A 53-year-old man was admitted to our hospital with 15 kg weight loss and anorexia over 6 months period. On admission, physical examination revealed clear consciousness, a temperature of 36.4 C, blood pressure of 104/66 mmHg, pulse rate of 92 beats/min, respiratory rate of 24/min, and oxygen saturation of 97% (room air). Chest auscultation revealed slight end-inspiratory fine crackles in both lungs. The heart sounds were normal. Chest radiography (CXR) revealed ground-glass opacities in both lung fields (Figure 1A). Chest computed tomography (CT) revealed diffuse ground-glass opacities with interlobular septal thickening (Figure 1D). The mediastinal lymph nodes were mildly enlarged. Mild hepatosplenomegaly and bilateral kidney enlargement were also observed (Figures 1G, 1H). Inflammatory markers were elevated as shown in Table 1. Hyponatremia and hypokalemia were also observed (Table 1). We considered sarcoidosis, lymphangitic carcinomatosis owing to gastric cancer, malignant lymphoma, lymphoproliferative disease, or anti-neutrophil cytoplasmic antibody (ANCA) - associated vasculitis as possible differential diseases. Tests performed to differentiate these diseases showed mildly elevated lactate dehydrogenase (LDH), soluble interleukin-2 receptor (sIL-2R), and angiotensin-converting enzyme (ACE) levels were observed (Table 1).
During the hospital stay, an upper gastrointestinal endoscopy was performed, but no specific findings were observed. Therefore, sarcoidosis and SIADH were suspected. After admission, plasma and urine osmolalities, urine electrolytes, and hormone tests were performed (Table 1). He met the diagnostic criteria and was diagnosed with SIADH. Salt loading, fluid restriction, furosemide, and tolvaptan were administered to treat hyponatremia. Furthermore, the patient underwent bronchoscopy with bronchoalveolar lavage (BAL) in the right middle lobe and transbronchial biopsy (TBB) from the right upper lobe. The recovery rate of BAL was greater than 50%. BAL cytology showed elevated cell counts and lymphocyte count ratios with a decreased cluster of differentiation (CD) 4/CD8 ratio (Table 1). TBB showed lymphocyte infiltration, but no non-caseating epithelioid cell granulomas were seen in sarcoidosis (Figure 2). Gallium scintigraphy, ophthalmologic and cardiovascular examination revealed no findings suggestive of sarcoidosis. Bilateral kidney enlargement and electrolyte abnormalities suggested nephritis as a complication; therefore, a renal biopsy was performed. The pathological diagnosis was interstitial nephritis (Figure 3). With some improvement in symptoms and a strong desire to be discharged, the patient was temporarily discharged 14 days after admission with a directive for a thorough outpatient evaluation.
However, seven days after discharge, he was readmitted to the hospital for management of decreased appetite, worsening fatigue, and worsening respiratory condition (oxygen saturation 90%, oxygen 3 L/min). The CXR and CT scans, in addition to diffuse ground-glass opacities, also showed the appearance of mass-like infiltrates with moderate pleural effusion in both lungs (Figures 1B, 1E). LDH and sIL-2R levels were mildly elevated (LDH 396 IU/L, sIL-2R 1,900 U/mL). Since LDH and sIL-2R are often elevated in patients with malignant lymphoma, considering the possibility of primary pulmonary malignant lymphoma or lymphoproliferative disease, VATS lung biopsy was performed on the seventh day of re-hospitalization. In VATS lung biopsy, the patient underwent partial resection of the right upper lobe. Subsequently, the biopsy specimen was cut into 1 cm thick slices in a plane perpendicular by the pathologist for flow cytometry, chromosome analysis, genetic testing and immunohistological examination. These examinations were performed using integrated analysis of malignant lymphoma, ML-NET (Figures 4, 5).
Flow cytometry revealed that cells characterized by CD2, CD56 positivity, CD3, CD4, CD5, and CD7 were low in the small cell area. Hematoxylin-eosin staining showed an increase in medium-sized lymphocytes and slightly larger lymphocyte-like cells (Figure 6). Immunostaining showed CD3, CD56 (partial positive) (Figure 7) and CD8 (Figure 8), CD2, T-cell intracellular antigen-1 (TIA-1) (Figure 9), granzyme B (Figure 10) positive, CD20 negative, Epstein-Barr virus (EBV)-encoded RNA in situ hybridization (ISH) positive (Figure 11), poor proliferation (G-band), and no ALK mutated gene (fluorescence ISH). Furthermore, the viral load of EBV-DNA quantified by quantitative polymerase chain reaction using whole blood was 380,000 copies/mL. Resultantly, the patient was diagnosed with primary pulmonary ENKL.
As our hospital did not have a hematologist, the patient was transferred to a high-volume center where a hematologist was available for chemotherapy, which was initiated on day 28 after the VATS lung biopsy. No bone marrow biopsy was performed during our hospitalization. After transfer to a high-volume center, he received chemotherapy with the SMILE regimen (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide), which showed improvement in his symptoms.