A 67-year-old woman with a history of asthma (adequately treated) was admitted with an intermittent night fever (39°C) lasting 1 month and general weakness that persisted after antibiotic treatment at a local hospital. Other vital signs were stable and there were no symptoms or signs other than fever, erythematous skin rash on the chest, and general weakness. Laboratory tests revealed slightly low white blood cell count, 3,090/mm³ (4000–10,000/mm³), and increased aspartate transaminase level of 99 U/L (0–37 U/L), alanine transaminase level of 42 U/L (0– 41 U/L), and lactate dehydrogenase level of 2,600 U/L (135– 225 U/L). Peripheral blood smear findings were normal. Immunological tests for antinuclear antibodies and rheumatoid factors were negative. Blood, cerebrospinal fluid (CSF), and urine cul-tures also yielded negative results. Chest computed tomography (CT) revealed a focal consolidative lesion in the right lower lobe and bronchial wall thickening in both lungs. Slightly enlarged lymph nodes were found in the mediastinum and both hilar regions. Positron emission tomography showed multiple focal hot uptake lesions in bones, suggesting the differential diagnosis of multiple myeloma. However, a bone marrow biopsy and protein electrophoresis revealed no evidence of multiple myeloma or other malignancies. Abdominal and brain CT showed no remarkable findings. There was no history or evidence of hemophagocytic syndrome. The origin of the fever remained unclear. Given the recurrent fever, skin rash, and lymphadenopathy, adult-onset Still disease was suspected, and high-dose prednisolone was prescribed. After treatment, the fever subsided, but the skin rash showed little improvement. The patient developed a fever again, accompanied by multiple erythematous skin lesions all over her body. Her mental status decreased, and she underwent episodes of seizure. Brain CT and magnetic resonance imaging scans showed no specific findings. An incisional skin biopsy of the anterior chest was performed.

Microscopic examination of skin specimen revealed mildly dilated capillaries in the dermis and superficial subcutaneous fat. Atypical lymphoid cells were confined to the lumen of the small blood vessels. The intravascular atypical cells were medium to large in size compared to normal lymphocytes and were poorly cohesive. The atypical cells had large, irregular nuclei and scanty cytoplasm (Fig. 1A). Occasional mitoses were observed. Immunohistochemistry (IHC) for CD31 highlighted the vasculature, and the intravascular presence of atypical cells was confirmed (Fig. 1B). Atypical cells were positive for CD3 (Fig. 1C), granzyme B (Fig. 1D), and EBV-encoded RNA (EBER) in situ hybridization (Fig. 1E). CD56 was weakly positive in the atypical cells (Fig. 1F). CD20, CD4, CD8, and CD30 expression were negative (Fig. 1G–J), and the Ki-67 proliferation index was >90% (Fig. 1K). A T-cell receptor (TCR) gene rearrangement test did not show monoclonal T-cell proliferation. In conclusion, the patient was diagnosed with cutaneous intravascular EBV-positive NK/T-cell lymphoma. After diagnosis, polymerase chain reaction (PCR) detected EBV DNA (445,000 copies/mL) in serum. The patient’s clinical condition deteriorated with acute respiratory failure, and her mental status did not improve. She and her family opted for hospice care and no further pathological examination was done, but the progression of symptoms suggested that multiorgan failure and brain involvement had occurred. The patient expired 18 days after diagnosis.

IVNKTL is an extremely rare, highly aggressive lymphoma that predominantly involves the skin and central nervous system. Histological diagnosis is essential. Twenty-seven cases of IVNKTL, including the present case, with sufficient immunohistochemical and clonality data, have been reported (Table 1). The patients included 13 men and 14 women aged 18–87 years. The clinical presentation varied, including skin rash, neurologic symptoms, fever, cytopenia, weight loss, and malaise. Most patients had skin lesions (23/27, 85.2%, skin lesion only in 11 patients). Central nervous system involvement was found in 10 patients (10/27, 37.0%). Most of tested cases showed EBER positivity (22/26, 84.6%). Seven cases with clonality data showed the presence of monoclonal proliferation (7/22, 31.8%).

A skin biopsy is the easiest and most effective way to diagnose IVNKTL; however, it is challenging in patients without obvious skin lesions. Of the four patients without skin lesions, two presented with neurological symptoms and were diagnosed by brain biopsy (cases No. 23 and 26), and the other two were confirmed on autopsy (cases No. 3 and 25). Brain biopsy is more burdensome than skin biopsy. In each case, brain biopsy was performed after neurological symptoms worsened, and EBV DNA was detected in the CSF. The other two patients showed various symptoms and signs, including pancytopenia at presentation, and were diagnosed by bone marrow biopsy and autopsy. Autopsies of the last two patients revealed multiorgan involvement of IVNKTL, including the brain, kidneys, and bone marrow.

Bone marrow involvement was uncommon (4/19, 21.1%) and seemed to be associated with poor prognosis. In the case reported by Gebauer et al. [13] (case no. 14), bone marrow biopsy revealed dense medullary infiltration of IVNKTL, constituting approximately 40% of the overall cellularity. However, bone marrow biopsies showed only subtle sinusoidal lymphomatous infiltration in the other two cases (cases Nos. 3 and 25). The remaining case exhibited no evidence of neoplastic infiltration in morphological and IHC analyses of the bone marrow biopsy, and only TCR gene rearrangement test of the bone marrow aspirate confirmed clonality (case No. 23). Although bone marrow involvement may be uncommon, it can also easily be missed. Meanwhile, patients with bone marrow involvement showed shorter survival (<1 month) after confirmation of bone marrow involvement. Bone marrow involvement may indicate rapid disease progression; however, further evaluation is needed.

Most reports did not mention EBV DNA PCR testing (24/27, 88.9%). In three recent cases, EBV DNA PCR of pleural effusion, lung tissue (case No. 25), CSF (case No. 26), and blood (present case) was positive. Serum EBV DNA load has been suggested as a biomarker in EBV-associated cancers such as nasopharyngeal carcinoma, Burkitt lymphoma, and EBV-positive Hodgkin lymphoma [24]. IVNKTL may also present with a high serum EBV DNA load. Since procedures for histopathological examination (e.g., brain biopsy) are invasive, detection of serum EBV DNA could provide a supportive basis for conducting further work-up for diagnosis, especially in patients without apparent skin lesions.

In conclusion, we reported a case of IVNKTL in which serum EBV DNA was detected. An active skin biopsy or other invasive biopsy based on EBV DNA detection may facilitate early diagnosis of IVNKTL.