Extranodal NK/T-Cell Lymphoma, Nasal Type

Fig. 11.1

Initial staging MRI of case 1

In the 2008 WHO criteria [3], update of the REAL classification [2], “nasal” NKTCL was defined as a disease occurring in the UADT, whereas “extranasal” NKTCL was defined as a disease occurring outside the UADT. Based on recent data, NKTCL consists of three distinct subgroups: nasal NKTCL, extranasal UADT NKTCL, and extra-UADT NKTCL [11, 12, 18]. The various clinical presentation and prognosis between the three subgroups are summarized in Table 11.1.

Table 11.1

Clinical and immunophenotypic differences between the three subgroups of extranodal nasal-type NK/T-cell lymphoma

	UADT-NKTCL
Feature	Nasal NKTCL	Extranasal UADT–NKTCL	Extra–UADT–NKTCL
Primary site	Nasal cavity or paranasal sinus with or without extension into adjacent structures	Waldeyer’s ring (nasopharynx, tonsil, oropharynx, base of the tongue), hypopharynx, larynx, and oral cavity	The skin and soft tissue, gastrointestinal tract, testis, et al. Accounts for 10–30 % of all cases
Phenotype	High expression of EBV (>90 %), CD3ε, CD56, and Ki-67. All cases express cytotoxic proteins.	High expression of EBV (>90 %). CD56 expression is less common than nasal variant, low proliferation index	EBV expression is relatively diverse (40–100 %). High proliferation index
Age	Usually adults, median age of 44 years	Usually adults, median age of 38–50 years	Usually adults, median age of 50 years
Sex	Male predominance, M/F = 2–4:1	Male predominance, M/F = 2.6:1	Male predominance, M/F = 1.5–2.3:1
Stage	Usually present with early-stage disease, majority with stage I (60–80 %); less common with stage III and IV (10–25 %).	Usually present with early-stage disease, stage I <20 %, stage II 50–60 %; more advanced-stage disease (20–30 %)	Usually present with disseminated and advanced-stage disease (>50 %)
Performance status	Good	Good	Poor, frequently ECOG ≥ 2
Elevated LDH	Frequency (20–50 %)	Frequency (20–50 %)	High frequency (50–70 %)
Lymph node involvement	Low frequency of lymph node involvement at diagnosis (<20 %)	Frequent involvement of the cervical lymph node (>50 %)	High frequency of regional lymph node involvement
IPI	Usually low risk, IPI 0–1 > 90 %	Usually low risk, IPI 0–1 ≥ 80 %	Usually high risk, IPI 0–1 25–58 %
Failure patterns	Extranodal organs. The skin is the most common site	Lymph nodes and extranodal organs	Extranodal organs
Clinical course	Aggressive	Less aggressive	Highly aggressive
Prognosis	Favorable outcome in stage I patients treated with appropriate radiotherapy, poor for stage II–IV patients	Relatively favorable outcome compared with nasal or extra-UADT variants	Extremely poor prognosis; median survival, 3–20 months

Modified from Liu et al. [18]

Abbreviations: UADT upper aerodigestive tract, NKTCL extranodal nasal-type NK/T-cell lymphoma, EBV Epstein-Barr virus, ECOG Eastern Cooperative Oncology Group, LDH lactate dehydrogenase, IPI International Prognostic Index

UADT NKTCL is characterized by predominance in young male, good performance status, elevated lactate dehydrogenase (LDH) in a large proportion of patients, high frequency of early-stage disease, and low-risk group according to International Prognostic Index (IPI) [10]. Patients usually have local tumor invasion or adjacent structure involvement (40–60 %). For nasal NKTCL, the most frequently involved adjacent sites are the maxillary and ethmoid sinuses, followed by the nasopharynx [15, 26]. The major pathway of lymph node spread for nasal NKTCL is to the submandibular and cervical lymph nodes [9]. The primary pattern of failure is distant extranodal sites such as the skin, lung, and liver. The propensity for NKTCL spread to the extranodal organs, especially the skin, is related to the homing capacity of NK/T-cell.

Extranasal UADT NKTCL represents different clinical features and prognosis [11, 12, 18]. The most frequent presenting symptoms for Waldeyer’s ring NK/T-cell lymphoma (WR NKTCL) are odynophagia, dysphagia, and cervical lymphadenopathy [11]. Patients are more likely to present with regional nodal involvement (60 %) and advanced-stage diseases (20–40 %) and have a relatively favorable prognosis [11, 12, 18]. The majority of patients with extranasal UADT NKTCL or WR NKTCL present with Ann Arbor stage II to IV disease, whereas only 10–20 % patients have stage I disease. This differed from reports in which the frequency distribution (60–80 %) of stage I disease was predominant in patients with nasal NKTCL [10, 14, 27]. Several studies have demonstrated that UADT NKTCL and extra-UADT NKTCL have different clinical features and prognoses [5, 16, 28–32, 34, 35, 41]. Extra-UADT NKTCL constitutes only 10–30 % of all NKTCL cases and is characterized by poor performance status, high frequency of elevated LDH, advanced-stage disease, high-risk IPI, and extremely poor prognosis (Table 11.1).

Pathology

Extranodal nasal-type NK/T-cell lymphoma was formerly named angiocentric lymphoma in REAL classification in 1994 [1]. Other terms such as lethal midline granuloma, malignant granuloma, midline malignant reticulosis, and angiocentric immunoproliferative lesion were used before 1994.

The typical morphology of this disease includes frequent angiocentricity with zone necrosis and polymorphism of individual cells with small or medium size of tumor cells and polymorphous inflammatory infiltrate. The histological features are similar irrespective of the anatomical sites involved [3]. Repeated biopsy is usually required for pathologic diagnosis, due to necrosis and small size of specimens.

NKTCL is derived mostly from activated NK cell, and rarely from cytotoxic T lymphocyte. The typical phenotype is CD2+, CD3s−, CD3ε+, CD56+, CD20−/CD79a−, and cytotoxic molecules (T-cell intracellular antigen-1 [TIA-1], granzyme B, perforin)+. The tumor cells are infected by Epstein-Barr virus (EBV), which is detected by in situ hybridization (ISH) for EBV-encoded RNA (EBER). Some cases also show a cytotoxic T-cell phenotype that is negative for CD56 but positive for CD3ε, cytotoxic molecules (TIA, Gram B, perforin), and EBER with TCR gene rearrangement. Patients with CD56-negative NKTCL have similar clinical features as those with CD56-positive NKTCL [15, 26]. However, NK-cell or T-cell lymphoma may have different prognosis [16]. Extranodal lymphomas that are CDε + CD56−, but negative for cytotoxic molecules and EBV should be defined as peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS).

TCR rearrangement is absent for NK-cell lineage, but present for T-cell lineage. NKTCL is strongly associated with EBV infection, which is observed in more than 90 % of cases [17, 18]. Gain of 1q and 7q and loss of 6q and 7p are relatively frequent genomic aberrations [19]. Mutation of JAK3, activation of STAT3, overexpression of matrix metalloproteinase 9, and interleukin-9 have been observed in this disease [20–22]. The inactivation or mutation of p53 is common [23, 24]. High expression of Ki-67 is associated with poor survival [18, 25].

Staging Procedure

Initial Evaluation

Our patient had a careful physical (including inspection of the skin) and endoscopic examination. Imaging included an MRI, CT of the head and neck, and a PET/CT (Figs. 11.1 and 11.2). Initial complete blood count, biochemistry, liver and renal function, and LDH were normal. Bone marrow biopsy was normal. Although it is rarely involved, bone marrow assessment is a crucial part of the staging [36, 37].

Fig. 11.2

Initial staging PET-CT of case 1

To accurately determine local disease extent in both the soft tissue and bone, both MRI and CT scan of the head and neck are recommended in all cases [38–40]. Additionally, PET/CT can alter the original staging and affect treatment planning in 20–50 % of patients [38]. Moreover, a high tumor FDG uptake was associated with poor prognosis in patients with NKTCL [35, 41].

Although it is not done in our case, many institutions perform quantitative measurement of circulating EBV-DNA viral load for the diagnosis, monitoring, and predicting prognosis of the disease. High load of plasma EBV-DNA correlates with advanced-stage disease, elevated lactate dehydrogenase (LDH), initial response to therapy, and poor survival [42–44, 56].

Stage and Risk Stratification

The Ann Arbor staging system is widely used for diffuse large B-cell lymphoma. However, it is not readily applicable to NKTCL. Primary tumor invasion (PTI) or local tumor invasion is an important prognostic factor for NKTCL [45–47, 105]. A modified Ann Arbor staging system is recommended, and stage I disease is subclassified into limited stage I or extended stage I disease [9, 10]. Limited stage I disease is defined as tumor confined to a single primary site without extension of adjacent organs, as in case 1, whereas extended stage I disease extends beyond the primary site into any neighboring structure or organ, without the presence of nodal or distant dissemination. Ann Arbor stage II disease is defined as involvement of supradiaphragmatic lymph node(s).

The International Prognostic Index (IPI) and Korean Prognostic Index (KPI) are commonly used for NKTCL. The IPI model includes five independent prognostic factors: age, stage, Eastern Cooperative Oncology Group (ECOG) performance status (PS), LDH, and extranodal involvement. The KPI identifies four risk factors: B symptoms, stage, LDH, and regional lymph node [30]. The Ann Arbor stage, IPI, and KPI assign patients to four risk groups with different survivals but are not consistent to segregate patients into risk groups or predict prognosis [12, 31, 45–47, 105]. Patients with NKTCL were predominantly young males with early-stage disease and good PS, which placed the majority of patients in the low-risk groups (0–1) according to the IPI or KPI. On the other hand, the value of KPI model in early-stage patients is limited because regional lymph node involvement duplicates Ann Arbor stage II disease. Based on a recent large, multi-institutional analysis of 1383 patients, a NKTCL-specific prognostic nomogram has been developed and validated as a reliable tool to individually predict overall survival (OS) and has been shown to be superior to Ann Arbor staging, IPI, or KPI [45, 47]. The nomogram model consisted of five variables from routine clinical practice: stage, PS, age, LDH, and primary tumor invasion (PTI). PTI was defined as the presence of primary disease that extended into adjacent structures or organs or the involvement of multiple, contiguous primary sites. Furthermore, patients with early-stage NKTCL can be classified as low-risk or high-risk group based on the absence or presence of risk factors including age >60 years, elevated LDH, ECOG PS ≥ 2, stage II disease, and PTI [45, 47]. Calculation of NKTCL prognostic index should be considered as part of initial work-up. In case 1, the patient belongs to the low-risk group, with normal LDH, PS < 2, age <60, and stage I disease.

Treatment Management

Our patient presented with an early-stage, low-risk disease [45, 47]. Although radiotherapy alone would have been a viable option, this patient was treated with radiation therapy followed by chemotherapy using VIPD (etoposide, ifosfamide, cisplatin, dexamethasone) for a total of three cycles, started 2 weeks after the completion of radiation.

Current data have indicated that radiotherapy is a critical component of curative treatment for early-stage NKTCL. Radiotherapy has been effective in achieving high complete response (CR) rates and favorable long-term survival. Except for two early studies with small-field and low-dose RT [48, 49], radiotherapy alone resulted in complete response (CR) rates of 70–90 %, 5-year locoregional control (LRC) rate of approximately 90 %, and 5-year OS of 50–90 % [10, 15, 26, 45–47, 50 – 52, 55, 105]. In contrast, outcome with doxorubicin-based chemotherapy alone in early-stage NKTCL has been poor, with CR rates of 10–50 % and overall response rate (ORR) of 60–80 %, 5-year OS rates of 10–35 %, and even lower progression-free survival (PFS) [5, 27, 32, 33, 50, 51]. The low initial response and poor prognosis after chemotherapy reflect the chemoresistance, which may be associated with high expression of P-glycoprotein and p53 mutation [23, 24, 54]. In 105 patients with early-stage nasal NKTCL who received primary radiotherapy, the 5-year OS and PFS rates were 71 and 59 % for all patients, with 78 and 63 % for stage I disease, and 46 and 40 % for stage II disease [10]. Tables 11.2 and 11.3 summarize series demonstrating the critical role of radiation therapy compared to chemotherapy alone for early-stage disease.

Table 11.2

Treatment outcome of radiotherapy with or without chemotherapy compared with that of chemotherapy alone in patients with early-stage extranodal nasal-type NK/T-cell lymphoma

Authors	Time	No	Primary site	Stage	Treatment	5-year OS
Authors	Time	No	Primary site	Stage	Treatment	(%)	P
You et al.	2004	46	Nasal	I–II	RT: 6	83.3	0.027
You et al.	2004				CT ± RT: 40	28.5
Li et al.	2004	56	Sinonasal	I–II	RT: 11	50	0.01
					RT + CT: 27	59
					CT: 18	15
Huang et al.	2008	82	Nasal	I–II	RT ± CT: 74	62.1 (3-years)	0.000
Huang et al.	2008				CT alone: 8	12.5 (3-years)
Kim et al.	2008	280	All sites	I	RT ± CT: NA	90.3	0.022
Kim et al.	2008				CT alone: NA	19.3 (median)
Au et al.	2009	57	UADT	I–II	RT + CT: 34	57	0.045
Au et al.	2009				CT alone: 23	30
Yang et al.	2009	177	UADT	I–II	RT ± CT: 140	53.4	<0.01
Yang et al.	2009				CT alone: 37	18.3
Nie et al.	2010	85	Nasal	I–II	RT + CT: 17	54	0.03
Nie et al.	2010				CT + RT: 48 CT alone: 20	47 13	0.049
Luo et al.	2010	60	Nasal	I–II	RT + CT: 37	56.7	<0.05
Luo et al.	2010				CT alone: 16	18.8
Yang et al.	2009	177	UADT	I–II	RT ± CT: 140	53.4	<0.01
Yang et al.	2009				CT alone: 37	18.3
Vazquez et al.	2014	123	UADT	I	RT: NA	63.5	<0.05
					CT alone: NA	47.7
		65	Extra-UADT	I	RT: NA	52.3	<0.005
			Extra-UADT		CT alone: NA	23.8
Ahn et al.	2012	20	Skin	I	RT ± CT: 10	About 60	<0.005
Ahn et al.	2012				CT alone: 10	12 m (median)
Yang et al.	2015	1273	All sites	I–II	RT ± CT: 1103	67.7	<0.001
					RT alone: 253	69.6	<0.001
					CT alone: 170	33.9

OS overall survival, RT Radiotherapy, CT Chemotherapy, UADT upper aerodigestive tract, NA not available

Table 11.3

Treatment outcome stratified by combined modality therapy and radiotherapy alone in patients with early-stage extranodal nasal-type NK/T-cell lymphoma

Authors	Time	No	Primary site	Stage	Treatment^a	5-year OS
Authors	Time	No	Primary site	Stage	Treatment^a	(%)	P
Cheung et al.	2002	79	Nasal	I–II	CT + RT: 61	40.3	0.870
					RT: 18	29.8
				I	CT + RT: 47	36.7	0.892
					RT: 16	46.0
Kim et al.	2001	143	UADT	I–II	CT + RT: 39	35	0.93
Kim et al.	2001				RT: 104	38
Kim et al.	2005	53	UADT	I–II	CT + RT: 20	59	0.27
Kim et al.	2005				RT: 33	76
Li et al.	2006	105	Nasal	I–II	RT + CT: 34	77	0.518
					CT + RT: 37	74
					RT: 31	66
Ma et al.	2008	64	Nasal	I–II	RT + CT: 41	61.5	0.469
Ma et al.	2008				RT: 23	57.9
Aikema et al.	2008	57	Nasal	I	RT + CT: 20	61.9	>0.05
Aikema et al.	2008				RT alone: 15	57.1
Luo et al.	2010	60	Nasal	I–II	RT + CT: 20	56.7	>0.05
Luo et al.	2010				RT alone: 7	60.2
Li et al.	2011	214	Nasal	I–II	RT + CT: 118	74.4	0.529
Li et al.	2011				RT alone: 96	69.8
Li et al.	2009	67	WR	II	CMT: 54	79	0.092
Li et al.	2009				RT alone: 13	57
Li	2012	69	UADT	I–II	CMT: 33	76.6 (3-years)	0.313
Li	2012				RT alone: 36	88.5 (3-years)
Aviles	2013	427	UADT	I–II	CMT: 202	86	<0.01
					RT alone: 109	64
					CT alone: 116	45
Fang	2014	124	UADT	II	CMT: 84	71.2	<0.001
Fang	2014				CT or RT: 40	26.7
Yang et al.	2015	276	All sites	Low-risk	RT + CT: 54	86.9	0.896
				stages I–II	CT + RT: 132	86.3	0.794
					RT alone: 90	88.8
Yang et al.	2015	827	All sites	High-risk	RT + CT: 155	72.2	0.017
				stages I–II	CT + RT: 509	58.3	0.004
					RT alone: 163	59.6

OS overall survival, CT chemotherapy, RT radiotherapy, CMT combined modality therapy, UADT upper aerodigestive tract, WR Waldeyer’s ring

^aMost patients received doxorubicin-based chemotherapy

The addition of chemotherapy to radiation therapy in the treatment of early-stage disease is controversial in Asia, with some studies showing limited benefit [10, 13, 15, 26, 46, 59, 60–63, 105], while others have demonstrated a better outcome with combined modality therapy (CMT)[11, 45, 47, 64, 65]. In the Western world, combined modality approach is generally favored.

Currently Used Combined Modality Therapy

Modern chemotherapy regimens for early-stage NKTCL (Table 11.4) including DeVIC, VIPD (etoposide, ifosfamide, cisplatin, dexamethasone), and GDP (gemcitabine, dexamethasone and cisplatin), in combination with radiotherapy, have all been shown to be associated with improved outcome compared to historical control of radiotherapy alone [67–72]. Less common regimens used include sandwich or sequential LVP (L-asparaginase, vincristine, prednisone), GELOX (gemcitabine, oxaliplatin, L-asparaginase) or CHOP-L (cyclophosphamide, doxorubicin, vincristine, prednisone, L-asparaginase), and radiotherapy ([66, 73, 74]) with limited follow-up and experience.

Table 11.4

Treatment outcome of concurrent or sequential new regimen chemotherapy and radiotherapy in patients with stage I and II extranodal nasal-type NK/T-cell lymphoma

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