Annals of Oncology Advance Access originally published online on February 23, 2006
Annals of Oncology 2006 17(5):794-800; doi:10.1093/annonc/mdl015
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© 2006 European Society for Medical Oncology
NK/T-cell lymphomas ‘nasal type’: an Italian multicentric retrospective survey
1 Istituto di Ematologia, Università Cattolica del Sacro Cuore, Roma; 2 Divisione di Ematologia, Ospedale di Cuneo; 3 Divisione di Ematologia, Ospedale di Montefiascone; 4 Istituto di Ematologia, Università di Verona; 5 Ematologia, Istituto Regina Elena Roma; 6 Divisone di Ematoncologia Medica, Istituto Europeo di Oncologia, Milano; 7 Istituto di Ematologia, Università di Palermo; 8 Istituto di Ematologia, Università ‘La Sapienza’, Roma; 9 Divisione di Ematologia, Ospedale Niguarda, Milano; 10 Divisione di Ematologia, Ospedale di Vicenza; 11 Reparto di Epidemiologia Clinica, Istituto Superiore della Sanità, Roma; 12 Istituto di Anatomia Patologica, Università Cattolica del Sacro Cuore, Roma, Italy
* Correspondence to: Dr L. Pagano, Istituto di Ematologia, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, I-00168 Roma, Italy. Fax +39-063051343; E-mail: lpagano{at}rm.unicatt.it
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Abstract |
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Objective: To evaluate the clinical characteristics and outcome of NK/T-cell lymphoma ‘nasal type’ developed in Italian patients.
Patients: Between 1997 and 2004, 26 new cases of NK/T-cell lymphoma ‘nasal type’ were diagnosed in 10 Italian Hematology institutions.
Results: All patients were Caucasian, male/female ratio was 19/7, with a median age of 50 years (range 20–80). In 23 cases presentation at the onset was in the nasal cavity or adjacent structures, in two cases the lymphoma onset with skin lesions was followed successively by rhynopharyngeal dissemination, while the remaining case had bone marrow and lymph node involvement followed by oro-pharyngeal involvement. Regarding the stage of disease: 12 patients were in stage I; six in stage II; eight in stage IV. Diagnosis was based on the finding of a NK/T-cell phenotype at the histological and immunophenotypic examination of oropharyngeal or cutaneous lesions. All patients but one were treated with chemotherapy, alone in nine cases or associated to radiotherapy in 14 cases; two patients had chemotherapy, radiotherapy and surgery, while one patient underwent only surgery. Chemotherapy was anthracycline-based in 17 out of 25 cases. In those patients in whom radiotherapy was performed, radiation dosages ranged between 36 Gy and 47.5 Gy, with a median dosage of 40 Gy. Nine patients (34%) were responsive to the treatments: six patients obtained a complete remission and other three a partial remission. The remaining 17 patients resulted refractory or presented a limited response to therapy. The median disease-free survival was 14 months and the median overall survival time was 9 months.
Conclusion: The results of this retrospective survey confirmed that NK/T-cell lymphoma ‘nasal type’ is a very rare lymphoma in the Italian population, and it is characterized by a very bad prognosis. Due to the rarity of this disease, a standardized therapeutic approach is lacking. More data are needed to know the epidemiology of this kind of lymphoma in Europe.
Key words: NK/T cell, lymphoma treatment
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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T/NK ‘nasal type’ lymphoma is a rare clinical event in western populations [1
–6]. Recently this group of neoplasms was redefined by the WHO classification as a distinct subgroup among peripheral T-cell lymphomas [7–9]. NK/T-cell lymphomas ‘nasal type’ are characterized by a very aggressive disease, with local destroying activity, and refractoriness to treatment. These patients show a peculiar geographical distribution, since they are most frequently observed in Far Eastern countries such as Hong Kong, Japan, Korea [10–20], and in Central American countries (i.e. Mexico, Guatemala) [21–24], while they are very uncommon in North America and Europe [1–6]. The presentation can mimic a dermatological or an oto-rino-laryngo-hyatrical pathology so that misdiagnosis is possible. Data collection is cumbersome due to the low incidence and to the polymorphic pattern of clinical presentation of the disease. As a consequence of these diagnostic and epidemiological difficulties, this type of lymphoma has been in the past treated in a non-homogeneous way: radiotherapy alone, or chemotherapy alone, or radio-chemotherapy, monochemotherapy, polychemotherapy, use of anthracyclines or high dose-schedules. Therefore, the best treatment is not individualized and these patients, in general, present a poor prognosis.
Considering the rarity of this kind of lymphoma in Europe, our study retrospectively collected a relative high number of NK/T-cell lymphoma ‘nasal type’ in Italy with the aim to identify the peculiar clinical features of these patients, and to analyze the treatment adopted and the following outcome.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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This survey was carried out in collaboration with 10 Italian hematological centres participating in Intergruppo Italiano Linfomi (IIL) between January 1997 and December 2004. All centres were invited to send data about patients suffering from NK/T-cell lymphoma ‘nasal type’ using a questionnaire that evaluated epidemiological, biological data together with therapy and outcome of the disease.
The form collected demographic data (race, age, gender), place and date of birth, residence at time of diagnosis, education, previous diseases and working activity at the time of diagnosis. Furthermore, data were collected about clinical presentation of NK/T-cell lymphoma such as: time elapsing between the onset of symptoms and diagnosis, International Prognostic Index (IPI) score (as defined by Shipp) [25]; W.H.O. performance status score; signs and symptoms at the onset of lymphoma; macroscopic presentation (i.e. mass lesion or lethal mid-line granuloma); serum biochemistry and hematological parameters; histopathologic reports with immunophenotypic analysis and EBV infection evaluation; kind of treatment (surgery, chemotherapy, radiotherapy). In each case chemotherapeutic schedule, radiotherapy dosages, and chronological succession of radiotherapy and chemotherapy were evaluated. Achievement of complete remission (CR), disease free-survival (DFS) and overall survival (OS) were evaluated as well. Response to treatment was assessed 1 month after the end of induction. CR was defined as the disappearance of all clinical evidence of disease and the normalization of all laboratory value and radiological findings that had been considered abnormal before starting therapy. Partial remission (PR) was defined as more than 50% reduction, for at least 1 month, of the largest dimension of each measurable anatomic site of disease localization. Non response (NR), or stable/progressive disease, was defined as less than 50% regression of tumor size. OS was measured from diagnosis to death or the data of the last follow-up and DFS was measured from date of CR assessment to the date of relapse evidence.
Diagnosis of NK/T-cell lymphoma ‘nasal type’ was based on the detection of the following immunophenotypical characteristics: cytoplasmatic CD3 (CD3
) positivity, and surface CD3 negativity; CD56 and cytotoxic granule associated proteins, such as Granzyme and TIA-1, positivity; EBV positivity.
Diagnosis was made by a pathologist of each center participating in the study. Furthermore all tissue stained was critically reviewed by a pathologist of the coordination center (LML) that confirmed the diagnosis.
All neoplastic samples included in this study were subjected to determination of tumor infection by EBV as previously described [26]. In situ hybridization of EBV-encoded small RNAs (EBERs) was performed using a cocktail of fluorescent-isothiocyanate-labeled oligonucleotides complementary to the two nuclear EBER (1/2) RNAs according to the manufacturer's instructions (Dakopatts, Golstrup, Denmark). In all samples immunostaining for LMP-1 was also performed with anti-LMP-1 antibody (Dakopatts) on formalin-fixed, paraffin-embedded tissue sections. Only samples EBV positive were included in this study.
statistical analysis
Stratified analysis and adjusted ORs were computed by Mantel-Haenszel method. 
2 test of Fisher's exact test was used for differences on frequencies. Kaplan-Meier method was used to analyze overall survival and event-free survival; the impact of prognostic variables on survival was evaluated by the log-rank test.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Among 30 cases collected, only 26 patients were suitable for evaluation. Four cases were excluded after histopathological revision for the following reasons: (a) Two patients were affected by blastic NK-cell lymphoma; (b) one patient presented aggressive NK leukemia; and (c) a NK/T cell lymphoma arising shortly after renal transplantation.
clinical features
The main clinical features of 26 patients are reported in Table 1. All patients were Italian, 19 male and seven female (sex ratio was 2.7), with a median age of 50.5 years (ranging from 20 to 80).
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Only three cases showed an extrafacial presentation: two patients had initially a cutaneous presentation followed by a rhynopharyngeal dissemination, while the other had bone marrow and lymph node involvement.
Among patients with a facial presentation (including rhynopharyngeal and oropharyngeal localizations), the majority (21 out of 23) suffered from obstructive symptomatology (i.e. nasal obstruction, orbital edema, dysphagia, odynophagia, rhinism) while two patients presented an excavating lesion.
Regarding the stage of lymphoma: 12 patients presented stage I (in 11 cases IA, 1 case IE); six patients were in stage II (two cases II A, two cases II B, two cases II EB); eight patients presented advanced stage disease (six cases IVA, two cases IVB). B symptoms occurred only in six patients (23%). According to the IPI score, 13 patients were classified as having a score 1; nine patients as having a score 2; three patients as having a score 3, and one patient was considered as a 4 IPI score. The median time from onset of symptoms to diagnosis (i.e. nasal or oropharyngeal obstruction or fever, or signs such as skin lesions) assessed in 24 patients, was 3.5 months, ranging between 1 and 30. The median value of serum lactate dehydrogenise (LDH) level was 388 UI/L ranging between 168 and 2365 UI/L (normal LDH limits ranging from 230 to 460 UI/L).
Ten patients showed extra-nasal site involvement at disease onset: in five cases the disease involved the bone marrow, in three cases cutis, in three cases central nervous system (CNS), in one case uterus, and in one case lymphonodes were affected. Positive serology for EBV was detected in 12 of 16 patients in which it was performed.
All patients were CD56 positive (26/26) and presented at least another positive marker: CD3 was positive in all cases when it was tested (16/16) with a concomitant sCD3 negative. Granzyme was tested in 11 patients and found positive in all cases as well as TIA-1, that resulted positive in all eight patients in which it was made. Other T markers are usually negative.
treatment
Twenty-five patients received chemotherapy alone (nine cases) or in combination with radiotherapy (14 cases CT/RT), or after surgery (two cases). Two patients performed autologous stem cell transplantation (ASCT) after chemotherapy: in one case as consolidation therapy after chemotherapy and in the other case in an unresponsive patient after CT/RT. One patient was treated with surgery only. Regimens containing anthracylines were adopted in 17 patients (10 patients were treated with CHOP; five patients with MACOP-B; two patients with ProMACE-Cytabom). The other eight patients received respectively: CVP regimen in three cases; cyclophosphamide-vinblastine-mithoxantrone-bleomicine (CVBM) in one case; cisplatin-cytosine arabinoside-dexamethasone (DHAP) courses in four cases.
Stratifying the treatments according the lymphoma's stage: Patients in stage I received CVP (3), CHOP (2), DHAP (2), CVBM (1), MACOP-B (1), ProMACE-Cytabom (1). Patients with stage II received CHOP in four cases and MACOP-B in the other two cases. The remaining eight patients that presented a stage IV were treated with CHOP in three cases, MACOP-B and DHAP in other two cases each and ProMACE-Cytabom in the last patient.
In those patients who received CT/RT (14 patients: eight stage 1, one stage II and five stage IV), radiation doses ranged between 36 Gray (Gy) and 47.5 Gy, with a median value of 40 Gy. The three patients who underwent surgery, with a demolishing intervention on facial structures, were then fitted with a synthetic protesis in order to allow an acceptable quality of life.
outcome
Nine patients (34%) responded: six patients achieved a CR (23%) and other three a PR (11%); while the other 17 patients resulted refractory (NR) to treatment (66%). Among the nine responsive patients, three patients relapsed and died, respectively at 6, 12 and 14 months from diagnosis. The cause of death was lymphoma progression in all cases; in two of 19 patients a fungal infection (one aspergillosis and one zygomycosis) was clinically evident at exitus. At last follow-up seven patients were still alive, at a time from diagnosis ranging from 4 to 96 months.
The DFS among the nine responsive patients was 14 months (95% IC 2.6–35.9). The median OS for all cases was 9 months (95% IC 5.02–12.38). The actuarial Kaplan-Meier curve shows an DFS of 13.3% at 5 years (Figure 1) and an OS of 17.7% at 5 years (Figure 2).
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At univariate analysis the following parameters were evaluated: age (< or
50 y.o.), IPI score (1–2 versus 3–4), WHO performance status (0–1 versus 2–3), LDH (normal versus abnormal), B symptoms, regimens containing anthracyclines, regimens including radiotherapy. DFS was significantly correlated to low IPI score, performance status and normal levels of LDH. The OS in our statistical model was significantly correlated only to WHO performance status (Table 2). The low number of patients did not allow a multivariate analysis.
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When we analyzed the outcome according to the stage: among 12 patients at stage I, three achieved CR and one a PR; among six patients at stage II, two CR and two PR. Only one patient among the eight patients at stage IV achieved CR. No statistical differences were found among patients with limited diseases (stage I and II) and those with advanced disease (stage IV) in the CR rate (Fisher test, P = 0.19), DFS (P = 0.28) and OS (P = 0.11).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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NK/T-cell lymphoma ‘nasal type’ is a rare neoplasm classified according to WHO classification among peripheral T-cell lymphomas, together with ‘enteropathy-associated T-cell lymphoma’, ‘subcutaneous panniculitis-like T-cell lymphoma’, ‘hepatosplenic T-cell lymphoma’, and ‘blastic NK-cell lymphoma’ [7
–9]. All these lymphoprolipherative malignancies share low incidence, difficult diagnosis, and a bad response to treatment. This kind of lymphoma is characterized by local, and eventually systemic, aggressiveness: the tumour bulk can be responsible, at presentation for respiratory obstruction and/or periorbitary oedema, while infiltrating lesions show a destroying activity against soft and bony oropharyngeal and nasal structures. Furthermore this neoplasm can spread to CNS, cutis, and testis, and be responsible for hemophagocytosis in bone marrow.
Histopathology is characterized by an angiocentric/angiodestructive growth pattern with fibrinoid changes in the blood vessels. Coagulative necrosis is very frequent as a consequence of vascular occlusion. The cytological spectrum of extranodal NK/T-cell lymphoma ‘nasal type’ is very broad. In most cases the lymphoma is composed of medium-sized cells with irregular nuclei and granular chromatin. Mitotic figures are easily found. The typical immunophenotype of extranodal NK/T-cell lymphoma ‘nasal type’ is: surface CD3 negative, cytoplasmic CD3e and CD56 positive. Most cases are also positive for cytotoxic granule associated protein such as TA-1 and granzyme B. We included lymphomas CD3e+, CD56–, cytotoxic molecule+ and EBV+.
The onset presentation can mimic symptoms of solid tumors of head and neck, and it can be confused with a dermatological disease. This disease is rare in Western countries, and reports are sporadic [1–6]. Conversely peaks of incidence were found in Eastern Asiatic countries and Central American countries [10–24]. The results of the larger series with the CR rates and OS are reported in Table 3; it is noteworthy that in some of these reports NK/T-cell lymphoma ‘nasal type’ patients are mixed with other T-cell lymphomas. In fact before the demonstration by the WHO classification of the peculiar biological and clinical characteristics of the NK/T-cell lymphoma that prompted pathologist to single out this aggressive lymphoma subset from the PTCL category as a peculiar entity, and this mixture could be responsible for the difference in survival time of these patients and rate of remission [13, 20].
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Asiatic series collected data during two decades, and showed differences in treatments [10
, 11–13, 20, 27–31]. Radiotherapy combined or not with chemotherapy seems the better approach for this lymphoma. In many reports radiotherapy is characterized by higher remission rate and prolonged survival, above all in localized disease [27–29], even if, in their recent experience, Li et al., reported that radiotherapy alone was unable to control locoregional disease in a large number of patients (77 cases) [10].
Chemotherapy alone does not seem to play a role in the treatment of this kind of patient, probably due to the lack of efficacy of conventional treatment. In fact a high variability in the results has been reported by the literature. In a study of Kim et al., CHOP regimen failed to demonstrate an improvement of CR rate [4, 11], also the addition of anthracyclines–based chemotherapies in the initial stages of disease does not appear to confer any survival benefit [13]. Conversely some cases report that anthracyclines-based approaches had a good outcome [30, 31], in other rare cases the use of platinum-based treatment was suggested [32]. The advantage of ASCT, performed also in patients in progression of disease, is rarely reported [33]. In our experience ASCT was made only in two cases and only the patient who was already in CR received an advantage from this procedure.
When a comparison was made between chemotherapy alone versus radiotherapy alone or CT/RT, the CR rate observed was significantly higher in patients treated with CT/RT [13, 17, 27–28].
Experience regarding the treatment of this kind of malignancy in Western countries, as already said, is poor. Ribrag et al. [1] reported the results on 24 cases observed during a 30 year-period at Gustave-Roussy Hospital. In this study the authors analyzed retrospectively the outcome of patients of Western origin. There was not a homogenous approach but while all patients treated with radiotherapy as front-line therapy achieved a CR, among 12 patients treated with chemotherapy (seven CHOP and five COP), only three were responsive. These poor results were observed also by Stanford University group in a subset of patients affected by NK/T cell lymphoma localized in the skin [3].
In our study we collected Caucasian patients born in Italy, observed over a 9-year period, in whom diagnosis of NK/T cell lymphoma ‘nasal type’ was thoroughly proven on histopathological and immunophenotypical grounds. The main characteristics of these patients, such as age at onset, sex ratio, and clinical aspect of the disease, such as prevalence of non advanced stages, and presence of B symptoms only in about 30% patients, are in keeping with those reported in literature [13, 19]. In Table 4 we reported the main characteristics of our patients and those observed in the other populations, Asiatic, Central American and European, obtained from literature data [1, 3, 17–22].
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Nasal localization was present in the majority of our patients, but in some cases other extra-nasal localizations were observed, and in these cases the lymphoma which resulted was very aggressive.
As can clearly be observed from literature data, NK/T-cell lymphoma ‘nasal type’ is very rare, and its rarity particularly in the Italian population is also confirmed in the study by IIL (Intergruppo Italiano Linfomi) in whose registry are collected all cases of peripheral T-cell lymphoma unspecified (PTCL-U) and other T-cell lymphomas [34]. In this study among 512 T-cell lymphomas observed between 1989 and 2001, 23 cases were classified as NK/T-cell lymphoma ‘nasal type’ (
4%).
The sporadic incidence of this neoplasm explains the differences in the treatments delivered, especially in the chemotherapeutic regimens adopted. From all the analyzed series of the literature radiotherapy turns out as the single most efficacious therapeutic tool in association with chemotherapy: the very poor treatment outcome of the present series could also be explained by the impossibility to deliver radiotherapy as planned at disease onset for lymphoma progression or death. A debulking approach seems to play a role: it is relevant that in our series surgical treatment seems to be associated with the only three long-surviving patients: in one case as the only therapy, in the other two in association with chemotherapy: to date, these three patients are the longest survivors of our survey.
Our remission rate seems to be lower than other Asiatic or American authors report (38% versus 50–60%) [10, 12, 13, 17, 20]. This result can be explained if we consider the long period of time the Asiatic reports refer to, spanning more than two decades; in these studies patients classified as affected by a ‘nasal type’ lymphoma are likely to be a mixture of T-cell and T/NK-cell lymphoma patients. The DFS too, in our patients is poor independently of the kind of approach used. The bad prognosis observed in our patients is probably influenced also by EBV+, that was observed in the majority of our patients who underwent this test (12/16 = 75%), as suggested by other authors reporting a worse prognosis in EBV+ T/NK lymphoma patients [18].
In our experience the stage of lymphoma resulted important for the achievement of a CR. In fact eight out nine responsive patients (five CR and three PR) presented an early-stage (stage I–II), conversely only one patient with advanced disease achieved CR. The low number of cases, however, does not allow us a correct statistical evaluation and the poor prognosis (patients alive at 5 years are mostly in stage I and II) does not seem positively influenced from the initial stage.
The ineffectiveness of all treatments we tried suggested the necessity for new approaches to NK/T-cell lymphoma ‘nasal type’. Recent reports have shown a good response in cutaneous T-cell lymphomas expressing CD52 treated with monoclonal antibody (MoAb) alemtuzumab [35, 36]. This kind of approach suggests a new perspective for this very aggressive lymphoma. In fact new MoAb combined with chemotherapy or radiotherapy, could be indicated also for the treatment of NK/T-cell lymphoma ‘nasal type’.
ASCT is potentially applicable to most patients [33, 37]. Indications include stage I/II disease in first or second CR. In the largest series of auto-HSCT in NK/T neoplasms reported to date, over 70% of patients transplanted at first CR had remained in remission at a median follow-up of about 24 months. However a comparison with a historical control group of stage I/II patients treated with chemotherapy and/or radiotherapy failed to show a significant difference in DFS and OS [37]. Allogeneic HSCT (allo HSCT) seems an interesting alternative, for the potential graft-versus-lymphoma effect. This is particularly relevant, as NK lymphoma cells express EBV antigens that may be allo-reactive targets. Only few reports on allo HSCT have been reported [38, 39]. In a retrospective study of 28 patients with NK-cell malignancies, that included NK/T nasal type lymphomas too, an OS of 40% was reported after a median follow-up of 34 months [39]. The major limit of this procedure is the precocious death of these patients.
Owing to the unsatisfactory results of conventional treatment, radio- and/or chemotherapy, prospective data on larger series of patients treated homogeneously also with innovative approaches is needed, in order to establish the best treatment for this very aggressive lymphoma.
Received for publication September 24, 2005. Revision received December 19, 2005. Revision received January 13, 2006. Accepted for publication January 13, 2006.
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