Aggressive Nasal Type Extranodal Natural killer / T-cell Lymphoma Presenting as Refractory Granulomatosis with Polyangiitis ( Wegener ’ s Granulomatosis )

Introducere: Limfomul extranodal NK/T de tip nazal este o tumoră local invazivă, caracterizată prin leziuni ulcerative și necrotice cu originea în cavităţile nazale și în sinusurile paranazale. Poate fi cu ușurinţă confundat cu o formă localizată a granulomatozei cu poliangiită (granulomatoza Wegener), care afectează căile respiratorii superioare prin același tip de leziuni. Prezentare de caz: Un pacient în vârsta de 39 de ani s-a prezentat în departamentul de reumatologie cu următoarele acuze: obstrucţie nazală bilaterală, dismorfi sm nazal, rinoree purulentă, durere orofaringiană, anosmie, halitoză, disfagie. Timp de doi ani s-au recoltat biopsii, care au relevat inflamaţie granulomatoasă cronică și necroză, fără celule maligne. S-a stabilit diagnosticul de granulomatoză cu poliangiita și s-a instituit CASE REPORT Andreea-Alexandra Aldea et al. Modern Medicine | 2018, Vol. 25, No. 3 164 be ANCA negative and sometimes lead to destructive mid line lesions1. Extranodal NK/T-cell lymphoma, nasal type is a serious and in most cases fatal disease, more typical for Asian (China, Japan, Korea, Southeast Asia) and South American (Mexico, Peru, Argentina) populations and very rare between Caucasian patients2. Th e rarity of this kind of lymphoma has now been more clearly elucidated as a result of progress in immunohistochemistry (IHC) and molecular biology3.

be ANCA negative and sometimes lead to destructive mid line lesions 1 .Extranodal NK/T-cell lymphoma, nasal type is a serious and in most cases fatal disease, more typical for Asian (China, Japan, Korea, Southeast Asia) and South American (Mexico, Peru, Argentina) populations and very rare between Caucasian patients 2 .Th e rarity of this kind of lymphoma has now been more clearly elucidated as a result of progress in immunohistochemistry (IHC) and molecular biology 3 .

CASE PRESENTATION
A 39-year-old man with bilateral nasal obstruction, fetid purulent rhinorrhea, oro-pharyngeal pain, oro-nasal regurgitation of liquids, anosmia, halitosis, severe upper dysphagia, and nasal dismorfi sm was referred for rheumatologic reevaluation, in July 2017 to the Department of Rheumatology, Cluj-Napoca.

BACKGROUND
We present a rare case of nasal type extranodal NK/Tcell lymphoma mimicking granulomatosis with polyangiitis (GPA), in order to highlight the diffi culties in the diff erential diagnosis of destructing nasal lesions.Extranodal NK/T-cell lymphoma, nasal type is a rare type of non-Hodgkin's lymphoma, often associated with Epstein-Barr virus (EBV) infection, characterised by destructive lesions arising in the naso-sinusal tract and progressively invading the midfacial bones.Early diagnosis can be very challenging because clinicopathological fi ndings overlap with various diseases including infections, necrotizing vasculitis, and neoplastic lesions.GPA is a necrotizing granulomatous vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA) that aff ects the upper respiratory tract, the lungs and the kidneys.Limited forms of GPA may tratament cu corticosteroizi și imunosupresoare.Boala a evoluat, însă, progresiv cu deteriorarea stării pacientului.A cincea biopsie a evidenţiat limfocite atipice, iar testul imunohistochimic a exprimat fenotipul CD3 + citoplasmatic și Granzime B+.Virusul Epstein-Barr a fost, de asemenea, identifi cat.S-a stabilit diagnosticul fi nal de limfom extranodal NK/T, de tip nazal.Pacientul a urmat tratament chimioterapic, la care boala a remis complet.Concluzie: În cazul evaluării unui pacient cu leziuni distructive la nivelul cavităţii nazale, trebuie suspectat un limfom extranodal NK/T, de tip nazal.Biopsii multiple, pe arii extinse și testarea imunohistochimică sunt necesare în depistarea diagnosticului.Cuvinte cheie: limfom extranodal NK/T, granulomatoza cu poliangiită, virusul Epstein-Barr, imunohistochimie Two years before the admission in our department, in October 2015, at the time of the fi rst symptoms, the patient was referred to the Ear-Nose-Th roat Department with progressive nasal obstruction and infl ammatory syndrome.Th e physical and endoscopic examination revealed complete obstruction of the nasal fosse with nasal dysmorphism and degenerated mucosa but no obstruction of the rhinopharynx.Th e fi rst tissue biopsy was taken with a specimen consisting of left nasal cavity mucosa.Th e result of the histopathological examination was unclear, which only revealed profuse infl ammatory reaction.A diagnosis of chronic sinusitis    of AspaMetDex (Escherichia coli L-asparagi nase, Methotrexate, Dexamethasone) were added as che motherapy regimen.Th e main side eff ects after chemotherapy were anaemia, medullary aplasia, allergic reaction with anaphylactic shock (angioedema, hypotension and bronchospasm) due to L-asparaginase and an acute faringitis with multidrug-resistant Candida krusei.Th erefore, the patient was transfused with two units of erythrocyte mass, granulocyte colony stimulating factor, antifungal and antibiotic treatment were administrated and L-asparaginase was totally removed from the therapeutic formula.
Outcome and follow-up: Th e patient's outcome was one of complete recovery.Head CT scan showed complete remission of the lymphoma.Autologous hematopoietic stem cell transplantation (HSCT) was considered when remission was achieved, but the patient refused the treatment.He is referred now for periodic controls.

DISCUSSION
It is a case on the edge of rheumatology and hematology and it illustrates the need of suspicion of an extranodal NK/T-cell lymphoma, nasal type in a background of chronic sinusitis mimicking GPA.Th e initial signs and symptoms of recurrent sinusitis, as well as the midline localization of the necrotic lesions with nasal soft tissue and bone invasion appear both in GPA and in extranodal NK/T-cell lymphoma, nasal type.
Another similar case report, published in Th e American Journal of the Medical Sciences, presented the case of a patient with recalcitrant periodontitis, who underwent multiple histopathological examinations which suggested GPA.Eventually, the fi nal biopsy together with the phenotypic markers pointed toward a diagnosis of extranodal, nasal type NK/T-cell lymphoma 4 .Another study compared the clinical course of patients diagnosed with sinonasal T-cell lymphoma with other recently treated patients with GPA in the upper airways and asserts that clinically, it may be almost impossible in the early stages of the disease to diff erentiate between T-cell lymphoma, GPA and nonspecifi c chronic infl ammation.One third of the T-cell lymphoma patients had a history of persistent "chronic rhinitis" for several years before the disease evolved into an ulcerative stage 5 .What led to further diagnostic dilemma in our case was the missing ANCA, which is usually a characteristic marker for GPA, but still not detectable in a quarter of patients with limited GPA 6 .
Th e result in hematoxylin-eosin (H-E) and periodic acid-Schiff (PAS) staining showed, this time, an intense granulocytic infi ltrate with the tendency to form granulomas and extensive areas of necrosis, with no malignant cells.Th e fi rst diff erential diagnoses taken into account were the following: nasal infl ammatory polyp, eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome) and GPA.
Th e paraclinical investigations showed leukocytosis, anaemia, important infl ammatory syndrome (CRP=6.7 mg/dl, ESR=60 mm/h); the bacteriological examination was negative and the blood level of procalcitonin was low.Although ANCA was negative, the histopathologic examination suggested GPA.Th e patient was treated with oral corticosteroids -Methylprednisolone and immunosuppresors -Azathioprine.
Unfortunately, the disease worsened progressively a few months later.Despite the administration of antibiotics, corticosteroids, addition of Methotrexate and endoscopic aspiration of nasal secretions, rapid destruction of the naso-sinusal region, purulent rhinorrhoea, halitosis, inappetence, fever of 40°C and dehydration occurred.Careful examination revealed granulomatous lesions of the lateral pharyngeal walls with narrowing of the oropharyngeal isthmus.Th e endoscopic debridement of the invading tissue was unsuccessful.
A group of doctors, consisting of a rheumatologist, otorhinolaryngologist, hematologist and a pathologist cooperated to establish the possibility of a midline lymphoma as diff erential diagnosis with GPA.A new rhinopharynx biopsy was performed and the histopathological examination unveiled scattered atypical lymphoid cells with atypical nuclei and clear cytoplasm (Figure 1).
Upon immunohistochemical characterization, the atypical cells showed cytoplasmic CD3+ (Figure 2) and granzyme B+ phenotype (Figure 3) as well as the pKi67 proliferative marker (Figure 4).Moreover, using in situ hybridization, EBV encoded RNA (EBER) was identifi ed (Figure 5).Th e new morphological picture with the IHC profi le, together with the entire clinical aspect pointed toward a diagnosis of extranodal NK/Tcell lymphoma, nasal type.Th e patient was transferred in September 2017 to the Department of Hematology.
Treatment: Th e fi rst treatment that the patient had underwent was a concurrent chemoradiation therapy with VIPD (Etoposide, Ifosfamide, Cisplatin, Dexamethasone) and radiation.Th e endoscopic reevaluation showed non-remission of the disease thus, three cycles Ki67 is a proliferation marker, fi rmly associated with tumor cell proliferation and growth and is correlated with tumor aggressiveness 13 .Th e expression of Ki67 was found in our case and was a diagnostic and prognostic marker.
Th ird, what indicates a diagnosis other than GPA, is the non-response to Azathioprine and the rapidly, progressively deterioration of the patient's clinical course.
Th e medical literature presents a large spectrum of diff erential diagnoses for destructive midline lesions.GPA, Churg Strauss syndrome, sarcoidosis, systemic lupus erythematousus, Sjögren's syndrome, syphilis, as well as cocaine abuse are just a few of them 4,7 .Despite diagnostic advances and improved understanding of the disease, an etiology is often not identifi ed 14 .Th erefore, a multidisciplinary collaboration between rheumatologists, otorhinolaryngologists, hematologists and experienced pathologists is required.

Acknowledgements:
Th e authors want to thank Dr. Bogdan Fetica from Oncologic Institute "Prof.Dr. Ion Chiricuţă", Cluj-Napoca, Department of Pathological Anatomy for providing the biopsy and immunhystochemistry images from Figure 1-5.

Compliance with ethics requirements:
Th e authors declare no confl ict of interest regarding this article.Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008 (5), as well as the national law.Informed consent was obtained from all the patients included in the study.
Nevertheless, there are some diff erences between the two pathological entities.Firstly, clonal Epstein-Barr virus (EBV) infection is almost invariably involved in nasal NK/T-cell lymphomas, appearing in 90% of cases, whereas between GPA and EBV there is no correlation 7,8 .Beside the etiological role of the EBV in extranodal NK/T-cell lymphomas, the virus has been shown to shape the tumor microenvironment by encoding a series of products that mimic several growth, transcription and anti-apoptotic factors, and in this way taking control over tumour cells pathways [9][10][11] .Our case consolidates these fi ndings, as our patient was detected with EBV-encoded RNA in the neoplastic cells.We want to underline the statement that we have to look in detail when we suspect a midline lymphoma and correlate the viral infection with oncogenicity.
Secondly, histologically, lesions present a mixture of infl ammatory cells and diff use infi ltrate of lymphoid cells together with substantial necrotic tissue, which make it diffi cult to distinguish between infectious, autoimmune or malignant processes 4 .Th e fi rst three biopsies showed reactive lymphoid hyperplasia, the fourth, necrosis and small sized lymphocytes with the tendency to form granulomas, suggesting the picture of GPA.Only the fi fth consistent biopsy unveiled the easily overlooked neoplastic cells, which present as small lymphocytes with nuclear atypia.Because the progressive necrosis and the infl ammatory infi ltrate covers the entire view of the histological picture, multiple, large enough biopsies specimens are required, to dig after scattered malignant cells 4 .
However, from IHC point of view, NK-T cell lymphoma exhibits a very specifi c and individual feature.Th erefore, once we have an adequate biopsy, IHC is the key for diff erentiating the two diagnoses from one another 7 .Our case wants to point out that histopathological exam is insuffi cient for the complete diagnosis of nasal extranodal NK/T-cell lymphoma and that performing immunohistochemistry is crucial in defi ning the diagnosis and diff erentiating it from GPA. Nasal extranodal NK/T-cell lymphoma arise from the malignant transformation of NK cells and express CD2, CD56, cytoplasmic CD3, perforin, and granzyme B2,5.Immunophenotypically, our patient presented cytoplasmic CD3+, granzyme B+, and negative CD56.


A nasal obstruction with purulent rhinorrhea and destructive midline lesions may be the initial signs of the extranodal, nasal type, NK/ T-cell lymphoma under the mask of a GPA. Multiple, large enough biopsies, immunohistochemistry studies and appropriate serological tests are the key in fi nding the correct diagnosis. Th e fi nding of EBV in the tumoral cells is an essential part in the diagnosis of NK/T-cell lymphoma.