Association of prediagnosis endoscopy with stage and survival in adenocarcinoma of the esophagus and gastric cardia

BACKGROUND: Barrett esophagus, a consequence of chronic gastroesophageal reflux disease, is a premalignant condition for adenocarcinoma of the esophagus and, possibly, the gastric cardia. However, the actual use and clinical impact of upper gastrointestinal endoscopy in screening and surveillance for Barrett esophagus are unknown. METHODS: A cohort included 1633 patients with adenocarcinoma (777 esophagus, 856 cardia) who were 70 years or older. They were diagnosed between 1993 and 1996 and were identified from the Surveillance, Epidemiology and End Results program registry. All claims for upper endoscopy and a diagnosis of Barrett esophagus from 1991 through 1 year before diagnosis were identified from linked Medicare files. RESULTS: One or more upper endoscopies before diagnosis were performed in 9.7% of patients (13.0% esophagus, 6.8% cardia) and a diagnosis of Barrett esophagus was present in only 3.7% of patients. A shift toward earlier stage at diagnosis was observed in patients with previous endoscopy or Barrett diagnosis. For example, 62% of patients with esophageal and 49% of patients with cardia tumors who underwent previous endoscopy presented with in situ or local stage carcinoma, compared with 35% and 27% of other patients, respectively. Receipt of endoscopy was also associated with a reduced risk of death for esophageal adenocarcinoma (relative hazard 0.73, 95% confidence interval 0.57-0.93; P = 0.01), but not for adenocarcinoma of the cardia. CONCLUSIONS: Receipt of upper endoscopy at least 1 year before diagnosis of adenocarcinoma, which may reflect prediagnosis screening, was associated with an earlier tumor stage and improved survival. These data support the role of endoscopic screening and surveillance for Barrett esophagus and highlight the underdiagnosis of populations at risk.     

Characteristic gene expression in stromal cells of gastric cancers among atomic‐bomb survivors

To elucidate the mechanism of radiation‐induced cancers, molecular analysis of cancers in atomic‐bomb survivors is important. In our study, we developed a custom oligonucleotide array of 208 genes. We analyzed gene expression profiles of gastric cancers (GCs) from atomic‐bomb survivors and identified 9 genes with significantly lower expression in GCs from exposed patients than in GCs from nonexposed patients. Among these 9 genes, expression of versican and osteonectin was investigated in greater detail using immunohistochemistry in 116 GCs from 64 exposed and 52 nonexposed patients who developed GC after the bombing. In the Stage I/II GCs, the clinicopathologic, phenotypic and proliferative characteristics of GCs from exposed and nonexposed patients did not differ significantly; however, versican and osteonectin were expressed at much lower levels in the area of tumor‐associated stroma of exposed patients than in nonexposed patients (p = 0.026 and p = 0.024, respectively). These results suggest that the characteristics of tumor‐associated stromal cells differ between GCs from exposed and nonexposed patients. © 2008 Wiley‐Liss, Inc.     

Endoscopic follow-up of 383 patients with colorectal adenoma: an observational study in daily practice.

Endoscopic removal of colorectal adenomas reduces the incidence and mortality of colorectal cancer (CRC), but follow-up surveillance is recommended. Compliance with the Dutch surveillance guidelines and detection of neoplasia during follow-up has been evaluated in daily practice. From 1987 to 1996, 383 consecutive patients with colorectal adenomas (56.4% male, 61.8+/-11.3 years) were included and followed until December 2000. The mean follow-up was 80.5+/-42.5 months with 2.2+/-0.9 follow-up endoscopies. A total of 32.5 and 27.3% of follow-up endoscopies were performed >25% (time between advised and actual endoscopy) too late or too early, respectively. At the end of follow-up, 33.4% of patients had left the follow-up (two-thirds died) and 60.1% were known with co-morbidity. A first, second, third, fourth and fifth follow-up endoscopy had been performed in 327, 238, 132, 64 and 35 patients, respectively. Adenomatous polyps (with high-risk polyps) were detected in 100% (42.6%) of the index endoscopies and in 25.1% (17.4%), 23.9% (10.5%), 28.0% (12.1%), 34.4% (25.0%) and 37.1% (17.1%) of the first to fifth follow-up endoscopy, respectively. CRC was diagnosed in seven patients (46.1+/-22.9 months after index endoscopy), resulting in a standardized incidence ratio of 1.4 (confidence interval 0.6-3.0, P=0.4) compared to the general population. In this daily practice, high numbers of total and high-risk adenomatous polyps were found during follow-up surveillance. The incidence of CRC was not significantly different from the general population, which might be due to the intensive follow-up and removal of polyps. These findings support the importance of follow-up surveillance. However, the high overall morbidity and mortality should be taken into account when selecting patients for an intensive follow-up programme.     

Combined analysis of three lynch syndrome cohorts confirms the modifying effects of 8q23.3 and 11q23.1 in MLH1 mutation carriers

Two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome (LS) patients. Recently, in a combined study of Australian and Polish LS patients, only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three data‐sets was performed to better define this association. This cohort‐study includes three sample populations combined totaling 1,352 individuals from 424 families with a molecular diagnosis of LS. Seven SNPs, from six different CRC susceptibility loci, were genotyped by both research groups and the data analyzed collectively. We identified associations at two of the six CRC susceptibility loci in MLH1 mutation carriers from the combined LS cohort: 11q23.1 (rs3802842, HR = 2.68, p ≤ 0.0001) increasing risk of CRC, and rs3802842 in a pair‐wise combination with 8q23.3 (rs16892766) affecting age of diagnosis of CRC (log‐rank test; p ≤ 0.0001). A significant difference in the age of diagnosis of CRC of 28 years was observed in individuals carrying three risk alleles compared to those with 0 risk alleles for the pair‐wise SNP combination. A trend (due to significance threshold of p ≤ 0.0010) was observed in MLH1 mutation carriers towards an increased risk of CRC for the pair‐wise combination (p = 0.002). This study confirms the role of modifier loci in LS. We consider that LS patients with MLH1 mutations would greatly benefit from additional genotyping of SNPs rs3802842 and rs16892766 for personalized risk assessment and a tailored surveillance program.     

Endoscopy for gastroesophageal reflux disease and survival in esophageal adenocarcinoma

Gastroesophageal reflux disease (GERD) is a risk factor of esophageal adenocarcinoma (EAC) and the most common indication for upper gastrointestinal endoscopy. Yet, whether GERD or endoscopy practice influence survival in EAC is largely unknown and was assessed in our study.This nationwide cohort study included all Swedish residents diagnosed with EAC in 1997–2013 with follow-up to 2018. Exposures were history of GERD and endoscopies prior to EAC. The main outcome was EAC-specific 5-year mortality. Multivariable Cox regression provided hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for potential confounders. Among 6,600 EAC patients (79.3% males, median age 70 years) followed for 9,138 person-years, 440 (6.7%) had GERD and 592 (9.0%) had ≥1 endoscopy before EAC diagnosis. GERD was associated with a decreased risk of mortality (adjusted HR 0.71, 95% CI 0.64–0.80), which was only slightly attenuated by adjustment for prior endoscopies (HR 0.79, 95% CI 0.70–0.90), and further adjustments also for tumor stage and surgical resection (HR 0.74, 95% CI 0.62–0.89). Compared to EAC patients without prior endoscopy, mortality was unchanged in GERD patients having undergone 1 or 2 endoscopies before EAC diagnosis (HR 1.02, 95% CI 0.80–1.31, for 1 endoscopy; HR 0.90, 95% CI 0.63–1.30, for 2 endoscopies), while the mortality was decreased in patients with ≥3 endoscopies (HR 0.55, 95% CI 0.36–0.85). Our study indicates that GERD may be associated with a better prognosis in the event of EAC; however, the use of endoscopy screening has a limited impact on survival unless performed very frequently.     

Serum olfactomedin 4 (GW112, hGC‐1) in combination with Reg IV is a highly sensitive biomarker for gastric cancer patients

Gastric cancer (GC) is 1 of the most common human cancers. Early detection remains the most promising approach to improving long‐term survival of patients with GC. We previously performed Serial Analysis of Gene Expression (SAGE) on 4 primary GCs and identified several GC‐specific genes including Reg IV. Of these genes, olfactomedin 4 (OLFM4, also known as GW112 or hGC‐1) is a candidate gene for cancer‐specific expression. In this study, we examined the expression of olfactomedin 4 in human GC by immunohistochemistry. We also assessed serum olfactomedin 4 levels in GC patients by enzyme‐linked immunosorbent assay. 94 (56%) of 167 GC cases were positive for olfactomedin 4 by immunostaining. Olfactomedin 4 staining was observed more frequently in stage I/II cases than in stage III/IV cases. The serum olfactomedin 4 concentration in presurgical GC patients (n = 123, mean ± SE, 36.3 ± 3.5 ng/mL) was significantly higher than that in healthy individuals (n = 76, 16.6 ± 1.6 ng/mL). In patients with stage I GC, the sensitivity of serum olfactomedin 4 (25%) and Reg IV (35%) was superior to that of CA19‐9 (5%) or CEA (3%). Furthermore, in patients with stage I GC, the combination of olfactomedin 4 and Reg IV elevated the diagnostic sensitivity to 52%. These results suggest that serum olfactomedin 4 is a useful marker for GC and its measurement alone or in combination with Reg IV has utility in the early detection of GC. © 2009 UICC     

Progression to advanced neoplasia is infrequent in post colectomy familial adenomatous polyposis patients under endoscopic surveillance

Background and Study Aims Advanced neoplasia may occur in the remaining colon and distal ileum of familial adenomatous polyposis (FAP) patients who have had a prophylactic colon resection. The role of post operative lower GI endoscopic surveillance and management of advanced neoplasia in FAP patients is not well defined. The aims of this study were to determine the prevalence of post operative neoplasia and to evaluate the safety and effectiveness of lower GI endoscopic surveillance and ablative therapy following prophylactic colon resection. Patients and Methods A retrospective analysis of 42 FAP patients with prior primary colon cancer preventative surgery undergoing lower GI surveillance and ablative therapy from 1992 to 2006. Results All patients had adenomatous disease identified upon initial endoscopy with advanced neoplasia identified in 6/42 (14%). Patients had a median of 4 endoscopic procedures of which 2 (range 0–12) were therapeutic, over a 49 month follow-up period (range 0–168) Thermal ablation with argon plasma coagulation, polypectomy and surgical intervention were required in 55%, 7% and 14% of patients. Ablative therapy complications were due to Nd: YAG laser and snare polypectomy (5%). Progression to advanced neoplasia from baseline pathology occurred despite ablative therapy in 3/42 (7%) patients. We propose a lower GI tract endoscopic surveillance program for post surgical FAP patients. Conclusion Despite prophylactic colon surgery, FAP patients continue to be at risk of neoplasia. The development of advanced neoplasia is infrequent in patients embarking upon endoscopic surveillance. Ablative therapy is effective and safe for the vast majority of FAP patients.     

HER2‐positive gastric cancer with concomitant MET and/or EGFR overexpression: A distinct subset of patients for dual inhibition therapy

Growth factor receptors, often carrying tyrosine kinase activities in their cytoplasmic domains, are overexpressed in many cancers. Coactivation of receptor tyrosine kinases (RTKs) plays a critical role in tumor response to targeted therapeutics. We examined concomitant overexpression of EGFR and MET in patients with HER2⁺ and HER2^? gastric cancers (GCs). Tissue microarray samples obtained from 1,589 GC patients who received R0 gastrectomy with extensive node dissection and adjuvant chemoradiationtherapy were analyzed by immunohistochemistry and fluorescence in situ hybridization. HER2⁺ was observed in 169 patients (11%). Out of 169 HER2⁺ patients, 15 (9%) were EGFR⁺ and MET⁺, 29 (17%) were EGFR⁺, 37 (22%) were MET⁺ and the remaining 88 patients (52%) were HER2⁺ only, without concomitant EGFR or MET overexpression. Greater number of overexpressed RTKs correlated with younger age (p < 0.001), larger tumor size (p = 0.027), intestinal histology (p < 0.001) and shorter overall survival (p = 0.002). The mean overall survival was 113 months for HER2^?/EGFR^?/MET^? and 63 months for HER2⁺/EGFR⁺/MET⁺ subgroups. Patients with HER2⁺/EGFR⁺/MET⁺ GCs had a substantial risk of death with a hazard ratio of 3.01 (95% CI: 1.54–5.90), compared with HER2^?/EGFR^?/MET^? GC patients. Using patient‐derived tumor cell models isolated from pericardial effusion of HER2⁺ and MET⁺ GC cases, we demonstrated that the combination of HER2‐inhibitor (lapatinib) and MET‐inhibitor offered a more profound inhibition in the ERK/AKT pathway and cell proliferation than lapatinib alone. Co‐overexpression of RTKs was demonstrated in small subsets of GC associated with aggressive behavior and in these cases, combination therapy may be considered as potential treatment options.     

The safety and efficacy of gi endoscopy in patients with acute-leukemia - a review of 27 cases

In the course of aggressive treatment for acute leukemia, the ensuing pancytopenia and intensive medical support may be accompanied by severe gastrointestinal (GI) complications. Therefore, to assess the safety and efficacy of GI endoscopy as a means of diagnosis, we analyzed the records of 16 patients undergoing 27 endoscopies a mean (+/-S.D.) of 18.4 +/- 11.9 days post chemotherapy. There were 6 procedures performed in patients with acute lymphocytic, 18 with acute myelogenous, including 3 with acute promyelocytic and 3 with blastic phase chronic myelogenous leukemia. 10/27 procedures were performed in patients with less than 1000 WBC/mm3 and 19/27 had less than 100,000 platelets. 15 patients had 25 upper endoscopies done for: bleeding (twenty-one), abdominal pain (two), and persistent vomiting (two). The principal bleeding sources were: esophagitis (eleven), Mallory Weiss tear (one), gastritis (three), gastric ulcer (one), duodenal ulcer (five). In the non-bleeding cases 2 exams were normal and the others had gastritis (one) and esophagitis (one). 15/25 procedures (64%) resulted in new diagnosis and 20/25 (80%) in additional therapies. 47% of patients undergoing upper GI endoscopy received specific new therapies as a result of that procedure. Nd: YAG laser photocoagulation was effective in stopping bleeding lesions in 4/6 cases. 10/12 bleeding patients had persistent or recurrent bleeding and 2 died from bleeding. None had surgery. Two patients underwent colonoscopy, both for colonic distention. One patient, who had been recently treated for Cl. difficile had submucosal petechiae. The other had non-specific colitis. No biopsies were done and both cases were successfully decompressed..No complications occurred from any GI endoscopy. We conclude that GI endoscopy can be safely performed in patients with acute leukemia, resulting in specific diagnoses and therapies. Esophagitis is a principal cause of GI bleeding in these patients. The role of therapeutic endoscopy in controlling bleeding is promising but requires further evaluation.     

Hereditary evaluation and genetic counselling in young individuals with colorectal cancer in a population-based cohort

AimEarly-onset colorectal cancer should raise suspicions of a hereditary colorectal cancer (CRC) syndrome, including Lynch syndrome (LS) and Familial Adenomatous Polyposis (FAP). Collection of family history and genetic counselling (GC) is mandatory but previous studies have revealed low awareness of hereditary CRC among clinicians why there has been an incentive to implement universal LS screening. In this population-based cohort study, we aimed to observe the uptake of GC in the Swedish South-Eastern medical care region for young CRC patients and to investigate the frequency of patients diagnosed with LS.MethodsPatients below 50 years of age diagnosed with CRC between 2008 and 2017 were identified from the national Swedish Colorectal Cancer Registry. Medical records were reviewed regarding family history, co-morbidity and referral for GC, with a follow-up time of at least three years.ResultsThe analysis included 278 patients with 287 tumours, 108 (38%) located in rectum and 179 (62%) in colon. One hundred sixteen (42%) individuals were referred to the Regional Clinical Genetics service, whereof 74 (27%) underwent complete investigation. Thirteen (18%) patients were identified with a mutation, eleven (15%) had LS and two (3%) FAP. The remaining 61 (82%), without proven mutation, were considered as familial CRC. Younger age correlated with a higher chance of referral for GC.ConclusionThe study found that only a minority of young CRC patients underwent genetic counselling, contrary to clinical guidelines. Hereditary CRC is therefore probably underdiagnosed even among young individuals.     

Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAF^V600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAF^V600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAF^V600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.     

Association of the interval between endoscopies with gastric cancer stage at diagnosis in a region of high prevalence

BACKGROUND:

Endoscopy screening in high‐risk populations may reduce gastric cancer mortality by detecting cancer earlier. We evaluated the association between the interval between upper gastrointestinal endoscopies and the gastric cancer stage at diagnosis in patients from a region of high prevalence.

METHODS:

The study cohort consisted of 2485 patients diagnosed with gastric adenocarcinoma. We evaluated the effect on cancer stage of the interval between the endoscopy that was diagnostic for gastric cancer and the endoscopy preceding it. Patients were stratified into 7 groups: 1‐, 2‐, 3‐, 4‐, 5‐, >5‐year intervals and those who were never screened.

RESULTS:

The risk of higher cancer stage at diagnosis increased by 23% per increase in interval length (odds ratio = 1.23, 95% confidence interval [CI] = 1.19‐1.28). Compared to the never‐screened, the odds ratio of having a higher stage of cancer decreased gradually from 0.53 (95% CI = 0.41‐0.69) in the >5‐year interval group to 0.31 (95% CI = 0.24‐0.40) in the 1‐year interval group. Compared to the 1‐year interval group, the risk of advanced gastric cancer was increased in the 4‐ and 5‐year, but not the 2‐ and 3‐year, interval groups. However, patients with a family history of gastric cancer were more likely to have a higher stage at diagnosis if they had a 3‐year interval rather than a 1‐year interval.

CONCLUSIONS:

A significant benefit in cancer stage at diagnosis was observed in all interval groups compared to never‐screened. Endoscopy intervals of 3 years or less showed similar benefits, but family members of gastric cancer patients may benefit from intervals of under 3 years. Cancer 2012. © 2012 American Cancer Society.     

Expression of E-Cadherin and the PTEN Gene in Relation to Invasion and Metastasis of Gastric Carcinomas

Objective To observe the expression of PTEN and E-Cadherin in gastric carcinomas (GCs): and to investigate the relationship between their expression and the pathology and prognosis of patients with GC. Methods The proposed markers were detected inmmunohistochemicaily by using the SABC method in 100 post-operated specimens of GC. The results were statically analyzed by the chi-square and log rank tests. Results Both E-Cadherin and PTEN proteins were expressed in noncancerous rnucosa. They were reduced or lost in GCs. The abnormal rate of expression of E-Cadherin was 42.0%. The decreased rate of expression in the diffuse-type GC (48.6%) was significantly higher than in the intestinaltype GC (26.7%, P< 0.05). The abnormal expression of E-Cadherin closely correlated to the depth of invasion (P< 0.05). The degree of loss of the PTEN protein was 59.0% in GCs. In the diffuse-type GC, the rate of toss of PTEN was (65.7%) which was significantly higher than that in the intestinal-type GC (43.3%,P< 0.05). The rate of loss of PTEN (64.5%) in GCs with lymph node metastasis was significantly higher than that in GCs without metastasis (41.7%, P< 0.05). The prognosis of patients with a loss of PTEN protein was worse than the patients with positive expression of PTEN (P=0.0066). E-Cadherin was normally expressed in 65.9% of GCs with positive expression of PTEN. Conclusion The loss of E-Cadherin and PTEN markers correlated with infusion and metastasis of GC. The expression of PTEN showed a close relationship to the prognosis of patients. Detection of the 2 markers together aided in the correct prediction of the prognosis of the GC patients and provided information for clinical treatment.     

Distinct molecular profiles in Lynch syndrome‐associated and sporadic ovarian carcinomas

Ovarian carcinoma in Lynch syndrome (LS) is associated with unexpectedly high survival; yet, beyond DNA mismatch repair (MMR) defects, the developmental mechanisms are unknown. We used established (genetic) and new (epigenetic) classifiers of ovarian cancer to explore similarities and differences between LS‐associated and sporadic diseases. To this end, all available ovarian carcinomas (n = 20) from MMR gene mutation carriers ascertained through a nation‐wide registry and 87 sporadic ovarian carcinomas of the main histological types were molecularly profiled. LS‐ovarian carcinomas were mostly of nonserous histology (12 endometrioid, seven clear cell and one serous), diagnosed at a mean age of 45.7 years, and associated with a 10‐year survival of 87%. Among LS‐ovarian carcinomas, 19/20 (95%) were MMR‐deficient vs. 11/87 (13%) among sporadic cases (p < 0.0001). In a striking contrast to the sporadic cases, the expression of p53 was normal and KRAS/BRAF mutations absent in all LS‐ovarian carcinomas. PIK3CA mutations, suggested to be a favorable prognostic factor, occurred with a frequency of 6/20 (30%), which was comparable to sporadic tumors of endometrioid or clear cell type. Tumor suppressor genes were more frequently methylated and LINE‐1 hypomethylation less common in LS‐ovarian carcinomas compared to their sporadic counterparts. The patterns of genetic and epigenetic alterations reflected the origin as LS vs. sporadic cases on one hand and the histological type on the other hand. In conclusion, the significant molecular differences observed between LS‐associated and sporadic ovarian carcinomas help explain the different behavior of these tumors and emphasize the need for tailored clinical management.     

Compliance and Satisfaction with Long-Term Surveillance in Finnish HNPCC Families

Objective: Nation-wide preventative colonoscopic surveillance for mutation carriers in HNPCC families has been organized since the early 1980 by the Finnish HNPCC registry. After characterization of MMR genes, a predisposing mutation has been verified in 111 HNPCC families and over 1500 family members at risk have been tested. The aim of this study was to evaluate the compliance and satisfaction of mutation carriers during life-long colonoscopic surveillance. Materials and Methods: Hospital records of long-term surveillance were obtained for all mutation carriers (n=664). A questionnaire assessing overall experience, willingness to continue the surveillance, painfulness (a three-rank scale), possible interruption of endoscopy and the need for pain relief medication during colonoscopy, was sent to all living mutation carriers (n=587). The questionnaire was returned by 441 persons (75%) of whom 415 persons under colonoscopic surveillance were included in the study and 26 young mutation carriers excluded as they were still pending their first endoscopy. Results: Out of 664 mutation carriers, surveillance had been interrupted in 8 cases (1.2%). Colonoscopies were described as painful by 151 (36%), uncomfortable by 161 (39%) and easy by 103 (25%) patients. Endoscopy was more often rated as painful by females (1.36, SD 0.71) than by males (0.86, SD 0.75), P<0.001. Medication for pain during colonoscopies was administered more often to females (32%) than males (15%), P<0.001. Colonoscopy had to be discontinued because of pain at least once in 10% of the patients. Conclusion: Patient compliance under life-long surveillance was excellent, but painfulness, especially in females, must be seen as a risk for compliance and the quality of endoscopies.     

Lynch‐like syndrome: Characterization and comparison with EPCAM deletion carriers

Colorectal cancers (CRCs) with microsatellite instability‐high (MSI+) but without detectable germline mutation or hypermethylation in DNA mismatch repair (MMR) genes can be classified as Lynch‐like syndrome (LLS). The underlying mechanism and clinical significances of LLS are largely unknown. We measured MSI and MMR protein expression in 4,765 consecutive CRC cases. Among these, MSI+ cases were further classified based on clinical parameters, germline sequencing of MMR genes or polymerase ε (POLE) and δ (POLD1) and promoter methylation analysis of MLH1 and MSH2. We found that MSI+ and MMR protein‐deficient CRCs comprised 6.3% (N = 302) of this cohort. On the basis of germline sequencing of 124 cases, we identified 54 LS with MMR germline mutation (LS‐MMR), 15 LS with EPCAM deletions (LS‐EPCAM) and 55 LLS patients. Of the 55 LLS patients, six (10.9%) had variants of unknown significance in the genes tested, and one patient had a novel somatic mutation (p.S459P) in POLE. In patients with biallelic deletions of EPCAM, all tumors and their matched normal mucosa showed promoter hypermethylation of MSH2. Finally, we found that patients with LLS and LS‐EPCAM shared clinical features that differed from LS‐MMR patients, including lower frequency of fulfillment of the revised Bethesda guidelines (83.6 and 86.7% vs. 98.1% for LS‐MMR) and older mean age at CRC diagnosis (52.6 and 52.7 years vs. 43.9 years for LS‐MMR). We identified somatic mutation in POLE as a rare underlying cause for MMR deficiency in LLS. The similarity between LLS and LS‐EPCAM suggests LLS as a subset of familial MSI+ CRC.     

The impact of additional malignancies in patients diagnosed with gastrointestinal stromal tumors

A higher incidence of additional malignancies has been described in patients diagnosed with gastrointestinal stromal tumors (GIST). This study aimed to identify risk factors for developing additional malignancies in patients diagnosed with GIST and evaluate the impact on survival. Individuals diagnosed with GIST from 2001 to2009 were identified from the SEER database. Logistic regression was used to identify predictors of additional malignancies and Cox‐proportional hazards regression used to identify predictors of survival. In the study period, 1705 cases of GIST were identified, with 181 (10.6%) patients developing additional malignancies. Colorectal cancer was the most common cancer developing within 6 months of GIST diagnosis (30%). The median time to diagnosis of a malignancy after 6 months of GIST diagnosis was 21.9 months. Older age (p < 0.0001) and extraoesophagogastric GIST (p = 0.0027) were significant prognostic factors associated with additional malignancies. The overall 5‐year survival was 65%, with the presence of additional malignancies within 6 months of GIST diagnosis associated with poor overall survival (54%, HR 1.55 1.05–2.3 95% CI, p = 0.04). Predictive factors of additional malignancies in patients diagnosed with GIST are increasing age and the primary disease site. Developing additional malignancies within 6 months of GIST diagnosis is associated with poorer overall survival. Targeted surveillance may be warranted in patients diagnosed with GIST that are at high risk of developing additional malignancies.     

Microsatellite instability and DNA ploidy in colorectal cancer

BACKGROUND:

Appropriate stratification tools for targeted surveillance after resection for colorectal cancer (CRC) are lacking. The objective of the current study was to investigate the effect of microsatellite instability (MSI) and DNA ploidy on surveillance after surgery.

METHODS:

The authors evaluated 186 consecutive, population‐based patients with stage I through III CRC who underwent surgery with curative intent and who entered a systematic surveillance program. MSI was analyzed with polymerase chain reaction for 5 known quasimonomorphic markers (BAT‐26, BAT‐25, NR‐21, NR‐24, and NR‐27), and DNA ploidy was analyzed with automated cytometry. Recurrence, recurrence‐free survival (RFS), and disease‐specific survival (DSS) were evaluated by univariate and multivariate statistical tests.

RESULTS:

Patients with MSI (20%) were significantly younger than patients without MSI (median age, 61 years vs 67 years; P = .016). Proximal location (adjusted odds ratio [AOR], 5.4; 95% confidence interval [95% CI], 2.1‐14.1 [P = .001]), large tumor size (≥5 cm: AOR, 3.5; 95% CI, 1.3–9.6 [P = .015]), and poor tumor differentiation (AOR, 6.6; 95% CI, 2–21.8 [P = .002]) were associated with MSI. MSI conveyed an increased risk for locoregional recurrence (OR, 2.9; 95% CI, 1.2–7 [P = .016]), with a trend toward a shorter time to recurrence (P = .060). Neither MSI status nor DNA ploidy predicted distant metastasis, RFS, or DSS. Lymph node status was the best predictor of distant spread (AOR, 3.9; 95% CI, 2–7.9 [P < .001]) and DSS (hazard ratio, 4.9; 95% CI, 2.6–9 [P < .001]).

CONCLUSIONS:

Patients who had microsatellite instable tumors were at increased risk for locoregional recurrence, whereas lymph node status was the best predictor of distant metastasis. Clinical surveillance and choice of modality (ie, endoscopy vs radiologic imaging) may be improved when patients are stratified according to these cancer features. Cancer 2009. © 2009 American Cancer Society.     

Aberrant immunoarchitecture distinguishes hyperplastic germinal centres in pattern 1 angioimmunoblastic T‐cell lymphoma from reactive follicles

We compare 30 biopsies each of Pattern 1 angioimmunoblastic T‐cell lymphoma (AITL1) and reactive lymphoid hyperplasia (RLH) by immunohistology, in‐situ hybridization for Epstein‐Barr virus‐encoded RNA and T‐cell receptor‐γ (TRG)‐clonality. AITL1 cases, more often than RLH controls, were older [median ages 61 (range 23–79) vs 46 (range 11–59) years, p < 10^‐4], non‐Chinese [16/30 (53%) vs 8/28 (29%), p = 0.035], presented nodally [29/30 (97%) vs 23/30 (77%), p = 0.024], showed: pan‐T cell antigen attenuation [25/29 (86%) vs 5/21 (24%), p = 1.0 × 10^‐5], CD4 predominance [25/28 (89%) vs 12/23 (52%), p = 3.4 × 10^‐3], interfollicular lymphoid CD10‐positivity [16/30 (53%) vs 1/29 (3%), p = 1.5 × 10^‐5], TRG clonality [16/28 (57%) vs 1/20 (5%), p = 1.4 × 10^‐4], higher maximum number of Epstein‐Barr virus‐encoded RNA + nuclei per 0.5‐mm high‐power field [median 6 (range 0–70) vs 1 (range 0–40), p = 0.012] and interfollicular Ki‐67 proliferation fraction [median 40% (range 10–80%) vs 20% (range 5–40), p < 10^‐4], whereas their germinal centres (GCs) more often showed attenuation of CD10 [30/30 (100%) vs 11/29 (38%), p = 5.3 × 10^‐8] and CD57 [18/25 (72%) vs 4/22 (18%), p = 2.4 × 10^‐4] (respectively). GC‐predominant PD‐1 and ICOS immunoreactivity were more often seen in RLH [20/22 and 9/19 controls (91% and 47%)] than AITL1 [9/25 and 3/19 cases (36% and 16%), p = 1.0 × 10^‐4 and 0.033, respectively]. Significant independent predictors against AITL1 were: solid GC CD10 immunoreactivity {p = 0.023, odds ratio (OR) for AITL1 0.01 [95% confidence interval (CI): 0.0002–0.529]}; lower interfollicular proliferation fraction [p = 0.047, OR for AITL1 1.1 (95% CI: 1.001–1.209) per % rise in Ki‐67]; younger presenting age [p = 0.028, OR for AITL1 1.136 (95% CI: 1.014–1.272) per year older]. Hence, GCs and perifollicular zones in AITL1 are distinct from those in RLH. Copyright © 2013 John Wiley & Sons, Ltd.