Natural killer/T cell lymphomas are uncommon lymphoid neoplasms that are usually diagnosed in persons from Asia and South America [3
]. NK/T cell lymphomas have only rarely been diagnosed in patients with HIV/AIDS with fewer than ten cases reported in the literature [5
]. Similar to our patient, two of the HIV/AIDS patients in the literature had CNS disease, including one who also had involvement of the orbit and the nasal/maxillary sinuses [7
]. The latter patient, a 42-year-old male, presented with double vision and eye-droop as did our patient. The primary sites of disease in the other HIV/AIDS patients with NK/T cell lymphoma reported in the literature include nasopharynx, tonsil, parotid gland, lung/mediastinum, and lymph node. However, in most of the patients, lymphoma was also identified in other sites, most commonly the liver, either at presentation or later in the course of their disease. Involvement of the colon, which occurs relatively frequently in HIV negative patients and was a major site of involvement in our patient, was not reported in the other seven cases identified in the literature [5
All but one of the reported NK/T cell lymphomas in HIV/AIDS patients have been diagnosed in men (median age of 42 years) with low CD4 counts (<200/dl, where reported) [5
]. The remaining case occurred in an 18-month-old Chinese girl with perinatal HIV infection [6
]. This child presented with an enlarged supraclavicular lymph node, which on biopsy revealed NK/T cell lymphoma. NK/T cell proliferations have been reported in children, termed severe chronic active EBV infection (CAEBV), but in general NK/T cell lymphomas only infrequently involve lymph nodes.
Interestingly, during the initial work-up of our patient, PET/CT scans showed mesenteric lymphadenopathy consistent with malignant lymphoma. A biopsy of a mesenteric lymph node, however, showed KS. The subsequent colon specimen, in contrast, contained a pleomorphic, high-grade large cell lymphoma. This finding, in a patient with KS, strongly suggested the possibility of a solid (extra-cavitary) PEL [2
]. However, work-up showed that the lymphoma, although EBV positive, was not a KSHV/HHV-8 positive extra-cavitary PEL as the cells were negative for the KSHV/HHV-8-associated LANA and did not contain a clonal rearrangement of the immunoglobulin heavy chain gene, but instead expressed CD56, CD2, and CD3 and was EBV positive, consistent with an extra-nodal NK/T cell lymphoma, nasal type. Thus, this patient had two completely separate neoplastic processes, both of which are associated with different herpes virus infections.
NK/T cell lymphomas are aggressive neoplasms [3
]. Of the previously reported HIV/AIDS patients with NK/T cell lymphoma reported in the literature, only one patient of the six with follow-up lived more than 1 month following diagnosis. The exception, a 42-year-old homosexual male, known to be HIV-positive for 14 years, who presented with parotid gland and liver disease and an absolute CD4 count of 0 and lived 22 months following diagnosis. He was treated with two rounds of chemotherapy, but did not complete the second course. He subsequently developed pulmonary nodules and died of probable lymphoma [8
]. Our patient received combination chemotherapy with alleviation of symptoms and has survived more than 1 year. Her follow-up CT scan 12 months after presentation showed no evidence of disease. However, her clinical course may also be influenced by her improved immune status by remaining compliant with her HAART therapy.
Our understanding of NK/T cell lymphomas, particularly in the HIV/AIDS patient population, is limited particularly due to the relatively small number of cases diagnosed. Furthermore, the diagnosis of NK/T cell neoplasms is complicated by the significant phenotypic and genotypic overlap between NK cells and cytotoxic T cells and by lack of a “clonality” marker in NK cell proliferations. Recently described antigens on NK cells and some cytotoxic T cells termed “kill inhibitory receptors” (KIRs) are thought to protect potential targets from NK-cell-mediated lysis. KIRs are of particular interest because they are stably expressed over multiple generations and thus may serve as a marker for clonality. Studies have shown that in normal NK cell populations, varying portions of NK cells are positive for each of multiple KIR antigens whereas NK neoplasms show restricted KIR expression or no KIR expression at all. To date, studies that test the use of KIRs for this purpose have been small, owing to the scarcity of NK cell neoplasms, however these antigens show potential as diagnostic tools for these rare and aggressive neoplasms [12
Our patient has experienced relatively long disease free survival. Not only is this unusual in patients with NK/T cell lymphoma, particularly one with HIV/AIDS, but is also surprising as our patient presented with other poor prognostic indicators including intestinal involvement, disseminated disease, high level of EBV DNA in the CSF, and a low CD4 count [3
]. Although therapy for NK/T cell lymphoma has focused on anthracycline-based chemotherapy with or without radiation [13
], because of the need to treat her CNS disease, a regimen utilizing methotrexate every 14 days was used [15
]. Furthermore, as she presented with disseminated disease, radiation was thought to be most likely of little benefit. Thus, she did not receive radiation therapy despite the fact that at least some investigators think that it supplies the greatest part of treatment efficacy [16
]. Although the impact of an improved CD4 count, secondary to HAART compliance, on survival is large, this patient’s complete response and relatively long survival raise the possibility that NK/T cell lymphomas may be more sensitive to methotrexate-based treatment regimens than those employing anthracycline as well as implying that radiation therapy may not be as important as has been previously thought. However, randomized trials are needed to clarify these possibilities.
In this study, we describe a severely immunosuppressed HIV/AIDS woman with gastrointestinal and central nervous system extra-nodal NK/T cell lymphoma, nasal type, an unusual diagnosis in a patient population where the vast majority of the lymphoid neoplasms are aggressive B cell lymphomas such as diffuse large B cell lymphoma, Burkitt lymphoma and in patients with very low CD4 counts and known KS, PEL/extra-cavitary PEL [1
]. However, the anatomic sites of involvement and the very rapid disease progression underscore the importance of considering other disease processes, such as NK/T lymphoma, in the differential diagnosis.