© 2005 Foundation for Promotion of Cancer Research
Treatment Outcome of Angiocentric T-cell and NK/T-cell Lymphoma, Nasal Type: Radiotherapy Versus Chemoradiotherapy
Departments of 1 Radiation Oncology and 2 Pathology and 4 Cancer Research Institute, Seoul National University College of Medicine and 3 Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, South Korea
For reprints and all correspondence: Il Han Kim, Department of Radiation Oncology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, South Korea. E-mail: ihkim{at}snu.ac.kr
Received August 9, 2004; accepted November 2, 2004
 |
Abstract |
|---|
 TOP Abstract INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Objective: The purpose of this study was to evaluate the treatment outcome of angiocentric T-cell and natural killer (NK)/T-cell lymphoma, nasal type.
Methods: Between February 1989 and March 2001, 53 patients with newly diagnosed angiocentric T-cell and NK/T-cell lymphoma, nasal type involving the head and neck, were treated with radiation therapy (RT). There were 37 males and 16 females. The median age of the patients was 45 years (range 19–73). Twenty of them were treated with chemoradiotherapy (CRT), while 33 with treated with RT alone. The median follow-up period was 74 months (range 6–173).
Results: The 5-year overall survival rate of all patients was 69%. CRT appeared to be inferior to RT alone in terms of 5-year overall survival, though the difference was not statistically significant (59 versus 76%, P = 0.27).
Conclusions: There was no difference in survival between RT and CRT in angiocentric T-cell and NK/T-cell lymphoma, nasal type.
Key Words: angiocentric T-cell lymphoma • NK/T-cell lymphoma • radiotherapy • chemoradiotherapy
|
INTRODUCTION |
|---|
|
TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Natural killer (NK)/T-cell lymphoma, nasal type is a rare subtype of non-Hodgkin's lymphoma (NHL). It was previously called LMG (lethal midline granuloma) (1,2), PMR (polymorphic malignant reticulosis) (3,4) or AIL (angiocentric immunoproliferative lesion) (5). In the REAL classification, this disease entity was classified as angiocentric T-cell lymphoma, reflecting its morphological characteristics (angiocentricity) and immunohistochemical features (T cell predominance) (6). In 2002, the World Health Organization (WHO) suggested the terminology ‘NK/T-cell lymphoma, nasal type’ (7). This means extranodal NHL of the nasal cavity presenting NK or T cell markers. It makes up <1% of cases of NHL, but is more common in Asia and Central or South America (8–13). Because of its rarity in Western countries and lack of a randomized controlled trial, the standard treatment for NK/T-cell lymphoma, nasal type is still unknown. Recently, several retrospective studies were published in both Eastern and Western countries, but their results were inconsistent (14–18).
In this study, the treatment outcome of radiation therapy (RT) or chemoradiotherapy (CRT) in a single institute was analyzed retrospectively for patients with angiocentric T-cell and NK/T-cell lymphoma, nasal type.
|
SUBJECTS AND METHODS |
|---|
|
TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
STUDY POPULATION
Between February 1989 and March 2001, 66 patients with angiocentric T-cell and NK/T-cell lymphoma, nasal type involving the head and neck underwent RT at Seoul National University Hospital. Of these, 13 patients were excluded from this study: four patients were initially Ann Arbor stage III or IV; four patients did not complete RT; three patients refused RT; and two patients were lost to follow-up just after treatment. Therefore, 53 patients were the subjects of this retrospective analysis.
There were 37 males and 16 females. The median age of all the patients was 45 years (range 19–73). The median follow-up period was 74 months (range 6–173). Patient characteristics are listed in Table 1.
|
Thirty-two (60%) patients had lesions of the nasal cavity and paranasal sinuses. As regards the performance status, 44 patients had an Eastern Cooperative Oncology Group (ECOG) performance score of 0–1, and nine patients had an ECOG score of 2–3.
Up until 1994, physical examination and chest X-ray were performed, and computed tomography (CT) or magnetic resonance imaging (MRI) of the head and neck was performed in two-thirds of patients (22 out of 33). Thereafter, staging work-up was routinely performed including complete history, physical examination, complete blood count, serum biochemistry, chest X-ray, abdomino-pelvic CT, bone marrow aspiration and biopsy, and CT or MRI of the head and neck. According to the Ann Arbor staging system, 42 patients were stage I, and 11 patients were stage II. B symptoms were present in 11 patients (21%).
Immunophenotyping was performed in 31 patients. Eleven patients were of NK/T-cell lineage, whereas 20 were of T-cell lineage. Epstein–Barr virus (EBV) in situ hybridization was performed in 12 patients, and was positive in seven of them. In the remaining 22 patients, we obtained information from the pathological description in the initial reports. Initial pathological reports were PMR for 14 patients and AIL for eight patients. The essential finding used to identify PMR and AIL was the pathological feature of angiocentric infiltration of atypical lymphoid cells with necrosis, which was identical to the microscopic finding of angiocentirc T-cell and NK/T-cell lymphoma, nasal type.
TREATMENT
Up until 1994, our treatment policy for localized (Ann Arbor stage I and II) angiocentric T-cell and NK/T-cell lymphoma, nasal type was RT alone, and thereafter it was switched to CRT comprised of 4–6 cycles of cyclophosphamide, adriamycin, vincristine and prednisolone (CHOP) or cyclophosphamide, vincristine, prednisolone, bleomycin, procarbazine and adriamycin (COPBLAM-V) and involved field RT (IFRT).
Thirty-three patients received RT alone. RT was delivered using 60Co 
-rays, 4 or 6 MV photon beams. A three-field technique (two lateral opposed fields and anteroposterior port) typically was employed in cases of nasal cavity or paranasal sinus lesion, whereas bilateral parallel-opposed fields were employed in nasopharyngeal, orophayngeal or hypopharyngeal lesions. The planning target volume included all gross lesions and sites of potential contiguous spread with adequate margins. If the primary lesion was located in the nasal cavity or paranasal sinuses, the regional lymph node areas were not included, unless they were clinically involved. If the primary lesion was in the naso-pharynx, oral cavity, oropharynx or hypopharynx, elective neck RT was routinely performed, regardless of neck node involvement. The radiation dose ranged from 37.8 to 55.8 Gy and the median dose was 50.0 Gy at 1.8 or 2.0 Gy per fraction 5 days a week.
Twenty patients were treated with CRT. Of these, 18 patients were scheduled to receive 4–6 cycles of CHOP or COPBLAM-V followed by IFRT. In two patients with severe complications during chemotherapy (CTX), RT was initiated. One patient received RT followed by CHOP due to abnormal liver function. Another patient received concurrent CRT with CHOP and IFRT. According to the chemotherapeutic regimen, 13 patients received CHOP and four patients received COPBLAM-V. Two patients received CHOP first, and then ifosfamide, methotrexate, etoposide and prednisolone (IMVP-16/Pd) due to progression of disease. One patient received COPBLAM-V first, and then IMVP-16/Pd due to toxicity. Patients received a median of six cycles (range 1–8) of CTX. Radiation dose ranged from 30.6 to 54.0 Gy and median dose was 45.0 Gy at 1.8 or 2.0 Gy per fraction 5 days a week.
The CHOP regimen consisted of cyclophosphamide [750 mg/m2 given intravenously (i.v.) over 30 min on day 1], adriamycin (50 mg/m2 i.v. over 30 min on day 1), vincristine (1.4 mg/m2 but not more than a 2.0 mg i.v. push on day 1) and prednisolone (100 mg daily orally on days 1–5). The COPBLAM-V regimen consisted of cyclophosphamide (a 400 mg/m2 i.v. push on day 1), vincristine (1.0 mg/m2 i.v. over 24 h on days 1–2), prednisolone (100 mg/m2 daily orally on days 1–5), bleomycin (a 4 mg/m2 i.v. push on day 1 and 4 mg/m2 over 24 h on days 1–5), procarbazine (100 mg/m2 daily orally on days 1–5) and adriamycin (40 mg/m2 i.v. over 30 min on day 1). The IMVP-16/Pd regimen consisted of ifosfamide (1.5 g/m2 i.v. over 1 h on days 1–3), methotrexate (a 30 mg/m2 i.v. push on days 3 and 10), etoposide (100 mg/m2 i.v. over 90 min on days 1–3) and prednisolone (120 mg daily orally on days 1–5). CTX was to be administered at 3-week intervals.
STATISTICAL ANALYSIS
The overall survival was calculated from the date of treatment initiation of RT or CTX. The actuarial survival rates were calculated using the Kaplan–Meier method, and statistical significance was evaluated by the log-rank test (19).
|
RESULTS |
|---|
|
TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
RESPONSE TO TREATMENT
Most patients showed an excellent response to RT. Of 33 patients treated with RT alone, 17 (52%) achieved complete remission (CR) and 14 achieved (42%) partial remission (PR) at the end of RT. All the patients with PR subsequently reached CR in 1–6 months. Of the remaining 2 patients one had stable disease and the other progressive disease.
In contrast, response to CTX was not satisfactory. Of 16 patients whose response to CTX was available, six (38%) attained CR, and they underwent elective RT. Three patients (19%) with PR also received RT as a protocol. However, in seven patients (44%) whose disease progressed during CTX, RT was initiated as salvage treatment. Of these, three patients were salvaged but treatment failed in four patients.
SURVIVAL AND PATTERNS OF TREATMENT FAILURE
The 5-year overall survival rate of all the patients was 69%. The overall survival curve is shown in Fig. 1. The outcome did not differ according to the treatment modalities. The 5-year overall survival rates for the RT group and CRT group were 76 and 59%, respectively (P = 0.27, Fig. 2).
|
|
Thirty patients are alive without evidence of relapse with a median follow-up of 74 months. Of these, a second primary cancer (prostate) was detected in one patient.
Treatment failed in 15 patients, and the patterns of failure were as follows: seven patients had local failure (two persistent and five true recurrent diseases); two patients had regional failure; and six patients had systemic failure. Sites of distant metastasis were skin (two; chest wall and sole), colon (one) and bone marrow (one). Two patients showed the clinical course of hemophagocytic syndrome, but bone marrow biopsy was not performed. Of these 15 patients, 13 died of the disease, while two patients are alive with the disease. Details of treatment failure, salvage treatment and treatment outcome are listed in Table 2.
|
Two patients were lost to follow-up; they were disease-free at 21 and 27 months, respectively. Among the remaining six patients who were dead, one died of coronary artery disease without relapse, while the cause of death was unknown in the remaining five patients.
TREATMENT RESULTS ACCORDING TO THE RESPONSE TO CHEMOTHERAPY
Except for four patients whose responses to CTX were not available, patients could be grouped into two subgroups according to the response to CTX (Table 3). Responders (patients who reached CR or PR to CTX, nine patients) achieved excellent local and distant control. In contrast, non-responders (those who showed disease progression during CTX, seven patients) had two local recurrences and two distant metastases. The 5-year overall survival rates of the RT group, and the CRT responder and non-responder groups were 76, 100 and 38%, respectively (P = 0.019).
|
|
DISCUSSION |
|---|
|
TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
As mentioned above, treatment for angiocentric T-cell and NK/T-cell lymphoma, nasal type is controversial. In the period of LMG or PMR, RT was the treatment of choice because of its rapid and excellent radiosensitivity (1–4,11).
As the characteristics of ‘PMR’ as lymphoma were revealed in the 1990s, CRT was tried in most institutions. Kim et al. compared the results of RT alone versus CRT for ‘angiocentric lymphoma’ (14). Patients in the CRT group received a median of three cycles of CTX of various regimens. Despite additional CTX, overall survival was not improved and the patterns of failure were similar in both the CRT and RT groups. Moreover, medical complications such as sepsis and intractable bleeding were more common in the CRT group, although there was no statistically significant difference. Recently, Kim et al. analyzed 17 NK/T-cell lymphoma, nasal type cases treated with CRT (15). Patients received four cycles of CHOP followed by IFRT. In this retrospective analysis, all the patients who completed RT gained CR. In contrast, the overall response rate for CHOP was 60%. Cheung et al. analyzed 79 NK/T-cell lymphoma, nasal type cases of Ann Arbor stage I or II treated with RT or CRT (16). Intent-to-treat analysis showed no statistically significant difference in CR rate and overall survival rate between the RT and CRT groups. Rather, 66.7% of patients revealed resistance to CTX, whereas resistance to RT occurred in only one-third (21.7%) of patients.
In our study, the addition of CTX did not improve the treatment outcome either. The main reason is the poor response to CTX. Although chemo-responders achieved excellent local and distant control, the overall response rate was poor (56%) compared with diffuse large B-cell lymphomas. Additionally, the salvage rate with RT after CTX was very low compared with the initial response rate to RT (43 versus 94%). Therefore, it is recommended that CTX should be reserved for the control of micrometastasis after local control using RT, until more effective chemotherapeutic drugs are developed. Two studies produced results suggestive of this view point. Ribrag et al. compared early RT versus late RT in 20 patients treated with CRT (17). Seven of eight patients with early RT remained disease-free, whereas only four of 12 with late RT remained well at a median follow-up of 97 months from the initial treatment. In addition, Aviles et al. reported an excellent 5-year survival rate of 86% with IFRT followed by CHOP (18), in comparison with 40% with RT after CTX in other series (14–16).
This study, we admit, has some limitations. First, angiocentric T-cell and NK/T-cell lymphoma, nasal type was included, but immunophenotyping was performed in 31 patients in the late study period. Secondly, the chemotherapy applied to these patients was not homogeneous. Some patients received CHOP, while others received COPBLAM-V. Despite these pitfalls, we believe this study has provided new insight into the importance of the timing of RT for angiocentric T-cell and NK/T-cell lymphoma, nasal type.
In conclusion, CRT did not improve the treatment outcome compared with RT alone, and delay of RT due to CTX might produce less favorable treatment results. Therefore, we recommend that CTX should be tried after local control is attained with RT, in order to control micrometastasis.
|
References |
|---|
|
TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
1 Chen HHW, Fong L, Su IJ, Ting LL, Hong RL, Leung HWC, et al. Experience of radiotherapy in lethal midline granuloma with special emphasis on centrofacial T-cell lymphoma: a retrospective analysis covering a 34-year period. Radiother Oncol 1996;38:1–6.[CrossRef][Web of Science][Medline]
2 Sakata KI, Hareyama M, Ohuchi A, Sido M, Nagakura H, Morita K, et al. Treatment of lethal midline granuloma type nasal T-cell lymphoma. Acta Oncol 1997;36:307–11.[Web of Science][Medline]
3 Itami J, Itami M, Mikata A, Tamaru JI, Kaneko T, Ogata H, et al. Non-Hodgkin's lymphoma confined to the nasal cavity: its relationship to the polymorphic reticulosis and results of radiation therapy. Int J Radiat Oncol Biol Phys 1991;20: 797–802.[Web of Science][Medline]
4 Smalley SR, Cupps RE, Anderson JA, Ilstrup DM, McDonald TJ, Weiland LH, et al. Polymorphic reticulosis limited to the upper aerodigestive tract. Natural history and radiotherapeutic considerations. Int J Radiat Oncol Biol Phys 1988;15:599–605.[Web of Science][Medline]
5 Medeiros LJ, Peiper SC, Elwood L, Yano T, Raffeld M, Jaffe ES. Angiocentric immunoproliferative lesions: a molecular analysis of eight cases. Hum Pathol 1991;22: 1150–7.[CrossRef][Web of Science][Medline]
6 Harris EC, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European–American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84:1361–92.
7 Harris EC, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the clinical advisory committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835–49.
8 Aviles A, Rodriguez L, Guzman R, Talavera A, Garcia EL, Diaz-Maqueo JC. Angiocentric T-cell lymphoma of the nose, paranasal sinus and hard palate. Hematol Oncol 1992;10:141–7.[Web of Science][Medline]
9 Cheung MMC, Chan JKC, Lau WH, Foo W, Chan PTM, Ng CS, et al. Primary non-Hodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. J Clin Oncol 1998;16:70–77.
10 Jaffe ES, Chan JKC, Su IJ, Frizzera G, Mori S, Feller AC, et al. Report of the workshop on nasal and related extranodal angiocentric T/natural killer cell lymphomas: definitions, differential diagnosis and epidemiology. Am J Surg Pathol 1996;20:103–11.[CrossRef][Web of Science][Medline]
11 Kim GE, Cho JH, Yang WI, Chung EJ, Suh CO, Park KR, et al. Angiocentric lymphoma of the head and neck: patterns of systemic failure after radiation treatment. J Clin Oncol 2000;18:54–63.
12 Ko YH, Kim CW, Park CS, Jang HK, Lee SS, Kim SH, et al. REAL classification of malignant lymphomas in the Republic of Korea. Cancer 1998;83:806–12.[CrossRef][Web of Science][Medline]
13 Liang R, Todd D, Chan TK, Chiu E, Lie A, Kwong YL, et al. Treatment outcome and prognostic factors for primary nasal lymphoma. J Clin Oncol 1995;13:666–70.
14 Kim GE, Lee S, Chang SK, Park HC, Pyo HR, Kim JH, et al. Combined chemotherapy and radiation versus radiation alone in the management of localized angiocentric lymphoma of the head and neck. Radiother Oncol 2001;61:261–9.[CrossRef][Web of Science][Medline]
15 Kim WS, Song SY, Ahn YC, Ko YH, Baek CH, Kim DY, et al. CHOP followed by involved field radiation: is it optimal for localized nasal natural killer/T-cell lymphoma? Ann Oncol 2001;12:349–52.
16 Cheung MMC, Chan JKC, Lau WH, Ngan RKC, Foo WWL. Early stage nasal NK/T-cell lymphoma: clinical outcome, prognostic factors, and the effect of treatment modality. Int J Radiat Oncol Biol Phys 2002;54:182–90.[Web of Science][Medline]
17 Ribrag V, Hajj ME, Janot F, Girinsky T, Domenge C, Schwaab G, et al. Early locoregional high-dose radiotherapy is associated with long-term disease control in localized primary angiocentric lymphoma of the nose and nasopharynx. Leukemia 2001;15:1123–6.[CrossRef][Web of Science][Medline]
18 Aviles A, Diaz NR, Neri N, Cleto S, Talavera A. Angiocentric nasal T/natural killer cell lymphoma: a single center study of prognostic factors in 108 patients. Clin Lab Haematol 2000;22:215–20.[CrossRef][Web of Science][Medline]
19 Kaplan EL, Meier PI. A nonparametric estimation from incomplete observations. J Am Statics Assoc 1958;53:457–81.[CrossRef]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y.-X. Li, Q.-F. Liu, H. Fang, S.-N. Qi, H. Wang, W.-H. Wang, Y.-W. Song, J. Lu, J. Jin, S.-L. Wang, et al. Variable Clinical Presentations of Nasal and Waldeyer Ring Natural Killer/T-Cell Lymphoma Clin. Cancer Res., April 15, 2009; 15(8): 2905 - 2912. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-X. Li, H. Fang, Q.-F. Liu, J. Lu, S.-N. Qi, H. Wang, J. Jin, W.-H. Wang, Y.-P. Liu, Y.-W. Song, et al. Clinical features and treatment outcome of nasal-type NK/T-cell lymphoma of Waldeyer ring Blood, October 15, 2008; 112(8): 3057 - 3064. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bossard, K. Belhadj, F. Reyes, N. Martin-Garcia, F. Berger, J. A. Kummer, J. Briere, A.-C. Baglin, S. Cheze, J. Bosq, et al. Expression of the granzyme B inhibitor PI9 predicts outcome in nasal NK/T-cell lymphoma: results of a Western series of 48 patients treated with first-line polychemotherapy within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials Blood, March 1, 2007; 109(5): 2183 - 2189. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Pagano, A. Gallamini, G. Trape, L. Fianchi, D. Mattei, G. Todeschini, A. Spadea, S. Cinieri, E. Iannitto, M. Martelli, et al. NK/T-cell lymphomas 'nasal type': an Italian multicentric retrospective survey Ann. Onc., May 1, 2006; 17(5): 794 - 800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-X. Li, B. Yao, J. Jin, W.-H. Wang, Y.-P. Liu, Y.-W. Song, S.-L. Wang, X.-F. Liu, L.-Q. Zhou, X.-H. He, et al. Radiotherapy As Primary Treatment for Stage IE and IIE Nasal Natural Killer/T-Cell Lymphoma J. Clin. Oncol., January 1, 2006; 24(1): 181 - 189. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||