Henrik Hjalgrim

Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium

Some autoimmune disorders are increasingly recognized as risk factors for non-Hodgkin lymphoma (NHL) overall, but large-scale systematic assessments of risk of NHL subtypes are lacking. We performed a pooled analysis of self-reported autoimmune conditions and risk of NHL and subtypes, including 29 423 participants in 12 case-control studies. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) in a joint fixed-effects model. Sjögren syndrome was associated with a 6.5-fold increased risk of NHL, a 1000-fold increased risk of parotid gland marginal zone lymphoma (OR = 996; 95% CI, 216-4596), and with diffuse large B-cell and follicular lymphomas. Systemic lupus erythematosus was associated with a 2.7-fold increased risk of NHL and with diffuse large B-cell and marginal zone lymphomas. Hemolytic anemia was associated with diffuse large B-cell NHL. T-cell NHL risk was increased for patients with celiac disease and psoriasis. Results for rheumatoid arthritis were heterogeneous between studies. Inflammatory bowel disorders, type 1 diabetes, sarcoidosis, pernicious anemia, and multiple sclerosis were not associated with risk of NHL or subtypes. Thus, specific autoimmune disorders are associated with NHL risk beyond the development of rare NHL subtypes in affected organs. The pattern of associations with NHL subtypes may harbor clues to lymphomagenesis.

Changing patterns of tonsillar squamous cell carcinoma in the United States

AbstractObjective: Tonsillar squamous cell carcinoma (SCC) may differ etiologically from other oral cancers. The aim of this study was to provide a detailed description of the incidence patterns of tonsillar SCC in the United States. Methods: Population-based incidence data from the Connecticut Tumor Registry (period 1945–1994) and from the SEER program (period 1973–1995) were used to calculate age-standardized (US 1970) and age-specific incidence rates and confidence intervals (CIs). Linear regression was used to evaluate trends. Results: The incidence of tonsillar SCC increased fourfold among white women in Connecticut during 1945–1994 but remained rather constant in white men. During 1973–1995, incidence rates per million person-years were considerably higher in blacks (31.6; 95% CI: 29.0–34.4 in men, and 9.6; 95% CI: 8.3–10.9 in women) than whites (14.8; 95% CI: 14.3–15.3 in men, and 6.1; 95% CI: 5.8–6.4 in women). Men, but not women, who were younger than 60 years experienced significant annual increases in tonsillar SCC incidence during 1973–1995 (2.7% in blacks and 1.9% in whites). No similar increases occurred for oral SCC at non-tonsillar sites. Conclusion: Incidence rates of tonsillar SCC vary considerably by sex, race and time in a way that cannot be explained by changes in tonsillectomy practices alone. Changes in environmental risk factors, including changes in smoking patterns and an increase in oral human papillomavirus infections, may have contributed.

Radioiodine treatment of multinodular non-toxic goitre

OBJECTIVE--To investigate the long term effect of radioactive iodine on thyroid function and size in patients with non-toxic multinodular goitre. DESIGN--Consecutive patients with multinodular non-toxic goitre selected for radioactive iodine treatment and followed for a minimum of 12 months (median 48 months) after an intended dose of 3.7 MBq/g thyroid tissue corrected to a 100% uptake of iodine-131 in 24 hours. PATIENTS--69 patients with a growing multinodular non-toxic goitre causing local compression symptoms or cosmetic inconveniences. The treatment was chosen because of a high operative risk, previous thyroidectomy, or refusal to be operated on. MAIN OUTCOME MEASUREMENTS--Standard thyroid function variables and ultrasonically determined thyroid volume before treatment as well as 1, 2, 3, 6, and 12 months after treatment and then once a year. RESULTS--56 patients were treated with a single dose of 131I, 12 with two doses, and one with four doses. In 45 patients treated with one dose and remaining euthyroid the median thyroid volume was reduced from 73 (interquartile range 50-106) ml to 29 (23-48) ml at 24 months in the 39 patients in whom this was measured during follow up. The median reduction was 40 (22-48) ml (60% reduction, p < 0.0001), half of which occurred within three months. Patients treated with two doses as well as those developing hypothyroidism and hyperthyroidism had a significant reduction in thyroid volume. Eleven patients developed hypothyroidism (cumulative five year risk 22%, 95% confidence interval 4.8% to 38.4%). Side effects were few: three cases of hyperthyroidism and two cases of radiation thyroiditis. Only one patient was dissatisfied with the result; she was referred for operation six months after treatment. CONCLUSIONS--A substantial reduction in thyroid volume accompanied by a low incidence of hypothyroidism and few side effects makes the use of radioactive iodine an attractive alternative to surgery in selected cases of non-toxic multinodular goitre.

A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 ( REL ), 8q24.21 and 10p14 ( GATA3 )

To identify susceptibility loci for classical Hodgkins lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10−8), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10−13) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10−8). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10−50). These data provide new insight into the pathogenesis of cHL.

Duration of red blood cell storage and survival of transfused patients (CME)

BACKGROUND: Disquieting reports of increased complication and death rates after transfusions of red blood cells (RBCs) stored for more than 14 days prompted us to perform an observational retrospective cohort study of mortality in relation to storage time.

Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32

To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 × 10−29 and rs7755224, combined P = 2.00 × 10−19; r2 = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 × 10−9).

Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia-A comparative study of four differently designed, high resolution microarray platforms.

Screening for gene copy‐number alterations (CNAs) has improved by applying genome‐wide microarrays, where SNP arrays also allow analysis of loss of heterozygozity (LOH). We here analyzed 10 chronic lymphocytic leukemia (CLL) samples using four different high‐resolution platforms: BAC arrays (32K), oligonucleotide arrays (185K, Agilent), and two SNP arrays (250K, Affymetrix and 317K, Illumina). Cross‐platform comparison revealed 29 concordantly detected CNAs, including known recurrent alterations, which confirmed that all platforms are powerful tools when screening for large aberrations. However, detection of 32 additional regions present in 2–3 platforms illustrated a discrepancy in detection of small CNAs, which often involved reported copy‐number variations. LOH analysis using dChip revealed concordance of mainly large regions, but showed numerous, small nonoverlapping regions and LOH escaping detection. Evaluation of baseline variation and copy‐number ratio response showed the best performance for the Agilent platform and confirmed the robustness of BAC arrays. Accordingly, these platforms demonstrated a higher degree of platform‐specific CNAs. The SNP arrays displayed higher technical variation, although this was compensated by high density of elements. Affymetrix detected a higher degree of CNAs compared to Illumina, while the latter showed a lower noise level and higher detection rate in the LOH analysis. Large‐scale studies of genomic aberrations are now feasible, but new tools for LOH analysis are requested.

Infectious aetiology of Hodgkin and non‐Hodgkin lymphomas: a review of the epidemiological evidence

Lymphomas constitute a heterogeneous group of malignant disorders with different clinical behaviours, pathological features and epidemiological characteristics. For some lymphoma subtypes, epidemiological evidence has long pointed to infectious aetiologies. A subset of Hodgkin lymphoma is strongly linked to Epstein–Barr virus (EBV) infection. In addition, infectious agents can directly infect and transform lymphocytes (e.g. EBV, human herpesvirus 8), induce immunosuppression (human immunodeficiency virus), or cause chronic immune stimulation (hepatitis C virus, Helicobacter pylori), all of which may play a role in the development of various non‐Hodgkin lymphoma subtypes. Here, we review the epidemiological evidence linking infections with malignant lymphoma.

Infectious Mononucleosis, Childhood Social Environment, and Risk of Hodgkin Lymphoma

Infectious mononucleosis (IM) has been associated with an increased risk of Hodgkin lymphoma (HL), implicating a role for Epstein-Barr virus (EBV) in HL development. Although essential to the understanding of the association, it has remained uncertain if the relationship is restricted to the EBV-positive subset of HL. We collected information on mononucleosis history and childhood socioenvironmental characteristics in a population-based study of 586 patients with classic HL and 3,187 controls in Denmark and Sweden. Tumor EBV status was established for 499 cases by immunohistochemistry and in situ hybridization techniques. Odds ratios (OR) for the relationship between HL risk and mononucleosis and other risk factors were estimated by logistic regression for HL in younger (18-44 years) and older (45-74 years) adults, overall and by tumor EBV status. All analyses were adjusted for country-specific measures of maternal education and mononucleosis history. IM was associated with an increased risk of EBV-positive [OR, 3.23; 95% confidence interval (95% CI) 1.89-5.55] but not EBV-negative HL (OR, 1.35; 95% CI, 0.86-2.14). Risk of EBV-positive HL varied with time since IM and was particularly pronounced in younger adults (OR, 3.96; 95% CI, 2.19-7.18). IM-associated lymphomas occurred with a median of 2.9 years (1.8-4.9 years) after infection. The EBV specificity of the IM association was corroborated by a case-case comparison of IM history between younger adult EBV-positive and EBV-negative HL patients (OR(IM EBV+ HL versus EBV- HL), 2.68; 95% CI, 1.40-5.12). We found further evidence that IM is associated only with EBV-positive HL. This finding is compatible with the notion that EBV-positive and EBV-negative HL may have different etiologies.

Risk for subsequent cancer after diagnosis of basal-cell carcinoma : A population-based, epidemiologic study

The high incidence of nonmelanoma skin cancer in white populations has prompted few reports on the subsequent risk for noncutaneous cancer in patients who have had this condition [1-6]. We recently examined the pattern of new cases of primary cancer in a cohort of 5100 persons in whom squamous-cell skin cancer was diagnosed in Denmark from 1978 to 1989. In addition to confirming that patients with squamous-cell skin cancer have a well-established excess risk for new nonmelanoma skin cancer, we documented a statistically significant excess risk of 30% for development of subsequent cancer other than nonmelanoma skin cancer in these patients. This increase in risk was due to increased risks for cancer of the buccal cavity or respiratory organs, malignant melanoma, and lymphoma and leukemia [6]. However, because of the paucity of population-based cancer registries that include nonmelanoma skin cancer in their files, we know of no large-scale study that has focused on the subsequent risk for cancer in patients with basal-cell carcinoma of the skin. The Danish Cancer Registry, which covers the entire Danish population (approximately 5.1 million persons in 1991), has kept records of all notifications of nonmelanoma skin cancer and other types of cancer for more than half a century. Since 1978, when the International Classification of Diseases for Oncology (ICD-O) was introduced as the coding system of the Cancer Registry [7], it has been possible to distinguish between basal-cell carcinoma and the other, less-common types of nonmelanoma skin cancer. By using population-based data available in the Danish Cancer Registry, we aim to provide valid and statistically stable estimates of the subsequent risk for cancer in patients who receive a diagnosis of basal-cell carcinoma of the skin. Because of the recently proposed hypothesis that ultraviolet light is involved in the steep increase in incidence of non-Hodgkin lymphoma [4, 8], we devoted special attention to the possible association between basal-cell carcinoma (a disease known to be caused by exposure to ultraviolet light [9]) and the risk for subsequent non-Hodgkin lymphoma. Methods The procedure for reporting skin cancer to the Danish Cancer Registry is the same as the procedure for reporting other types of cancer. Physicians in hospitals and outpatient settings are required to report all incidents of cancer to the registry. To ensure a high degree of completeness of data in the registry, computerized identity-secure links with other data sources (established by means of a 10-digit personal identity number unique to every Danish citizen) are done at regular intervals to fill in missing data. An annual link is done with the Danish Hospital Discharge Register to ensure that any diagnoses of cancer that have been made in hospitalized patients and that have not been reported to the cancer registry are subsequently included in the cancer files. Similarly, an annual link with the computerized death file of the National Board of Health ensures that the small proportion of cases of cancer known only from death certificates is included [7]. By these means, and because of the thorough scrutiny and centralized coding of all notifications, the accuracy of the Cancer Registry data can be considered to be high. For most types of cancer, the data are believed to be almost 100% complete [10]. We considered a case of cancer to be basal-cell carcinoma if topography, according to the ICD-O [11], was between 1731 and 1739 (skin, excluding lip and external genitalia) and histology was between 80903 and 80933 (variants of basal-cell carcinoma). The files of 37 756 patients with a histologically verified first diagnosis of basal-cell carcinoma were retrieved from the Cancer Registry for 1978 to 1991. The anatomical distribution is shown in Table 1. Some patients had two or more histologically identical basal-cell carcinomas diagnosed either simultaneously or at different times; the interval between these diagnoses differed for each patient. In the registry, such multiple identical cases of skin cancer are coded as only one basal-cell carcinoma (topography code 1738), and patients who have more than one type of cancer retain the date of the first type as the date of diagnosis. In one patient, two basal-cell carcinomas with slightly different histologic characteristics were diagnosed. Such cancers are coded individually, and this patients date of diagnosis was the date of the first skin cancer. Eighty-two patients (0.2%) were excluded from the analysis: Twenty-eight (15 men and 13 women) were not at risk for subsequent cancer because their skin cancer was diagnosed at autopsy or because they died before the end of the month in which basal-cell carcinoma was diagnosed; 9 (3 men and 6 women) received their diagnosis after they were 100 years of age; and 45 (25 men and 20 women) received a diagnosis of basal-cell carcinoma after they had emigrated from Denmark. Table 1. Distribution of Basal-Cell Carcinoma of the Skin in 37 756 Patients in Denmark, 1978-1991 The remaining 37 674 patients (median age, 68 years [range, 8 to 99 years]) were followed for the occurrence of subsequent cancer. We did stratified analyses of the risk for cancer to evaluate the possible importance of various characteristics of the patients, including sex, age (patients were stratified into those <60 and those 60 years of age at the time of diagnosis of basal-cell carcinoma), the anatomical site of the initial skin cancer, and the number of basal-cell carcinomas (patients were stratified into those with only one basal-cell carcinoma and those with two or more). In each analysis, patients were followed from the month after the date of diagnosis of basal-cell carcinoma to 100 years of age, death, emigration, or 31 December 1991, whichever came first. Information about the end of follow-up was obtained through a link with the Civil Registration System, which keeps a continuously updated file on demographic variables (including death and emigration) for all citizens in Denmark. The sex-, age-, and period-specific patient-years of observation in the cohort (in 5-year blocks) were multiplied by the corresponding sex-, age-, and period-specific national incidence rates to determine the expected number of cases of cancer in the cohort. Ratios of actual to expected number of cases of cancer (standardized incidence ratios [SIRs]) measured the relative risk. Assuming a Poisson distribution of the observed cancer events, we calculated 95% CIs for the SIRs using Byar limits [12]. Likelihood ratio tests were done to determine whether SIRs among young and old patients were statistically different at various cancer sites. Results We followed 18 925 men for 94 162 patient-years (median duration of follow-up, 4.2 years) and 18 749 women for 96 783 patient-years (median duration of follow-up, 4.4 years). After a diagnosis of basal-cell carcinoma, 2234 new cases of cancer were diagnosed in men and 1429 new cases of cancer were diagnosed in women within a maximum of 14 years (Table 2). Compared with the incidence of cancer in the general Danish population, this corresponded to SIRs of 1.18 (95% CI, 1.13 to 1.23) in men and 1.05 (CI, 1.00 to 1.11) in women. When subsequent cutaneous cancer, such as malignant melanoma (n = 134) and other skin cancer (mainly squamous-cell skin cancer, n = 411), were excluded from the analysis, the risk for subsequent cancer in patients with basal-cell carcinoma was almost unchanged (SIR, 1.19 [CI, 1.13 to 1.24] in men and 1.09 [CI, 1.03 to 1.16] in women). Certain types of cancer occurred in statistically significant excess, including cancer of the lip (SIR, 2.07; n = 39), salivary glands (SIR, 2.45; n = 12), larynx (SIR, 1.41; n = 41), lung (SIR, 1.40; n = 589), breast (SIR, 1.13; n = 283), and kidney (SIR, 1.30; n = 114) and malignant melanoma (SIR, 2.64; n = 134), non-Hodgkin lymphoma (SIR, 1.36; n = 87), and leukemia (SIR, 1.34; n = 104) (Table 2). Table 2. New Cancer in 37 674 Patients with Basal-Cell Carcinoma of the Skin in Denmark, 1978-1991* To evaluate the possible effect of cancer and treatment of cancer that may have occurred before basal-cell carcinoma of the skin, we did a supplementary analysis of 34 146 patients in whom basal-cell carcinoma was their first cancer. The overall risk for all types of subsequent cancer in these patients (SIR, 1.18 for men [observed incidence, 2052] and 1.03 for women [observed incidence, 1264]) did not differ from the pattern seen for the entire cohort. The similarity pertained to all sites at increased risk, including cancer of the lip (SIR, 2.02; n = 35), salivary glands (SIR, 2.46; n = 11), larynx (SIR, 1.49; n = 40), lung (SIR, 1.37; n = 530), breast (SIR, 1.13; n = 254), and kidney (SIR, 1.37; n = 110) and malignant melanoma (SIR, 2.70; n = 126), non-Hodgkin lymphoma (SIR, 1.25; n = 73), and leukemia (SIR, 1.30; n = 92). Consequently, because previous cancer and its treatment had no measurable effect on the risk for cancer after the basal-cell carcinoma, all subsequent analyses were done for the entire cohort of 37 674 patients, regardless of the presence or absence of cancer before the basal-cell carcinoma. The cohort was split into two groups according to the age at which the patients first received a diagnosis of basal-cell carcinoma. Patients who were younger than 60 years of age at the time of diagnosis of basal-cell carcinoma had a significantly higher relative risk (P < 0.01) for subsequent cancer (SIR, 1.26 [CI, 1.16 to 1.37]; n = 583) than did patients 60 years of age or older (SIR, 1.11 [CI, 1.07 to 1.14]; n = 3080) (Table 3). The moderate but significant excess of breast cancer was entirely caused by an elevated risk in younger patients. Of those who were younger than 60 years of age at the diagnosis of basal-cell carcinoma, 84 patients (of whom 1 was male) developed breast cancer where approximately 61 cases of breast cancer were expected (SIR, 1