Rare extranodal NK/T-cell lymphoma: a diagnostic challenge and therapeutic approach
Year: 2024
Type: article
Abstract: To the Editor: The term “nasal T-cell lymphoma” was introduced in 1982 by Ishii et al, who identified tumour cells expressing CD3. Extranodal NK/T cell lymphoma (NKTL) is a rare and aggressive disease more commonly observed in Asia and America but infrequent in Western countries. This condition predominantly affects male patients and commonly originates in the nasal cavity and sinuses, leading to nonspecific symptoms. The qualifier “nasal type” was dropped in the 5th Edition of the World Health Organization Classification of Hematolymphoid Tumours (WHO-HAEM5) because this disease can present in several extranodal locations.1-5 We report a case that accentuates the diagnostic challenges associated with NKTL and provides valuable insights, addressing an area where knowledge is limited. A 60-year-old man with a history of complete metabolic syndrome and multifactorial heart disease, and a smoking history of 140 pack-years, was admitted in the emergency department for fever. His medical history included no known allergies. Bottled water is his preferred choice, and his alcohol consumption is limited to 14 g per week, mainly in the form of wine. He denied consuming nonprescription substances, herbal products, unpasteurized articles nor mushrooms. No history of significant occupational or recreational exposure was identified, and the patient denied engaging in risky sexual behavior. The patient was born and resides in Portugal and worked as a mechanic before retiring. He remains active by doing small jobs at home, tending to a vegetable garden. The patient complained of 1 month duration of astenia, unintentional weight loss of approximately 12 kg (more than 10% of his weight), night sweats, and persistent fever, characterized by daily peaks and which partially responded to paracetamol. He had a unilateral nasal obstruction of unknown duration, which he did not value. No history of blood loss or other complaints in the symptoms and systems revision were found. His physical examination revealed vitals within normal range, unremarkable pulmonary, and cardiac auscultation. No skin lesions, palpable masses, or lymphadenopathies were detected. No tender or pain areas were found. Considering his medical history, B symptoms for 1 month, along with nasal obstruction of unknown duration, further evaluation and diagnostic investigations were warranted to determine the underlying cause of the patient's condition, motivating admission in the internal medicine ward. The initial blood workup revealed an elevated Lactate Dehydrogenase (LDH) of 340 U/L at 37°C and discrete liver cytolysis with Aspartate Aminotransferase (ASAT)/Alanine Aminotransferase (ALAT) levels of 116/199 U/L at 37°C, without cytopenias. C-reactive protein and procalcitonin were negative, and no microbiological isolates were found. Ultrasound of the abdomen and pelvis, as well as the chest radiography, were normal. A cervical-thoracic-abdominal-pelvic CT scan was performed, showing no evidence of adenopathy or organomegaly, nor any other noteworthy abnormal findings. The transthoracic echocardiogram was not suggestive of endocarditis. Microbiological serologies for cytomegalovirus, coxiella burnetii, borrelia, brucella, and rickettsia conorii were negative. Seric molecular biology for leptospira was also negative. Infectious tuberculosis was excluded. The Venereal Disease Research Laboratory (VDRL) test, Human Immunodeficiency Virus (HIV) Tridot test, and Hepatitis B surface Antigen (HbsAg) test were nonreactive. The Epstein-Barr virus (EBV) testing showed positive results (serology compatible with past infection and a viral load of 1090 cp/mL). Erythrocyte sedimentation rate (ESR) was normal; antinuclear antibodies (ANA), rheumatoid factor (RA), and heterophile antibody tests were all negative. On otorhinolaryngology examination, a vegetating lesion was identified in the left nasal fossa. A computerized tomography (CT) scan of the sinuses revealed a polypoid lesion with contrast uptake, without bone invasion (Fig. 1). An initial biopsy yielded inconclusive results, prompting a second biopsy, which, on histopathological and immunohistochemical analysis, disclosed an extranodal NK-cell lymphoma (Figs. 2 and 3). EBV in situ testing was positive. A hybrid CT-Positron Emission Tomography (PET) scan with F-18-FDG with late qSUVmax of 28.2 showed an intense uptake of F-18-FDG in the lesion in the nasal fossa left (Fig. 1) and excluded distant disease. Medullary and liver biopsies were taken, which excluded lymphoma involvement.Figure 1.: Hybrid PET-CT with F-18-FDG, showing hypermetabolic cells (both malignant and activated macrophages) intensively uptake F-18-FDG. CT image on the left and PET on the right, with arrows pointing to the lesion in the left nasal fossa.Figure 2.: Histologic features of the lymphoma observed through H&E staining in 20x (A) and 40x (B).Figure 3.: Expression of marker proteins determined by immunohistochemical staining (10x) positive for CD2 (A), CD43 (B), and Granzyme B (C). Ki67 is positive in 80% of neoplastic cells (D). They are negative for CD5, CD7 and CD20.The history of smoking and alcohol, and presence of B symptoms indicated that we should pursue a malignancy workup. Physical examination and blood tests revealed no relevant findings, other than increased DHL, and liver cytolysis, in the absence of cytopenias or elevation of inflammatory markers. Abdominal ultrasound and cervical-thoracic-abdominal-pelvic CT were normal. In the absence of solid findings in the initial investigation, it was decided to broaden our differential diagnosis. The patient presented with a fever of unknown origin, prompting investigations into infectious and autoimmune etiologies. An extensive workup, including tests for endocarditis, tuberculosis (TB), zoonoses, HIV, and syphilis, yielded no definitive answers, although an elevated EBV viral load was noted. Further evaluation of the patient's nasal obstruction, using imaging and biopsy, revealed a polypoid lesion. While the initial biopsy was inconclusive, a second biopsy confirmed the diagnosis of extranodal NK-cell lymphoma. A subsequent PET scan was performed to stage the disease and, fortunately, ruled out any distant involvement. Treatment for NKTL involves concomitant/sequential chemotherapy and radiotherapy for stage I/II disease and systemic chemotherapy for stage III/IV or disseminated lymphomas.5-8 EBV DNA monitoring aids risk stratification.1-9 Given the clinical context of ischemic heart disease, toxicities of possible treatments, and in absence of other sites of involvement on PET, the case was discussed at the Hematology Group, and radiotherapy alone was proposed. He was discharged under corticotherapy for control of B symptoms (prednisolone 20 mg daily). He was submitted to radical radiotherapy to the nasal cavity and sinus, namely volumetric modulated arc therapy (VMAT), 28x 1.8Gy. The patient successfully completed all radiation therapy sessions with manageable tolerance. As a complication of the radiotherapy, the patient experienced nasal mucositis and occasional episodes of epistaxis, which were effectively managed with the administration of oral aminocaproic acid. 3-month follow-up PET showed F-18-FDG uptake in the left nasal fossa with reduced metabolic activity (SUV 3.4; previously 4.9) suggestive of postinflammatory uptake after radiotherapy. After a period of two and a half years of follow-up, the patient showed no signs of disease recurrence, being in complete remission. Notably, the patient's EBV viral load remained negative. This reassuring trend was reinforced by 2-year CT scan (Fig. 4), where the disappearance of the polypoid lesion in the nasal fossa was documented, interposed between the middle and lower nasal turbinates and the nasal septum, and no nodular lesions suggesting residual or recurrent tumor lesion. This collectively attests to the robustness of the monitoring process.Figure 4.: Two-year follow-up CT of the sinus, with no signs suggestive of recurrence. Arrow points to the left nasal fossa.NKTN has a poor prognosis, even with treatment, it carries a 5-year overall survival rate of approximately 50%.1,8 While it most commonly involves the nasal cavity and sinuses, NKTL can also manifest in other anatomical regions, including the airway, gastrointestinal tract, skin, lung, and soft tissues.1-3 The typical clinical presentation often includes nasal complaints such as obstruction, epistaxis, rhinorrhea, or anosmia. In addition, up to 35% of patients may present with B symptoms, further complicating the diagnostic process. In advanced cases, NKTN may lead to facial edema, necrosis, structural destruction, and even the formation of oronasal fistulas.3,4,9 Diagnosing NKTN poses challenges, particularly when considering the context of inflammation often observed in the nasal cavity, paranasal sinuses, and hard palate. Such inflammation can confound the identification of neoplastic cells, potentially leading to erroneous or inconclusive biopsy results. To achieve an accurate diagnosis, it becomes crucial to distinguish atypical hematopoietic cells amidst an intense inflammatory, necrotic, and degenerating cellular milieu. This emphasizes the significance of obtaining biopsies of sufficient size and high technical quality. It is also important to note that, despite angiocentric T-cell lymphoma's potential lack of classic histopathological features typically seen in lymphomas under microscopic examination, it behaves malignantly and responds to treatments similarly to other lymphomas.1-9 NK/T-cell lymphoma is notably associated with EBV. High circulating EBV viral loads correlate with a worse prognosis and shorter overall survival, making EBV both a diagnostic marker and a potential prognostic tool. The virus plays a crucial role in lymphomagenesis, primarily by establishing viral latency, evading immune detection, and promoting oncogenic processes. EBV also upregulates inflammatory pathways, leading to chronic immune activation while simultaneously using immune evasion strategies that allow for unchecked cell proliferation. Importantly, a high EBV titer, as seen in this case, reinforces the significance of the virus and can lead clinicians to suspect high-grade EBV-related lesions, especially when an initial biopsy is inconclusive. This underscores the importance of considering EBV viral load in the diagnostic workup of suspected NKTL, particularly when initial histopathological findings are ambiguous. EBV's persistence within the tumor microenvironment is critical for disease progression. This is reflected in the latest WHO-HAEM5 classification, which categorizes NKTL as an EBV-associated lymphoid proliferation. Understanding EBV's involvement could guide therapeutic decisions, including the consideration of antiviral therapies or immunomodulatory strategies alongside conventional treatments. Although the exact mechanisms by which EBV drives NKTL are not fully understood, the clinical implications are clear: patients with high EBV loads may require more intensive monitoring and treatment to mitigate the virus's role in driving malignancy.1,3 In conclusion, extranodal NK/T cell lymphoma is a rare and aggressive malignancy with distinct clinical manifestations, which can pose diagnostic challenges, especially in areas with limited experience in managing this disease. The association with EBV and the complex interplay of inflammatory processes further complicate the diagnosis. A multidisciplinary approach, involving clinicians, pathologists, and otorhinolaryngology specialists, is essential to achieve timely and accurate diagnosis, leading to appropriate therapeutic interventions and improved patient outcomes. Further research and collaboration are warranted to better understand the pathophysiology of NKTL and develop effective treatment strategies for this rare lymphoma.
Source: Porto Biomedical Journal
Authors: Sofia Moura de Azevedo, Francisco Sousa, Rita Peixeiro, Manuela Bertão
Institution: Hospital de Santo António
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4404344397