Serrated polyps of the colon and rectum (hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed polyps)—proposal for diagnostic criteria

Until recently, two major types of colorectal epithelial polyps were distinguished: the adenoma and the hyperplastic polyp. While adenomas—because of their cytological atypia—were recognized as the precursor lesions for colorectal carcinoma, hyperplastic polyps were perceived as harmless lesions without any potential for malignant progression mainly because hyperplastic polyps are missing cytological atypia. Meanwhile, it is recognized that the lesions, formerly classified as hyperplastic, represent a heterogeneous group of polyps with characteristic serrated morphology some of which exhibit a significant risk of neoplastic progression. These serrated lesions show characteristic epigenetic alterations not commonly seen in colorectal adenomas and progress to colorectal carcinoma via the so-called serrated pathway (CpG-island-methylation-phenotype pathway). This group of polyps is comprised not only of hyperplastic polyps, but also of sessile serrated adenomas, traditional serrated adenomas and mixed polyps, showing serrated and “classical” adenomatous features. Diagnostic criteria and nomenclature for these lesions are not uniform and, therefore, somewhat confusing. In a consensus conference of the Working Group of Gastroenterological Pathology of the German Society of Pathology, standardization of nomenclature and diagnostic criteria as well as recommendations for clinical management of these serrated polyps were formulated and are presented herein.     

Constipation, polyps, or cancer? Let PTEN predict your future

The inherited hamartoma polyposis syndromes encompass several distinct clinical syndromes with different genetic bases, Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), juvenile polyposis syndrome (JPS), and Peutz-Jeghers syndrome (PJS). Germline mutations in PTEN, encoding a tumor suppressor phosphatase on 10q23.3, is associated with 80% of CS and 60% of BRRS. JPS is caused by mutations in MADH4 and BMPR1A, encoding two members of the TGFB superfamily. Germline mutations in LKB1 (STK11) are associated with a subset of PJS. The number, distribution, and histologic type of polyps differ amongst these syndromes as do component cancer risks. While rare, usually asymptomatic, hamartomatous polyps are felt to be component to CS. Hamartomatous polyposis is usually prominent and symptomatic in BRRS. Polyposis, which can be quite symptomatic, is a cardinal component feature of PJS and JPS. Interestingly, glycogenic acanthosis of the esophagus is highly predictive of CS and the presence of PTEN mutation. PTEN mutation positive CS have been shown to be at increased risk of breast, thyroid, and endometrial cancer. PTEN mutation positive BRRS are at increased risk of at least breast cancer, possibly that of the thyroid as well. In contrast, JPS and PJS have increased risk of gastrointestinal cancers in particular. Thus, molecular-based diagnoses to differentiate each of these syndromes are important for medical management.     

β-Catenin mutations in sporadic fundic gland polyps

Fundic gland polyp (FGP) is the most common gastric polyp. It occurs sporadically or in association with familial adenomatous polyposis (FAP). FAP patients carry germline mutations of the adenomatous polyposis coli (APC) gene, and previous studies have revealed frequent somatic mutations of the APC gene in FGPs associated with FAP. Although inactivation of the APC gene contributes to histogenesis of FGPs associated with FAP, this rarely happens in sporadic cases. Loss of the APC gene promotes abnormal accumulation of beta-catenin, and mutation of GSK-3 beta phosphorylation sites in the beta-catenin gene can have a similar effect. To elucidate the contribution of beta-catenin gene mutation to the histogenesis of sporadic FGP, we analyzed beta-catenin gene mutation in exon 3 in 45 FGP lesions obtained from 35 patients. Somatic mutations were found in 29 lesions: 28 were missense mutations and one was an in-frame deletion. All of the missense mutations were confined to the former two serine residues of the GSK-3 beta phosphorylation sites and their flanking residues (codons 32, 33, 34, 37). Analysis in cases with multiple FGPs revealed a different mutation in each lesion, indicating their multicentric origin. Therefore, a significant proportion of sporadic FGPs have genetic alterations involving beta-catenin stabilization, as did FAP-associated FGPs.     

Comparison of morphological, immunohistochemical, and molecular genetic features of inflammatory fibroid polyps (Vanek´s tumors)

Vanek′s tumor (inflammatory fibroid polyp) is a rare benign lesion occurring throughout the digestive tract. Histologically, two patterns can be recognized. Classical Vanek′s tumor contains concentric formations of proliferating spindle cells which are CD34 positive. Atypical, inflammatory pseudotumor-like Vanek′s tumor lacks concentric formations and is CD34 negative. Recently, mutations in platelet-derived growth factor receptor alpha (PDGFRA) were reported in gastric and small intestinal Vanek′s tumors. In this study, KIT exons 9, 11, 13, and 17, PDGFRA exons 12, 14, and 18, and a part of exon 15 BRAF for point mutation V600E were screened in 23 cases of Vanek′s tumor, both classical (n = 16) and inflammatory pseudotumor-like (n = 7). No mutations in all analyzed exons of KIT and BRAF and in exon 14 of PDGFRA were detected. Six Vanek′s tumors harbored activating mutations in PDGFRA exons 12 (n = 5) and 18 (n = 1), respectively: S566_E571delinsK (n = 1), S566_E571delinsR (n = 4), and D842 del (n = 1). The mutations were detected in the classical (n = 5), as well as inflammatory pseudotumor-like (n = 1) Vanek′s tumors. The results of this study suggest that the two morphological patterns of Vanek′s tumor more probably represent only variants of one type of tumor than two different lesions. Furthermore, BRAF mutations were not shown to drive growth of PDGFRA wild-type Vanek′s tumors.     

Thymosin ß4 expression in colorectal polyps and adenomas

OBJECTIVE:

Thymosin beta 4 (Tβ4) is a ubiquitous peptide that plays pivotal roles in the cytoskeletal system and in cell differentiation. Recently, a role for Tβ4 has been proposed in experimental and human carcinogenesis, including gastrointestinal cancer. This study was aimed at evaluating the relationship between Tβ4 immunoreactivity and the initial steps of carcinogenesis.

METHODS:

In total, 60 intestinal biopsies, including 10 hyperplastic polyps, 10 sessile serrated adenomas/polyps, 15 colorectal adenomas with low-grade dysplasia, 15 adenomas with high-grade dysplasia, 15 adenocarcinomas and 10 samples of normal colon mucosa, were analyzed for Tβ4 expression by immunohistochemistry.

RESULTS:

Weak cytoplasmic reactivity for Tβ4 was detected in the normal colon mucosa. No reactivity for Tβ4 was found in hyperplastic and sessile serrated polyps/adenomas. Tβ4 expression was observed in 10/15 colorectal adenocarcinomas. In adenomas with low-grade dysplasia, Tβ4 immunoreactivity was mainly detected in dysplastic glands but was absent in hyperplastic glands. Tβ4 immunoreactivity was characterized by spot-like perinuclear staining. In high-grade dysplastic polyps, immunostaining for Tβ4 appeared diffuse throughout the entire cytoplasm of dysplastic cells. Spot-like perinuclear reactivity was detected in adenocarcinoma tumor cells.

CONCLUSIONS:

Our study shows for the first time that Tβ4 is expressed during different steps of colon carcinogenesis. The shift of Tβ4 immunolocalization from low-grade to high-grade dysplastic glands suggests a role for Tβ4 in colorectal carcinogenesis. However, the real meaning of Tβ4 reactivity in dysplastic intestinal epithelium remains unknown.     

Are endometrial polyps from pre-menopausal women similar to post-menopausal women? An immunohistochemical comparison of endometrial polyps from pre- and post-menopausal women

OBJECTIVE: Do endometrial polyps from pre- and post-menopausal women have similar immunohistochemical expression of oestrogen and progesterone receptors (ER, PR) and markers of cellular proliferation/apoptosis (Ki67 and Bcl-2). DESIGN: Prospective cohort study. Non-parametric statistical analysis was used. SETTING: Polyps recruited from women attending an out-patient hysteroscopy clinic in a UK district general hospital. PATIENTS: Fourteen pre-menopausal and 16 post-menopausal women who presented with abnormal bleeding with endometrial polyps. INTERVENTIONS: Immunohistochemical staining was performed on endometrial polyps. MAIN OUTCOME MEASURES: Significant differences or correlations between hormone receptor expression (oestrogen and progesterone) and cell growth indices (Ki67 and Bcl-2). RESULTS: Endometrial polyps from pre- and post-menopausal women had significant differences in their expression of hormone receptors and Ki67. However, polyps from both groups of women had similarly increased levels of Bcl-2, an inhibitor of apoptosis. CONCLUSIONS: Pre- and post-menopausal polyps exhibit differing hormone receptor and proliferation markers, presumably a result of their hormonal milieu. However, both groups appear to have lost the usual control mechanisms for apoptotic regulation, this appears to be responsible for their growth.     

Anti-IgE for the treatment of allergic rhinitis--and eventually nasal polyps?

In allergic rhinitis, cross-linking of IgE molecules upon allergen contact induces degranulation of mast cells and basophils within the mucosal tissue and results in the release of typical mediators, which consecutively induce the well-known symptoms. Omalizumab counteracts these interactions by reducing serum levels of free IgE. Therapy targeted at IgE also interferes with its binding to the low-affinity receptors inhibiting the amplification of the Th(2)-type response. Treatment of allergic rhinitis with anti-IgE has been shown to be safe and to reduce specific symptoms. Furthermore, the combination of omalizumab with specific immunotherapy may not only increase efficacy but also safety in selected patients. Therefore, we reviewed previously published studies on omalizumab therapy in allergic rhinitis, either as monotherapy or in combination with immunotherapy. In patients with nasal polyps, a local multiclonal IgE response has recently been described, initiated by Staphylococcus aureus-derived enterotoxins, which at least modifies the inflammatory reaction within the tissue. Evidence accumulates that these enterotoxins act as superantigens resulting in a multiclonal T- and B-cell activation with massive IgE formation within the airways. Because of the multiclonality, a range of allergens could possibly maintain a constant degranulation of mast cells present in the polyp tissue, which may contribute to disease severity. We here discuss a proof-of-concept treatment trial with omalizumab in nasal polyposis, which--in case of a positive therapeutic response--would also pave the way for anti-IgE treatment approaches for severe non-atopic lower airway disease.     

Serrated polyps of the colon: how reproducible is their classification?

For several years, the lack of consensus on definition, nomenclature, natural history, and biology of serrated polyps (SPs) of the colon has created considerable confusion among pathologists. According to the latest WHO classification, the family of SPs comprises hyperplastic polyps (HPs), sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs). The term SSA/P with dysplasia has replaced the category of mixed hyperplastic/adenomatous polyps (MPs). The present study aimed to evaluate the reproducibility of the diagnosis of SPs based on currently available diagnostic criteria and interactive consensus development. In an initial round, H&E slides of 70 cases of SPs were circulated among participating pathologists across Europe. This round was followed by a consensus discussion on diagnostic criteria. A second round was performed on the same 70 cases using the revised criteria and definitions according to the recent WHO classification. Data were evaluated for inter-observer agreement using Kappa statistics. In the initial round, for the total of 70 cases, a fair overall kappa value of 0.318 was reached, while in the second round overall kappa value improved to moderate (kappa?=?0.557; p?<?0.001). Overall kappa values for each diagnostic category also significantly improved in the final round, reaching 0.977 for HP, 0.912 for SSA/P, and 0.845 for TSA (p?<?0.001). The diagnostic reproducibility of SPs improves when strictly defined, standardized diagnostic criteria adopted by consensus are applied.     

Vaginal polyps and hormones—is there a link?: A case series

Fibroepithelial stromal polyps (FSP) of the vault after hysterectomy are an uncommon, though well recognised finding. Both tibolone and tamoxifen have been reported to cause polyps in the endometrium but their connection with the same pathology in the vagina has never been described. Here, we report a case of a patient presenting with a symptomatic FSP 30 years after her hysterectomy while on treatment with both tamoxifen and tibolone. This prompted us to see if there was an association between these hormone-modulating agents with vaginal polyp formation. We reviewed all the cases notes of patients having FSP surgically removed in Hull over a 4 years period. Thirty-four women were identified. Some kind of hormonal influence, natural or otherwise, was found in 22 out of the 34 women. Endogenous or exogenous gonadal hormones or hormones modulators thus appear to influence the formation of vaginal polyps, but in this cohort a precise contribution of specific drugs could not be established.     

Proximal versus distal hyperplastic polyps of the colorectum: different lesions or a biological spectrum?

BACKGROUND: Because of their suggested link with microsatellite instability high colorectal cancers, right sided hyperplastic polyps (HPs) may differ from their distally located counterparts. This is highlighted by the recognition of a variant HP, termed sessile serrated adenoma (SSA), which predominates in the proximal colon. HPs displaying the morphological features now associated with SSAs have been shown to have altered expression of "cancer associated" markers, but no studies have investigated whether this is dependent on anatomical location of the polyps. AIMS: To evaluate morphological and functional features in right versus left sided HPs from patients without colorectal cancer with the aim of identifying distinguishing characteristics. METHODS: HPs originating in the proximal and distal colorectum were histochemically and immunohistochemically stained to evaluate a panel of markers related to proliferation and differentiation. In addition, a series of morphological features was evaluated for each polyp. RESULTS: Crypt serration, crypt dilatation, and horizontal crypt growth were more common among HPs from the right side, whereas histochemical factors including mucin changes, global methylation status, and expression of carcinoembryonic antigen were not significantly different. An age disparity was also seen between patients with right versus left sided lesions, with patients with right sided lesions being an average of more than 10 years younger than those with left sided lesions. CONCLUSIONS: These findings suggest that right and left sided HPs differ mainly in terms of growth regulation rather than cellular differentiation, implying that these lesions belong to a continuous spectrum of serrated polyps that differ quantitatively rather than qualitatively.     

What is a juvenile polyp? An analysis based on 21 patients with solitary and multiple polyps

BACKGROUND: Juvenile polyps, the most common pediatric gastrointestinal polyp, have been typically characterized as either hamartomatous overgrowths or reactive inflammatory proliferations. Recent observations of excessive colonic and gastric carcinoma and dysplasia in juvenile polyposis have prompted reclassification of this entity as a premalignant condition. The relationship between solitary or multiple juvenile polyps and malignancy is less clear. PATIENTS AND METHODS: To further investigate the frequency and significance of dysplasia in juvenile polyps, we analyzed 28 polyps from 21 patients histologically and immunohistochemically for substances previously associated with neoplastic transformation in the colorectal adenomacarcinoma sequence. RESULTS: Fifteen patients had a solitary polyp, two had 2 to 9 polyps, and four had polyposis with 10 or more polyps. Most polyps exhibited inflammatory or regenerative atypia. Foci of dysplasia were noted in polyps from 11 patients, and immunoreactivity for p53 and human chorionic gonadotropin was present in 12 of the 28 polyps each. These findings were all more frequent in the polyposis specimens than in solitary polyps. CONCLUSIONS: These observations, in combination with reports of an increased risk of carcinoma in juvenile polyposis, suggest that juvenile polyps are lesions with a potential for neoplastic and malignant transformation, although they share features of an inflammatory reactive process. The implications for clinical management of patients and pathologic evaluation of juvenile polyps warrant further investigation.     

Serrated polyps of the colorectum: is sessile serrated adenoma distinguishable from hyperplastic polyp in a daily practice?

The distinction between serrated polyps of the colon is complex, particularly between hyperplastic polyps (HP) and sessile serrated adenomas (SSA). Recent data show that SSA might be the precursors of serrated colonic cancers, underlining the necessity of identifying them. We characterized the demographic and pathologic characteristics of 102 serrated lesions among 321 polyps of the colorectum and determined if SSA can be microscopically distinguished from HP in biopsy material of a daily practice. There were 81 HP (79%) and 7 SSA (7%) of which one displayed low-grade dysplasia. Only six serrated polyps (6%) could not be correctly classified. The main architectural criteria for distinguishing SSA from HP is the serrated feature along the crypt axis and the rarity of undifferentiated cells in the lower third of the crypts. SSA was significantly more often located in the right colon and larger (median, 11 vs 4 mm) than HP. SSA are rare serrated polyps that can be distinguished from HP based on their morphology, location in the right colon, and larger size. One SSA of our series showed low-grade dysplasia supporting the concept that this lesion might be a precursor of serrated adenocarcinoma.     

Fundic gland polyps (Elster's cysts) of the gastric mucosa. A marker for colorectal epithelial neoplasia?

The results of several retrospective studies allow us to conclude that the detection of fundic gland polyps (Elster's cysts) is associated with an increased incidence of colorectal tumors. In this survey, we present the results of a prospective study investigating such a possible relationship. A total of 144 patients were investigated, of whom 80 had fundic gland polyps of the gastric corpus mucosa. Sixty-four of these patients underwent a colonoscopy, whereas the other 64 patients belonged to a sex- and age-matched control group with no fundic gland polyps. In the group with known fundic gland polyps, colorectal neoplasias were found in 29 (45.3%) patients. Eight of these patients had (12.5%) adenocarcinomas, 3 (4.7%) had high-grade intraepithelial neoplasia, and 18 (28.1%) had tubular adenomas. In one patient, a synchronous carcinoma of the rectum and the colon was detected. In comparison, 6 patients of the control group (9.3%) developed tubular adenomas and 9 (14.1%) had hyperplastic polyps of the colonic and rectal mucosa. Our results suggest that it is necessary to conduct a careful diagnostic work-up of the colon in patients with gastric fundic gland polyps.     

Why do we not find polyps in the lungs? Bronchial mucosa as a model in the treatment of polyposis

The link between lower and upper airways has been reported since the beginning of 1800s. They share the same pseudostratified ciliated columnar epithelium lining and the concept of one airway, one disease is quite well widespread.     

Inflammatory myofibroblastic tumors (inflammatory pseudotumors) of the gastrointestinal tract: how closely are they related to inflammatory fibroid polyps?

Inflammatory myofibroblastic tumors (inflammatory pseudotumors) and inflammatory fibroid polyps of the gastrointestinal tract both feature prominent inflammatory infiltrates admixed with spindle-shaped fibroblasts/myofibroblasts set in a collagenous, fibrovascular, or myxoid stroma. Erroneously, some have considered inflammatory fibroid polyps to be intraluminal manifestations of inflammatory myofibroblastic tumors. In this study, we have characterized the histopathology of inflammatory myofibroblastic tumors, tumors that have only rarely been reported in the gastrointestinal tract, and have focused on whether inflammatory myofibroblastic tumors and inflammatory fibroid polyps in the gastrointestinal tract are distinct or similar. Clinical, histopathologic, and immunohistochemical features of 38 inflammatory myofibroblastic tumors limited to the wall of the gastrointestinal tract were compared with those of 45 inflammatory fibroid polyps. Compared to patients with inflammatory fibroid polyps, those with inflammatory myofibroblastic tumors were younger (mean age 41 years vs. 53 years); had larger tumors (mean 8 +/- 5.2 cm vs. 3.6 +/- 4.6 cm); presented with abdominal pain, fever, and weight loss more frequently and less frequently had bowel obstruction. Inflammatory fibroid polyps had more eosinophils and fibrosis and fewer lymphoid cell infiltrates than inflammatory myofibroblastic tumors. A regular vascular pattern was a feature of inflammatory fibroid polyps but not of inflammatory myofibroblastic tumors. Most (82%) inflammatory fibroid polyps were positive for CD34 versus none of the inflammatory myofibroblastic tumors. Smooth muscle actin was more frequently positive in inflammatory myofibroblastic tumors than in inflammatory fibroid polyps (86% versus 13%). Inflammatory myofibroblastic tumors were much less frequent and were more evenly distributed in the gastrointestinal tract than inflammatory fibroid polyps. Both appear to be benign processes. Inflammatory myofibroblastic tumors, but not inflammatory fibroid polyps, had a tendency to recur. In conclusion, inflammatory myofibroblastic tumors of the gastrointestinal tract are extremely rare and differ clinically, histologically, and immunohistochemically from inflammatory fibroid polyps.