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 Table of Contents  
Year : 2020  |  Volume : 11  |  Issue : 3  |  Page : 145-148

Mendelian susceptibility to mycobacterial disease masquerading as lymphoproliferative disorder

1 Department of Hematology, Apollo Cancer Centre, Chennai, Tamil Nadu, India
2 Department of Pediatric Hematology, Kanchi Kamakoti CHILDS Trust Hospital, Chennai, Tamil Nadu, India

Date of Submission16-Apr-2020
Date of Decision20-Apr-2020
Date of Acceptance26-Apr-2020
Date of Web Publication16-Sep-2020

Correspondence Address:
Dr. Thulasi Raman Ramalingam
Department of Hematology, Apollo Cancer Centre, Chennai, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/joah.joah_45_20

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Mendelian susceptibility to mycobacterial diseases (MSMDs) is a rare disorder where histiocytes lack the interferon-gamma receptor and are not activated by the cytokine secreted by T-lymphocyte. The lymph node biopsy in these cases lack granuloma but show sheets of histiocytes with effacement of architecture, which may mimic a lymphoproliferative disorder. The predominance of a histiocytic population in immunodeficient children should alert the pathologist, and ancillary techniques such as immunohistochemistry and flow cytometry should be used to establish the correct diagnosis. Here, we report a case of MSMD which mimicked as a lymphoproliferative disorder.

Keywords: Granuloma, interferon-gamma, lymphoproliferative disorder, Mendelian susceptibility to mycobacterial diseases

How to cite this article:
Ramalingam TR, Munirathnam D. Mendelian susceptibility to mycobacterial disease masquerading as lymphoproliferative disorder. J Appl Hematol 2020;11:145-8

How to cite this URL:
Ramalingam TR, Munirathnam D. Mendelian susceptibility to mycobacterial disease masquerading as lymphoproliferative disorder. J Appl Hematol [serial online] 2020 [cited 2020 Oct 22];11:145-8. Available from: https://www.jahjournal.org/text.asp?2020/11/3/145/295123

  Introduction Top

Mendelian susceptibility to mycobacterial diseases (MSMDs) is a rare primary immunodeficiency disorder (PID) characterized by increased susceptibility to low pathogenic mycobacterial species and Salmonella. Interferon (IFN) GR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, IRF8, NEMO, and CYBB are the nine MSMD causing genes that have been found. The hallmark of this disease is the defect in the interleukin (IL)-12–IFN-gamma axis, and this may result in ill-defined or virtually no granuloma formation in these patients.[1]

  Case Report Top

A 3-month-old infant presented with fever, abdominal distention, erythematous maculopapular rash, and swelling in the left axillary region for 10-day duration. The child was born to second-degree consanguineous marriage and had no significant antenatal or natal history. The child had Bacillus Calmette–Guerin (BCG), oral polio vaccine, and hepatitis B vaccines soon after the birth. On examination, the child had pallor, periorbital puffiness, left axillary lymphadenopathy, and hepatosplenomegaly. Ultrasonogram of the abdomen revealed bilateral nephromegaly apart from hepatosplenomegaly. Peripheral smear revealed leukocytosis (total count 51.8 × 109/L) with significant eosinophilia and showed reactive lymphocytes. CRP and lactate dehydrogenase levels were elevated. Other blood investigations like blood culture, HIV serology was negative. Preliminary immunodeficiency work up with nitroblue tetrazolium reduction test, and flow cytometry for lymphocytes subpopulation and natural killer cells enumeration were also within the normal limits. Bone marrow aspiration showed only reactive features.

An excised gray-white 2 cm × 1 cm axillary lymph node excisional biopsy showed complete effacement of nodal architecture with absent lymphoid follicles [Figure 1]. There were large cells with moderate eosinophilic cytoplasm and vesicular nuclei exhibiting prominent nucleoli, with some binucleated cells mimicking Reed–Sternberg (RS) cells. There were also a few vacuolated cells in the cortical region. No definite granulomas or Langerhans cells with nuclear grooves were noted. With these histological features, the possibility of lymphoproliferative disorder was considered, and a panel of immunohistochemistry markers were done. Many cells showed strong positivity for leukocyte common antigen and CD68 and focal positivity for CD20 and CD3. Few cells were CD30 positive, and other markers such as CD15, EBVLMP, PAX5, EMA, MPO, and CD34 were negative. The strong and diffuse CD68 positivity revealed the histiocytosis in the lymph node and ruled out the possibility of a lymphoproliferative disorder. The lymph node H and E section was reviewed back along with the deeper sections. There were focal sheets and individual vacuolated cells. Ziehl–Neelsen staining highlighted many clusters of acid-fast bacilli (AFB) [Figure 2]. Flow cytometry for PID workup showed the absence of IFN-gamma receptor on monocytes [Figure 3]. Genetic studies were done to confirm the diagnosis and revealed an autosomal recessive defect in the IFNGR1 gene leading to complete absence of the IFN-gamma receptor. The child was finally diagnosed with systemic BCG-Osis due to the absence of IFN-gamma receptors, a type of MSMD. The child was treated with antitubercular therapy and subsequently taken up for haploidentical stem cell transplant with reduced intensity conditioning and on follow-up [Figure 4].
Figure 1: Photomicrographs (a-c) showing lymph node with effaced architecture and absence of normal follicles. Immunohistochemistry highlighting the distribution of T-lymphocytes, B-lymphocytes, and histiocytes in (d-f), respectively

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Figure 2: Acid-fast bacilli staining shows clusters of mycobacteria in the lymph node section

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Figure 3: Flow cytometry histogram demonstrates a complete absence of interferon-gamma receptor (CD119) in monocytes

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Figure 4: Summary and sequence of events. BCG = Bacillus Calmette–Guérin; OPV = Oral polio vaccine; LDH = Lactate dehydrogenase; NBT = Nitroblue tetrazolium test; AFB = Acid-fast bacilli; MSMD = Mendelian susceptibility to mycobacterial diseases; IFN-γ=Interferon-gamma; AR IFN-γ=Autosomal recessive Interferon-gamma

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  Discussion Top

MSMD is an immunodeficiency disorder characterized by increased susceptibility to low pathogenic mycobacterial species such as bovis, BCG vaccine strain, and other environmental mycobacteria. It was first reported in an Algerian child in 1951, who presented with disseminated BCG disease. Children with MSMD are relatively asymptomatic compared to other PIDs that are associated with life-threatening serious infections. It is caused by the defect in the interaction between CD4-TH1 cells and phagocytes due to the break in IL-12 and IFN-gamma axis pathway. Various mutations have been found in four genes (IFNGRI, IFNGR2, IL12B, and IL12RB1), causing different disorders with impaired IFN-gamma-mediated immunity. The severity of the clinical phenotype depends on the genotype. The most severe variant of MSMD is the complete gamma IFN receptor deficiency due to autosomal recessively inherited mutation in the IFNGR1 gene.[2] Hence, children with this disorder are more prone to develop disseminated mycobacterial infections on exposure to a less virulent nontuberculous mycobacterium like the BCG vaccine strain. This child is a typical prototype of this condition. In patients with Autosomal Recessive (AR) mutation in IFNGR gene, there is a complete lack of IFN-gamma receptor (C-GRID) in the phagocytic histiocytes. Hence, the histiocytes will not be activated to form a granuloma by mediator IFN-gamma secreted by CD4+ TH1 cells. Hence, these cases have no granuloma formation.

The incidence of disseminated BCG infection is between 0.06 and 1.56 per million vaccinated children, with mortality in approximately 60% of cases. Bernatowska et al. suggested typical histopathological changes with granulomas as one of the criteria for the diagnosis of disseminated BCG infection in children with PID.[3] However, in our case, although there was disseminated Mycobacterial tuberculosis infection, there were no typical histopathological changes neither in the lymph nodes nor in the skin biopsy. Hence, these criteria may not hold good in some of the cases. Demonstrating the mycobacterium by polymerase chain reaction or culture, especially in patients with MSMD, may be required.

There is a paucity of articles in the literature that has described the lymph node histology in these cases, but few have highlighted its similarity to histology seen in AIDS patients with disseminated Mycobacterium avium-intracellulare infection. Lammas et al. have described this type of histiocytic response as Type-2 (lepromatous-like granulomas).[4]

Effacement of nodal architecture by the population of lymphoid cells without necrosis and granuloma often initially misdirects the diagnosis toward a lymphoproliferative disorder. There were also many mononuclear and occasional binucleated RS-like atypical cells with prominent acidophilic nuclei. The presence of scattered eosinophils among the lymphoid cells still favored the diagnosis of mixed cellularity variant of Hodgkin's disease. The eosinophilic infiltrate is probably the reflection of peripheral blood eosinophilia. The cause for eosinophilia in this case is not known. The occurrence of foamy vacuolated cells also has been reported in Hodgkin's disease. However, the frequency and typical morphology of RS cells were relatively lacking in this case.

Mycobacterium infection was missed in biopsy due to the lack of granuloma or necrosis. On reviewing the slide, the vacuolated cells were striking and were similar to “lepra cells” in lepromatous leprosy. The AFB stain highlighted the clump of bacilli and confirmed the diagnosis. Jouanguy et al. reported a similar case, where no granuloma was found in the lymph node biopsy.[5] Mohapatra et al. reported a case of TH1 immunodeficiency with BCG-osis, in which the lymph node histology revealed poorly formed granuloma with foamy histiocytes. However, in their cases, the absolute CD4+ T-helper cell count was 2064/μl (71.63%), which is normal and adequate to stimulate the granuloma formation through IL-12/IFN-gamma axis.[6]

The diagnosis of MSMD can be made through flow cytometry by checking for IFN-gamma and IL-12 receptors on monocytes and T-cells, respectively. Serum IFN-gamma levels are also used, which are either elevated in IFN-gamma receptor deficient type or decreased in IL 12 and IL-12R deficient type. However, genetic studies should be done to confirm all the types.[7]

  Conclusion Top

BCG-induced lymphadenitis should be considered as one of the differential diagnoses while interpreting lymph node biopsies, especially of the axillary region in the early infants. In immunodeficient children, the nodal architecture may be totally effaced with scattered atypical cells, and eosinophils mimic a lymphoproliferative disorder. Epithelioid cells and granulomas may be seen in BCG adenitis patients with Autosomal Dominant (AD) mutation in IFNGR gene or other MSMD variants, but not in patients with AR mutation in IFNGR gene. In such cases, the presence of vacuolated cells with a predominant histiocytic population in the background should alert the pathologist and should be confirmed with AFB stain. Stem cell transplantation not only appears to be the only curative option but also carries the risk of graft rejection in some of the cases.[8]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal parent has given his consent for images and other clinical information to be reported in the journal. The parent understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Wu UI, Holland SM. A genetic perspective on granulomatous diseases with an emphasis on mycobacterial infections. Semin Immunopathol 2016;38:199-212.  Back to cited text no. 1
Bustamante J, Picard C, Boisson-Dupuis S, Abel L, Casanova JL. Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases. Ann N Y Acad Sci 2011;1246:92-101.  Back to cited text no. 2
Bernatowska EA, Wolska-Kusnierz B, Pac M, Kurenko-Deptuch M, Zwolska Z, Casanova JL, et al. Disseminated bacillus Calmette-Guérin infection and immunodeficiency. Emerg Infect Dis 2007;13:799-801.  Back to cited text no. 3
Lammas DA, de Heer E, Edgar JD, Novelli V, Ben-Smith A, Baretto R, et al. Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-gamma production pathway. Int J Exp Pathol 2002;83:1-20.  Back to cited text no. 4
Jouanguy E, Altare F, Lamhamedi S, Revy P, Emile JF, Newport M, et al. Interferon-gamma-receptor deficiency in an infant with fatal bacilli Calmette-Guerin infection. N Engl J Med 1996;335:1956-61.  Back to cited text no. 5
Mohapatra S, Sethy S, Mohanty P, Mohapatra A, Pradhan S. Primary paediatric TH1 immunodeficiency with BCG-osis. Int J Case Rep Images 2012;3:36-40.  Back to cited text no. 6
Remus N, Reichenbach J, Picard C, Rietschel C, Wood P, Lammas D, et al. Impaired interferon gamma-mediated immunity and susceptibility to mycobacterial infection in childhood. Pediatr Res 2001;50:8-13.  Back to cited text no. 7
Olbrich P, Martínez-Saavedra MT, Perez-Hurtado JM, Sanchez C, Sanchez B, Deswarte C, et al. Diagnostic and therapeutic challenges in a child with complete interferon-γ receptor 1 deficiency. Pediatr Blood Cancer 2015;62:2036-9.  Back to cited text no. 8


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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