Extranodal NK/T cell lymphoma, nasal type, with retrobulbar extraconal phlegmon and naso-oral fistula

Abstract

Extranodal natural killer (NK-)/T cell lymphoma, nasal type (ENKL), ¹ is a rare disease that often mimics rheumatological and infectious conditions and can therefore be difficult to diagnose. The authors present a case of a 55-year-old Vietnamese woman who was misdiagnosed with severe atrophic rhinitis and chronic sinus osteitis. Over a period of 8 months from initial referral, she underwent multiple biopsies and was treated with various antimicrobial regimens until the histopathological diagnosis of ENKL was finally made. Her presentation was complicated by bacterial dacrocystitis, preseptal cellulitis and a retrobulbar extraconal phlegmon requiring surgical drainage. She also subsequently developed a naso-oral fistula on treatment. This case highlights the importance of repeated biopsies, in particular from non-necrotic regions of the sinonasal tract when a patient does not respond to therapy and clinical suspicion of neoplastic pathology remains. This is the first case of ENKL to describe significant orbital complication.

Background

Extranodal natural killer (NK-)/T cell lymphoma (ENKL)¹ is a rare condition, with a reported incidence between 2% to 10% of non-Hodgkin’s lymphoma.² It is more common in Southern Chinese and Southeast Asian populations, associated with consumption of salted fish. It is important to draw attention to ENKL, as it is difficult to diagnose and commonly mistaken for chronic rhinosinusitis or vasculitis. This can have devastating consequences for patients given the rapid progression of this disease. It is an aggressive disease with a 5 year survival of 40%–59% following treatment.³ Up to one-third of patients relapse, with most recurrences occurring within 2 years.

Case presentation

A 55-year-old Vietnamese woman was referred to the otolaryngology outpatient department with a long history of nasal crusting and chronic sinonasal disease on a background of augmentation rhinoplasty in Vietnam over 20 years ago. She was systemically well with no weight loss, fevers or night sweats. Her history was notable for degenerative lumbosacral back pain and a previous episode of lobar pneumonia, with no family history of cancer.

Her initial examination revealed a large anterior septal defect, nasal crusting and malodorous discharge. She underwent examination under anaesthesia, which demonstrated exposed bone at the left frontal process of the maxilla and posterior nasal floor. The endoscopic appearance of the nasal cavity is demonstrated in figure 1. Surgical specimens were collected and she was provisionally diagnosed with severe atrophic rhinitis. Histopathological examination revealed only extensive necrosis and inflammation. Streptococcus dysgalactiae and staphylococcus aureus were demonstrated on samples.

Figure 1.

Endoscopic appearance of nasal cavity with large septal perforation and significant crusting.

Over 6 months, she developed progressive erythema and oedema below the left medial canthus but remained systemically well. She was admitted on one occasion for periorbital cellulitis. A bone scan during that admission did not demonstrate osteomyelitis. Specimens had again demonstrated Staphylococcus, Streptococcus and mixed anaerobic flora. She was treated with intravenous cephazolin and oral cephalexin on discharge. She was subsequently commenced on long-term moxifloxacin.

She was seen frequently for nasal toileting and commenced on a rigorous regimen of nasal douches. However, there was progressive necrosis of the nasal septum, inferior turbinates and left middle turbinate, with ongoing crusting despite regular toileting.

Her nasal and periorbital symptoms progressed despite oral moxifloxacin and fortnightly outpatient reviews for nasal debridement. She had monthly biopsies with histology consisting of severe necrosis and multiple organisms isolated. One biopsy revealed a patch of atypical lymphocytes, however repeat sampling failed to demonstrate this due to extensive necrotic tissue.

On follow-up CT imaging at 7 months, there was further partial erosion of the vomer and inferomedial margin of the left orbit, as well as a suspected left retrobulbar extraconal collection along the left inferomedial orbit (figures 2 and 3). She had left-sided proptosis but no change in her visual acuity, peripheral or colour vision. She was admitted to hospital for intravenous antibiotics and taken to theatre to drain her periorbital collection via a Lynch incision. Intraoperatively her nasolacrimal sac was necrotic and her periorbita involved in a thick phlegmon with no discrete collection. Her nasal cavity was toileted and further biopsies were taken – including a large 1.5 cm portion of her relatively normal looking right inferior turbinate which finally proved to be diagnostic.

Figure 2.

Coronal CT showing bony destructive of the midline septum, with adjacent osteitic reaction.

Figure 3.

Axial CT demonstrating left inferomedial extraconal phlegmon.

Investigations

Auto-immune screening was negative for ANCA, ANA, dsDNA and serum ACE. Multiple biopsies were taken over a 10 month period which yielded only necrotic tissue and inflammatory infiltrate, with inconsistent and varied culture results. (Her pertinent radiological and histopathological features are presented by time course in online supplementary table 1.)

During her most recent admission, a positron emission topography (PET)/CT scan demonstrated the aggressive inflammatory process eroding the nasal cavity and left inferomedial orbit. There was no other avid disease except for inflammatory changes in the lung fields. Her erythrocyte sedimentation rate (ESR) was elevated at 33 mm/hour (range, 0–19).

The histopathology of the right inferior turbinate revealed a focal section of lymphoid atypia. Immunohistochemistry revealed a T cell infiltrate (CD2 and CD3 positive) with a population of CD56 positive cells (figures 4 and 5). Staining for granzyme B (figure 6) and TIA-1 was positive. EBV - encoded RNA (EBER) in-situ hybridisation was positive (figure 7), consistent with an Epstein-Barr virus (EBV) associated NK/T cell lymphoma. There was significant angiocentric necrosis and inflammation on the biopsies (figure 8).

Figure 4.

Angiocentric cell population expressing CD2 T cell marker.

Figure 5.

Atypical lymphocytes expressing CD56.

Figure 6.

Atypical lymphocytes with cytotoxic granules, granzyme positive.

Figure 7.

Atypical lymphocytes, angiocentric destruction, EBERish, EBV positive.

Figure 8.

Biopsy showing angiocentric necrosis and inflammation.

Differential diagnosis

Initial differential diagnoses included severe atrophic rhinitis, an anti-nuclear cytoplasmic antibodies (ANCA) positive vasculitis (such as granulomatosis with polyangiitis), or atypical infection. Chronic or invasive fungal rhinosinusitis was also considered as a differential, although less likely. Clinically the patient had a longstanding history of chronic nasal crusting with inflammation likely to be present some time longer prior to initial consultation. Aspergillus was only identified scantly on one sample and thus there was a low clinical suspicion for fungal invasive infection. The identification of fungus was more thought to be a commensal. Overwhelming, most of the swabs and biopsies had demonstrated streptococcus and staphylococcus – so concern was raised regarding osteomyelitis. For this reason, a bone scan was performed but was negative.

Treatment

Following diagnosis, she was discussed at a lymphoma multi-disciplinary meeting. Given her delay in initiating radiotherapy, she was commenced on her first cycle of modified SMILE chemotherapy (dexamethasone, methotrexate, ifosfamide, pegylated-L-asparaginase and etoposide). Following the first cycle there was significant improvement in left periorbital oedema, and resolution of malodorous discharge. She remained on antifungal prophylaxis during treatment.

Outcome and follow-up

Following initiation of chemotherapy, she developed a naso-palatal fistula with nasal escape and regurgitation when drinking thin fluids. She was managed conservatively with diet modification, but a palatal obturator remains an option. She is still undergoing concurrent chemoradiotherapy from cycle 2 onwards with RT-DeVIC regimen (50 Gy in 25 fractions, dexamethasone, etoposide, ifosfamide and carboplatin). Following completion of her treatment, she could be considered for reconstructive surgery.

Discussion

ENKL is a distinct diagnosis of non-Hodgkin’s lymphoma, mostly derived by natural killer cell or cytotoxic T cell lineage. There is a consistent association with EBV infection. The angiocentric cellular infiltrate on histological examination can mimic the vasculitic picture of granulomatosis with polyangiitis. The infiltrate consists of atypical lymphoid cells, inflammatory cells, and eosinophils. Clinically, ENKL can rarely present with disseminated disease with metastatic infiltration to the liver, spleen, lymph nodes and bone marrow. It is characteristically locally invasive with progressive destruction of midline facial structures.⁴

Several cases of ENKL, nasal type, have been described in the literature. All cases were difficult to diagnose and often mimicked chronic rhinosinusitis. Many were described with rapid disease progression and death.^{5 6} Two cases were associated with dacrocystitis or orbital cellulitis,^{7 8} but no previous cases have described orbital complications to the extent of the formation of an extraconal subperiosteal phlegmon. NK/T cell lymphoma is known to cause palatal perforation⁹ and naso-oral fistulae in some cases.¹⁰ In one case, ENKL was diagnosed after the patient failed to respond to antifungal treatment, prompting repeated debridement and biopsies.¹¹

Chemotherapy and radiotherapy are the main treatment options, with early-stage localised nasal disease highly curable with combination therapy.¹² However, the optimal dose and regimen is undefined. Patients with extra-nasal and disseminated disease have a much poorer prognosis. In one large case series of 115 of patients with ENKL, nasal type, approximately 45% of patients achieved complete remission after treatment, but more than half died (56%) from local recurrence or metastases by the end of the follow-up period.¹³ RT-DeVIC therapy which is now recognised as standard treatment for localised NK/T cell lymphoma has been shown to be effective, with excellent local control.¹⁴

Learning points.

• Multiple biopsies may be necessary to diagnose Extranodal natural killer (NK-)/T  cell lymphoma (ENKL).

• Non-necrotic tissue needs to be biopsied especially when previous biopsies have not demonstrated viable tissue. In this case, the diagnosis was made from a biopsy from a normal-appearing inferior turbinate from the contralateral side.

• A neoplastic cause must be considered in cases of suspected invasive fungal or atypical bacterial disease not responsive to targeted antimicrobial therapy.

• Radiology can be largely unhelpful in making a diagnosis of ENKL, as a large mass is rarely found, unlike other forms of lymphoma. Imaging remains important in the investigation of differential diagnoses and for subsequent staging.