Quiescent nasal T/NK cell lymphoma manifested as primary central nervous system lymphoma

A 57-year-old man was diagnosed as primary T/NK-cell central nervous system lymphoma (CNSL) with intraocular involvement. However, review of a surgical specimen taken three years before for chronic paranasal sinusitis revealed an overlooked nasal T/NK cell lymphoma (TNKL), which showed similar histomorphology and immunophenotype with the CNS disease. Another patient, a 43-year-old woman, was initially diagnosed as a rare primary leptomeningeal T-cell lymphoma with ocular manifestation. Three years later, an isolated nasal TNKL emerged. Immunohistochemical and cytogenetic studies confirmed the same nature of the CNSL and the nasal TNKL. The nasal TNKLs of both patients had a strong expression of CD3, CD56, and Epstein-Barr virus antigens, but features of angiodestruction and mucosal ulceration were absent. We propose that: 1. a locally silent “quiescent” form of nasal TNKL may exist; and 2. a thorough examination and even blind biopsy of the nasal cavity is indicated when primary T/NK-cell CNSL is diagnosed. Am. J. Hematol. 60:161–163, 1999. © 1999 Wiley-Liss, Inc.     

Racial patterns of extranodal natural killer/T-cell lymphoma, nasal type, in California: a population-based study

In order to investigate whether the clinical behaviour of extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) varies by race within a geographic region, we identified a total of 213 non-Hispanic whites, Hispanics and Asians/Pacific islanders (APIs) diagnosed with ENKTL in the California Cancer Registry between 2001 and 2008. The incidence and outcomes of the disease in these racial groups were analysed. The incidence rates in non-Hispanic whites, Hispanics and APIs were 0.05, 0.18 and 0.23 per 100,000 person-years, respectively, among males; and 0.03, 0.07 and 0.10 per 100,000 person-years, respectively, among females. The overall survival (OS) at 5 years was 28.6% in non-Hispanic whites, 30.4% in Hispanic, and 24.0% in APIs. In multivariate analysis, distant versus local/regional disease (Hazard Ratio [HR]=2.01, 95% confidence interval [CI]: 1.36, 2.96), initial treatment with chemotherapy plus radiotherapy (HR=0.39, 95% CI: 0.22, 0.70) or radiotherapy alone (HR=0.48, 95% CI: 0.23, 0.99) versus no therapy were associated with OS. However, OS was not affected by age, sex, race, chemotherapy alone, socioeconomic status, or human immunodeficiency virus infection. In conclusion, ENKTL is more common and clinically more similar among Hispanics and APIs than non-Hispanic whites with poor outcome in all racial groups.     

Chromosome aberrations are restricted to the CD56+, CD3− tumour cell population in natural killer cell lymphomas: a combined immunophenotyping and FISH study

Natural killer (NK) cell lymphomas are a newly recognized entity of non-Hodgkin's lymphoma with a highly aggressive clinical course and strong association with Epstein-Barr virus (EBV) infection. Although no recurrent chromosome aberrations have been identified in NK-cell lymphoma, deletions of 6q and trisomy 7 have been described repeatedly in this type of lymphoma. In this study we attempted to determine the immunophenotypes of tumour cells with certain chromosome aberrations, i.e. deletions of 6q and trisomy 7, in three cases of NK cell lymphomas by means of combined immunophenotyping and fluorescence in situ hybridization (FISH). In all three cases clonal chromosome aberrations were detected only in CD56+ cells but not in CD3+ or CD5+ cells. However, not all CD56+ cells were shown to contain these chromosome aberrations. Double immunophenotyping combined with FISH confirmed that the chromosome aberrations occurred only in CD56+CD3- cells. This study indicates that chromosome aberrations in NK-cell lymphomas are restricted to the CD56+, CD3- and CD5- cell population and that NK-cell lymphomas are indeed derived from mature true NK cells and not from T lymphocytes.     

Post-transplantation lymphoproliferative disease of natural killer cell lineage: a clinicopathological and molecular analysis

Post-transplantation lymphoproliferative disorders (PTLD) occur after solid organ and bone marrow transplantation. They are predominantly of B-cell and occasionally of T-cell lineage. We report a case of PTLD of natural killer (NK) cell lineage. A renal allograft recipient developed progressive pancytopenia 1 year after transplantation. Serial bone marrow biopsies showed an increasing infiltration by large granular lymphoid cells. A subsequent leukaemic phase also developed with systemic infiltration of other organs. Immunophenotyping showed that these cells were CD2+, CD3-, CD3epsilon+, CD56+, CD94+, CD158a- and CD158b-. In situ hybridization showed Epstein-Barr virus (EBV) infection of the neoplastic cells. Genotypical analysis showed the T-cell receptor gene in germline configuration and clonal EBV episomal integration. The overall features were consistent with NK cell lymphoma/leukaemia. The patient did not respond to cessation of immunosuppression or anti-EBV treatment. Combination chemotherapy was given, but the patient died ultimately of disseminated fungal infection. In conclusion, we have demonstrated that NK cell lymphoma is another rare type of PTLD that appears to be highly aggressive and therefore may require early chemotherapy to improve treatment outcome.     

An unusual extranodal natural killer/T-cell lymphoma presenting as chronic laryngitis: A case report

Rationale:Nasal-type, extranodal natural killer (NK)/T-cell lymphoma is a rare lymphoma. The tumor usually shows ulcerative and necrotic lesions in the nasal cavities and sinuses. Tissue involvement outside the nasal cavity is uncommon.Patient concern:We describe a 30-year-old man with a 2-month history of hoarseness, weight loss, and dyspnea.Diagnosis:Magnetic resonance image (MRI) showed edema of the larynx with obliteration of the airway. Laryngoscopic examination described necrotic tissue in the glottis and larynx. The biopsy showed chronic, necrotizing laryngitis, with no granulomas, vasculitis, or atypical cells. The immunologic and microbiologic study was negative. Later, after immunosuppressive therapy, the patient presented erythema and diffuse enlargement of the right arm. MRI showed myositis of the biceps and brachial muscles. Infection was rule out, and direct microscopy showed an extensive muscle infiltration by mononuclear cells and abundant mitosis. Immunohistochemistry was positive for CD3, CD8, Ki 67 (90%), and CD56 compatible with extranodal NK/T cell lymphoma.Interventions:The patient initially received immunosuppression treatments (corticoids, cyclofosfamide, and Rituximab) with relapsing episodes. When lymphoma was diagnosed, chemotherapy was started.Outcomes:The patient died during chemotherapy.Lessons:Nasal-type, extranodal NK/T-cell lymphoma should be suspected even when there are no classical findings of neoplasms on histology. Immunohistochemistry is mandatory to rule it out.     

Clonal disease of natural killer large granular lymphocytes in Taiwan

Lymphoproliferative diseases of large granular lymphocytes (LDGL) may arise from either CD3⁺ T cells or CD3⁻ natural killer (NK) cells. LDGL with clonal proliferation of large granular lymphoeytes (LGL) is defined as LGL leukaemia. The number of patients with NK-LGL leukaemia reported is limited and the pathogenesis of the disease is not yet clear. From 1991 to 1998 six patients with cytogenetically proved clonal disease of NK-LGL were identified in our institute. All were seropositive for Epstein-Barr virus (EBV). EBV RNA or DNA could be detected in LGL from four patients by EBV in situ hybridization or Southern blot analysis. Most patients ran an aggressive clinical course and five died of the disease. Nonrandom clonal chromosomal abnormalities, including duplication of 1q, rearrangement at 3q and loss of chromosomes Y, 13 or 10, were noted in the six patients from this study and in eight from the literature. The implications of these recurrent cytogenetic aberrations in the development and progression of the disease deserve further studies.     

Prognostic factors for classifying extranodal NK/T cell lymphoma, nasal type, as lymphoid neoplasia

This study evaluated the applicability of prognostic factors commonly used for diagnosis of classical lymphoma outcomes to extranodal NK/T cell lymphoma, nasal type (NTCL). Clinical features and their associations with lactate dehydrogenase (LDH) were evaluated in 70 patients. RLDH was defined as the ratio of LDH to the upper normal limit. RLDH was associated with stage (I-II vs. III-IV), lymph node involvement (LNI), and International Prognostic Index score (<2 vs. > or =2). Poor performance status and advanced stage were common in patients with local tumor invasiveness (LTI). LDH level, classified into three levels (low, high, and very high) was associated with survival (P < 0.001). In multivariate analysis, the predictive values of LDH level, B symptom, performance status, and stage remained significant whereas those of LTI and LNI did not. Scoring was performed by weighting each factor with 0.5 or 1.0 according to its hazard ratio. Scores were classified into four groups. Groups with high scores were associated with unfavorable outcomes (P < 0.001). Current study suggests that prognostic factors for NHL may be useful to predict the outcome of NTCL but the model should take LDH level and the prognostic weight of each factor into account.     

Invariant natural killer T cells in chronic obstructive pulmonary disease

Background and objective: Invariant natural killer T (iNKT) cells may play an important role in regulating the innate and acquired immune systems in chronic obstructive pulmonary disease (COPD). However, there is little information regarding the potential role of iNKT cells in the pathogenesis of COPD. To investigate whether iNKT cells have an important role in COPD, the frequency of iNKT cells in peripheral blood of patients with COPD was analysed. Methods: This was a comparative study of 28 patients with COPD and 19 age‐matched healthy control subjects. Blood iNKT cells were stained with 6B11 mAb, anti‐T cell receptor Vα24 mAb, anti‐T cell receptor Vβ11 mAb or α‐galactosylceramide‐loaded CD1d‐tetramer, and analysed by flow cytometry. Results: The frequency of CD4⁺ 6B11⁺ iNKT, CD4⁺ Vα24⁺ iNKT, CD4⁺ Vβ11⁺ iNKT and CD3⁺ 6B11⁺ iNKT cells was significantly lower in peripheral blood of patients with COPD than in that of healthy control subjects. The frequency of CD4⁺ 6B11⁺ iNKT cells was significantly lower in patients with exacerbations of COPD compared with those with stable COPD. Conclusions: The frequency of iNKT was decreased in peripheral blood of patients with COPD. These results strongly suggest that iNKT cells may play an important role in the pathogenesis of COPD.     

Aggressive natural killer cell leukemia/lymphoma: a comprehensive cytogenetic study by spectral karyotyping

 A 38-year-old male presented with fever and hepatosplenomegaly. Cells that had infiltrated to the bone marrow were consistent immunophenotypically and genotypically with natural killer (NK) cells. Oligoclonal Epstein-Barr virus infection was detected in the bone marrow cells. The patient was diagnosed as a case of aggressive NK cell leukemia/lymphoma. Combined chemotherapy was not effective and death occurred shortly after presentation. Although the karyotype of this case was too complicated to be accurately identified only by G-banding, spectral karyotyping (SKY) analysis not only identified all chromosomal materials of unknown origin, but also detected the cryptic translocation on the apparently normal chromosome. Moreover, SKY analysis identified der(4)t(4;14)(q12;q11.2). The chromosomal band 14q11.2 is a recurring breakpoint in T-cell non-Hodgkin's lymphoma, and is also the locus of the δ chain of the T-cell receptor. To our knowledge, t(4;14)(q12;q11.2) in T-cell or NK-cell malignancies has not been previously reported. Received: 6 September 1999 / Accepted: 31 January 2000     

Aberrant promoter CpG methylation as a molecular marker for disease monitoring in natural killer cell lymphomas

Natural killer (NK) cell lymphomas lack suitable clonal markers for tumour cell detection, making the monitoring of minimal residual lymphoma difficult. Aberrant promoter CpG methylation occurs frequently in NK cell lymphomas. The objective of this study was to assess the potential of aberrant methylation as a surrogate tumour marker. Twenty-five primary tumours and 105 serial biopsies taken at various time points after treatment were examined using a methylation-specific polymerase chain reaction (MSP) for a panel of genes, comprising p73, p16, hMLH1, RARbeta and p15, previously shown to be methylated in NK cell lymphomas. All samples underwent independent morphological examination, supplemented by immunostaining for CD56 and in-situ hybridization for Epstein-Barr-virus-encoded RNA. Primary tumours showed the frequent methylation of the genes p73 (92%), p16 (71%), hMLH1 (61%), RARbeta (56%) and p15 (48%). MSP results in serial post-treatment biopsies were correlated with clinicopathological findings. Results were concordant in 89 follow-up samples (18 samples, histology positive/MSP positive; 71 samples, histology negative/MSP negative) and discordant in 16. Fifteen samples were histology negative/MSP positive, and tumour involvement was subsequently confirmed (positive re-biopsies or relapses at the same sites), indicating that MSP was more sensitive for minimal lymphoma detection. One sample was histology positive/MSP negative; a subsequent histological review and continuous clinical remission of the patient did not support tumour involvement. Our findings suggest that MSP for aberrantly methylated genes is a potentially valuable molecular marker for detecting either residual or relapsed disease in NK cell lymphoma patients.     

A case of nasal‐type NK/T cell lymphoma in a patient with dermatomyositis

The association of malignancy with dermatomyositis is well known, and the frequency is reported to be up to 30%. However, cutaneous lymphoma associated with dermatomyositis has rarely been reported. We experienced a case of nasal‐type NK/T‐cell lymphoma in a 40‐year‐old woman with a 2‐year history of dermatomyositis. To our knowledge, this is the first report of cutaneous involvement of nasal‐type NK/T‐cell lymphoma developing in a dermatomyositis patient. When skin lesions are resistant to aggressive conventional treatment in dermatomyositis patients, we should consider the possibility of malignancy, especially cutaneous lymphoma.     

Lymphomatoidgastropathy mimicking extranodal NK/T cell lymphoma, nasal type: a case report

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, exhibits aggressive tumor behavior and carries a poor prognosis. Recently, lymphomatoid gastropathy with NK/T cell infiltration into gastric mucosa has been recognized as a pseudo-malignant disease which regresses without treatment. Because the conventional immunohistochemical criteria of lymphomatoid gastropathy is similar to that of extranodal NK/T-cell lymphoma nasal type, it is difficult to distinguish between the two conditions by histopathological evaluation only. Here, we report a rare case of lymphomatoid gastropathy in a 57-year-old female. Gastroendoscopy on routine check-up revealed elevated reddish lesions < 1 cm in diameter in the gastric fornix and body. Although repeat endoscopies at 1 and 6 mo later revealed no gastric lesions at any locations without any treatments, at 12 mo later gastric lymphomatoid lesions recurred at gastric fornix and body. Histological examination of endoscopic biopsy specimens at 12 mo showed atypical NK cell infiltration with CD3⁺, CD4^-, CD5^-, CD7⁺, CD8^-, CD20^-, CD30^-, CD56⁺, CD79a^- and T-cell-restricted intracellular antigen-1⁺ into gastric mucosa. After treatment for Helicobacter pylori (H. pylori) eradication, the lesions disappeared in all locations of the gastric fornix and body over the subsequent 12 mo. Here, we report a case of H. pylori-positive lymphomatoid gastropathy with massive NK-cell proliferation, and also review the literature concerning newly identified lymphomatoid gastropathy based on comparison of extra nodal NK/T-cell lymphoma nasal type. In any case, these lesions are evaluated with biopsy specimens, the possibility of this benign entity should be considered, and excessive treatment should be carefully avoided. Close follow-up for this case of lymphomatoid gastropathy is necessary to exclude any underlying malignancy.     

CD56+ NK lymphomas:clinicopathological features and prognosis

The surface molecule CD56 marks a category of malignant lymphoma of putative natural killer (NK) cell origin. We conducted a retrospective analysis of 24 cases of CD56⁺ NK lymphoma/leukaemia to define the clinicopathologic and prognostic features of this specific group of lymphomas. 56 cases of nasal lymphomas and 204 cases with an initial diagnosis of peripheral T-cell lymphoma were retrospectively analysed. To specifically examine lymphomas of putative NK origin, only those that were negative for surface expression of CD3 but positive for CD56 were analysed. 24 cases were identified. The initial predominant sites of involvement were nasal (n =18), palate (n = 1), nodal (n = 1) and multi-organ (n =4). Clinically, in patients with disease localized to one anatomical site (n = 20), most had symptoms confined to the nose, with a high percentage in early stage (I: 91%; IV: 9%). The marrow was not involved in any of these cases. However, patients with multi-organ involvement at presentation (n = 4) behaved differently. All presented acutely with pancytopenia, hepatosplenomegaly, and marrow infiltration with haemophagocytosis. A leukaemic phase was observed in one case. Anthracycline containing combination chemotherapy resulted in complete remission in 75% of patients with localized disease, but only in 25% with multi-organ involvement. The median survival of patients with localized disease was 12 months, compared with 2 months in the multi-organ group (P =0.06); the disease-free survival was significantly better in the former (P <0.01). The overall median survival of all patients was still poor at 11 months. We conclude that CD56⁺ NK lymphomas could be divided into two main patterns of disease presentations: localized (predominantly nasal), and multi-organ involvement. Each has different clinicopathologic and prognostic features. Conventional chemotherapy appeared ineffective for the majority of patients, and innovative treatment modalities are needed to improve outcome.     

Primary adrenal natural killer/T-cell nasal type lymphoma: first case report in adults

We report the first case of a primary adrenal natural killer (NK)/T-cell nasal type lymphoma in adults. The patient presented with an enlarging left adrenal mass and the initial concern was for adrenocortical carcinoma. Surgical resection revealed NK/T-cell lymphoma. Rapid recurrence in the contralateral adrenal gland was treated with a single cycle of chemotherapy before he died due to infectious complications and progressive disease. This case demonstrates the aggressive presentation of a novel subset of primary adrenal lymphoma that should be considered in the differential diagnosis of a rapidly enlarging adrenal mass.