NK/T-cell lymphoma of the nasal cavity: an unexpected diagnosis

Abstract

Nasal-type Natural Killer/T-cell Lymphoma (NKTL) is a rare form of extranodal non-Hodgkin’s lymphoma, typically arising in the nasopharynx and displaying an aggressive and ultimately fatal clinical course. The disease is linked to Epstein-Barr virus infection and is endemic to Asia and South America, but extremely few cases have been reported in Europe. We present two cases of nasal NKTL unexpectedly diagnosed in elderly patients, following very different presentations to our otolaryngology service. The first case is that of a 73-year-old Irish man with recurrent nasal vestibulitis despite antibiotic treatment. The second case involves a 79-year-old Irish woman presenting with a large mass on the hard palate, found to invade into the floor of the nose. NKTL can pose diagnostic challenges, as the initial clinical presentation can be non-specific and overlap with other nasal conditions, leading to a delay in diagnosis. Biopsy with histopathological and immunohistochemistry analysis is required to establish the definitive diagnosis. Treatment involves multidisciplinary input from radiotherapy and medical oncologists. Clinicians must be aware of this disease and have an index of suspicion when dealing with persistent or aggressive nasal conditions.

Background

Nasal-type Natural Killer/T-cell lymphoma (NKTL) is a rare clinical entity, now recognised as a distinct type of extranodal non-Hodgkin’s lymphoma (NHL). The clinical course is aggressive, with extensive destruction of the midline nasal cavity and palate which is generally fatal if left untreated. The first descriptions of potential cases date back to 1897, and historically it was described as ‘lethal midline granuloma’ due to the dramatic clinical progression.¹ Diagnosis of early stage disease can be challenging, as the clinical features are non-specific and may overlap with other conditions including rhinosinusitis.² This disease has been extensively documented in Asia and South America but is much rarer in Europe and the Western world.¹

Case presentation

Case 1

A 73-year-old Irish man presented with a 3-week history of gradually worsening external nasal swelling. On examination, a localised area of erythematous swelling was evident involving the right nasal alar region and vestibule, which was tender to touch. Routine blood tests including leucocyte count and C reactive protein were within normal ranges. He was otherwise systemically well with no other symptoms. A diagnosis of nasal vestibulitis was made and treatment with intravenous antibiotics were commenced. The nasal swelling improved significantly and he was discharged home. However, 3 weeks later, he presented again with worsening nasal swelling and erythema.

CT imaging of the area was performed, demonstrating a solid soft-tissue mass in the right nasal vestibule measuring 4×2 cm with adjacent subcutaneous inflammatory changes. There was no bony destruction or paranasal sinus involvement. A biopsy was taken from this area, and histopathology showed fibroconnective tissue extensively infiltrated by a proliferation of lymphoid cells varying in size and morphology. Immunohistochemistry was negative for cytokeratin (AE1/3), positive for CD3, CD4, CD30 and strongly positive with CD56. Epstein-Barr virus was detected by in-situ hybridization. This indicated a diagnosis of extranodal NK/T-cell lymphoma, nasal type. Subsequent investigations confirmed localised Ann Arbor stage IE disease.

Case 2

A 79-year-old Irish woman presented with a 7-month history of a painful mass on the hard palate. This mass continued to grow in size and was causing severe difficulty with eating and fitting her dentures. Associated symptoms included intermittent fevers and unintended weight loss, along with nasal congestion and epistaxis. On examination, a large fungating mass was evident over the hard palate. The tumour was noted to infiltrate superiorly into the floor of the nose.

CT and MRI scans demonstrated a significant soft-tissue neoplasm involving the entire hard palate. Biopsies were taken, showing a dense atypical mononuclear cell infiltrate with immunohistochemical testing positive for CD 3, CD 30and strongly positive for CD56, as well as positivity for Epstein-Barr virus. This was diagnostic of extranodal NK/T-cell lymphoma. Staging investigations confirmed the disease to be localised, with Ann Arbor stage IE.

Outcome and follow-up

Case 1

After multidisciplinary discussion, treatment was commenced with radiotherapy alone. Chemotherapy was omitted due to the patient’s poor functional status. He tolerated radiotherapy well and had a good clinical response, with complete resolution of the nasal symptoms. Two years later, he remains stable with no evidence of disease recurrence.

Case 2

The multidisciplinary decision was to commence gemcitabine, dexamethasone, cisplatin chemotherapy immediately, with a plan for subsequent consolidation radiotherapy. The disease responded well to the first cycle of chemotherapy. Unfortunately, the patient suffered complications including myelosuppressive toxicity and recurrent respiratory infections. She passed away from a lower respiratory tract infection 4 months after the initial diagnosis was made.

Discussion

NKTL is a rare type of Non-Hodgkin's Lymphoma, typically arising in the nasal cavity and upper aerodigestive tract. It is, therefore, classified as ‘nasal type’ lymphoma by WHO.³ It is endemic to East Asia and South America, where it accounts for 7%–10% of all NHL. By comparison, it is much rarer in North America and Europe where it comprises less than 1% of NHL.⁴ NKTL is strongly associated with Epstein-Barr virus (EBV) infection,¹ and geographical variation in EBV strains may account for this distribution.

Sinonasal NKTL typically presents in the sixth decade of life and is more prevalent in males.⁵ It can often present with non-specific nasal symptoms including obstruction, discharge and epistaxis.^{6 7} On clinical examination, intranasal features of NKTL include erosion, dry nasal crusting, touch bleeding and granulation. This may be frequently misdiagnosed as rhinosinusitis, granulomatous disease or infection, causing a delay in diagnosis.² Only 37.5% of cases have a visible mass on nasoendoscopy.² Systemic symptoms of fever, night sweats and weight loss are not usually present.

Our two cases demonstrate how the initial presenting features of NKTL may suggest other pathologies. In the first case, the patient was initially diagnosed with a nasal infection. When symptoms persisted despite treatment, a biopsy was taken which revealed an unexpected diagnosis of NKTL. The second case presented quite differently, with a large fungating mass on the hard palate which was immediately concerning for infiltrating squamous cell carcinoma. Again, biopsy and immunohistochemical analysis was necessary to yield the final diagnosis of NKTL.

Radiological features of NKTL are also non-specific. One sign which may differentiate NKTL from rhinosinusitis is the presence of thickened mucosa in the nasal cavity with absence of mucosal thickening in the paranasal sinuses.² Disease location shows a propensity for the lower region of the nose, most commonly the inferior turbinate, nasal floor and septum. Bony invasion was present in 25% of cases, and may involve paranasal sinuses, orbit and hard palate.

Diagnosis of NKTL is confirmed on histopathological analysis. This usually shows an angiocentric and angiodestructive growth pattern with necrosis, without evidence of vasculitis.⁶ Immunohistochemistry confirms the presence of specific markers of NK-cell phenotype such as CD2+ and CD56+, with intracytoplasmic expression of anti-CD3 antibody and negative expression of CD3 on the cell surface. The presence of EBV can also be detected using molecular analysis.⁶

Sinonasal NKTL is staged according to the Ann Arbor system. Most cases present with localised stage I disease.⁵ Despite this, survival outcomes remain poor, with a 5-year disease-specific survival of 31%.⁸ As NKTL is a rare disease, treatment is not yet standardised and remains guided by population-based studies. In all cases, multidisciplinary input from radiotherapy and medical oncology is essential. Radiotherapy remains the most important treatment modality, particularly in localised disease.⁹ In early stage disease, radiotherapy alone may be sufficient and can be consolidated with chemotherapy in higher-risk patients.¹⁰ Chemotherapy strategies focus on platinum or L-asparaginase-containing agents and avoid the use of anthracyclines. Modern treatment protocols are based around a combination of chemoradiation, given either concurrently or sequentially. Clinical trials to establish the optimal regimen are still in progress.⁹

Learning points.

• Sinonasal NK/T-cell lymphoma is a rare disease in the western world.

• It is most commonly diagnosed as stage I localised disease, and responds well to radiotherapy.

• Most commonly, it presents with non-specific symptoms and features, leading to diagnostic delays.

• Urgent biopsy should be considered for any persistent or aggressive nasal condition.