Surveillance and follow-up strategies in patients with high-grade dysplasia in Barrett's esophagus: a Dutch population-based study.

OBJECTIVES: In patients with high-grade dysplasia (HGD) in Barrett's esophagus (BE), it is incompletely known which factors are associated with developing esophageal adenocarcinoma (EAC). We analyzed prior biopsy and follow-up strategies in a large nationwide population-based cohort of patients with HGD in BE, and identified predictors of EAC progression. METHODS: Prior biopsy records and follow-up evaluations were studied in patients with HGD in BE diagnosed between 1999 and 2008, using PALGA, a nationwide network and registry of histopathology and cytopathology in the Netherlands. Multivariate Cox proportional hazards regression analysis was performed to identify predictors for prevalent (≤ 6 months) and incident (> 6 months) EAC. RESULTS: In total, 827 patients with HGD in BE were included. Follow-up data after HGD diagnosis were available in 699 (85%) patients. In 249 (36%) of these patients, an EAC was detected (14.1 EACs per 100 person-years). The risk of prevalent EAC (n=177) was lower with previous surveillance (hazards ratio 0.7; 95% confidence interval 0.5-0.9), unifocal HGD (0.3;0.2-0.6), diagnosis in a university hospital (0.5;0.3-0.9), endoscopic resection (0.5;0.3-0.7), or ablation (0.0;0.0-0.3); and higher when patients were 65-75 years (1.5;1.04-2.04). After exclusion of prevalent EACs, the progression rate was 4.2 EACs per 100 person-years. The risk of progression to incident EAC (n = 72) was lower with previous surveillance (0.6;0.3-0.9) and ablation (0.2;0.0-0.8), and higher when > 75 years (3.8;2.0-7.2) or with an interval > 6 months between HGD diagnosis and first follow-up (e.g., 7-12 months 2.9;1.3-6.3). CONCLUSIONS: In this cohort of patients with HGD in BE, the EAC detection rate was 14.1 per 100 person-years and 4.2 per 100 person-years after excluding prevalent cases. The risk of both prevalent and incident EAC was reduced with previous surveillance and endoscopic treatment, while it was increased with older age.

Premalignant gastric lesions in patients with gastric mucosa-associated lymphoid tissue lymphoma and metachronous gastric adenocarcinoma: a case-control study.

BACKGROUND: Patients with gastric mucosa-associated lymphoid tissue lymphoma or diffuse large B-cell lymphoma have an increased risk of developing gastric carcinoma (GC). Identifying patients at high GC risk may lead to improved survival and prognosis. The aim of this case-control study was to evaluate whether premalignant gastric lesions are more prevalent and severe in gastric lymphoma (GL) patients with a subsequent diagnosis of GC than in those without GC. METHODS: Patients with a first GL diagnosis from 1991-2008 were identified in the Dutch histopathology registry (PALGA). Cases were patients with a diagnosis of GL and a subsequent diagnosis of GC. Controls were patients with a diagnosis of GL without GC development. RESULTS: In total, eight cases (mean follow-up 5.5 years) and 31 controls (mean follow-up 5.3 years) were included (mean age 60 years). At lymphoma diagnosis, six (75%) cases were diagnosed with premalignant lesions, whereas in the control group, 21 (68%) had histological evidence for premalignant lesions (P=0.69). At GC diagnosis, five (63%) cases showed intestinal metaplasia in the surrounding gastric mucosa. In 22 (71%) controls premalignant lesions were present at the end of follow-up (P=0.47). CONCLUSION: No differences were demonstrated in the prevalence of premalignant lesions of cases and controls at GL diagnosis or the end of follow-up. As the prevalence of premalignant lesions is substantial in both the groups of patients, careful endoscopic surveillance of GL patients is warranted not only for recurrence of lymphoma, but also for progression to adenocarcinoma.

Cervix smear abnormalities: linking pathology data in female twins, their mothers and sisters.

Mass screening for cervical cancer precursors has decreased the incidence of cervical cancer in several countries, including the Netherlands. Persistent infections of certain types of human papillomavirus are strongly associated with the development of cervical cancer. A number of factors may affect the liability to infection and subsequent progression to cervical intraepithelial neoplasia and cancer. This paper examines whether genetic factors are involved in explaining individual differences in liability. Data of 3178 women registered with the Netherlands Twin Register were successfully linked to the nationwide Dutch Pathology database that contains all results of mass screening for cervical cancer. The data from mono- and dizygotic twins and their female relatives were used to disentangle the influence of heritable and environmental factors on cervix smear abnormalities. Results showed that differences in cervix smear results clustered within families and resemblance was stronger in monozygotic twins (correlation 0.37, 95% confidence interval: 0.12-0.58) compared with other first-degree relatives (correlation 0.14, 95% confidence interval: -0.01-0.29). The familial clustering for an abnormal cervix smear is due to shared genetic factors that explain 37% of the variance in liability. The largest proportion of the variation in cervical smear abnormalities is due to unique environmental factors.

Risk of malignant progression in patients with Barrett's oesophagus: a Dutch nationwide cohort study.

BACKGROUND: Reported incidence rates of oesophageal adenocarcinoma (OAC) in Barrett's oesophagus (BO) vary widely. As the effectiveness of BO surveillance is crucially dependent on this rate, its clarification is essential. METHODS: To estimate the rate of malignant progression in patients with BO, all patients with a first diagnosis of BO with no dysplasia (ND) or low-grade dysplasia (LGD) between 1991 and 2006 were identified in the Dutch nationwide registry of histopathology (PALGA). Follow-up data were evaluated up to November 2007. RESULTS: 42 207 patients with BO were included; 4132 (8%) of them had LGD. Re-evaluation endoscopies at least 6 months after initial diagnosis were performed in 16 365 patients (39%), who were significantly younger than those not re-examined (58+/-13 vs 63+/-16 years, p<0.001). These patients were followed-up for a total of 78 131 person-years, during which 666 (4%) high-grade dysplasia (HGD)/OACs occurred, affecting 4% of the surveillance patient population (mean age: 69+/-12 years, 76% male). After excluding HGD/OAC cases detected within 1 year after BO diagnosis (n=212, 32%), incidence rates per 1000 person-years were 4.3 (95% CI 3.4 to 5.5) for OAC and 5.8 (95% CI 4.6 to 7.0) for HGD/OAC combined. Risk factors for HGD/OAC were increased age (eg, >75 years HR 12; 95% CI 8.0 to 18), male sex (2.01; 1.68 to 2.60) and presence of LGD at baseline (1.91; 1.53 to 2.40). CONCLUSION: In this largest reported cohort of unselected patients with BO, the annual risk of OAC was 0.4%. Male sex, older age and LGD at diagnosis are independent predictors of malignant progression, and should enable an improved risk assessment in BO.

Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer.

PURPOSE: The use of cytochrome P450 2D6-inhibiting drugs (CYP2D6 inhibitors) during tamoxifen treatment leads to a decrease in plasma concentration of endoxifen, the major active tamoxifen metabolite. Concomitant use of CYP2D6 inhibitors, such as selective serotonin reuptake inhibitors, as well as low tamoxifen adherence may negatively impact tamoxifen efficacy in patients with breast cancer. The objectives of this study were to relate concomitant CYP2D6 inhibitor use and tamoxifen adherence to breast cancer event-free time (EFT). PATIENTS AND METHODS: Data were from PHARMO and included a community pharmacy dispensing database; PALGA, a nationwide pathology database; and the Dutch Medical Register in the Netherlands. Patients with breast cancer treated with adjuvant tamoxifen between 1994 and 2006 were included. A Cox proportional hazards model with a time-dependent definition for concomitant CYP2D6 inhibitor exposure was used. Adherence calculated over the first year after tamoxifen initiation was related to breast cancer events in the following period. RESULTS: In total, 1,962 patients with breast cancer using tamoxifen were included, among whom 150 (7.6%) frequently used a CYP2D6 inhibitor during tamoxifen treatment. No association between concomitant CYP2D6 inhibitor use and breast cancer recurrence was observed (adjusted hazard ratio [HR], 0.87; 95% CI, 0.42 to 1.79; P = .69). Poor tamoxifen adherence was associated with lower EFT (adjusted HR, 0.987; 95% CI, 0.975 to 0.999; P = .029). CONCLUSION: This observational study did not show an association between concomitant CYP2D6 inhibitor use and breast cancer recurrence among patients treated with adjuvant tamoxifen despite the strong biologic rationale. This study shows, to the best of our knowledge for the first time, that poor tamoxifen adherence is associated with an increased risk of breast cancer events.

Risk of colorectal cancer in patients with Barrett's esophagus: A Dutch population-based study.

OBJECTIVES: The association between Barrett's esophagus (BE) and colorectal cancer (CRC) is controversial. Population-based studies on the risk of CRC in BE are scarce. The aim of this study was to determine the risk of CRC in a nationwide cohort of patients with BE in the Netherlands with long-term follow-up. METHODS: Patients diagnosed with BE between 1991 and 2006 were identified in the Dutch nationwide histopathology registry (Pathologisch Anatomisch Landelijk Geautomatiseerd Archief (PALGA)). The incidence of CRC observed in these patients was compared with that in the general Dutch population aged >40 years. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated using a Poisson model. RESULTS: A total of 42,207 patients with a first diagnosis of BE were included in this study. During a mean follow-up of 5.6 years (s.d. 4), 713 patients (1.7%) were diagnosed with CRC (overall rate: 3.4/1,000 person-years at risk), at a mean age of 73.7 years (s.d. 10). All CRCs occurred in BE patients aged >40 years, and the majority (96%) in those over 50 years of age. Of those CRCs, 317 (44%) were detected within the first year after initial BE diagnosis, and 396 (54%) thereafter. For all patients with BE, CRC risk was 1.70 (95% CI: 1.58-1.83), as compared with the general Dutch population aged >40 years. However, CRC risk within the first year of follow-up after BE diagnosis (RR: 4.76 (95% CI: 4.26-5.31)) was significantly higher than within 1-5 years of follow-up (RR: 0.99 (95% CI: 0.86-1.14)) or more than 5 years of follow-up (RR: 1.28 (95% CI: 1.11-1.47)) (P<0.001). CONCLUSIONS: This population-based study shows an overall increased risk of CRC in patients with BE as compared with the general Dutch population, which can for the greater part be explained by diagnostic bias. The magnitude of the association between BE and CRC does not merit a more extensive CRC screening strategy in BE patients than has currently been recommended for the general population.

Non-steroidal anti-inflammatory drugs and melanoma risk: large Dutch population-based case-control study.

This case-control study investigates the potential chemoprophylactic properties of non-steroidal anti-inflammatory drugs (NSAIDs) on the incidence of cutaneous melanoma (CM). Data were extracted from the Dutch PHARMO pharmacy database and the PALGA pathology database. Cases had a primary CM between 1991 and 2004, were >or=18 years, and were observed for 3 years in PHARMO before diagnosis. Controls were matched for date of birth, gender, and geographical region. NSAIDs and acetylsalicylic acids (ASAs) were analyzed separately. Adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated using multivariable logistic regression, and the results were stratified across gender. A total of 1,318 CM cases and 6,786 controls were eligible to enter the study. CM incidence was not significantly associated with ever ASA use (adjusted OR: 0.92, 95% CI: 0.76-1.12) or ever non-ASA NSAID use (adjusted OR: 1.10, 95% CI: 0.97-1.24). However, continuous use of low-dose ASAs was associated with a significant reduction of CM risk in women (adjusted OR: 0.54, 95% CI: 0.30-0.99) but not in men (OR: 1.01, 95% CI: 0.69-1.47). A significant trend (P=0.04) from no use, non-continuous use to continuous use was observed in women. Continuous use of low-dose ASAs may be associated with a reduced incidence of CM in women, but not in men.

Does use of estrogens decrease the Breslow thickness of melanoma of the skin? Oral contraceptives and hormonal replacement therapy.

Recently, we showed there was a cumulative dose-dependent association between the use of estrogens and the incidence of cutaneous melanoma (CM). This association was shown for both oral contraceptives (OC) and hormonal replacement therapy (HRT). Some in-vitro studies, however, have suggested a direct inhibitory effect on melanoma tumor growth. Therefore, the use of different types of estrogens, OC and HRT, may be associated with a decreased Breslow thickness. Consequently, the clinical impact of our earlier findings may be limited. In this study, we investigated whether estrogen use (0.5 year), OC or HRT, is associated with a decreased Breslow thickness. For this study, we linked the national Dutch pathology database (PALGA) to a pharmacy database (PHARMO). Cases were women with a primary CM between 1 January 1991 and 14 December 2004, aged > or =18 years and having > or =3 years of follow-up before diagnosis of CM. In total, 687 women with melanoma were included. Univariable linear regression analysis suggested a decreased Breslow thickness with the use of OC and HRT. Statistically significant interaction was observed between age and estrogen use (P<0.01) suggesting effect modification by age. However, in stratified multivariable analyses for different age groups (<45, 45-55, > or =55 years), no statistically significant associations between the use of OC or HRT and Breslow thickness were observed. In conclusion, an association between use of OC and HRT and Breslow thickness could not be confirmed.

Increased risk of esophageal squamous cell carcinoma in patients with gastric atrophy: independent of the severity of atrophic changes.

An association between gastric atrophy and esophageal squamous cell carcinomas (ESCC) has been described. However, the mechanism of this association is unknown. In this study, we aimed to examine this relationship in a cohort of patients with varying grades of gastric atrophy to increase the understanding about the causality of the association. Patients diagnosed with gastric atrophy between 1991 and 2005 were identified in the Dutch nationwide histopathology registry (PALGA). The incidence of ESCC and, presumably unrelated, small cell lung carcinomas (SCLC) observed in these patients was compared with that in the general Dutch population. Relative risks (RRs) and 95% confidence intervals were calculated by a Poisson model. At baseline histological examination, 97,728 patients were diagnosed with gastric atrophy, of whom 23,278 with atrophic gastritis, 65,934 with intestinal metaplasia and 8,516 with dysplasia. During follow-up, 126 patients were diagnosed with ESCC and 263 with SCLC (overall rates 0.19, respectively 0.39/1,000 person-years at risk). Compared with the general Dutch population, patients with gastric atrophy ran a RR of developing ESCC of 2.2 [95% CI 1.8-2.6] and of SCLC of 1.8 [95% CI 1.6-2.1]. The risk of ESCC did not increase with increasing severity of gastric atrophy (p = 0.90). In conclusion, this study found an association between gastric atrophy and both ESCC and SCLC, but the risk of ESCC did not increase with the severity of gastric atrophy. Therefore, a causal relationship seems unlikely. Confounding factors, such as smoking, may explain both associations.

Anaplastic large-cell lymphoma in women with breast implants.

CONTEXT: Recently, we identified 2 patients with anaplastic large T-cell lymphoma (ALCL) negative for tyrosine kinase anaplastic lymphoma kinase (ALK-negative) in the fibrous capsule of silicone breast prostheses, placed for cosmetic reasons. Similar cases have been reported in the literature. Although an increased risk of ALCL in patients with breast prostheses has been speculated, no studies have been conducted so far. OBJECTIVE: To determine whether ALCL risk is associated with breast prostheses. DESIGN: A search for all patients with lymphoma in the breast diagnosed in The Netherlands between 1990 and 2006 was performed through the population-based nationwide pathology database. Subsequently, we performed an individually matched case-control study. Conditional logistic regression analysis was performed to estimate the relative risk of ALCL associated with breast prostheses. SETTING AND PATIENTS: Eleven patients with breast ALCL were identified in the registry. For each case patient with ALCL in the breast, we selected 1 to 5 controls with other lymphomas in the breast, matched on age and year of diagnosis. For all cases and controls (n = 35), pathological and clinical information was obtained with special emphasis on the presence of a breast prosthesis. MAIN OUTCOME MEASURE: Association between breast implants and ALCL of the breast. RESULTS: The 11 patients with ALCL of the breast were diagnosed between 1994 and 2006 at a median age of 40 years (range, 24-68 years). In 5 of these patients, bilateral silicone breast prostheses had been placed 1 to 23 years before diagnosis. All received prostheses for cosmetic reasons. Lymphoma classes of 35 eligible control patients were 12 diffuse large B-cell lymphomas, including 1 T-cell rich B-cell lymphoma; 5 Burkitt lymphomas; 10 mucosa-associated lymphoid tissue-type lymphoma; 3 follicular lymphomas; 3 peripheral T-cell lymphomas; and 2 indolent B-cell lymphomas, unclassified. One of 35 control patients had a breast implant placed before diagnosis of lymphoma. The odds ratio for ALCL associated with breast prostheses was 18.2 (95% confidence interval, 2.1-156.8). CONCLUSIONS: These preliminary findings suggest an association between silicone breast prostheses and ALCL, although the absolute risk is exceedingly low due to the rare occurrence of ALCL of the breast (11 cases in The Netherlands in 17 years). These findings require confirmation in other studies.

Trends in incidence and mortality of thyroid carcinoma in The Netherlands between 1989 and 2003: correlation with thyroid fine-needle aspiration cytology and thyroid surgery.

A persistent increase in incidence of thyroid carcinoma (TC) has been reported worldwide. The aim of our study was to assess trends in incidence and mortality of TC in The Netherlands between 1989 and 2003 and to examine whether these trends correlate with changes in diagnostic practices such as changes in the number of fine needle aspiration biopsies (FNAB) and/or thyroid surgeries. Population-based incidence and mortality data were retrieved from the Netherlands Cancer Registry. Data concerning FNAB and thyroid surgeries were obtained through the nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA). Overall, the incidence of TC remained unchanged. However, there was a slight increase in incidence of papillary TC of 2.1% per year (p < 0.001) particularly in stage I tumors, possibly, in part, because of a marked increase in use of FNAB. Appropriate iodine intake, reduced radiation exposure and a more conservative diagnostic approach toward asymptomatic thyroid nodules may explain why this increase is less pronounced compared to other countries. Incidence of other subtypes of TC decreased (follicular TC, 1.3% per year, p = 0.02 and anaplastic TC, 7.1% per year, p = 0.006) or remained unchanged (medullary TC). The number of FNABs per year progressively increased from 1,093 in 1989 to 4,123 in 2003, whereas the number of thyroid surgeries decreased from 3,419 in 1989 to 2,825 in 2003. The mortality rates decreased by 2.3% per year (p = 0.01). The decrease in incidence of both follicular and anaplastic TC is assumed to be largely responsible for the decrease in TC mortality rates.

Gastric cancer risk in patients with premalignant gastric lesions: a nationwide cohort study in the Netherlands.

BACKGROUND & AIMS: A cascade of precursor lesions (eg, atrophic gastritis, intestinal metaplasia, and dysplasia) precedes most gastric adenocarcinomas. Quantification of gastric cancer risk in patients with premalignant gastric lesions is unclear, however. Consequently, endoscopic surveillance is controversial, especially in Western populations. METHODS: To analyze current surveillance practice and gastric cancer risk in patients with premalignant gastric lesions, all patients with a first diagnosis between 1991 and 2004 were identified in the Dutch nationwide histopathology registry (PALGA); follow-up data were evaluated until December 2005. RESULTS: In total, 22,365 (24%) patients were diagnosed with atrophic gastritis, 61,707 (67%) with intestinal metaplasia, 7616 (8%) with mild-to-moderate dysplasia, and 562 (0.6%) with severe dysplasia. Patients with a diagnosis of atrophic gastritis, intestinal metaplasia, or mild-to-moderate dysplasia received re-evaluation in 26%, 28%, and 38% of cases, respectively, compared with 61% after a diagnosis of severe dysplasia (P < .001). The annual incidence of gastric cancer was 0.1% for patients with atrophic gastritis, 0.25% for intestinal metaplasia, 0.6% for mild-to-moderate dysplasia, and 6% for severe dysplasia within 5 years after diagnosis. Risk factors for gastric cancer development were increasing severity of premalignant gastric lesions at initial diagnosis (eg, severe dysplasia, hazard ratio 40.14, 95% confidence interval 32.2-50.1), increased age (eg, 75-84 years, hazard ratio 3.75, 95% confidence interval 2.8-5.1), and male gender (hazard ratio 1.50, 95% CI 1.3-1.7). CONCLUSIONS: Patients with premalignant gastric lesions are at considerable risk of gastric cancer. As current surveillance of these patients is inconsistent with their cancer risk, development of guidelines is indicated.

Melanocytic nevi of the oral mucosa - no evidence of increased risk for oral malignant melanoma: an analysis of 119 cases.

Pigmented nevi of the oral mucosa are rare benign melanocytic tumours. Epidemiological data are scanty, and the etiology and pathogenesis of these lesions are poorly understood. Reports are mainly based on isolated cases or a relatively small series of cases. Some reviews have drawn attention to the frequent localization of these lesions on the hard palate, the site of preference for oral malignant melanoma (OMM). However, as yet, there is no direct proof that oral melanocytic nevi (OMNs) constitute precursor lesions of OMM. 119 cases of OMNs, registered at the nationwide Registry of Pathology (PALGA) in The Netherlands during the period 1980-2005, have been evaluated. Subepithelial OMNs were the most commonly recorded lesions (96 cases), followed by blue (10 cases), compound (7 cases) and junctional OMNs (5 cases). Only one case of a combined nevus was recorded. None of the patients developed OMM during a mean follow-up period of 8.6years. We present an analysis of this series of cases, together with a review of the literature. The findings of the present evaluation do not give support for the hypothesis of OMN being a marker for an increased risk of future development of OMM.