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Year : 2020  |  Volume : 63  |  Issue : 2  |  Page : 315-318
Granuloma in marrow with lurking “Leuk”: Two happenstances

1 Department of Pathology, First Floor, Light House Hill Road, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India
2 Department of Medicine, Consultant Hematologist, Kasturba Medical College Hospital, Attavara, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India

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Date of Web Publication18-Apr-2020


Granulomas are described very rarely in marrow biopsies. They have hardly been reported in association with acute lymphoblastic leukemia. We herein report two cases of ALL associated with granulomas each at different stage of their clinical course that led to a diagnostic and therapeutic dilemma. First case was of a 42-year-old woman diagnosed with tuberculosis who presented with bleeding gums during anti-tubercular therapy. In the second scenario, a 51-year-old man presented with pyrexia of unknown origin and splenomegaly who was put on a trial of ATT. Peripheral smear showed only 1–2% abnormal cells, however, bone marrow aspiration and flow cytometry pattern was diagnostic of ALL. Both the patients received chemotherapy and have been on remission so far. These case scenarios put forward a relevant question on this rare coexistence, as the implications on management are manifold.

Keywords: Acute lymphoblastic leukemia, granuloma, tuberculosis

How to cite this article:
Sreeram S, Basavaiah SH, Murali N, Balanthimogru P. Granuloma in marrow with lurking “Leuk”: Two happenstances. Indian J Pathol Microbiol 2020;63:315-8

How to cite this URL:
Sreeram S, Basavaiah SH, Murali N, Balanthimogru P. Granuloma in marrow with lurking “Leuk”: Two happenstances. Indian J Pathol Microbiol [serial online] 2020 [cited 2021 Nov 27];63:315-8. Available from: https://www.ijpmonline.org/text.asp?2020/63/2/315/282721

   Introduction Top

Granulomas are like gold dust in a bone marrow (BM) biopsy. Reports describe their incidence as low as 0.3% to as high as 2.2% in biopsies.[1] Many disease processes can show granulomas in the marrow, however, they are not pathognomonic for a certain disease. Malignancies like Hodgkin lymphoma and to a lesser extent, Non-Hodgkin lymphoma (NHL) have been described to show granulomas.[2] Tuberculosis (TB) is the chief granulomatous disease, which is prevalent in our country.[3] We herein report two cases where acute lymphoblastic leukemia (ALL) was associated with granulomas on bone marrow evaluation leading to a theranostic dilemma.

   Case History Top

Patient 1

A 42-year-old woman, presented with fever, loss of appetite and left neck swelling of three weeks duration. Bilateral pedal edema and maculopapular rash were present since one week. The cervical lymph nodes were non tender, discrete and partly mobile measuring 4 × 3 × 3 cm. Lymph node biopsy revealed granulomatous lymphadenitis [Figure 1]a and antitubercular therapy (ATT) was started. After 3 days of starting ATT, a bone marrow evaluation was planned in view of pancytopenia. Bone marrow aspiration did not yield good cellularity apart from presence of collections of epithelioid histiocytes forming granulomas [Figure 1]b. However, the BM biopsy showed focal aggregates of lymphoid cells and histiocytes with normal hematopoiesis [Figure 1]c. There was no evidence of caseous necrosis in lymph node and bone marrow biopsies. Ziehl Neelsen stain on these tissue biopsies was negative for acid fast bacilli (AFB). Patient showed response to ATT and was discharged. During the continuation phase of ATT, i.e., 3 months after the diagnosis, the patient presented with burning sensation in mouth and throat for a duration of 7 days. She was pale on examination and had palpable lymphadenopathy. There was no organomegaly. Oral ulcers, blackish discoloration of tongue and gum swelling were present. Blood investigations showed raised leukocyte counts of 1.57 lakhs/cu.mm with 96% lymphoblasts. Platelet count was markedly reduced. The flow cytometry proved the leukemia is of lymphoblastic origin with a diagnosis of precursor B acute lymphoblastic leukemia (Pre B-ALL). The patient received chemotherapy for ALL, completed ATT and has been on remission so far.
Figure 1: (a-f) Initial presentation of Case 1 and 2: (a-c) Case 1: (a) Lymph node biopsy: The lymph node architecture is disrupted with extensive caseous necrosis (arrow). [H and E stain: 40×]. Inset: Note the presence of Langhans giant cells (arrow heads) adjacent to caseous necrosis [H and E stain: 400×]. (b) Bone marrow aspirate: Presence of epithelioid granulomas admixed with lymphocytes [Leishman stain: 400×]. (c) Bone marrow biopsy: Lymphoid aggregates (arrow) were noted. Occasional histiocytic aggregates were noted. Megakaryocyte (arrow head) is seen [H and E stain: 200×]. (d-f) Case 2: (d) Bone marrow aspirate: Epithelioid granulomas seen [H and E stain: 400×]. (e, f) Bone marrow biopsy: Discrete epithelioid granulomas composed of epithelioid cells rimmed by lymphocytes [Leishman stain: 400×]

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Patient 2

A 51-year-old man presented with intermittent fever of 1 month duration associated with chills, headache and dry cough. On examination, there was no organomegaly or lymphadenopathy. Complete blood count and peripheral smear examination showed anemia, leukopenia, and normal platelet count with absence of abnormal cells. Empirical antibiotics were given, however, blood culture was negative. Computed Tomography of chest and abdomen showed mediastinal and celiac lymphadenopathy along with hypodense lesions in spleen. Granulomatous process versus lymphoma was suspected. ATT was started and the patient responded well. Later in the course of admission, in view of persistent cytopenias and generalized lymphadenopathy, bone marrow examination was planned and marrow aspiration showed 90% abnormal lymphoid cells of small to medium size, scant cytoplasm, coarse nuclear chromatin and 1-2 nucleoli [Figure 2]a, [Figure 2]b, [Figure 2]c with scattered granulomas [Figure 1]d. Biopsy showed lymphoblasts along with discrete collections of epithelioid cells [Figure 1]e and [Figure 1]f, but was negative for necrosis or AFB. Flow cytometry confirmed the diagnosis to be Pre B-ALL [Figure 2]d, [Figure 2]e, [Figure 2]f. Bone marrow culture and polymerase chain reaction (PCR) for AFB turned out to be negative, and the case was concluded as ALL with granulomas. The patient received chemotherapy for ALL, completed ATT and has recovered well.
Figure 2: (a-f) Transformation into acute lymphoblastic leukemia. (a-c) Bone marrow aspirate: (a) Highly cellular marrow particles [Leishman stain: 400×]. (b) Diffuse infiltration by lymphoblasts. (c) Lymphoblasts with high N:C ratio, scant cytoplasm with single prominent nucleoli [Leishman stain: 400×]. (d-f) Immunophenotypic analysis: (d) Blasts with CD34 and HLADR positivity. (e) Blasts co-expressed B-cell markers CD10 and CD19. (f) B-lymphoblasts with cytoplasmic CD79a expression. Note the cytoplasmic MPO is negative

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Both the patients were not neutropenic at the time of clinical diagnosis. Both patients had no past history of TB and were non-reactive for human immunodeficiency virus (HIV). Both the cases had no evidence of any other infection after detailed microbiological investigations.

   Discussion Top

The mean prevalence of TB in India is 5/1000, the annual risk of acquiring the infection being 1.5%.[3] TB is seen in 0.72–2.6% of cancer patients as per available data.[4] The approximate frequency of TB in acute leukemia ranges from 3 to 4/1000 newly diagnosed cases of leukemia in the West to 22–28/1000 in India.[3],[5]

Cancers and cytotoxic therapy augment the peril of bacterial and fungal infections. TB has not been the prevailing infection in nearly all case series. TB in acute leukemia might have been underrated, since antibiotics used during chemotherapy like amikacin and quinolones are also potent against TB.[3] High prevalence of TB in India, damage to host defenses, reactivation of latent organism in impaired immunity, nutritional deficiency and frailty are some factors which contribute to the occurrence of TB among cancer patients, substantially during treatment. Intensity of treatment augments the risk of TB especially, with use of radiotherapy, steroids and other immune-suppressants. Hence, an increased frequency of TB would be expected in ALL. However, review of literature suggests that acute myeloid leukemia (AML) patients are more likely to develop TB compared to ALL.[3] In contrast to development of TB during leukemia therapy, the first patient in this case series developed leukemia during ATT. To the best of our knowledge, there are no reported data in the literature on development of ALL in patients with TB. We authors assume that this association of TB with subsequent development of ALL may be by chance occurrence. More documentation, if any, might prove whether such association exists or not.

Granulomas have been reported previously in AML in association with sarcoidosis.[6] Also, the pathogenesis of granulomas in AML was attributed to be a response to anti-tumor antigens and circulating immune complexes in leukemia. The second patient in this series had granulomas with ALL and presence of granulomas added to the diagnostic dilemma.[7] The patient showed clinical improvement with ATT. However, microbiological investigations did not yield tubercle bacilli. Nonetheless, ALL with a granulomatous tumor reaction, without any associated disease, has so far not been reported to the best of our knowledge.

The quandaries in our cases were many: (1) diagnostic, between TB and leukemia/lymphoma with granuloma or the synchronism of both; (2) therapeutic, in terms of effectiveness of ATT in the context of leukemia; (3) prognostic, atypical presentation of leukemia with TB culminating in a possible delayed diagnosis and hence, poor outcome. The current American Thoracic Society (ATS)/Centers for Disease Control (CDC)/Infectious Disease Society of America (IDSA) guidelines state that, if, after correlating the epidemiological, clinical, radiological, microbiological and pathological features, the clinician concludes that TB is likely, the patient should be started on ATT.[8] Response to ATT was seen in both our patients. TB generally has a benign course in acute leukemia with a good response to ATT.[3] Kim and colleagues stated that malignancy does not have an effect on the presentation or response to ATT.[9] Both of our patients, likewise, showed a good response.

To conclude, granulomas are incidental findings in biopsy, especially when they occur simultaneously with another pathology, and warrant a detailed clinical workup. Granulomas are uncommon in acute leukemia and hence, a systematic approach by correlating clinical features with pathological and microbiological findings is needed to identify the cause of granuloma especially in TB endemic regions. Exclusion of an active mycobacterial disease is recommended before commencing chemotherapy. In fact, even chemoprophylaxis can be indicated in TB endemic areas.

Declaration of patient consent

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

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Conflicts of interest

There are no conflicts of interest.

   References Top

Basu D, Saravana R, Purushotham B, Ghotekar LH. Granulomas in bone marrow—A study of fourteen cases. Indian J Pathol Microbiol 2005;48:13–6.  Back to cited text no. 1
Eid A, Carion W, Nystrom JS. Differential diagnoses of bone marrow granuloma. West J Med 1996;164:510–5.  Back to cited text no. 2
Mishra P, Kumar R, Mahapatra M, Sharma S, Dixit A, Chatterjee T, et al. Tuberculosis in acute leukaemia: A clinico-hematological profile. Hematology 2006;11:335–40.  Back to cited text no. 3
Omoti CE, Olu-Eddo AN, Nwannadi AI. Co-existence of TB and adult hematological cancers in Benin City, Nigeria. Trop Doct 2009;39:205–7.  Back to cited text no. 4
Jagarlamudi R, Kumar L, Kochupillai V, Kapil A, Banerjee U, Thulkar S. Infections in acute leukemia: An analysis of 240 febrile episodes. Med Oncol 2000;17:111–6.  Back to cited text no. 5
Ozbudak O, Ozbudak IH, Wang KP. Association between acute myeloblastic leukaemia and sarcoidosis. West Indian Med J 2009;58:185–7.  Back to cited text no. 6
Greiner J, Schmitt M, Li L, Giannopoulos K, Bosch K, Schmitt A. Expression of tumor-associated antigens in acute myeloid leukaemia: Implications for specific immunotherapeutic approaches. Blood 2006;108:4109–17.  Back to cited text no. 7
Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A. Official American thoracic society/centers for disease control and prevention/infectious diseases society of America clinical practice guidelines: Treatment of drug-susceptible tuberculosis. Clin Infect Dis 2016;63:e147–95.  Back to cited text no. 8
Kim DK, Lee SW, Yoo CG, Kim YW, Han SK, Shim YS, et al. Clinical characteristics and treatment responses of tuberculosis in patients with malignancy receiving anticancer chemotherapy. Chest 2005;128;2218–22.  Back to cited text no. 9

Correspondence Address:
Sridevi Hanaganahalli Basavaiah
Department of Pathology, First Floor, Light House Hill Road, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_96_19

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