paywalled: Phenotype and Polyp Landscape in Serrated Polyposis Syndrome: A Series of 100 Patients From Genetics Clinics (Lynch Syndrome...)

 define: hyperplastic

hyperplastic colon polyps

What is a hyperplastic colon polyp?

                    ~~~~~~~~~~~~~~~~~~~~~~~~~~

Phenotype and Polyp Landscape in Serrated Polyposis Syndrome: A Series of 100 Patients From Genetics Clinics

Abstract

Serrated polyposis syndrome (SPS), also known as hyperplastic polyposis, is a syndrome of unknown genetic basis defined by the occurrence of multiple serrated polyps in the large intestine and associated with an increased risk of colorectal cancer (CRC). There are a variety of SPS presentations, which may encompass a continuum of phenotypes modified by environmental and genetic factors. To explore the phenotype of SPS, we recorded the histologic and molecular characteristics of multiple colorectal polyps in patients with SPS recruited between 2000 and 2010 from genetics clinics in Australia, New Zealand, Canada, and the United States. Three specialist gastrointestinal pathologists reviewed the polyps, which they classified into conventional adenomas or serrated polyps, with various subtypes, according to the current World Health Organization criteria. Mutations in BRAF and KRAS and mismatch repair protein expression were determined in a subset of polyps. A total of 100 patients were selected for the study, of whom 58 were female and 42 were male. The total polyp count per patient ranged from 6 to 150 (median 30). The vast majority of patients (89%) had polyposis affecting the entire large intestine. From this cohort, 406 polyps were reviewed. Most of the polyps (83%) were serrated polyps: microvesicular hyperplastic polyps (HP) (n=156), goblet cell HP (n=25), sessile serrated adenoma/polyps (SSA/P) (n=110), SSA/P with cytologic dysplasia (n=28), and traditional serrated adenomas (n=18). A further 69 polyps were conventional adenomas. BRAF mutation was mainly detected in SSA/P with dysplasia (95%), SSA/P (85%), microvesicular HP (76%), and traditional serrated adenoma (54%), whereas KRAS mutation was present mainly in goblet cell HP (50%) and in tubulovillous adenoma (45%). Four of 6 SSA/Ps with high-grade dysplasia showed loss of MLH1/PMS2 expression. CRC was diagnosed in 39 patients who were more often found to have a conventional adenoma compared with patients without CRC (P=0.003). Patients with SPS referred to genetics clinics had a pancolonic disease with a high polyp burden and a high rate of BRAF mutation. The occurrence of CRC was associated with the presence of conventional adenoma.

paywalled: Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study : The Lancet Oncology

Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study : The Lancet Oncology

Methods
"Resections done for small and large bowel cancer between January, 2002, and January, 2011, were retrieved. We systematically analysed non-tumorous mucosa from carriers of a Lynch syndrome mutation (set 1: ten patients) and control patients without Lynch syndrome (set 1: nine patients) for MMR protein expression (MLH1, MSH2, and EPCAM) with immunohistochemistry.....

paywalled: ncreased risk of neoplasm in appendicitis treated w... [Am Surg. 2012] - PubMed - NCBI

Increased risk of neoplasm in appendicitis treated w... [Am Surg. 2012] - PubMed - NCBI

Am Surg. 2012 Mar;78(3):339-43.

Increased risk of neoplasm in appendicitis treated with interval appendectomy: single-institution experience and literature

Abstract

Appendicitis is a common diagnosis encountered by the acute care surgeon. Management of complicated appendicitis is controversial and often involves initial nonoperative therapy with interval appendectomy. This study reviews single-institutional experience with management of complicated appendicitis with interval appendectomy and addresses an unusually high occurrence of incidental appendiceal malignancies observed with a review of relevant literature. A retrospective review of all diagnoses of appendicitis was performed over 5 years at a tertiary care center. Patient demographics, time to surgery, operative technique, pathologic diagnosis, and clinical outcomes were examined. Three hundred fifteen patients were diagnosed with acute appendicitis. Of these, 24 (7.6%) were deemed complicated and did not undergo immediate appendectomy, and 18 ultimately underwent appendectomy at our institution and were included in analysis. There were no statistical demographic or symptomatic differences between the immediate and interval appendectomy patients. Ninety-nine per cent of the immediate appendectomy patients were treated laparoscopically; 78 per cent of the interval group underwent attempted laparoscopic treatment with 56 per cent completed without conversion to open (P < 0.01). Neoplasms were discovered in 1 per cent of the acute appendectomy group and 28 per cent of the interval appendectomy group (P < 0.0001). Two of the three neoplasms in the acute group were carcinoid, whereas three of the five neoplasms in the interval group were adenocarcinoma. Surgeons should consider appendiceal or colonic neoplasms in cases of complicated appendicitis when nonoperative management is considered. This is most important in patients older than 40 years, in those who forego interval appendectomy, or in those who could be lost to follow-up.

abstract: Postmenopausal hormone therapy is associated with a reduced risk of colorectal cancer lacking CDKN1A expression

 http://cancerres.aacrjournals.org/content/early/2012/04/17/0008-5472.CAN-11-2619.abstract
  
Abstract

Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell cycle regulators. However, epidemiologic studies evaluating hormone therapy (HT) use and colorectal cancer risk by the status of cell cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between HT use and colorectal cancer risk differs by the molecular pathological status of microsatellite instability (MSI) and expression of cell cycle-related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between HT use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105520 postmenopausal women. We found a difference between HT use and colorectal cancer risk according to CDKN1A expression (p-value for heterogeneity=0.01). Current HT use was associated with a reduced risk for CDKN1A-nonexpressed (multivariate relative risk (RR)=0.61, 95% confidence interval (CI), 0.46-0.82), but not for CDKN1A-expressed (RR=1.32, 95% CI, 0.76-2.31) tumors. The lower risk for CDKN1A-nonexpressed, but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between HT use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular epidemiology findings suggest a preventive effect of HT against colorectal carcinogenesis which depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A.

Genetic Variations in Stem Cell-Related Genes and Colorectal Cancer Prognosis

Genetic Variations in Stem Cell-Related Genes and Colorectal Cancer Prognosis:

Abstract

Background  

Many properties of cancer cells are reminiscent of those in normal stem cells. Genes important to stem cell development have been significantly implicated in the etiology and clinical outcome of colorectal cancer (CRC). However, the associations of genetic variations in these genes with CRC prognosis have not yet been elucidated.

Methods  

We analyzed the effects of eight potentially functional single nucleotide polymorphisms (SNPs) in six stem cell-related genes on the prognosis of a well-characterized population of 380 Chinese CRC patients diagnosed from February 2006 to January 2010.

Results 

The most significant finding was related to rs879882, a variant in the 5′ region of POU5F1 gene which encodes a protein essential for embryonic stem cell self-renewal and pluripotency, and induced pluripotent stem cell reprogramming. The variant-containing genotypes of rs879882 were associated with an increased risk of recurrence (hazard ratio [HR] = 2.10, 95 % confidence interval [CI] 1.17–3.76, P = 0.01). In chemotherapy-stratified analysis, the association remained borderline significant in patients receiving chemotherapy (HR = 1.97, 95 % CI 0.89–4.34, P = 0.09). In addition, a nonsynonymous SNP of APC gene was also significantly associated with recurrence risk in chemotherapy-treated patients (HR = 2.63, 95 % CI 1.14–6.06 P = 0.02). Further analyses showed a combined effect of the two SNPs in predicting CRC recurrence in patients receiving chemotherapy (P = 0.04) but not in those without chemotherapy (P = 0.43). Moreover, an exploratory multivariate assessment model indicated that these two variants enhanced the power to predict recurrence after chemotherapy.

Conclusion 

We presented one of the first epidemiologic studies showing that stem cell-related genetic variants may impact CRC clinical outcomes, especially in chemotherapy-treated patients.

• Journal Journal of Gastrointestinal Cancer

open access: Microsatellite Instability and DNA Mismatch Repair Protein Deficiency in Lynch Syndrome Colorectal Polyps - multinational study

Blogger's Note: as determined by the title, focus is on colorectal cancer in Lynch Syndrome; see also prior posting Diagnosing Lynch Syndrome: More Light at the End of the Tunnel which gives a more comprehensive overall view of Lynch Syndrome

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Microsatellite Instability and DNA Mismatch Repair Protein Deficiency in Lynch Syndrome Colorectal Polyps

"Lynch syndrome results from germline mutations in one
of the genes involved with DNA mismatch repair (MMR):
MLH1, MSH2, MSH6, PMS2, or EPCAM/TACSTD."

"The aim of this study was to determine the prevalence
of MSI and loss of MMR protein expression by immunohistochemistry
in colorectal polyps from patients with genetically confirmed Lynch syndrome."

Stopping menopausal hormone therapy: If breast cancer really decreased, why did colorectal cancer not increase? Maturitas "Alternative explanations must be found."

Abstract

Objective

The Women's Health Initiative (WHI) study of postmenopausal hormone therapy (HT) found that estrogen plus progestogen therapy (EPT) decreased colorectal cancer risk. 

Thus, the decline in EPT use from 2002 to 2003 should have precipitated an increase in the incidence of colorectal cancer. We tested this prediction using the SEER 9 epidemiologic database.

Methods

We analyzed WHI data concerning the effects of EPT and estrogen therapy (ET) on colorectal cancer risks. We also examined HT prescription sales data, as well as SEER 9 colorectal cancer incidences from 2001 to 2004.

Results

In the WHI study, the incidence of colorectal cancer was comparable in EPT placebo-users, ET users, and ET placebo-users, but significantly lower in EPT users. Assuming that 30% of eligible women used HT in 2001, the decline in EPT sales from 2002 to 2003 of 63% should have increased the incidence of colorectal cancer by 2.8% in the overall population at risk. However, the SEER 9 colorectal cancer incidence fell by 5.9% in this population, which is comparable to the 6.7% decrease observed for invasive breast cancer from 2002 to 2003.

Conclusions

Declining EPT use from 2002 to 2003 should have precipitated an increase in the incidence of colorectal cancer, but the opposite trend was seen in the SEER 9 database during this time. The incidences of invasive breast cancer and colorectal cancer both declined by a similar amount from 2002 to 2003, despite the results of the WHI study predicting opposing trends for the two different types of cancer. Thus, the SEER 9 findings are fundamentally incompatible with expectations from the WHI findings. This implies that reductions in HT use from 2002 to 2003 cannot account for the contemporaneous changes in invasive breast cancer and colorectal cancer incidences. 

Alternative explanations must be found.

BMC Medicine | Abstract/free full text: Septin 9 methylated DNA is a sensitive and specific blood test for colorectal cancer (small study)

The complete article is available as a provisional PDF.

Background
About half of Americans 50 to 75 years old do not follow recommended colorectal cancer (CRC) screening guidelines, leaving 40 million individuals unscreened. A simple blood test would increase
screening compliance, promoting early detection and better patient outcomes. The objective of this study is to demonstrate the performance of an improved sensitivity blood-based Septin 9 (SEPT9) methylated
DNA test for colorectal cancer. Study variables include clinical stage, tumor location and histologic grade.

Risk for CRC in Lynch Syndrome May Be Lower Than We Thought: Prevalence of Alterations in DNA Mismatch Repair Genes in Patients With Young-Onset Colorectal Cancer - Medscape Oncology

"Clearly, as we develop more accurate estimates of risks associated with specific mutations, personalized screening methods and intervals will need to be further clarified among those with LS. Although it appears that the overall risk for CRC among those with LS may be lower than previously thought, there are likely to be specific mutations that confer a higher risk and require more intensive screening protocols."

full free access: Pan-Canadian initiatives in colorectal cancer screening: adopting knowledge translation tools to accelerate uptake and impact | Bryant | Current Oncology

full free access: Lessons From the Adjuvant Bevacizumab Trial on Colon Cancer: What Next?

"........Finally, how should we consider the use of antiangiogenic therapy in general in the adjuvant setting? Will VEGF blockade ever suffice when administered as single antiangiogenic agent in combination with chemotherapy, or will we need to combine bevacizumab with other antiangiogenic agents? Although an easy solution at this stage would be to lose interest in the therapeutic potential of antiangiogenic therapy in the adjuvant setting because of these initial disappointing results, the more challenging way forward will require a better understanding of the underlying mechanisms of why bevacizumab treatment differs so much in the adjuvant setting versus the macrometastatic setting. Only by achieving this goal will it be possible to make a more informed decision on this important matter"

AVANT Says No Avastin Benefit in Stage III Colon Cancer - Colorectal Cancer Coalition

High detection rate of adenomas in familial colorectal cancer - Gut

Conclusion
The yield of colonoscopic surveillance in familial CRC is substantially higher than the yield of screening reported for the general population."

Longer HRT Duration Tied to Lower Colon Cancer Risk

"It is possible that widespread use of HRT is partially responsible for the reductions that we have observed in distal large bowel cancer incidence over time," the authors write.

Abstract: Red meat and colorectal cancer: a critical summary of prospective epidemiologic studies.

"Colinearity between red meat intake and other dietary factors (e.g. Western lifestyle, high intake of refined sugars and alcohol, low intake of fruits, vegetables and fibre) and behavioural factors (e.g. low physical activity, high smoking prevalence, high body mass index) limit the ability to analytically isolate the independent effects of red meat consumption. Because of these factors, the currently available epidemiologic evidence is not sufficient to support an independent positive association between red meat consumption and colorectal cancer."

full access: Risk Factors for Colorectal Cancer in Patients with Multiple Serrated Polyps: A Cross-Sectional Case Series from Genetics Clinics-multi-national study

 Introduction

Familial non-syndromic colorectal cancer (CRC) constitutes one of the most difficult and diverse patient groups encountered in a genetics clinic, with no apparent germline mutation, an often-indeterminant mode of inheritance, and questions arising as to how to manage the probands, and how to identify which family members are also at risk for CRC........ The clinical significance of HPS is that it is associated with an increased personal and familial risk of CRC , and extra-colonic cancers in the wider family setting .

 Conclusion

A decreased odds for CRC was identified in females with multiple serrated polyps who currently smoke, independent of age and the presence of a traditional adenoma. Investigations into the biological basis for these observations could lead to non-smoking-related therapies being developed to decrease the risk of CRC and colectomy in these patients.

Menopausal hormone therapy and risk of colorectal cancer in the European prospective investigation into cancer and nutrition

"Our results show no significant association of estrogen-only or estrogen plus progestin therapy with colorectal cancer risk."

One to 2-Year Surveillance Intervals Reduce Risk of Colorectal Cancer in Families With Lynch Syndrome

Background & Aims
Two percent to 4% of all cases of colorectal cancer (CRC) are associated with Lynch syndrome. Dominant clustering of CRC (non-Lynch syndrome) accounts for 1%–3% of the cases. Because carcinogenesis is accelerated in Lynch syndrome, an intensive colonoscopic surveillance program has been recommended since 1995. The aim of the study was to evaluate the effectiveness of this program.

Conclusions
With surveillance intervals of 1–2 years, members of families with Lynch syndrome have a lower risk of developing CRC than with surveillance intervals of 2–3 years. Because of the low risk of CRC in non-Lynch syndrome families, a less intensive surveillance protocol can be recommended.

Association of Fiber and Colorectal Cancer Risk Differs Depending on Dietary Assessment Method -- 102 (9): NP -- JNCI Journal of the National Cancer Institute

New study confirms HRT helps ward off colon cancer | Reuters

 Note: this issue of a protective effect was known at the time the original WHI study information was published but also received very little attention

 New study confirms HRT helps ward off colon cancer

Fri Apr 9, 2010 5:19pm EDT

NEW YORK (Reuters Health) - Hormone replacement therapy (HRT) cuts a woman's risk of developing colon cancer, new research confirms.

Health

Millions of women stopped taking HRT when a Women's Health Initiative study showed in 2002 that the hormones raised the risk of stroke, heart disease and breast cancer.
But the Women's Health Initiative had also found that HRT protected against colon cancer. Some studies have also suggested that oral contraceptives might reduce the risk of the disease, while the fact that women are at lower risk of colon cancer than men also hints at a hormonal role in disease risk.
To investigate ties between HRT and colon cancer further, Dr. Millie D. Long of the University of North Carolina at Chapel Hill and her colleagues matched 443 women diagnosed between 2001 and 2006 with distal large bowel cancer (meaning tumors at the far end of the colon and the rectum) to 405 healthy control women. The average age of the study participants was around 63.
Long's team found that women who had ever used HRT were at half the risk of this type of colon cancer compared to women who'd never used hormone replacement, and the longer a woman was on HRT, the lower the risk.
For example, women who used hormones for less than four years cut their colon cancer risk by about one-quarter; four to eight years of HRT cut risk by a third; nine to 14 years of use halved risk; and 15 years or more of HRT reduced risk by two-thirds. The effects were the same for African-American women and white women.
However, there was no relationship between oral contraceptive use and colon cancer risk, the study team reports in the American Journal of Gastroenterology.
Long-term hormone therapy is no longer recommended for postmenopausal women, Long and her team note, although it is still sometimes prescribed on a short-term basis to help women with menopausal symptoms such as hot flashes. The major drop off in distal large bowel cancer in recent years could have been related to widespread use of HRT, the researchers say.
More research is needed to determine if HRT's protective effects persist after women stop taking hormones, the researchers add, or whether there might be a "rebound" effect with more pre-cancerous polyps developing after a woman halts
HRT.
"It may become important in the future to tailor timing of women's colorectal screening based on cessation of hormonal therapy," Long and her colleagues conclude.

SOURCE: The American Journal of Gastroenterology, online March 30, 2010.