This weeks case dealt with the presentation of a rare lymphoma. James was found to have an NK cell lymphoma of the sinuses with a single cervical lymph node. He had an IPI score of 0 and no other co-morbidity. He was HIV negative and had EBV positivity. He has a Korean mother and English father and as discussed this lymphoma is more prevalent in Asia.
He was discussed at MDT and commenced on SMILE chemotherapy and sandwiched DXT. Due to this tumour having Glycophorin P making anthracycline a less effective. He has a CR at end of treatment on PET He remains under follow up for late relapses can be seen up to decades later.
NK/T cell lymphomas are rare entities in the UK, however in the Asian subcontinent they are much more common accounting for 9% of the total diagnosed lymphomas in Korea. In Asia 45-70% of patients presenting with sinonasal lymphoma will have NK cell lymphoma. In the UK sinonasal lymphomas are more likely to be due to DLBCL but NK cell lymphoma should still be considered as a differential. There is a male preponderance of cases with around 2:1 males to females. Patients classically present in their 5th decade of life.
NK/T cell lymphomas present most commonly in sinonasal area as previously described, this classical presentation is seen in around 70% of patients. There are no differences seen in age, sex or ethnicity in determining how the disease presents. There are 3 distinct patterns of disease that have been described in NK/T cell lymphomas:
1) Nasal – Including nose, oropharynx and upper GI tract.
2) Non-Nasal – Particularly Skin, Gut and Testes.
3) Disseminated type – Leukaemic phase with Bone Marrow infiltration. Extremely poor prognosis median survival 58 days.
Diagnosis is often challenging due to high level of necrosis in tumours so a large excision biopsy should be attempted. Histologically it has an angiocentric and angiodestructive pattern with large cells showing frequent mitosis. Tumour cells express CD56, cytoplasmic CD3 and are negative for surface CD 3 and should express cytotoxic proteins (e.g TIA-1, Granzyme B and Perforin). EBV positivity is a pre-requisite for the diagnosis and can be shown by EBER studies.
Prognosis is variable and there is evidence to show that IPI still has prognostic information to offer for patients with NK/T cell lymphoma, particularly if elevated IPI score. Stage remains of key importance in determining prognosis and time should be taken to establish this at diagnosis. Other factors demonstrated to be predictive of poor outcome include low serum Albumen, Hb <110, plt <150, Ki67 >50%, Female sex and elevated CRP.
Staging should include PET CT scans where possible to gain accurate assessment of disease. Serum EBV PCR should be performed as it will be a useful marker of disease activity if positive at diagnosis and allows monitoring for relapse post treatment.
It is important when considering treatment to note like many other T cell lymphomas the optimal treatment has yet to be fully established and therefore enrolling in clinical trials if available should be considered.
Early stage disease (stage I or II) accounts for 70% of cases. Traditionally CHOP given in 4 cycles was used and had a 3 year OS of 59% with a 50% CR rate. Up to 65% of patients progressed on CHOP chemotherapy and this is due to the NK/T cell lymphomas expressing high P-glycoprotein concentrations causing efflux of the anthracycline out of the cells allowing them to evade its cytotoxic effects.
In unfit patients the role of single agent Radiotherapy should not be forgotten with local control of disease achieved in >90% of patients with a 5yr OS 66% with PFS at 5yrs 61%.
In 2012 SMILE (Dexamethasone, Methotrexate, Ifosfamide, L-Asparaginase and Etoposide) chemotherapy was established as a valuable chemotherapy backbone for NK/T cell lymphoma as >80% response rates for all patient groups were seen for the first time in this lymphoma. This regimen is effective as Dexamethasone, Methotrexate and Ifosfamide are all P Glycoprotein independent. Etoposide is useful in treatment of Haematophagocytosis which can be linked to this type of lymphoma and L-Asparaginase has been shown to be effective in vitro against NK cells.
In early stage disease SMILE gave best results with 3-4 cycles combined with sandwiched Radiotherapy after first two cycles. It had an ORR 90% with CR in 69% with an ongoing 90% CR during follow up. There is however 7% mortality linked to this intensive chemotherapy regimen.
In advanced stage disease combination chemotherapy regimens offer the best chance of ongoing disease remission. SMILE chemotherapy given in patients with stage IV disease gives a 1 year OS 45% with PFS 45%.
It is encouraging to note that patients with relapsed disease treated first line with anthracycline based chemotherapy seem to respond well to re-induction with L-Asparginase based regimens with 1 year PFS of 71% and OS 79%.
The role of autologous and allogenic transplantation is unclear. For patients with advanced disease or relapsed disease this may be considered as an option and if possible in context of clinical trials.
Patients with NK/T cell lymphomas do require follow up long-term as relapses have been reported after decades. Plasma EBV DNA PCR should be monitored and rising levels investigated. Post treatment patients often still have residual sinus disease that can make CT scans difficult to interpret in these cases PET should be considered.
Although rare NK/T cell lymphomas are occasionally seen in clinical practice. There are ongoing advances in the molecular basis of NK cell lymphomas and in 2015 Chen et al established that receptor-type tyrosine-protein phosphatase K (PTPRK) was lost in del 6q that is commonly seen in NK/T cell lymphoma. Loss of PTPRK is the mechanism that causes unregulated activity of STAT-3 signalling, potentially offering a therapeutic target of the future in these patients.
Tse et al. How I treat NK/T cell lymphomas. Blood 2013; 121(25):4997-5005.
Chen et al. Receptor-type tyrosine-protein phosphatase k directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma. Blood 2015;125 (10):1589-1600).
Lee et al. Extranodal Natural Killer T-Cell Lymphoma, Nasal-Type: A Prognostic Model From a Retrospective Multicenter Study. J Clin Oncol 24:612-618.
Kwong et al. SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group. Blood 2012;120(15):2973-2980.
Chim et al. Primary nasal natural killer cell lymphoma: long-term treatment outcome and relationship with the International Prognostic Index. Blood 2004;103:216-221.