Israel Medical Association Journal

Background: Evaluation of mismatch repair (MMR) deficiency is conducted via immunohistochemistry or by microsatellite instability (MSI) analysis. Heterogeneous immunohistochemistry staining for MMR proteins may show different patterns; however, according to current guidelines, all of those patterns should be interpreted as MMR proficient. This conclusion might lead to false negative results because although most cases of heterogeneity stem from technical factors and biological variability, other types of heterogeneity represent true MMR deficiency.

Objectives: To identify a unique heterogeneity pattern that is associated with true MMR loss.

Methods: We analyzed 145 cases of colorectal carcinoma. Immunohistochemistry staining for MLH1, PMS2, MSH2, and MSH6 were performed. We defined geographic heterogeneity as areas of tumor nuclear staining adjacent to areas of loss of tumor nuclear staining with intact staining in the surrounding stroma. All cases were evaluated for the presence of geographic heterogeneity. In addition, 24 cases were also evaluated by MSI testing.

Results: Of the 145 cases, 24 (16.5%) were MMR deficient. Of the 24 cases for which MSI analysis was also available, 10 cases (41.7%) demonstrated biological heterogeneity, 5 (20.8%) demonstrated technical heterogeneity, and 2 (8.3%) demonstrated geographic heterogeneity. Only the two cases with geographic heterogeneity were MSI-high via MSI analysis. In addition, a germline mutation in MSH-6 was identified in one of these cases.

Conclusions: Geographic heterogeneity may raise a suspicion for a MMR-deficient case, which should be further analyzed using additional methodologies such as MSI analysis.

Background: Nasal polyps are three-dimensional structures arising from the mucosa of the upper airway. Due to their complexity, the reliability of single-layer cell cultures and animal systems as research models is limited.

Objectives: To evaluate the feasibility of an ex vivo organ culture of human polyps, preserving tissue structure and function.

Methods: Nasal polyps were excised during routine endoscopic sinus surgery for chronic rhinosinusitis and polyposis. Fresh tissue samples were used for pathological evaluation and for the preparation of 250–500 µm sections, which were incubated in culture media. Tissue viability was assessed by visualisation of cilia motility, measurement of glucose uptake, and an infectivity assay. Cytokine secretion was evaluated by enzyme-linked immunosorbent assay and real-time polymerase chain reaction before and after the introduction of steroids.

Results: Polyp tissue viability was retained for 2–3 days as demonstrated by cilia motility, glucose uptake and preserved cellular composition. Tissue samples maintained their capacity to respond to infection by herpes simplex virus 1 and adenovirus. Introduction of dexamethasone to cultured tissue samples led to suppression of interferon-g production.

Conclusions: The ex vivo nasal polyp organ culture reproduces the physiological, metabolic, and cellular features of nasal polyps. Furthermore, it shows a preserved capacity for viral infection and response to drugs. This system is a useful tool for the investigation nasal-polyps and for the development of novel therapies.

Background: Patients with multiple (< 100) colorectal adenomatous polyps are at increased risk for colorectal cancer. Genetic evaluation of those patients who test negative for APC gene mutation is both a clinical and economic burden but is critical for counseling and surveillance. In Israel, this is confounded by the fact that national health insurance does not fully cover genetic evaluation of APC gene exon 16.

Objectives: To perform a comprehensive genetic evaluation of APC gene mutation-negative polyposis patients with the aim of developing a future evaluation protocol.

Methods: Genetic analyses were performed in 29 APC gene mutation-negative Jewish individuals with 5 to ≥ 40 colonic adenomas who did not fulfill Amsterdam (clinical) criteria for Lynch syndrome. Analyses included completion of APC gene exon 16 sequencing, analysis for APC gene copy number variations (deletions or duplications), MUTYH gene sequencing, and microsatellite instability in CRC[1] patients fulfilling “Bethesda” (laboratory investigation) criteria for Lynch syndrome.

Results: Completion of APC gene exon 16 sequencing revealed one patient with the E1317Q polymorphism. All were normal by APC multiplex ligation-dependent probe amplification analysis. Pathogenic MUTYH mutations were found in three patients, all of North African origin; two additional patients had variants of unknown significance. One of six patients with Bethesda-positive criteria was MSI²-High with immunohistology consistent with MLH1 mutation.

Conclusions: Based on this small but well-characterized cohort with multiple colorectal adenomas, Lynch syndrome needs to be excluded if there are compatible criteria; otherwise MUTYH sequencing is probably the first step in evaluating APC-negative patients, especially for Jews of North African descent. Completing APC exon 16 sequencing and copy number variations analysis should probably be the last evaluations.

Objectives: To evaluate operative procedures, complications, early and late results and long-term functional outcome in FAP[1] patients operated in our department.

Methods: The study group included all patients with FAP who were operated between 1988 and 2003. Demographic data, length of follow‑up, complications, colorectal cancer, pouch function and extracolonic manifestations were recorded.

Results: Median age at surgery was 33 years (range 13–61 years). The final operative breakdown was: 48 proctocolectomies, 41 ileal pouch-anal anastomoses, 2 Kock’s pouch, 5 permanent ileostomies, and 2 colectomies with ileorectal anastomosis. There was no perioperative mortality. Early and late complications occurred in 20 and 9 patients, respectively. Twelve patients required re‑operation. Colorectal carcinoma was diagnosed in eight patients, three of whom were in an advanced stage. The mean follow‑up was 74 months (range 3–288 months). Four patients were lost to follow‑up. Extracolonic manifestations developed in 38 patients, including desmoid tumors (in 12), duodenal adenomas (in 9), pouch adenomas (in 5), and rectal stump adenomas (in 3). Two patients died (4%) because of desmoid tumor and malignant fibrous histiocytoma. At last follow‑up, 37 IPAA[2] patients have (median) six bowel movements/24 hours and good fecal control.

Conclusions: Restorative proctocolectomy can be performed with low mortality, acceptable morbidity, and good functional results. Patients should be closely followed after surgery for development of other manifestations of the syndrome. Relatives of the affected patients should be referred to a specialist multidisciplinary clinic.

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[1] FAP = familial adenomatous polyposis

[2] IPAA = ileal pouch-anal anastomosis

Background: Restorative proctocolectomy eliminates the risk of colorectal cancer in patients with familial adenomatous polyposis. Complications and extra‑intestinal manifestations are inherent to the procedure.

Objectives: To evaluate operative procedures, complications, early and late results and long-term functional outcome in FAP[1] patients operated in our department.

Methods: The study group included all patients with FAP who were operated between 1988 and 2003. Demographic data, length of follow‑up, complications, colorectal cancer, pouch function and extracolonic manifestations were recorded.

Results: Median age at surgery was 33 years (range 13–61 years). The final operative breakdown was: 48 proctocolectomies, 41 ileal pouch-anal anastomoses, 2 Kock’s pouch, 5 permanent ileostomies, and 2 colectomies with ileorectal anastomosis. There was no perioperative mortality. Early and late complications occurred in 20 and 9 patients, respectively. Twelve patients required re‑operation. Colorectal carcinoma was diagnosed in eight patients, three of whom were in an advanced stage. The mean follow‑up was 74 months (range 3–288 months). Four patients were lost to follow‑up. Extracolonic manifestations developed in 38 patients, including desmoid tumors (in 12), duodenal adenomas (in 9), pouch adenomas (in 5), and rectal stump adenomas (in 3). Two patients died (4%) because of desmoid tumor and malignant fibrous histiocytoma. At last follow‑up, 37 IPAA[2] patients have (median) six bowel movements/24 hours and good fecal control.

Conclusions: Restorative proctocolectomy can be performed with low mortality, acceptable morbidity, and good functional results. Patients should be closely followed after surgery for development of other manifestations of the syndrome. Relatives of the affected patients should be referred to a specialist multidisciplinary clinic.

Background: Restorative proctocolectomy with ileal pouch-anal anastomosis has become the surgical procedure of choice for patients with ulcerative colitis and familial adenomatous polyposis.

Objectives: To evaluate the long-term functional outcome of patients who underwent this surgical procedure.

Methods: We performed this observational study in 174 consecutive patients: 146 with UC[1] and 28 with FAP[2]. The patients, 91 males and 83 females with a mean age of 34.1 ± 10.6 years (range 6–67 years), underwent the procedure between January 1984 and January 2004 (mean follow-up 64.8 months, range 1–240 months). The indications for surgery were intractable disease in 124 patients (71%), dysplasia in 36 (21%), severe bleeding in 8 (5%), and perforation in 6 (3%).

Results: A protective ileostomy was performed in 140 patients (96%) with UC and 12 (43%) with FAP. An urgent three-stage procedure was necessary in 14 patients (8.4%). A mucosal proctectomy was performed in 94 (54%), and a double stapling technique in 80 (46%). Mean length of hospital stay was 9.4 ± 6.6 days (range 5–34 days, median 8). Complications included pelvic sepsis in 7 patients (4.2%), anastomotic leakage in 8 (4.8%), bowel obstruction in 22 (13.2%), incisional hernia in 12 (7.2%), anastomotic stenosis that usually responded to manual dilatation in 46 (27.6%), pouchitis in 106 (61%), recto-vaginal fistula in 3 (1.8%), retrograde ejaculation in 3 (1.8%), and impotence in 2 (1.2%). There was no mortality in this group of patients. The median number of bowel movements per 24 hours was six in UC patients and five in FAP patients, with at least one bowel movement during the night. Complete daytime and night-time continence was documented in 124 patients (71%). Overall satisfaction was 95%.

Conclusions: Restorative proctocolectomy with ileal pouch-anal anastomosis confers a long-term good quality of life to both UC and FAP patients, and the majority of patients are fully continent with five to six bowel movements per day.