Natural killer cell enteropathy

Most cases of NKCE[9] and LG[5] have been reported in middle-aged or older individuals. Patients diagnosed with NKCE (medium age 46 years) have presented with vague abdominal pain, indigestion, vomiting, diarrhea,[5] constipation,[6] weight loss, anemia, and/or GI bleeding.[5] Two patients complained of biliary colic (i.e. gallbladder pain) and were found to have typical lesions of NKCE in their cystic ducts.[5] These two cases indicate that NKCE involvement is not totally limited to the alimentary canal. Three of 15 individuals diagnosed with NKCE disease reported no symptoms, their disease being found on endoscopy conducted for screening purposes. Typically, patients diagnosed with LG (medium age 58 years) have been asymptomatic at presentation with their disease being detected during GI tract examinations done for other reasons. Three of twenty patients diagnosed with LG complained of pain or discomfort in the upper abdominal region. Symptomatic individuals with either disease generally have a long history of persistent or intermittent symptoms.[5]

NK cells normally occupy the GI tract where they contribute to innate immunity[7] by becoming active in killing pathogen-infected and cancerous cells.[10] The proliferating lymphocytes in NKCE and LG express CD56 and CD7 proteins on their cell surface membrane, CD3γ protein in their cytoplasm, and granzyme B, perforin, and T-cell intracellular antigen-1 cytotoxic proteins within their cytoplasmic granules. This pattern of protein expression identifies these cells as NK cells that, because of their expression of the cytotoxic granule-bound proteins, have been activated.[7] However, the cause(s) for the activation of these cells as wells as for their rapid proliferation to produce NKCE[5] and LG[8] is unknown. To date, no evidence of NK cell clonality (i.e. cells developing from a single precursor) or for these cells to bear gene mutations or chromosome abnormalities have been reported in NKCE or LG. These findings help distinguish LB and NKCE from many lymphomas and support the conclusion that neither disease is malignant.[6] The NK cells in LG and NKCE are not infected with the Epstein-Barr virus (EBV), as evidenced by their failure to express this virus's latency proteins and latency ncRNAs. This finding indicates that EBV is not the cause for the NK cell activation and excessive proliferation seen in NKCE and LG and distinguishes these diseases from malignant diseases they can mimic such as extranodal NK/T-cell lymphoma, nasal type.[5] In isolated reports, LG has occurred in individuals with Helicobacter pylori infection of the stomach or a history of stomach cancer,[7] while NKCE has been reported to occur in patients with gluten sensitivity[10] or circulating anti-gliadin antibodies. Both of the latter conditions are associated with the development of GI tract lymphomas.[5] However, the relationship of any of these findings to the etiology of LB and NKCE is unclear.[5]

Biopsies of NKCE tissues reveal atypical medium to large lymphocytes identified by immunohistochemistry to be NK cells that are multiplying at a moderately rapid rate[9] and that lack evidence of being infected by the Epstein-Barr virus.[2] These cells are located primarily in the lamina propria, i.e. loose connective tissue lying just below the epithelium lining the GI tract. There is generally little invasion of these cells into the epithelium, submucosa, or glands of the GI tract, and the lesions almost always show a complete absence of vascular injury due to invasion by these cells.[9] The lesions in LG closely resemble those of NKCE.[5]

The diagnoses of NKCE and LG depends on clinical and pathological findings indicating that the two diseases: a) are indolent and non-malignant; b) usually manifested by mild, vague, or no symptoms; c) localize to the GI tract without involvement of the head, neck, or organs such as the liver and spleen; d) consist of one or more lesions localized primarily to the lamina propria of the esophagus, stomach, small intestine, and/or large intestine (for NKCE} or to the stomach (for LG); and e) involve lesions which contain medium-to large-sized, atypical, and non-clonal lymphocytes that are activated NK cells (see Pathophysiology section) which proliferate at moderately rapid rates (as gauged by, e.g. analysis of their Ki-67 protein levels), lack evidence of Epstein-Barr virus infection, gene mutations, or chromosome abnormalities, and show little evidence of centering around, and destroying, blood vessels.[9]

Patients with NKCE or LG should be treated for symptom relief but, as currently recommended, not for the underlying NK cell proliferative disease. Regular follow-ups that include repeated endoscopic analyses of their GI tracts and tests for the spreading of the disease to other organs are recommended to insure the original diagnosis is correct.[2][6][9][13]

NKCE and LG usually follow a persistent or regressing-relapsing coarse but uncommonly spontaneously relapses without a recurrence even in cases that have been mistreated with chemotherapy, bone marrow transplantation, or gastric resection. Patients with LG are less likely to have persistent or regressing-relapsing coarse. Symptoms of the disease usually remain vague and mild.[5]