Encyclopedia
Please note this is a comparison between Version 1 by Yasuharu Sato and Version 2 by Rita Xu.
Primary gastrointestinal (GI) T-cell neoplasms are extremely rare heterogeneous disease entities with distinct clinicopathologic features. Given the different prognoses of various disease subtypes, clinicians and pathologists must be aware of the key characteristics of these neoplasms, despite their rarity.
- primary gastrointestinal T-cell lymphoma
- enteropathy-associated T-cell lymphoma
- EATL
- monomorphic epitheliotropic intestinal T-cell lymphoma
- MEITL
- indolent T-cell lymphoproliferative disorder
- ITLPD-GI
- NK-cell enteropathy
1. Introduction
The gastrointestinal (GI) tract is a common site for extranodal lymphoma involvement. Primary GI lymphomas are predominately of the B-cell lineage, and T-cell neoplasms are rare, accounting for 13–15% of GI lymphomas [1][2][3][1,2,3]. The majority (>90%) of primary GI T-cell neoplasms exhibit aggressive behavior and are associated with short progression-free survival and overall survival. In contrast, an indolent condition termed indolent T-cell lymphoproliferative disorder of the GI tract (ITLPD-GI) has been identified. GI T-cell lymphoma and lymphoproliferative disorders are heterogeneous entities consisting of various subtypes with distinct clinicopathological features and prognoses. Therefore, both clinicians and pathologists must be aware of the distinct characteristics of these lesions to ensure that appropriate care is provided.
The revised 4th World Health Organization (WHO) classification in 2017 broadly classifies primary GI T-cell lymphoma as enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). In the 2001 WHO classification, primary GI T-cell lymphoma with digestive symptoms was initially treated as a separate category, termed enteropathy-type T-cell lymphoma (ETL). In 2008, the entity was renamed EATL and further classified into type I and type II. Type I is associated with celiac disease and has a high incidence in Northern Europe. Conversely, Type II is not associated with celiac disease and has a higher incidence in Asian and Hispanic populations [4]. Type I and type II EATLs differ clinically and morphologically, and also exhibit distinct immunological and genetic features. In the revised 4th WHO classification, EATL types I and II have been revised to EATL and MEITL, respectively [5].
In the revised 4th WHO classification, intestinal T-cell lymphoma, not otherwise specified (ITL, NOS) and ITLPD-GI were newly defined. ITL, NOS is defined as T-cell lymphomas arising in the GI tract that are not otherwise specified as EATL, MEITL, anaplastic large cell lymphoma, or extranodal natural killer (NK)/T-cell lymphoma. The clinical course of ITL, NOS is generally aggressive, and this entity may include cases with insufficient immunohistochemical evaluation and cases of secondary involvement of extra-intestinal lymphoma. Currently, ITL, NOS is considered to be a provisional entity [6]. Extranodal NK/T-cell lymphoma of the nasal type (ENKTCL) and anaplastic large cell lymphoma (ALCL) may also occur in the GI tract or involve it secondarily. Furthermore, NK-cell enteropathy has been reported as a pseudomalignant lesion that is often misdiagnosed as lymphoma.
2. Enteropathy-Associated T-Cell Lymphoma
2.1. Definition and Epidemiology
EATL is a rare and aggressive intestinal T-cell lymphoma. The geographic distribution of the incidence of EATL is distinct, with a high incidence in Europe and in individuals of northern European descent. A previous report demonstrated that the proportion of EATL in peripheral T-cell lymphoma was 9.1%, 5.8%, and 1.9% in Europe, North America, and Asia, respectively [7]. EATL typically occurs in older individuals (60–70 years), and large studies have reported either an equal sex distribution or slight male predominance (male: female ratio of 1.04–2.8:1) [7][8][9][10][11][7,8,9,10,11].
EATL is a complication of celiac disease [12][13][12,13], one of the most common genetic disorders that affects approximately 1% of individuals worldwide [14], with a high prevalence in Europe. Celiac disease is characterized by intolerance to dietary gluten that occurs in individuals with HLA-DQ2 or DQ8, haplotypes of human leukocyte antigen (HLA) class II [14]. The association between celiac disease and EATL was first established in a study demonstrating that the HLA risk alleles (HLADQA1*0501 and DQB1*0201 (HLA-DQ2)) of celiac disease are present in majority of patients with EATL [15]. Moreover, serological evidence of gluten sensitivity in patients with EATL has been reported [12]. Notably, a gluten-free diet reduces the risk of lymphoma in patients with celiac disease [16].
2.2. Pathogenesis
EATL may be preceded by refractory celiac disease (RCD), which is defined as the persistent or recurrent symptoms of malabsorption and mucosal damage despite a strict gluten-free diet for over 12 months. Exclusion of other etiologies, including autoimmune enteropathy, tropical sprue, and lymphoma, is mandatory to diagnose RCD [17]. RCDs are biologically heterogeneous and can be divided into RCD type I (RCD I) and RCD type II (RCD II) based on immunophenotypic and molecular characteristics of intraepithelial lymphocytes (IELs). RCD I is characterized by increased polyclonal intraepithelial IELs of normal immunophenotype (sCD3+, CD8+, and CD103+), whereas RCD II is characterized by monoclonal IELs of aberrant immunophenotype (sCD3−, cCD3+, CD8−, CD5−, and CD103+). IELs in celiac disease and RCD I show downregulated expression of CD5, but they are not entirely CD5-negative, and they may have a mixture of CD5-positive and negative subsets in some cases. Although the vast majority of RCD II show negative CD8, some patients who meet the clinical criteria for RCD and show CD8 positivity have been reported to show consistent monoclonality by PCR analysis of the TCR gene throughout the follow-up [18]. Progression of RCD I to RCD II is considered to be rare [19], and the risk of developing EATL is lower in RCD I (3–14% over 5 years) than in RCD II (33–52%) [20][21][22][23][24][20,21,22,23,24] (Table 1).
Table 1. Comparison of celiac disease, RCD I, RCD II, and EATL [5][9][19][20][21][22][23][24][25][5,9,19,20,21,22,23,24,25].
| Investigations | Celiac Disease | RCD I | RCD II | EATL | |||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Disease type | Chronic enteropathy triggered by dietary gluten | Persistent autoinflammatory immune response, gluten independent | Low-grade lymphoproliferative disorder |
High-grade lymphoma | |||||||||||||||||||||||||||||||||||
| Immunophenotype | sCD3 | + | , cCD3 | + | , CD5 | −/+ | , CD8 | + | , CD103 | + | sCD3 | + | , cCD3 | + | , CD5 | −/+ | , CD8 | + | , CD103 | + | sCD3 | − | , cCD3 | + | , CD5 | − | , CD8 | − | , CD103 | + | , CD30 | − | CD3 | + | , CD8 | − | , CD30 | + | , Ki67 LI: high (>50%) |
| T-cell receptor | polyclonal | polyclonal | monoclonal | monoclonal | |||||||||||||||||||||||||||||||||||
| 5-year survival | 80–96% [18][20][21] | 80–96% [18,20,21] | 45–58% [18][20][21] | 45–58% [18,20,21] | ~20% [5][9][20] | ~20% [5,9,20] | |||||||||||||||||||||||||||||||||
| Rate of progression to EATL in 5 years | 0.7% [24] | 3–14% [19][20][21][22][23] | 3–14% [19,20,21,22,23] | 33–52% [19][20][21][22][23] | 33–52% [19,20,21,22,23] | - |
Abbreviations: RCD; refractory celiac disease, EATL; enteropathy-associated T-cell lymphoma, sCD3; surface CD, cCD3; cytoplasmic CD, Ki-67 LI; Ki-67 labeling index.
The NK receptor NKp46 was recently reported to be expressed in larger numbers of IELs in RCD II and EATL, whereas only a few IELs were positive in celiac disease and RCD I, suggesting that NKp46 may be a novel biomarker to clarify diagnosis [26].
Currently, two pathways are recognized for the pathogenesis of lymphoma, which are associated with different clinical presentations and outcomes. EATL secondary to RCD II (54% of all EATLs, according to one study [9]) is associated with severe GI symptoms and higher mortality (5-year survival of 0–8%). In contrast, “de novo” EATL (46%), which occurs in patients with uncomplicated celiac disease or RCD I, has higher survival rates (5-year survival of 59%) [9][21][9,21]. Nevertheless, the pathogenesis of de novo EATL remains unclear.
2.3. Cell Origin
Cells that proliferate in RCD and EATL were formerly thought to be thymic-derived conventional intraepithelial T cells, which is T-cell receptor (TCR) αβ+, due to their immunophenotypic similarity to normal intraepithelial T-cells, which account for approximately 80% of IELs [9][27][9,27]. Recent molecular and immunophenotypic analyses suggest that lineage-negative innate IELs are the origin of a proportion of RCD II cases [28][29][30][31][28,29,30,31], and EATL arising from RCD II may have the same origin.
2.4. Histopathology
In EATL, diffuse proliferation of pleomorphic medium to large lymphoma cells is observed. Lymphoma cells have abundant eosinophilic to pale cytoplasm and nuclei that are round or irregular with distinct nucleoli. Infiltration of inflammatory cells, including histiocytes, eosinophils, neutrophils, and plasma cells, is often present in the background [32]. Angiocentric proliferation and vascular invasion are present, and extensive necrosis associated with vascular occlusion is often observed [5][33][5,33]. The peripheral intestinal mucosa often exhibits features of celiac disease such as intraepithelial lymphocytosis and villous atrophy.
2.5. Immunophenotype and Genetic Alternations
Neoplastic cells are typically CD3+ (cytoplasmic), CD5−, CD4−, CD56−, and diffusely positive for cytotoxic granule proteins (TIA-1, granzyme B, and perforin) and intraepithelial homing integrin CD103. CD8 tends to be negative but may be expressed in 19–30% cases [4][9][34][4,9,34] and has been reported to be present at a higher frequency in patients without a history of RCD II [9]. CD30 positivity depends on tumor cell morphology but is almost exclusively positive in large cell-based tumors [9]. Neoplastic cells are negative for anaplastic lymphoma kinase (ALK) and Epstein-Barr virus (EBV). Surface TCR expression is typically absent, but intracellular TCRβ (βF1) expression is observed in approximately 25% of cases [9].
Several studies have used microsatellite markers or array-based approaches to detect recurrent copy number gains at chromosomes 9q (the most common in EATL: 46–70%) [35][36][37][35,36,37], 7q, 1q, and 5q; and losses at chromosomes 16q, 8p, 13q, and 9p. Mutually exclusive gains at 9q and losses at 16q are observed in up to 80% of EATL cases [35][37][38][39][35,37,38,39]. Moreover, recent studies have reported recurrent mutations of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway with frequent activating mutations in STAT5B (26.5–29%), JAK1 (14.7–23%), JAK3 (23–27.3%), and STAT3 (12.1–16%) [36][40][36,40].
Targeted next-generation sequencing (NGS) of RCD II cases revealed recurrent activating mutation in JAK1 (75%) and STAT3 (25%) genes [30], which may implicate JAK-STAT pathway mutations to be early events in EATL. Targeted NGS analysis of RCD II also revealed frequent occurrence of deleterious mutations in nuclear factor kappa-light chain-enhancer of activated B-cells (NF-κB) regulators and in several epigenetic regulators [41].
2.6. Clinical Manifestations
Approximately 90% of EATLs occur in the small intestine [7][8][7,8]. Multiple lesions occur in 32–54% of cases, and single lesions in the stomach or colon are rare [7][8][9][7,8,9]. Given the close association between EATL and celiac disease, symptoms such as diarrhea, abdominal pain, weight loss, and hypoalbuminemia may precede EATL [7][9][10][42][43][44][7,9,10,42,43,44]. However, the diagnosis of celiac disease is made prior to the diagnosis of EATL in 20–73% of cases [8][9][42][8,9,42]. EATL also causes vomiting due to intestinal obstruction, intestinal bleeding, and intestinal perforation in 25–50% of patients [7][8][9][43][44][45][7,8,9,43,44,45]. Hemophagocytic syndrome is reported in 16–40% of cases [9][46][9,46].
EATLs can also spread beyond the GI tract, and the most common sites of involvement are abdominal lymph nodes (35%), followed by bone marrow (3–18%), lung and mediastinal lymph nodes (5–16%), liver (2–8%), and skin (5%) [7][9][10][7,9,10]. Involvement of the central nervous system (CNS) has also been reported [47][48][49][47,48,49]. Endoscopically, EATL can manifest as a large mass, ulceration, or stricture [7][9][7,9].
2.7. Prognosis and Treatment Strategies
The prognosis of EATL is very poor. Gale et al. reported 1- and 5- year survival rates of 38.7% and 9.7%, respectively, and 1- and 5-year failure-free survival rates of 19.4% and 3.2%, respectively [8]. Other studies have estimated 5-year survival rates of 11–20% [10][42][43][45][50][10,42,43,45,50]. Standard validated treatment strategies for EATL have yet to be established. Surgery and chemotherapy are the treatments of choice, but EATL tends to be refractory to these therapies [50]. CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone) regimen is the most widely implemented approach, but its overall median survival has been reported to be only 7 months [8][42][43][45][8,42,43,45]. Recently, autologous stem cell transplant (ASCT) following chemotherapy has been reported to significantly enhance survival [9][10][50][51][52][9,10,50,51,52]. One study demonstrated that the novel regimen IVE/MTX (ifosfamide, vincristine, etoposide, methotrexate) followed by ASCT improved survival rates compared to anthracycline-based chemotherapy, with a 5-year overall survival rate of 60% [10]. Although surgery is not considered as first-line treatment for lymphoma, tumor reduction surgery has been reported to be an independent prognostic factor of nutritional status [9]. Further, it is estimated that the combination of surgery and chemotherapy will reduce tumor necrosis, peritonitis, and intestinal hemorrhage associated with chemotherapy, underscoring the potential of surgery as a treatment option at the appropriate time.
One case report of a CD30-positive patient with EATL demonstrated that targeted therapy using brentuximab vedotin resulted in complete remission [53]. In another report, a patient with EATL who had multiple relapses following ASCT achieved sustained remission with CD30 chimeric antigen receptor-modified T-cell therapy [54].
For RCD, various immunosuppressive medications such as azathioprine, systemic corticosteroids, or regular budesonide have been used. Although conventional immunosuppressive medications fail in about half of the cases, recent study revealed open-capsule Budesonide has shown clinical and histological improvement in about 90% of the cases, including those in which conventional treatments have failed [55]. Furthermore, in follow-up, 53% of RCDII patients treated with open-capsule budesonide showed absence of the former clonal TCR gene rearrangement and aberrant IEL phenotype. This indicates that open-capsule budesonide may reduce the risk of developing from RCDII to EATL, although longer follow-up is needed [55].
