Primary Intestinal Epstein–Barr Virus-associated Natural Killer/T-cell Lymphoproliferative Disorder: A Disease Mimicking Inflammatory Bowel Disease

Primary Intestinal Epstein–Barr Virus-associated Natural Killer/T-cell Lymphoproliferative... Abstract Background and Aims Primary intestinal Epstein–Barr virus [EBV]-associated natural killer/T-cell lymphoproliferative disorder [PIEBV+ NK/T-LPD] is a rare clinical entity, which is difficult to differentiate from inflammatory bowel disease [IBD]. We present a series of Chinese patients with PIEBV+ NK/T-LPD to increase awareness among clinicians of this condition. Methods Patients diagnosed with PIEBV+ NK/T-LPD at West China hospital between 2014 and 2016 were included. Clinical and histopathological characteristics were reviewed, and key aspects of differential diagnosis were presented. Results Twelve patients diagnosed with PIEBV+ NK/T-LPD were identified. Initial symptoms included intermittent fever [11/12 patients], abdominal pain [9/12], haematochezia [8/12], and diarrhoea [3/12]. Main endoscopic findings included multisegmental irregular, variable-sized ulcers, isolated giant ulcers, and diffuse inflammation. Colon and ileocaecum were mainly affected in 11 patients. The main PIEBV+ NK/T-LPD immunophenotypic profile of the infiltrating cells was CD3ε-positive NK/T cells characterised by positive T-cell intracellular antigen-1 and granzyme B, with CD5 deletion. In situ hybridisation was positive for EBV-encoded small RNAs 1/2 in all patients. Eleven patients were misdiagnosed with ulcerative colitis [4/11], Crohn’s disease [4/11], or tuberculosis [TB, 3/11], owing to the similar endoscopic and histopathological features. The mean number of endoscopic procedures performed before reaching the diagnosis of PIEBV+ NK/T-LPD was 3.58; in four patients, the diagnosis was confirmed only after surgical resection following complications. Conclusions PIEBV+ NK/T-LPD may be difficult to differentiate from IBD or TB owing to overlapping endoscopic and pathological findings. Early identification of EBV reactivation in tissue samples is essential for the accurate diagnosis. Primary intestinal EBV-associated NK/T-cell lymphoproliferative disorders, inflammatory bowel disease, differential diagnosis 1. Introduction More than 90% of adults are infected with Epstein–Barr virus [EBV] in their life; however, most of them remain asymptomatic throughout their life span. A miniscule proportion of these people develop EBV-associated lymphoproliferative disorder [EBV+ LPD], which has a wide clinical spectrum and exhibits considerable heterogeneity with respect to clinical manifestation and pathological presentation.1–11 EBV can invade T, B, and natural killer [NK] cells. Compared with predominant EBV+ B-cell LPD in Western countries, EBV-associated NK- and T-cell LPD [EBV+ NK/T-LPD] is more common in East Asia and South America.5,10,12–14 EBV+ NK/T-LPD was first incorporated into the 4th World Health Organization classification of tumours of haematopoietic and lymphoid tissues in 2008.4,6,15 Subsequently, Ohshima et al.8 classified EBV+ NK/T-LPD into four categories based on pathological features, ranging from polyclonal pleomorphic to monoclonal monomorphic LPD [including lymphoma]. Other classifications are based on the heterogeneous clinical characteristics, mainly ranging from indolent to aggressive and even a fulminant course.1,7 EBV+ LPD was initially documented in children and young adults with infectious mononucleosis, whereas accumulating evidence has demonstrated that EBV+ NK/T-LPD can occur in adults even older than 30 years, sharing similar clinical features to those in paediatric patients,2–5,10 particularly in patients with comorbidities such as inflammatory bowel disease [IBD], Sjogren’s syndrome, rheumatic arthritis, HIV infection, and those with an organ transplant.16–18 More studies are warranted to explore the clinicopathological features in adult-onset EBV+ NK/T-LPD. Recently, EBV+ NK/T-LPD in adults has become a research focus, whereas published studies have largely pertained to LPD that affects extraintestinal organs. Studies on EBV+ NK/T-LPD with the primary involvement of the gastrointestinal tract [GI tract] have been scarce. Primary intestinal EBV-associated NK/T-Cell LPD [PIEBV+ NK/T-LPD] is defined as NK/T-cell lymphoproliferation that primarily occurs in the GI tract, resulting in gastrointestinal lesions such as inflammation, ulcers, etc. The gut is the most common location for extranodal LPD,19 and the frequency of small intestinal involvement in patients in Western countries is relatively higher than that in patients in Asian countries.20 Clinically, PIEBV+ NK/T-LPD may be associated with atypical symptoms and exhibit non-specific histopathological and radiological characteristics. The clinical presentation of PIEBV+ NK/T-LPD may mimic that of IBD, making differential diagnosis challenging. Zheng et al.21 reported a patient with PIEBV+ T-cell LPD initially misdiagnosed as ulcerative colitis [UC]. Similarly, Na et al.22 reported a patient with PIEBV+ T-cell LPD initially misdiagnosed as tuberculosis [TB] and subsequently as Crohn’s disease [CD], before the final diagnosis was reached. Currently, the literature regarding PIEBV+ NK/T-LPD is limited to sporadic case reports, and comprehensive clinical guidance regarding the differential diagnosis between PIEBV+ NK/T-LPD and IBD is lacking in the published literature. Therefore, we conducted a retrospective study to characterise the clinical and histopathological features of PIEBV+ NK/T-LPD. Our findings may facilitate a better understanding among clinicians of this subset of LPD and aid in the differential diagnosis in clinical settings. 2. Materials and Methods All patients diagnosed with PIEBV+ NK/T-LPD between January 2014 and April 2017 were identified from electronic medical records at the West China Hospital. Inclusion and exclusion criteria are shown in Table 1. In general, included are patients with a pathological diagnosis of NK/T-LPD and definitive evidence of EBV infection in the GI tract lesions.8,11,19,23–25 Patients diagnosed with IBD,26,27 TB, or non-primary intestinal NK/T-LPD were excluded. In total, 12 patients with PIEBV+ NK/T-LPD were included; data regarding demographic, endoscopic, surgical, pathological, virological, and follow-up characteristics were collected. Table 1. Definition of PIEBV+ NK/T-LPD in this study. [1] Illness ≥3 months duration  [2] EBER+ cells [T or NK cells] in affected intestinal tissues  [3] Characteristic pathological findings of lymphoid proliferation of T or NK cells with positive cytotoxic molecules of TIA-1 or granzyme B  [4] No identifiable underlying immunological abnormalities  [5] Presenting with predominantly digestive symptoms and gastrointestinal extranodal lesions  [6] Excluded comorbid IBDa or TB  [1] Illness ≥3 months duration  [2] EBER+ cells [T or NK cells] in affected intestinal tissues  [3] Characteristic pathological findings of lymphoid proliferation of T or NK cells with positive cytotoxic molecules of TIA-1 or granzyme B  [4] No identifiable underlying immunological abnormalities  [5] Presenting with predominantly digestive symptoms and gastrointestinal extranodal lesions  [6] Excluded comorbid IBDa or TB  EBER, EBV-encoded small RNA; TIA-1, T-cell intracellular antigen-1; IBD, inflammatory bowel disease; TB, tuberculosis. aIBD is diagnosed based on accepted criteria including characteristic clinical, endoscopic, radiographic, and histological findings.26,27 View Large Table 1. Definition of PIEBV+ NK/T-LPD in this study. [1] Illness ≥3 months duration  [2] EBER+ cells [T or NK cells] in affected intestinal tissues  [3] Characteristic pathological findings of lymphoid proliferation of T or NK cells with positive cytotoxic molecules of TIA-1 or granzyme B  [4] No identifiable underlying immunological abnormalities  [5] Presenting with predominantly digestive symptoms and gastrointestinal extranodal lesions  [6] Excluded comorbid IBDa or TB  [1] Illness ≥3 months duration  [2] EBER+ cells [T or NK cells] in affected intestinal tissues  [3] Characteristic pathological findings of lymphoid proliferation of T or NK cells with positive cytotoxic molecules of TIA-1 or granzyme B  [4] No identifiable underlying immunological abnormalities  [5] Presenting with predominantly digestive symptoms and gastrointestinal extranodal lesions  [6] Excluded comorbid IBDa or TB  EBER, EBV-encoded small RNA; TIA-1, T-cell intracellular antigen-1; IBD, inflammatory bowel disease; TB, tuberculosis. aIBD is diagnosed based on accepted criteria including characteristic clinical, endoscopic, radiographic, and histological findings.26,27 View Large Histological review: immunohistochemistry [CD3ε, CD5, CD56, granzyme B [GB], T-cell intracellular antigen-1 [TIA-1], and Ki67], in situ hybridisation for EBV-encoded small RNA 1/2 [EBER] and T-cell clonality for the T-cell receptor γ [TCRγ] were performed [see Supplementary Methods, available as Supplementary data at ECCO-JCC online]. EBV-positive cell lineage was determined using staining for CD3ε, CD56, and T-cell clonality as previously described [details shown in Supplementary Methods]. This study was approved by the local Ethics Committee of West China Hospital. The study protocol complied with the principles of the Declaration of Helsinki. 3. Results 3.1. Demographics Demographic and clinical characteristics of 12 patients are listed in Table 2. The mean age at diagnosis was 38.75 [range, 24–54] years; the mean duration between initial presentation and final diagnosis was 2.53 years [3 months-10 years]. Initial symptoms included intermittent moderate-to-high fever [11/12 patients], abdominal pain [9/12], haematochezia [8/12], diarrhoea [3/12], and weight loss [1/12]. Complications related to the GI tract included bowel perforation [6/12], haemorrhage [2/12], and obstruction [1/12]. None of these patients had a history of transplantation, HIV infection, or exposure to immunosuppressants (except for one patient who received infliximab [IFX] owing to the misdiagnosis of CD). Table 2. Clinical characteristics of 12 patients with PIEBV+ NK/T-LPD. Case  Age/sex  DCBC  Initial symptoms  Treatment history  Affected sites  Complications  Endoscopic findings  1  54/M  5 y  Abdominal pain, haematochezia, fever  5-ASA, GC  AC, TC, DC, SC  Perforation, haemorrhage  MIVUs [0.6-4.0 cm] including a longitudinal ulcer  2  31/F  10 y  Abdominal pain, haematochezia, fever  5-ASA, GC  Whole colorectum  Haemorrhage and HLH  Diffuse inflammation, sporadic small [0.2-0.6 cm] ulcers  3  24/F  3 m  Haematochezia, fever  Anti-TB therapy  IC, AC, SC, rectum  -  MIVUs [0.4-1.2 cm]  4  49M  1 y  Abdominal pain, weight loss  5-ASA, IFX [four times]  IC  Perforation  Isolated annular ulcer  5  40/M  3 y  Abdominal pain, haematochezia, fever  5-ASA  IC and whole colorectum  -  Diffuse inflammation, sporadic [0.2-0.6 cm] ulcers  6  35/M  3 y  Abdominal pain, haematochezia, fever  None  AC, TC, SC  Perforation  Multiple irregular [0.3-1.6 cm] ulcers  7  47/M  9 m  Diarrhoea, fever  Anti-TB therapy  IC, AC, TC, DC, SC, rectum  -  MIVUs [0.2-4.0 cm] including one transverse ulcer  8  30/F  2 y  Abdominal pain, diarrhoea, fever  5-ASA, Anti-TB therapy  TC, rectum  -  Two irregular [both transverse-like] ulcers  9  39/F  4 y  Haematochezia, fever  None  IC, AC, TC, DC  Perforation  MIVUs [1.0-2.0 cm] including one transverse ulcer  10  53/F  9 m  Abdominal pain, diarrhoea, fever  5-ASA, GC  IC, AC, TC, DC, SC  -  MIVUs [0.4-1.2 cm] including one transverse ulcer  11  34/F  5 m  Abdominal pain, haematochezia, fever  None  Ileum  Perforation, obstruction  Multiple round [0.4-1.6 cm] ulcers  12  29/M  3 m  Abdominal pain, haematochezia, fever  Anti-TB therapy  IC, AC, DC, SC  Perforation  MIVUs [0.6-4.0 cm] including one transverse ulcer  Case  Age/sex  DCBC  Initial symptoms  Treatment history  Affected sites  Complications  Endoscopic findings  1  54/M  5 y  Abdominal pain, haematochezia, fever  5-ASA, GC  AC, TC, DC, SC  Perforation, haemorrhage  MIVUs [0.6-4.0 cm] including a longitudinal ulcer  2  31/F  10 y  Abdominal pain, haematochezia, fever  5-ASA, GC  Whole colorectum  Haemorrhage and HLH  Diffuse inflammation, sporadic small [0.2-0.6 cm] ulcers  3  24/F  3 m  Haematochezia, fever  Anti-TB therapy  IC, AC, SC, rectum  -  MIVUs [0.4-1.2 cm]  4  49M  1 y  Abdominal pain, weight loss  5-ASA, IFX [four times]  IC  Perforation  Isolated annular ulcer  5  40/M  3 y  Abdominal pain, haematochezia, fever  5-ASA  IC and whole colorectum  -  Diffuse inflammation, sporadic [0.2-0.6 cm] ulcers  6  35/M  3 y  Abdominal pain, haematochezia, fever  None  AC, TC, SC  Perforation  Multiple irregular [0.3-1.6 cm] ulcers  7  47/M  9 m  Diarrhoea, fever  Anti-TB therapy  IC, AC, TC, DC, SC, rectum  -  MIVUs [0.2-4.0 cm] including one transverse ulcer  8  30/F  2 y  Abdominal pain, diarrhoea, fever  5-ASA, Anti-TB therapy  TC, rectum  -  Two irregular [both transverse-like] ulcers  9  39/F  4 y  Haematochezia, fever  None  IC, AC, TC, DC  Perforation  MIVUs [1.0-2.0 cm] including one transverse ulcer  10  53/F  9 m  Abdominal pain, diarrhoea, fever  5-ASA, GC  IC, AC, TC, DC, SC  -  MIVUs [0.4-1.2 cm] including one transverse ulcer  11  34/F  5 m  Abdominal pain, haematochezia, fever  None  Ileum  Perforation, obstruction  Multiple round [0.4-1.6 cm] ulcers  12  29/M  3 m  Abdominal pain, haematochezia, fever  Anti-TB therapy  IC, AC, DC, SC  Perforation  MIVUs [0.6-4.0 cm] including one transverse ulcer  DCBC:disease course before confirmation; M, male; F, female; y, year; m, month; 5-ASA, 5-aminosalicylic acid; GC, glucocorticoid; IFX, infliximab; TB, tuberculosis; IC: ileocaecum, AC, ascending colon; TC, transverse colon; DC, descending colon; SC, sigmoid colon; HLH, haemophagocytic lymphohistiocytosis; MIVUs, multiple irregular, variable-sized ulcers. View Large Table 2. Clinical characteristics of 12 patients with PIEBV+ NK/T-LPD. Case  Age/sex  DCBC  Initial symptoms  Treatment history  Affected sites  Complications  Endoscopic findings  1  54/M  5 y  Abdominal pain, haematochezia, fever  5-ASA, GC  AC, TC, DC, SC  Perforation, haemorrhage  MIVUs [0.6-4.0 cm] including a longitudinal ulcer  2  31/F  10 y  Abdominal pain, haematochezia, fever  5-ASA, GC  Whole colorectum  Haemorrhage and HLH  Diffuse inflammation, sporadic small [0.2-0.6 cm] ulcers  3  24/F  3 m  Haematochezia, fever  Anti-TB therapy  IC, AC, SC, rectum  -  MIVUs [0.4-1.2 cm]  4  49M  1 y  Abdominal pain, weight loss  5-ASA, IFX [four times]  IC  Perforation  Isolated annular ulcer  5  40/M  3 y  Abdominal pain, haematochezia, fever  5-ASA  IC and whole colorectum  -  Diffuse inflammation, sporadic [0.2-0.6 cm] ulcers  6  35/M  3 y  Abdominal pain, haematochezia, fever  None  AC, TC, SC  Perforation  Multiple irregular [0.3-1.6 cm] ulcers  7  47/M  9 m  Diarrhoea, fever  Anti-TB therapy  IC, AC, TC, DC, SC, rectum  -  MIVUs [0.2-4.0 cm] including one transverse ulcer  8  30/F  2 y  Abdominal pain, diarrhoea, fever  5-ASA, Anti-TB therapy  TC, rectum  -  Two irregular [both transverse-like] ulcers  9  39/F  4 y  Haematochezia, fever  None  IC, AC, TC, DC  Perforation  MIVUs [1.0-2.0 cm] including one transverse ulcer  10  53/F  9 m  Abdominal pain, diarrhoea, fever  5-ASA, GC  IC, AC, TC, DC, SC  -  MIVUs [0.4-1.2 cm] including one transverse ulcer  11  34/F  5 m  Abdominal pain, haematochezia, fever  None  Ileum  Perforation, obstruction  Multiple round [0.4-1.6 cm] ulcers  12  29/M  3 m  Abdominal pain, haematochezia, fever  Anti-TB therapy  IC, AC, DC, SC  Perforation  MIVUs [0.6-4.0 cm] including one transverse ulcer  Case  Age/sex  DCBC  Initial symptoms  Treatment history  Affected sites  Complications  Endoscopic findings  1  54/M  5 y  Abdominal pain, haematochezia, fever  5-ASA, GC  AC, TC, DC, SC  Perforation, haemorrhage  MIVUs [0.6-4.0 cm] including a longitudinal ulcer  2  31/F  10 y  Abdominal pain, haematochezia, fever  5-ASA, GC  Whole colorectum  Haemorrhage and HLH  Diffuse inflammation, sporadic small [0.2-0.6 cm] ulcers  3  24/F  3 m  Haematochezia, fever  Anti-TB therapy  IC, AC, SC, rectum  -  MIVUs [0.4-1.2 cm]  4  49M  1 y  Abdominal pain, weight loss  5-ASA, IFX [four times]  IC  Perforation  Isolated annular ulcer  5  40/M  3 y  Abdominal pain, haematochezia, fever  5-ASA  IC and whole colorectum  -  Diffuse inflammation, sporadic [0.2-0.6 cm] ulcers  6  35/M  3 y  Abdominal pain, haematochezia, fever  None  AC, TC, SC  Perforation  Multiple irregular [0.3-1.6 cm] ulcers  7  47/M  9 m  Diarrhoea, fever  Anti-TB therapy  IC, AC, TC, DC, SC, rectum  -  MIVUs [0.2-4.0 cm] including one transverse ulcer  8  30/F  2 y  Abdominal pain, diarrhoea, fever  5-ASA, Anti-TB therapy  TC, rectum  -  Two irregular [both transverse-like] ulcers  9  39/F  4 y  Haematochezia, fever  None  IC, AC, TC, DC  Perforation  MIVUs [1.0-2.0 cm] including one transverse ulcer  10  53/F  9 m  Abdominal pain, diarrhoea, fever  5-ASA, GC  IC, AC, TC, DC, SC  -  MIVUs [0.4-1.2 cm] including one transverse ulcer  11  34/F  5 m  Abdominal pain, haematochezia, fever  None  Ileum  Perforation, obstruction  Multiple round [0.4-1.6 cm] ulcers  12  29/M  3 m  Abdominal pain, haematochezia, fever  Anti-TB therapy  IC, AC, DC, SC  Perforation  MIVUs [0.6-4.0 cm] including one transverse ulcer  DCBC:disease course before confirmation; M, male; F, female; y, year; m, month; 5-ASA, 5-aminosalicylic acid; GC, glucocorticoid; IFX, infliximab; TB, tuberculosis; IC: ileocaecum, AC, ascending colon; TC, transverse colon; DC, descending colon; SC, sigmoid colon; HLH, haemophagocytic lymphohistiocytosis; MIVUs, multiple irregular, variable-sized ulcers. View Large 3.2. Endoscopy and radiology In this study, all patients underwent gastroscopy and colonoscopy. A key finding was that the disease may involve any site from the jejunum to the rectum; however, the colon and ileocaecum were most commonly affected in this cohort. The most frequently affected segments were the ascending colon [9/12], transverse colon [8/12], sigmoid colon [8/12], ileocaecum [7/12], descending colon [7/12], and rectum [5/12]. Ileal involvement was only observed in one case [Table 2]. The disease affected more than one intestinal segment in most cases. For example, eight patients exhibited ulcers in multiple segments, five of which exhibited ileocaecal involvement. A single intestinal segment was involved in only two patients [ileocaecum in Case 4 and ileum in Case 11]. The remaining two patients showed diffuse colorectal inflammation [Case 2 and Case 5]. The lesions were mainly in the form of ulcers with variable morphological characteristics. The ulcers were variable in size and included isolated or multisegmental, annular, round, and irregular ulcers [Table 2 and Figure 1]. For example, lesions in patients with multisegmental involvement included multiple irregular, variable-sized ulcers that were interspersed with normal mucosa between ulcers; some giant ulcers were transverse [5/8] or longitudinal [1/8] [Table 2]. In addition, all 12 patients underwent computed tomography enterography or magnetic resonance imaging, which showed non-specific manifestations such as multisegmental thickening of the intestinal walls and enlarged peripheral intestinal and mesenteric lymph nodes, in all cases. Figure 1. View largeDownload slide Typical endoscopic findings of PIEBV+ NK/T-LPD. [A] Diffuse inflammation with sporadic ulcers in the descending colon [case 5]; [B] longitudinally arranged ulcers in the ascending colon [case 1]; [C] isolated annular ulcer in the ileocaecum [Case 4]; [D] multifocal irregular ulcers in the ascending colon [Case 9]. Figure 1. View largeDownload slide Typical endoscopic findings of PIEBV+ NK/T-LPD. [A] Diffuse inflammation with sporadic ulcers in the descending colon [case 5]; [B] longitudinally arranged ulcers in the ascending colon [case 1]; [C] isolated annular ulcer in the ileocaecum [Case 4]; [D] multifocal irregular ulcers in the ascending colon [Case 9]. 3.3. Histopathology and virology 3.3.1. Histomorphology The common histomorphological findings in biopsy included chronic mucosal/submucosal inflammatory infiltrates with clusters of medium- or small-sized lymphoid cells, erosions, and ulcers, in all patients. Moreover, all surgical specimens demonstrated transmural lesions. Atypical lymphoid cells [ALCs; 9/12], lymphoepithelial lesions [LELs; 3/12], and angiocentric infiltration [3/12] were observed in some patients. However, some patients exhibited crypt abscesses [3/12], anomalies in structure or number of glands [6/12], gangliocyte hyperplasia [4/12], and even non-caseating granulomas [1/12], which mimicked the histological characteristics of IBD [Table 3 and Figure 2]. Figure 2. View largeDownload slide Histopathological findings of PIEBV+ NK/T-LPD. Haematoxylin and eosin [H&E] staining showed fissure ulcer [A], reduced number of glands [A], gangliocyte hyperplasia [B], and transmural medium-sized lymphoid cell infiltrates with atypical lymphoid cell infiltrates [B]. H&E staining showed mucosal lymphoid cell infiltrates with atypical lymphoid cell infiltrates [C and D], lymphoepithelial lesions [C], and angiocentric infiltration [D]. Immunohistochemical staining revealed positive expressions of CD3ε [E], CD56 [F], granzyme B [G], and T-cell intracellular antigen-1 [H]. In situ hybridisation indicates positive EBER [I]. Immunohistochemical staining revealed Ki67 index at 30% [J]. A, original magnification ×100; B, original magnification ×400 [Case 1]; C, original magnification ×200; D, original magnification ×400 [Case 8]; E, F, G, and H, original magnification ×400 [Case 8]; I, original magnification×400 [Case 8]; J, original magnification ×400 [Case 8]. Figure 2. View largeDownload slide Histopathological findings of PIEBV+ NK/T-LPD. Haematoxylin and eosin [H&E] staining showed fissure ulcer [A], reduced number of glands [A], gangliocyte hyperplasia [B], and transmural medium-sized lymphoid cell infiltrates with atypical lymphoid cell infiltrates [B]. H&E staining showed mucosal lymphoid cell infiltrates with atypical lymphoid cell infiltrates [C and D], lymphoepithelial lesions [C], and angiocentric infiltration [D]. Immunohistochemical staining revealed positive expressions of CD3ε [E], CD56 [F], granzyme B [G], and T-cell intracellular antigen-1 [H]. In situ hybridisation indicates positive EBER [I]. Immunohistochemical staining revealed Ki67 index at 30% [J]. A, original magnification ×100; B, original magnification ×400 [Case 1]; C, original magnification ×200; D, original magnification ×400 [Case 8]; E, F, G, and H, original magnification ×400 [Case 8]; I, original magnification×400 [Case 8]; J, original magnification ×400 [Case 8]. 3.3.2. Immunophenotype Among the 12 patients, the main phenotype of EBV-infected cells was T cell in six patients and NK cell in the remaining six patients. For the infiltrating lymphocytes, positive expression of CD3ε was observed in all 12 patients, that of CD56 was observed in 7/12 patients, and monoclonal TCRγ chain gene rearrangement was confirmed in 4/10 patients. CD5 deletion was observed in 9/12 patients. Positive expression of cytotoxic molecules of GB and TIA-1 was observed in 8/10 and in 8/8 patients, respectively. Ki67 positivity ranged from 5% to 80%, and high Ki67 index [≥65%]28 was found in 3/11 patients [Table 3 and Figure 2]. Table 3. Histopathological expressions of 12 patients with PIEBV+ NK/T-LPD. Case  Histological findings  Cell lineage  EBER  CD3ε  CD5  CD56  TIA-1  GB  Ki67, %  TCRγ  1  Transmural medium-sized LCI, ALCs, angiocentric infiltration, erosions, ulcers, reduced number of glands, gangliocyte hyperplasia, non-caseating granulomas  NK  +  +  −  +  +  +  20  −  2  Transmural medium-sized LCI, ALCs, LELs, erosions, distorted glands and reduced gland secretion, gangliocyte hyperplasia  T  +  +  −  −  +  NA  70  −  3  Mucosal medium-sized LIC, ALCs, ulcers, erosions, crypt abscesses  NK  +  +  −  +  +  ±  30  −  4  Mucosal focal LCI, ALCs, ulcers, atrophic glands  T  +  +  +  −  +  NA  10  +  5  Mucosal focal LCI, distorted glands  T  +  +  +  −  +  −  NA  NA  6  Transmural small-sized LCI, ALCs, ulcers  NK  +  +  −  +  NA  +  70  NA  7  Mucosal/submucosal LCI, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  NK  +  +  −  +  NA  +  40  −  8  Mucosal/submucosal LCI, ALCs, LELs, angiocentric infiltration, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  T  +  +  −  −  NA  +  30  +  9  Transmural small-sized LCI, erosions, ulcers  T  +  +  +  +  +  +  5–10  +  10  Transmural medium- or small-sized LCI, ALCs, ulcers  T  +  +  −  −  NA  +  50  +  11  Transmural small-sized LCI, ALCs  NK  +  +  −  +  +  +  80  −  12  Mucosal LCI, ALCs, LELs, angiocentric infiltration  NK  +  +  −  +  +  +  60  −  Case  Histological findings  Cell lineage  EBER  CD3ε  CD5  CD56  TIA-1  GB  Ki67, %  TCRγ  1  Transmural medium-sized LCI, ALCs, angiocentric infiltration, erosions, ulcers, reduced number of glands, gangliocyte hyperplasia, non-caseating granulomas  NK  +  +  −  +  +  +  20  −  2  Transmural medium-sized LCI, ALCs, LELs, erosions, distorted glands and reduced gland secretion, gangliocyte hyperplasia  T  +  +  −  −  +  NA  70  −  3  Mucosal medium-sized LIC, ALCs, ulcers, erosions, crypt abscesses  NK  +  +  −  +  +  ±  30  −  4  Mucosal focal LCI, ALCs, ulcers, atrophic glands  T  +  +  +  −  +  NA  10  +  5  Mucosal focal LCI, distorted glands  T  +  +  +  −  +  −  NA  NA  6  Transmural small-sized LCI, ALCs, ulcers  NK  +  +  −  +  NA  +  70  NA  7  Mucosal/submucosal LCI, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  NK  +  +  −  +  NA  +  40  −  8  Mucosal/submucosal LCI, ALCs, LELs, angiocentric infiltration, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  T  +  +  −  −  NA  +  30  +  9  Transmural small-sized LCI, erosions, ulcers  T  +  +  +  +  +  +  5–10  +  10  Transmural medium- or small-sized LCI, ALCs, ulcers  T  +  +  −  −  NA  +  50  +  11  Transmural small-sized LCI, ALCs  NK  +  +  −  +  +  +  80  −  12  Mucosal LCI, ALCs, LELs, angiocentric infiltration  NK  +  +  −  +  +  +  60  −  LCI, lymphoid cell infiltrate; ALCs, atypical lymphoid cells; LELs, lymphoepithelial lesions; EBER, EBV-encoded small RNA; TIA-1, T-cell intracellular antigen-1; GB, granzyme B, NA, not available. View Large Table 3. Histopathological expressions of 12 patients with PIEBV+ NK/T-LPD. Case  Histological findings  Cell lineage  EBER  CD3ε  CD5  CD56  TIA-1  GB  Ki67, %  TCRγ  1  Transmural medium-sized LCI, ALCs, angiocentric infiltration, erosions, ulcers, reduced number of glands, gangliocyte hyperplasia, non-caseating granulomas  NK  +  +  −  +  +  +  20  −  2  Transmural medium-sized LCI, ALCs, LELs, erosions, distorted glands and reduced gland secretion, gangliocyte hyperplasia  T  +  +  −  −  +  NA  70  −  3  Mucosal medium-sized LIC, ALCs, ulcers, erosions, crypt abscesses  NK  +  +  −  +  +  ±  30  −  4  Mucosal focal LCI, ALCs, ulcers, atrophic glands  T  +  +  +  −  +  NA  10  +  5  Mucosal focal LCI, distorted glands  T  +  +  +  −  +  −  NA  NA  6  Transmural small-sized LCI, ALCs, ulcers  NK  +  +  −  +  NA  +  70  NA  7  Mucosal/submucosal LCI, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  NK  +  +  −  +  NA  +  40  −  8  Mucosal/submucosal LCI, ALCs, LELs, angiocentric infiltration, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  T  +  +  −  −  NA  +  30  +  9  Transmural small-sized LCI, erosions, ulcers  T  +  +  +  +  +  +  5–10  +  10  Transmural medium- or small-sized LCI, ALCs, ulcers  T  +  +  −  −  NA  +  50  +  11  Transmural small-sized LCI, ALCs  NK  +  +  −  +  +  +  80  −  12  Mucosal LCI, ALCs, LELs, angiocentric infiltration  NK  +  +  −  +  +  +  60  −  Case  Histological findings  Cell lineage  EBER  CD3ε  CD5  CD56  TIA-1  GB  Ki67, %  TCRγ  1  Transmural medium-sized LCI, ALCs, angiocentric infiltration, erosions, ulcers, reduced number of glands, gangliocyte hyperplasia, non-caseating granulomas  NK  +  +  −  +  +  +  20  −  2  Transmural medium-sized LCI, ALCs, LELs, erosions, distorted glands and reduced gland secretion, gangliocyte hyperplasia  T  +  +  −  −  +  NA  70  −  3  Mucosal medium-sized LIC, ALCs, ulcers, erosions, crypt abscesses  NK  +  +  −  +  +  ±  30  −  4  Mucosal focal LCI, ALCs, ulcers, atrophic glands  T  +  +  +  −  +  NA  10  +  5  Mucosal focal LCI, distorted glands  T  +  +  +  −  +  −  NA  NA  6  Transmural small-sized LCI, ALCs, ulcers  NK  +  +  −  +  NA  +  70  NA  7  Mucosal/submucosal LCI, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  NK  +  +  −  +  NA  +  40  −  8  Mucosal/submucosal LCI, ALCs, LELs, angiocentric infiltration, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  T  +  +  −  −  NA  +  30  +  9  Transmural small-sized LCI, erosions, ulcers  T  +  +  +  +  +  +  5–10  +  10  Transmural medium- or small-sized LCI, ALCs, ulcers  T  +  +  −  −  NA  +  50  +  11  Transmural small-sized LCI, ALCs  NK  +  +  −  +  +  +  80  −  12  Mucosal LCI, ALCs, LELs, angiocentric infiltration  NK  +  +  −  +  +  +  60  −  LCI, lymphoid cell infiltrate; ALCs, atypical lymphoid cells; LELs, lymphoepithelial lesions; EBER, EBV-encoded small RNA; TIA-1, T-cell intracellular antigen-1; GB, granzyme B, NA, not available. View Large 3.3.3. Virological expression In situ hybridisation revealed mucosal EBER positivity in all 12 patients, whereas peripheral blood EBV-DNA [>1000 copies/mL] and EBV-capsid antigen-IgA [EBV-CA-IgA] were positive in 9/12 and 2/9 patients, respectively [Table 3 and Figure 2]. 3.4. Diagnostic data 3.4.1. Endoscopic and surgical data The mean number of endoscopic examinations performed for each patient before eventual confirmation of diagnosis was 3.58. In none of the patients was LPD diagnosis confirmed after a single endoscopy. In one patient [Case 9], the final diagnosis was confirmed after two endoscopic examinations based on biopsies. Two patients [Case 6 and Case 11] developed bowel perforation after two endoscopic procedures; the final diagnosis in these two patients was based on the histopathological examination of surgical specimens. In two patients [Case 1 and Case 2], the correct diagnosis was not made even after multiple endoscopic procedures; the diagnosis was finally confirmed based on histopathological examination of surgical specimens obtained in an emergency surgery that was necessitated owing to serious complications [perforation and haemorrhage]. The remaining seven patients underwent three to five endoscopic examinations before the diagnosis was confirmed [Table 4]. 3.4.2. Misdiagnosis data Patients with PIEBV+ NK/T-LPD are at high risk for misdiagnosis, considering that clinical manifestations are largely indistinguishable from other disorders. Routine histopathological examinations may not reveal characteristic features of LPD. In this series, 11 patients were misdiagnosed as having UC [4 cases], CD [4], or TB [3] before the eventual confirmation of diagnosis [Table 4]. Two patients [Cases 1 and 8] were initially misdiagnosed as having UC and later as having CD, considering the endoscopic and radiological characteristics of multisegmental involvement; moreover, non-caseating granuloma was found in one patient [Case 1] histologically. Eventually, all 12 cases were pathologically confirmed as PIEBV+ NK/T-LPD. Furthermore, in seven patients, a more specific diagnosis of NK/T lymphoma, an advanced stage of PIEBV+ NK/T-LPD, was made [Table 4]. Table 4. Diagnosis and follow-up of 12 patients with PIEBV+ NK/T-LPD. Case  Misdiagnosis  EBV-DNA  EBV-CA-IgA  Endoscopic times/ surgery  Confirmation approach  Development of lymphoma  Chemotherapy/HSCT  Follow-up [month]  1  UC→CD  4.40E+03  [−]  4/ subtotal colectomy  Surgery  Yes  None  Dead [1]  2  UC  1.56E+04  [−]  5/ subtotal colectomy  Surgery  No  GLIDE and HSCT  ANED [21]  3  TB  6.50E+03  [−]  3  Endoscopy  Yes  GLIDE  NA  4  CD  2.88E+03  [+]  5  Endoscopy  Yes  None  Dead [1]  5  UC  4.40E+04  [−]  3  Endoscopy  No  GLIDE  AWD [17]  6  CD  5.95E+04  [−]  2/ partial colectomy  Surgery  Yes  None  Dead [1]  7  TB  1.19E+03  NA  5  Endoscopy  No  GLIDE  AWD [10]  8  UC→CD  [−]  [−]  5  Endoscopy  Yes  GLIDE  Dead [7]  9  None  2.15E+03  [+]  2/ subtotal colectomy  Endoscopy  No  LVD  NA  10  CD  2.61E+02  NA  3/ total colectomy  Endoscopy  Yes  None  Dead [2]  11  CD  1.65E+03  NA  2/ ileal resection  Surgery  Yes  None  Dead [2]  12  TB  1.59E+02  [−]  4/ perforation repair  Endoscopy  No  None  AWD[1]  Case  Misdiagnosis  EBV-DNA  EBV-CA-IgA  Endoscopic times/ surgery  Confirmation approach  Development of lymphoma  Chemotherapy/HSCT  Follow-up [month]  1  UC→CD  4.40E+03  [−]  4/ subtotal colectomy  Surgery  Yes  None  Dead [1]  2  UC  1.56E+04  [−]  5/ subtotal colectomy  Surgery  No  GLIDE and HSCT  ANED [21]  3  TB  6.50E+03  [−]  3  Endoscopy  Yes  GLIDE  NA  4  CD  2.88E+03  [+]  5  Endoscopy  Yes  None  Dead [1]  5  UC  4.40E+04  [−]  3  Endoscopy  No  GLIDE  AWD [17]  6  CD  5.95E+04  [−]  2/ partial colectomy  Surgery  Yes  None  Dead [1]  7  TB  1.19E+03  NA  5  Endoscopy  No  GLIDE  AWD [10]  8  UC→CD  [−]  [−]  5  Endoscopy  Yes  GLIDE  Dead [7]  9  None  2.15E+03  [+]  2/ subtotal colectomy  Endoscopy  No  LVD  NA  10  CD  2.61E+02  NA  3/ total colectomy  Endoscopy  Yes  None  Dead [2]  11  CD  1.65E+03  NA  2/ ileal resection  Surgery  Yes  None  Dead [2]  12  TB  1.59E+02  [−]  4/ perforation repair  Endoscopy  No  None  AWD[1]  Cases 9 and 10 were confirmed by endoscopic biopsy performed before the surgery. UC, ulcerative colitis; CD, Crohn’s disease; TB, tuberculosis; GLIDE, gemcitabine, pegaspargase, ifosfamide, dexamethasone, etoposide; LVD, L-asparaginasum, vincristine, dexamethasone; HSCT, haematopoietic stem cell transplantation; ANED, alive no evidence of disease; AWD, alive with disease;NA, not available. View Large Table 4. Diagnosis and follow-up of 12 patients with PIEBV+ NK/T-LPD. Case  Misdiagnosis  EBV-DNA  EBV-CA-IgA  Endoscopic times/ surgery  Confirmation approach  Development of lymphoma  Chemotherapy/HSCT  Follow-up [month]  1  UC→CD  4.40E+03  [−]  4/ subtotal colectomy  Surgery  Yes  None  Dead [1]  2  UC  1.56E+04  [−]  5/ subtotal colectomy  Surgery  No  GLIDE and HSCT  ANED [21]  3  TB  6.50E+03  [−]  3  Endoscopy  Yes  GLIDE  NA  4  CD  2.88E+03  [+]  5  Endoscopy  Yes  None  Dead [1]  5  UC  4.40E+04  [−]  3  Endoscopy  No  GLIDE  AWD [17]  6  CD  5.95E+04  [−]  2/ partial colectomy  Surgery  Yes  None  Dead [1]  7  TB  1.19E+03  NA  5  Endoscopy  No  GLIDE  AWD [10]  8  UC→CD  [−]  [−]  5  Endoscopy  Yes  GLIDE  Dead [7]  9  None  2.15E+03  [+]  2/ subtotal colectomy  Endoscopy  No  LVD  NA  10  CD  2.61E+02  NA  3/ total colectomy  Endoscopy  Yes  None  Dead [2]  11  CD  1.65E+03  NA  2/ ileal resection  Surgery  Yes  None  Dead [2]  12  TB  1.59E+02  [−]  4/ perforation repair  Endoscopy  No  None  AWD[1]  Case  Misdiagnosis  EBV-DNA  EBV-CA-IgA  Endoscopic times/ surgery  Confirmation approach  Development of lymphoma  Chemotherapy/HSCT  Follow-up [month]  1  UC→CD  4.40E+03  [−]  4/ subtotal colectomy  Surgery  Yes  None  Dead [1]  2  UC  1.56E+04  [−]  5/ subtotal colectomy  Surgery  No  GLIDE and HSCT  ANED [21]  3  TB  6.50E+03  [−]  3  Endoscopy  Yes  GLIDE  NA  4  CD  2.88E+03  [+]  5  Endoscopy  Yes  None  Dead [1]  5  UC  4.40E+04  [−]  3  Endoscopy  No  GLIDE  AWD [17]  6  CD  5.95E+04  [−]  2/ partial colectomy  Surgery  Yes  None  Dead [1]  7  TB  1.19E+03  NA  5  Endoscopy  No  GLIDE  AWD [10]  8  UC→CD  [−]  [−]  5  Endoscopy  Yes  GLIDE  Dead [7]  9  None  2.15E+03  [+]  2/ subtotal colectomy  Endoscopy  No  LVD  NA  10  CD  2.61E+02  NA  3/ total colectomy  Endoscopy  Yes  None  Dead [2]  11  CD  1.65E+03  NA  2/ ileal resection  Surgery  Yes  None  Dead [2]  12  TB  1.59E+02  [−]  4/ perforation repair  Endoscopy  No  None  AWD[1]  Cases 9 and 10 were confirmed by endoscopic biopsy performed before the surgery. UC, ulcerative colitis; CD, Crohn’s disease; TB, tuberculosis; GLIDE, gemcitabine, pegaspargase, ifosfamide, dexamethasone, etoposide; LVD, L-asparaginasum, vincristine, dexamethasone; HSCT, haematopoietic stem cell transplantation; ANED, alive no evidence of disease; AWD, alive with disease;NA, not available. View Large 3.5. Therapy and follow-up Data regarding clinical management and follow-up are shown in Table 4. The mean duration of follow-up was 6.3 [range, 1–21] months. In general, the follow-up data exhibit considerable heterogeneity among the patients with respect to prognosis. Among the seven patients with confirmed PIEBV+ NK/T lymphoma, one was lost to follow-up and six patients passed away because of progressive deterioration over a period of 1–7 months after confirmation, despite surgery or chemotherapy in some patients. Among the five remaining patients who did not develop lymphoma, one was lost to follow-up; two patients underwent chemotherapy with GLIDE and maintained a stable condition for 10 and 17 months; and one patient [Case 12] underwent repair of colon perforation 5 days after confirmation and still had recurrent haematochezia and fever during follow-up while waiting for chemotherapy. The other patient [Case 2], who developed secondary haemophagocytic lymphohistiocytosis [HLH], underwent haematopoietic stem cell transplantation [HSCT] and has not demonstrated any evidence of relapse during a 21-month follow-up. 4. Discussion Here we presented the clinical challenge associated with the differential diagnosis of PIEBV+ NK/T-LPD from IBD. In this study, nearly all patients were initially misdiagnosed as having UC or CD. Thus, increased awareness regarding PIEBV+ NK/T-LPD is important for avoiding misdiagnosis. Analysis of this series demonstrated considerable heterogeneity among patients and a strong similarity between PIEBV+ NK/T-LPD and IBD. The possible reasons for misdiagnosis and key aspects of the differential diagnosis between these two entities are further discussed in detail below. In this study, a distinct heterogeneity in clinical progression was observed regardless of lymphoma development. The time to arrive at a definite diagnosis ranged from months to years [up to a decade in one case]. The prolonged disease course is more common in chronic inflammation associated with IBD rather than that with LPD, which is liable to mislead doctors in clinical practice. In addition to a prolonged medical history, PIEBV+ NK/T-LPD may have other symptomatic overlaps with IBD, such as diarrhoea and fever.29–31 In our study, fever was the most common symptom, whereas diarrhoea was much less common. However, among these patients, fever was typically moderate-to-high grade and recurrent in nature, with spontaneous attenuation observed within 24 h in the absence of any treatment in most cases; this fever pattern is quite distinct from that typically observed in patients with IBD. Secondly, transmural inflammation is a hallmark pathological characteristic of CD, which can lead to intestinal perforation and fistula. Perforation also occurs in patients with primary intestinal NK/T-cell lymphoma [prevalence ranging 32.7–57.9%].32–36 In our series, intestinal perforation occurred in six cases [50%]; of these, colectomy was performed in five and transmural lesions were clearly demonstrated on histopathological examination of all surgical specimens. However, despite the relatively high frequency of perforation in this series, perianal lesions were less common compared with typical CD cases. PIEBV+ NK/T-LPD could not be differentiated from IBD based on routine endoscopic or pathological findings. In contrast, sporadic reports have documented similar endoscopic findings in patients with PIEBV+ LPD and those with UC, CD, or TB.21,22,37 In the present series, the patients had diffuse inflammation with sporadic ulcers throughout the colorectum or have normal mucosa in between multisegmental ulcers, which resembles typical endoscopic findings associated with UC and CD, respectively. Although cobblestone appearance was not found in any of the patients in this series, irregular, varying-sized ulcers with longitudinal, transverse, or even annular configuration were observed in most patients. Pathological features of LPD also resemble those of IBD and TB. For example, Braylan et al.38 described a case of B-cell lymphoma characterised by non-necrotic granulomas with no associated CD. Blanco et al.39 identified necrotic granulomas in a case of B-cell lymphoma with no associated TB. Likewise, a non-caseating granuloma was found in a patient with confirmed PIEBV + NK/T lymphoma in the present series [Case 1]. Furthermore, although NK/T-LPD is associated with some characteristic histological presentations such as clusters of medium- or small-sized lymphoid cells with ALCs, LELs, and angiocentric infiltrates, EBV-induced lymphoid cells tend to be dispersed in the mucosa at the early stage, making it difficult to distinguish these from reactive ones. Despite the similar clinical, endoscopic, and even histopathological features between these two disorders, PIEBV+ NK/T-LPD possess some distinctive immunophenotypic features, including NK/T cells [CD3ε positive] expressing EBER, CD56 [NK-cell type] and monoclonal TCRγ gene [T-cell type], and negative expression of CD5.32–36 Furthermore, NK/T-LPD with positive EBER usually shows positive expression of activated cytotoxic phenotype of TIA-1, GB, and perforin.4 EBV is strongly associated with NK/T-LPD, with a prevalence of 76–97.6%.37,40,41 However, there is no definitive evidence of the association between EBV status and the prognosis of patients with LPD.42–44 In contrast, T-cell LPD with monoclonal TCRγ gene rearrangement may be associated with poor clinical outcomes.45,46 Ki67 is also a predictive prognostic marker for NK/T-LPD.47 However, there is much variability in the current series with respect to Ki67 index, even in lymphoma patients. This is possibly related to the heterogeneity in stage of disease progression or focal distribution. As reported above, PIEBV+ NK/T-LPD may present with a prolonged clinical course similar to IBD. However, the intermittent pattern of fever should be an alarming sign for considering a diagnosis of PIEBV+ NK/T-LPD in patients who exhibit atypical symptoms such as abdominal pain, haematochezia, and diarrhoea, or those who develop complications such as perforation and fistula. Such patients may present with ulcers of variable sizes and irregular shape, or diffuse inflammation, on endoscopy. Some of the findings may mimic findings seen in IBD or TB. In these patients, biopsies obtained from repeat colonoscopy should be reviewed by experienced pathologists to rule out EBV-induced lymphoid proliferation. We retrospectively re-examined the pathological features of the biopsies in the early stage of disease course for this series before their finally confirmed diagnosis, and found that these tissues already exhibited some characteristic histopathological features of LPD, including clusters of small- or medium-sized lymphoid cells, ALCs, LELs, and angiocentric infiltrates [details shown in Supplementary Table 1, available as Supplementary data at ECCO-JCC online]. In addition, reasonable intestinal surgery may play an important role; sometimes proper diagnosis can only be made in surgical specimens, as endoscopic biopsy only offers limited histopathological data mainly based on mucosal presentation. Primary intestinal LPD may also occur in the setting of IBD. Thiopurine and anti-tumour necrosis factor-alpha [anti-TNF-α] agents (particularly for infliximab [IFX]) may increase the risk of primary intestinal LPD in patients with IBD.17,23 However, such increase has not been observed in large populations of IBD not exposed to immunosuppressants.23,48,49 Nissen et al.50 suggested that occurrence of EBV+ LPD in an IBD setting is liable to have a less aggressive disease course. Since immunosuppressants or anti-TNF therapy may activate EBV, EBV infection should be routinely excluded before initiating such treatment. With respect to the survival benefit of treatments, EBV+ LPD are generally refractory to chemotherapy or immunosuppressants, except in some cases with complicated HLH.4,51 HSCT is an independent predictor of reduced mortality.4 Kimura et al.4 reported a survival rate of 56.48% and lymphoma development rate of 12.04% among 108 patients with EBV+ NK/T-LPD, regardless of lesion characteristics and therapy. In contrast, in this series, we found a relative lower overall survival rate [40%] and a quite higher lymphoma development rate [58.3%]. The differences may be attributable to bias caused by the smaller sample size and smaller proportion of patients who underwent HSCT in our study. In line with this argument, HSCT induced a sustained clinical remission for 21 months in one patient with PIEBV+ NK/T-LPD and HLH [Case 2] in the present study. However, most patients in our study only underwent chemotherapy. This study has three limitations. The first is that it just retrospectively analysed a small-scale case series of PIEBV+ NK/T-LPD. The second is that the study was done at a single medical centre. The last is that the description of this condition sounds quite novel and strange to many clinicians, and the diagnostic criteria were made by us based on literature. In order to further explore the clinical and pathological characteristics of PIEBV+ NK/T-LPD, more studies, in particular large-scale, multi-centre, prospective/retrospective ones, are warranted. In summary, we reported 12 Chinese patients with PIEBV+ NK/T-LPD, who manifested heterogeneous clinicopathological and prognostic characteristics. The disease may affect any segment of the GI tract, with colon and ileocaecum being the most commonly affected segments. Owing to overlapping clinicopathological features, differential diagnosis of PIEBV+ NK/T-LPD from IBD and TB poses a clinical challenge. The possibility of PIEBV+ NK/T-LPD should be considered for patients who exhibit atypical symptoms, particularly those with intermittent fever and showing irregular ulcers of varying sizes endoscopically. Repeat endoscopy combined with deep biopsy or colectomy may increase the possibility of definitive pathological diagnosis. Comprehensive histopathological and virological examinations are critical for confirming a diagnosis. Funding This work was supported by the National Natural Science Foundation of China [Grant Number: 81570502], and by the Research Fund for the Doctoral Program of Higher Education of China [RFDP] [Grant Number: 20130181120041]. Conflict of Interest All the authors declare no conflict of interests. Author Contributions ZW analysed data and drafted the manuscript. WZ reviewed the pathological slides. CL, MZ, YZ, and JM collected and analysed the data, YZ, RH, YW, ZW, and HZ took care of the patients, OQ designed the study. SX edited the manuscript and comments to reviewers. HZ designed the study, edited manuscript, and acted as corresponding author. All authors approved the final version of the manuscript. Supplementary Data Supplementary data to this article can be found online at ECCO-JCC online References 1. Sawada A, Inoue M, Kawa K. 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Primary Intestinal Epstein–Barr Virus-associated Natural Killer/T-cell Lymphoproliferative Disorder: A Disease Mimicking Inflammatory Bowel Disease

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Elsevier Science
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Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1873-9946
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1876-4479
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10.1093/ecco-jcc/jjy043
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Abstract

Abstract Background and Aims Primary intestinal Epstein–Barr virus [EBV]-associated natural killer/T-cell lymphoproliferative disorder [PIEBV+ NK/T-LPD] is a rare clinical entity, which is difficult to differentiate from inflammatory bowel disease [IBD]. We present a series of Chinese patients with PIEBV+ NK/T-LPD to increase awareness among clinicians of this condition. Methods Patients diagnosed with PIEBV+ NK/T-LPD at West China hospital between 2014 and 2016 were included. Clinical and histopathological characteristics were reviewed, and key aspects of differential diagnosis were presented. Results Twelve patients diagnosed with PIEBV+ NK/T-LPD were identified. Initial symptoms included intermittent fever [11/12 patients], abdominal pain [9/12], haematochezia [8/12], and diarrhoea [3/12]. Main endoscopic findings included multisegmental irregular, variable-sized ulcers, isolated giant ulcers, and diffuse inflammation. Colon and ileocaecum were mainly affected in 11 patients. The main PIEBV+ NK/T-LPD immunophenotypic profile of the infiltrating cells was CD3ε-positive NK/T cells characterised by positive T-cell intracellular antigen-1 and granzyme B, with CD5 deletion. In situ hybridisation was positive for EBV-encoded small RNAs 1/2 in all patients. Eleven patients were misdiagnosed with ulcerative colitis [4/11], Crohn’s disease [4/11], or tuberculosis [TB, 3/11], owing to the similar endoscopic and histopathological features. The mean number of endoscopic procedures performed before reaching the diagnosis of PIEBV+ NK/T-LPD was 3.58; in four patients, the diagnosis was confirmed only after surgical resection following complications. Conclusions PIEBV+ NK/T-LPD may be difficult to differentiate from IBD or TB owing to overlapping endoscopic and pathological findings. Early identification of EBV reactivation in tissue samples is essential for the accurate diagnosis. Primary intestinal EBV-associated NK/T-cell lymphoproliferative disorders, inflammatory bowel disease, differential diagnosis 1. Introduction More than 90% of adults are infected with Epstein–Barr virus [EBV] in their life; however, most of them remain asymptomatic throughout their life span. A miniscule proportion of these people develop EBV-associated lymphoproliferative disorder [EBV+ LPD], which has a wide clinical spectrum and exhibits considerable heterogeneity with respect to clinical manifestation and pathological presentation.1–11 EBV can invade T, B, and natural killer [NK] cells. Compared with predominant EBV+ B-cell LPD in Western countries, EBV-associated NK- and T-cell LPD [EBV+ NK/T-LPD] is more common in East Asia and South America.5,10,12–14 EBV+ NK/T-LPD was first incorporated into the 4th World Health Organization classification of tumours of haematopoietic and lymphoid tissues in 2008.4,6,15 Subsequently, Ohshima et al.8 classified EBV+ NK/T-LPD into four categories based on pathological features, ranging from polyclonal pleomorphic to monoclonal monomorphic LPD [including lymphoma]. Other classifications are based on the heterogeneous clinical characteristics, mainly ranging from indolent to aggressive and even a fulminant course.1,7 EBV+ LPD was initially documented in children and young adults with infectious mononucleosis, whereas accumulating evidence has demonstrated that EBV+ NK/T-LPD can occur in adults even older than 30 years, sharing similar clinical features to those in paediatric patients,2–5,10 particularly in patients with comorbidities such as inflammatory bowel disease [IBD], Sjogren’s syndrome, rheumatic arthritis, HIV infection, and those with an organ transplant.16–18 More studies are warranted to explore the clinicopathological features in adult-onset EBV+ NK/T-LPD. Recently, EBV+ NK/T-LPD in adults has become a research focus, whereas published studies have largely pertained to LPD that affects extraintestinal organs. Studies on EBV+ NK/T-LPD with the primary involvement of the gastrointestinal tract [GI tract] have been scarce. Primary intestinal EBV-associated NK/T-Cell LPD [PIEBV+ NK/T-LPD] is defined as NK/T-cell lymphoproliferation that primarily occurs in the GI tract, resulting in gastrointestinal lesions such as inflammation, ulcers, etc. The gut is the most common location for extranodal LPD,19 and the frequency of small intestinal involvement in patients in Western countries is relatively higher than that in patients in Asian countries.20 Clinically, PIEBV+ NK/T-LPD may be associated with atypical symptoms and exhibit non-specific histopathological and radiological characteristics. The clinical presentation of PIEBV+ NK/T-LPD may mimic that of IBD, making differential diagnosis challenging. Zheng et al.21 reported a patient with PIEBV+ T-cell LPD initially misdiagnosed as ulcerative colitis [UC]. Similarly, Na et al.22 reported a patient with PIEBV+ T-cell LPD initially misdiagnosed as tuberculosis [TB] and subsequently as Crohn’s disease [CD], before the final diagnosis was reached. Currently, the literature regarding PIEBV+ NK/T-LPD is limited to sporadic case reports, and comprehensive clinical guidance regarding the differential diagnosis between PIEBV+ NK/T-LPD and IBD is lacking in the published literature. Therefore, we conducted a retrospective study to characterise the clinical and histopathological features of PIEBV+ NK/T-LPD. Our findings may facilitate a better understanding among clinicians of this subset of LPD and aid in the differential diagnosis in clinical settings. 2. Materials and Methods All patients diagnosed with PIEBV+ NK/T-LPD between January 2014 and April 2017 were identified from electronic medical records at the West China Hospital. Inclusion and exclusion criteria are shown in Table 1. In general, included are patients with a pathological diagnosis of NK/T-LPD and definitive evidence of EBV infection in the GI tract lesions.8,11,19,23–25 Patients diagnosed with IBD,26,27 TB, or non-primary intestinal NK/T-LPD were excluded. In total, 12 patients with PIEBV+ NK/T-LPD were included; data regarding demographic, endoscopic, surgical, pathological, virological, and follow-up characteristics were collected. Table 1. Definition of PIEBV+ NK/T-LPD in this study. [1] Illness ≥3 months duration  [2] EBER+ cells [T or NK cells] in affected intestinal tissues  [3] Characteristic pathological findings of lymphoid proliferation of T or NK cells with positive cytotoxic molecules of TIA-1 or granzyme B  [4] No identifiable underlying immunological abnormalities  [5] Presenting with predominantly digestive symptoms and gastrointestinal extranodal lesions  [6] Excluded comorbid IBDa or TB  [1] Illness ≥3 months duration  [2] EBER+ cells [T or NK cells] in affected intestinal tissues  [3] Characteristic pathological findings of lymphoid proliferation of T or NK cells with positive cytotoxic molecules of TIA-1 or granzyme B  [4] No identifiable underlying immunological abnormalities  [5] Presenting with predominantly digestive symptoms and gastrointestinal extranodal lesions  [6] Excluded comorbid IBDa or TB  EBER, EBV-encoded small RNA; TIA-1, T-cell intracellular antigen-1; IBD, inflammatory bowel disease; TB, tuberculosis. aIBD is diagnosed based on accepted criteria including characteristic clinical, endoscopic, radiographic, and histological findings.26,27 View Large Table 1. Definition of PIEBV+ NK/T-LPD in this study. [1] Illness ≥3 months duration  [2] EBER+ cells [T or NK cells] in affected intestinal tissues  [3] Characteristic pathological findings of lymphoid proliferation of T or NK cells with positive cytotoxic molecules of TIA-1 or granzyme B  [4] No identifiable underlying immunological abnormalities  [5] Presenting with predominantly digestive symptoms and gastrointestinal extranodal lesions  [6] Excluded comorbid IBDa or TB  [1] Illness ≥3 months duration  [2] EBER+ cells [T or NK cells] in affected intestinal tissues  [3] Characteristic pathological findings of lymphoid proliferation of T or NK cells with positive cytotoxic molecules of TIA-1 or granzyme B  [4] No identifiable underlying immunological abnormalities  [5] Presenting with predominantly digestive symptoms and gastrointestinal extranodal lesions  [6] Excluded comorbid IBDa or TB  EBER, EBV-encoded small RNA; TIA-1, T-cell intracellular antigen-1; IBD, inflammatory bowel disease; TB, tuberculosis. aIBD is diagnosed based on accepted criteria including characteristic clinical, endoscopic, radiographic, and histological findings.26,27 View Large Histological review: immunohistochemistry [CD3ε, CD5, CD56, granzyme B [GB], T-cell intracellular antigen-1 [TIA-1], and Ki67], in situ hybridisation for EBV-encoded small RNA 1/2 [EBER] and T-cell clonality for the T-cell receptor γ [TCRγ] were performed [see Supplementary Methods, available as Supplementary data at ECCO-JCC online]. EBV-positive cell lineage was determined using staining for CD3ε, CD56, and T-cell clonality as previously described [details shown in Supplementary Methods]. This study was approved by the local Ethics Committee of West China Hospital. The study protocol complied with the principles of the Declaration of Helsinki. 3. Results 3.1. Demographics Demographic and clinical characteristics of 12 patients are listed in Table 2. The mean age at diagnosis was 38.75 [range, 24–54] years; the mean duration between initial presentation and final diagnosis was 2.53 years [3 months-10 years]. Initial symptoms included intermittent moderate-to-high fever [11/12 patients], abdominal pain [9/12], haematochezia [8/12], diarrhoea [3/12], and weight loss [1/12]. Complications related to the GI tract included bowel perforation [6/12], haemorrhage [2/12], and obstruction [1/12]. None of these patients had a history of transplantation, HIV infection, or exposure to immunosuppressants (except for one patient who received infliximab [IFX] owing to the misdiagnosis of CD). Table 2. Clinical characteristics of 12 patients with PIEBV+ NK/T-LPD. Case  Age/sex  DCBC  Initial symptoms  Treatment history  Affected sites  Complications  Endoscopic findings  1  54/M  5 y  Abdominal pain, haematochezia, fever  5-ASA, GC  AC, TC, DC, SC  Perforation, haemorrhage  MIVUs [0.6-4.0 cm] including a longitudinal ulcer  2  31/F  10 y  Abdominal pain, haematochezia, fever  5-ASA, GC  Whole colorectum  Haemorrhage and HLH  Diffuse inflammation, sporadic small [0.2-0.6 cm] ulcers  3  24/F  3 m  Haematochezia, fever  Anti-TB therapy  IC, AC, SC, rectum  -  MIVUs [0.4-1.2 cm]  4  49M  1 y  Abdominal pain, weight loss  5-ASA, IFX [four times]  IC  Perforation  Isolated annular ulcer  5  40/M  3 y  Abdominal pain, haematochezia, fever  5-ASA  IC and whole colorectum  -  Diffuse inflammation, sporadic [0.2-0.6 cm] ulcers  6  35/M  3 y  Abdominal pain, haematochezia, fever  None  AC, TC, SC  Perforation  Multiple irregular [0.3-1.6 cm] ulcers  7  47/M  9 m  Diarrhoea, fever  Anti-TB therapy  IC, AC, TC, DC, SC, rectum  -  MIVUs [0.2-4.0 cm] including one transverse ulcer  8  30/F  2 y  Abdominal pain, diarrhoea, fever  5-ASA, Anti-TB therapy  TC, rectum  -  Two irregular [both transverse-like] ulcers  9  39/F  4 y  Haematochezia, fever  None  IC, AC, TC, DC  Perforation  MIVUs [1.0-2.0 cm] including one transverse ulcer  10  53/F  9 m  Abdominal pain, diarrhoea, fever  5-ASA, GC  IC, AC, TC, DC, SC  -  MIVUs [0.4-1.2 cm] including one transverse ulcer  11  34/F  5 m  Abdominal pain, haematochezia, fever  None  Ileum  Perforation, obstruction  Multiple round [0.4-1.6 cm] ulcers  12  29/M  3 m  Abdominal pain, haematochezia, fever  Anti-TB therapy  IC, AC, DC, SC  Perforation  MIVUs [0.6-4.0 cm] including one transverse ulcer  Case  Age/sex  DCBC  Initial symptoms  Treatment history  Affected sites  Complications  Endoscopic findings  1  54/M  5 y  Abdominal pain, haematochezia, fever  5-ASA, GC  AC, TC, DC, SC  Perforation, haemorrhage  MIVUs [0.6-4.0 cm] including a longitudinal ulcer  2  31/F  10 y  Abdominal pain, haematochezia, fever  5-ASA, GC  Whole colorectum  Haemorrhage and HLH  Diffuse inflammation, sporadic small [0.2-0.6 cm] ulcers  3  24/F  3 m  Haematochezia, fever  Anti-TB therapy  IC, AC, SC, rectum  -  MIVUs [0.4-1.2 cm]  4  49M  1 y  Abdominal pain, weight loss  5-ASA, IFX [four times]  IC  Perforation  Isolated annular ulcer  5  40/M  3 y  Abdominal pain, haematochezia, fever  5-ASA  IC and whole colorectum  -  Diffuse inflammation, sporadic [0.2-0.6 cm] ulcers  6  35/M  3 y  Abdominal pain, haematochezia, fever  None  AC, TC, SC  Perforation  Multiple irregular [0.3-1.6 cm] ulcers  7  47/M  9 m  Diarrhoea, fever  Anti-TB therapy  IC, AC, TC, DC, SC, rectum  -  MIVUs [0.2-4.0 cm] including one transverse ulcer  8  30/F  2 y  Abdominal pain, diarrhoea, fever  5-ASA, Anti-TB therapy  TC, rectum  -  Two irregular [both transverse-like] ulcers  9  39/F  4 y  Haematochezia, fever  None  IC, AC, TC, DC  Perforation  MIVUs [1.0-2.0 cm] including one transverse ulcer  10  53/F  9 m  Abdominal pain, diarrhoea, fever  5-ASA, GC  IC, AC, TC, DC, SC  -  MIVUs [0.4-1.2 cm] including one transverse ulcer  11  34/F  5 m  Abdominal pain, haematochezia, fever  None  Ileum  Perforation, obstruction  Multiple round [0.4-1.6 cm] ulcers  12  29/M  3 m  Abdominal pain, haematochezia, fever  Anti-TB therapy  IC, AC, DC, SC  Perforation  MIVUs [0.6-4.0 cm] including one transverse ulcer  DCBC:disease course before confirmation; M, male; F, female; y, year; m, month; 5-ASA, 5-aminosalicylic acid; GC, glucocorticoid; IFX, infliximab; TB, tuberculosis; IC: ileocaecum, AC, ascending colon; TC, transverse colon; DC, descending colon; SC, sigmoid colon; HLH, haemophagocytic lymphohistiocytosis; MIVUs, multiple irregular, variable-sized ulcers. View Large Table 2. Clinical characteristics of 12 patients with PIEBV+ NK/T-LPD. Case  Age/sex  DCBC  Initial symptoms  Treatment history  Affected sites  Complications  Endoscopic findings  1  54/M  5 y  Abdominal pain, haematochezia, fever  5-ASA, GC  AC, TC, DC, SC  Perforation, haemorrhage  MIVUs [0.6-4.0 cm] including a longitudinal ulcer  2  31/F  10 y  Abdominal pain, haematochezia, fever  5-ASA, GC  Whole colorectum  Haemorrhage and HLH  Diffuse inflammation, sporadic small [0.2-0.6 cm] ulcers  3  24/F  3 m  Haematochezia, fever  Anti-TB therapy  IC, AC, SC, rectum  -  MIVUs [0.4-1.2 cm]  4  49M  1 y  Abdominal pain, weight loss  5-ASA, IFX [four times]  IC  Perforation  Isolated annular ulcer  5  40/M  3 y  Abdominal pain, haematochezia, fever  5-ASA  IC and whole colorectum  -  Diffuse inflammation, sporadic [0.2-0.6 cm] ulcers  6  35/M  3 y  Abdominal pain, haematochezia, fever  None  AC, TC, SC  Perforation  Multiple irregular [0.3-1.6 cm] ulcers  7  47/M  9 m  Diarrhoea, fever  Anti-TB therapy  IC, AC, TC, DC, SC, rectum  -  MIVUs [0.2-4.0 cm] including one transverse ulcer  8  30/F  2 y  Abdominal pain, diarrhoea, fever  5-ASA, Anti-TB therapy  TC, rectum  -  Two irregular [both transverse-like] ulcers  9  39/F  4 y  Haematochezia, fever  None  IC, AC, TC, DC  Perforation  MIVUs [1.0-2.0 cm] including one transverse ulcer  10  53/F  9 m  Abdominal pain, diarrhoea, fever  5-ASA, GC  IC, AC, TC, DC, SC  -  MIVUs [0.4-1.2 cm] including one transverse ulcer  11  34/F  5 m  Abdominal pain, haematochezia, fever  None  Ileum  Perforation, obstruction  Multiple round [0.4-1.6 cm] ulcers  12  29/M  3 m  Abdominal pain, haematochezia, fever  Anti-TB therapy  IC, AC, DC, SC  Perforation  MIVUs [0.6-4.0 cm] including one transverse ulcer  Case  Age/sex  DCBC  Initial symptoms  Treatment history  Affected sites  Complications  Endoscopic findings  1  54/M  5 y  Abdominal pain, haematochezia, fever  5-ASA, GC  AC, TC, DC, SC  Perforation, haemorrhage  MIVUs [0.6-4.0 cm] including a longitudinal ulcer  2  31/F  10 y  Abdominal pain, haematochezia, fever  5-ASA, GC  Whole colorectum  Haemorrhage and HLH  Diffuse inflammation, sporadic small [0.2-0.6 cm] ulcers  3  24/F  3 m  Haematochezia, fever  Anti-TB therapy  IC, AC, SC, rectum  -  MIVUs [0.4-1.2 cm]  4  49M  1 y  Abdominal pain, weight loss  5-ASA, IFX [four times]  IC  Perforation  Isolated annular ulcer  5  40/M  3 y  Abdominal pain, haematochezia, fever  5-ASA  IC and whole colorectum  -  Diffuse inflammation, sporadic [0.2-0.6 cm] ulcers  6  35/M  3 y  Abdominal pain, haematochezia, fever  None  AC, TC, SC  Perforation  Multiple irregular [0.3-1.6 cm] ulcers  7  47/M  9 m  Diarrhoea, fever  Anti-TB therapy  IC, AC, TC, DC, SC, rectum  -  MIVUs [0.2-4.0 cm] including one transverse ulcer  8  30/F  2 y  Abdominal pain, diarrhoea, fever  5-ASA, Anti-TB therapy  TC, rectum  -  Two irregular [both transverse-like] ulcers  9  39/F  4 y  Haematochezia, fever  None  IC, AC, TC, DC  Perforation  MIVUs [1.0-2.0 cm] including one transverse ulcer  10  53/F  9 m  Abdominal pain, diarrhoea, fever  5-ASA, GC  IC, AC, TC, DC, SC  -  MIVUs [0.4-1.2 cm] including one transverse ulcer  11  34/F  5 m  Abdominal pain, haematochezia, fever  None  Ileum  Perforation, obstruction  Multiple round [0.4-1.6 cm] ulcers  12  29/M  3 m  Abdominal pain, haematochezia, fever  Anti-TB therapy  IC, AC, DC, SC  Perforation  MIVUs [0.6-4.0 cm] including one transverse ulcer  DCBC:disease course before confirmation; M, male; F, female; y, year; m, month; 5-ASA, 5-aminosalicylic acid; GC, glucocorticoid; IFX, infliximab; TB, tuberculosis; IC: ileocaecum, AC, ascending colon; TC, transverse colon; DC, descending colon; SC, sigmoid colon; HLH, haemophagocytic lymphohistiocytosis; MIVUs, multiple irregular, variable-sized ulcers. View Large 3.2. Endoscopy and radiology In this study, all patients underwent gastroscopy and colonoscopy. A key finding was that the disease may involve any site from the jejunum to the rectum; however, the colon and ileocaecum were most commonly affected in this cohort. The most frequently affected segments were the ascending colon [9/12], transverse colon [8/12], sigmoid colon [8/12], ileocaecum [7/12], descending colon [7/12], and rectum [5/12]. Ileal involvement was only observed in one case [Table 2]. The disease affected more than one intestinal segment in most cases. For example, eight patients exhibited ulcers in multiple segments, five of which exhibited ileocaecal involvement. A single intestinal segment was involved in only two patients [ileocaecum in Case 4 and ileum in Case 11]. The remaining two patients showed diffuse colorectal inflammation [Case 2 and Case 5]. The lesions were mainly in the form of ulcers with variable morphological characteristics. The ulcers were variable in size and included isolated or multisegmental, annular, round, and irregular ulcers [Table 2 and Figure 1]. For example, lesions in patients with multisegmental involvement included multiple irregular, variable-sized ulcers that were interspersed with normal mucosa between ulcers; some giant ulcers were transverse [5/8] or longitudinal [1/8] [Table 2]. In addition, all 12 patients underwent computed tomography enterography or magnetic resonance imaging, which showed non-specific manifestations such as multisegmental thickening of the intestinal walls and enlarged peripheral intestinal and mesenteric lymph nodes, in all cases. Figure 1. View largeDownload slide Typical endoscopic findings of PIEBV+ NK/T-LPD. [A] Diffuse inflammation with sporadic ulcers in the descending colon [case 5]; [B] longitudinally arranged ulcers in the ascending colon [case 1]; [C] isolated annular ulcer in the ileocaecum [Case 4]; [D] multifocal irregular ulcers in the ascending colon [Case 9]. Figure 1. View largeDownload slide Typical endoscopic findings of PIEBV+ NK/T-LPD. [A] Diffuse inflammation with sporadic ulcers in the descending colon [case 5]; [B] longitudinally arranged ulcers in the ascending colon [case 1]; [C] isolated annular ulcer in the ileocaecum [Case 4]; [D] multifocal irregular ulcers in the ascending colon [Case 9]. 3.3. Histopathology and virology 3.3.1. Histomorphology The common histomorphological findings in biopsy included chronic mucosal/submucosal inflammatory infiltrates with clusters of medium- or small-sized lymphoid cells, erosions, and ulcers, in all patients. Moreover, all surgical specimens demonstrated transmural lesions. Atypical lymphoid cells [ALCs; 9/12], lymphoepithelial lesions [LELs; 3/12], and angiocentric infiltration [3/12] were observed in some patients. However, some patients exhibited crypt abscesses [3/12], anomalies in structure or number of glands [6/12], gangliocyte hyperplasia [4/12], and even non-caseating granulomas [1/12], which mimicked the histological characteristics of IBD [Table 3 and Figure 2]. Figure 2. View largeDownload slide Histopathological findings of PIEBV+ NK/T-LPD. Haematoxylin and eosin [H&E] staining showed fissure ulcer [A], reduced number of glands [A], gangliocyte hyperplasia [B], and transmural medium-sized lymphoid cell infiltrates with atypical lymphoid cell infiltrates [B]. H&E staining showed mucosal lymphoid cell infiltrates with atypical lymphoid cell infiltrates [C and D], lymphoepithelial lesions [C], and angiocentric infiltration [D]. Immunohistochemical staining revealed positive expressions of CD3ε [E], CD56 [F], granzyme B [G], and T-cell intracellular antigen-1 [H]. In situ hybridisation indicates positive EBER [I]. Immunohistochemical staining revealed Ki67 index at 30% [J]. A, original magnification ×100; B, original magnification ×400 [Case 1]; C, original magnification ×200; D, original magnification ×400 [Case 8]; E, F, G, and H, original magnification ×400 [Case 8]; I, original magnification×400 [Case 8]; J, original magnification ×400 [Case 8]. Figure 2. View largeDownload slide Histopathological findings of PIEBV+ NK/T-LPD. Haematoxylin and eosin [H&E] staining showed fissure ulcer [A], reduced number of glands [A], gangliocyte hyperplasia [B], and transmural medium-sized lymphoid cell infiltrates with atypical lymphoid cell infiltrates [B]. H&E staining showed mucosal lymphoid cell infiltrates with atypical lymphoid cell infiltrates [C and D], lymphoepithelial lesions [C], and angiocentric infiltration [D]. Immunohistochemical staining revealed positive expressions of CD3ε [E], CD56 [F], granzyme B [G], and T-cell intracellular antigen-1 [H]. In situ hybridisation indicates positive EBER [I]. Immunohistochemical staining revealed Ki67 index at 30% [J]. A, original magnification ×100; B, original magnification ×400 [Case 1]; C, original magnification ×200; D, original magnification ×400 [Case 8]; E, F, G, and H, original magnification ×400 [Case 8]; I, original magnification×400 [Case 8]; J, original magnification ×400 [Case 8]. 3.3.2. Immunophenotype Among the 12 patients, the main phenotype of EBV-infected cells was T cell in six patients and NK cell in the remaining six patients. For the infiltrating lymphocytes, positive expression of CD3ε was observed in all 12 patients, that of CD56 was observed in 7/12 patients, and monoclonal TCRγ chain gene rearrangement was confirmed in 4/10 patients. CD5 deletion was observed in 9/12 patients. Positive expression of cytotoxic molecules of GB and TIA-1 was observed in 8/10 and in 8/8 patients, respectively. Ki67 positivity ranged from 5% to 80%, and high Ki67 index [≥65%]28 was found in 3/11 patients [Table 3 and Figure 2]. Table 3. Histopathological expressions of 12 patients with PIEBV+ NK/T-LPD. Case  Histological findings  Cell lineage  EBER  CD3ε  CD5  CD56  TIA-1  GB  Ki67, %  TCRγ  1  Transmural medium-sized LCI, ALCs, angiocentric infiltration, erosions, ulcers, reduced number of glands, gangliocyte hyperplasia, non-caseating granulomas  NK  +  +  −  +  +  +  20  −  2  Transmural medium-sized LCI, ALCs, LELs, erosions, distorted glands and reduced gland secretion, gangliocyte hyperplasia  T  +  +  −  −  +  NA  70  −  3  Mucosal medium-sized LIC, ALCs, ulcers, erosions, crypt abscesses  NK  +  +  −  +  +  ±  30  −  4  Mucosal focal LCI, ALCs, ulcers, atrophic glands  T  +  +  +  −  +  NA  10  +  5  Mucosal focal LCI, distorted glands  T  +  +  +  −  +  −  NA  NA  6  Transmural small-sized LCI, ALCs, ulcers  NK  +  +  −  +  NA  +  70  NA  7  Mucosal/submucosal LCI, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  NK  +  +  −  +  NA  +  40  −  8  Mucosal/submucosal LCI, ALCs, LELs, angiocentric infiltration, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  T  +  +  −  −  NA  +  30  +  9  Transmural small-sized LCI, erosions, ulcers  T  +  +  +  +  +  +  5–10  +  10  Transmural medium- or small-sized LCI, ALCs, ulcers  T  +  +  −  −  NA  +  50  +  11  Transmural small-sized LCI, ALCs  NK  +  +  −  +  +  +  80  −  12  Mucosal LCI, ALCs, LELs, angiocentric infiltration  NK  +  +  −  +  +  +  60  −  Case  Histological findings  Cell lineage  EBER  CD3ε  CD5  CD56  TIA-1  GB  Ki67, %  TCRγ  1  Transmural medium-sized LCI, ALCs, angiocentric infiltration, erosions, ulcers, reduced number of glands, gangliocyte hyperplasia, non-caseating granulomas  NK  +  +  −  +  +  +  20  −  2  Transmural medium-sized LCI, ALCs, LELs, erosions, distorted glands and reduced gland secretion, gangliocyte hyperplasia  T  +  +  −  −  +  NA  70  −  3  Mucosal medium-sized LIC, ALCs, ulcers, erosions, crypt abscesses  NK  +  +  −  +  +  ±  30  −  4  Mucosal focal LCI, ALCs, ulcers, atrophic glands  T  +  +  +  −  +  NA  10  +  5  Mucosal focal LCI, distorted glands  T  +  +  +  −  +  −  NA  NA  6  Transmural small-sized LCI, ALCs, ulcers  NK  +  +  −  +  NA  +  70  NA  7  Mucosal/submucosal LCI, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  NK  +  +  −  +  NA  +  40  −  8  Mucosal/submucosal LCI, ALCs, LELs, angiocentric infiltration, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  T  +  +  −  −  NA  +  30  +  9  Transmural small-sized LCI, erosions, ulcers  T  +  +  +  +  +  +  5–10  +  10  Transmural medium- or small-sized LCI, ALCs, ulcers  T  +  +  −  −  NA  +  50  +  11  Transmural small-sized LCI, ALCs  NK  +  +  −  +  +  +  80  −  12  Mucosal LCI, ALCs, LELs, angiocentric infiltration  NK  +  +  −  +  +  +  60  −  LCI, lymphoid cell infiltrate; ALCs, atypical lymphoid cells; LELs, lymphoepithelial lesions; EBER, EBV-encoded small RNA; TIA-1, T-cell intracellular antigen-1; GB, granzyme B, NA, not available. View Large Table 3. Histopathological expressions of 12 patients with PIEBV+ NK/T-LPD. Case  Histological findings  Cell lineage  EBER  CD3ε  CD5  CD56  TIA-1  GB  Ki67, %  TCRγ  1  Transmural medium-sized LCI, ALCs, angiocentric infiltration, erosions, ulcers, reduced number of glands, gangliocyte hyperplasia, non-caseating granulomas  NK  +  +  −  +  +  +  20  −  2  Transmural medium-sized LCI, ALCs, LELs, erosions, distorted glands and reduced gland secretion, gangliocyte hyperplasia  T  +  +  −  −  +  NA  70  −  3  Mucosal medium-sized LIC, ALCs, ulcers, erosions, crypt abscesses  NK  +  +  −  +  +  ±  30  −  4  Mucosal focal LCI, ALCs, ulcers, atrophic glands  T  +  +  +  −  +  NA  10  +  5  Mucosal focal LCI, distorted glands  T  +  +  +  −  +  −  NA  NA  6  Transmural small-sized LCI, ALCs, ulcers  NK  +  +  −  +  NA  +  70  NA  7  Mucosal/submucosal LCI, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  NK  +  +  −  +  NA  +  40  −  8  Mucosal/submucosal LCI, ALCs, LELs, angiocentric infiltration, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  T  +  +  −  −  NA  +  30  +  9  Transmural small-sized LCI, erosions, ulcers  T  +  +  +  +  +  +  5–10  +  10  Transmural medium- or small-sized LCI, ALCs, ulcers  T  +  +  −  −  NA  +  50  +  11  Transmural small-sized LCI, ALCs  NK  +  +  −  +  +  +  80  −  12  Mucosal LCI, ALCs, LELs, angiocentric infiltration  NK  +  +  −  +  +  +  60  −  Case  Histological findings  Cell lineage  EBER  CD3ε  CD5  CD56  TIA-1  GB  Ki67, %  TCRγ  1  Transmural medium-sized LCI, ALCs, angiocentric infiltration, erosions, ulcers, reduced number of glands, gangliocyte hyperplasia, non-caseating granulomas  NK  +  +  −  +  +  +  20  −  2  Transmural medium-sized LCI, ALCs, LELs, erosions, distorted glands and reduced gland secretion, gangliocyte hyperplasia  T  +  +  −  −  +  NA  70  −  3  Mucosal medium-sized LIC, ALCs, ulcers, erosions, crypt abscesses  NK  +  +  −  +  +  ±  30  −  4  Mucosal focal LCI, ALCs, ulcers, atrophic glands  T  +  +  +  −  +  NA  10  +  5  Mucosal focal LCI, distorted glands  T  +  +  +  −  +  −  NA  NA  6  Transmural small-sized LCI, ALCs, ulcers  NK  +  +  −  +  NA  +  70  NA  7  Mucosal/submucosal LCI, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  NK  +  +  −  +  NA  +  40  −  8  Mucosal/submucosal LCI, ALCs, LELs, angiocentric infiltration, ulcers, distorted glands and reduced gland secretion, crypt abscesses, gangliocyte hyperplasia  T  +  +  −  −  NA  +  30  +  9  Transmural small-sized LCI, erosions, ulcers  T  +  +  +  +  +  +  5–10  +  10  Transmural medium- or small-sized LCI, ALCs, ulcers  T  +  +  −  −  NA  +  50  +  11  Transmural small-sized LCI, ALCs  NK  +  +  −  +  +  +  80  −  12  Mucosal LCI, ALCs, LELs, angiocentric infiltration  NK  +  +  −  +  +  +  60  −  LCI, lymphoid cell infiltrate; ALCs, atypical lymphoid cells; LELs, lymphoepithelial lesions; EBER, EBV-encoded small RNA; TIA-1, T-cell intracellular antigen-1; GB, granzyme B, NA, not available. View Large 3.3.3. Virological expression In situ hybridisation revealed mucosal EBER positivity in all 12 patients, whereas peripheral blood EBV-DNA [>1000 copies/mL] and EBV-capsid antigen-IgA [EBV-CA-IgA] were positive in 9/12 and 2/9 patients, respectively [Table 3 and Figure 2]. 3.4. Diagnostic data 3.4.1. Endoscopic and surgical data The mean number of endoscopic examinations performed for each patient before eventual confirmation of diagnosis was 3.58. In none of the patients was LPD diagnosis confirmed after a single endoscopy. In one patient [Case 9], the final diagnosis was confirmed after two endoscopic examinations based on biopsies. Two patients [Case 6 and Case 11] developed bowel perforation after two endoscopic procedures; the final diagnosis in these two patients was based on the histopathological examination of surgical specimens. In two patients [Case 1 and Case 2], the correct diagnosis was not made even after multiple endoscopic procedures; the diagnosis was finally confirmed based on histopathological examination of surgical specimens obtained in an emergency surgery that was necessitated owing to serious complications [perforation and haemorrhage]. The remaining seven patients underwent three to five endoscopic examinations before the diagnosis was confirmed [Table 4]. 3.4.2. Misdiagnosis data Patients with PIEBV+ NK/T-LPD are at high risk for misdiagnosis, considering that clinical manifestations are largely indistinguishable from other disorders. Routine histopathological examinations may not reveal characteristic features of LPD. In this series, 11 patients were misdiagnosed as having UC [4 cases], CD [4], or TB [3] before the eventual confirmation of diagnosis [Table 4]. Two patients [Cases 1 and 8] were initially misdiagnosed as having UC and later as having CD, considering the endoscopic and radiological characteristics of multisegmental involvement; moreover, non-caseating granuloma was found in one patient [Case 1] histologically. Eventually, all 12 cases were pathologically confirmed as PIEBV+ NK/T-LPD. Furthermore, in seven patients, a more specific diagnosis of NK/T lymphoma, an advanced stage of PIEBV+ NK/T-LPD, was made [Table 4]. Table 4. Diagnosis and follow-up of 12 patients with PIEBV+ NK/T-LPD. Case  Misdiagnosis  EBV-DNA  EBV-CA-IgA  Endoscopic times/ surgery  Confirmation approach  Development of lymphoma  Chemotherapy/HSCT  Follow-up [month]  1  UC→CD  4.40E+03  [−]  4/ subtotal colectomy  Surgery  Yes  None  Dead [1]  2  UC  1.56E+04  [−]  5/ subtotal colectomy  Surgery  No  GLIDE and HSCT  ANED [21]  3  TB  6.50E+03  [−]  3  Endoscopy  Yes  GLIDE  NA  4  CD  2.88E+03  [+]  5  Endoscopy  Yes  None  Dead [1]  5  UC  4.40E+04  [−]  3  Endoscopy  No  GLIDE  AWD [17]  6  CD  5.95E+04  [−]  2/ partial colectomy  Surgery  Yes  None  Dead [1]  7  TB  1.19E+03  NA  5  Endoscopy  No  GLIDE  AWD [10]  8  UC→CD  [−]  [−]  5  Endoscopy  Yes  GLIDE  Dead [7]  9  None  2.15E+03  [+]  2/ subtotal colectomy  Endoscopy  No  LVD  NA  10  CD  2.61E+02  NA  3/ total colectomy  Endoscopy  Yes  None  Dead [2]  11  CD  1.65E+03  NA  2/ ileal resection  Surgery  Yes  None  Dead [2]  12  TB  1.59E+02  [−]  4/ perforation repair  Endoscopy  No  None  AWD[1]  Case  Misdiagnosis  EBV-DNA  EBV-CA-IgA  Endoscopic times/ surgery  Confirmation approach  Development of lymphoma  Chemotherapy/HSCT  Follow-up [month]  1  UC→CD  4.40E+03  [−]  4/ subtotal colectomy  Surgery  Yes  None  Dead [1]  2  UC  1.56E+04  [−]  5/ subtotal colectomy  Surgery  No  GLIDE and HSCT  ANED [21]  3  TB  6.50E+03  [−]  3  Endoscopy  Yes  GLIDE  NA  4  CD  2.88E+03  [+]  5  Endoscopy  Yes  None  Dead [1]  5  UC  4.40E+04  [−]  3  Endoscopy  No  GLIDE  AWD [17]  6  CD  5.95E+04  [−]  2/ partial colectomy  Surgery  Yes  None  Dead [1]  7  TB  1.19E+03  NA  5  Endoscopy  No  GLIDE  AWD [10]  8  UC→CD  [−]  [−]  5  Endoscopy  Yes  GLIDE  Dead [7]  9  None  2.15E+03  [+]  2/ subtotal colectomy  Endoscopy  No  LVD  NA  10  CD  2.61E+02  NA  3/ total colectomy  Endoscopy  Yes  None  Dead [2]  11  CD  1.65E+03  NA  2/ ileal resection  Surgery  Yes  None  Dead [2]  12  TB  1.59E+02  [−]  4/ perforation repair  Endoscopy  No  None  AWD[1]  Cases 9 and 10 were confirmed by endoscopic biopsy performed before the surgery. UC, ulcerative colitis; CD, Crohn’s disease; TB, tuberculosis; GLIDE, gemcitabine, pegaspargase, ifosfamide, dexamethasone, etoposide; LVD, L-asparaginasum, vincristine, dexamethasone; HSCT, haematopoietic stem cell transplantation; ANED, alive no evidence of disease; AWD, alive with disease;NA, not available. View Large Table 4. Diagnosis and follow-up of 12 patients with PIEBV+ NK/T-LPD. Case  Misdiagnosis  EBV-DNA  EBV-CA-IgA  Endoscopic times/ surgery  Confirmation approach  Development of lymphoma  Chemotherapy/HSCT  Follow-up [month]  1  UC→CD  4.40E+03  [−]  4/ subtotal colectomy  Surgery  Yes  None  Dead [1]  2  UC  1.56E+04  [−]  5/ subtotal colectomy  Surgery  No  GLIDE and HSCT  ANED [21]  3  TB  6.50E+03  [−]  3  Endoscopy  Yes  GLIDE  NA  4  CD  2.88E+03  [+]  5  Endoscopy  Yes  None  Dead [1]  5  UC  4.40E+04  [−]  3  Endoscopy  No  GLIDE  AWD [17]  6  CD  5.95E+04  [−]  2/ partial colectomy  Surgery  Yes  None  Dead [1]  7  TB  1.19E+03  NA  5  Endoscopy  No  GLIDE  AWD [10]  8  UC→CD  [−]  [−]  5  Endoscopy  Yes  GLIDE  Dead [7]  9  None  2.15E+03  [+]  2/ subtotal colectomy  Endoscopy  No  LVD  NA  10  CD  2.61E+02  NA  3/ total colectomy  Endoscopy  Yes  None  Dead [2]  11  CD  1.65E+03  NA  2/ ileal resection  Surgery  Yes  None  Dead [2]  12  TB  1.59E+02  [−]  4/ perforation repair  Endoscopy  No  None  AWD[1]  Case  Misdiagnosis  EBV-DNA  EBV-CA-IgA  Endoscopic times/ surgery  Confirmation approach  Development of lymphoma  Chemotherapy/HSCT  Follow-up [month]  1  UC→CD  4.40E+03  [−]  4/ subtotal colectomy  Surgery  Yes  None  Dead [1]  2  UC  1.56E+04  [−]  5/ subtotal colectomy  Surgery  No  GLIDE and HSCT  ANED [21]  3  TB  6.50E+03  [−]  3  Endoscopy  Yes  GLIDE  NA  4  CD  2.88E+03  [+]  5  Endoscopy  Yes  None  Dead [1]  5  UC  4.40E+04  [−]  3  Endoscopy  No  GLIDE  AWD [17]  6  CD  5.95E+04  [−]  2/ partial colectomy  Surgery  Yes  None  Dead [1]  7  TB  1.19E+03  NA  5  Endoscopy  No  GLIDE  AWD [10]  8  UC→CD  [−]  [−]  5  Endoscopy  Yes  GLIDE  Dead [7]  9  None  2.15E+03  [+]  2/ subtotal colectomy  Endoscopy  No  LVD  NA  10  CD  2.61E+02  NA  3/ total colectomy  Endoscopy  Yes  None  Dead [2]  11  CD  1.65E+03  NA  2/ ileal resection  Surgery  Yes  None  Dead [2]  12  TB  1.59E+02  [−]  4/ perforation repair  Endoscopy  No  None  AWD[1]  Cases 9 and 10 were confirmed by endoscopic biopsy performed before the surgery. UC, ulcerative colitis; CD, Crohn’s disease; TB, tuberculosis; GLIDE, gemcitabine, pegaspargase, ifosfamide, dexamethasone, etoposide; LVD, L-asparaginasum, vincristine, dexamethasone; HSCT, haematopoietic stem cell transplantation; ANED, alive no evidence of disease; AWD, alive with disease;NA, not available. View Large 3.5. Therapy and follow-up Data regarding clinical management and follow-up are shown in Table 4. The mean duration of follow-up was 6.3 [range, 1–21] months. In general, the follow-up data exhibit considerable heterogeneity among the patients with respect to prognosis. Among the seven patients with confirmed PIEBV+ NK/T lymphoma, one was lost to follow-up and six patients passed away because of progressive deterioration over a period of 1–7 months after confirmation, despite surgery or chemotherapy in some patients. Among the five remaining patients who did not develop lymphoma, one was lost to follow-up; two patients underwent chemotherapy with GLIDE and maintained a stable condition for 10 and 17 months; and one patient [Case 12] underwent repair of colon perforation 5 days after confirmation and still had recurrent haematochezia and fever during follow-up while waiting for chemotherapy. The other patient [Case 2], who developed secondary haemophagocytic lymphohistiocytosis [HLH], underwent haematopoietic stem cell transplantation [HSCT] and has not demonstrated any evidence of relapse during a 21-month follow-up. 4. Discussion Here we presented the clinical challenge associated with the differential diagnosis of PIEBV+ NK/T-LPD from IBD. In this study, nearly all patients were initially misdiagnosed as having UC or CD. Thus, increased awareness regarding PIEBV+ NK/T-LPD is important for avoiding misdiagnosis. Analysis of this series demonstrated considerable heterogeneity among patients and a strong similarity between PIEBV+ NK/T-LPD and IBD. The possible reasons for misdiagnosis and key aspects of the differential diagnosis between these two entities are further discussed in detail below. In this study, a distinct heterogeneity in clinical progression was observed regardless of lymphoma development. The time to arrive at a definite diagnosis ranged from months to years [up to a decade in one case]. The prolonged disease course is more common in chronic inflammation associated with IBD rather than that with LPD, which is liable to mislead doctors in clinical practice. In addition to a prolonged medical history, PIEBV+ NK/T-LPD may have other symptomatic overlaps with IBD, such as diarrhoea and fever.29–31 In our study, fever was the most common symptom, whereas diarrhoea was much less common. However, among these patients, fever was typically moderate-to-high grade and recurrent in nature, with spontaneous attenuation observed within 24 h in the absence of any treatment in most cases; this fever pattern is quite distinct from that typically observed in patients with IBD. Secondly, transmural inflammation is a hallmark pathological characteristic of CD, which can lead to intestinal perforation and fistula. Perforation also occurs in patients with primary intestinal NK/T-cell lymphoma [prevalence ranging 32.7–57.9%].32–36 In our series, intestinal perforation occurred in six cases [50%]; of these, colectomy was performed in five and transmural lesions were clearly demonstrated on histopathological examination of all surgical specimens. However, despite the relatively high frequency of perforation in this series, perianal lesions were less common compared with typical CD cases. PIEBV+ NK/T-LPD could not be differentiated from IBD based on routine endoscopic or pathological findings. In contrast, sporadic reports have documented similar endoscopic findings in patients with PIEBV+ LPD and those with UC, CD, or TB.21,22,37 In the present series, the patients had diffuse inflammation with sporadic ulcers throughout the colorectum or have normal mucosa in between multisegmental ulcers, which resembles typical endoscopic findings associated with UC and CD, respectively. Although cobblestone appearance was not found in any of the patients in this series, irregular, varying-sized ulcers with longitudinal, transverse, or even annular configuration were observed in most patients. Pathological features of LPD also resemble those of IBD and TB. For example, Braylan et al.38 described a case of B-cell lymphoma characterised by non-necrotic granulomas with no associated CD. Blanco et al.39 identified necrotic granulomas in a case of B-cell lymphoma with no associated TB. Likewise, a non-caseating granuloma was found in a patient with confirmed PIEBV + NK/T lymphoma in the present series [Case 1]. Furthermore, although NK/T-LPD is associated with some characteristic histological presentations such as clusters of medium- or small-sized lymphoid cells with ALCs, LELs, and angiocentric infiltrates, EBV-induced lymphoid cells tend to be dispersed in the mucosa at the early stage, making it difficult to distinguish these from reactive ones. Despite the similar clinical, endoscopic, and even histopathological features between these two disorders, PIEBV+ NK/T-LPD possess some distinctive immunophenotypic features, including NK/T cells [CD3ε positive] expressing EBER, CD56 [NK-cell type] and monoclonal TCRγ gene [T-cell type], and negative expression of CD5.32–36 Furthermore, NK/T-LPD with positive EBER usually shows positive expression of activated cytotoxic phenotype of TIA-1, GB, and perforin.4 EBV is strongly associated with NK/T-LPD, with a prevalence of 76–97.6%.37,40,41 However, there is no definitive evidence of the association between EBV status and the prognosis of patients with LPD.42–44 In contrast, T-cell LPD with monoclonal TCRγ gene rearrangement may be associated with poor clinical outcomes.45,46 Ki67 is also a predictive prognostic marker for NK/T-LPD.47 However, there is much variability in the current series with respect to Ki67 index, even in lymphoma patients. This is possibly related to the heterogeneity in stage of disease progression or focal distribution. As reported above, PIEBV+ NK/T-LPD may present with a prolonged clinical course similar to IBD. However, the intermittent pattern of fever should be an alarming sign for considering a diagnosis of PIEBV+ NK/T-LPD in patients who exhibit atypical symptoms such as abdominal pain, haematochezia, and diarrhoea, or those who develop complications such as perforation and fistula. Such patients may present with ulcers of variable sizes and irregular shape, or diffuse inflammation, on endoscopy. Some of the findings may mimic findings seen in IBD or TB. In these patients, biopsies obtained from repeat colonoscopy should be reviewed by experienced pathologists to rule out EBV-induced lymphoid proliferation. We retrospectively re-examined the pathological features of the biopsies in the early stage of disease course for this series before their finally confirmed diagnosis, and found that these tissues already exhibited some characteristic histopathological features of LPD, including clusters of small- or medium-sized lymphoid cells, ALCs, LELs, and angiocentric infiltrates [details shown in Supplementary Table 1, available as Supplementary data at ECCO-JCC online]. In addition, reasonable intestinal surgery may play an important role; sometimes proper diagnosis can only be made in surgical specimens, as endoscopic biopsy only offers limited histopathological data mainly based on mucosal presentation. Primary intestinal LPD may also occur in the setting of IBD. Thiopurine and anti-tumour necrosis factor-alpha [anti-TNF-α] agents (particularly for infliximab [IFX]) may increase the risk of primary intestinal LPD in patients with IBD.17,23 However, such increase has not been observed in large populations of IBD not exposed to immunosuppressants.23,48,49 Nissen et al.50 suggested that occurrence of EBV+ LPD in an IBD setting is liable to have a less aggressive disease course. Since immunosuppressants or anti-TNF therapy may activate EBV, EBV infection should be routinely excluded before initiating such treatment. With respect to the survival benefit of treatments, EBV+ LPD are generally refractory to chemotherapy or immunosuppressants, except in some cases with complicated HLH.4,51 HSCT is an independent predictor of reduced mortality.4 Kimura et al.4 reported a survival rate of 56.48% and lymphoma development rate of 12.04% among 108 patients with EBV+ NK/T-LPD, regardless of lesion characteristics and therapy. In contrast, in this series, we found a relative lower overall survival rate [40%] and a quite higher lymphoma development rate [58.3%]. The differences may be attributable to bias caused by the smaller sample size and smaller proportion of patients who underwent HSCT in our study. In line with this argument, HSCT induced a sustained clinical remission for 21 months in one patient with PIEBV+ NK/T-LPD and HLH [Case 2] in the present study. However, most patients in our study only underwent chemotherapy. This study has three limitations. The first is that it just retrospectively analysed a small-scale case series of PIEBV+ NK/T-LPD. The second is that the study was done at a single medical centre. The last is that the description of this condition sounds quite novel and strange to many clinicians, and the diagnostic criteria were made by us based on literature. In order to further explore the clinical and pathological characteristics of PIEBV+ NK/T-LPD, more studies, in particular large-scale, multi-centre, prospective/retrospective ones, are warranted. In summary, we reported 12 Chinese patients with PIEBV+ NK/T-LPD, who manifested heterogeneous clinicopathological and prognostic characteristics. The disease may affect any segment of the GI tract, with colon and ileocaecum being the most commonly affected segments. Owing to overlapping clinicopathological features, differential diagnosis of PIEBV+ NK/T-LPD from IBD and TB poses a clinical challenge. The possibility of PIEBV+ NK/T-LPD should be considered for patients who exhibit atypical symptoms, particularly those with intermittent fever and showing irregular ulcers of varying sizes endoscopically. Repeat endoscopy combined with deep biopsy or colectomy may increase the possibility of definitive pathological diagnosis. Comprehensive histopathological and virological examinations are critical for confirming a diagnosis. Funding This work was supported by the National Natural Science Foundation of China [Grant Number: 81570502], and by the Research Fund for the Doctoral Program of Higher Education of China [RFDP] [Grant Number: 20130181120041]. Conflict of Interest All the authors declare no conflict of interests. Author Contributions ZW analysed data and drafted the manuscript. WZ reviewed the pathological slides. CL, MZ, YZ, and JM collected and analysed the data, YZ, RH, YW, ZW, and HZ took care of the patients, OQ designed the study. SX edited the manuscript and comments to reviewers. HZ designed the study, edited manuscript, and acted as corresponding author. All authors approved the final version of the manuscript. Supplementary Data Supplementary data to this article can be found online at ECCO-JCC online References 1. Sawada A, Inoue M, Kawa K. 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Journal of Crohn's and ColitisOxford University Press

Published: Apr 7, 2018

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