The infant arrived with a five-day history of progressive abdominal distention, respiratory distress, irritability, occasional non-bilious vomiting, pallor, and a striking protrusion of the right eye with yellow-green discoloration of the eyelid. Physical examination revealed a pale, tachycardic, tachypneic child in moderate respiratory distress with grunting and subcostal retractions. The abdomen was markedly distended, and eczematous dermatitis was noted on the scalp. Laboratory work-up showed a white blood cell count of 29.4 K/uL, hemoglobin of 7.3 g/dL, and a platelet count of 128 K/uL, a combination of leukocytosis, anemia, and thrombocytopenia that signaled serious underlying pathology.

Imaging told an even more alarming story. A chest radiograph revealed a left paraspinal density projecting into the retrocardiac region with a vague opacity in the right upper lobe. Computed tomography then demonstrated a right retroocular density along the optic nerve and superior orbits, a 2.5 cm low-attenuation thymic mass, a 4.0 cm left paraspinal mass in the posterior mediastinum, and a separate 2.1 cm elliptical soft tissue mass anterior to the paraspinal mass at the base of the left lower lobe. Multifocal pericardial and myocardial involvement were noted at the right ventricular outflow tract and surrounding the left ventricle. Conglomerated lymph nodes were present in the left axillary region, and abdominal imaging showed masses totally replacing both adrenal glands in addition to involvement of both kidneys and the pancreas.

Shortly after admission, the patient’s condition deteriorated rapidly, requiring transfer to the pediatric intensive care unit, intubation, mechanical ventilation, and hemodynamic support. A profound metabolic acidosis was identified and treated with fluid resuscitation, packed red blood cell transfusion, sodium bicarbonate, and vasoactive infusions. After initial improvement, the child acutely worsened, becoming bradycardic with marked deterioration in perfusion despite adequate oxygenation. Cardiopulmonary resuscitation was initiated, but the cardiac rhythm deteriorated to asystole, and the patient was pronounced dead. With parental consent, an unrestricted autopsy was performed.

Post-mortem examination revealed multiple ill-defined and hemorrhagic tumor nodules involving the thymus, heart, lungs, liver, pancreas, spleen, small intestines, adrenal glands, and kidneys. No primary site of origin could be identified. Microscopic examination demonstrated extensive replacement of each organ by a diffuse and infiltrative lymphoid proliferation composed of monotonous, small to medium-sized cells with clear cytoplasm and round to irregular nuclei. The tumor cells displayed an angiocentric and angiodestructive predilection, producing prominent areas of tissue necrosis and vascular damage, with abundant apoptotic bodies in adjacent necrotic regions.

Immunohistochemical staining proved decisive. The tumor was positive for CD56, cytoplasmic CD3, TIA-1, and granzyme-B, while staining for lysozyme, myeloperoxidase, CD57, CD79a, and CD117 was negative. Polymerase chain reaction testing for T-cell receptor gene rearrangement was also negative, a pattern consistent with an NK-cell rather than T-cell lineage. Together, these findings pointed to ENKTCL. However, in situ hybridization for EBV was negative, which is atypical for this diagnosis. The authors acknowledge that because the testing was performed on post-mortem tissue, RNA degradation could have contributed to the negative result, leaving open the possibility that the tumor was EBV-positive in life.

The diagnostic challenge was considerable. Several other CD3- and CD56-positive neoplasms had to be excluded. Aggressive NK-cell leukemia shares cytoplasmic CD3, surface CD56, and cytotoxic molecule expression, but typically shows leukemic involvement that was absent here. Large granular lymphocytic leukemias express similar markers but follow an indolent course, strikingly different from the fulminant progression observed. EBV-positive nodal T- and NK-cell lymphoma requires EBV positivity and only a minor subset express CD56. Hepatosplenic T-cell lymphoma, anaplastic large cell lymphoma, and peripheral T-cell lymphoma can express CD3, CD56, and cytotoxic markers, but show positive T-cell receptor rearrangement. T-lymphoblastic leukemia usually has clonal TCR rearrangements, and blastic plasmacytoid dendritic cell neoplasm is typically CD3-negative. None fit perfectly, and ENKTCL remained the best diagnosis.

Under the current WHO classification, EBV positivity is a required diagnostic criterion for ENKTCL, identified by in situ hybridization in almost all nasal cases, particularly in patients of Asian descent. Historically, however, EBV-positivity has been less consistent in extranasal disease and in Caucasian populations. An international database review found that only 3 percent of ENKTCL cases occur in patients under 20 years of age, underscoring the rarity of pediatric disease. Although adult and pediatric tumors are histologically similar, outcomes in children vary widely, ranging from 30 to 80 percent depending on the literature source, with poorer survival at higher stage.

Treatment data are limited because all reported clinical studies are retrospective series or case reports. One of the largest pediatric cohorts, comprising 34 patients, demonstrated much poorer overall survival in those with Stage III/IV disease (26.0 percent) than in those with Stage I/II (66.2 percent). Extranodal disease carried lower event-free and overall survival compared to nasal disease. Chan and colleagues reported 34 cases of extranodal ENKTCL with poor response to multi-agent chemotherapy, among whom 83 percent died within one week to three years from diagnosis. Wang and colleagues reported better outcomes in a series of 22 pediatric patients, with overall survival of approximately 63 percent regardless of treatment modality. Chemotherapy resistance is thought to be associated with expression of the multi-drug resistance 1 gene and poor drug delivery through significant tissue necrosis.

For advanced or relapsed disease, hematopoietic stem cell transplant has shown promise, with survival rates dependent on tumor burden at the time of transplant and geographic region. Suzuki and colleagues reviewed 22 patients treated with transplant and found better overall survival (approximately 55 percent) than with chemotherapy alone (approximately 30 percent), with significantly improved survival in those who achieved complete remission before transplant. Meanwhile, targeted therapies are being explored with encouraging results. PD-L1 inhibitors such as pembrolizumab and nivolumab have been successful, apparently independent of PD-L1 expression levels. JAK inhibitors, including ruxolitinib, have demonstrated efficacy in vitro and induced remission in a single case report when combined with chemotherapy. HDAC inhibitors and mTOR inhibitors are also under investigation, particularly for EBV-positive tumor cell lines. The authors emphasize that dedicated pediatric studies are required to truly understand the efficacy and outcomes of these approaches in children, and that much remains to be learned about the biology, immunology, natural history, and treatment response of ENKTCL, particularly in the youngest patients.

Subject of Research: Pathology and Oncology Research

Article Title: Pediatric extranasal, EBV-negative, extranodal natural killer/T-cell lymphoma; case report

Article References: Gallant, R., & Khan, O. (2026). Pediatric extranasal, EBV-negative, extranodal natural killer/T-cell lymphoma; case report. Pathology & Oncology Research, 32, Article 1612318. https://doi.org/10.3389/pore.2026.1612318

Image Credits: AI Generated

DOI: 10.3389/pore.2026.1612318

Keywords: ENKTCL, natural killer cell lymphoma, EBV-negative, pediatric oncology, case report, extranodal lymphoma, NK-cell neoplasms, WHO classification, targeted therapy, hematopoietic stem cell transplant, Pediatric, extranasal