Benign Causes of Bone Marrow Abnormalities Including Infections, Storage Diseases, Systemic Disorders, and Stromal Changes

Epstein-Barr Virus

An acute EBV infection in an immunocompetent host (i.e., infectious mononucleosis [IM]) is typically characterized by the presence of atypical lymphocytosis in association with sore throat, fever, and lymphadenopathy. Laboratory findings include the presence of IgM antibody to EBV. More commonly the heterophile antibody, or monospot, test is performed to confirm acute infection. The peripheral blood usually has lymphocytosis with 10% or more large, atypical lymphocytes ( Fig. 6.1 ). These large lymphocytes appear approximately 3 to 4 days after the appearance of symptoms. The lymphocytosis may persist for several months.

The bone marrow is not typically examined in cases of IM. The changes in bone marrow associated with acute EBV infection are generally nonspecific and include lymphoid aggregates; increased CD8+ lymphocytes, including atypical forms; increased M:E ratio; and a left shift in myeloid. maturation. Confirmation of the diagnosis on a bone marrow sample can be accomplished with various immunohistochemical stains or in situ techniques for EBV in acute infections.

Chronic active EBV infection is a systemic lymphoproliferative disorder occurring primarily in children and young adults of Asian or Latin American descent, although rare older individuals may be affected. Patients exhibit IM-like symptoms (fevers, lymphadenopathy, and organomegaly) that occur at least 3 months after primary infection and with no known immunodeficiency. The bone marrow shows subtle interstitial and/or sinusoidal infiltrates of small mature T or natural killer cells that are EBV positive by in situ hybridization. These cells might not be apparent on H&E staining and become apparent only on staining for EBV; therefore a high index of suspicion is required. High-titer EBV viral capsid antigen IgG and early antigen IgG can be demonstrated in serum as can EBV DNA by polymerase chain reaction. By definition, T-cell receptor gene rearrangement studies are polyclonal; if monoclonal, a diagnosis of EBV-positive T-cell lymphoma of childhood (World Health Organization [WHO] 2016) is warranted. This bona fide T-cell malignancy is covered in Chapter 9 , Peripheral T-cell Lymphomas. Prognosis is guarded with indolent behavior in some patients, whereas others may die of the disease. Evolution to monoclonal disease, overt T-cell lymphoma, or macrophage activation syndrome or hemophagocytic lymphohistiocytosis may occur.

Macrophage Activation Syndrome/Hemophagocytic Lymphohistiocytosis/Hemophagocytosis

Hemophagocytic lymphocytic histiocytosis (HLH) clinically present with high fever, myalgia, fatigue and myalgia. Accompanying physical findings and laboratory abnormalities include hepatosplenomegaly, jaundice, severe cytopenias, abnormal liver function tests, hypertriglyceridemia, hyperferritinemia, and coagulopathy. It has many causes and can be divided into primary and secondary forms. Primary forms of HLH (also termed familial HLH) are rare and can occur in familial patterns or as sporadic cases. While in many cases the genetic defect may be unknown, primary HLH is often due to mutation of genes that affect cytotoxic functions in T and NK cells (such as perforin [PRF1] UNC13D, STX11, and STXBP2 ) or genes that result in lysosomal trafficking disorders that also impair cytotoxic function. These include syndromic immunologic disorders Chediak-Higashi syndrome (LYST), Griscelli syndrome (RAB27A), and Hermansky-Pudlak syndrome (AP3B1).

Secondary HLH can be seen in an association with rheumatologic/inflammatory disorder associated macrophage activation syndrome (MAS), malignancy, or infection. MAS has an associated mortality rate of about 20% and criteria for MAS in systemic juvenile arthritis are presented in Box 6.1 . Associated secondary etiologies for infection and malignancy associated (secondary) HLH are shown in Box 6.2 . Malignancy-associated HPS can be seen in conjunction with peripheral T-cell lymphomas, B-cell lymphomas, Hodgkin lymphoma, epithelial malignancies, and leukemias, in roughly that order of frequency. In cases of T-cell lymphomas, the malignant cells can be inconspicuous relative to the background of hemophagocytosis.

Hemophago­cytosis describes the presence of ingestion of hematologic cells by macrophages. The morphologic appearance of hemophagocytosis, regardless of the underlying etiology, of all types is similar. Core biopsy specimens and aspirate smears show macrophages with ingested cellular elements ( Fig. 6.2 ), most often erythrocytes; however, other hematopoietic cells can also be seen within the macrophages. The macrophages may also contain cell fragments or amorphous debris, which are remnants of hematopoietic components. The macrophages are benign and lack cytologic atypia. In core biopsy specimens, the marrow may have an unusual appearance. The inter­trabecular space is filled with cells (hemophagocytic macrophages), but there is an overall decrease in hematopoiesis. In all cases of hemophagocytosis, the marrow should be assessed carefully for signs of viral inclusions and of atypical cells that may represent an associated malignancy. The differential diagnosis also includes true histiocytic malignancies that, although rare, may also phagocytize other cellular elements. More details on MAS/HLH are presented in Chapter 19 .

HIV/AIDS

A wide variety of hematologic changes are seen in patients with HIV/AIDS ( Table 6.1 ). It is important to remember that although these findings are common in HIV/AIDS, they are also not entirely specific.

Macrocytosis with or without anemia is a common finding in HIV/AIDS peripheral blood. These effects are multifactorial, and causes include direct effects of the virus, medications, and secondary dietary deficiencies. The macrocytosis is generally mild to moderate. Rouleaux resulting from hypergammaglobulinemia, hyperviscosity, and amyloidosis have been rarely associated with HIV infection.

The most common finding in peripheral blood is lymphopenia, as a result of reduced numbers of CD4+ T cells. Occasionally there may be leukocytosis in patients with HIV/AIDS. If lymphocytosis is present, it may be composed of large granular lymphocytes, which are either CD8+ T cells or natural killer cells, or B cells with lymphoplasmacytic features. Increases in granulocytes, often with toxic changes (e.g., vacuolation, toxic granules, and Döhle bodies), may be due to bacterial infections. Nuclear fragmentation or other degenerative changes of white blood cells (WBCs) can be seen and may be due to infections or drug effects. Eosinophilia is often seen in these patients.

Autoimmune cytopenias (i.e., immune thrombocytopenic purpura [ITP], autoimmune hemolytic anemia, autoimmune neutropenia) can be seen in association with HIV/AIDS infection and can have a significant effect on the peripheral blood findings. Thrombocytopenia may be one of the earliest findings in HIV infection. The two main causes of thrombocytopenia are immune-mediated destruction and decreased production. Hypersplenism and drug effects may also contribute to low platelets.

The bone marrow findings in HIV/AIDS are protean ( Fig. 6.4 ). A wide variety of relatively specific and numerous nonspecific findings are found in the bone marrow (see Box 6.2 ). The constellation of findings is referred to as HIV myelopathy. Some of the more common findings include hypercellularity, granulomas, poorly formed histiocytic aggregates, lymphoid aggregates, plasmacytosis (with occasional Russell or Dutcher bodies), focal serous fat atrophy (gelatinous transformation), dilated sinuses, increased iron, and marrow fibrosis. Some of the less common findings include hypocellularity, infection without granuloma (low CD4 count), ring sideroblasts, hemorrhage, and diffuse serous fat atrophy or gelatinous transformation. Megakaryocytes can be infected directly by the HIV virus and consequently show several changes in HIV/AIDS. The megakaryocytes often have distinctive morphologic findings, the most pathognomonic of which is the presence of naked nuclei. Other changes include an absolute increase in number, clustering (mimicking myeloproliferative neoplasms), unilobated megakaryocytes (mimicking myelodysplastic syndromes), large forms, and abnormal nuclear chromatin.

Infectious agents of a variety of types may be seen in HIV/AIDS marrows; they may present confusing or unusual marrow findings that can mimic lymphomas, sarcomas, or epithelial malignancies. Clinical suspicion, culture results, and the use of organism stains can be beneficial. Relatively common infections in HIV/AIDS include cryptococcosis, histoplasmosis, coccidioidomycosis, pneumocystosis, HHV-8, cytomegalovirus (CMV), adenovirus, EBV, toxoplasmosis, and leishmaniasis.

Lymphoma (including Hodgkin and non-Hodgkin types), plasma cell dyscrasia, and spindle cell lesions (including Kaposi sarcoma, inflammatory pseudotumor, and mast cell disease) can also be discovered initially in the bone marrow.

Mycobacterial

A number of mycobacterial species can involve the bone marrow. Although not the most common in the United States, marrow involvement by Mycobacterium tuberculosis can be rarely associated with a diagnosis of myelophthisis (i.e., marrow failure resulting from replacement of hematopoietic marrow by an abnormal tissue causing a leukoerythroblastic blood picture). In typical cases of marrow involvement by tuberculosis, the marrow will show granulomatous inflammation, occasionally with central, caseous necrosis. The degree of involvement is variable, but immunocompetent hosts will typically form granulomas. In severely immunosuppressed patients, granulomas may be poorly formed or absent. Instead small, indistinct histiocytic aggregates may be seen. In either case, organisms are usually rare when visualized with an acid-fast stain. Immunohistochemical staining may allow visualization of more organisms.

Mycobacterium avium-intracellulare is more commonly seen in marrows of immunosuppressed patients. In the most obvious cases, there are aggregates of histiocytes filled with granular cytoplasm ( Fig. 6.5 ). Acid-fast (AFB) staining usually reveals numerous organisms that, in contrast with M. tuberculosis, stain positively with periodic acid-Schiff (PAS).