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Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project

Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International... From www.bloodjournal.org by guest on December 4, 2015. For personal use only. LYMPHOID NEOPLASIA Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project 1 2 3 4 5 6 6 Jan Delabie, Harald Holte, Julie M. Vose, Fred Ullrich, Elaine S. Jaffe, Kerry J. Savage, Joseph M. Connors, 7 8 9 10 11 12 Lisa Rimsza, Nancy L. Harris, Konrad Mu ¨ ller-Hermelink, Thomas Ru ¨ diger, Bertrand Coiffier, Randy D. Gascoyne, 13 14 15 15 16 17 Franc ¸ oise Berger, Kensei Tobinai, Wing Y. Au, Raymond Liang, Emili Montserrat, Ephraim P. Hochberg, 18 19 20 3 21 Stefano Pileri, Massimo Federico, Bharat Nathwani, James O. Armitage, and Dennis D. Weisenburger 1 2 3 4 Departments of Pathology and Oncology, University Hospital of Oslo, Oslo, Norway; Department of Internal Medicine and College of Public Health, University 5 6 of Nebraska Medical Center, Omaha, NE; Department of Pathology, National Cancer Institute, Bethesda, MD; Department of Medical Oncology, British 7 8 Columbia Cancer Agency, Vancouver, BC; Department of Pathology, University of Arizona, Tucson, AZ; Department of Pathology, Massachusetts General 9 10 Hospital, Boston, MA; Institute of Pathology, University of Wu ¨ rzburg, Wu ¨ rzburg, Germany; Institute of Pathology, Sta ¨ dtisches Klinikum Karlsruhe, Karlsruhe, 11 12 Germany; Department of Hematology, Centre Hospitalier Lyon-Sud, Lyon, France; Department of Pathology, British Columbia Cancer Agency, Vancouver, 13 14 BC; Department of Pathology, Centre Hospitalier Lyon-Sud, Lyon, France; Hematology and Stem cell Transplantation Division, National Cancer Center 15 16 Hospital, Tokyo, Japan; Department of Medicine, University of Hong Kong, Hong Kong, China; Institute of Hematology and Oncology, University of Barcelona 17 18 Hospital, Barcelona, Spain; Center for Lymphoma, Massachusetts General Hospital Cancer Center, Boston, MA; Department of Pathology, University of 19 20 Bologna Hospital, Bologna, Italy; Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy; Department of Pathology, Cedars Sinai Medical Center and University of Southern California Keck School of Medicine, Los Angeles, CA; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE Few large, international series of prised 5.4% of all lymphomas in the International Prognostic Index (IPI) was enteropathy-associated T-cell lymphoma study and was most common in Europe not as good a predictor of survival as (EATL) have been reported. We studied (9.1%), followed by North America (5.8%) the Prognostic Index for Peripheral a cohort of 62 patients with EATL among and Asia (1.9%). EATL type 1 was more T-Cell Lymphoma (PIT). Clinical sprue 1153 patients with peripheral T-cell or common (66%) than type 2 (34%), and predicted for adverse survival indepen- natural killer (NK)–cell lymphoma from was especially frequent in Europe (79%). dently of the PIT. Neither EATL subtype 22 centers worldwide. The diagnosis A clinical diagnosis of celiac sprue was nor other biologic parameters accu- was made by a consensus panel of made in 32.2% of the patients and was rately predicted survival. Our study con- 4 expert hematopathologists using associated with both EATL type 1 and firms the poor prognosis of patients World Health Organization (WHO) crite- type 2. The median overall survival was with EATL and the need for improved ria. Clinical correlations and survival only 10 months, and the median failure- treatment options. (Blood. 2011;118(1): analyses were performed. EATL com- free survival was only 6 months. The 148-155) Introduction Enteropathy-associated T-cell lymphoma (EATL) is a primary intestinal by chromosome 8q24 gain and, less commonly, by 1q and 5q gains. 1-9 EATL type 2 is less frequently associated with celiac sprue and the lymphoma that is often, but not always, associated with celiac sprue. It 13,16 HLA-DQ2 haplotype and is characterized by monomorphic is a rare disease in most parts of the world, with an annual incidence rate 10,11 cytology with frequent expression of CD56. of 0.5-1 per million. Because EATL is rare, large systematic studies In an effort to assess the clinical applicability of the World Health of this lymphoma are scarce. EATL occurs predominantly in middle- Organization (WHO) classification of peripheral T- and natural killer aged men and is localized primarily in the small bowel. This lymphoma (NK)–cell lymphomas, and to evaluate the efficacy of the therapies used, is strongly associated with celiac sprue, with a variable time lapse of a a large international study was conducted. The clinical and pathologic few months to several decades between the diagnosis of celiac sprue and 10,12 findings of the EATL cases included in the study are reported here. the onset of lymphoma. EATL has a poor prognosis due to treatment resistance and sepsis or perforation of the bowel at diagnosis or during the course of treatment. Recent studies indicate that EATL consists of 2 diseases that are Methods morphologically and genetically distinct and differ with respect to 13-20 their frequency of association with celiac sprue. The first type Case selection and collection of clinical data of EATL (type 1) is characterized genetically by chromosome 9q31.3 gain or 16q12.1 deletion and is strongly associated with The cases in this study are part of the International Peripheral T-Cell celiac sprue and the HLA-DQ2 haplotype. Interestingly, these Lymphoma Project. The study was approved by the institutional review lymphomas frequently have a large-cell or pleomorphic cytology boards of all participating centers, and an overview of the entire project has and may express CD30. In contrast, EATL type 2 is characterized been published previously by Vose et al. Briefly, the cases were collected Submitted February 4, 2011; accepted April 26, 2011. Prepublished online as The publication costs of this article were defrayed in part by page charge Blood First Edition paper, May 12, 2011; DOI 10.1182/blood-2011-02-335216. payment. Therefore, and solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 USC section 1734. The online version of this article contains a data supplement. 148 BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 From www.bloodjournal.org by guest on December 4, 2015. For personal use only. BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA 149 Figure 1. Typical EATL type 1 histology from one of the cases in the study. (A) The cells are large with irregularly shaped or angulated nuclei and a variable amount of cytoplasm (magnification, 250). (B) The cells in this case expressed CD30 (magnification, 250). The mucosa adjacent to the tumor had shortened villi (C; magnification, 100) and “top-heavy” intra-epithelial infil- tration by T cells (D; CD3 staining, magnification, 100). from 22 centers in North America, Europe, and Asia. All patients were monomorphic infiltrate of medium-sized to large lymphoma cells with adults ( 19 years) with a primary diagnosis of peripheral T-cell lymphoma irregular nuclear contours and a variable amount of cytoplasm or large (PTCL) or NK-cell lymphoma made between January 1, 1990 and anaplastic lymphoma cells. EATL type 1 may also show a marked December 31, 2002. The clinical features of the patients were required for polymorphism with variable numbers of eosinophils, histiocytes, small all cases and data were collected as described by Vose et al. Cases of lymphocytes, and plasma cells. For EATL type 1, histologic features of mycosis fungoides and Se´zary syndrome were excluded. celiac sprue in the adjacent mucosa not infiltrated with lymphoma were investigated. However, adjacent noninfiltrated mucosa was not present Histology review in all cases. Celiac sprue was diagnosed when increased numbers of intra-epithelial lymphocytes ( 30 of 100 enterocytes) along with either Local pathologists submitted representative diagnostic materials, including crypt hyperplasia or villus atrophy was noted, as reviewed by Green et a paraffin-embedded tissue block, to a regional center for more detailed and al. EATL type 2 is characterized by a monomorphic infiltrate of small- standardized immunophenotyping and review. The immunophenotyping to medium-sized lymphoid cells with round, hyperchromatic nuclei consisted of stains for CD20, CD3, CD4, CD5, CD8, CD30, CD56, having a stippled chromatin pattern. We also investigated whether TCR-beta, TIA-1, and Ki67. In situ hybridization for EBV was also intra-epithelial infiltration of the mucosa by lymphoma cells was performed. Clonality analyses or FISH studies for defined genetic aberra- present. tions were performed as necessary to classify the cases according to the 2001 WHO classification. Panels of 4 expert hematopathologists drawn from the contributing local sites and regional centers traveled to the Statistical analysis regional centers to review the cases. The composition of the panels differed Treatment outcomes were measured by failure-free survival (FFS) and at the various regional centers. A consensus diagnosis was rendered when at overall survival (OS). FFS was defined as the time from initial diagnosis to least 3 experts in the respective panel agreed on the diagnosis. the first occurrence of progression, relapse after response, or death from any In total, 1314 cases were reviewed and a diagnosis of PTCL or cause. Follow-up of patients not experiencing one of these events was NK-cell lymphoma was confirmed in 1153 cases. A diagnosis of censored at the date of last contact. OS was measured from the time of enteropathy-type TCL was made when the patient presented with a initial diagnosis to death from any cause, with surviving patient follow-up tumor in the intestine composed of EBV-negative lymphoma cells with a censored at the last contact date. Estimates of FFS and OS were determined mature T-cell immunophenotype. Cases diagnosed as enteropathy-type using the method of Kaplan and Meier, and time-to-event distributions TCL were renamed EATL and were subsequently further classified were compared using the log-rank test. The Cox proportional hazards by 2 of the hematopathologists (D.D.W. and J.D.) into 2 subtypes according to the 2008 WHO classification. This subdivision was based regression model was used to test whether pathologic or clinical features or on histologic analysis and did not take into account clinical evidence of a history of celiac sprue predicted for FFS or OS. This was done after celiac sprue. The first subtype is called EATL type 1 for the purposes of controlling for clinical prognostic indices such as the International Prognos- 27 28 this study, although this terminology is not used in the WHO classifica- tic Index (IPI) and the Prognostic Index for PTCL, unspecified (PIT), tion. EATL type 1 shows a variable histology consisting of either a respectively. From www.bloodjournal.org by guest on December 4, 2015. For personal use only. 150 DELABIE et al BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 Figure 2. Typical EATL type 2 histology from one of the cases in the study. (A) The lymphoma consists of monotonous, medium-sized cells with round nuclei hav- ing a stippled chromatin pattern (magnification, 250). (B) The cells express CD56 (magnification, 250). The mucosa adjacent to the lymphoma, shows villous atrophy (C; magnification, 100) and intra-epithelial infiltration by lymphoma cells (D; CD56 staining, magnification, 400). cases were most frequently associated with celiac sprue when the clinical history and histologic features were combined (Figure 3). Results All 13 cases of EATL type 2 in which adjacent mucosa was Histology included in the biopsy showed intra-epithelial lymphoma with or without villous atrophy. This feature precluded histological evalua- Of the 68 cases in the study cohort in which a local diagnosis of tion for celiac disease in EATL type 2. EATL was submitted, only 62 cases were considered to be EATL after review. Three cases were diagnosed as PTCL, unspecified; Clinical data 1 as anaplastic large-cell lymphoma; and 2 as extranodal NK-/T- The clinical features of the cases are given in Table 3. EATL cell lymphoma, nasal type. In total, 5.4% of the cases (62 of 1153) occurred most frequently in the sixth decade, with an almost equal were considered to be EATL after review, thus representing the distribution among the sexes. Abdominal pain, fatigue, and an- seventh largest category of PTCL in the cohort. The expert orexia were the most frequent symptoms. Approximately one-fifth agreement with the consensus diagnosis of EATL was 79%. of the patients presented with signs of infection, but there was no Significant regional differences were noted in the relative fre- clinical information on perforation of the bowel available in the quency of EATL, which represented 1.9%, 5.8%, and 9.1% of study. Whereas the clinical disease stage was usually advanced at PTCL in Asia, North America, and Europe, respectively (P  .0001). diagnosis, bone marrow involvement was a rare occurrence. Except EATL type 1 constituted 66% (38 of 58) and EATL type 2 constituted 34% (20 of 58) of the cases available for subclassifi- cation. In 4 cases, the materials were no longer available for Table 1. Immunophenotype of EATL subclassification at the time this analysis was performed. The EATL type 1 EATL type 2 P typical histology of EATL type 1 and type 2 is illustrated in Figures CD3e 89% 95% NS 1 and 2, respectively, and the immunophenotypes are given in Table CD2 43% 53% NS 1. As expected, EATL type 2 expressed CD8 and CD56 more often CD5 17% 6% NS than EATL type 1. EATL type 1 was more common than type 2 in CD4 11% 5%* NS Europe, whereas the latter was more common in Asia. EATL types CD8 43% 63% NS 1 and 2 were equally frequent in North America (Figure 3). An CD30 37.5% 12.5%* .09 association with a clinical history of celiac sprue was noted for both CD56 30% 73% .01 TIA-1 81% 87.5% NS EATL type 1 and type 2, representing 16 of 33 cases and 4 of EBV (EBER-ISH) 10%* 12%* NS 20 cases, respectively (Table 2). Histological features of celiac sprue were seen in 11 of 28 cases of EATL type 1 in which the NS indicates not significant. mucosa adjacent to the tumor could be investigated. European *Only a subpopulation of likely reactive cells were positive. From www.bloodjournal.org by guest on December 4, 2015. For personal use only. BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA 151 Figure 3. EATL and celiac sprue. The percentage of EATL cases (dark area) among all PTCL cases (circle) in the 3 geographic regions is depicted on top. The number of cases of EATL type 1 (blue columns) and type 2 (red columns) is also depicted for the different regions. The crossed areas of the columns represent the number of cases with a clinical history of celiac sprue. for tumor size at diagnosis, no significant clinical differences were and the FFS was only 6 months. The 5-year OS was 20%, but the noted between EATL types 1 and 2, including a clinical history of 5-year FFS was only 4%. In univariate analysis, there was a celiac sprue (P  .13). A tumor of  5 cm at diagnosis was significantly decreased FFS in cases with a history of celiac sprue reported in 11 of 24 patients with EATL type 1 versus 15 of 18 with compared with those without sprue documented in the clinical EATL type 2 (P  .02). There was no correlation between the records (P  .02); however, there were no significant differences in tumor size at diagnosis and a history of celiac sprue. As expected, OS between these 2 groups (P  .17). When survival with respect the small intestine was the most commonly involved site at to a history of celiac sprue was analyzed only for EATL type 1, diagnosis (90%), followed by the large intestine (16%), with similar results were obtained; a lower FFS was seen in the patients frequent involvement of mesenteric (35%) and para-aortic or iliac with celiac sprue (P  .03), but no significant difference in OS was lymph nodes (11%; Table 4). In one case, EATL type 1 involved the noted (P  .18; Figure 4A). The survival analysis for EATL type stomach but not the small intestine. In 3 cases, EATL involved the 1 was repeated to include cases with either a clinical history or large intestine without involving the small intestine; 2 of these histological evidence of celiac disease (Figure 4B). Interestingly, a cases were EATL type 2 but the slides of the third case were not significantly decreased OS was observed for patients with celiac available for subtype review. The small and large intestine were sprue (P  .039), whereas only a borderline decrease in FFS was simultaneously involved in 7 cases, of which 3 were EATL type seen (P  .069). The number of EATL type 2 cases with a clinical 1 and 4 were type 2. history of celiac sprue was too small (n  4) to perform survival Treatment was administered in 56 of the patients, whereas no analysis. Disease stage (stage III or IV) and age  60 years did not treatment could be given in 5 patients because of their general predict for OS or FFS (P  .95 and P  .73, P  .34 and P  .72, condition. In one patient, no information on treatment could be respectively), but a large tumor mass ( 5 cm) at diagnosis (Figure retrieved. Initial treatment in 52 patients consisted of combination 5A), a nonambulatory performance status, an elevated serum LDH chemotherapy containing anthracycline; of these patients, 27 received level, and increased C-reactive protein (CRP) were adverse predic- CHOP, 8 CHOP-like, 3 MACOP-B, 2 ACVB, 2 CEOP, and 2 CHO tors of survival (P values for OS are P  .018, P  .005, P  .008, chemotherapy. The remaining 8 patients received a diverse combination and P  .003 for OS, and P  .008, P  .001, P  .001, and of chemotherapy regimens. Complete response, partial response, or no P  .01 for FFS, respectively). The use of anthracycline- response was observed in 40%, 16%, and 38% of the patients, containing chemotherapy improved the OS and FFS compared with respectively, whereas no data were available for the other patients. None other therapies or no therapy (P  .001 and P  .007, respec- of the patients received consolidative autologous stem cell transplanta- tively), although the number of patients not receiving an anthracy- tion in first remission. No data with respect to salvage therapy was cline-containing regimen was small (n  9) compared with those recorded for this study. receiving such a regimen (n  51; Figure 5B). No analysis of Survival analysis second-line treatment could be performed because this information was not recorded in the study. The IPI did not stratify patients well Survival data were available for 61 of the 62 patients. The median with regard to OS or FFS (P  .13 and P  .34, respectively), but follow-up was 10.5 months. The median OS was only 10 months the PIT was a better predictor of survival (P  .001 and P  .001, respectively; Figure 6). Table 2. Association of EATL with celiac sprue In multivariate analysis, only a clinical history of celiac sprue EATL type 1 EATL type 2 predicted FFS when controlling for the PIT (P  .03). A history of Clinical history of celiac sprue 16 of 33 (48%)* 4 of 15 (27%)* celiac sprue did not predict OS (P  .17). A history of celiac sprue Histological features of celiac sprue 11 of 28 (39%)* also predicted FFS when only EATL type 1 was considered Clinical history or histologic features of 21 of 35 (60%)* (P  .04), but did not predict OS (P  .15). None of the other celiac sprue clinical features of EATL predicted for OS or FFS when controlling *Total number of patients with available data or slides to evaluate for celiac sprue. for the PIT. From www.bloodjournal.org by guest on December 4, 2015. For personal use only. 152 DELABIE et al BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 Table 3. Clinical features of the 62 patients with EATL Feature Discussion Age, y 7,13,29,30 Median 60 (61) As seen in previously published studies of EATL and Range 33-81 (61) corroborated by the present study, it is evident that EATL as defined Sex by the WHO classification has distinctive histological and clinical Male 53% (33) characteristics. This lymphoma usually involves the small intes- Female 47% (29) tine, and most patients present with abdominal pain or signs of Stage intra-abdominal sepsis. The majority of EATL patients have IE 10% (6) advanced-stage disease and their prognosis is dismal. The latter IIE 21% (13) may be explained, at least in part, by frequent perforation of the IIIE 5% (3) bowel and infection related to tumor progression or treatment. IV 64% (39) 7,29,30 Three previous studies consisting of 30, 31, and 80 patients, B symptoms respectively, reported a significant predominance of men affected No 37% (23) Yes 63% (39) by EATL. However, our series of 62 patients, as well as the study of Largest mass 70 patients by Chott et al, showed only a slight predominance of 5 cm 37% (17) men. Agreement between the expert hematopathologists and the 5 cm 63% (29) consensus diagnosis of EATL was relatively high (79%), indicating Bone marrow involvement that criteria for the diagnosis of EATL in the WHO classification No 97% (60) are well established. The 2001 WHO classification was used in this Yes 3% (2) study because the pathology review was done before 2008. The Elevated LDH 2001 criteria are similar to those in the 2008 classification, with the No 65% (37) exception of recognition of EATL type 2 in the latter. However, Yes 35% (20) EATL type 2 would still have been diagnosed as EATL in the 2001 Hypercalcemia No 91% (46) WHO classification. Yes 9% (3) EATL comprised only 5.4% of all PTCL in our study, which Elevated CRP makes it rather rare, and there were notable regional differences in No 17% (9) its relative frequency. In our study, EATL was 5 times more Yes 33% (25) frequent in Europe than in Asia, whereas the frequency in North History of celiac sprue America was intermediate. These data are interesting but need to be No 52% (32) interpreted with caution in view of the fact that our study was not Yes 32% (20) population based, but rather institution based, which may lead to a Symptoms biased selection of cases. Data from another institution-based study Abdominal pain 88% (30) from Taiwan of 600 PTCL cases showed EATL to have a relative Fatigue 38% (13) Anorexia 38% (13) frequency of 8.1%, which is almost as high as we observed in Infection 23% (8) Europe. Additional studies of this disease in different parts of the Adenopathy 15% (5) world are needed to clarify this issue. Hepatomegaly 6% (2) 13-20 Previous studies have identified 2 subtypes of EATL. EATL Splenomegaly 6% (2) type 1 consists of medium-sized to large or pleomorphic cells and Pruritus 3% (1) usually develops in the background of celiac sprue. As with celiac IPI score sprue, EATL type 1 is usually associated with the HLA-DQ2 or, 0/1 25% (14) less frequently, with the HLA-DQ8 haplotype. EATL type 1 may 2 30% (17) 3 32% (18) Table 4. Sites of involvement in 62 patients with EATL 4/5 12% (7) PIT score Site % 0 25% (14) Small intestine 90 1 34% (19) Mesenteric/intra-abdominal LNs 35 2 32% (18) Large intestine 16 3-4 9% (5) Para-aortic/iliac LNs 11 5-yr OS 20% (61) Stomach 8 5-yr FFS 4% (61) Inguinal/femoral LNs 6 Lung 5 The numbers in parentheses represent the number of patients with the respec- tive feature or the number of patients analyzed for this parameter. Skin 5 Cervical/supraclavicular LNs 3 Axillary LNs 3 None of the immunohistochemical markers, including CD8, Bone marrow 3 CD56, CD30, or TIA1, were predictors of OS (P  .80, P  .49, Liver 2 P  .16, and P  .55, respectively) or FFS (P  .73, P  .46, Spleen 2 P  .33, and P  .47, respectively) in univariate analysis. When Mediastinal LNs 2 using several cutoff scores at 10% intervals for the proliferation- Intrathoracic LNs 2 associated marker Ki67, no significant correlation with survival was Paranasal sinus 2 found (P .41 for OS and and P .16 for FFS for a 70% cutoff value). Other extranodal sites 13 In addition, there were no significant differences in OS (P .28) or FFS (P .22) between patients with EATL type 1 and type 2. LNs indicates lymph nodes. From www.bloodjournal.org by guest on December 4, 2015. For personal use only. BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA 153 Figure 4. Survival of patients with EATL type 1 according to the presence of celiac disease. (A) Celiac disease as evidenced by review of the clinical records alone. (B) Celiac disease as evidenced either by review of the clinical records or review of the histology. sometimes develop from an in situ lesion associated with celiac EATL types 1 and 2 do not display significantly different clinical sprue that is refractory to therapy. EATL type 2 consists of features, with the exception of larger tumor masses in those with monomorphic small- to medium-sized cells that usually express EATL type 2. In addition, EATL type 1 and type 2 have an equally CD8 and CD56, and is not strongly associated with either celiac poor prognosis, which is in agreement with a previous study. sprue or with the HLA-DQ2 or HLA-DQ8 haplotypes. A precursor Our study showed a significant correlation between a clinical lesion is not described for this subtype, although an intra-epithelial history of celiac sprue and FFS in EATL that was independent of component of T cells with an immunophenotype similar to the the PIT. Such a correlation could not be shown for OS. However, 23 32 tumor cells is frequently observed, as confirmed by our study. because celiac sprue is often undiagnosed, it was likely underesti- The two subtypes of EATL also have different patterns of mated in our series. Celiac sprue is the most common genetic 14-16,18,20 genetic aberrations. In this international series, EATL type disease in North America and Europe, affecting 0.5% to 1% of the 1 was the most frequent subtype (66%). Previous reports indicate population. As many as 90% of cases are undiagnosed because of that EATL type 1 has a high frequency in Western countries, the diversity of symptoms with which patients present. Therefore, comprising approximately 80% of cases. In contrast, EATL type 2 the association of EATL with celiac sprue is likely to underesti- has been reported to be the predominant subtype in Asia, represent- mated in most studies. Future studies should include more sensitive 18-20 ing  90% of cases. The predominance of EATL type 1 in the methods for the detection of celiac sprue, such as measurement of West and type 2 in the East is confirmed by our study, although the anti-endomysial and anti-tissue transglutaminase antibodies in number of cases from the East was low. Celiac sprue is a known addition to endoscopic small bowel biopsy, to determine the true predisposing factor for EATL, and has been reported to be incidence of celiac sprue among EATL patients and to determine especially associated with EATL type 1, as reviewed by Van de more accurately its correlation with survival. Water et al. However, our data show that EATL type 2 can also A large tumor mass ( 5 cm), nonambulatory performance arise in patients with celiac sprue. This latter association does not status, and elevated serum LDH and CRP levels are risk factors seem to show a regional variation despite the observed differences significantly associated with a worse OS and FFS in EATL. A large in the frequency of EATL (Figure 3). These observations need to be tumor mass often results in complications such as perforation or confirmed by a study consisting of a larger number of well- infection, and nonambulatory patients may have disease complica- documented cases from Asia. Our data also show that patients with tions or not be able to receive aggressive therapy. Similarly, a high Figure 5. Survival of patients with EATL according to tumor size (A) and therapy with or without an anthra- cycline (B). From www.bloodjournal.org by guest on December 4, 2015. For personal use only. 154 DELABIE et al BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 Figure 6. Survival of patients with EATL according to IPI scores (A) and PIT scores (B). serum LDH level is usually a reflection of high tumor burden. CRP It is increasingly clear that celiac disease is also associated with is produced by hepatocytes secondary to inflammatory cytokines lymphomas other than EATL, in particular diffuse large B-cell 33-35 such as IL6, TNF, and IL1 and is a marker of inflammation. lymphoma. However, the latter was not studied in the Interna- High serum CRP levels may reflect extensive tissue damage, tional Peripheral T-Cell Lymphoma Project. ulceration, perforation, and secondary inflammation in EATL, and therefore may explain the adverse prognosis. Interestingly, the IPI Acknowledgments did not stratify patients well into prognostic subgroups, whereas the PIT was more predictive of survival. This may have been due to We thank Martin Bast for the data collection; Ventana Medical the fact that age, the number of extranodal sites, and tumor stage, Systems, Inc. (Tucson, AZ) for donation of the use of a Vantana XT 3 of the 5 components of the IPI, are irrelevant for EATL prognosis. immunostainer for the project; and Dr Inger-Nina Farstad for Indeed, our study indicates that tumor size rather than tumor stage carefully reading the manuscript. defines the prognosis in EATL. In contrast, the PIT uses only 4 parameters: LDH, age, bone marrow involvement, and perfor- mance status. Of these, only bone marrow involvement may not be Authorship relevant to prognosis in EATL, because only a few patients (3.2%) had this feature in our study. Contribution: J.D. collected the data, contributed materials, partici- Patients treated with anthracycline-based chemotherapy regi- pated in the pathology review, analyzed and interpreted the data, mens had better survival rates than those treated with other forms and wrote the manuscript; H.H., K.J.S., J.M.C., B.C., M.F., K.T., of therapy (including surgery) or no therapy at all. However, these W.Y.A., R.L., E.M., and E.P.H collected and interpreted the data; results can be explained by the likely possibility that patients not J.M.V. designed the research and collected and interpreted the data; receiving anthracycline-based chemotherapy either died before any F.U. analyzed the data; E.S.J., L.R., N.L.H, K.M.-H., T.R., R.D.G., therapy could be given or shortly after surgery for advanced or F.B., and B.N. contributed materials, participated in the pathology complicated disease. In addition, the number of patients not review, and interpreted the data; S.P. contributed materials and receiving anthracycline-based chemotherapy (n  9) was rather reagents, participated in the pathology review, and interpreted the low. It is clear that novel treatment strategies are needed for data; J.O.A. designed the research and collected, analyzed, and patients with EATL. A recent study by Sieniawski et al showed interpreted the data; and D.D.W. designed the research, collected that patients treated with high-dose ifosfamide, etoposide and the data, contributed materials and reagents, participated in the epirubicin/methotrexate followed by autologous stem cell transplan- pathology review, and analyzed and interpreted the data. tation had a significantly improved survival. However, this might Conflict-of-interest disclosure: The authors declare no compet- have been due, at least in part, to the selection of patients who ing financial interests. better tolerate this intensive therapy. Nevertheless, high-dose A complete list of the participants in the International Peripheral chemotherapy with stem cell transplantation was well tolerated in T-Cell Lymphoma Project appears in the supplemental Appendix this patient group, and it was estimated that approximately 70% of (available on the Blood Web site; see the Supplemental Materials link at all EATL patients may benefit from this therapy. In addition, the the top of the online article). early detection of celiac sprue using improved screening methods Correspondence: Jan Delabie, MD, PhD, Department of Pathol- and close clinical follow-up would likely result in earlier detection ogy, The Norwegian Radium Hospital, University of Oslo, Monte- of EATL and perhaps better survival rates. bello N-0310, Oslo, Norway; e-mail: jan.delabie@medisin.uio.no. References 1. Gough KR, Read AE, Naish JM. Intestinal reticu- 3. Isaacson P, Wright DH. Intestinal lymphoma as- tinal lymphoma associated with celiac sprue. Ann sociated with malabsorption. Lancet. 1978; Intern Med. 1986;104(1):44-47. losis as a complication of idiopathic steatorrhea. 1(8055):67-70. Gut. 1962;3(3):232-239. 6. O’Farrelly C, Feighery C, O’Briain DS, et al. Hu- 4. Swinson CM, Slavin G, Coles EC, Booth CC. Co- 2. Holmes GK, Stokes PL, Sorahan TM, Prior P, moral response to wheat protein in patients with eliac disease and malignancy. Lancet. 1983; Waterhouse JA, Cooke WT. Coeliac disease, glu- coeliac disease and enteropathy associated T cell 1(8316):111-115. ten-free diet, and malignancy. Gut. 1976;17(8): lymphoma. Br Med J (Clin Res Ed). 1986; 612-619. 5. Loughran TP Jr., Kadin ME, Deeg HJ. T-cell intes- 293(6552):908-910. From www.bloodjournal.org by guest on December 4, 2015. For personal use only. BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA 155 7. Egan LJ, Walsh SV, Stevens FM, Connolly CE, lymphoma subtypes. Gastroenterology. 2007; 27. The International Non-Hodgkin’s Lymphoma Egan EL, McCarthy CF. Celiac-associated lym- 132(5):1902-1911. Prognostic Factors Project: A predictive model for phoma. A single institution experience of 30 aggressive non-Hodgkin’s lymphoma. N Engl 17. Isaacson PG, Du M-Q. Gastrointestinal lym- cases in the combination chemotherapy era. J Med. 1993;329(14):987-994. phoma: where morphology meets molecular biol- J Clin Gastroenterol. 1995;21(2):123-129. ogy. J Pathol. 2005;205(2):255-274. 28. Gallamini A, Stelitano C, Calvi R, et al. Peripheral 8. Pricolo VE, Mangi AA, Aswad B, Bland KI. Gas- 18. Akiyama T, Okino T, Konishi H, et al. CD8, T-cell lymphoma unspecified (PTCL-U): a new trointestinal malignancies in patients with celiac CD56 (natural killer-like) T-cell lymphoma in- prognostic model from a retrospective multicen- sprue. Am J Surg. 1998;176(4):344-347. volving the small intestine with no evidence of tric clinical study. Blood. 2004;103(7):2474-2479. enteropathy: clinicopathology and molecular 9. Smedby KE, Akerman M, Hildebrand H, Glimelius B, 29. Gale J, Simmonds PD, Mead GM, Sweetenham study of five Japanese patients. Pathol Int. 2008; Ekbom A, Askling J. Malignant lymphomas in coeliac JW, Wright DH. Enteropathy-type intestinal T-cell 58(10):626-634. disease: evidence of increased risks for lymphoma lymphoma: clinical features and treatment of 31 types other than enteropathy-type T cell lymphoma. 19. Chuang S-S, Chang S-T, Chuang W-Y, et al. patients in a single center. J Clin Oncol. 2000; Gut. 2005;54(1):54-59. NK-cell lineage predicts poor survival in primary 18(4):795-803. intestinal NK-cell and T-cell lymphomas. Am J 10. Catassi C, Bearzi I, Holmes GK. Association of 30. Sieniawski M, Angamuthu N, Boyd K, et al. Evalu- Surg Pathol. 2009;33(8):1230-1240. celiac disease and intestinal lymphomas and ation of enteropathy-associated T-cell lymphoma other cancers. Gastroenterology. 2005;128(4 20. Ko YH, Karnan S, Kim KM, et al. Enteropathy- comparing standard therapies with a novel regi- suppl 1):S79-S86. associated T-cell lymphoma – a clinicopathologic men including autologous stem cell transplanta- and array comparative genomic hybridization 11. Verbeek WHM, van de Water JMW, Al-Toma A, tion. Blood. 2010;115(18):3664-3670. study. Hum Pathol. 2010;41(9):1231-1237. Oudejans JJ, Mulder CJJ, Coupe ´ VMH. Incidence 31. Lee M-Y, Tsou M-H, Tan T-D, Lu M-C. Clinico- of enteropathy-associated T-cell lymphoma: a 21. Vose J, Armitage J, Weisenburger D. Interna- pathological analysis of T-cell lymphoma in Tai- nation-wide study of a population-based registry tional T-cell lymphoma project. International Pe- wan according to WHO classification: high inci- in The Netherlands. Scand J Gastroenterol. 2008; ripheral T-cell Lymphoma Project: International dence of enteropathy-type intestinal T-cell 43(11):1322-1328. peripheral T-cell and NK/T-cell lymphoma study: lymphoma. Eur J Haematol. 2005;75(3):221-226. pathology findings and clinical outcomes. J Clin 12. van de Water JM, Cillessen SAGM, Visser OJ, 32. Ravikumara M, Nootigattu VKT, Sandhu BK. Oncol. 2008;26(25):4124-4130. Verbeek WHM, Meijer CJLM, Mulder CJJ. Enter- Ninety percent of celiac disease is being missed. opathy associated T-cell lymphoma and its pre- 22. Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. J Pediatr Gastroenterol Nutr. 2007;45(4):497- cursor lesions. Best Pract Res Clin Gastroenterol. World Health Organization Classification of Tu- 2010;24(1):43-56. mours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, 33. Catassi C, Fabiani E, Corrao G, et al. Italian 13. Chott A, Haedicke W, Mosberger I, et al. Most France: IARC Press; 2001. Working Group on Coeliac Disease and Non- CD56 intestinal lymphomas are CD8, CD5- Hodgkin’s-Lymphoma. Risk of non Hodgkin lym- T-cell lymphomas of monomorphic small to me- 23. Swerdlow SH, Campo E, Harris NL, et al. World phoma in celiac disease. JAMA. 2002;287(11): dium size morphology. Am J Pathol. 1998;153(5): Health Organization Classification of Tumours. 1413-1419. 1483-1490. Pathology and Genetics of Tumours of Haemato- poietic and Lymphoid Tissues. Lyon, France: 14. Zettl A, Ott G, Makulik A, et al. Chromosomal 34. Mearin ML, Catassi C, Brousse N, et al. Biomed IARC Press; 2008. Gains at 9q characterize enteropathy-type T-cell Study Group on Coeliac Disease and Non-Hodg- lymphoma. Am J Pathol. 2002;161(5):1635-1645. 24. Green PHR, Rostami K, Marsh MN. Diagnosis of kin Lymphoma. European multi-centre study on coeliac disease. Best Pract Res Gastroenterol. coeliac disease and non-Hodgkin lymphoma. Eur 15. Baumga ¨ rtner AK, Zettl A, Chott A, Ott G, Muller- 2005;19(13):389-400. J Gastroenterol Hepatol. 2006;18(2):187-194. Hermelink HK, Starostik P. High frequency of ge- netic aberrations in enteropathy-type T-cell lym- 25. Kaplan EL, Meier P. Nonparametric estimation 35. Smedby KE, Akerman M, Hildebrand H, Glimelius B, phoma. Lab Invest. 2003;83(10):1509-1516. from incomplete observations. J Am Stat Assoc. Ekbom A, Askling J. Malignant lymphomas in coeliac 1958;53(282):457-481. 16. Deleeuw RJ, Zettl A, Klinker E, et al. Whole- disease: evidence of increased risks for lymphoma genome analysis and HLA genotyping of enter- 26. Cox DR. Regression models and life-tables. JR types other than enteropathy-type T cell lymphoma. opathy-type T-cell lymphoma reveals 2 distinct Stat Soc. 1972;34(2):187-220. Gut. 2005;54(1):54-49. From www.bloodjournal.org by guest on December 4, 2015. For personal use only. 2011 118: 148-155 doi:10.1182/blood-2011-02-335216 originally published online May 12, 2011 Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project Jan Delabie, Harald Holte, Julie M. Vose, Fred Ullrich, Elaine S. Jaffe, Kerry J. Savage, Joseph M. Connors, Lisa Rimsza, Nancy L. Harris, Konrad Müller-Hermelink, Thomas Rüdiger, Bertrand Coiffier, Randy D. Gascoyne, Françoise Berger, Kensei Tobinai, Wing Y. Au, Raymond Liang, Emili Montserrat, Ephraim P. Hochberg, Stefano Pileri, Massimo Federico, Bharat Nathwani, James O. 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From www.bloodjournal.org by guest on December 4, 2015. For personal use only. LYMPHOID NEOPLASIA Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project 1 2 3 4 5 6 6 Jan Delabie, Harald Holte, Julie M. Vose, Fred Ullrich, Elaine S. Jaffe, Kerry J. Savage, Joseph M. Connors, 7 8 9 10 11 12 Lisa Rimsza, Nancy L. Harris, Konrad Mu ¨ ller-Hermelink, Thomas Ru ¨ diger, Bertrand Coiffier, Randy D. Gascoyne, 13 14 15 15 16 17 Franc ¸ oise Berger, Kensei Tobinai, Wing Y. Au, Raymond Liang, Emili Montserrat, Ephraim P. Hochberg, 18 19 20 3 21 Stefano Pileri, Massimo Federico, Bharat Nathwani, James O. Armitage, and Dennis D. Weisenburger 1 2 3 4 Departments of Pathology and Oncology, University Hospital of Oslo, Oslo, Norway; Department of Internal Medicine and College of Public Health, University 5 6 of Nebraska Medical Center, Omaha, NE; Department of Pathology, National Cancer Institute, Bethesda, MD; Department of Medical Oncology, British 7 8 Columbia Cancer Agency, Vancouver, BC; Department of Pathology, University of Arizona, Tucson, AZ; Department of Pathology, Massachusetts General 9 10 Hospital, Boston, MA; Institute of Pathology, University of Wu ¨ rzburg, Wu ¨ rzburg, Germany; Institute of Pathology, Sta ¨ dtisches Klinikum Karlsruhe, Karlsruhe, 11 12 Germany; Department of Hematology, Centre Hospitalier Lyon-Sud, Lyon, France; Department of Pathology, British Columbia Cancer Agency, Vancouver, 13 14 BC; Department of Pathology, Centre Hospitalier Lyon-Sud, Lyon, France; Hematology and Stem cell Transplantation Division, National Cancer Center 15 16 Hospital, Tokyo, Japan; Department of Medicine, University of Hong Kong, Hong Kong, China; Institute of Hematology and Oncology, University of Barcelona 17 18 Hospital, Barcelona, Spain; Center for Lymphoma, Massachusetts General Hospital Cancer Center, Boston, MA; Department of Pathology, University of 19 20 Bologna Hospital, Bologna, Italy; Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy; Department of Pathology, Cedars Sinai Medical Center and University of Southern California Keck School of Medicine, Los Angeles, CA; and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE Few large, international series of prised 5.4% of all lymphomas in the International Prognostic Index (IPI) was enteropathy-associated T-cell lymphoma study and was most common in Europe not as good a predictor of survival as (EATL) have been reported. We studied (9.1%), followed by North America (5.8%) the Prognostic Index for Peripheral a cohort of 62 patients with EATL among and Asia (1.9%). EATL type 1 was more T-Cell Lymphoma (PIT). Clinical sprue 1153 patients with peripheral T-cell or common (66%) than type 2 (34%), and predicted for adverse survival indepen- natural killer (NK)–cell lymphoma from was especially frequent in Europe (79%). dently of the PIT. Neither EATL subtype 22 centers worldwide. The diagnosis A clinical diagnosis of celiac sprue was nor other biologic parameters accu- was made by a consensus panel of made in 32.2% of the patients and was rately predicted survival. Our study con- 4 expert hematopathologists using associated with both EATL type 1 and firms the poor prognosis of patients World Health Organization (WHO) crite- type 2. The median overall survival was with EATL and the need for improved ria. Clinical correlations and survival only 10 months, and the median failure- treatment options. (Blood. 2011;118(1): analyses were performed. EATL com- free survival was only 6 months. The 148-155) Introduction Enteropathy-associated T-cell lymphoma (EATL) is a primary intestinal by chromosome 8q24 gain and, less commonly, by 1q and 5q gains. 1-9 EATL type 2 is less frequently associated with celiac sprue and the lymphoma that is often, but not always, associated with celiac sprue. It 13,16 HLA-DQ2 haplotype and is characterized by monomorphic is a rare disease in most parts of the world, with an annual incidence rate 10,11 cytology with frequent expression of CD56. of 0.5-1 per million. Because EATL is rare, large systematic studies In an effort to assess the clinical applicability of the World Health of this lymphoma are scarce. EATL occurs predominantly in middle- Organization (WHO) classification of peripheral T- and natural killer aged men and is localized primarily in the small bowel. This lymphoma (NK)–cell lymphomas, and to evaluate the efficacy of the therapies used, is strongly associated with celiac sprue, with a variable time lapse of a a large international study was conducted. The clinical and pathologic few months to several decades between the diagnosis of celiac sprue and 10,12 findings of the EATL cases included in the study are reported here. the onset of lymphoma. EATL has a poor prognosis due to treatment resistance and sepsis or perforation of the bowel at diagnosis or during the course of treatment. Recent studies indicate that EATL consists of 2 diseases that are Methods morphologically and genetically distinct and differ with respect to 13-20 their frequency of association with celiac sprue. The first type Case selection and collection of clinical data of EATL (type 1) is characterized genetically by chromosome 9q31.3 gain or 16q12.1 deletion and is strongly associated with The cases in this study are part of the International Peripheral T-Cell celiac sprue and the HLA-DQ2 haplotype. Interestingly, these Lymphoma Project. The study was approved by the institutional review lymphomas frequently have a large-cell or pleomorphic cytology boards of all participating centers, and an overview of the entire project has and may express CD30. In contrast, EATL type 2 is characterized been published previously by Vose et al. Briefly, the cases were collected Submitted February 4, 2011; accepted April 26, 2011. Prepublished online as The publication costs of this article were defrayed in part by page charge Blood First Edition paper, May 12, 2011; DOI 10.1182/blood-2011-02-335216. payment. Therefore, and solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 USC section 1734. The online version of this article contains a data supplement. 148 BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 From www.bloodjournal.org by guest on December 4, 2015. For personal use only. BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA 149 Figure 1. Typical EATL type 1 histology from one of the cases in the study. (A) The cells are large with irregularly shaped or angulated nuclei and a variable amount of cytoplasm (magnification, 250). (B) The cells in this case expressed CD30 (magnification, 250). The mucosa adjacent to the tumor had shortened villi (C; magnification, 100) and “top-heavy” intra-epithelial infil- tration by T cells (D; CD3 staining, magnification, 100). from 22 centers in North America, Europe, and Asia. All patients were monomorphic infiltrate of medium-sized to large lymphoma cells with adults ( 19 years) with a primary diagnosis of peripheral T-cell lymphoma irregular nuclear contours and a variable amount of cytoplasm or large (PTCL) or NK-cell lymphoma made between January 1, 1990 and anaplastic lymphoma cells. EATL type 1 may also show a marked December 31, 2002. The clinical features of the patients were required for polymorphism with variable numbers of eosinophils, histiocytes, small all cases and data were collected as described by Vose et al. Cases of lymphocytes, and plasma cells. For EATL type 1, histologic features of mycosis fungoides and Se´zary syndrome were excluded. celiac sprue in the adjacent mucosa not infiltrated with lymphoma were investigated. However, adjacent noninfiltrated mucosa was not present Histology review in all cases. Celiac sprue was diagnosed when increased numbers of intra-epithelial lymphocytes ( 30 of 100 enterocytes) along with either Local pathologists submitted representative diagnostic materials, including crypt hyperplasia or villus atrophy was noted, as reviewed by Green et a paraffin-embedded tissue block, to a regional center for more detailed and al. EATL type 2 is characterized by a monomorphic infiltrate of small- standardized immunophenotyping and review. The immunophenotyping to medium-sized lymphoid cells with round, hyperchromatic nuclei consisted of stains for CD20, CD3, CD4, CD5, CD8, CD30, CD56, having a stippled chromatin pattern. We also investigated whether TCR-beta, TIA-1, and Ki67. In situ hybridization for EBV was also intra-epithelial infiltration of the mucosa by lymphoma cells was performed. Clonality analyses or FISH studies for defined genetic aberra- present. tions were performed as necessary to classify the cases according to the 2001 WHO classification. Panels of 4 expert hematopathologists drawn from the contributing local sites and regional centers traveled to the Statistical analysis regional centers to review the cases. The composition of the panels differed Treatment outcomes were measured by failure-free survival (FFS) and at the various regional centers. A consensus diagnosis was rendered when at overall survival (OS). FFS was defined as the time from initial diagnosis to least 3 experts in the respective panel agreed on the diagnosis. the first occurrence of progression, relapse after response, or death from any In total, 1314 cases were reviewed and a diagnosis of PTCL or cause. Follow-up of patients not experiencing one of these events was NK-cell lymphoma was confirmed in 1153 cases. A diagnosis of censored at the date of last contact. OS was measured from the time of enteropathy-type TCL was made when the patient presented with a initial diagnosis to death from any cause, with surviving patient follow-up tumor in the intestine composed of EBV-negative lymphoma cells with a censored at the last contact date. Estimates of FFS and OS were determined mature T-cell immunophenotype. Cases diagnosed as enteropathy-type using the method of Kaplan and Meier, and time-to-event distributions TCL were renamed EATL and were subsequently further classified were compared using the log-rank test. The Cox proportional hazards by 2 of the hematopathologists (D.D.W. and J.D.) into 2 subtypes according to the 2008 WHO classification. This subdivision was based regression model was used to test whether pathologic or clinical features or on histologic analysis and did not take into account clinical evidence of a history of celiac sprue predicted for FFS or OS. This was done after celiac sprue. The first subtype is called EATL type 1 for the purposes of controlling for clinical prognostic indices such as the International Prognos- 27 28 this study, although this terminology is not used in the WHO classifica- tic Index (IPI) and the Prognostic Index for PTCL, unspecified (PIT), tion. EATL type 1 shows a variable histology consisting of either a respectively. From www.bloodjournal.org by guest on December 4, 2015. For personal use only. 150 DELABIE et al BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 Figure 2. Typical EATL type 2 histology from one of the cases in the study. (A) The lymphoma consists of monotonous, medium-sized cells with round nuclei hav- ing a stippled chromatin pattern (magnification, 250). (B) The cells express CD56 (magnification, 250). The mucosa adjacent to the lymphoma, shows villous atrophy (C; magnification, 100) and intra-epithelial infiltration by lymphoma cells (D; CD56 staining, magnification, 400). cases were most frequently associated with celiac sprue when the clinical history and histologic features were combined (Figure 3). Results All 13 cases of EATL type 2 in which adjacent mucosa was Histology included in the biopsy showed intra-epithelial lymphoma with or without villous atrophy. This feature precluded histological evalua- Of the 68 cases in the study cohort in which a local diagnosis of tion for celiac disease in EATL type 2. EATL was submitted, only 62 cases were considered to be EATL after review. Three cases were diagnosed as PTCL, unspecified; Clinical data 1 as anaplastic large-cell lymphoma; and 2 as extranodal NK-/T- The clinical features of the cases are given in Table 3. EATL cell lymphoma, nasal type. In total, 5.4% of the cases (62 of 1153) occurred most frequently in the sixth decade, with an almost equal were considered to be EATL after review, thus representing the distribution among the sexes. Abdominal pain, fatigue, and an- seventh largest category of PTCL in the cohort. The expert orexia were the most frequent symptoms. Approximately one-fifth agreement with the consensus diagnosis of EATL was 79%. of the patients presented with signs of infection, but there was no Significant regional differences were noted in the relative fre- clinical information on perforation of the bowel available in the quency of EATL, which represented 1.9%, 5.8%, and 9.1% of study. Whereas the clinical disease stage was usually advanced at PTCL in Asia, North America, and Europe, respectively (P  .0001). diagnosis, bone marrow involvement was a rare occurrence. Except EATL type 1 constituted 66% (38 of 58) and EATL type 2 constituted 34% (20 of 58) of the cases available for subclassifi- cation. In 4 cases, the materials were no longer available for Table 1. Immunophenotype of EATL subclassification at the time this analysis was performed. The EATL type 1 EATL type 2 P typical histology of EATL type 1 and type 2 is illustrated in Figures CD3e 89% 95% NS 1 and 2, respectively, and the immunophenotypes are given in Table CD2 43% 53% NS 1. As expected, EATL type 2 expressed CD8 and CD56 more often CD5 17% 6% NS than EATL type 1. EATL type 1 was more common than type 2 in CD4 11% 5%* NS Europe, whereas the latter was more common in Asia. EATL types CD8 43% 63% NS 1 and 2 were equally frequent in North America (Figure 3). An CD30 37.5% 12.5%* .09 association with a clinical history of celiac sprue was noted for both CD56 30% 73% .01 TIA-1 81% 87.5% NS EATL type 1 and type 2, representing 16 of 33 cases and 4 of EBV (EBER-ISH) 10%* 12%* NS 20 cases, respectively (Table 2). Histological features of celiac sprue were seen in 11 of 28 cases of EATL type 1 in which the NS indicates not significant. mucosa adjacent to the tumor could be investigated. European *Only a subpopulation of likely reactive cells were positive. From www.bloodjournal.org by guest on December 4, 2015. For personal use only. BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA 151 Figure 3. EATL and celiac sprue. The percentage of EATL cases (dark area) among all PTCL cases (circle) in the 3 geographic regions is depicted on top. The number of cases of EATL type 1 (blue columns) and type 2 (red columns) is also depicted for the different regions. The crossed areas of the columns represent the number of cases with a clinical history of celiac sprue. for tumor size at diagnosis, no significant clinical differences were and the FFS was only 6 months. The 5-year OS was 20%, but the noted between EATL types 1 and 2, including a clinical history of 5-year FFS was only 4%. In univariate analysis, there was a celiac sprue (P  .13). A tumor of  5 cm at diagnosis was significantly decreased FFS in cases with a history of celiac sprue reported in 11 of 24 patients with EATL type 1 versus 15 of 18 with compared with those without sprue documented in the clinical EATL type 2 (P  .02). There was no correlation between the records (P  .02); however, there were no significant differences in tumor size at diagnosis and a history of celiac sprue. As expected, OS between these 2 groups (P  .17). When survival with respect the small intestine was the most commonly involved site at to a history of celiac sprue was analyzed only for EATL type 1, diagnosis (90%), followed by the large intestine (16%), with similar results were obtained; a lower FFS was seen in the patients frequent involvement of mesenteric (35%) and para-aortic or iliac with celiac sprue (P  .03), but no significant difference in OS was lymph nodes (11%; Table 4). In one case, EATL type 1 involved the noted (P  .18; Figure 4A). The survival analysis for EATL type stomach but not the small intestine. In 3 cases, EATL involved the 1 was repeated to include cases with either a clinical history or large intestine without involving the small intestine; 2 of these histological evidence of celiac disease (Figure 4B). Interestingly, a cases were EATL type 2 but the slides of the third case were not significantly decreased OS was observed for patients with celiac available for subtype review. The small and large intestine were sprue (P  .039), whereas only a borderline decrease in FFS was simultaneously involved in 7 cases, of which 3 were EATL type seen (P  .069). The number of EATL type 2 cases with a clinical 1 and 4 were type 2. history of celiac sprue was too small (n  4) to perform survival Treatment was administered in 56 of the patients, whereas no analysis. Disease stage (stage III or IV) and age  60 years did not treatment could be given in 5 patients because of their general predict for OS or FFS (P  .95 and P  .73, P  .34 and P  .72, condition. In one patient, no information on treatment could be respectively), but a large tumor mass ( 5 cm) at diagnosis (Figure retrieved. Initial treatment in 52 patients consisted of combination 5A), a nonambulatory performance status, an elevated serum LDH chemotherapy containing anthracycline; of these patients, 27 received level, and increased C-reactive protein (CRP) were adverse predic- CHOP, 8 CHOP-like, 3 MACOP-B, 2 ACVB, 2 CEOP, and 2 CHO tors of survival (P values for OS are P  .018, P  .005, P  .008, chemotherapy. The remaining 8 patients received a diverse combination and P  .003 for OS, and P  .008, P  .001, P  .001, and of chemotherapy regimens. Complete response, partial response, or no P  .01 for FFS, respectively). The use of anthracycline- response was observed in 40%, 16%, and 38% of the patients, containing chemotherapy improved the OS and FFS compared with respectively, whereas no data were available for the other patients. None other therapies or no therapy (P  .001 and P  .007, respec- of the patients received consolidative autologous stem cell transplanta- tively), although the number of patients not receiving an anthracy- tion in first remission. No data with respect to salvage therapy was cline-containing regimen was small (n  9) compared with those recorded for this study. receiving such a regimen (n  51; Figure 5B). No analysis of Survival analysis second-line treatment could be performed because this information was not recorded in the study. The IPI did not stratify patients well Survival data were available for 61 of the 62 patients. The median with regard to OS or FFS (P  .13 and P  .34, respectively), but follow-up was 10.5 months. The median OS was only 10 months the PIT was a better predictor of survival (P  .001 and P  .001, respectively; Figure 6). Table 2. Association of EATL with celiac sprue In multivariate analysis, only a clinical history of celiac sprue EATL type 1 EATL type 2 predicted FFS when controlling for the PIT (P  .03). A history of Clinical history of celiac sprue 16 of 33 (48%)* 4 of 15 (27%)* celiac sprue did not predict OS (P  .17). A history of celiac sprue Histological features of celiac sprue 11 of 28 (39%)* also predicted FFS when only EATL type 1 was considered Clinical history or histologic features of 21 of 35 (60%)* (P  .04), but did not predict OS (P  .15). None of the other celiac sprue clinical features of EATL predicted for OS or FFS when controlling *Total number of patients with available data or slides to evaluate for celiac sprue. for the PIT. From www.bloodjournal.org by guest on December 4, 2015. For personal use only. 152 DELABIE et al BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 Table 3. Clinical features of the 62 patients with EATL Feature Discussion Age, y 7,13,29,30 Median 60 (61) As seen in previously published studies of EATL and Range 33-81 (61) corroborated by the present study, it is evident that EATL as defined Sex by the WHO classification has distinctive histological and clinical Male 53% (33) characteristics. This lymphoma usually involves the small intes- Female 47% (29) tine, and most patients present with abdominal pain or signs of Stage intra-abdominal sepsis. The majority of EATL patients have IE 10% (6) advanced-stage disease and their prognosis is dismal. The latter IIE 21% (13) may be explained, at least in part, by frequent perforation of the IIIE 5% (3) bowel and infection related to tumor progression or treatment. IV 64% (39) 7,29,30 Three previous studies consisting of 30, 31, and 80 patients, B symptoms respectively, reported a significant predominance of men affected No 37% (23) Yes 63% (39) by EATL. However, our series of 62 patients, as well as the study of Largest mass 70 patients by Chott et al, showed only a slight predominance of 5 cm 37% (17) men. Agreement between the expert hematopathologists and the 5 cm 63% (29) consensus diagnosis of EATL was relatively high (79%), indicating Bone marrow involvement that criteria for the diagnosis of EATL in the WHO classification No 97% (60) are well established. The 2001 WHO classification was used in this Yes 3% (2) study because the pathology review was done before 2008. The Elevated LDH 2001 criteria are similar to those in the 2008 classification, with the No 65% (37) exception of recognition of EATL type 2 in the latter. However, Yes 35% (20) EATL type 2 would still have been diagnosed as EATL in the 2001 Hypercalcemia No 91% (46) WHO classification. Yes 9% (3) EATL comprised only 5.4% of all PTCL in our study, which Elevated CRP makes it rather rare, and there were notable regional differences in No 17% (9) its relative frequency. In our study, EATL was 5 times more Yes 33% (25) frequent in Europe than in Asia, whereas the frequency in North History of celiac sprue America was intermediate. These data are interesting but need to be No 52% (32) interpreted with caution in view of the fact that our study was not Yes 32% (20) population based, but rather institution based, which may lead to a Symptoms biased selection of cases. Data from another institution-based study Abdominal pain 88% (30) from Taiwan of 600 PTCL cases showed EATL to have a relative Fatigue 38% (13) Anorexia 38% (13) frequency of 8.1%, which is almost as high as we observed in Infection 23% (8) Europe. Additional studies of this disease in different parts of the Adenopathy 15% (5) world are needed to clarify this issue. Hepatomegaly 6% (2) 13-20 Previous studies have identified 2 subtypes of EATL. EATL Splenomegaly 6% (2) type 1 consists of medium-sized to large or pleomorphic cells and Pruritus 3% (1) usually develops in the background of celiac sprue. As with celiac IPI score sprue, EATL type 1 is usually associated with the HLA-DQ2 or, 0/1 25% (14) less frequently, with the HLA-DQ8 haplotype. EATL type 1 may 2 30% (17) 3 32% (18) Table 4. Sites of involvement in 62 patients with EATL 4/5 12% (7) PIT score Site % 0 25% (14) Small intestine 90 1 34% (19) Mesenteric/intra-abdominal LNs 35 2 32% (18) Large intestine 16 3-4 9% (5) Para-aortic/iliac LNs 11 5-yr OS 20% (61) Stomach 8 5-yr FFS 4% (61) Inguinal/femoral LNs 6 Lung 5 The numbers in parentheses represent the number of patients with the respec- tive feature or the number of patients analyzed for this parameter. Skin 5 Cervical/supraclavicular LNs 3 Axillary LNs 3 None of the immunohistochemical markers, including CD8, Bone marrow 3 CD56, CD30, or TIA1, were predictors of OS (P  .80, P  .49, Liver 2 P  .16, and P  .55, respectively) or FFS (P  .73, P  .46, Spleen 2 P  .33, and P  .47, respectively) in univariate analysis. When Mediastinal LNs 2 using several cutoff scores at 10% intervals for the proliferation- Intrathoracic LNs 2 associated marker Ki67, no significant correlation with survival was Paranasal sinus 2 found (P .41 for OS and and P .16 for FFS for a 70% cutoff value). Other extranodal sites 13 In addition, there were no significant differences in OS (P .28) or FFS (P .22) between patients with EATL type 1 and type 2. LNs indicates lymph nodes. From www.bloodjournal.org by guest on December 4, 2015. For personal use only. BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA 153 Figure 4. Survival of patients with EATL type 1 according to the presence of celiac disease. (A) Celiac disease as evidenced by review of the clinical records alone. (B) Celiac disease as evidenced either by review of the clinical records or review of the histology. sometimes develop from an in situ lesion associated with celiac EATL types 1 and 2 do not display significantly different clinical sprue that is refractory to therapy. EATL type 2 consists of features, with the exception of larger tumor masses in those with monomorphic small- to medium-sized cells that usually express EATL type 2. In addition, EATL type 1 and type 2 have an equally CD8 and CD56, and is not strongly associated with either celiac poor prognosis, which is in agreement with a previous study. sprue or with the HLA-DQ2 or HLA-DQ8 haplotypes. A precursor Our study showed a significant correlation between a clinical lesion is not described for this subtype, although an intra-epithelial history of celiac sprue and FFS in EATL that was independent of component of T cells with an immunophenotype similar to the the PIT. Such a correlation could not be shown for OS. However, 23 32 tumor cells is frequently observed, as confirmed by our study. because celiac sprue is often undiagnosed, it was likely underesti- The two subtypes of EATL also have different patterns of mated in our series. Celiac sprue is the most common genetic 14-16,18,20 genetic aberrations. In this international series, EATL type disease in North America and Europe, affecting 0.5% to 1% of the 1 was the most frequent subtype (66%). Previous reports indicate population. As many as 90% of cases are undiagnosed because of that EATL type 1 has a high frequency in Western countries, the diversity of symptoms with which patients present. Therefore, comprising approximately 80% of cases. In contrast, EATL type 2 the association of EATL with celiac sprue is likely to underesti- has been reported to be the predominant subtype in Asia, represent- mated in most studies. Future studies should include more sensitive 18-20 ing  90% of cases. The predominance of EATL type 1 in the methods for the detection of celiac sprue, such as measurement of West and type 2 in the East is confirmed by our study, although the anti-endomysial and anti-tissue transglutaminase antibodies in number of cases from the East was low. Celiac sprue is a known addition to endoscopic small bowel biopsy, to determine the true predisposing factor for EATL, and has been reported to be incidence of celiac sprue among EATL patients and to determine especially associated with EATL type 1, as reviewed by Van de more accurately its correlation with survival. Water et al. However, our data show that EATL type 2 can also A large tumor mass ( 5 cm), nonambulatory performance arise in patients with celiac sprue. This latter association does not status, and elevated serum LDH and CRP levels are risk factors seem to show a regional variation despite the observed differences significantly associated with a worse OS and FFS in EATL. A large in the frequency of EATL (Figure 3). These observations need to be tumor mass often results in complications such as perforation or confirmed by a study consisting of a larger number of well- infection, and nonambulatory patients may have disease complica- documented cases from Asia. Our data also show that patients with tions or not be able to receive aggressive therapy. Similarly, a high Figure 5. Survival of patients with EATL according to tumor size (A) and therapy with or without an anthra- cycline (B). From www.bloodjournal.org by guest on December 4, 2015. For personal use only. 154 DELABIE et al BLOOD, 7 JULY 2011 VOLUME 118, NUMBER 1 Figure 6. Survival of patients with EATL according to IPI scores (A) and PIT scores (B). serum LDH level is usually a reflection of high tumor burden. CRP It is increasingly clear that celiac disease is also associated with is produced by hepatocytes secondary to inflammatory cytokines lymphomas other than EATL, in particular diffuse large B-cell 33-35 such as IL6, TNF, and IL1 and is a marker of inflammation. lymphoma. However, the latter was not studied in the Interna- High serum CRP levels may reflect extensive tissue damage, tional Peripheral T-Cell Lymphoma Project. ulceration, perforation, and secondary inflammation in EATL, and therefore may explain the adverse prognosis. Interestingly, the IPI Acknowledgments did not stratify patients well into prognostic subgroups, whereas the PIT was more predictive of survival. This may have been due to We thank Martin Bast for the data collection; Ventana Medical the fact that age, the number of extranodal sites, and tumor stage, Systems, Inc. (Tucson, AZ) for donation of the use of a Vantana XT 3 of the 5 components of the IPI, are irrelevant for EATL prognosis. immunostainer for the project; and Dr Inger-Nina Farstad for Indeed, our study indicates that tumor size rather than tumor stage carefully reading the manuscript. defines the prognosis in EATL. In contrast, the PIT uses only 4 parameters: LDH, age, bone marrow involvement, and perfor- mance status. Of these, only bone marrow involvement may not be Authorship relevant to prognosis in EATL, because only a few patients (3.2%) had this feature in our study. Contribution: J.D. collected the data, contributed materials, partici- Patients treated with anthracycline-based chemotherapy regi- pated in the pathology review, analyzed and interpreted the data, mens had better survival rates than those treated with other forms and wrote the manuscript; H.H., K.J.S., J.M.C., B.C., M.F., K.T., of therapy (including surgery) or no therapy at all. However, these W.Y.A., R.L., E.M., and E.P.H collected and interpreted the data; results can be explained by the likely possibility that patients not J.M.V. designed the research and collected and interpreted the data; receiving anthracycline-based chemotherapy either died before any F.U. analyzed the data; E.S.J., L.R., N.L.H, K.M.-H., T.R., R.D.G., therapy could be given or shortly after surgery for advanced or F.B., and B.N. contributed materials, participated in the pathology complicated disease. In addition, the number of patients not review, and interpreted the data; S.P. contributed materials and receiving anthracycline-based chemotherapy (n  9) was rather reagents, participated in the pathology review, and interpreted the low. It is clear that novel treatment strategies are needed for data; J.O.A. designed the research and collected, analyzed, and patients with EATL. A recent study by Sieniawski et al showed interpreted the data; and D.D.W. designed the research, collected that patients treated with high-dose ifosfamide, etoposide and the data, contributed materials and reagents, participated in the epirubicin/methotrexate followed by autologous stem cell transplan- pathology review, and analyzed and interpreted the data. tation had a significantly improved survival. However, this might Conflict-of-interest disclosure: The authors declare no compet- have been due, at least in part, to the selection of patients who ing financial interests. better tolerate this intensive therapy. Nevertheless, high-dose A complete list of the participants in the International Peripheral chemotherapy with stem cell transplantation was well tolerated in T-Cell Lymphoma Project appears in the supplemental Appendix this patient group, and it was estimated that approximately 70% of (available on the Blood Web site; see the Supplemental Materials link at all EATL patients may benefit from this therapy. In addition, the the top of the online article). early detection of celiac sprue using improved screening methods Correspondence: Jan Delabie, MD, PhD, Department of Pathol- and close clinical follow-up would likely result in earlier detection ogy, The Norwegian Radium Hospital, University of Oslo, Monte- of EATL and perhaps better survival rates. bello N-0310, Oslo, Norway; e-mail: jan.delabie@medisin.uio.no. References 1. Gough KR, Read AE, Naish JM. Intestinal reticu- 3. Isaacson P, Wright DH. Intestinal lymphoma as- tinal lymphoma associated with celiac sprue. Ann sociated with malabsorption. Lancet. 1978; Intern Med. 1986;104(1):44-47. losis as a complication of idiopathic steatorrhea. 1(8055):67-70. Gut. 1962;3(3):232-239. 6. O’Farrelly C, Feighery C, O’Briain DS, et al. Hu- 4. Swinson CM, Slavin G, Coles EC, Booth CC. Co- 2. Holmes GK, Stokes PL, Sorahan TM, Prior P, moral response to wheat protein in patients with eliac disease and malignancy. 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Whole- disease: evidence of increased risks for lymphoma genome analysis and HLA genotyping of enter- 26. Cox DR. Regression models and life-tables. JR types other than enteropathy-type T cell lymphoma. opathy-type T-cell lymphoma reveals 2 distinct Stat Soc. 1972;34(2):187-220. Gut. 2005;54(1):54-49. From www.bloodjournal.org by guest on December 4, 2015. For personal use only. 2011 118: 148-155 doi:10.1182/blood-2011-02-335216 originally published online May 12, 2011 Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project Jan Delabie, Harald Holte, Julie M. Vose, Fred Ullrich, Elaine S. Jaffe, Kerry J. Savage, Joseph M. Connors, Lisa Rimsza, Nancy L. Harris, Konrad Müller-Hermelink, Thomas Rüdiger, Bertrand Coiffier, Randy D. Gascoyne, Françoise Berger, Kensei Tobinai, Wing Y. Au, Raymond Liang, Emili Montserrat, Ephraim P. Hochberg, Stefano Pileri, Massimo Federico, Bharat Nathwani, James O. 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