Increasing Incidence of Enteropathy-associated T Cell Lymphoma in the United States (1973-2008)

Abstract

Introduction

Enteropathy-associated T cell lymphoma (EATL) is a rare lymphoma subtype that is strongly associated with celiac disease (CD), an autoimmune disease triggered by the ingestion of gluten. Since CD rates are increasing in the U.S., we sought to determine whether the incidence rates of EATL are increasing as well.

Method

We identified primary, pathologically confirmed lymphoma cases from the SEER database registries from 1973 to 2008. To ensure capture of all cases of EATL, we included the following lymphoma subtypes, limited to the small bowel: non-Hodgkin lymphoma (NOS) T-cell, Peripheral T-cell lymphoma (NOS), and enteropathy type T-cell lymphoma, and calculated their age and sex-adjusted incidence rates over time. Survival was estimated using Kaplan-Meier curves.

Results

We identified 161 small bowel lymphomas diagnosed between 1973 and 2008. The overall age and sex-adjusted annual incidence for all bowel lymphomas was 0.016 per 100,000, which increased over the study period from 0.006 to 0.024 per 100,000. These tumors were most common in males (age-adjusted incidence rate= 0.021 per 100,000) with the highest incidence rate in Hispanics (age-adjusted incidence rate =0.033 per 100,000). The median overall survival was 7 months. There was no difference in survival by race/ethnicity (p=0.09), or gender (P= 0.06).

Conclusion

Our results indicate a significant increase in the incidence of EATL in the U.S., which could reflect the increasing seroprevalence of CD and better recognition of rare types of T-cell lymphomas. The incidence may continue to rise given the large ratio of undiagnosed-to-diagnosed individuals with CD in the U.S.

Introduction

Celiac disease (CD) is an autoimmune disease affecting genetically susceptible individuals that is triggered by the ingestion of gluten.[1] Based on seroprevalence studies, the incidence of celiac disease has increased markedly in the United States (US) over the last 50 years. [3, 4] In addition, the rate of diagnosis has risen, [2-5] owing in part to the availability of serologic tests and increased physician and patient awareness. Parallel to this is the increasing prevalence of CD in the US, [6, 7] indicating that detection bias cannot fully explain the rise in cases. However, the vast majority of people with celiac disease remain undiagnosed.

CD is associated with a modest increased risk of mortality [8, 9]. Despite an increase in diagnosis and improvement in care, the mortality excess has remained unchanged over the last few decades. This excess is primarily explained by an increase in malignancy [8, 10], notably lymphomas, especially those occurring in the small bowel.

Enteropathy-associated T cell lymphoma (EATL) is a rare lymphoma subtype that is strongly associated with CD and carries a poor prognosis.[11, 12] The term “Enteropathy Associated T cell lymphomas” was first introduced by O’Farrelly in 1986 [13], but it was only in 1991 when the World Health Organization International Classification Project updated the terminology to “Enteropathy type intestinal T-cell lymphoma” that EATL formally became a recognized subtype. [14] Currently, two groups of EATL are recognized: type I, which refers to a large cell lymphoma thought to be exclusively associated with CD [12] and EATL type II, the rarer form, which consists of small to medium-sized cells and presents often with obstruction or perforation of the small bowel. The latter type has no known association with CD.[14] Despite the longstanding recognition of these entities, there has been a paucity of studies investigating the epidemiology of EATL in CD patients.

In two European studies, in which large cohorts of non-Hodgkin lymphoma (NHL) patients were screened serologically for CD and compared with controls, CD was found to be associated with an overall increased risk for developing NHL with a standardized incidence ratio (SIR) of 2.2 (95% confidence interval (CI) 1.2–3.6)[15] and 3.1 (95% CI, 1.3- 7.6). [16] The SIR for small bowel lymphoma was 16.9 (95% CI, 7.4-38.7) and was 19.2 (95% CI, 7.9-46.6) for T-cell lymphoma.[17] The odds of developing EATL was 28 times higher (95%; CI 6-144) in the CD group. [16]

In a nationwide study in the Netherlands, the crude incidence of EATL was 0.1/100,000 with a male predominance.[18] In contrast, the epidemiology of EATL in the United States is unknown. The risk of EATL may be increased in individuals with undiagnosed CD [15, 19], and the diagnosis rates of CD in the United States remain low as compared to European nations.[2]

We aimed to evaluate and describe trends in the incidence and survival of EATL in the United States. We hypothesized that this incidence is increasing, due to the increased prevalence of CD and the large proportion of undiagnosed CD patients.

Methods

Description of SEER Data

In the US, the Surveillance, Epidemiology, and End Results (SEER) database is the National Cancer Institute–supported, national cancer surveillance program that collects cancer statistics from 17 geographic areas representing approximately 26% of the US population.[20] The program collects demographic data, clinical information at diagnosis, first course of treatment, and active follow-up for vital status. These data are updated yearly and are publically available for use in incidence and survival studies. The current study used these data for analysis of patients diagnosed between 1973 and 2008.

Study Population/Case Selection

Our analysis was limited to primary, pathologically confirmed lymphoma cases. EATL did not have a specific or discrete ICD code until 1991, as it had previously been described as “intestinal lymphoma” or “malignant histiocytosis of the intestine”. Therefore, to ensure capture of all cases of EATL, a subtype of T-cell lymphoma, we included the following lymphoma subtypes, limited to the small intestine: Non-Hodgkin lymphoma (NOS) T-cell, Peripheral T-cell lymphoma (NOS), and Enteropathy type T-cell lymphoma. It was reasoned that primary T-cell lymphomas of the small bowel in the western world, and US specifically, appear less likely to be associated with other etiologies. Because the SEER 9,13,17 registries are linked to different population data sets, we computed the age-adjusted incidence by combining the time periods SEER 9 1973-1991, SEER 13 1992-1999, and SEER 17 2000-2008.

Variables

Variables of interest included age at diagnosis, sex, race and ethnicity. Age at diagnosis was divided into six groups: 0–9 years, 10–19 years, 20–29 years, 30–39 years, 40–49 years, 50–59 years , 60–69 years , 70–79 years , 80 years and above. The age-adjusted (2000 US Standard Population) incidence rates were calculated per 100,000 person-years for overall, as well as by sex, race, and age category. Observed survival rates (5-year) and survival case listing files for small bowel lymphomas were obtained by using the SEER*Stat software [20]; only actively followed cases of known age were selected. Poisson regression was used to calculate the statistical difference in incidence between the different groups. The observed survival rate was obtained by the Kaplan-Meier method. Survival curves were generated using SAS version 9.2 (SAS Institute Inc, Cary, NC). Overall survival, from date of diagnosis to date of death in months, was calculated as well as survival stratified by gender, race and age groups. Between-group comparisons were performed using the Log rank test.

Results

Overall Incidence of EATL

There were 161 pathologically confirmed lymphomas of the small intestine diagnosed between 1973 and 2008, which were analyzed. Table 1 shows the demographics and basic characteristics of patients with EATL. The overall age-adjusted annual incidence for all small bowel lymphomas was 0.016 per 100,000. These tumors had a higher incidence in males (age-adjusted incidence rate= 0.021per 100,000) and Hispanics (age-adjusted incidence rate =0.033 per 100,000); even though 69% of the population of EATL cases were white.

Table 1.

Incidence and Survival of enteropathy-associated T cell lymphoma in adults in the SEER Registries, 1973–2008

Variable of interest	No of Cases (%)	Incidence rate per 100,000 PY	P value
Overall	161	0.016	0.001
Age at diagnosis  •20-29  •30-39  •40-49  •50-59  •60-69  •70-79  •≥80	6 (4) 13 (8.2) 20(12.3) 25 (16.4) 40 (25.3) 32 (17.8) 25 (15.1)	0.003 0.006 0.010 0.017 0.039 0.046 0.063	<0.001
Sex  •Male  •Female	100(62) 61(38)	0.021 0.012	0.003
Race  •White  •Black  •Hispanic  •Other	111 (69) 14 (9) 15 (9) 21 (13)	0.015 0.017 0.033 0.011	0.004

Incidence Patterns over Time and Age

The overall age-adjusted incidence of small bowel lymphoma showed a statistically significant increase over time between 1973 and 2008 (p <0.001), from 0.006 per 100,000 to 0.024 per 100,000, respectively (Figure 1), as well as with increasing age (P <0.0001) (Figure 2).

fig 1.

fig 2.

For both males and females, incidence increased significantly with age, but males had a higher incidence than females at all time points. Overall, the incidence was statistically significantly higher in males (p=0.003) (Figure 2) and 58% of all EATL patients were in the over 50 year age group. Female EATL incidence peaked in the 70-79 age group and then declined in the older age groups, whereas in men it did not peak until 80+ years.

Overall survival

The median overall survival was 7 months (Figure 3a). Survival was not significantly different between genders (P= 0.062, Figure 3b), or race/ethnicity groups (P=0.093, Figure 3c). There was a statistically significant difference in survival for the subjects diagnosed in their 40s and 60s compared to subjects in their 80s (P=0.004 and P=0.0003, respectively).

fig 3.

This increasing incidence of EATL was compared to the overall incidence of T cell lymphoma over the same time period (data not shown). There was no significant increase in T cell lymphoma (P=0.1) compared to the increase in EATL incidence (P=0.001) from 1973-2008.

Discussion

Our results indicate a significant increase in the incidence of enteropathy-associated T cell lymphoma (EATL) over time in the United States based on cases in the SEER database. There were more male than female EATL patients. Although the overall incidence was 0.016/100000, in the population over 60 years of age, the incidence was 0.05/100,000, with the highest incidence observed in subjects who were 80 years of age or older (0.06/100,000). These findings are consistent with other studies demonstrating the increasing incidence of EATL in the elderly. [18, 21, 22]

The reasons for the incidence of EATL in the U.S. being much lower than in Europe are unclear. This may reflect differences in the pattern or rate of detection of CD in the US population. The only other population study is the Netherlands-based Nationwide Network and Registry of Histopathology and cytopathology (PALGA) study, which estimated the incidence of EATL in Europe to be 0.1/100,000, with an increasing incidence noted with age and males being affected more commonly than females. [18] This may be due in part to different rates of CD and hence EATL in the US versus the European population.

Patients with celiac disease whose symptoms and villous atrophy do not respond to a gluten free diet are said to have refractory celiac disease (RCD). There are two main groups of RCD, type I and II. [23] A study by Roshan et al. demonstrated that the rates of RCD, both type I and type II, are lower in the US population (<2% of all CD patients) compared to Europe. [23-25] These authors also demonstrated that the incidence of RCD II, which is considered a precursor to, or a more indolent variant of EATL, was proportionally lower in the US population (17%) compared to Europe (28-75%), [25] which may explain why the rate of EATL is also lower in the U.S.

These differences may also in part be due to the different genetic backgrounds of the US populations compared to the more homogenous European genetic pool. It has been reported that RCD II correlates with HLA-DQ2 homozygosity, and interestingly, the HLA-DQ8 allele was found to be more common in CD patients diagnosed at a United States center compared to a European center.[26, 27] It is also possible that other modifier genes are different, as well as environmental factors. The amount or type of gluten consumed before diagnosis, could also contribute to the discrepancy.

There is no established standard first line treatment for EATL patients. They are usually treated with anthracycline-containing chemotherapy, preceded at times by resection of the tumor or surgical debulking, followed by stem cell transplantation. [28] A more promising treatment has been an induction regimen with ifosfamide, etoposide, and epirubicin alternating with intermediate-dose methotrexate, followed by autologous stem cell transplantation. [29] Relapse occurs in approximately 80% of people who respond to initial therapy.[21] Despite these therapies, the outcome of EATL remains very poor with a 5-year mortality of 80–92% from either progressive disease or complications of therapy.[19, 28] The poor overall survival in our analysis is similar to that found in a recent study by the International Peripheral T-Cell lymphoma Project, demonstrating a median overall survival of only 10 months.[22]

This increasing incidence of EATL is in stark contrast to the relatively stable overall incidence of T cell lymphomas in general. We postulate several reasons for this. In the last five years with the advent of immunophenotyping using flow cytometry, there has been an increase in the diagnoses of intestinal lymphomas as EATL more accurately and this might have led to and/or account in part for the increasing incidence in diagnosing this entity. However these techniques also enable diagnosis and lineage assignment for other rare, non CD-associated types of intestinal T cell lymphoma more precisely. To attempt to account for these potential confounders we compared the rate of EATL with the overall rate of intestinal lymphoma in the United States, thus helping us control for new techniques, but despite this there was an actual increase in cases diagnosed as EATL (data not shown). This increase could likely reflect in part the better detection of EATL due to early symptomatology, but also might be attributed to the rise in CD incidence that has been demonstrated in several studies and hence a greater number of patients developing EATL as a complication of longstanding undiagnosed CD.[6, 7]

The gender difference in incidence is striking. Females are more likely to be diagnosed with CD, [2] but males more often have unrecognized CD compared to females.[30] Males also appear to have evidence of more severe CD than females at diagnosis.[31] A possible explanation might be that more males remain undiagnosed, with a greater duration of gluten exposure, and therefore are more likely to present with EATL, and CD is only diagnosed after the lymphoma has developed. The risk of EATL appears to be increased in individuals with undiagnosed CD. [15, 19] Interestingly, the seroprevalence of CD is equal across genders, despite the higher diagnosis rate among females. [32] Women who are diagnosed and treated, would be on a gluten free diet, and therefore would have less inflammation, which may also in turn decrease the rate of lymphomagenesis. Diagnosis of CD is important, since adherence to a gluten-free diet may prevent or reduce the risk of lymphoma development in patients with this disease [33].

There has been a demonstrable rise in the incidence of CD over the last 40 years.[6, 7] These studies have shown a fourfold rise in the prevalence of CD in the US. Figure 4 shows the rise in the seroprevalence of CD depicted from the study of Rubio-Tapia et al, [7] in parallel to the rise in EATL described in our paper. This further supports the theory of an increasing incidence of undiagnosed CD in the general population, leading to an increased duration of intestinal inflammation, and thus malignancy.

fig 4.

The main limitation of this study is the under-reporting and estimation of the incidence, as well as misclassification of other rare lymphomas that may have been included in this analysis (such as rare T-cell and NK-cell lymphoma subtypes), and the inability to differentiate between the two types of EATL currently recognized. It is important to note however that in the Seer registry there is a separate entity for Nasal type and T/NK cell lymphoma.

Although the highest incidence of EATL was in the Hispanic population, it was most common in whites. There have been several studies from South and Central America (Brazil, Argentina, Chile, and Mexico) showing that celiac disease is quite common people from those regions (1-8%). [34-37] A possible explanation might be that more Hispanics remain undiagnosed, and therefore are more likely to present with the EATL. However it is important to note recent publications have described and better characterized intestinal T-cell lymphomas, including those occurring in the Asian and Hispanic populations. [38-40]These studies have indicated that EATL II might be frequent in these populations [38-41]. Moreover, a number of cases with histopathologic presentation similar to EATL type II have been shown to derive from gamma-delta T-cells, again arguing an etiology distinct from CD associated with the pathogenesis of such lymphomas. [18, 41] As histopathology and phenotype data are not available from the SEER database, and EATL type II cases could not be distinguished (from type I cases) in our study, we acknowledge that some of the increase in incidence of intestinal lymphomas observed, especially that in the Hispanic population, could reflect the inadvertent classification of the aforementioned non-CD-associated intestinal T-cell lymphomas as EATL.

We also do not have data regarding the incidence of CD in the SEER population. However, the increased incidence of EATL persisted in our study despite excluding the Hispanic population from analysis and the majority of the cases captured in this study likely reflect EATL type I, and that type II EATL and types of intestinal lymphomas, would make up not more than 10-20% of the total number of cases based on disease distribution in published case series.[22, 28, 29] To minimize misclassification, we limited the cases to the small intestine only.

Although our method of obtaining the cases is novel, it may have limited detection of EATL diagnosed at sites besides the small intestine. An additional concern is that the rise in incidence of EATL observed in our study might represent an overall improvement in the detection of T-cell lymphoma. However when comparing the incidence of T cell lymphoma overall vs. EATL in the same time period, no significant increase in T cell lymphomas (P=0.1) was observed, thus suggesting a true rise in EATL.

In conclusion, we note that the incidence of EATL in the United States is increasing, in parallel to the increasing seroprevalence of CD. This incidence may continue to rise in the future given the large ratio of undiagnosed-to-diagnosed individuals with CD in the United States. Survival, however, remains dismal. In addition to further research on therapeutics for this disease that carries a poor prognosis, efforts should be made to increase the recognition and treatment of CD among symptomatic individuals.