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European Annals of Otorhinolaryngology, Head and Neck diseases (2012) 129, 141—147

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ORIGINAL ARTICLE

Extranodal NK/T-cell lymphoma, nasal type: Reportof 15 casesLymphome T/NK nasal. À propos de 15 cas

S. Tababi, S. Kharrat, M. Sellami ∗, J. Mamy, R. Zainine,N. Beltaief, S. Sahtout, G. Besbes

Service d’ORL et de chirurgie maxillofaciale, CHU la Rabta, 1007 Bab Saadoun, Tunis, Tunisia

KEYWORDSMalignant lymphoma;Extranodal NK/T-celllymphoma;Nasal lymphoma;Radiotherapy;Chemotherapy

SummaryObjectives: To define the epidemiological and clinical features and complementary investi-gation findings of extranodal NK/T-cell lymphoma, nasal type and to discuss the diagnosticdifficulties and the various treatment options.Patients and methods: This retrospective study was based on 15 patients with extranodal NK/T-cell lymphoma, nasal type, managed between 1990 and 2009.Results: This series comprised 13 men and two women (sex ratio = 6.5) with a mean age of 52years (range: 35—81 years). The mean time to first consultation was 6 months. The most commonsymptoms were nasal obstruction (87%) and purulent nasal discharge (73%), followed by epistaxis(60%). Physical examination demonstrated the presence of a tumour of the nasal cavity in 11patients. The diagnosis was confirmed by histological examination of a biopsy completed byimmunohistochemistry. CT scan of the facial bones was performed in all patients of this series.The site of extranodal NK/T-cell lymphoma was essentially nasal (12 cases). Orbital extensionwas observed in four cases, associated with intracranial extension in two cases and osteolysiswas observed in 11 patients. Lymphomas were classified as stage IE in 74% of cases and stageIIE in 26% of cases. Only one patient was lost to follow-up during treatment. Three patientsdied before any treatment. Treatment therefore concerned 12 patients. Stage IE lymphomaswere treated by radiotherapy and/or chemotherapy. All stage IIE lymphomas were treated bychemotherapy alone. Stage IE patients had a better prognosis.

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Conclusion: Extranodal NK/T-cell lymphoma, nasal type, is an aggressive form of non-Hodgkin’slymphoma comprising specific clinicopathological characteristics. The addition of chemothe-rapy for advanced stages does not appear to improve survival compared radiotherapy alone,which remains the treatment of choice especially for localized stages.

© 2012 Elsevier Masson SAS. All

∗ Corresponding author. Tel.: +21624050980.E-mail address: Sellami moncef@yahoo.fr (M. Sellami).

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1879-7296/$ – see front matter © 2012 Elsevier Masson SAS. All rights redoi:10.1016/j.anorl.2011.08.004

rights reserved.

ntroduction

reviously known as lethal midline granuloma, extranodalK/T-cell lymphoma, nasal type (ENKL) is a serious and

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enerally fatal disease. Extranodal NK/T-cell lymphoma,asal type, is a clinical entity causing necrosis, preferen-ially starting in the nasal cavities and progressively invadingid-facial bones, causing centrifugal destruction of the

acial bones with no tendency to healing.Extranodal NK/T-cell lymphoma, nasal type is a rare

isease [1], which has now been more clearly elucidated as result of progress in immunohistochemistry and moleculariology.

The pathogenesis of this disease is unknown, but it iselated to Epstein-Barr virus (EBV) infection, which is asso-iated with a poor prognosis [1].

A retrospective review of 15 patients with extranodalK/T-cell lymphoma, nasal type, was conducted in order toefine the epidemiological and clinical features and com-lementary investigation findings of extranodal NK/T-cellymphoma, nasal type, and to discuss the diagnostic diffi-ulties and the various treatment options.

atients and methods

his retrospective study was based on 15 patients withxtranodal NK/T-cell lymphoma, nasal type, managed inhe department of Otolaryngology-Head and Neck Surgeryf Rabta hospital in Tunis over a 20-year period (January990—December 2009).

All patients in whom the diagnosis of extranodal NK/T-ell lymphoma, nasal type, was confirmed on histology andmmunohistochemistry were included in this study and allistological slides labelled as midline granuloma were sys-ematically reviewed.

All information available in medical files, including epi-emiological and clinical data results of complementarynvestigations and treatment modalities, was collected andnalysed.

The mean follow-up of this series was 13.6 monthsrange: 2—62 months).

esults

his series comprised 15 patients, most of whom (11atients, i.e. 73% of the series) were diagnosed between999 and 2006, i.e. a mean of one case per year. A markedale predominance was observed, with a sex ratio of 6.5

13 M/2 F). The mean age of patients in this series was 52ears (range: 35—81 years) and the mean time to first consul-ation was 6 months.

The presenting complaint in the majority of cases (13atients) was nasal obstruction associated with purulentasal discharge (11 patients) and epistaxis (nine patients).wo patients presented decreased visual acuity, while oneatient presented with blindness. Upper dysphagia with

history of aspiration was reported by two patients dueo tumour extension into the oropharynx. Five patientsresented marked alteration of performance status withuctuating fever in two cases.

Inspection of the face revealed the presence of a malarwelling in two patients and a mandibular swelling innly one patient. Hemifacial oedema was observed in twoatients and deformity of the nasal pyramid was observed

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igure 1 a: left exophthalmos with chemosis; b: necroticlceration of the mucosa of the hard palate.

n four patients. Exophthalmos was noted in three patients,ssociated with chemosis in two patients (Fig. 1a).

Nasal endoscopy, performed in all patients, demon-trated an ulcerative and necrotic, friable and haemorrhagicumour filling the nasal cavities in 11 patients, while nobnormality was detected in the other patients. The tumouras responsible for deviation of the nasal septum in threeases.

Examination of the oral cavity and oropharynx demon-trated necrotic ulceration of the mucosa of the hard palaten three cases, resulting in an oronasal communication inne case (Fig. 1b).

Cervical lymphadenopathy was demonstrated in threeatients. A cranial nerve lesion was observed in fouratients, comprising concomitant lesions of the 2nd, 3rd,th and 5th cranial nerves in one patient.

Biopsies were performed in all patients and histologi-al examination completed by immunohistochemical study

onfirmed the diagnosis of extranodal NK/T-cell lymphoma,asal type, in every case.

Histological examination demonstrated lymphomatousnvasion of the lamina propria composed of sheets

Extranodal NK/T-cell lymphoma, nasal type: Report of 15 cases 143

Figure 3 Immunohistochemical study.A. Tumour cells are positive for anti-CD56 antibody (CD56 × 25).Bl

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Figure 2 A. Great lymphomatous cells with clear cytoplasm(HE × 10). B. Tumour cells destroying the vessel walls (HE × 25).

of medium-sized to large cells with clear cytoplasm(Fig. 2a). Tumour cells were sometimes arranged in‘‘angiocentric’’ perivascular cuffs destroying the vesselwall (‘‘angiodestructive’’) with haemorrhagic suffusions andtumour necrosis (Fig. 2b).

Immunohistochemical examination demonstrated, inevery case, intense and diffuse positive cytoplasmic stain-ing of tumour cells by anti-CD3 antibody and negative stai-ning for anti-CD20 antibody and cytokeratin. CD56 stainingwas positive for all patients, while CD30 (performed in ninecases) was positive in only six patients (Fig. 3).

Computed tomography (CT) of the facial bones was per-formed in all patients, completed by magnetic resonanceimaging (MRI) in four patients. The NK/T-cell lymphoma wasessentially located in the nasal cavity (12 patients). Sinusinvolvement concerned the ethmoid sinus in seven patients,the maxillary sinus in six patients, the frontal sinus in threepatients and the sphenoid sinus in only one patient.

Orbital extension was observed in four patients, associ-ated with intracranial extension in two patients (Fig. 4).Extension to the nasopharynx was present in three patients,

associated with extension to the oropharynx in two patients.Osteolysis was demonstrated in 11 patients. Soft tissue inva-sion was demonstrated in five patients, involving the malar

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. Epitheliotropism: tumour cells penetrating into cytokeratin-abelled glands (cytokeratin × 40).

ucosa in two patients, premandibular soft tissues in oneatient (Fig. 5) and frontal subcutaneous soft tissues in oneatient.

Patients were staged according to the Ann Arbor classi-cation (Table 1) as stage IE in 11 cases (73%) and stage IIE

n four cases (26%). Three patients died before initiation ofreatment in a context of septic shock.

Radiotherapy alone was performed for four patientsith stage IE disease. Combined treatment (radiothe-

apy and chemotherapy) was administered to four patientsith diffuse stage IE, while cyclophosphamide, doxorubicin,incristine, prednisolone (CHOP) chemotherapy alone wasdministered in four patients: three stage IIE patients andne patient with diffuse stage IE disease.

Most patients had a poor outcome and nine patients died:wo during radiotherapy, one during chemoradiotherapy andhree during chemotherapy. Only four patients are in clinical

Follow-up head and neck CT scan was performed ineven patients, demonstrating complete radiological eradi-ation of the lesions in four cases. Progressive disease was

144 S. Tababi et al.

Figure 4 Axial (A) and coronal (B) CT scans of facial bones:oo

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eadelayed management, as the clinical presentation of this

steolysis of the medial wall of the orbit and the superior wallf the left frontal sinus with orbital and intracranial extension.

bserved in only one patient in this series. This patientad received radiotherapy for a very large space-occupyingaso-ethmoido-frontal lesion with orbital and intracranialxtension, followed by intensive chemotherapy. This patienturrently presents stable disease after the 4th cycle ofhemotherapy.

The mean follow-up of this series was 13.6 monthsrange: 2—62 months).

iscussion

xtranodal NK/T-cell lymphoma, nasal type, is a clinicalntity comprising ulcerative and necrotic lesions preferen-ially arising in the nasal cavities and sinuses (70%), but

hich can also arise at the expense of Waldeyer’s ring (38%),

he oral cavity (14%), larynx, hypopharynx (10%) and even inhe mandible or cheek [2].

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f the mandible measuring 58 × 41 × 35 mm with infiltration ofdjacent fat.

The incidence of extranodal NK/T-cell lymphoma, nasalype, varies considerably in different parts of the world,ut it remains a rare disease since the first description in933. However, the number of new cases per year is on thencrease due to a better knowledge of this disease. Extran-dal NK/T-cell lymphoma, nasal type, represents 45% of allrimary nasal lymphomas, while T-cell lymphoma representsnly 21% of all primary nasal lymphomas [3].

Extranodal NK/T-cell lymphoma, nasal type, can occur atny age, but essentially affects subjects during the fourthnd fifth decades [1]. The mean age of the patients in oureries was 52 years (range: 35—81 years).

Extranodal NK/T-cell lymphoma, nasal type, is more fre-uent in men and the sex ratio varies between 2 and 4.5 inhe literature [4,5] with a sex ratio of 6.5 in our series.

The pathogenesis of extranodal NK/T-cell lymphoma,asal type, is unknown. However, it is strongly associatedith Epstein-Barr virus (EBV) infection [1]. EBV infection isssociated with a poor prognosis with a high local recurrenceate, possible extension to other extranodal areas and deve-opment of macrophage activation syndrome [5], the mostreaded complication that occurs in 8 to 12% of cases due toecretion of cytokines by tumour cells, frequently inducingystemic symptoms such as fever and weight loss [5].

Some studies have attributed these lymphomas to over-xpression of protein p53, possibly associated with a p53ene mutation, often induced by the presence of EBV [6].

Extranodal NK/T-cell lymphoma, nasal type, is a rare dis-ase characterized by polymorphic clinical features that canccount for the diagnostic difficulties and the frequently

isease is non-specific and can often be misleading, resul-ing in an incorrect diagnosis. This misleading appearanceas observed by Kyrmizakis et al. [7] in their series of three

Extranodal NK/T-cell lymphoma, nasal type: Report of 15 cases 145

Table 1 Ann Arbor staging.

Stage Definition

I Involvement of a single lymph node region

II Involvement of two or more lymph node regions on the same side of the diaphragm(the mediastinum is a single site, hilar lymph nodes are each counted as a site)

III Involvement of several lymph node regions on both sides of the diaphragm

E designation, when applicable,to stages I, II or III

Extranodal disease contiguous to lymph node involvement that can be encompassedwithin an irradiation field; different from the disseminated nature of stage IV disease

IV Diffuse or disseminated foci of involvement of one or more extralymphatic organs ortissues, with or without associated lymphatic involvement

SymptomsA No symptomsB At least one of the following symptoms

Unexplained weight loss of > 10% of body weight during the 6 months beforestaging investigationUnexplained fever with temperatures > 38 ◦C for at least 7 days

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cases, in which extranodal NK/T-cell lymphoma, nasal type,was initially mistaken for chronic sinusitis.

Most patients present a localized lesion with nasalobstruction caused by an aggressive tumour invading thesinuses, palate and nasal cavities [8]. Symptoms consistof non-specific nasal symptoms (epistaxis, nasal obstruc-tion, nasal discharge), dysphagia, hemifacial pain or facialoedema [4]. Twenty to 40% of cases present a dissemi-nated form consisting of generalized granulomatosis withcutaneous, subcutaneous, ocular, gastrointestinal, lung andnerve involvement [5,9,10].

It is now generally accepted that a large numberof biopsies must be performed to confirm the diagno-sis of extranodal NK/T-cell lymphoma, nasal type [11].The histological features of NK/T-cell lymphoma are simi-lar regardless of the site of the lesion [5,10], consistingof sheets of atypical small, medium-sized, large or giantSternberg-like cells.

The characteristic feature of extranodal NK/T-cell lym-phoma, nasal type, is the presence of vascular lesions withtumour cells arranged in perivascular (angiocentric) cuffs,with occasional penetration of these cells across the vesselwall and proliferation in the lumen, causing vascular thrombi(angiodestructive lesions). Areas of necrosis and fibrosis areobserved, with marginal pseudoepitheliomatous hyperplasiaof the nasal mucosa [12].

Immunophenotyping reveals expression of T lympho-cyte as well as NK lymphocyte cell markers, hence theterm: extranodal NK/T-cell lymphoma [13]. The most typicalimmunophenotype of extranodal NK/T-cell lymphoma, nasaltype, is: CD2+, CD56+, which is the specific marker of NK,cells with intracytoplasmic expression of anti-CD3 antibodyand negative expression of CD3 on the cell surface [14].

EBV can be detected in tumour cells in the great majo-

rity of cases, as confirmed by several immunolabelling andmolecular biology studies [15].

Cytogenetic studies have concluded on the presence ofa variety of cytogenetic aberrations, such as mutation of

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he Fas and p53 tumour suppressor genes [16]. However, theost common cytogenetic abnormality is a deletion in the21 q25 region or the p10 region of chromosome 6.

Computed tomography is the essential examination fornvestigation of extranodal NK/T-cell lymphoma, nasal type.t allows precise staging of the lesions by defining the tumourite, the presence of osteolysis and possible extension todjacent structures [17]. It is also essential for pretreatmentvaluation, assessment of the response to treatment andollow-up.

MRI more reliably demonstrates soft tissue invasion,s it is able to distinguish inflammation and soft tissueedema from tumour invasion. MRI shows a lesion with aomogeneous low to intermediate intensity signal, which issointense to muscles on T1-weighted sequences and mod-rately hyperintense to muscle on T2-weighted sequencesnd hypointense to mucus. Gadolinium enhancement is alsooderate and heterogeneous and is useful to evaluate the

natomical relations of the tumour with intracranial struc-ures [1].

The laboratory work-up is non-specific and of little valueor the positive diagnosis of this disease [18].

When the diagnosis of extranodal NK/T-cell lymphoma,asal type, has been confirmed, a staging assessmentust be performed prior to any treatment, comprisinghysical examination looking for superficial lymph nodes,epatomegaly or splenomegaly, chest x-ray, abdominalltrasound, chest and abdomen CT, bone marrow biopsy, gas-rointestinal endoscopy and possibly lumbar puncture in theresence of a lesion of the skull base [18].

Despite progress in immunohistochemistry and molecu-ar biology, extranodal NK/T-cell lymphoma, nasal type, stillemains a diagnosis of exclusion due to the absence of anypecific clinical and histological features. Many diseases can

resent in the form of nasal and mid-facial ulceration andestruction, similar to that caused by extranodal NK/T-cellymphoma [19], such as Wegener’s granulomatosis, syphilis,uberculosis, other malignant tumours and cocaine abuse.

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The treatment of extranodal NK/T-cell lymphoma, nasalype, is difficult and complex. Some authors consider thaturgery is ineffective and may even cause deterioration ofhe lesions by inducing rapid progression of the disease. Sur-ical resection of the lesions has been proposed, essentiallyor diagnostic purposes, but also to promote drainage ofecrotic cavities.

External beam radiotherapy with a minimum dose ofbout 52 Gy delivered according to classical fractionations recommended for localized stages (stages I and II) [5]. Itchieves complete remission in 40 to 80% of cases with a-year overall survival of between 40 and 59% [20].

Aggressive chemotherapy is the only available treatmentption for advanced forms (stage III and IV), inducing a com-lete response in less than 15% of cases [21]. Accordingo the study by Hatta et al. [22], CHOP chemotherapy inombination with radiotherapy is ineffective for advancedxtranodal NK/T-cell lymphoma, nasal type, beyond stageIE and stage B NK/T-cell lymphoma. This combination couldlso significantly improve survival in stage IE and IIE NK/T-ell lymphoma [21].

Other so-called ‘‘salvage’’ chemotherapy protocols areometimes used in the absence of response to first-linehemotherapy or in the case of early relapse, consistingf intensive chemotherapy (2nd or 3rd generation combi-ation chemotherapy) (ranimustine, etoposide, carboplatinnd cyclophosphamide), possibly followed by autologousone marrow transplantation [5]. According to Mikhaeelsnd Spittle [23], intensive chemotherapy is necessary evenor localized stages due to the highly aggressive nature ofhis lymphoma. Chemotherapy is now increasingly replacedy haematopoietic stem cell transplantation or addition ofrowth factors. Interferon therapy has not been shown to beffective.

This tumour has a poor prognosis, with a 5-year overallurvival ranging between 10 and 45% depending on the series24,25].

onclusion

xtranodal NK/T-cell lymphoma, nasal type, is a rareisease, but the number of new cases reported each yearas been continually increasing over recent years due to

better knowledge of this disease. This disease has beenore clearly elucidated as a result of progress in immuno-

istochemistry and molecular biology.Extranodal NK/T-cell lymphoma, nasal type, is charac-

erized by its polymorphic clinical features, responsible foriagnostic difficulties and frequently delayed management.istological examination of biopsy samples completed by

mmunohistochemistry is essential to establish the positiveiagnosis.

The pathogenesis of extranodal NK/T-cell lymphoma,asal type, is unknown, but it is strongly associated withpstein-Barr virus infection. These EBV-associated lym-homas have a poor prognosis with a high local recurrenceate and the presence of macrophage activation syndrome

n the majority of cases.

Optimal management of extranodal NK/T-cell lymphoma,asal type, must be based on multidisciplinary collaborationetween otorhinolaryngologists, radiotherapists, medical

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S. Tababi et al.

ncologists and nutritionists in order to improve the prog-osis of this disease.

EBV immunotherapy, monoclonal antibodies and geneherapy have been proposed as possible treatments for theuture, as the EBV virus could become a major therapeu-ic target in combination with conventional combinationhemotherapy. Research into p53 expression is currentlynderway to elucidate the carcinogenesis of extranodalK/T-cell lymphoma and probably also as an approach to thereatment and prognosis of these aggressive lymphomas.

isclosure of interest

he authors declare that they have no conflicts of interestoncerning this article.

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