The IQMH Bone Marrow surveys allow IQMH to share a variety of interesting and educational cases, which promotes quality improvement through inter-laboratory comparison of participants’ responses and provides an external reference for a facility’s own quality assurance purposes.

Committee comments are published after the close of each survey. This educational commentary includes a clinical review of the significance of the case and its findings. Committee comments are based on the collective experience and expertise of the scientific committee and will often include recommendations based on diagnostic guidelines with reference to published scientific literature.

The discussion below is an excerpt from the BONE-2301-VSB committee comments:

The purpose of the BONE-2301-VSB survey was not to necessarily arrive at diagnostic consensus, but rather illustrate and raise awareness of potential complications that may arise from emerging therapies. In this case, the therapy was for a non-hematopoietic malignancy but resulted in hematopoietic abnormalities necessitating a bone marrow examination. Two main diagnostic findings were identified in this marrow, namely the presence of marked erythroid hypoplasia, bordering on pure red cell aplasia (PRCA) and sarcoid-like granulomas. Both findings are rare complications of therapy with immune checkpoint inhibitors.^1–3

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target inhibitory checkpoint molecules expressed by cell membrane of antigen presenting cells and CD4+ T cells, including CTLA-4, PD-1 and PD-L1.⁴ This development has opened a new pathway in the treatment of several malignancies including melanoma, kidney, and lung cancer, with the potential for many others. As with any therapy, there is the risk of adverse events in addition to the benefits of the therapy. In the case of ICIs, most of the adverse events are immune related, affecting many organ systems, particularly the gastrointestinal tract, endocrine system, skin, liver, lungs, and joints.¹ Autoimmune hematologic adverse events are quite rare but have been encountered, with the range of disorders including autoimmune hemolytic anemia, PRCA, hemophagocytic lymphohistiocytosis, immune thrombocytopenia, and aplastic anemia.

In this particular case, proerythroblasts are still present in the aspirate smear and confirmed by immunohistochemical staining for E-cadherin, but they are significantly reduced with very little evidence of maturation. PRCA may be suspected in the peripheral blood by the presence of normochromic, normocytic anemia with marked reticulocytopenia. The bone marrow demonstrates significantly reduced or absent erythroblasts.^1,5 When investigating the cause for PRCA, congenital disorders such as Diamond-Blackfan anemia should be considered in younger patients. Acquired PRCA is more common and may be caused by infection, particularly with parvovirus B19, as a side effect of various medications, as a complication of other autoimmune disorders or associated with neoplasms including thymoma, lymphoma or various carcinomas.^1,5

Granulomas are present in a small number of bone marrow specimens with clinically insignificant lipogranulomas more frequently observed (up to 10% of bone marrow samples).⁶ Epithelioid granulomas may be clinically significant with multiple subtypes identified, including caseating, ring-form, sarcoid-type and foreign body-type. Although each subtype has their own differential diagnosis, epithelioid granulomas in general are caused by various infectious diseases, noninfectious inflammatory conditions and neoplasms. Sarcoid-type granulomas are associated with sarcoidosis and provide histological confirmation of the diagnosis when identified in lymph nodes, upper respiratory tract tissue or salivary glands.⁷ These granulomas are defined as very distinct, discrete, compact collections of epithelioid histiocytes with admixed or surrounding lymphocytes. There may be variable multinucleated giant cells admixed, often Touton type. Sarcoid-like reactions have been identified in patients receiving immunotherapy, particularly with ICIs.² Of particular interest in this case, sarcoid-like granulomas associated with immunotherapy appear to be mainly reported in pulmonary and cutaneous locations with no identified cases of bone marrow involvement in literature.

*Case Discussion provided by Dr. David Good, chair of the IQMH Hematology Scientific Committee.

TAKE AWAY MESSAGE

1. With advances in treatment modalities for both neoplastic and non-neoplastic conditions, there will inevitably be adverse events affecting hematological parameters, potentially leading to bone marrow examination.
    
2. Awareness of potential treatment complications, even if quite rare, may prevent misinterpretation of bone marrow findings and incorrect reporting to
   treating physicians.
    
3. The importance of ascertaining and incorporating the patient’s clinical history, including treatment into bone marrow assessment and reporting is highlighted, to ensure correct interpretation and diagnosis.

References

1. Guo Q, Gao J, Guo H, Xie J, Cheng J. Immune checkpoint inhibitor-induced pure red cell aplasia: Case series and large-scale pharmacovigilance analysis. Int Immunopharmacol. 2023;114:109490.
    
2. Cabanié C, Ammari S, Hans S, Pobel C, Laparra A, Danlos FX, et al. Outcomes of patients with cancer and sarcoid-like granulomatosis associated with immune checkpoint inhibitors: A case-control study. Eur J Cancer. 2021;156:46-59.
    
3. Miedema J, Nunes H. Drug-induced sarcoidosis-like reactions. Curr Opin Pulm Med. 2021;27(5):439-447.
    
4. Marei HE, Hasan A, Pozzoli G, Cenciarelli C. Cancer immunotherapy with immune checkpoint inhibitors (ICIs): potential, mechanisms of resistance, and strategies for reinvigorating T cell responsiveness when resistance is acquired. Cancer Cell Int. 2023;23(1):64.
    
5. Foucar K. Erythroblastopenia. In: Foucar K, Reichard K, Czuchlewski D. Bone Marrow Pathology 3^rd Edition. Chicago: ASCP Press. 2010; 151-167.
    
6. Foucar K. Bone marrow stroma and bone disorders. In: Foucar K, Reichard K, Czuchlewski D. Bone Marrow Pathology 3^rd Ed. Chicago: ASCP Press. 2010;151-167.
    
7. Costabel U, Hunninghake GW. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur Respir J. 1999;14(4):735-7.