Lymph node involvement by enteropathy-like indolent NK-cell proliferation

Natural killer (NK)-cell enteropathy (NKCE) and lymphomatoid gastropathy (LG) are closely related lymphoproliferative disorders (LPDs) composed of mature and Epstein–Barr virus (EBV)-negative NK-cells. Although these uncommon and indolent lymphoid proliferations mostly arise within the gastrointestinal (GI) tract as their designations implies, a few cases have been reported outside the GI tract. We hereby describe a unique case of lymph node infiltration by such EBV-negative NK-cell proliferation fortuitously found during routine examination of a gallbladder resected for biliary lithiasis. The histologic, phenotypic, and molecular features of this NK-cell proliferation, which were very similar if not identical to those previously reported in NKCE or LG, suggest that similar indolent EBV-negative NK-cell LPDs may also occasionally involve lymph nodes.

Based on these findings, an "enteropathy-like" NK-cell lymphoproliferation was considered. An extensive clinical work-up, including peripheral blood analysis, computed tomography (CT) scan, positron emission tomography (PET) scan, esophagogastroduodenoscopy, and colonoscopy, did not demonstrate any abnormal finding. Multiple biopsies from the stomach, duodenum, ileum, and colon showed essentially normal histology. PET scan disclosed a small thyroid nodule, benign by fine needle aspiration cytology. No further therapy was given. The patient is still asymptomatic 18 months later.
Some studies have suggested that an abnormal immune response, possibly related to yet unknown antigen(s), could underline NKCE pathogenesis [3,5,9,13,16]. In one patient with high titers of antigliadin antibodies, the lesions regressed significantly under gluten-free and lactose-free diet [1]. Several gastric cases had concomitant Helicobacter pylori infection [2, 6-8, 10, 12]. However, overall, no firm relationship with a specific factor or condition could be demonstrated   [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. In a recent study using a large hematology-oriented NGS panel, a somatic JAK3 mutation consisting of a small in frame deletion in exon 12 was identified in 3/10 patients with NKCE [15]. Other non-recurrent mutations involving PTPRS, AURKB, AXL, ERBB4, IGF1R, PIK3CB, CUL3, CHEK2, RUNX1T1, CIC, SMARCB1, and SETD5 were found in seven cases [15]. In a few cases subject to extensive genetic testing including 3/10 NKCE and the vaginal mass recently reported [15,16], however, no mutation was identified. In our patient, NGS analysis of 26-genes T-cell lymphoma panel found no pathogenic mutation and in particular no JAK3 deletion, but one cannot exclude genetic aberration(s) in other genes not tested in this panel. Thus, indolent NK-cell LPDs may represent a spectrum ranging from polyclonal to clonal, the latter related to mutations promoting the clonal expansion of NK cells, notably those deregulating the JAK/STAT pathway which represent oncogenic drivers in a variety of other NK/T-cell neoplasms. Due to significant prognostic differences and therapeutic implications, indolent NK-cell LPDs must be distinguished from other mature NK-cell neoplasms like aggressive NKcell leukemia and extranodal NK/T-cell lymphoma, nasaltype. Marked cellular atypia, significant mitotic activity, cellular necrosis, angiocentricity, or angiodestructive pattern of growth and positive EBER ISH are features of aggressive NKcell disorders and clues against NKCE [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Distinction from the exceptional cases of EBV-negative NK-cell lymphoma may be more challenging due to EBV-negativity, but those cases as the one reported by Koo et al. in the small bowel show clearly malignant features [17]. Because of clear cells and possible epitheliotropism, NKCE may first elicit consideration of a marginal zone B cell lymphoma or monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). Even after immunophenotyping, the distinction with MEITL may remain difficult, given expression of antigens common to T and NK cell lineages and strong CD56 positivity in both conditions [14]. However, MEITL typically presents as a tumor mass, harbors clonal TR gene rearrangements, and recurrent SETD2 alterations, not found in NKCE [18].
In conclusion, we describe herein a case of nodal EBVnegative NK-cell proliferation, akin to NKCE. This observation further expands the spectrum of NKCE outside the GI tract. Awareness of pathologic features of these underrecognized LPDs is advisable, in order to avoid overdiagnosis and inappropriate treatment.
Author contributions JLD and LDL performed pathologic examination and wrote the paper; NT contributed essential clinical information; MT performed molecular analysis. All authors gave final approval for publication.
Funding Open access funding provided by University of Lausanne.

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Conflict of interest The authors declare that they have no conflict of interest.
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