The First Case of Concomitant Mycobacterium Genavense Lymphadenitis and EBV-Positive Lymphoproliferative Disorder
Yusuke Ito1, Kensuke Takaoka1, Kazuhiro Toyama1, Kazuki Taoka1, Yoshitaka Wakabayashi2, Aya Shinozaki-Ushiku3, Aiko Okazaki2, Kinuyo Chikamatsu4, Satoshi Mitarai4, Tetsuo Ushiku3 and Mineo Kurokawa1,5.
1 Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo.
2 Department of Infectious Diseases, The University of Tokyo Hospital.
3 Department of Pathology, Graduate School of Medicine, The University of Tokyo.
4 Department of Mycobacterium Reference and Research, Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association.
5 Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital.
Received: February 14, 2020
Accepted: June 2, 2020
Mediterr J Hematol Infect Dis 2020, 12(1): e2020035 DOI 10.4084/MJHID.2020.035
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
This is the first case of concurrent Mycobacterium genavense lymphadenitis and Epstein-Barr virus (EBV)-positive lymphoproliferative disorder (LPD) in the same lymph node with no immunocompromised history. M. genavense infection is a rare opportunistic infection mainly for human immunodeficiency virus (HIV)-infected patients. Although no immunodeficiency was detected in our patient, our case indicates that the immunodeficiency in the background of EBV latency type III and the immunosuppression by malignant lymphoma itself might induce the M. genavense lymphadenitis. This case highly alerts clinicians to the immunosuppressive state of EBV-positive LPD with latency type III even if any immunodeficient serological factors are not detected.
On admission, laboratory data showed a white blood cell count of 14,400 /μL (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 /μL, CD4-positive T cell count of 678 /μL (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.
|Figure 1. PET-CT images on admission. PET-CT on admission shows (a) multiple enlargement of subphrenic lymph nodes and (b) SUVmax 11.1 in the right inguinal lymph node.|
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.
Three cases reported the relation between M. genavense infection and lymphoma (Table 1A). An 80-year-old female patient with chronic lymphocytic leukemia, a 51-year-old female patient with peripheral T cell lymphoma, and a 63-year-old male patient with non-Hodgkin lymphoma (NHL) caused M. genavense infection. All cases were under chemotherapy or immunosuppressive therapy when M. genavense infection was detected; thus, the situation is different from our patient with concurrent M. genavense infection and EBV positive LPD with no immunosuppressive therapy.
|Table 1(A). The summary of patients with M. genavense infection and malignant lymphoma.|
Meanwhile, a simultaneous diagnosis of NTM infection and malignant lymphoma has been reported in four cases (Table 1B). Two of them were patients with AIDS, a 27-year-old male patient with MAC infection and HL, and a 31-year-old male patient with NTM infection and NHL. Since NTM infection and malignant lymphoma are both included in AIDS-defining diseases, the possibility of simultaneous onset may be relatively high in AIDS patients. The other two cases were a 13-year-old male with M. avium infection and HL, and a 5-year-old male with MAC infection and HL. These cases were compatible with the evidence that NTM lymphadenitis has mainly occurred in children, and MAC accounts for 80-90%. Consequently, our patient is the first adult non-HIV case with concomitant NTM lymphadenitis and lymphoma.
|Table 1(B). The summary of patients with concomitant NTM infection and malignant lymphoma.|
This patient presents with an EBV latency type III. It is typically observed in immunodeficiency-associated LPD and a part of EBV-positive diffuse large B cell lymphoma (DLBCL), not otherwise specified (NOS), which indicates the highly immunodeficient background. Furthermore, this patient suffered from M. genavense lymphadenitis, MRSA bacteremia, widespread esophageal candidiasis, and herpes zoster infection. These bacterial, fungal, and viral infections further suggest an immunocompromised condition. However, this case did not have primary immune disorders, HIV infection, or another iatrogenic immunodeficiency, or pathological features of DLBCL. White blood count, CD4-positive T cell count, and immunoglobulin levels were normal. T cell receptors in the peripheral blood were polyclonal, and the lymphocyte blastoid transformation test by phytohemagglutinin (PHA) was normal, which suggested no apparent T cell dysfunction. Mycobacterial, fungal, and viral infections can be caused by monocytopenia and mycobacterial infection (MonoMAC) syndrome. However, the differential blood count, including the monocyte count of this patient was normal, which exclude the possibility of MonoMAC syndrome. Furthermore, we analyzed the sequence of GATA binding protein 2 (GATA2) using DNA extracted from peripheral blood and found a single-nucleotide polymorphism c.490 G>A (p.A164T) and a silent mutation c.15 C>G. In addition, our case did not have the age like suffering from severe immunosenescence, which is critical for the pathogenesis of EBV-positive DLBCL, NOS. Based on these results, no immunodeficiency could be detected in our patient.
Patients with HL are often complicated with tuberculosis. HL cells are known to highly express PD-L1 and cause intratumoral T cell exhaustion, leading to T cell dysfunction. Generally, high PD-L1 expression on malignant lymphoma cells is due to either the amplification of the PD-L1 locus on chromosome 9p24.1, which is a recurrent abnormality seen in HL, or EBV infection. EBV infection upregulates PD-L1 expression via EBNA2, the characteristic of EBV latency type III. In our case, EBNA2 induced PD-L1 expression on the lymphoma cells and might activate PD-1/PD-L1 signaling on the surrounding T cells. Immune checkpoint players such as PD-1, cytotoxic T lymphocyte antigen 4 (CTLA-4), and T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) have been well known for the role of not only cancer immune escape but also immunosuppression during chronic infection.[19,20] For example, during chronic Mycobacterium tuberculosis infection, T cells express multiple inhibitory receptors, including PD-1 and TIM-3, which cause T cell exhaustion. It promotes impairment of T cell function and impairs host resistance to M. tuberculosis. These reports suggest that T cell exhaustion may induce the exacerbation of infections against mycobacterium species. Therefore, the immunosuppressive effect through the PD-1/PD-L1 axis might promote the simultaneous M. genavense infection in our case. Consequently, our case indicates that the immunodeficiency in the background of EBV latency type III and the immunosuppression by malignant lymphoma itself might induce the M. genavense lymphadenitis and other bacterial, fungal, and viral infections. Our case highly alerts clinicians of the immunosuppressive state of EBV-positive LPD with latency type III even if any immunodeficient serological factors are not detected.
- Böttger EC, Teske A, Kirschner P, Bost S, Chang HR,
Beer V, Hirschel B. Disseminated "Mycobacterium genavense" infection in
patients with AIDS. Lancet 1992;340:76-80 https://doi.org/10.1016/0140-6736(92)90397-L
M, Ajmal S, Abu Saleh OM, Bryson A, Marcelin JR, Wilson JW.
Mycobacterium genavense infections in non-HIV immunocompromised hosts:
a systematic review. Infect Dis. 2018;50:329-39 https://doi.org/10.1080/23744235.2017.1404630 PMid:29157060
Dongen JJ, Langerak AW, Brüggemann M, Evans PA, Hummel M, Lavender FL,
Delabesse E, Davi F, Schuuring E, García-Sanz R, van Krieken JH, Droese
J, González D, Bastard C, White HE, Spaargaren M, González M, Parreira
A, Smith JL, Morgan GJ, Kneba M, Macintyre EA. Design and
standardization of PCR primers and protocols for detection of clonal
immunoglobulin and T-cell receptor gene recombinations in suspect
lymphoproliferations: report of the BIOMED-2 Concerted Action
BMH4-CT98-3936. Leukemia 2003;17:2257-2317 https://doi.org/10.1038/sj.leu.2403202 PMid:14671650
S, Esen N, Pan X, Musser JM. Routine rapid Mycobacterium species
assignment based on species-specific allelic variation in the
65-kilodalton heat shock protein gene (hsp65). Arch Pathol Lab Med.
- Ombelet S, Van
Wijngaerden E, Lagrou K, Tousseyn T, Gheysens O, Droogne W, Doubel P,
Kuypers D, Claes KJ. Mycobacterium genavense infection in a solid organ
recipient: a diagnostic and therapeutic challenge. Transpl Infect Dis.
2016;18:125-31 https://doi.org/10.1111/tid.12493 PMid:26688125
T, Zimmerli S, Bodmer T, Lämmle B. Mycobacterium genavense infection in
a patient with long-standing chronic lymphocytic leukaemia. J Intern
Med.2000;248:343-8 https://doi.org/10.1046/j.1365-2796.2000.00730.x PMid:11086646
N, Demeure F, Van Bleyenbergh P, De Visscher N. Disseminated
Mycobacterium genavense infection in a patient with immunosuppressive
therapy and lymphoproliferative malignancy. Acta Clin Belg.
2014;69:142-5 https://doi.org/10.1179/0001551213Z.00000000016 PMid:24724760
W, van Ingen J, Peters EJ, Magis-Escurra C, Dekhuijzen PN, Boeree MJ,
van Soolingen D. Mycobacterium genavense in the Netherlands: an
opportunistic pathogen in HIV and non-HIV immunocompromised patients.
An observational study in 14 cases. Clin Microbiol Infect.
2013;19:432-7 https://doi.org/10.1111/j.1469-0691.2012.03817.x PMid:22439918
P, Marchou B, Chittal SM, Delsol G. Concomitant Mycobacterium avium
complex infection and Epstein-Barr virus associated Hodgkin's disease
in a lymph node from a patient with AIDS. Histopathology 1994;24:586-8 https://doi.org/10.1111/j.1365-2559.1994.tb00583.x PMid:8063291
MS, Fadzilah I, Maizaton AA, Sani A. Concurrent mycobacterial infection
and non-Hodgkin's lymphoma at the same site in an AIDS patient. Med J
- de Armas Y,
Capó V, González I, Mederos L, Díaz R, de Waard JH, Rodríguez A, García
Y, Cabanas R. Concomitant Mycobacterium avium Infection and Hodgkin's
Disease in a Lymph Node from an HIV-negative Child. Pathol Oncol Res.
2011;17:139-140 https://doi.org/10.1007/s12253-010-9275-5 PMid:20467849
S, Cogbill CH, Gheorghe G, Rao AR, Kumar S, Havens PL, Camitta BM,
Warwick AB. Mycobacterium avium intracellulare Infection Coexistent
With Nodular Lymphocyte Predominant Hodgkin Lymphoma Involving the
Lung. J Pediatr Hematol Oncol. 2011;33:e127-31 https://doi.org/10.1097/MPH.0b013e3181faf89a PMid:21399527
PW, Plaza-Fornieles M, Menasalvas-Ruiz A, Ruiz-Pruneda R, Paredes-Reyes
P, Miguelez SA. Risk factors of non-tuberculous mycobacterial
lymphadenitis in children: a case-control study. Eur J Pediatr.
2017;176:607-13 https://doi.org/10.1007/s00431-017-2882-3 PMid:28265761
JJ, Beltran BE, Miranda RN, Young KH, Chavez JC, Sotomayor EM.
EBV-positive diffuse large B-cell lymphoma, not otherwise specified:
2018 update on diagnosis, risk-stratification and management. Am J
Hematol. 2018;93:953-62 https://doi.org/10.1002/ajh.25112 PMid:29984868
AP, Sampaio EP, Khan J, Calvo KR, Lemieux JE, Patel SY, Frucht DM, Vinh
DC, Auth RD, Freeman AF, Olivier KN, Uzel G, Zerbe CS, Spalding C,
Pittaluga S, Raffeld M, Kuhns DB, Ding L, Paulson ML, Marciano BE,
Gea-Banacloche JC, Orange JS, Cuellar-Rodriguez J, Hickstein DD,
Holland SM. Mutations in GATA2 are associated with the autosomal
dominant and sporadic monocytopenia and mycobacterial infection
(MonoMAC) syndrome. Blood. 2011;118:2653-5 https://doi.org/10.1182/blood-2011-05-356352 PMid:21670465 PMCid:PMC3172785
J, Alexanian R, Hersh EM, Leary W. Hodgkin's Disease Complicated by
Infection with Mycobacterium kansasii. Can Med Assoc J. 1969;101:231-4
SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster
SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH,
Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P. PD-1
Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma. N
Engl J Med. 2014;372:311-9 https://doi.org/10.1056/NEJMoa1411087 PMid:25482239 PMCid:PMC4348009
E, Stroopinsky D, Alimperti S, Jiao AL, Pyzer AR, Cippitelli C, Pepe G,
Severa M, Rosenblatt J, Etna MP, Rieger S, Kempkes B, Coccia EM, Sui
SJH, Chen CS, Uccini S, Avigan D, Faggioni A, Trivedi P, Slack FJ.
Epstein−Barr virus-encoded EBNA2 alters immune checkpoint PD-L1
expression by downregulating miR-34a in B-cell lymphomas. Leukemia
2019;33:132-47 https://doi.org/10.1038/s41375-018-0178-x PMid:29946193 PMCid:PMC6327052
VP, Ratnatunga CN, Smith DJ, Kupz A, Doolan DL, Reid DW, Thomson RM,
Bell SC, Miles JJ. Anomalies in T Cell Function Are Associated With
Individuals at Risk of Mycobacterium abscessus Complex Infection. Front
Immunol 2018;9:1319 https://doi.org/10.3389/fimmu.2018.01319 PMid:29942313 PMCid:PMC6004551
- Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev. 2017;276:97-111 https://doi.org/10.1111/imr.12520 PMid:28258697 PMCid:PMC5512889
P, Jacques MK, Zhu C, Steblenko KM, Stowell BL, Madi A, Anderson AC,
Kuchroo VK, Behar SM. TIM3 Mediates T Cell Exhaustion during
Mycobacterium tuberculosis Infection. PLoS Pathog. 2016;12:e1005490 https://doi.org/10.1371/journal.ppat.1005490 PMid:26967901 PMCid:PMC4788425