The relevance of extra-nodal natural killer/T-cell lymphoma to the oral health care providers- A clinical review with case report

Abstract

Lymphomas are the second most common malignancy in the oral cavity after squamous cell carcinoma. Non-specific clinical presentation of lymphoma mimics the other common oral pathologies thereby; delaying its diagnosis, ensuing definitive treatment, and leading to a guarded prognosis. The present clinical review and accompanying case report highlights the clinical presentation, diagnostic challenges, progression, manifestations, and holistic management of a rare extra-nodal, nasal variant of Natural Killer T-cell lymphoma and underscores the importance of interdisciplinary coordination in the overall management of this aggressive tumor.

1. Introduction

Lymphomas are a heterogeneous cluster of hematopoietic malignancies originating from somatic mutations in lymphocyte progenitors namely the B-cells, T-cells, and Natural killer (NK) cells.¹ Lymphomas are classified mainly in two variants: Hodgkin and Non-Hodgkin Lymphomas (NHL).^2,3 While Hodgkin lymphomas are categorically characterized by the presence of Reed-Sternberg cells and have a predominantly nodal predisposition, nearly half of the NHL are found in the extra-nodal sites, thereby resulting in the widespread dissemination of the malignant cells.4, 5, 6 Amongst the extra-nodal sites for NHL, the gastrointestinal tract remains the most common site followed by the head and neck region constituting 11–33% of the cases.⁷ The extra-nodal lymphomas of the head and neck region are more frequently located in the salivary glands, followed by maxillary and mandibular occurrence in approximately 40% of cases. Other sites involved are the paranasal sinus, the Waldeyer ring, and the orbit.⁸ Histologically, the B-cell lineage originated lymphomas account for nearly 80% of the NHL, whereas the rest include the T-cell and NK cell variants.⁹

Clinically, a lymphoma may present with lymphadenopathy, mid-facial swelling, unhealed oral ulceration, and facial paraesthesia.¹⁰ Oral lesions show aggressive growth patterns including the presence of soft tissue enlargements, tooth mobility, necrosis, and bone destruction.¹¹ Radiographically, lesions with diffuse boundaries and associated bone resorption are suggestive of lymphomas. Due to their clinical features resembling other commonly occurring pathologies such as; osteomyelitis and mucormycosis, lymphomas are late to be diagnosed and are associated with a poor prognosis.

A rare and aggressive form of mature T and NK NHL neoplasm is the extra-nodal NK/T cell lymphoma (ENKTL) as classified by 2016 WHO classification of mature lymphoid, histiocytic and dendritic neoplasms.¹² In addition to the rarity of the ENKTL, its biopsy specimens are typically small and necrotic and the availability of unfixed tissue for molecular genetic studies is limited, thereby resulting in delayed diagnosis and overall poor prognosis of the illness. The ENKTL is strongly associated with CD3, CD56, cytotoxic markers, elevated levels of serum lactate dehydrogenase, and Epstein Barr Virus (EBV).¹³

The tumor may have a genetic predisposition as evident by the higher propensity of cases amongst young males in South Asian countries. Pathologically, nasal type and aggressive NK-cell leukemia are the two types of ENKTL. Despite the two variants having a similar histological picture, they differ in their anatomical localization. The nasal form is predominantly located close to the nasal and upper aero-digestive tract, is locally invasive, often showing midline anatomical predilection, and palatal perforation.¹⁴ Symptomatically, patients present with prolonged ulceration, nasal stuffiness, and purulent discharge. The aggressive type shows a disseminated presentation, though rarely showing infiltration in the liver, spleen, and bone marrow.¹³

Currently, the treatment modalities for stage I/II NK/T-cell lymphoma (Ann-Arbor staging) include radiotherapy (RT), chemotherapy (CT), or their combination.¹⁵ However, for the stage III/IV ENKTL, CT remains the main treatment option. The overall survival rate of the nasal variant has been less than 50% when the conventional anthracycline-based chemotherapy was adopted, due to the increased levels of P-glycoprotein expressions.¹⁶ The l-asparaginase-based regimens proved useful for ENKTL.¹⁷ For advanced cases, special regimes such as SMILE protocol (Dexamethasone, Methotrexate, Ifosfamide, l-asparaginase, Etoposide) and DeVic protocol (Dexamethasone, Etoposide, Ifosfamide, and Carboplatin) have been designed for the tumor control, concurrent with radiotherapy.¹⁷ Such treatment regimens are often associated with side effects such as febrile neutropenia, altered gastrointestinal symptoms resulting in compromised nutrition and overall health of the patient. Value-based treatment goals focuses on improving the quality of life of patients in addition to improving the prognosis of a disease, therefore, it is important that the nutritional support of the patient is not compromised and is maintained perpetually.

This clinical report describes one such patient affected with a rare nasal variant ENKTL where prosthodontic intervention was sought to improve his quality of life.

2. Case report

An 18-year-old male patient was referred from the department of internal medicine with the request to address his chief complaint of nasal regurgitation of liquids and mobility in teeth. The patient was undergoing treatment for ENKTL. Intra-oral examination showed the absence of left lateral incisor, necrotic alveolus, and loss of palatal soft tissue exposing the anterior palate and extending from left to right side crossing the midline (Fig. 1).

Fig. 1.

Intraoral clinical picture at first oral consultation. Loss of lateral incisor, necrotic alveolus, and loss of palatal soft tissue can be appreciated.

On inquiry, the patient revealed that he was healthy a year back when he developed symptoms of left nasal obstruction with purulent discharge, associated with pain and swelling in the left facial aspect, and perceptible mobility in his upper front teeth. No immediate medical consultation was made at that time due to ignorance and non-significant initial symptoms. However, two months later he met with an accidental trauma to the nose (an elbow blow to the nose), that increased in the severity of nasal blockage and swelling. It is then he took medical consultation when it started affecting his appearance (Fig. 2). A pus culture at a local hospital came suggestive of coccobacilli infection (Staphylococcal and Klebsiella species), for which treatment with intravenous antibiotic, Tab Sulphamethoxazole-Trimethoprim combination (twice daily for 7 days), and Methylprednisolone (8 ​mg once daily for 7 days) was given. However, upon non-responsiveness to the prescribed regimen, patient reported at a tertiary care center where endoscopic debridement was performed under general anesthesia. The histopathologic examination of the biopsy specimen obtained from the endoscopic debridement confirmed the diagnosis of NK/T cell lymphoma (nasal type). A bone marrow trephine biopsy was also performed to rule out any metastatic infiltration. As the symptoms and signs were located primarily in the upper aero-digestive tract, it was staged as a stage 1 ​E tumor according to the Ann-Arbor classification. Keeping in mind the stage and prognosis of the lymphoma, it was decided to subject the patient to CT and RT. Owing to the aggressive nature of the tumor, the patient was put on a salvage five-cycle chemotherapeutic DeVic protocol concurrent with RT. The RT was given in two phases: phase 1 of 40 ​Gy in 20 fractions and phase 2 of 10 ​Gy in 5 fractions.

Fig. 2.

Extra-oral picture showing nasal swelling on the left facial aspect.

At the first oral consultation, the patient presented with the loss of the left lateral incisor along with slight mobility in both the central incisors and nasal regurgitation of fluids. Due to the imposed restrictions related to ongoing COVID-19 pandemic during the treatment time, the patient re-visited for oral consultation after one month. There was a subsequent loss of left central incisor and an increase in the loss of palatal soft tissue with an associated increase in nasal regurgitation of fluids. An oro-nasal communication was observed with respect to the anterior labial sulcus and palatal region (Fig. 3A–C). No regenerative treatment option was available for this patient owing to the nature of the disease and extensive loss of soft and hard tissue. For a better prosthodontic treatment outcome, the patient was prepared for the surgical excision of the necrotic bone and the involved tissue. An impression in irreversible hydrocolloid was made at this appointment to fabricate a surgical obturator. Both maxillary first molars were endodontically managed.

Fig. 3.

(A–C). Intra-oral presentation at second oral consultation. (A) Loss of left central and lateral incisor, necrotic alveolus. Arrow shows connectivity of the oral and nasal cavity from the vestibule. (B) Extensive loss of palatal soft tissue, perforated palatal bone leading to nasal regurgitation. (C) A computed tomographic scan image showing oro-nasal communication due to necrosis of the palatal bone.

The histopathological examination of the resected specimen suggested osteonecrosis of the palate with no fungal or metastatic elements. Post-resection, a satisfactory fit of the surgical obturator was confirmed by nasal endoscopy. Video calls and telephonic consultations were used for subsequent follow-up and evaluation.

Consequent to satisfactory healing at the surgical site, an interim obturator was fabricated (Fig. 4). The patient's esthetic concern concerning un-supported left nostril and restricted breathing was addressed by fabricating a custom, hollow nasal-stent in clear, heat-cure polymerizing resin (Fig. 5A–B). The purpose of the nasal stent was to lift and push the ala of the left nostril laterally, thereby facilitating a better airflow and esthetics. 6 months follow up of the patient showed satisfactory function and esthetics (Fig. 6).

Fig. 4.

Well healed site post-surgery.

Fig. 5.

(A–B). Breathing difficulty and esthetic deficiency post-treatment. (A) Depressed columella post-treatment leading to difficulty in breathing and esthetic deficiency. (B) Improvement in nasal contours and breathing due to insertion of a custom-made nasal stent.

Fig. 6.

6 month follow-up with interim obturator and nasal stent for improved function and esthetics.

3. Discussion

Lymphomas account for the second most frequently reported malignancy in the head and neck region after squamous cell carcinoma.¹⁸ The NK/T-cell lymphoma is one of the uncommon variants of NHL, invariably associated with EBV.^13,19 The initial clinical picture of this disease is often misleading, resulting in the use of multiple antibiotic regimens to treat its commonly associated sign of nasal obstruction and stuffiness, as reported in the patient as well. Moreover, the excessive crusting of the tissues results in impaired biopsy samples for histological evaluation, thereby warranting the need for multiple biopsies.²⁰ This often results in delayed diagnosis, advancement in the stage till the time of histopathological confirmation, secondary infections, and guarded prognosis.²⁰ The life expectancy of this tumor variant has been around 2–3 years.²¹

The aggressive nature of the disease may be explained by its microscopic and clinical manifestations. Histologically, the tumor is characterized by the presence of angiodestruction and angiocentricity with perivascular foci of infiltration of densely populated lymphoid cells that culminates in fibrinoid necrosis of the blood vessels. Clinically, signs and symptoms are an extension of the microscopic findings.²² The presence of necrotic tissue along with the rapidly progressive spread of the cells is a result of ischemic injury occurring in the tissues and organs. The ambiguous terminology of ‘lethal midline granuloma’ was initially used for this tumor due to its propensity to cause the characteristic midline palatal perforation.²³

Oral healthcare providers may also be responsible to see the presentation of the disease primarily as non-purulent swelling, soft tissue ulceration, and/or mobility in teeth. Therefore, it is of paramount importance to have adequate knowledge of the disease and its differential diagnosis. Prompt diagnosis and timely referrals for definitive treatment are important considerations in the overall prognosis of the pathology.

Even though the CT and RT were administered after a considerable delay due to the travel restrictions during the Covid-19 pandemic, a satisfactory consolidation of the disease was achieved. Currently, the patient is in remission and is maintained on a close and regular follow-up.

The present case report describes the disease right from its initial presentation, diagnosis, progression, and comprehensive management. Multidisciplinary coordination between haemato-oncologist, histopathologist, otolaryngologist, and prosthodontist made it possible to achieve a desirable outcome.

4. Conclusion

This clinical review with an accompanying case report attempts to sensitize oral health care providers to explore beyond the frequently documented etiologies of tooth mobility, tooth loss, and loss of gingival tissues. Early identification, prompt definitive treatment, and multidisciplinary coordination are the mainstay in achieving desirable outcome in a disease with such ambiguous clinical presentations.

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Declaration of competing interest

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