The microscopic evaluation of the bone marrow is interpreted in conjunction with current hemogram results to try to identify abnormalities. Some of the more common or important interpretations and descriptions are given below.
Descriptive terms
- Left-shifted maturation: This term is used to indicate that the pyramidal maturation of cells in marrow is not present and that there is an expansion of early progenitors with fewer later stage progenitors. There could be several reasons for this finding, such as an early marrow response to cytopenias or marrow injury (a recovering or regenerating marrow) or destruction of later stage cells. The neutrophil lineage may be “left-shifted” if there is release of the storage pool of band and mature neutrophils in response to peripheral demand.
- “Maturation arrest”: This term, which is actually a misnomer as there really is not true arrested maturation, is used by some when maturation only proceeds to a particular stage with very few more mature cells being seen beyond that stage, e.g. when erythroid maturation proceeds until basophilic rubricytes but few more mature cells are seen. The latter usually implies the more mature cells are being destroyed or are dying in marrow.
- Dysplasia: This indicates that there is morphologic evidence of abnormal maturation or abnormal features in hematopoietic cells. This can be a primary bone marrow neoplastic disorder, called myelodysplastic syndrome, or secondary to drugs (e.g. vincristine), other tumors (e.g. lymphoma) or mineral/vitamin deficiencies (e.g. vitamin B12, folate). Mild dysplasia may be seen in hematopoietic precursors if the involved lineage is hyperplastic for any reason. Dysplasia is also an interpretation (see below).
Hyperplasia
This refers to an increase in a particular cell line. For myeloid cells, the term myeloid hyperplasia or granulocytic hyperplasia usually refers to neutrophils, unless a qualifying term is used (e.g. monocytic hyperplasia etc). This is an appropriate bone marrow response to a peripheral cytopenia and usually takes 3-5 days after the onset of the cytopenia to become established. The hyperplasia may be accompanied by increased marrow cellularity and an altered M:E ratio, depending on the relative changes in the myeloid and erythroid lineages. Hyperplasia is also an expected response to an increase in the relevant cell numbers. If all lineages are increased, the term “panmarrow” hyperplasia may be used. Expanded cell lines or a high marrow cellularity in the absence of cytopenia or cytosis can be difficult to interpret. We sometimes also use the term “relative” hyperplasia. This is when there is an altered M:E ratio, without an apparent explanation. For example, a high M:E ratio without a neutrophilia or anemia in a hypercellular marrow may be a relative myeloid hyperplasia and we would speculate as to reasons why.
Hypoplasia
This refers to a decrease in a particular cell line when there is concurrent peripheral cytopenias and is not the expected bone marrow response, supporting decreased bone marrow production as being one of the reasons for the cytopenias. This is usually accompanied by low marrow cellularity unless it only affects one cell line and the other cell line is expanded or there is an infiltrative or primary bone marrow neoplasm. As for hyperplasia, the term myeloid or granulocytic hypoplasia refers to neutrophils specifically, because low numbers of eosinophils, basophils and monocytes are expected in marrow. If all lineages are decreased, we can use the term “panmarrow” hypoplasia. Similar to hyperplasia, we also use the term relative hypoplasia if there is an altered M:E ratio without a cytopenia in blood.
Aplasia
This is when there are very low numbers, usually <5%, of erythroid or myeloid precursors, or no megakaryocytes and can be accompanied by decreased cellularity if it involves more than one lineage. A severe decrease in all hematopoietic cells in marrow, such that aspirates consist of fat with stromal cells (macrophages, dendritic cells, fibroblasts, mast cells, lymphocytes and plasma cells) is called bone marrow aplasia or “aplastic anemia”. Unilineage aplasia (e.g. pure red cell aplasia, pure white cell aplasia, megakaryocytic aplasia) is usually an immune-mediated condition. Bone marrow aplasia results in pancytopenia and can be due to drugs, hormones (e.g. estrogen), infectious agents (e.g. Ehrlichia canis), radiation, immune-mediated or idiopathic causes
Ineffective hematopoiesis
The term “ineffective” is used when the marrow is hyperplastic and appears to be “doing the right thing” and responding but there are still cytopenias in peripheral blood (i.e. the marrow is not effective at getting cells out into blood). It usually indicates intramedullary death of precursor cells by apoptosis, cell lysis or immune-mediated phagocytosis. The best example is precursor-directed or non-regenerative immune-mediated anemias, where there can be a severe non-regenerative anemia but an erythroid hyperplasia in bone marrow. This is attributed to immune-mediated destruction of precursor cells in marrow, which may or may not be accompanied by concurrent destruction of mature erythrocytes in blood. In some cases, there may be left-shifted erythroid maturation or “maturation arrest” and cytophagia of erythrocytes or progenitor cells (rubriphagia) by reactive macrophages in the marrow. Increased marrow iron and a lymphocytosis and plasmacytosis can also be seen in some cases and the marrow in affected dogs can be fibrotic. The severest manifestation of this immune-mediated anemia is pure red cell aplasia.
Plasmacytosis
Plasma cells usually comprise <2% of total marrow cells and are found diffusely throughout the marrow, usually associated with spicules. Plasma cells can be expanded as a reactive response in many conditions, but high numbers of cells, particularly when in sheets or large groupings, is characteristic of multiple myeloma in dogs (if infectious disease testing is negative). Whether an increase in plasma cells (lymphocytes, macrophages, mast cells) is reactive or neoplastic must be determined in each case using the bone marrow results in conjunction with other clinical, imaging and laboratory findings. Note, that multiple myeloma is not a primary bone marrow tumor. Rather, the tumor cells home to and like to live in the marrow because stromal cells are a rich source of tumor cytokines (e.g. IL-6)
Lymphocytosis
Lymphocytes, usually small mature cells, are seen in low numbers in dogs (<5-10%, with higher numbers in dogs under a year of age) with more in cats (up to 20%). They are usually a mixed population of T and B cells. As for plasma cells, a lymphocytosis can be reactive but infiltrates with mature lymphoid neoplasms (small cell lymphoma, chronic lymphocytic leukemia) or accompanying more immature neoplasms (or part of rare lymphoid tumors, such as follicular lymphoma) can be seen as diffuse or focal/multifocal dense infiltrates. Note that chronic lymphocytic leukemia is not a primary marrow disease but can infiltrate the marrow secondarily (particularly with B chronic lymphocytic leukemia in dogs),
Histiocytosis
This is an expansion of macrophages, usually demonstrating cytophagic activity to some degree, in marrow. We generally only see low numbers of macrophages in marrow aspirates (some of which could be erythrophagocytic) and expanded numbers, even if found in aggregates, can be a reactive phenomenon or part of a histiocytic neoplasm.
Mastocytosis
This is an increase in mast cells, which are generally seen very rarely in normal bone marrow. An increase in mast cells can be seen in animals with severely hypoplastic bone marrows (where it may be a relative versus a true increase – the same is true for plasma cells and lymphocytes in a bone marrow hypoplasia or aplasia), as a reactive response (rare) or part of mast cell tumor neoplasia (systemic or metastatic).
Necrosis
This is when the hematopoietic cells are dead. It usually results in pancytopenia and is associated with ischemia, sepsis, drugs, or idiopathic causes.
Fibrosis
Myelofibrosis is always a secondary and not a primary condition and is typically reticulin and not collagen fibrosis. It is best identified by a core biopsy and can be graded (I, II, III) with a reticulin stain. Collagen fibrosis occurs in the later stages of grade III reticulin fibrosis. Myelofibrosis can be suspected in an aspirate if there is difficulty obtaining marrow (repeat “dry tap”) or the obtained particles are “rubbery” and do not spread well (subtle). The most common cause of myelofibrosis in dogs is precursor-directed immune-mediated anemia and in cats is myelodysplastic syndrome or acute myeloid leukemia (very different prognoses for dogs versus cats). The fibrosis can be reversible with successful treatment of the anemia in dogs.
Primary bone marrow neoplasia
This consists of tumors that arise from the HSCs or later stages of differentiation and then differentiate down a particular path and either accumulate (chronic disease), proliferate and die (myelodysplastic syndrome) or proliferate and overtake (acute leukemia):
- Chronic myeloproliferative disease or the different types of chronic myeloid leukemia. These are generally characterized by a cytosis in blood and hyperplasia in marrow of the involved cell lineage, e.g. a high HCT and erythroid hyperplasia in a dog or cat with chronic erythroid leukemia or polycythemia vera. These leukemias are difficult to impossible to differentiate from reactive expansions on an aspirate, although a core biopsy for abnormal architectural patterns may help.
- Myelodysplastic syndrome: This is characterized by peripheral cytopenias (uni-, bi- or multiple lineages) with concurrent bone marrow hyperplasia AND evidence of dysplasia of the involved cell lines in blood and marrow, i.e. this is a variant of ineffective hematopoiesis where the cells are dying because they are neoplastic and abnormal (or their environment is) and not from immune-mediated attack. Some variants can have increased myeloid blasts (<20% of cells). Dysplasia is far easier to see in an aspirate versus a core biopsy, however the latter may show abnormal architectural features (e.g. clustering of megakaryocytes or groups of blasts) that will not be evident in an aspirate.
- Chronic myeloproliferative disease/myelodysplasia: This encompasses specific subtypes of hematopoietic neoplasms that bridge the chronic leukemias (hyperplasia of lineages in blood and marrow with extramedullary infiltrates) and the myelodysplastic syndromes (dysplasia in lineages). We have seen these in dogs, but not cats and the main types are chronic myelomonocytic leukemia, which has a neutrophilia and a monocytosis and prominent neutrophil and monocyte dysplasia in peripheral blood and myeloid (neutrophilic and monocytic hyperplasia) with dysplasia in marrow. We have also seen cases of atypical chronic myeloid leukemia in dogs, which differs from chronic myelomonocytic leukemia in that it consists of neutrophils primarily and differs from chronic neutrophilic leukemia in that there is prominent dysplasia in neutrophils and/or other lineages (e.g. micromegakaryocytes) (Marino et al 2017).
- Acute leukemia: This can be myeloid (any lineage), lymphoid, undifferentiated or mixed lineage/phenotype. Acute leukemia is when there is >20% myeloid or >25% lymphoid blasts in marrow. Blasts cannot be identified as to lineage by morphologic features alone, therefore phenotyping (immunologic- or cytochemical-based methods) are needed to distinguish the type of leukemia. Blasts are far easier to identify in aspirates versus core biopsies. An extensive intermediate or large cell lymphoma infiltrate can be difficult to distinguish from a primary acute lymphoid leukemia (in human medicine, these are considered to be a spectrum of the same disorder of immature lymphoid neoplasms).
Infiltrative neoplasms
These are tumors that do not arise in the marrow but infiltrate the marrow secondarily. They can replace marrow cells (called myelophthisis) or alter the marrow environment, causing cytopenias, or may only be found in low numbers during staging (e.g. lymphoma). Although low numbers of infiltrating cells can be readily identified in marrow aspirates, multifocal or focal aggregates may be missed on aspiration and will best be identified on a core biopsy with immunohistochemical staining to identify B (Pax-5, CD20) or T cells (e.g. CD3). In the case of histiocytic sarcoma, the tumor cells themselves may be hemophagocytic, resulting in cytopenias. The most common neoplasms that infiltrate the bone marrow in small animals are lymphoma, multiple myeloma (also called a systemic plasma cell tumor), histiocytic sarcoma (dogs), mast cell tumor, and chronic lymphocytic leukemia.
