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Extranodal NK-Cell Lymphoma
Introduction
Extranodal NK/T-cell lymphoma, nasal type, is a rare subtype of non-Hodgkin lymphoma, characterized by a universal association with Epstein-Barr virus (EBV), and disfiguring clinical presentations.[1][2][3] With the application of modern therapies, the clinical outcomes of these patients have improved significantly.[4] Nevertheless, survival is still heavily dependent on the type of disease and stage at diagnosis.
Etiology
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Etiology
Irrespective of the ethnic origin of patients, there is a strong association of EBV infection in almost all cases of extranodal NK/T-cell lymphoma, suggesting an important role of the virus in the etiology of this disease.[2][5][6][7][8][9]
Epidemiology
Extranodal NK/T-cell lymphoma is regarded as a rare subtype of non-Hodgkin lymphoma.[1] The disease is more prevalent in Asian countries than in Europe and the United States.[4] It often affects adults and is more common in men than in women.
Pathophysiology
Genetic abnormalities, EBV infection, and tumor microenvironment have been shown to play significant roles in the molecular pathogenesis of extranodal NK/T-cell lymphoma.[10][11]
1. Genetic Abnormalities
JAK/STAT Pathway
The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is important for hematopoiesis and immune development. In extranodal NK/T-cell lymphoma, STAT3 of the JAK/STAT cascade is the most frequently mutated genes followed by TP53, JAK3, JAK1, and SOCS1.[12][13][14] STAT3 mutations promote STAT3 phosphorylation and transcriptional activity of STAT3 in the absence of cytokines. By binding to the programmed cell death-ligand 1 (PD-L1) gene promoter, activated STAT3 then upregulates the expression of PD-L1. Increased PD-L1 interacts with the programmed cell death protein 1 (PD-1), an inhibitory co-receptor on T-cells, and suppresses T-cell activation and receptor signaling.[15] This leads to T-cell exhaustion which favors tumor cell survival.
Epigenetic Dysregulation
Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and a catalytic component of the polycomb repressive complex 2 (PRC2) molecule.[16] The PRC2 molecule is one of the polycomb group proteins that form chromatin-modifying complexes essential for embryonic development and stem cell renewal but are commonly deregulated in cancer.
EZH2 is aberrantly overexpressed in extranodal NK/T-cell lymphoma, which is mediated by MYC-induced repression of regulatory microRNAs.[17][18][19] It exerts its oncogenic function by inducing gene repression through its effect on chromatin via its histone methyltransferase activity, and by promoting the transcription of cyclin D1.
Besides, phosphorylation by JAK3 promotes EZH2 as a transcriptional activator.[20] Through the upregulation of genes involved in DNA replication, cell cycle, biosynthesis, stemness, and invasiveness, phosphorylated EZH2 promotes a higher proliferative capacity of the tumor cells.
PD-L1 Genetic Abnormalities
Structural variations and focal copy number alterations affecting PD-L1 are associated with an overexpression of PD-L1 in extranodal NK/T-cell lymphoma.[21]
Hereditary Susceptibility
A genome-wide association study found out that a single-nucleotide polymorphism located in HLA-DPB1, namely rs9277378, was associated with a 2.3 times higher risk of extranodal NK/T-cell lymphoma compared to baseline, rendering its hereditary susceptible to the disease.[22]
Other Gene Mutations
Extranodal NK/T-cell lymphoma is associated with the deletion in the chromosome 6q21-25, and mutations in the cell surface receptor FAS (Apo-1/CD95), p53, K-ras, and c-kit.[23][24][25][26][27][28][29][30][31][32][33]
2. EBV Infection
EBV infection is believed to play an important role in the pathogenesis of extranodal NK/T-cell lymphoma though its actual mechanism is still undetermined. It is known to integrate its genomic fragment into different repeat families of the human genome, such as SINE, LINE, and satellite.[34] By integrating its genomic fragment into the intron of the human non-homologous end-joining factor 1 (NHEJ1) gene, EBV downregulates NHEJ1, which is an important DNA repair factor for the NHEJ pathway that mediates repair of double-stranded breaks. This results in genome-wide instability with the onset of extranodal NK/T-cell lymphoma.
By expressing EBV nuclear antigen 1 (EBNA1), latent membrane protein (LMP) 1, LMP2A, and LMP2B (latency phase II), EBV modulates cell signaling, and forms barriers to apoptotic signals to escape from T-cell-mediated immune response.[35] Besides, the EBV BART RNAs, which are highly transcribed in extranodal NK/T-cell lymphoma, is thought to play an important role in driving the disease and immune evasion.[34]
3. Tumor Microenvironment
Chemokines play a crucial role in the proliferation of tumor cells with the recruitment of inflammatory cells.[36][37] Tumor cells secrete IP-10 (interferon gamma-induced protein 10), CCL2 (C-C motif chemokine ligand 2), and CCL22 (C-C motif chemokine ligand 22) which are monocyte-attractant chemokines. Monocytes, in turn, promote proliferation, LMP-1 expression, and IP-10 production of tumor cells via membrane-bound IL-15/IL-15 receptor alpha complex. This positive feedback loop between tumor cells and monocytes may contribute to lymphoma progression.
Histopathology
Angioinvasiveness and necrosis are distinguishing pathologic features in most cases of extranodal NK/T-cell lymphoma.[38] Surrounded by various inflammatory cells such as granulocytes, lymphocytes, monocytes, and macrophages, the lymphoma cells are usually medium-sized or a mixture of small and large cells. They usually reveal surface CD3−, cytoplasmic CD3ε+, CD56+, CD16+/−, and germline T-cell receptor (TCR) on immunophenotyping, demonstrating NK-cell lineage. In a subset of lymphoma cells of T-cell origin, positive surface CD3 and negative CD56 may be detected. EBV-encoded RNA in situ hybridization (EBER-ISH) and cytotoxic granule protein TIA-1 are always positive.
History and Physical
Most patients with extranodal NK/T-cell lymphoma are of nasal type, which is localized to the upper aerodigestive tract.[3] They commonly present with a nasal mass, nasal obstruction, or nasal bleeding. Other clinical presentations include hoarseness of voice, dysphagia, halitosis, airway obstruction, and dysphonia. Bone marrow involvement is not common in initial presentation.[39]
In patients with an extranasal involvement, skin, testis, and gastrointestinal (GI) tract are typically affected.[2][40] Abdominal pain, GI bleeding, and bowel perforation are the most common presentations in patients with GI involvement.
Evaluation
A definitive diagnosis requires an adequate biopsy with histopathological and immunohistochemical examinations. It is followed by proper staging with positron emission tomography/computed tomography (PET/CT) scans to assess the extent of the disease and to guide therapy.[41] Contrast-enhanced CT scans and magnetic resonance imaging scans can also be used. The PET/CT results are interpreted using the 2014 Lugano classification as follows:[42]
- Stage I: a single lymph node, a group of adjacent lymph nodes or single extranodal lesions without nodal involvement
- Stage II: two or more lymph node groups on the same side of the diaphragm or limited contiguous extranodal involvement
- Stage II bulky: stage II as above with a bulky feature defined as a single nodal mass of 10 centimeters or greater than a third of the transthoracic diameter
- Stage III: nodes on both sides of diaphragm or nodes above diaphragm with spleen involvement
- Stage IV: additional noncontiguous extralymphatic involvement
A useful prognostic model for patients with extranodal NK/T-cell lymphoma is the prognostic index of natural killer lymphoma (PINK), which includes age above 60 years, stage III to IV disease, distant lymph node involvement, and non-nasal disease.[43] A modified PINK model that includes EBV-DNA viral load at the time of diagnosis (PINK-E) can also be used. EBV-DNA viral load by quantitative PCR correlates well with clinical stage, treatment response, and prognosis; therefore, it plays an important role in the diagnosis and monitoring of the disease.[44][45]
Treatment / Management
The therapeutic approach of extranodal NK/T-cell lymphoma is based on several factors, such as the age of patients, the extent of disease, potential toxicities, and survivorship.
1. Induction Therapy
Nasal Disease (Stage I–II)
Patients with nasal disease (stage I–II) may be treated with concurrent chemoradiotherapy (CRT) regimens such as DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin) with radiation therapy (RT), or VIPD (etoposide, ifosfamide, cisplatin, dexamethasone) with RT.[46][47][48][49] Other regimens that may be considered include sequential CRT with modified SMILE [dexamethasone (steroid), methotrexate, ifosfamide, pegaspargase, and etoposide] with RT, and sandwich CRT with P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) with RT.[50][51][52] For patients who are unfit for chemotherapy, RT alone may be considered.[53](B2)
Nasal Disease (Stage IV) and Extranasal Disease (Stage I–IV)
Pegaspargase-based combination chemotherapy regimens such as AspaMetDex (L-asparaginase, methotrexate, and dexamethasone), modified SMILE, or P-GEMOX, with or without RT may be considered in patients with nasal disease (stage IV) or extranasal disease (stage I–IV).[50][52][54] Other regimens that may be considered include concurrent CRT regimens such as DeVIC with RT, or VIPD with RT.[46][47][48][49](B2)
2. Response Assessment
At the end of induction therapy, patients should undergo an evaluation with PET/CT scans, ear, nose, and throat examination, and EBV viral load to establish remission status. Results from PET/CT scans are interpreted using the Deauville criteria.[41][44][45][55](B2)
Patients with nasal disease (stage I–II) with complete remission (disappearance of all disease) may be observed without further treatment.[56] In contrast, those with partial remission (regression of disease) should undergo a biopsy.[42] Patients with a positive biopsy should be treated as refractory disease while those with a negative biopsy may be observed without further treatment.
In patients with nasal disease (stage IV) or extranasal disease (stage I–IV), hematopoietic stem cell transplant may be considered in those with complete remission or partial remission with a negative biopsy.[57][58] However, patients with a positive biopsy should be treated as refractory disease.[42](B2)
3. Relapsed or Refractory Disease
A diagnosis of relapsed or refractory disease must be confirmed histologically by biopsy.[42] These patients may be treated with a second-line therapy using pegaspargase-based combination chemotherapy regimens such as AspaMetDex, modified SMILE, or P-GEMOX.[50][52][54] Pembrolizumab, an anti-PD-1 monoclonal antibody, has shown remission in relapsed or refractory disease and may be considered in these patients.[59] Other treatment options include supportive care and participation in a clinical trial.[56](B2)
Differential Diagnosis
Conditions that mimic extranodal NK/T-cell lymphoma include aggressive NK-cell leukemia, nasopharyngeal carcinoma, and other mature T- and NK-cell neoplasms. Therefore, it is crucial to have an adequate biopsy with histopathological and immunohistochemical examinations to make a definitive diagnosis.
Prognosis
Clinical outcomes of extranodal NK/T-cell lymphoma have improved significantly with the application of modern therapies.[4] Nevertheless, survival is still heavily dependent on the type of disease and stage at diagnosis. In patients with nasal disease, the 5-year overall survival rate was 54%, but it was 34% in those with extranasal disease.
Complications
The most common cause of death among patients with extranodal NK/T-cell lymphoma is non-Hodgkin lymphoma, followed by other malignant cancers, heart disease, and infection.[60] On rare occasions, patients may present with a hemophagocytic syndrome, a rare and life-threatening disease characterized by high fever, pancytopenia, hepatosplenomegaly, liver dysfunction, coagulopathy, hyperferritinemia, and hemophagocytosis in bone marrow or other organs.[2][61]
Deterrence and Patient Education
Being diagnosed with extranodal NK/T-cell lymphoma and undergoing treatment can have significant psychosocial impacts on patients and their families, as these can bring dramatic changes in their physical, spiritual, emotional, and interpersonal dimensions. Every clinic visit should include screening and assessment of emotional and social concerns of patients and their families. They should also be well-informed of the types of treatment, such as CRT and combination chemotherapy regimens, pros and cons of each treatment, side effects, supportive measures, and long-term management plan. Regular follow-up with primary care physicians and oncologists is also important to monitor treatment response and treatment-related toxicities.
Enhancing Healthcare Team Outcomes
Patient-centered teamwork approach is essential when managing patients with extranodal NK/T-cell lymphoma. An interprofessional team should work together in every step of management—treatment of the disease, prevention and management of complications related to disease or treatment, and providing comprehensive care for patients and their families, with regular follow-ups, psychosocial support, survivorship care, and in end-of-life care.
Media
(Click Image to Enlarge)
Subcutaneous Panniculitis. High-power image of subcutaneous panniculitis, like a T-cell lymphoma showing rimming of fat cells by lymphocytes with frequent apoptotic debris (400x).
Contributed by D Lynch, MD
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