Extranodal NK/T Cell Lymphoma, Nasal Type with Palatal Involvement: A Rare Case Report and Literature Review

Abstract

T-cell lymphomas are infrequently encountered in the head and neck area, with the most common subtype being Extranodal NK/T cell lymphoma, nasal type (ENKTL-NT). ENKTL-NT shows a predilection for midline facial structures presenting with ulcerative destructive lesions, whereas palatal involvement is one of the most prominent signs from the oral cavity. Herein, we describe a case of a 76-year-old Greek man with nasal obstruction and an extensive painful necrotic ulcer with ragged borders on the left distal portion of the soft palate and palatine tonsil of 4-months duration. After an initial non-diagnostic biopsy from the nasopharynx, a second incisional biopsy from the palatal lesions was performed. Histopathology was suggestive of an angiocentric lymphoproliferative neoplasm and immunohistochemical examination and in situ hybridization for EBV RNA led to a final diagnosis of ENKTL-NT. The patient was placed under combined chemotherapy and radiotherapy and no recurrence has been noted. Additionally, a retrospective review of the cases in the English literature with an established diagnosis of ENTKL-NT between 2000 and 2019, based on the latest WHO classification of Head and Neck tumors, is performed.

Introduction

Εxtranodal non-Hodgkin lymphomas of the head and neck area represent 3–5% of all malignancies in this region and are predominantly of the B cell lineage. T-cell lymphomas are not frequently encountered in this area, with the most common being the Extranodal NK/T-cell lymphoma, nasal type (ENKTL-ΝΤ) [1].

ENKTL-ΝΤ, is a rare, aggressive, Epstein–Barr virus (EBV)-associated non-Hodgkin lymphoma with poorly understood pathogenesis and unfavorable prognosis [1, 2].

The term “nasal type” suggests a lymphoma which occurs predominantly in the nasal cavity and the upper aerodigestive tract, hence affecting midline facial structures [2, 3]. As the disease spreads, non-specific lesions may appear in the oral cavity prompting high suspicion for its diagnosis to oral health practitioners.

The aim of our study is to present a rare case of ENKTL-ΝΤ in the Greek population, affecting a 76-year old Caucasian male and discuss the clinical, histological features and management of this disease entity.

Case Report

A 76-year-old male presented for evaluation of painful palatal lesions of 4-months duration, causing dysphagia. He also reported a progressive onset of nasal obstruction, hoarseness, decreased appetite and weight loss during the same period.

His medical history was remarkable for insulin-dependent diabetes mellitus treated with injectable insulin-aspart, liraglutide and metformin per os, hypertension managed with triple oral therapy including amlodipine, irbesartan and hydrochlorothiazide, hypercholesterolemia under simvastatin, anemia managed with ferrous gluconate and duodenal ulcer under control.

Two months after the emergence of symptoms, he visited an ENT specialist who performed nasal endoscopy which demonstrated a friable, hemorrhagic mass in the nasopharynx. An incisional biopsy revealed non-specific histological findings, consisting of granulation tissue and necrotic debris.

Clinically, an extensive necrotic ulcer with ragged borders, covered by a thick gray-yellowish pseudomembrane on the left distal portion of the soft palate and palatine tonsil crossing the midline and extending to the uvula and the oropharynx was observed, accompanied by intense malodour (Fig. 1). Neither cervical lymphadenopathy nor enlargement of the major salivary glands were present.

Fig. 1.

Deep necrotic ulcer with ragged borders covered by a thick pseudomembrane and surrounded by erythema affecting the soft palate

Based on the patient’s medical history and the clinical findings, a provisional clinical diagnosis of rhinocerebral mucormycosis was rendered and the patient was referred to a hospital-based care for further evaluation.

Laboratory and serological investigations and pus sample cultures were carried out. High blood glucose levels [157 mg/dL (70–110 mg/dL)], anemia [RBC = 3. 79 M/μL (4. 5–6. 3 M/μL)], lymphopenia [LYM% = 15% (25–45%)] and mild neutrophilia [NEU% = 73,5% (40–70%)] were noted, whereas bacterial and fungal cultures were negative.

Computed Tomography (CT) scan of visceral skull showed occupation of the maxillary, ethmoidal, sphenoidal and frontal sinuses by a hyperdense soft tissue mass.

Additionally, an incisional biopsy of the palatal lesions was performed under local anesthesia. Histopathological examination revealed a diffuse infiltrate of large or/and medium-sized lymphoid cells with atypical nuclei demonstrating perivascular distribution and infiltrating vessel walls as well as the adjacent minor salivary glands (Fig. 2a).Further immunohistochemical analysis showed that the atypical lymphoid cells expressed the NK-cell marker CD56, cytotoxic enzymes Granzyme-B and Perforin, T-cell markers CD3, CD8, whereas CD20, CD5, CD2 and CD30 markers were negative (Fig. 2b, 2c). Proliferation rate was high with ki-67 > 60%, and proto-oncogene C-myc expression > 80%. In situ hybridization disclosed abundant and diffuse positive Epstein-Barr virus–encoded RNA (EBER) staining (Fig. 2d). The histological and immunohistochemical findings were consistent with the diagnosis of ENKTL-ΝΤ.

Fig. 2.

a Diffuse infiltration consisting of clusters and sheets of large and/or medium-sized lymphoid cells extending to the adjacent mucous glands (hematoxylin and eosin, × 100 magnification) b Abundant immunohistochemical positivity for CD56 and c Abundant immunohistochemical positivity for CD3 d In situ hybridization. Diffuse positive Epstein-Barr virus–encoded RNA (EBER) staining

Fluorodeoxyglucose (FDG)-positron emission tomography (PET) was performed to investigate disease extent and indicated hypermetabolic areas of active malignant disease in the soft palate expanding into the oropharynx, uvula and the left palatine tonsil (Fig. 3a, b). Final diagnosis of ENKTL-ΝΤ, locally extensive (Stage I/II), was rendered.

Fig. 3.

FDG-PET scan. Hypermetabolic areas in a the soft palate extending to the posterior boarder of the oropharynx and uvula and b left palatine tonsil

The patient was initially placed under chemotherapeutic regimen DeViC (dexamethasone, etoposide, ifosfamide, carboplatin-3 cycles/25 days) combined with radiotherapy (RT) (total dose 50 grays). Due to adverse effects, chemotherapy was discontinued.

Five months post-treatment, complete resolution of the intraoral lesion was observed, whereas CT and PET scans were indicative of stable disease (Fig. 4).

Fig. 4.

Complete remission of the oral lesions 5 months post-treatment

Discussion

ENKTL-ΝΤ, historically referred to as “midline lethal granuloma” is a rare non-Hodgkin lymphoma, characterized by a strong association with EBV and represents almost 10% of all non-Hodgkin lymphomas [3–5].

Regarding epidemiology, most patients with ENKTL-ΝΤ are diagnosed in the 4^th or 5^th decade with several authors reporting a male preponderance (M:F 2:1). There is a racial predilection with typical distribution of the disease in Asian, Central and South American populations, whereas it is rare (less than 1%) in North America and Europe [5–7].

The upper aerodigestive tract is commonly affected, with more than 80% of the cases being classified as ENKTL-ΝΤ. In a subset of patients, the neoplasm develops in other sites, skin, gastrointestinal tract, testis, or lungs, (20–30% of cases) displaying identical morphologic and immunophenotypical features, hence termed extra-nasal type ENKTL [2, 6, 8].

The pathogenesis of ENKTL remains unclear, however lifestyle and environmental factors have been implicated [3]. Epigenetic modifications of several tumor suppressive or oncogenic pathways have been associated with this type of lymphoma (TP53,FAS, DDXD3, BCOR) [8–10]. Numerous studies have highlighted the role of EBV latent infection in the development of ENKTL [5, 11]. Unlike other EBV-associated lymphoproliferative disorders, systemic immunosuppression is not always present in patients affected by ENKTL, thus alternative theories on the mechanism by which EBV-infected cells escape immunosurveillance and promote lymphomagenesis need to be explored [11].

ENKTL-ΝΤ leads to destruction of the midline facial structures and manifests with necrotizing lesions which may extend locoregionally to the paranasal sinuses, orbits, and lymph nodes. Non- specific symptoms such as nasal obstruction, headache may last for months to years preceding more common and pronounced manifestations [2, 6, 12]. As disease progresses, the oral cavity may be affected usually with necrotic ulceration of the hard and/or soft palate with or without fistulae formation [13].

Review of the English literature from 1/1/2000 until 31/12/2019 on ENKTL-ΝΤ cases with palatal involvement was conducted. Only cases which fulfilled the WHO classification 2017 diagnostic criteria for ENKTL-ΝΤ [3] regarding appropriate immunohistochemical evaluation and EBV detection in neoplastic tissue were included. Epidemiological studies reporting the percentage of palatal involvement combined with other oral sites were excluded.

The literature review yielded a total of 21 studies reporting 69 cases of ENKTL-ΝΤ with hard and/or soft palate involvement (Table 1) [5, 6, 14–32]. As expected, 54,5% of the publications originated from Asian countries [5, 6, 14–16, 18, 19, 23, 24, 26, 28, 32] and 33 cases provided adequate data for clinicopathological analysis [5, 14, 15, 17–22, 24–32].The mean age at diagnosis was 43.5 ± 15.9 years and male (20 cases) to female (13 cases) ratio was 1.5:1. The prominent clinical sign was palatal ulceration and/or perforation. Regardless of the therapeutic management, 61% of the patients died (19/33 cases reported an average follow up period of 16 months, range: 15 days to 5 years) reflecting the advanced stage of the disease. Other oral manifestations in isolated cases included gingival and tongue ulcerations, loosening and exfoliation of teeth, infiltration of masticatory muscles leading to trismus, oral malodour, odynophagia and sore throat [7, 17, 33, 34].

Table 1.

Case reports and case series of ENKTL, nasal type with palatal involvement (1/1/2000 to 31/12/2019)

Authors	Year	Country	No of cases	Age	Gender	Palatal involvement	Follow up (time period)
Tsang et al. [14]	2000	China	1	37	M	Soft palate ulceration	Recurrence
			1	28	M	Hard palate ulceration	Died (9 weeks)
Ikeda et al. [15]	2005	Japan	1	62	M	Hard palate (manifestation NR)	Died
Kim et al. [16]	2005	Korea	1	54	M	Hard palate perforation	Died (15 months)
			1	67	F	Hard palate perforation	Died (9 months)
			1	69	M	Hard palate perforation	Died (2 months)
			1	42	M	Hard palate perforation	Died (5 months)
			1	61	M	Hard palate perforation	Died (18 months)
			1	38	F	Hard palate perforation	Died (14 months)
			1	24	M	Hard palate perforation	Died (20 months)
			1	52	F	Hard palate perforation	Died (11 months)
			1	45	M	Hard palate perforation	Died (11 months)
Reinartz et al. [17]	2007	Netherlands	1	28	M	Soft palate,tonsil ulceration	Died (1 month)
Wu et al. [6]	2008	China	13	NR	NR	Hard and soft palate ulcers	NR
Jaguar et al. [18]	2009	Japan	1	50	F	Left hard palate ulceration	Died (2 months)
Meng et al. [19]	2010	China	1	63	F	Hard palate ulceration	NR
MacDonald et al. [20]	2011	Canada	1	61	F	Soft palate ulceration	No recurrence (25 months)
Bhatt et al. [21]	2011	Guatemala	1	21	M	Hard palate ulceration	Lost to follow-up
Nikitakis et al. [22]	2012	Greece	1	40	M	Hard palate ulceration	No recurrence (5 years)
Bi et al. [23]	2013	China	12	NR	NR	Soft palate (manifestation NR)	NR
Lee et al. [24]	2015	Korea	1	39	F	Hard palate ulcerations	Died
Lanzel et al. [25]	2016	USA	1	59	M	Hard palate ulcerated swelling	NR
Arora et al. [26]	2016	India	1	31	F	Palatal ulceration	NR
			1	39	M	Palatal ulceration	Complete remission
			1	41	F	Palatal ulceration	Died
			1	55	F	Palatal ulceration	Complete remission
Harabuchi et al. [5]	2016	Japan	11	NR	NR	Hard palate (manifestation NR)	NR
Celentano et al. [27]	2017	Italy	1	37	M	Hard palate ulcerations	No recurrence (3 years)
Deng et al. [28]	2017	China	1	43	M	Hard, soft palate swelling and ulceration	No recurrence (2 years)
Taali et al. [29]	2017	Morocco	1	22	F	Extensive facial necrosis involving the palate	Died
O'Sullivan et al. [30]	2018	Ireland	1	73	F	Soft palate ulceration and sloughing	Died
Missaoui et al. [31]	2019	Tunisia	1	54	M	Palatal involvement (manifestation NR)	Died (2 months)
Kaur et al. [32]	2019	India	1	20	M	Palatal ulceration	No recurrence (52 months)
			1	15	M	Palatal ulceration	Died
			1	22	M	Ulcerated swelling on the palate	Died (15 days)
			1	42	F	Mass on the palate	On treatment
Present case	2020	Greece	1	76	M	Soft palate ulceration	No recurrence (5 months)

M male, F female, NR not reported

The differential diagnosis of palatal ulcerations with or without oropharyngeal, nasal or sinonasal involvement and upper aerodigestive tract symptoms, encompasses a wide variety of disease entities, which range from rapidly involving neoplastic processes which include oropharyngeal and sinonasal carcinomas, immune-related vasculities such as granulomatosis with polyangiitis and infectious diseases, more prominently deep fungal infections [4, 22]. The abovementioned entities share similar clinical manifestations which along with the medical history and/or the imaging findings may cause confusion and lead to misdiagnosis, as in the case of our patient. The clinical signs and symptoms and the positive history of insulin-dependent diabetes initially led to an incorrect provisional diagnosis of mucormycosis.

Thus, a multidisciplinary diagnostic approach is warranted in such cases including laboratory and serological investigations, bacterial swabs and several specialized imaging techniques.

Another issue regarding the diagnostic approach of these lesions, especially when the nasal cavity is involved, is the difficulty of access, in order to obtain adequate representative specimens for histopathologic examination. Moreover, histopathology is often hampered due to extensive necrotic tissue which eventually leads to repeated biopsies of lesional and perilesional tissues in order to establish a correct final diagnosis in a large number of patients [5, 6]. Therefore, accessible intra-oral lesions are potentially more likely to aid early diagnosis [2, 22].In the case presented herein, the final diagnosis of ENKTL-ΝΤ was rendered based on the biopsy of the palatal lesion.

Considering that early clinical signs and symptoms are non-specific, histological and immunohistochemical evaluation of the lesion is crucial in order to establish diagnosis. Atypical variably-sized lymphoid cells with irregular-shaped nuclei and granular chromatin, geographic necrosis and angiocentric pattern of invasion along with an admixture of other types of inflammatory cells are consistently observed in hematoxylin and eosin slides [5, 8]. Immunohistochemistry is the cornerstone for definitive diagnosis of ENKTL-NT. Demonstration of EBV infection via ISH, as detected in our case, is a prerequisite for the diagnosis of this type of lymphoma and lack of EBV detection should raise doubts about accurate diagnosis [7].However, positivity for additional immunophenotypical markers is required for the establishment of definite diagnosis. Lymphoma cells express the typical immunophenotype of cytoplasmic CD3 + , CD56 + , surface CD3–, CD2 + , and cytotoxic molecules (perforin, granzyme B, T-cell intracellular antigen 1) [8].

The prognosis of ENKTL-ΝΤ is dependent on the staging of the disease, lymph node involvement and patient’s age [35]. A variety of treatment modalities has been used as there is no consensus regarding the optimal treatment due to the rarity of the tumor and the absence of large randomized controlled trials [10]. Treatment options include radiotherapy, chemotherapy, or combination. ENKTL-ΝΤ is highly radiosensitive and radiotherapy is usually used as the first line of treatment, although if applied as monotherapy is accompanied by high relapse rate [35]. Various multi-agent regimens have been used, with those containing L-asparaginase being most effective. Combined chemotherapy and radiotherapy is the best approach when can be tolerated by the patient. Other treatment options include immunotherapy and autologous or allogeneic haematopoietic stem cell transplantation [5, 36, 37]. The role of surgery is limited to biopsy implement and tissue rehabilitation [33].

Conclusion

ENKTL-ΝΤ is a rare lymphoma which can first manifest in the oral cavity. Chronic palatal necrotic ulcerations in patients with non-specific symptoms from the nasal cavity should raise suspicion for ENKTL-ΝΤ. A multidisciplinary team approach including a general dental practitioner, an oral medicine practitioner, a hematopathologist and hematologist-oncologist is necessary for early diagnosis, prompt therapeutic intervention and improved prognosis.

Funding

The authors have no funding, financial relationships.

Compliance with Ethical Standards

Conflict of interest

No conflict of interest to disclose.

Ethical Approval

All authors have read and approved the manuscript. This manuscript is original, is not under consideration elsewhere, has not been published previously in any form and its content has not been anticipated by any previous publication.