A 55-year-old woman with no past medical history presented with three weeks of hemorrhage of the oral mucosa at the Department of Hematology in August 2019. There were no complaints of fever, cough, fatigue, or ostalgia. Vital signs revealed a temperature of 36.5 C, heart rate of 80 beats/min, respiratory rate of 20 breaths/min, and blood pressure of 125/81 mmHg. The physical examination revealed unremarkable findings. Laboratory test results revealed a white blood cell count of 88.13x109/L (normal range, 3.5-9.5x109/L) with 67% neutrophils, 2% lymphocytes, 5% basophils, 1% eosinophils, 1% monocytes, 14% myelocytes, 10% metamyelocytes, with an erythrocyte count of 4.18x1012/L (normal range, 3.8-5.1x1012/L) and a platelet count of 640x109/L (normal range, 125-350x109/L). The lactate dehydrogenase level was 647 U/L (normal range, 135-214 U/L), while erythrocyte sedimentation rate, procalcitonin, liver, and renal function tests were normal. The abdominal ultrasound showed an enlarged spleen. Bone marrow examination showed markedly proliferated granulocytes. The quantitative reverse transcription polymerase chain reaction (RT-PCR) test for BCR/ABL p210 was positive at the time of diagnosis. Chromosomal analysis revealed 46, XX, t (9,22) (q34; q11). The patient was diagnosed with CML-CP and was started on imatinib (400 mg/daily).
Due to sudden respiratory distress, she was admitted again 11 months later. Her temperature was 36.5 C, heart rate was 137 beats/min, respiratory rate was 34 breaths/min, and blood pressure was 89/64 mmHg. Her cough started 2 months before admission. A physical examination revealed moist rales at the base of the lung. Sputum culture revealed Stenotrophomonas maltophilia, filamentous fungi, and traces of Aspergillus fumigatus. Routine blood tests showed a white blood cell count of 6.78 x109/L, an erythrocyte count of 4.00x1012/L, and a platelet count of 269x109/L. A peripheral blood smear revealed no abnormal cells. Procalcitonin was 1.035 ng/mL (normal range, 0-0.05 ng/mL). The serum IgM test for toxoplasma, rubella virus, cytomegalovirus, herpes simplex virus and parvovirus B19 (TORCH) was negative. Influenza, mycoplasma pneumoniae, T cell spot test, Epstein-Barr virus (EBV), cytomegalovirus plasma 1-3-beta-d glucan test, and plasma galactomannan tests were also negative. An electrocardiogram showed sinus tachycardia. There were no abnormalities on the cardiac ultrasound. Chest computed tomography (CT) revealed ground-glass opacities, patchy shadows, and multiple nodules in both lungs and enlarged mediastinal lymph nodes ( Figure 1A ). She was diagnosed with septic shock and was treated with biapenem and voriconazole. The combination of antibiotic treatments was effective. The patient's respiratory distress was relieved; however, intermittent coughing remained. Another chest CT showed decreased patchy shadows and multiple nodules in both lungs ( Figures 1B, C ).
She was readmitted 3 months later due to a fever (maximum of 38.5C). A CT scan showed an increase of the masses in the left lung compared with previous findings ( Figures 1D, G ). CT-guided percutaneous lung biopsy was conducted on October 28, 2020. The pathological examination showed extensive necrosis of the examined tissue. Periodic acid-silver methenamine staining was negative. Simultaneously, she underwent flexible fiberoptic bronchoscopy, which showed thick and yellow secretions. BAL fluid was sent for next-generation sequencing (NGS), which revealed EBV and Actinomyces odontolyticus. The patient received penicillin sodium and acyclovir for anti-infective treatment. The patient's symptoms improved, and she was discharged home from the hospital.
One month later, the patient presented with worsening cough, white sputum, and intermittent fever (maximum of 38.5 C), and was readmitted. CT revealed a reduction in the size of the masses in the upper lobe of the left lung (  Figure 1E  ) and an increase in the size of the masses in the lower lobe of the left lung compared with the previous scan ( Figure 1H ). Therefore, a second bronchoscopy and bronchoalveolar lavage were performed. Bronchoscopy revealed a white substance in the entrance of the dorsal segment of the left lower lobe. The BAL fluid was sent for NGS, which revealed EBV and Enterobacter cloacae complex Hoffmann cluster III. The patient underwent a second CT-guided percutaneous lung biopsy. Histopathological examination of the biopsied lung tissue showed proliferation and vascular infiltration of polymorphic lymphoid cells ( Figure 2 ). Immunohistochemical staining showed that the tumor cells were positive for Pax5, CD20, Bcl-2, EBER and (60%) Ki-67 and negative for Bcl-6, c-MYC, CD10, TdT, CD34, CD117, and MPO. MUM-1 staining was positive (20%); admixed T cells were positive for CD3 and CD7; tuberculosis-polymerase chain reaction was negative; and staining of mycobacteria and fungi were negative. Positron emission tomography/computed tomography (PET/CT) revealed an 18 F-fludeoxyglucose (FDG) increased uptake in the dorsal segment, posterior basal segment, and lateral basal segment of the left lower lobe ( Figure 3 ). FDG uptake was not detected in the mediastinal lymph nodes, thus excluding secondary lung infiltration of nodal/mediastinal DLBCL ( Figures 3G   -I ). Bone marrow aspiration did not show involvement of lymphoma cells. BCR-ABL (RT-PCR) was 0.0%. Furthermore, laboratory results showed an EBV DNA load of 2.07x104 IU/mL (normal range, <5000 IU/mL) and lactate dehydrogenase level of 348 U/L. The patient was diagnosed with lymphomatoid granulomatosis (grade 3). She stopped imatinib treatment and instead received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy. Her clinical manifestations improved, and chest CT scan revealed a reduction of the multiple nodules and masses in both lungs after 2 courses of chemotherapy ( Figures 1F, I ). Moreover, five months following imatinib withdrawal, flumatinib was then administered as a treatment for CML. The hematological remission of CML was maintained, and BCR-ABL transcript level remained undetectable by RT-PCR. As of August 16, 2022, the patient was still alive.