Extranodal NK/T-cell lymphoma, nasal type, presenting as a necrotic palatal ulcer

ABSTRACT

Extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, is an aggressive Epstein–Barr virus (EBV)-associated lymphoma that predominantly involves the nasal cavity and upper aerodigestive tract. Primary oral manifestations are rare and may clinically mimic benign inflammatory or infectious conditions, resulting in delayed diagnosis. This report presents a rare case of ENKTL initially manifesting as a rapidly progressive necrotizing palatal ulcer. A 44-year-old man presented with a three-week history of a necrotic ulcer on the posterior hard palate. Imaging revealed extensive midfacial destruction, including palatal perforation, nasal septal erosion, turbinate destruction, ethmoidal involvement, and medial orbital wall extension. Histopathologic examination demonstrated atypical large lymphoid cells with extensive necrosis and infiltration into adipose and muscle tissue. Immunohistochemical staining demonstrated diffuse expression of LCA and CD3, focal expression of CD30, absence of CD20, ALK, and CD56 expression, and a high proliferative activity, as evidenced by a Ki-67 index of approximately 90%. Based on the histomorphologic and immunophenotypic features, extranodal NK/T-cell lymphoma was suspected. Chromogenic in situ hybridization (CISH) for Epstein–Barr virus-encoded RNA (EBER) demonstrated strong nuclear positivity in atypical lymphoid cells, confirming the diagnosis of ENKTL, nasal type. The patient achieved complete remission after chemotherapy; however, eight months later, the patient developed a systemic relapse that was diagnosed as peripheral T-cell lymphoma. This case highlights the diagnostic complexity of ENKTL presenting as a destructive palatal lesion. Comprehensive histopathologic evaluation, detailed immunophenotyping, and EBV confirmation by EBER are essential for accurate diagnosis and timely oncologic management. ENKTL should be considered in the differential diagnosis of rapidly progressive oral necrotic lesions unresponsive to conventional therapy.

INTRODUCTION

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), is a rare, aggressive malignancy characterized by the cytotoxic proliferation of NK or T-cells, consistently associated with Epstein–Barr virus (EBV) infection [1]. According to the 2022 WHO classification of hematolymphoid tumors and the International Consensus Classification (ICC), this entity is defined by its distinct immunophenotype and tendency for vascular destruction [2,3].

ENKTL most commonly affects the nasal cavity and upper aerodigestive tract; however, primary involvement of the oral cavity, especially the palate, is exceptionally uncommon [4,5]. In these instances, the disease often manifests as rapidly progressive, necrotic ulcers [6]. They may mimic conditions such as severe periodontal disease, osteomyelitis, other malignancies, or reactive lesions [7]. The presence of extensive tissue necrosis may resemble an infectious process, potentially masking the lesion's malignant nature [8].

Consequently, clinicians often misdiagnose these lesions as benign oral conditions, leading to critical delays in oncologic intervention [9].

This case report details an aggressive ENKTL presenting as a necrotizing palatal ulcer, highlighting the diagnostic complexity inherent in its clinical and histopathological features, as well as the essential role of early immunophenotyping and EBV confirmation in clinical management.

CASE PRESENTATION

A 44-year-old Iranian man with no significant past medical history presented to the Department of Oral and Maxillofacial Medicine, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran, in 2024 with a 3-week history of a non-healing ulcer on the palate. The patient denied systemic complaints, including fever, weight loss, and night sweats, and reported nasal obstruction as the only associated symptom. Initial laboratory investigations, including routine hematologic tests, were unremarkable.

An intraoral examination revealed a necrotic ulcer approximately 1 × 1 cm in size located in the posterior midline of the hard palate. Peripheral pigmentation was observed along the margin of the lesion (Figure 1).

Fig. 1.

The image of the necrotic ulcer located in the hard palate, at admission.

Cone-beam computed tomography (CBCT) revealed a well-defined destructive lesion measuring approximately 40 × 36 × 20 mm, associated with perforation of the hard palate and contiguous extension into the nasal cavity. Marked destructive involvement of the nasal septum with a characteristic “moth-eaten” appearance was observed, along with involvement of the middle and inferior turbinates. Additional radiologic findings included opacification of the maxillary sinus, infiltration of the left ethmoidal air cells, and extension toward the medial orbital wall. Involvement of the anterior nasal spine (ANS) was also noted; however, no evidence of extension into the alveolar bone was identified (Figure 2).

Fig. 2.

CBCT of the maxillofacial region. Coronal (left) and axial (right) views reveal a destructive lesion centered in the hard palate and nasal cavity with erosion of adjacent bony structures (arrow).

Based on the clinical presentation and the radiologic pattern, an incisional biopsy of the palatal lesion was performed to obtain a definitive diagnosis.

Microscopic examination revealed sheets of predominantly small lymphocytic cells with occasional larger atypical cells embedded within fibrotic connective tissue. The neoplastic cells exhibited markedly irregular nuclear contours and pleomorphism, with a pronounced lack of intercellular cohesion. Perivascular accentuation of lymphocytic cell density was observed. Extensive areas of necrosis and a prominent crush figure were present. In addition, infiltrative growth of the small lymphocytic cells into the adjacent adipose tissue and skeletal muscle bundles was evident.

Immunohistochemical studies revealed diffuse expression of LCA and CD3 in atypical lymphoid cells. CD20 and ALK were negative, whereas CD30 was focally positive. CD56 expression was negative. The Ki-67 labeling index was markedly elevated (approximately 90%).

Given the morphologic features and available immunophenotypic findings, ENKTL was strongly considered. Subsequent EBER chromogenic in situ hybridization demonstrated diffuse nuclear positivity in atypical lymphoid cells, confirming the diagnosis of extranodal NK/T-cell lymphoma, nasal type. (Figures 3, 4)

Fig. 3.

Histopathological features of the palatal lesion on H&E staining. (A) Low-magnification image showing diffuse infiltration of atypical lymphoid cells with an angiocentric growth pattern, necrosis, and marked crush artifact. (B) High-magnification image demonstrating atypical lymphoid cells with irregular nuclear contours, nuclear pleomorphism, and an angiocentric growth pattern, consistent with extranodal NK/T-cell lymphoma, nasal type.

Fig. 4.

. Immunophenotypic characterization of the neoplastic cells. The atypical lymphoid cells show positivity for CD3 and EBER, negativity for CD56, and a high Ki-67 proliferation index (approximately 90%).

On subsequent follow-up visits, the lesion progressively enlarged and developed deeper necrotic changes (Figure 5).

Fig. 5.

The image of the necrotic ulcer located in the hard palate (2 weeks after biopsy).

Upon establishing the diagnosis of ENKTL, the patient was initiated on a standardized systemic chemotherapy regimen consisting of dexamethasone (40 mg/day, D1–D4), etoposide (200 mg/day, D1–D3), ifosfamide (2500 mg/day, D1–D3, with mesna 2500 mg/day for uroprotection), and cisplatin (70 mg/day, D1–D3). The patient completed a total of four cycles of chemotherapy. The palatal lesion demonstrated complete clinical resolution after the first cycle (Figure 6). Following completion of the chemotherapy course, the patient underwent consolidation with involved-field radiotherapy to ensure local tumor control.

Fig. 6.

The image of the necrotic ulcer located in the hard palate (after chemotherapy).

Eight months after the initial presentation, the patient developed disseminated ulcerative cutaneous lesions on the leg and back. Histopathological and immunohistochemical evaluation of these lesions was consistent with peripheral T-cell lymphoma (PTCL). This subsequent lymphoid neoplasm underscores the aggressive clinical course and complexity of EBV-associated T/NK-cell lymphoproliferative disorders. Following this relapse, the patient was assessed for high-risk management and consideration of hematopoietic stem cell transplantation (HSCT). While the patient demonstrated good treatment compliance, continuity of follow-up was intermittently affected by logistical constraints and limitations in access to healthcare services.

Table 1.

Timeline of clinical events.

Time	Clinical Event
Week 0	Onset of necrotic palatal ulcer and nasal obstruction
Week 3	Presentation to the Department of Oral Medicine; clinical examination and CBCT performed
Week 4	Incisional biopsy of the palatal lesion
Week 6	Histopathological and immunohistochemical evaluation was completed; EBER positivity confirmed the diagnosis of ENKTL.
Week 7	Initiation of chemotherapy
After first chemotherapy cycle	Complete clinical resolution of the palatal lesion
After four chemotherapy cycles	Completion of chemotherapy and consolidation radiotherapy
Month 8 after initial presentation	Development of disseminated cutaneous lesions; biopsy findings consistent with peripheral T-cell lymphoma (PTCL)
Month 8 after initial presentation	Evaluation for hematopoietic stem cell transplantation (HSCT)

DISCUSSION

Overview, Epidemiology, and Clinical Context

Extranodal NK/T-cell lymphoma (ENKTL), nasal type, is an aggressive, EBV-associated malignancy that shows marked geographic clustering in East Asia and Latin America, with a clear male predominance and peak incidence in the fourth to fifth decades [8,10]. Although most cases arise in the nasal cavity or paranasal sinuses, true oral cavity involvement is distinctly uncommon, accounting for approximately 2% of reported cases [11]. Oral lymphomas can present with a wide spectrum of clinical manifestations, including painful ulcerative lesions, soft-tissue swelling, paraesthesia, tooth mobility or displacement, and regional lymphadenopathy. Nevertheless, their often non-specific or asymptomatic presentation may contribute to substantial delays in diagnosis [12]. Such atypical presentations—particularly when the disease manifests initially as a palatal ulcer with subsequent nasal extension—significantly complicate the clinical course. The destructive midline pattern observed in our patient is consistent with the classic clinical behavior of nasal-type ENKTL, albeit arising from an unusual primary site [4].

Diagnostic Challenges and the Immunophenotypic Paradox

Diagnosing extranodal NK/T-cell lymphoma (ENKTL), nasal type, is notoriously challenging due to extensive coagulative necrosis, which often obscures diagnostic cellular morphology and leads to non-diagnostic biopsies [13]. A critical diagnostic hurdle in the present case was the immunophenotypic profile. ENKTL is classically characterized by cytoplasmic CD3ε, CD56, and cytotoxic molecules; however, CD56 negativity has been reported in a subset of cases, which may complicate diagnosis [14]. In such instances, the reliance on CD56 can lead to misdiagnosis or diagnostic delay. Our case underscores that the absence of CD56 should not exclude ENKTL, especially when the clinical context of a “midline destructive lesion” is present.

Although additional immunohistochemical markers could have further supported the diagnosis, their use was limited by restricted access to specialized laboratory facilities and logistical constraints during the study period. The absence of additional cytotoxic markers (e.g., TIA-1, granzyme B, perforin, CD2, CD4, CD7, CD8) represents a limitation of the present report. Furthermore, the small size of the biopsy specimen restricted the number of ancillary studies that could be performed while preserving sufficient tissue for essential diagnostic evaluation. These limitations posed significant diagnostic challenges and influenced the overall diagnostic workup of this case.

Definitive Diagnosis: The Role of EBER and Morphologic Criteria

In the present case, the diagnosis was established based on diffuse nuclear positivity for Epstein–Barr virus-encoded RNA (EBER) detected by in situ hybridization (ISH). The 2022 WHO and ICC classifications recognize Epstein–Barr virus (EBV) positivity as an essential diagnostic criterion for extranodal NK/T-cell lymphoma (ENKTL). Accordingly, diffuse EBER positivity by in situ hybridization, in conjunction with characteristic histopathological features such as angiocentric/angiodestructive lymphoid infiltration and extensive geographic necrosis, is considered diagnostic even in the absence of CD56 expression [1,2]. Although additional T-cell markers (CD4 and CD8) were not available, the combination of EBER positivity, angiocentric growth, and extensive necrosis strongly favored ENKTL over PTCL-NOS [1]. The combination of EBV positivity, characteristic angiocentric morphology, extensive necrosis, and the immunophenotypic findings strongly supports the diagnosis of ENKTL despite the absence of additional cytotoxic marker studies.

Differential Diagnosis and Pathogenesis

The initial clinical presentation—a necrotic ulcer of the hard palate—necessitated consideration of granulomatosis with polyangiitis, deep fungal infections, and destructive sinonasal malignancies. GPA lacks clonal EBV-driven proliferation, whereas fungal infections were excluded by negative PAS/GMS stains [15]. The pathogenesis in ENKTL is driven by EBV-infected cytotoxic NK or cytotoxic T cells, in conjunction with recurrent epigenetic and genetic alterations (e.g., DDX3X, TP53, BCOR) that promote immune escape and aggressive behavior [16,17].

Management and Prognostic Implications

Therapeutic strategies for ENKTL have evolved from conventional CHOP-based protocols to intensive platinum-containing regimens, which have demonstrated superior efficacy in achieving local control and managing systemic disease [18]. Our patient's treatment with a combination of etoposide, ifosfamide, cisplatin, and dexamethasone (EIVP-like), followed by consolidative radiotherapy, adheres to current international consensus for optimizing frontline outcomes [19].

Despite achieving initial remission, the occurrence of relapse emphasizes the guarded prognosis of disseminated ENKTL. In addition, at eight months of follow-up after the initial treatment course, the patient was diagnosed with peripheral T-cell lymphoma (PTCL). This raises the possibility of disease progression, clonal evolution, transformation, or the emergence of a second independent lymphoid neoplasm; however, the exact relationship remains unclear. This finding underscores the biological complexity of T/NK-cell neoplasms and highlights the need for careful longitudinal assessment in such cases [1].

In this context, hematopoietic stem cell transplantation (HSCT) has emerged as a vital consolidation strategy. For fit patients who achieve a partial or complete response to induction therapy, early consideration of autologous or even allogeneic HSCT is increasingly supported by recent data to reduce the high risk of relapse and improve long-term survival [20]. Given the aggressive biological behavior of our case and its progression toward systemic involvement, early referral for HSCT evaluation is imperative in the post-remission phase. This case highlights that while early EBER-based diagnosis is the cornerstone of management, multimodal approaches incorporating consolidative HSCT are essential to mitigate the poor prognosis associated with high-risk or recurrent disease.

CONCLUSION

This case underscores the diagnostic difficulty of recognizing extranodal NK/T-cell lymphoma (ENKTL) when its initial manifestation occurs within the oral cavity. Clinicians and pathologists alike should consider ENKTL in the differential diagnosis of destructive palatal ulcers, particularly when lesions fail to respond to conventional therapy. Early biopsy, immunophenotyping, and EBV confirmation are essential for timely diagnosis and appropriate oncologic management.

DECLARATIONS

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Availability of Data and Materials

All data generated or analyzed during this study are included in this published article.

Competing Interests

The authors declare no conflicts of interest.

Consent for Publication

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editor-in-chief of this journal.

Ethics Approval and Consent to Participate

Not applicable (case report).