Extranodal natural killer/T cell lymphoma, nasal type: a diagnostic challenge

Abstract

Extranodal natural killer/T cell lymphoma, nasal type (ENKL) is a rare and aggressive tumour that can, clinically and histologically, mimic infectious and inflammatory conditions, presenting a diagnostic challenge. The authors report the case of a 69-year-old Portuguese woman previously misdiagnosed with chronic recurrent sinusitis. Despite maximal medical and surgical treatments, the disease was refractory and progressed. The patient had undergone multiple biopsies when the histopathological diagnosis of ENKL was made, 5 months after the initial complaints. Multiagent chemotherapy was offered, but during the first cycle, the patient developed severe infection and pancytopenia, which culminated in her death. This case highlights the need to consider a neoplastic cause when faced with aggressive sinonasal disease not responsive to maximal treatment and the difficulties in establishing the diagnosis of ENKL, with multiples biopsies of deep-tissue usually being required.

Background

Natural killer (NK-)/T cell lymphoma is a rare, aggressive, subtype of non-Hodgkin lymphomas that occurs more commonly at extranodal sites.^1–3 The majority of extranodal natural killer (NK-)/T cell lymphomas (ENKL) occur in the upper respiratory tract, namely the nasal cavity, paranasal sinuses, nasopharynx, tonsils, hypopharynx, or larynx, being referred to as ENKL, nasal type.³ Other locations include skin, gastrointestinal tract, testis and, rarely, central nervous system.⁴ These tumours are more common in Asians and South Americans than in Europeans, North Americans and Africans.⁵

ENKL are extremely aggressive tumours, made of cytotoxic T cells and putative NK cells (majority), known for their association with Epstein-Barr virus (EBV) and angiotropism, causing vascular damage, tissue necrosis and cytotoxicity.^5–7 Diagnosis of this condition might be challenging and there are reports of misdiagnosing ENKL for chronic rhinosinusitis or vasculitis in cases of negative biopsies for malignancy.^{3 8} Delays in diagnosis might be attributable to both, the unspecific symptoms of ENKL, commonly nasal obstruction and epistaxis, and the presence of inflammatory changes and necrosis that prevent an accurate pathological diagnosis.⁹ Timely diagnosis is essential, given the poor prognosis of these tumours, with 5-year overall survival of 50%, in early clinical stages.³

We report the case of a female patient with recurrent episodes of left-side facial oedema. Ipsilateral nasal obstruction and purulent discharge, who were misdiagnosed as having recurrent sinusitis. Multiples nasal biopsies were undertaken, most of them negative for malignancy, until the final pathological diagnosis of ENKL was made. This case highlights the need for suspicion of this rare and extremely aggressive condition, as timely diagnosis might provide better outcomes.

Case presentation

A 69-year-old Caucasian woman was admitted in our department in March 2014 with a painful lesion on the palate that had slowly grown for the previous 3 months. On physical examination, an ulcerated, friable, of irregular borders mass was found in the anterior one-third of the hard palate. The patient underwent successful surgery for this hard palate tumour and histopathological examination of the specimen revealed a moderately differentiated squamous cell carcinoma, pT1N0M0, according to the eighth edition of the American Joint Committee on Cancer tumour, node, metastases staging system.

After 4 months of follow-up, the patient presented to our emergency department with sudden onset of left-sided facial erythema and oedema, ipsilateral nasal obstruction and purulent nasal discharge. She denied fever, headaches, otalgia, hearing loss, eye pain, changes in vision, dysphagia or any symptom of the oral cavity. On physical examination, she had middle swelling of the left side of the face, which was erythematous and tender to palpation. There was no periorbital oedema. Extraoculomotor movements, pupillary reflexes and conjunctiva were normal. Oral cavity was unremarkable, without any evidence of carcinoma recurrence. Cranial nerves II to XII were intact. Diagnostic endoscopy revealed thick purulent discharge from the left middle meatus, crusts and granulation tissue. CT of paranasal sinuses showed partial opacification of left anterior ethmoidal cells and frontal sinus. The diagnosis of acute rhinosinusitis complicated with facial cellulitis was made and empiric antibiotic therapy and systemic steroids were initiated with full recover of the symptoms.

During 2015, three similar episodes were observed. In the latest, the patient was hospitalised for further investigation.

Investigations

• Laboratory tests showed the following results (reference ranges provided parenthetically): leucocytes, 5.1×10⁹/L (1.8–10.8×10⁹/L); neutrophils, 3.2×10⁹/L (1.8–7.7×10⁹/L); haemoglobin, 9-9 g/L (120–160 g/L); platelets, 198×10⁹/L (150–400×10⁹/L); serum sodium, 138 mEq/L (135–145 mEq/L); potassium, 4.26 mmol/L (3.5–5.1 mmol/L); chloride, 100 mmol/L (95–105 mmol/L); blood urea nitrogen, 42 mg/dL (15–39 mg/dL); creatinine, 0.77 mg/dL (0.5–1.1 mg/dL); ACE, 51 U/L(35–90 U/L); anti-neutrophil cytoplasmatic and antinuclear antibodies were negative.

• Punch biopsy of the crusts and granulation tissue of the left nasal cavity was performed and histological examination revealed the presence of fragments of inflamed mucosa, whose overlying respiratory-type epithelial was eroded and reactive lymphoid tissue consisting of B and T lymphocytes within the connective tissue. No dysplastic or malignant lesions were identified.

• The patient underwent CT scan and MR of the nose and paranasal sinuses (figures 1 and 2) which revealed the presence of heterogeneous tissue fulfilling the left paranasal sinuses and ipsilateral nasal cavity with identifiable areas of mucoid-like filling, namely in the frontal sinus, sphenoid sinus, maxillary sinus and some ethmoid cells, in relation to obstructive inflammatory phenomena and associated with reactive osteitis (best appreciated in CT scan). Signs of remodelling and bone erosion of the middle ethmoid cells and maxillary sinus wall were noted. In addition, orbital extension of the aforementioned process was documented with erosion and lateral bulging of the medial orbital wall, with slight deviation of orbital structures and proptosis. Involvement of the masticatory muscles and tissue filling of the pterygopalatine space was apparent, without extension to the carotid space. No signs of intracranial, nasopharyngeal or pre-vertebral invasion was shown.

Figure 1.

Axial MRI T1 WI revealing the presence of heterogeneous tissue fulfilling the left paranasal sinuses and ipsilateral nasal cavity (A) with enhancement after contrast agent injection (B).

Figure 2.

Coronal MRI T1 WI FS post-contrast demonstrating a soft tissue mass in the anterior ethmoidal cells (A), erosion and lateral bulging of the medial orbital wall with deviation of orbital structures (B) and extension of the process into the masticatory space (C). FS; Fat supression.

Differential diagnosis

Differential diagnosis included lymphoma, squamous cell carcinoma (given the history of the patient), granulomatous disease with polyangiitis, sarcoidosis and chronic or invasive fungal rhinosinusitis. To establish a definitive diagnosis, tissue biopsy and culture is the mainstay. Conversely, based on the clinical and histological findings the presumptive diagnosis of recurrent rhinosinusitis was made.

The patient underwent endoscopic medial maxillectomy and sphenoethmoidectomy. During surgery, the nasal cavity and paranasal sinus were filled with granulation tissue with areas of necrosis, crusts and pus (figure 3). Debridement of tissues in the pterygopalatine fossa was undertaken. In the postoperative period, intravenous corticosteroid (dexamethasone 8 mg/day), antibiotics (ceftriaxone 1 g, 12/12 hour and metronidazole 500 mg, 8/8 hour), analgesics (acetaminophen 1 g, 8/8 hour) and salt water rinses (beginning 2 days after surgery) were prescribed.

Figure 3.

Endoscopic view of left nasal cavity showing a nasal mass (arrow) with areas of necrosis (asterisk) and pus (arrow head).

Outcome and follow-up

On the day after the surgery the patient showed great attenuation of the periorbital and facial oedema, presenting a residual area of tenderness in the left paranasal region. Physical examination findings and inflammatory markers progressively diminished and the patient was discharged 20 days after the surgery, fully asymptomatic.

Histopathological analysis of the surgical specimen revealed the presence of granulation tissue of non-specific inflammatory characteristics and rulled outmalignant diagnoses. P. aeruginosa and E. faecallis were isolated in the sample.

Forty days later, the patient presented to the emergence department with left-side facial oedema, periorbital oedema and bilateral purulent discharge. A new course of antibiotics and corticosteroids was prescribed with clinical improvement. On the eighth after admission, deterioration of the clinical status was observed, with increasing of facial oedema, proptosis and inability to completely close the eye. An endoscopic revision surgery with debridement of necrotic tissue was performed, in order to provide symptomatic relief and to obtain additional tissue for further histological analysis.

Despite initial improvement, disease progression was documented with the development of left amaurosis, right periorbital oedema and progressive decline of the clinical status (figure 4). Histological and immunophenotypic results (CD2+, CD3cit+, CD56+, CD45+, EBER+, Granzyme B positive, Ki-67 +CD20–, CD10–, CD5–, CD57– and EMA–) established the diagnosis of ENKL, nasal type (figures 5 and 6). Pretreatment evaluation included bone marrow biopsy and CT scan of the chest, abdomen and pelvis, which were unremarkable. In addition, MR of the head and 18-fluorodeoxyglucose positron emission tomography/CT) were performed, revealing orbital, infratemporal fossa, pterygopalatine space, cavernous sinus and intracranial invasion (figure 7). The tumour was, conversely, clinically staged III, according to the classification of Yan et al.¹⁰

Figure 4.

Clinical deterioration with right periorbital oedema, left-sided facial oedema and left amaurosis.

Figure 5.

Micropathology showing angiocentric necrosis, inflammation and immature lymphocytes, on H&E staining, 200×.

Figure 6.

Immunohistochemical staining of specimen showing positive for cytoplasmic CD3, CD56 and granzyme B, 400×.

Figure 7.

18-fluorodeoxyglucose positron emission tomography/CT revealing extension of the lymphoma into the orbita, masticator space, infratemporal fossa, pterygopalatine space, cavernous sinus and intracranial space.

Chemotherapy was initiated on 7 December 2015, and consisted of the SMILE regimen (methotrexate 2000 mg intravenous over 6 hours, day 1; ifosfamide 1500 mg intravenous over 2 hours, days 2–4; etoposide 100 mg intravenous over 2 hours, days 2–4; L-asparaginase 1000 UI intravenous over 30 min, day 8; L-asparaginase 6000 UI intravenous over 2 hours, days 8, 10, 12, 14, 16, 18 and 20; dexamethasone 40 mg per os, days 2–4) given every 28 days. Supportive measures included ondansetron 8 mg intravenous, 8/8 hour, days 1–3; folinic acid 15 mg intravenous, 36 hours after the start of methotrexate infusion and repeated every 6 hours until methotrexate level <0.1 micromol/L; mesna 600 mg intravenous 10–15 min prior to the start of ifosfamide, days 2–4; and mesna 600 mg intravenous 3, 6, and 9 hour after the start of ifosfamide, days 2–4. The first cycle of chemotherapy was complicated by febrile pancytopenia and infection, which culminated in multiple organ failure. Patient died on the 16th day of treatment.

Discussion

ENKL, nasal type, is a rare condition with an inherent challenging diagnosis. Given the fact that nasal or nose-related symptoms, such as nasal obstruction, purulent discharge epistaxis and/or facial pain are highly unspecific, features of neoplasms may be undistinguishable from inflammatory conditions. Indeed, in the literature, there are several reports of cases of ENKL nasal type mimicking chronic sinusitis.⁵

Definite diagnosis of ENKL is dependent on a biopsy and histopathological examination, which commonly shows pleomorphic tumour cell infiltration with vascular damage and the typical immunophenotype: CD2+, CD56+, cytoplasmic CD3+, surface CD3-, Granzyme B+ and TIA-1+.^{6 7} EBV-encoded small RNA is also positive.^{6 7} Detection of EBV by in situ hybridisation is, indeed, highly recommended,² as, besides reinforcing the diagnosis, it is of critical importance for prognosis and follow-up.^{2 6} Obtaining tissue samples useful for diagnosis may not be possible in superficial punch biopsies, given the secondary rhinosinusitis usually found in nasal neoplasms.¹¹ Conversely, surgery is rottenly necessary to perform deep tissue biopsy.¹²

In the present case, although the patient presented common symptoms of rhinosinusitis, there was high concern that a neoplasm was the underlying cause of the sudden recurrent facial cellulitis, especially given the history of hard palate carcinoma. Nonetheless, several biopsies were made, revealing necrotic inflammatory tissue, without evidence of malignancy. Although there was growth of P. aeruginosa and E. faecallis, treatment with antibiotics was not efficient and, in few months, a deterioration of the clinical status and extension of the disease into the adjacent structures, namely, orbita, pterygopalatine fossa, infratemporal fossa and anterior cranial fossa was documented. Given the rapidly progressive course of the disease, revision surgery in order to perform new deep biopsy was undertaken. Features on H&E staining and immunophenotypic analysis of this specimen were consistent with the diagnostic standards of ENKL. Saavedra Ramírez reported similar difficulties, regarding the diagnosis of ENKL.³

Chemotherapy and radiotherapy, either concurrently or sequentially, are the main treatment options for early-stage ENKL.^{4 8} Early-stage localised nasal disease is highly curable with combination therapy.¹³ ENKL, nasal type, does not respond to anthracycline-based regimens.³ Conversely, L-asparaginase-based protocols are the standard treatment for ENKL.^{2 7} In the present case, given the advanced stage of the disease, it was decided, on a multidisciplinary board, to give the patient chemotherapy, namely, the SMILE regimen, which includes dexamethasone, MTX, ifosfamide, L-asparaginase and etoposide, but the patient developed febrile pancytopenia and infection and died before the end of the first cycle of chemotherapy.

This case highlights the difficulty in obtaining a timely diagnosis of ENKL and raises the concern about the presence of infection of soft tissues refractory to targeted treatment, as it may be a covert lymphoma. It is noteworthy that, whenever the initial pathological analysis is inconclusive, another biopsy of deep tissue shall be obtained.

Learning points.

• Extranodal natural killer (NK-)/T cell lymphomas (ENKL) is a rare and aggressive condition that represents a clinical and histological diagnostic challenge.

• Recurrent rhinosinusitis not responsive to targeted therapy should raise the suspicion for a neoplasm.

• Multiple biopsies may be necessary to accurately diagnose ENKL.

• If diagnosis is not possible from one specimen, further invasive procedures, as surgery, shall be performed to obtain deep, non-necrotic tissues.