In this issue of Blood, Perry et al describe cases of an indolent T-cell lymphoproliferative disorder (LPD) of the gastrointestinal tract (GIT) that mimics inflammatory bowel disease or peripheral T-cell lymphoma (PTCL).1  The lesions involved all sites in the GIT, and mucosal infiltrates consisted of small lymphoid cells with minimal atypia. The cases were phenotypically heterogeneous but predominantly CD8+/CD4, and all had clonal T-cell receptor (TCR) gene rearrangements.

The intestinal epithelium is the largest surface in the body exposed to antigens. The mucosal T cells are essential to maintaining the barrier function of the gut, preventing penetration by commensal and pathogenic bacteria via antigen recognition and cytokines, and sustaining epithelial health as well as selective immune tolerance.2  Mucosal T cells include naive T cells located in the gut-associated lymphoid tissue, which includes the Peyer’s patches. Lamina propria and intraepithelial lymphocytes (IEL) have potent cytolytic and immunoregulatory capacities and >70% are CD8+ cells. Unlike circulating T cells, CD4 CD8 “double negatives” account for >10%, and CD4+ αβ T cells are sparse. IEL also include greater numbers of γδ T cells. For purposes of simplification, IEL have been divided into just 2 types: a and b.3  Type a includes TCR αβ T cells that mainly recognize antigens presented by conventional major histocompatibility complex classes I and II. Type b includes TCR αβ and γδ T cells, which typically express CD8αα homodimer and detect and respond to ligands and products not restricted by conventional major histocompatibility complex but instead are representative of products of the molecular stress response.

Given this complexity, it is not surprising that a spectrum of T-cell LPD is encountered in the GIT (see table). Cases of enteropathy-associated T-cell lymphoma (EATL) are likely derived from type b cells, and although usually αβ, may be γδ or T-cell silent. Type I EATL is related to celiac disease, and refractory celiac disease type II may be an early form of EATL.4  Type II EATL has distinctive histologic features and phenotype, and is generally unrelated to celiac disease. The time may have come for a change in nomenclature to reflect this distinction.

T-cell LPD of the GIT

TypeClinicalHistologyPhenotypeOutcome
EATL type I Overt or silent gluten-sensitive enteropathy Polymorphous medium to large cells including CD4, CD8−/+ Aggressive 
Hodgkin-like cells TCR αβ (usually) 
or γδ 
Variable expression of CD30 
EATL type II Worldwide, not clearly linked to celiac disease Monomorphic with epitheliotropism TCR γδ (usually) or αβ Aggressive 
CD8+, CD56+ 
Extranodal NK-/T-cell lymphoma nasal type Upper aerodigestive tract and small bowel most often involved Medium to large cells NK/cytotoxic T cells, EBV+ Aggressive 
PTCL-NOS No history of celiac disease No significant epitheliotropism Variable Aggressive 
More often TCR silent 
NK-cell enteropathy Vague gastrointestinal symptoms, can involve entire GIT Medium to large irregular cells do not invade glandular epithelium CD56+ Indolent chronic relapsing course 
Cytotoxic granules, cytoplasmic CD3+ 
Indolent T-cell lymphoproliferative disease of the GIT Diarrhea, abdominal pain Superficial infiltrate of small uniform lymphoid cells Mostly CD8+ cytotoxic T cell Indolent chronic relapsing course 
TypeClinicalHistologyPhenotypeOutcome
EATL type I Overt or silent gluten-sensitive enteropathy Polymorphous medium to large cells including CD4, CD8−/+ Aggressive 
Hodgkin-like cells TCR αβ (usually) 
or γδ 
Variable expression of CD30 
EATL type II Worldwide, not clearly linked to celiac disease Monomorphic with epitheliotropism TCR γδ (usually) or αβ Aggressive 
CD8+, CD56+ 
Extranodal NK-/T-cell lymphoma nasal type Upper aerodigestive tract and small bowel most often involved Medium to large cells NK/cytotoxic T cells, EBV+ Aggressive 
PTCL-NOS No history of celiac disease No significant epitheliotropism Variable Aggressive 
More often TCR silent 
NK-cell enteropathy Vague gastrointestinal symptoms, can involve entire GIT Medium to large irregular cells do not invade glandular epithelium CD56+ Indolent chronic relapsing course 
Cytotoxic granules, cytoplasmic CD3+ 
Indolent T-cell lymphoproliferative disease of the GIT Diarrhea, abdominal pain Superficial infiltrate of small uniform lymphoid cells Mostly CD8+ cytotoxic T cell Indolent chronic relapsing course 

EBV, Epstein-Barr virus; NOS, not otherwise specified.

Although the majority of intestinal T-/natural killer (NK)-cell lymphomas are aggressive, there are exceptional NK- or T-cell proliferations that may persist and require minimal if any therapeutic intervention. One example is NK-cell enteropathy that presents with vague abdominal symptoms and extensive mucosal lesions mimicking NK-cell lymphoma.5  Similarly, although PTCL is considered highly aggressive by the World Health Organization,6  indolent cases have been documented, usually in extranodal sites with low clinical stage, and comprising small cells with mild nuclear atypia and low proliferation rate.7  Primary cutaneous CD4+ small/medium T-cell lymphoma, a provisional entity by the World Health Organization,6  is another indolent lesion that may be indistinguishable from what has previously been termed cutaneous pseudo-T-cell lymphoma.8  Indolent CD8+ lymphoid proliferation of the ear or face is also slow-growing and remains localized.9 

At a recent international workshop on peripheral T- and NK-cell lymphomas and their mimics, organized by the European Association for Haematopathology and the Society for Hematopathology, there was a spectrum of cases from patients with extranodal T-cell infiltrates, some of which had been treated aggressively and were considered indolent and indeterminate for malignancy by an expert panel.10  DNA sequencing has identified recurrent genetic alterations in some T-cell proliferations and is paving the way to an objective molecular classification of T-cell proliferations. Until that time, astute clinicopathologic studies such as those reported by Perry et al are critical in drawing attention to anomalous entities such as low-grade LPD of the GIT, which can easily be misinterpreted as inflammatory bowel disease or lymphoma.

Conflict-of interest disclosure: The author declares no competing financial interests.

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