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958 Part VII Hematologic Malignancies

Lymphoid Lineage TABLE
60.3 Diagnostic Criteria for Myelodysplastic Syndrome
A number of abnormalities in the lymphoid lineage have been
described in subsets of patients with MDS. Some patients have been A. Presence of at Least One Unexplained Cytopenia for at Least 6
a
Months
shown to have global decreases in NK cells, 226,320 some have deficient
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receptor localization on B cells, and some have abnormal T-cell Hemoglobin <11 g/dL, or
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responses to mitogenic stimuli. Certain types of immune functions, Absolute neutrophil count <1.5 × 10 /L, or
however, appear to be preserved, such as antibody-dependent cellular Platelet count <100 × 10 /L
9
cytotoxicity. 321 plus B. Presence of One or More MDS-Qualifying Criteria:
The mechanism by which these abnormalities develop in MDS is >10% dysplasia in one or more hematopoietic lineage, or
unclear. One hypothesis proposes that they could be indirectly reflec-
tive of shared somatic defects in a multipotent progenitor. Although 5%–19% blasts in bone marrow, or
this has not been directly proven, it is theoretically possible given data MDS-defining cytogenetic abnormality, such as:
showing that most driver mutations in MDS patients are present in t(1;3)(p36.3;q21.1) t(2;11)(p21;q23) inv(3)(q21;q26.2)
the long-term hematopoietic stem cells (LT-HSC) compartment and
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could therefore be passed both to myeloid and lymphoid cells. t(3;21)(q26.2;q22.1) −5 or del(5q) t(6;9)(p23;q34)
Alternatively, a number of immune functions, including both B-cell −7 or del(7q) del(9q)
and T-cell diversity, diminish as a function of normal aging, 322,323 and del(11q) t(11;16)(q23;p13.3) del(12p) or t(12p)
in this context, deficiencies of immune function could develop as a −13 or del(13q) i(17q) or del(17p) idic(X)(q13)
consequence of lymphoid cells arising from and interacting with an
abnormally aged hematopoietic niche. plus C. Exclusion of Alternative Diagnoses
AML (i.e., <20% blasts, and no t(8;21), inv(16), t(16;16), t(15;17),
or erythroleukemia) or ALL
Other Objective Findings Other hematologic diseases (aplastic anemia, PNH, LGL, lymphoma,
myelofibrosis and other MPN)
Patients with MDS may have a variety of other laboratory abnormali- Viral infections (HIV, EBV, parvovirus)
ties as a consequence of their disease. Ineffective erythropoiesis may
lead to inappropriate iron deposition, resulting in abnormally elevated Nutritional deficiencies (iron, copper, B 12 , folate)
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ferritin and transferrin saturation. Nonspecific markers of cellular Medications (methotrexate, azathioprine, isoniazid, cytotoxic
325
turnover, such as elevations in lactate dehydrogenase, uric acid, chemotherapy)
and phosphate, may also be seen. Reflective of underlying immune Alcohol or other toxins
dysregulation, some patients may have abnormalities of immuno-
globulins (Igs), including hypogammaglobulinemia, polyclonal Autoimmune diseases (SLE, Felty syndrome, ITP, autoimmune
hypergammaglobulinemia, and even monoclonal gammopathies. 326,327 hemolytic anemia)
Whether this latter phenomenon is directly related to MDS or to an Congenital disorders (Diamond-Blackfan anemia, Shwachman-
unrelated, early plasma cell dyscrasia has not been definitively estab- Diamond syndrome, Fanconi anemia, and others)
lished, and the answer may indeed be different in different patients. a Diagnosis can be made earlier than 6 months if no other cause is apparent for
cytopenias, or there are excess blasts or an MDS-defining cytogenetic
abnormality
DIAGNOSTIC SYSTEMS AND CLINICAL SYNDROMES ALL, Acute lymphoblastic leukemia; AML, acute myeloid leukemia;
EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; ITP, immune
thrombocytopenic purpura; LGL, large granular lymphocyte leukemia;
As discussed throughout this chapter, MDS is heterogeneous in both MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm;
morphology and clinical course, a characteristic that requires diag- PNH, paroxysmal nocturnal hemoglobinuria; SLE, systemic lupus
nostic criteria sufficiently broad to capture the entire spectrum of erythematosus.
disease, and diagnostic criteria are typically left purposefully vague to
allow for inclusion of patients in whom a high suspicion of MDS
exists but who do not specifically meet these formal criteria (Table complexity of the criteria themselves, which can make them cumber-
60.3). Patients with MDS typically have at least one persistent, some for clinicians to use. Second, as described previously, there are
otherwise unexplained cytopenia (hemoglobin less than 11 g/dL, a number of conditions that can mimic aspects of MDS, and the
3
3
ANC <1,500/mm , or platelet count less than 100,000/mm ), plus diagnostic criteria assume these diagnostic possibilities have been
one of the following: (1) ≥5% blasts in the bone marrow, (2) any of eliminated. Third, morphologic criteria are still based around strict,
several chromosomal abnormalities that are found recurrently in arbitrary percentages of dysplasia and blasts, which can be interpreted
MDS; (3) a meaningful degree of dysplasia, usually 10% or more, differently by different pathologists or may be vulnerable to sampling
detectable in at least one cell lineage on bone marrow examination, variations. 328,329 Finally, although WHO criteria incorporate cytoge-
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or (4) other evidence of clonal hematopoiesis. In the past this latter netics to a limited extent, the criteria have not yet been updated to
category has usually comprised either karyotype or FISH results include types of newer genetic results that have been shown to have
demonstrating chromosomal abnormalities missed by conventional diagnostic value, and it is likely that incorporating some of these
karyotype, but evidence of clonal hematopoiesis based on detection features will improve diagnostic clarity. A 2016 revision of the WHO
of recurrent somatic mutations may need to be considered as well. criteria eliminated the term “refractory anemia” so that, for example,
However, given that at least 10% of the population aged 70 or older RAEB-1 is now known as “MDS with excess blasts” (MDS-EB). This
harbor point mutations in genes associated with myeloid malignan- revision also noted that MDS with ring sideroblasts (MDS-RS) can
cies, 31,32 detection of such a mutation in the absence of other diag- be diagnosed with 5% to 14% ring sideroblasts if a somatic SF3B1
nostic criteria cannot be considered equivalent to MDS. mutation is present; if SF3B1 is wild-type, at least 15% ring sidero-
As described elsewhere, the 2008 WHO criteria divide adult MDS blasts are needed.
into six general categories: RCUD (including RA, RARS, refractory
neutropenia, and refractory thrombocytopenia), RCMD, RAEB-1,
RAEB-2, MDS with isolated del(5q), and MDS-U. Despite the detail IPSS and IPSS-R
of the criteria, they still have a number of limitations, a fact that is
probably inescapable when attempting to categorize a disease with so Although the WHO classification system (and the FAB system before
many disparate manifestations. The most obvious limitation is the it) is the accepted standard for diagnosing MDS, it does not confer