent studies have shown associations of SSA/Ps with lost MLH1 expression, a CpG island methylator phenotype, and BRAF mutations. However, the molecular biological features of SSA/Ps with early neoplastic progression have not yet been fully elucidated, owing to the rarity of cases of SSA/P with advanced histology such as cytologic dysplasia or invasive carcinoma. In this study, we aimed to elucidate the molecular biological features of SSA/Ps with dysplasia/carcinoma, representing relatively early stages of the serrated neoplasia pathway. METHODS: We performed immunostaining for ß-catenin, MLH1, and mucins (e.g., MUC2, MUC5AC, MUC6, and CD10); targeted next-generation sequencing; and microsatellite instability (MSI) testing in 8 SSA/P lesions comprised of 4 SSA/Ps with high-grade dysplasia and 4 SSA/Ps with submucosal carcinoma. RESULTS: Lost MLH1 expression was found in 5 cases. All lesions studied were positive for nuclear ß-catenin expression. Regarding phenotypic mucin expression, all lesions were positive for MUC2, but negative for CD10. MUC5AC and MUC6 positivity was observed in 7 cases. Genetically, the most frequently mutated gene was BRAF (7 cases), and other mutations were detected in FBXW7 (3 cases); TP53 (2 cases), and KIT, PTEN, SMAD4, and SMARCB1 (1 case each). Furthermore, 4 of 8 lesions were MSI-high and the remaining 4 lesions were microsatellite-stable (MSS). Interestingly, all 4 MSI-high lesions displayed MLH1 loss, 3 of which harbored a FBXW7 mutation, but not a TP53 mutation. However, 2 MSS lesions harbored a TP53 mutation, although none harbored a FBXW7 mutation. CONCLUSIONS: SSA/Ps with dysplasia/carcinoma frequently harbored BRAF mutations. Activation of the WNT/ß-catenin signaling pathway may facilitate the development of dysplasia in SSA/Ps and progression to carcinoma. Furthermore, our results suggested that these lesions might be associated with both MSI-high and MSS colorectal cancer, which might be distinguished by distinct molecular biological features such as lost MLH1 expression, FBXW7 mutations, and TP53 mutations.

Factors related to colorectal cancer in advanced adenomas and serrated polyps: a further step toward individualized surveillance.

AIM: The risk of presenting synchronous or metachronous neoplasm, either adenoma or carcinoma, increases after an initial colonic lesion develops. It is known as tumor multicentricity and constitutes the rationale for surveillance programs. This study was designed to identify the clinical, pathologic, and molecular features related to previous or synchronous colorectal cancer (CRC) in patients with advanced adenomas (AA) or serrated polyps (SP). PATIENTS AND METHODS: We carried out a prospective analysis of 4143 colonoscopies performed at our medical department between 1 September 2014 and 30 September 2015. Patients with AA/SP associated with previous or synchronous CRC are compared with patients with solitary AA/SP. We also performed immunohistochemical for the mismatch repair proteins in 120 AA or SP, 60 of them related to CRC. RESULTS: Three-hundred and seventy-nine AA or SP were removed. Among these, 66 (17.3%) were associated with a previous (n=31) or synchronous CRC (n=35). Age older than or equal to 65 years (odds ratio: 1.15, 95% confidence interval: 1.05-1.26, P=0.002) and male sex (odds ratio: 2.13, 95% confidence interval: 1.3-3.49, P=0.003) were found to be independent predictive factors for CRC in patients with AA/SP by multivariate analysis. Only one of the 120 AA/SP available for immunohistochemical testing showed loss of staining and it was not related to CRC. CONCLUSION: In patients with AA or SP, it is possible to identify a subgroup that is more likely to be associated with CRC and then prone to tumor multicentricity. These results have potential implications for establishing criteria for a more targeted surveillance.

Squamoid morules in the pseudoinvasive foci of colonic polyp morphologically mimic invasive carcinoma.

Colorectal adenomas can show focal squamous differentiation or squamoid morules. We describe histologic findings of squamoid morules in the pseudoinvasive foci of colorectal polyps mimicking invasive carcinoma. Five colonic polyps with squamoid morules in the pseudoinvasive foci were collected. Histologic review and immunostains for cytokeratin 5/6, p63, synaptophysin, and chromogranin were performed on cases with squamoid morules. Forty-seven consecutive colorectal polyps with pseudoinvasion, none of which showed squamoid morules by histology review, and their clinicopathologic features were compared with the cases containing squamoid morules. Cases with squamoid morules more frequently occurred in younger patients (P=.047) and were located in right colon (P=.027) than those without squamoid morules. Diagnosis of the polyps included tubular/tubulovillous adenoma with low-grade (with squamoid morules, n=3; versus without squamoid morules, n=29) or high-grade dysplasia (n=2 versus n=15) and sessile serrated adenoma (none versus n=3). Squamoid morules formed nodules protruding into the lumen of glandular structures or partially replaced adenomatous glands without forming a discrete nodule. They also presented as solid nests showing a well-formed morular structure around the bottom of adenomatous glands or myxoinflammatory stroma. Importantly, squamoid morules often formed a pseudocribriform or solid nest sitting in the stroma of pseudoinvasive foci. All cases (n=4) showed cytokeratin 5/6 positivity and p63 negativity in squamoid morules. Three and 1 of 4 cases showed focal positivity for synaptophysin and chromogranin, respectively, in squamoid morules. Squamoid morules in colonic adenomatous polyps can mimic invasive carcinoma when present in the pseudoinvasive foci. Pathologists should be aware of their presence.

IMP3 expression in biopsy specimens as a diagnostic biomarker for colorectal cancer.

No single biological marker is used in routine diagnosis of colorectal cancer (CRC) in endoscopic biopsies. IMP3 is a good independent prognostic biomarker for CRC. However, the expression of IMP3 in hyperplastic polyp (HP) and adenoma has not yet been studied. Moreover, no studies have established the diagnostic value of IMP3 in biopsies. This study aims to assess IMP3 expression in HP, adenoma, and CRC in resection specimens and to investigate its value in diagnosis of CRC in biopsies. A total of 1328 specimens (633 of polypectomy, 395 surgical resections, 300 biopsies) were retrospectively analyzed. IMP3 expression was observed in 0 of 197 (0%) normal tissues, 0 of 130 (0%) HPs, 14 of 504 (2.8%) adenomas, and 139 of 197 (70.6%) CRCs. IMP3 was found to be overexpressed in CRC compared with adenoma (P<.001). Among the 300 biopsies, 56 were diagnosed as adenoma, and 244 were CRCs. Of the 56 adenoma cases, 22 (39.3%) were confirmed, whereas 34 (60.7%) were diagnosed as CRC in resection specimens. All 244 CRC biopsies were confirmed by resection specimens. IMP3-positive expression was observed in 204 of 300 (68.0%) biopsies, including in 22 of 56 (39.3%) adenomas and 182 of 244 (74.6%) CRCs. All IMP3-positive expressions in the biopsies were finally diagnosed as CRC. Our findings demonstrated that IMP3 is a reliable marker for the diagnosis of CRC in endoscopic biopsies.

MCM2 expression in serrated polyps demonstrates aberrant cellular proliferation.

In normal colonic epithelium, the proliferative zone is limited to the lower half of the colonic crypt. Evaluating the changes in the colonic epithelial proliferation can be useful in understanding pathophysiology of various diseases. Our aim was to investigate the proliferative compartment of serrated polyps (SPs) using MCM2, a protein involved in DNA replication, and assess for changes along the SP spectrum. Immunohistochemistry was performed on serrated polyps (16 microvesicular-type hyperplastic polyps (HP), 58 sessile serrated adenomas (SSA), 7 SSAs with dysplasia) and 6 sections of normal colon using anti-MCM2 antibody. Multiple sections of normal colon showed the following pattern for MCM2 and Ki-67 staining: positive nuclear staining of the lower half of the colonic crypts and/or slightly expanded to the lower two-thirds of the crypt. By MCM2, SPs show expansion of the proliferative compartments; 81.3% of HPs and 100% of SSAs showed some degree of full crypt MCM2 staining. SSAs with dysplasia showed consistent diffuse polyp staining. Aberrant staining in adjacent normal mucosa was also seen in SSAs with dysplasia and in a subset of non-dysplastic SSAs. By using MCM2, we show that serrated polyps exhibit changes in proliferation during progression along the pathway. HPs and SSAs show a similar highly proliferative profile. Aberrant proliferative cell staining patterns in adjacent normal colonic mucosa as seen in SSAs with dysplasia and a subset of SSAs suggest a field effect phenomenon. This indicates that changes in the colonic micro-environment may promote adenoma morphogenesis and predisposition to malignancy.

Immunohistochemical study of mucins in human intestinal spirochetosis.

Most patients with human intestinal spirochetosis (HIS; a colorectal bacterial infection caused by Brachyspira species) seem asymptomatic, and its pathogenicity remains unclear. Recently, alterations in mucin expression were reported in animal Brachyspira infection. The present question was "Is mucin expression altered in HIS?" Using antibodies for MUCs 1, 2, 4, 5AC, and 6, we immunohistochemically compared 215 specimens from 83 histology-confirmed HIS cases with 106 specimens from 26 non-HIS cases. Positive staining (which included even focal positive staining) was rated "high (+)" or "low (+)." Results were analyzed for 4 categories of lesions, and associations between MUC expression and spirochetal presence were also analyzed. In the "specimens without polyps or adenocarcinoma" category, high (+) MUC2 positivity was more frequent in HIS than in control. In the hyperplasia/serrated polyp category, in HIS (versus control), the MUC5AC positivity rate was lower, whereas high (+) MUC4 positivity was more frequent. In the conventional adenoma category, in HIS (versus control), the MUC1 positivity rate was lower, whereas both high (+) MUC2 positivity and high (+) MUC5AC positivity were less frequent. In the adenocarcinoma category, high (+) MUC2 positivity was more frequent in HIS than in control. Among the above mucins, only MUC1 positivity was significantly associated with an absence of the so-called fringe formation, an absence of spiral organisms within mucus, and an absence of strong immunopositive materials within the epithelial layer and within the subepithelial layer. The results suggest that Brachyspira infection or a related change in the microbiome may alter the large intestine mucin expression profile in humans.

Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma.

OBJECTIVE: Sessile serrated adenomas (SSAs) are the precursors of at least 15% of colorectal carcinomas, but their biology is incompletely understood. We performed a clinicopathological and molecular analysis of a large number of the rarely observed SSAs with dysplasia/carcinoma to better define their features and the pathways by which they progress to carcinoma. DESIGN: A cross-sectional analysis of 137 SSAs containing regions of dysplasia/carcinoma prospectively collected at a community GI pathology practice was conducted. Samples were examined for BRAF and KRAS mutations, the CpG island methylator phenotype (CIMP) and immunostained for MLH1, p53, p16, ß-catenin and 0-6-methylguanine DNA methyltransferase (MGMT). RESULTS: The median polyp size was 9 mm and 86.5% were proximal. Most were BRAF mutated (92.7%) and 94.0% showed CIMP. Mismatch repair deficiency, evidenced by loss of MLH1 (74.5%) is associated with older age (76.7 versus 71.0; p<0.0029), female gender (70% versus 36%; p<0.0008), proximal location (91% versus 72%; p<0.02), CIMP (98% versus 80%; p<0.02) and lack of aberrant p53 (7% versus 34%; p<0.001) when compared with the mismatch repair-proficient cases. Loss of p16 (43.1%) and gain of nuclear ß-catenin (55.5%) were common in areas of dysplasia/cancer, irrespective of mismatch repair status. CONCLUSIONS: SSAs containing dysplasia/carcinoma are predominantly small (<10 mm) and proximal. The mismatch repair status separates these lesions into distinct clinicopathological subgroups, although WNT activation and p16 silencing are common to both. Cases with dysplasia occur at a similar age to cases with carcinoma. This, together with the rarity of these 'caught in the act' lesions, suggests a rapid transition to malignancy following a long dwell time as an SSA without dysplasia.

Genetic instability, CpG island methylator phenotype, and proliferative activity are distinct differences between diminutive and small tubular adenoma of the colorectum.

It is recommended that small (6-10 mm) lesions be treated with endoscopic resection (ER), whereas diminutive (≤5 mm) lesions are not currently an indication for ER according to the Japanese guidelines. The aim of this study was to evaluate the molecular alterations, and therefore treatment indications, in diminutive versus small tubular adenoma (TA). We prospectively analyzed genetic instability, including microsatellite instability and loss of heterozygosity, methylation status, KRAS/BRAF mutations, and Ki-67 staining in 96 TAs without a villous component. Although no microsatellite instability was identified in either diminutive or small TAs, genetic instability was seen in small TAs (9.1%) but not diminutive TAs (P = .04). In addition, the low-level CpG island methylator phenotype (CIMP-L) was more frequently observed in small TAs (31.8%) than in diminutive TAs (P = .01). Thus, genetic instability and CIMP-L were associated with small TAs, and only CIMP-L was an independent predictive marker for small TAs (odds ratio, 3.29; P = .03). Intriguingly, the Ki-67 proliferative index tended to be higher in small TAs than in diminutive TAs (P = .06) and higher in TAs with CIMP-L than in those without CIMP (P = .08). KRAS mutations were seen in codon 12 in 5.2% of TAs, but no BRAF gene mutations were found. As the molecular events and proliferative activity for the progression may increase from diminutive to small TAs, small TAs should be treated with ER, whereas a "predict, resect, and discard" strategy may be acceptable in most diminutive lesions except flat and depressed-type lesions, in keeping with the current strategy in the West.

Immunohistochemistry in the diagnosis of dysplasia in chronic inflammatory bowel disease colorectal polyps.

BACKGROUND AND STUDY AIMS: Development of cancer is the most significant complication in inflammatory bowel disease (IBD). Distinguishing true dysplasia from reactive atypia in polyps is difficult, leading sometimes to the unsatisfactory diagnosis of "indefinite for dysplasia". Therefore, there is a need for the development of markers that can help improve diagnosis. We evaluated the diagnostic value of the expression of AMACR, Ki67 and p53 by immunohistochemistry in the diagnosis of dysplasia in polyps developed on IBD. PATIENTS AND METHODS: Forty colorectal polyps in IBD were studied. These had been diagnosed over a period of 11years. Dysplasia was classified according to the Vienna Classification (version 2000). Immunohistochemistry was performed using anti-AMACR, anti-Ki67 and anti-p53 antibodies. RESULTS: Polyps were classified as follows: 21 negative for dysplasia (ND), 10 indefinite for dysplasia (IFD), 6 low-grade dysplasia (LGD), 1 high-grade dysplasia (HGD) and 2 adenocarcinomas (ACA). AMACR positivity was observed in all polyps with HGD and ACA, 5 of the 6 LGD polyps and 3 of the 10 IFD (p=0.007). p53 immunostaining showed nuclear staining in the basal part of the crypts in 8 of the 10 IFD lesions. In ACA and HGD polyps, p53 positivity was typically observed in all epithelial cell layers (p=0.004). ACA and HGD showed diffuse and scattered staining of Ki67 along the full length of the crypts. Five lesions with LGD had extension of Ki-67 positive cells up to and into the surface epithelium. Ki67 staining in all IFD lesions was restricted to the basal third of the crypt (p<0.001). By combining the three markers, a relationship with dysplasia was statistically significant (p<0.001). Sensitivity ranged from 66.7% to 88.9% and specificity from 71.4% to 100%. The positive predictive value (PPV) for detecting dysplasia using these different antibodies ranged from 66.7% to 100% and the negative predictive value (NPV) for excluding dysplasia ranged from 85.7% to 93.3%. CONCLUSIONS: The high degree of sensitivity and specificity of AMACR, p53 and Ki67 for dysplasia in IBD suggests that these antibodies, when combined, may be useful to detect neoplastic epithelium in this condition.

Non-coding RNAs as Biomarkers for Colorectal Cancer Screening and Early Detection.

Early detection of colorectal cancer (CRC) is the key for prevention and the ability to impact long-term survival of CRC patients. Current CRC screening modalities are inadequate for global application because of low sensitivity and specificity in case of conventional stool-based screening tests, and high costs and a low participation compliance in colonoscopy. An accurate stool- or blood-based screening test with use of innovative biomarkers is an appealing alternative as it is non-invasive and poses minimal risk to patients. It is easy to perform, can be repeated at shorter intervals, and therefore would likely lead to a much higher compliance rates. Non-coding RNAs (ncRNAs) have recently gained attention because of their involvement in different biological processes, such as proliferation, differentiation, migration, angiogenesis and apoptosis. An increasing number of studies have demonstrated that mutations or abnormal expression of ncRNAs are closely associated with various cancers, including CRC. The discovery that ncRNAs (mainly microRNAs) are stable in stool and in blood plasma and serum presents the opportunity to develop novel strategies taking advantage of circulating ncRNAs as early diagnostic biomarkers of CRC. This chapter is a comprehensive examination of aberrant ncRNAs expression levels in tumor tissue, stool and blood of CRC patients and a summary of the current findings on ncRNAs, including microRNAs, small nucleolar RNAs, small nuclear RNAs, Piwi-interacting RNAs, circular RNAs and long ncRNAs in regards to their potential usage for screening or early detection of CRC.

Morphologic characterization of hamartomatous gastrointestinal polyps in Cowden syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome.

The morphologic features of the gastrointestinal polyps in hamartomatous polyposis syndromes are poorly defined. Our aim was to better characterize the gastrointestinal hamartomas in these syndromes. A blinded review was performed regarding many histologic features for every polyp. The study included 15 Cowden syndrome, 13 Peutz-Jeghers (PJS), 12 juvenile polyposis (JuvPS) patients, and 32 cases of sporadic hamartomatous polyps. A total of 375 polyps were examined. Cowden syndrome polyps were characteristically colonic, sessile, small, without surface erosion, and showing mildly inflamed fibrotic lamina propria with smooth muscle proliferation and lymphoid follicles. They showed the least degree of cystic glands and had no thick mucin. Uncommon but specific features were ganglion cells and nerve fibers within the lamina propria and mucosal fat. PJS polyps were typically of small or large bowel origin, often exophytic, seldom eroded, with inflamed edematous and fibrotic lamina propria and dilated cystic glands filled with often thick mucin. All PJS polyps showed smooth muscle proliferation, frequently widespread. The polyps of JuvPS were typically colonic, large, exophytic, eroded, with strikingly edematous, fibrotic markedly inflamed lamina propria, cystic glands filled with frequently thick mucin, and the least degree of smooth muscle proliferation. Nonsyndromic hamartomatous polyps were similar to JuvPS polyps; however, they were more often colonic, were smaller, showed more widespread smooth muscle proliferation, and were less likely to contain thick mucin. In conclusion, we were able to define the characteristic hamartomatous polyp for each hamartomatous polyposis syndrome. Awareness to these features may aid in the diagnosis of these rare syndromes.

Loss of Hes1 Differentiates Sessile Serrated Adenoma/Polyp From Hyperplastic Polyp.

Sessile serrated adenoma/polyp (SSA/p) is a precancerous lesion, and its differential diagnosis from hyperplastic polyp (HP) could be challenging in certain circumstances based on morphology alone. Hes1 is a downstream target of Notch-signaling pathway and plays an important role in intestinal development by regulating differentiation of enterocytes. In this study, we evaluated the expression patterns of Hes1 in SSA/p and HP, and determine whether Hes1 immunostaining can help differentiate between these 2 entities. Serrated polyps with cytologic dysplasia (SSA with cytologic dysplasia, tubular adenoma, and traditional serrated adenoma) were also studied. Hes1 is ubiquitously expressed in the nuclei of normal colon epithelial cells. The complete loss or a very weak expression of Hes1 is observed in the majority of the SSA/p in the study (58/63, 92%) compared with the normal expression of Hes1 in HP (35/35,100%). In SSA/p with cytologic dysplasia, dysplastic area demonstrated cytoplasmic and/or nuclear staining for Hes1. Tubular adenoma and traditional serrated adenoma showed variability of Hes1 staining within the polyp with a mixed positive and negative staining pattern. Our study suggests that loss of Hes1 could be used as a sensitive and specific marker to differentiate SSA/p from HP, which helps the diagnosis in morphologically challenging cases.