Risk of malignant lymphoma in patients with inflammatory bowel diseases: a Dutch nationwide study.

BACKGROUND: Immune suppressant medications such as thiopurines and anti-tumor necrosis factor agents are important for maintaining disease control in most patients with inflammatory bowel diseases (IBDs); however, their use has been associated with the development of malignant lymphoma. The purpose of this Dutch nationwide study was to estimate the relative risk of malignant lymphoma in IBD patients. METHODS: IBD patients who developed a lymphoma between 1997 and 2004 were identified using the Dutch National Database of PALGA. Data from confirmed cases were collected from individual hospitals, including data on Epstein-Barr virus (EBV). The age-adjusted 8-year incidence of malignant lymphoma in the Netherlands was retrieved from the Central Bureau of Statistics. RESULTS: Forty-two hospitals were visited and 285 matches evaluated in the total cohort of 17,834 IBD patients. Forty-four lymphomas were observed, resulting in a relative risk of 1.27 (95% confidence interval [CI]: 0.92-1.68). Only 19 of 44 patients (43%) were exposed to azathioprine/6-mercaptopurine (AZA/6-MP). Remarkably, 92% of patients (11/12) with EBV-positive lymphoma used AZA/6-MP, in contrast to only 19% patients (4/21) with EBV-negative lymphoma, suggesting a strong relation between EBV-positive lymphoma and thiopurine use. CONCLUSIONS: This nationwide study does not suggest a significant overall increased risk for lymphoma in IBD patients. A distinct correlation between EBV-positive lymphoma and AZA/6-MP use was observed.

Electronic reminders for pathologists promote recognition of patients at risk for Lynch syndrome: cluster-randomised controlled trial.

We investigated success factors for the introduction of a guideline on recognition of Lynch syndrome in patients recently diagnosed with colorectal cancer (CRC) below age 50 or a second CRC below age 70. Pathologists were asked to start microsatellite instability (MSI) testing and report to surgeons with the advice to consider genetic counselling when MSI test or family history was positive. A multicentre cluster-randomised controlled trial (ClinicalTrials.gov, number NCT00141466) was performed in 12 pathology laboratories (clusters), serving 29 community hospitals. All received an introduction to the new guideline. In the intervention group, surgeons received education and tumour test result reminders; pathologists were provided with inclusion criteria cards, an electronic patient inclusion reminder system and feedback on inclusion. Two hundred sixty-six CRC patients were eligible for recognition as at risk for Lynch syndrome. The actual recognition was 18% more successful in the intervention as compared to the control arm (77% (120 of 156) compared to 59% (65 of 110)), with an adjusted odds ratio (OR) = 2.8 (95% confidence interval (CI) 1.1-7.0). The electronic reminder system for pathologists was most strongly associated with recognition of high-risk patients, OR = 4.2 (95% CI 1.7-10.1). An electronic reminder system for pathologists appeared effective for adherence to a new complex guideline and will enhance the recognition of Lynch syndrome.

Estrogens, oral contraceptives and hormonal replacement therapy increase the incidence of cutaneous melanoma: a population-based case-control study.

BACKGROUND: Multiple studies showed conflicting results on the association between oral contraceptive (OC) use and the development of cutaneous melanoma (CM). We investigated the association between estrogen use and CM incidence. PATIENTS AND METHODS: Data from PHARMO Pharmacy database and PALGA, the pathology database in The Netherlands, were linked. Women, >or=18 years, with a pathology report of a primary CM from 1 January 1991 to 14 December 2004 and >or=3 years of follow-up before CM diagnosis were eligible cases. Controls were matched for age and geographic region. Multivariate logistic regression was used to calculate adjusted odds ratio (OR) and 95% confidence interval (CI) for the association between CM incidence and estrogen use, OCs and hormonal replacement therapy (HRT), separately. RESULTS: In total, 778 cases and 4072 controls were included. CM risk was significantly associated with estrogen use (>or=0.5 year; adjusted OR = 1.42, 95% CI 1.19-1.69). This effect was cumulative dose dependent (P trend < 0.001). CM risk was also significantly associated with the use of HRT (>or=0.5 year: OR = 2.08; 95% CI 1.37-3.14) and OC (>or=0.5 year: OR = 1.28; 95% CI 1.06-1.54). CONCLUSION: Our study suggests a cumulative dose-dependent increased risk of CM with the use of estrogens.

Gastric MALT lymphoma: epidemiology and high adenocarcinoma risk in a nation-wide study.

BACKGROUND: Gastric marginal zone non-Hodgkin lymphomas MALT type (gMALT) and gastric adenocarcinomas (GC) are long-term complications of chronic Helicobacter pylori gastritis, however, the incidence of gMALT and the GC risk in these patients is unclear. OBJECTIVE: To evaluate epidemiological time trends of gMALT in the Netherlands and to estimate GC risk. METHODS: Patients with a first diagnosis of gMALT between 1991 and 2006 were identified in the Dutch nation-wide histopathology registry (PALGA). Age-standardised incidence rates were calculated. The incidences of GC in patients with gMALT and in the Dutch population were compared. Relative risks were calculated by a Poisson Model. RESULTS: In total, 1419 patients were newly diagnosed with gMALT, compatible with an incidence of 0.41/100,000/year. GC was diagnosed in 34 (2.4%) patients of the cohort. Patients with gMALT had a sixfold increased risk for GC in comparison with the general population (p<0.001). This risk was 16.6 times higher in gMALT patients aged between 45 and 59 years than in the Dutch population (p<0.001). CONCLUSIONS: GC risk in patients with gMALT is six times higher than in the Dutch population and warrants accurate re-evaluation after diagnosis and treatment for gMALT.

Is statin use associated with a reduced incidence, a reduced Breslow thickness or delayed metastasis of melanoma of the skin?

BACKGROUND: Statins show anticancer activity in melanoma cells. We investigated the association between statins and incidence and Breslow thickness of cutaneous melanoma (CM). METHODS: Data were used from PHARMO, a pharmacy database, and PALGA, a pathological database, in the Netherlands. Cases had a primary CM diagnosis between January 1st 1991 and December 14th 2004, were 18 years and had 3 years of follow up in PHARMO before CM diagnosis. Controls were matched for gender, date of birth and geographic region. Analyses were adjusted for age, gender, year of diagnosis, number of medical diagnoses and the use of NSAIDs and oestrogens. FINDINGS: Finally, 1318 cases and 6786 controls were selected. CM risk was not associated with statin use (> or = 0.5 years) (adjusted odds ratio (OR)=0.98, 95% confidence interval (CI)=0.78-1.2). However, statin use was associated with a reduced Breslow thickness (-19%, 95% CI=-33, -2.3, p=0.03). CONCLUSION: Our study suggests protective effects of statins on melanoma progression.

Epidemiological trends of pre-malignant gastric lesions: a long-term nationwide study in the Netherlands.

BACKGROUND: The pre-malignant gastric lesions atrophic gastritis (AG), intestinal metaplasia (IM) and dysplasia (DYS) have long been identified as principal risk factors for gastric cancer. OBJECTIVE: To evaluate epidemiological time trends of pre-malignant gastric lesions in the Netherlands. METHODS: Patients with a first diagnosis of AG, IM or DYS between 1991 and 2005 were identified in the Dutch nationwide histopathology registry. The number of new diagnoses per year were evaluated relative to the total number of patients with a first gastric biopsy. Time trends were evaluated with age-period-cohort models using logistic regression analysis. RESULTS: In total, 23 278 patients were newly diagnosed with AG, 65 937 patients with IM, and 8517 patients with DYS. The incidence of AG declined similarly in men and women with 8.2% per year [95% CI 7.9% to 8.6%], and DYS with 8.1% per year [95% CI 7.5% to 8.6%]. The proportional number of new IM cases declined with 2.9% per year [95% CI 2.7% to 3.1%] in men and 2.4% [95% CI 2.2% to 2.6%] in women. With age-period-cohort models a cohort phenomenon was demonstrated for all categories of pre-malignant gastric lesions in men and in women with IM and DYS. Period phenomena with a larger decline in number of diagnoses after 1996 were also demonstrated for AG and IM. CONCLUSIONS: The incidence of pre-malignant gastric lesions is declining. Period and cohort phenomena were demonstrated for diagnoses of AG and IM. These findings imply that a further decrease of at least 24% in the incidence of gastric cancer in the coming decade may be anticipated in Western countries without specific intervention.

Pathology databanking and biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data network and archive.

Since 1991, a nationwide histopathology and cytopathology network and archive is in operation in The Netherlands under the name PALGA, encompassing all sixty-four pathology laboratories in The Netherlands. The overall system comprises decentralized systems at the participating laboratories, a central databank, and a dedicated communication and information exchange tool. Excerpts of all histopathology and cytopathology reports are generated automatically at the participating laboratories and transferred to the central databank. Both the decentralized systems and the central system perform checks on the quality and completeness of excerpts. Currently, about 42 million records on almost 10 million patients are stored in the central databank. Each excerpt contains patient identifiers, including demographic data and the so-called PALGA diagnosis. The latter is structured along five classification axes: topography, morphology, function, procedure, and diseases. All data transfer and communication occurs electronically with encryption of patient and laboratory identifiers. All excerpts are continuously available to all participating pathology laboratories, thus contributing to the quality of daily patient care. In addition, external parties may obtain permission to use data from the PALGA system, either on an ongoing basis or on the basis of a specific permission. Annually, 40 to 60 applications for permission to use PALGA data are submitted. Among external users are the Dutch cancer registry, population-based screening programs for cancer of the uterine cervix and breast cancer in The Netherlands, and individual investigators addressing a range of research questions. Many scientific papers and theses incorporating PALGA data have been published already. In conclusion, the PALGA system is a unique system that requires a minimal effort on the part of the participating laboratories, while providing them a powerful tool in their daily practices.

The association between antihypertensive drugs and glioma.

We pursued an association between hypertension and gliomas by investigating whether antihypertensive drugs (AHD) are associated with an increased glioma risk by a population-based nested case-control study using the PHARMO database; this links dispensing records of prescription drugs to hospital discharge data on an individual basis. Pathological data were derived from the Dutch nationwide registry of histo- and cytopathology. A total of 306 glioma cases incident between 1997 and 2003 were matched to 1108 controls for year of birth, sex, geographical region and duration of follow-up. Exposure was defined as cumulative duration of AHD use and, in an alternative analysis, as cumulative dose. We estimated the magnitude of the association with conditional logistic regression analysis. Cumulative use of any AHD for more than 6 months was associated with an increased risk of glioma (OR 1.45; 95% CI 1.03-2.04). After stratification for different groups of AHD, no significantly increased risk of glioma was found for any class of AHD. After excluding a latency period of 3 years before the date of diagnosis, no association was found. In conclusion, the use of AHD seems to be associated with an increased risk of glioma, but this is probably not causal.

[Rapid tracing of new patients with cancer through the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA) in order to freeze tumour material for molecular-epidemiological research]. / Snelle signalering van nieuwe patiënten met kanker via het Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief (PALGA) zodat tumormateriaal kan worden ingevroren voor moleculair-epidemiologisch onderzoek.

OBJECTIVE: To examine the viability of tracing new patients with a malignancy preoperatively through the Nationwide Network And Registry Of Histo- and Cytopathology in the Netherlands (PALGA) in order to obtain fresh-frozen tumour tissue for molecular-epidemiological research. DESIGN: Prospective. METHOD: Gene expression analysis using the microarray technique has become an important tool in cancer research. To use this technique, however, it is necessary to have fresh-frozen tumour tissue. This study examines if a weekly search in the PALGA registration makes it possible to trace patients before they undergo tumour surgery and to ask the treating physician to reserve some tumour material to be frozen. In this case it was for the benefit of the 'tamoxifen-associated malignancies: aspects of risk' (TAMARISK)-study in which the clinical-pathological and molecular characteristics of malignancies of the uterine corpus following the use of tamoxifen were examined. Results. From July 2003 to October 2004 133 patients eligible for inclusion in the TAMARISK study were indicated by PALGA. Ultimately freshfrozen tissue from a uterine tumour was obtained for 83 of the 133 patients. For the majority of the patients that could not be included the information came too late or there was no certain histopathological diagnosis prior to the hysterectomy. CONCLUSION: The system developed through PALGA turned out to be very effective in practice and can also be of great value to other clinical epidemiological studies that involve molecular analyses of patients with relatively rare diseases.

[The epidemiology of tumors of the testes in the Netherlands: accurate rendering by the Registry of Histopathology and Cytopathology (PALGA)]. / Epidemiologie van testistumoren in Nederland: accurate weergave in de PALGA-registratie.

OBJECTIVE: To investigate recent trends in the incidence of testicular cancer and to describe epidemiological characteristics of various subtypes of testicular cancer. DESIGN: Descriptive. METHOD: Using the nationwide registry of pathology reports (PALGA), the incidence of all newly-diagnosed cases of testicular cancer between the years 1991 and 2002 was analyzed according to age and subtype. To test the accuracy of the PALGA figures, a comparison was made with incidence figures (1991-1998) produced by the Netherlands Cancer Registry. RESULTS: 5856 cases of testicular cancer were diagnosed. The age-adjusted incidence increased from 4.8 to 6.6 per 100,000. The incidence of non-seminoma increased to a larger extent than that of seminoma. The incidence of malignant lymphoma of testicular origin did not increase, but it remained the most frequent testicular tumour beyond the age of 65. Non-seminoma was the most common tumour below the age of 30, while seminoma was the most commonly found tumour between the ages of 30 and 65. When PALGA began recording statistics, the incidence figures showed a difference of up to 10% with the figures produced by the cancer registry, but this has decreased to 1-2% in more recent years. CONCLUSION: The incidence of testicular cancer increased from the 1990s up to 2002. The incidence figures of histopathologically confirmed cases of cancer in the PALGA registry were timely and accurate.

The incidence of pediatric inflammatory bowel disease in the Netherlands: 1999-2001.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) seems to be rising. Incidence studies could provide more insight into geographical differences and thereby lead to the identification of etiological factors. The aim of this study was to prospectively assess the incidence of pediatric IBD in the Netherlands from 1999 to 2001, using both an active physician case-reporting registry and a nationwide pathology database. METHODS: All pediatricians in the Netherlands were sent monthly identification cards to be returned if they had diagnosed a new case of IBD in a pediatric patient. Follow-up questionnaires were sent to physicians reporting new cases of IBD. The pathology database contains reports from all cytologic and histologic diagnoses made in the Netherlands. Two independent raters searched the database for new IBD cases. Cases identified from the pathology database were labeled as "probable IBD" and "possible IBD." Cases were cross-checked across databases on the basis of gender, date of birth, date of biopsy, and place of residence. Age-specific incidence rates were calculated for the Dutch population for the year 2000. RESULTS: Five hundred forty-six probable cases of IBD were identified; 217 cases were labeled as possible. The incidence rate was 5.2 new cases per 100000 children (<18 years) per year. An increase in incidence with age was observed. Only 24% of the cases were ascertained through the clinical registry. CONCLUSION: The incidence of IBD cases in the Netherlands is comparable with that reported in other European countries. Epidemiological studies using case reporting by physicians may be underestimates of true incidence rates.

Soft tissue sarcoma: the predominant primary malignancy in the retroperitoneum.

Purpose. In the clinical work-up of a retroperitoneal mass, the diagnosis of soft tissue sarcoma is often not considered. Incidence rates of various malignant and benign retroperitoneal tumours were studied to determine the incidence of soft tissue sarcoma in comparison with other neoplasms in the retroperitoneal space.Method. Nation-wide data on retroperitoneal tumours, collected prospectively over a 5-year period (1 January 1989- 1 January 1994), were supplied by the Netherlands Cancer Registry and The Dutch Network and National Database for Pathology.Results. Seven hundred and six patients with a primary retroperitoneal neoplasm were identified; 566 patients had a malignant tumour (80%). A soft tissue sarcoma (STS) was the most frequently diagnosed malignant tumour (n = 192), The agestandardised incidence of retroperitoneal STS was 2.5 per million person-years. The male/female ratio for STS was 0.73. In females, STS comprised 41%of all malignant retroperitoneal tumours, carcinoma of unknown primary tumour site (CUP) comprised 31%, and malignant lymphomas (ML) comprised 22%, whereas in males these values were 28% (STS), 30% (CUP), and 32% (ML), respectively.Discussion. Soft tissue sarcomas, albeit rare, are relatively common primary tumours in the retroperitoneum, especially in women.

Endoscopic and histopathologic features of Degos' disease.

The case is reported of a 69-year-old female with atrophic papules on the skin who developed multiple spontaneous intestinal perforations of which she eventually died. The skin lesions in combination with lesions in the gastrointestinal tract are typical for Degos' disease or malignant atrophic papulosis. The characteristic histopathological and endoscopic features of this rare disease are reported. This case demonstrates the importance of routinely performing endoscopy in Degos' disease to detect silent perforation, even in patients without gastrointestinal complaints.

[The value of selective screening for the diagnosis of hypercholesterolemia]. / De waarde van selectieve screening voor het opsporen van hypercholesterolemie.

The aim of this study was to evaluate the decision of the Dutch Cholesterol Consensus Meeting in 1987 to screen selected groups of persons for the identification of individuals with hypercholesterolemia. During 8 weeks serum cholesterol levels were measured in all 305 newly referred patients to the outpatient clinic of general internal medicine of the University Hospital Nijmegen. Information on age, sex, smoking habits and the selection variables was obtained. Of the patients 4 were referred because of hypercholesterolemia, 11 were excluded because of disease which could influence cholesterol levels. The results of 270 patients were available for evaluation. For statistical analysis the t test and linear and logistic regression analysis were used. Of the patients 87 individuals (32%) would have been candidates for selective screening; in 20 (23%) serum cholesterol levels were increased (greater than or equal to 6.5 mmol/l). Selective screening would have identified 20 of 42 hypercholesterolemic individuals (48%). Age showed a significant correlation with serum cholesterol levels (p less than 0.001); after correction for age, selective screening did not identify more hypercholesterolemic patients (p greater than 0.4). The serum cholesterol level appeared to be higher in the group meeting the selection criteria (p = 0.04). Among these criteria only hypertension was significantly correlated with serum cholesterol levels (p = 0.02) but sensitivity and predictive value for hypercholesterolemia were low. To identify a larger proportion of hypercholesterolemic individuals selective screening does not appear useful. If selective screening is chosen however, it should focus on hypertensive patients, also because the identification of patients with several risk factors is important from a prevention point of view.