The patient was a 53-year-old male with no significant past medical history. Since December 2017, the fever up to 40 C emerged intermittently, followed by weight loss and right inguinal lymphadenopathy. In February 2018, a CT scan showed multiple subphrenic lymphadenopathies. A blood culture detected the bloodstream infection of methicillin-resistant Staphylococcus aureus (MRSA), and a gastrointestinal endoscopy revealed the widespread esophageal candidiasis. In March, he was complicated by herpes zoster infection. The right inguinal lymph node biopsy showed mycobacterium infection with malignant lymphoma, and he was transferred to our hospital.
On admission, laboratory data showed a white blood cell count of 14,400/muL (band cell 3.0%, segmented cell 81.0%, monocyte 8.5%, lymphocyte 7.5%), hemoglobin level of 9.0 g/dL, platelet count of 18.3 x 104/muL, CD4-positive T cell count of 678/muL (50.3% of T cells), aspartate transaminase (AST) of 16 U/L, alanine aminotransferase (ALT) of 15 U/L, blood urea nitrogen (BUN) of 5.3 mg/dL, creatine of 0.60 mg/dL, C-reactive protein (CRP) of 26.52 mg/dL, immunoglobulin G of 1764 mg/dL, and soluble IL-2R of 16,523 U/mL. HIV antibody, HTLV-1 antibody, mycobacterium avium complex (MAC) antibody, candida antigen, aspergillus antigen and Interferon-Gamma release assay were negative. Polymerase chain reaction (PCR) assays for the detection of clonally rearranged T cell receptors in the peripheral blood showed no clonality, and lymphocyte blastoid transformation test by phytohemagglutinin (PHA) was 29,300 count per minute (cpm) (normal range: 20,500-56,800 cpm), which suggested no apparent T cell dysfunction.
PET-CT demonstrated multiple enlargements of subphrenic lymph nodes (SUVmax 11.1 in the right inguinal lymph node) (Figure 1a-b). The histopathological examination of the right inguinal lymph node biopsy showed the destruction of normal structure and the mixture of the proliferation of abnormal large lymphoma cells and epithelioid cell granuloma. With small T cells and histiocytes as a background, Hodgkin cells, Reed-Sternberg cells and Lacunar cells invaded. These malignant cells were positive for CD30 and PD-L1, partially positive for CD15, and negative for CD3, CD4, CD8, and CD20 in immunohistochemistry. EBER-ISH was positive, and LMP-1 and EBNA-2 were also partially positive, which suggested EBV infection with latency type III (Figure 2a-e). This case showed more atypical and various cell appearance than Hodgkin lymphoma (HL). EBV-associated HL typically shows EBV infection with latency type II. Based on these pathological findings, EBV-positive LPD with Hodgkin lymphoma-like features was diagnosed.
PCR tests of the right inguinal lymph node were negative for Mycobacterium tuberculosis and MAC, and culture tests of bacteria, fungi, and mycobacterium species were also negative. However, Ziehl-Neelsen staining of the biopsy specimen showed acid-fast bacilli in granulomas (Figure 2a). In PCR, we revealed 100% sequence identity of both 16s ribosomal RNA and heat shock protein 65 (hsp65) of M. genavense, targeting 710 base pair (bp) sequences out of 1500 bp and 361 bp sequences out of 1623 bp respectively. The detection of M. genavense infection by culture is troublesome due to its fastidious growth requirements; therefore, negative culture result cannot exclude M. genavense infection. Consequently, EBV-positive LPD and M. genavense lymphadenitis were concomitantly diagnosed. We treated him with rifampicin, ethambutol and clarithromycin against M. genavense, and adriamycin, vinblastine and dacarbazine for EBV-positive LPD. We excluded bleomycin due to emphysema. Although fever and lymphadenopathy promptly subsided with these double therapies, PET-CT after six cycles showed multiple lymphadenopathies. The right inguinal lymph node re-biopsy demonstrated the relapse of EBV-positive LPD with no signs of mycobacterium infection. We started salvage chemotherapy and continued triplet antibiotics. The optimal treatment duration against M. genavense remains unclear, and we continued the triplet therapy for more than one year. We stopped the triplet antibiotics after 17 months' duration, and subsequently, the patient has had NTM free follow-up for 14 months.