Nasal type extranodal natural killer/T-cell lymphoma (ENKTL) is a rare lymphoma in the USA and Europe but endemic in East Asia and in areas of South and Central America. Clinically natural killer cell lymphomas are divided into three categories; nasal, non-nasal and aggressive lymphoma/leukemia subtypes. ENKTL, nasal type occurs in the nose and can extend to the upper aero-digestive tract as reported in this longitudinal case study. This is a longitudinal report of progress of a 14-year-old boy with ENKTL originating in the nasal cavity with subsequent extension and recurrence in the contralateral nose, nasopharynx, larynx and trachea presenting with varying degrees of respiratory problems and eventually, respiratory distress. Caregiver refusal of stem cell transplantation prompted an alternative diagnostic and therapeutic approach. Clinical course with recurrences, extensions and remissions over 6 years with tailored endoscopic surgical treatment and radiochemotherapy is documented to present a guide in the multidisciplinary management of this rare disease.
Extranodal natural killer/T-cell lymphoma (ENKTL), nasal type is a rare type of lymphoma that is endemic in eastern Asia and some places in South and Central America . It is extremely rare in the USA and Europe , comprising less than 1% of lymphomas . It is most commonly associated with Epstein–Barr virus (EBV) . Clinically, NK cell lymphomas are divided into three categories; nasal, non-nasal and aggressive lymphoma/leukemia subtypes . Two thirds of patients have disease in the nasal cavities or adjacent sites . ENKTL, nasal type occurs in the nose and may extend to the upper aerodigestive tract . The disease is commonly reported in the fifth decade of life and the male:female ratio is about 3:1 . The majority of these patients have localized disease involving the nasal cavity, nasopharynx, paranasal sinuses. Rare reports also include the tonsils, hypopharynx, larynx, skin and testes . Common presenting symptoms include increased nasal secretions, epistaxis, nasal obstruction, sore throat and dysphagia . As these symptoms are non-specific and the initial presentation highly variable, accurate diagnosis can be delayed, leading to complications and advanced disease, especially in the pediatric population . Once diagnosed, caregiver preferences and other circumstances may preclude certain treatment options such as stem cell transplantation and alternative strategies have to be developed.
Our patient is a 14-year-old African American male who presented with a seven month history of recurrent left sided nasal obstruction, rhinorrhea and epistaxis at age 8. Initially, the patient presented to primary care physicians and was advised only symptomatic treatment for his non-specific symptoms. He was treated with multiple courses of antibiotics without resolution of symptoms. He developed recurrent fever, weight loss, poor appetite and change in tone of voice. Family history was positive for leukemia (type unknown) in a second cousin. On examination, nasal mucosa was pale and boggy with thick mucoid discharge bilaterally. Oral cavity and ear examinations were normal. No cervical lymphadenopathy was noted. Liver and spleen were not palpable, and the remainder of the physical examination was normal.
A contrast-enhanced CT scan of the face showed a poorly circumscribed non-enhancing mass completely filling the left nasal cavity without extension into the nasopharynx. The mass displaced the inferior turbinate and the nasal septum slightly to the right ( Fig. 1 ).
At the request of his referring physician (MAJ) he then underwent an endoscopic exam by ENT under general anesthesia showing a large obstructing mass that appeared friable and papillomatous. It seemed to be originating from the anterior portion of the inferior turbinate. A biopsy was taken, showing infiltration of the submucosa by heterogeneous sheets of atypical lymphocyte populations ( Fig. 2 ). Mitoses were focally conspicuous. The majority of the tumor cells were positive for in-situ hybridization stains for Epstein–Barr virus encoded RNA (EBER). These biopsy findings were suggestive of ENKTL. For additional assurance, the specimens were re-interpreted at the affiliated St Jude’s hospital pathology department and their interpretation did not support the diagnosis of ENKTL, referring to the specimens as displaying atypical EBV-positive mixed lymphoid infiltrates. The discrepancy dictated a repeat biopsy.
A biopsy of the right inferior turbinate at St Jude’s confirmed the diagnosis of ENKTL since at this time both nasal passages were involved and the mucosa appeared inflamed without a distinct mass.
Overall he required three nasal biopsies until a definitive diagnosis could be obtained (11/2010). The neoplastic cell population was CD2+, CD3+ and CD7+ and appearred CD5 (−). The atypical infiltrate contained a prominent population of small, medium and large cells that are CD56+++, TIA −1++ and granzyme B++ as well as EBV+++ on immune-peroxidase staining ( Fig. 2 ). Full staging included bone marrow biopsy, CSF examination, and PET scan and showed that the disease was not present at any other site.
He was started on a chemotherapy regimen consistent of dexamethasone, ifosfamide, carboplatin, etoposide (DeVIC chemotherapy) concurrent with local radiotherapy (54 Gy). The regimen was based on studies showing concurrent chemo-radiotherapy to be superior to radiotherapy alone or sequential chemo-radiotherapy for this aggressive lymphoma . He received biweekly triple treatment with MTX, HC and ARA-C.
He tolerated 2 cycles of chemotherapy relatively well. However, he had an episode of generalized tonic–clonic seizures during the 2nd course. This prompted neurological evaluation for intracranial disease including MRI brain and was within normal limits. Levetiracetam was started as per neurologist’s advice and a decision was made to omit the last cycle. He completed his radiation therapy. His evaluation showed full remission and repeat MRI of the face showed resolution of the mass. He was regularly followed up in the outpatient clinic with serial MRIs and endoscopic office examinations by ENT to monitor for recurrence.
A repeat right sided endoscopic nasal biopsy (3/2011) showed only scar tissue without evidence for ENKTL recurrence. Bone marrow biopsy was repeated to exclude medullary involvement, and was negative. Nine months later, pain, epistaxis and nasal obstruction prompted a repeat MRI of the face showing new thickening of the nasal mucosa. Repeat nasal endoscopy and bilateral biopsies showed bilateral ENKTL recurrence in both posterior nasal cavities. The primary caregiver (patient’s biological mother) was offered treatment with stem cell transplant however, despite detailed discussion about the aggressive nature of the tumor and poor prognosis, she refused on the basis of hardship on the family from required travel. Salvage therapy was given after full staging. MRI on 12/2011 showed persistence of partially enhancing mass in the nasal cavity left greater than right which protruded into the nasopharynx. The patient was treated with high dose methotrexate (3 g/m 2 ), dexamethasone and l -asparaginase. The regimen has been found to be effective in relapsed NK cell NHL . He received three cycles with a partial response. Leucovorin and pegfilgrastim rescue were also given along with chemotherapy.
Following chemotherapy, repeat endoscopic biopsies of the left nasal and sinus mucosa were negative. Further chemotherapy was planned due to this change in the proposed management with fludarabine added to the l -asparaginase regimen. Fludarabine, a purine nucleoside analogue, has shown an added effect in patients with non-HD lymphomas . Fludarabine (25 mg/m 2 IV) from days 1 to 5 and l -asparaginase (6000 units/m 2 IV) on days 2, 5 and 8 were both given. Each cycle was 28 days in length and six such cycles were undertaken. Patient tolerated the chemotherapy well and subsequently remained in remission; clinical, pathological, endoscopic and radiological follow-up were continued. Sixteen months later (9/13) both nasal and sinus mucosal biopsies showed only focal atypical lymphoid infiltrates (FALI), however, biopsy of the adenoid tissue also was suspicious for involvement with ENKTL due to the presence of FALI. No new treatment was initiated. Six months later (3/14) the patient presented with progressive hoarseness, difficulty breathing and stridor. Endoscopic airway evaluation under general anesthesia showed an exophytic mass of the postcricoid area as well as the right false cord and the subglottic area extending into the trachea. The tissue was very friable and biopsies from separate anatomical locations were taken. A microdebrider was used to excise/debulk the mass from the supraglottic and postcricoid area. The subglottic debridement was conservative dictated by anatomical limitations. Biopsy results indicated ENKTL relapse in the larynx ( Fig. 3 ). The subglottic tissue had FALI, and the nasal biopsies showed FALI in the R ethmoid, ENKTL in the left nose.