Presentation

Most patients with AA present with symptoms of anemia or bleeding due to deficient red blood cell and platelet production. Infection associated with low neutrophil numbers is not a common initial presentation. Often, AA is uncovered incidentally; patients may remain asymptomatic for a long time due to the latent onset of anemia. Consequently, the latency period and the onset of the disease are difficult to determine. In some cases, when AA is discovered early, a follow-up blood examination will reveal progressive worsening of cytopenia.

DEFINITION, DIAGNOSIS, AND DIFFERENTIAL DIAGNOSIS Definitions and classification

According to the useful definition of the AA Working Party, AA is defined by bone marrow cellularity (usually <10%) and a decrease in two out of three blood lineages. Cytopenia secondary to other hematologic diseases and systemic conditions has to be excluded. The issue of the requirement of normal cytogenetics is a subject of some controversy, especially that in a proportion of patients, cytogenetic analysis may not be informative. Most experts believe that the presence of karyotypic abnormalities at presentation is consistent with the diagnosis of MDS, excluding idiopathic AA. According to the severity classification proposed by Camitta69 (Table 41.3), patients with moderately depressed counts have an excellent prognosis even if untreated, while those with severely affected blood counts have poor survival in the absence of therapy.

Differential diagnosis

A large number of conditions may mimic AA in all or some of its aspects and features, and depending on the clinical circumstances, some alternate diagnoses have to be excluded (Figure 41.4). Several systemic diseases can present with an aplastic bone marrow; bone marrow biopsies can be hypocellular in up to 10% of patients with MDS.1-3 In addition, marrow aplasia can be encountered in hairy cell leukemia, or be iatro-genic. Discrimination of AA and MDS may be particularly challenging if hypocellularity precludes proper morphologic evaluation and cytogenetic examination is not informative. Clues may be provided by presence of micromegakaryocytes, myeloid dysplasia, and residual blasts.

Table 41.3 Classification of aplastic anemia by severity

Aplastic anemia Severe aplastic anemia Moderate aplastic anemia

Bone marrow cellularity, 10% Depression of at least two out of three hematopoietic linegages: ANC,500/uL Transfusion dependence with absolute reticulocyte count (ARC), 60,000/uL Platelets count

Decreased bone marrow cellularity

Depression of at least two out of three hematopoietic lineages not fulfilling the severity criteria as specified in the right column

Figure 41.3 Bone marrow finding in AA. (a) Peripheral blood smear from a patient with aplastic anemia demonstrates severe pancytopenia with normocytic to slightly macrocytic anemia, neutropenia, and thrombocytopenia (peripheral blood, Wright-Giemsa stain, original magnification X 100). (b) Bone marrow touch imprints may be helpful in excluding mimics of aplastic anemia, such as hairy cell leukemia, which can result in a dry tap. This low-power image of a touch imprint reflects the overall hypocellularity encountered in aplastic anemia (bone marrow biopsy touch imprint, Wright-Giemsa stain, original magnification X 10). (c) Bone marrow biopsy in aplastic anemia illustrates severe panhypoplasia with only rare scattered lymphocytes and plasma cells (bone marrow core biopsy, hematoxylin-eosin stain, original magnification X40). (d) Because marrow cellularity may vary geographically within the biopsy, with the area immediately subjacent to the cortex often being hypocellular, it is essential to obtain an adequately sized core biopsy when evaluating for possible aplastic anemia (bone marrow core biopsy, hematoxylin-eosin stain, original magnification X 10). (e) Hypocellular MDS can mimic aplastic anemia. In this biopsy, mature myeloid elements are reduced, and the presence of occasional mononuclear cells consistent with blasts (arrow) can be a subtle feature. Marrow aspirate smear (inset) showed 9% myeloid blasts with dysplastic changes in erythroid precursors (bone marrow core biopsy, hematoxylin-eosin stain, original magnification X40; inset: bone marrow aspirate, Wright-Giemsa stain, original magnification X 100) (courtesy of Dr. Karl Theil, Cleveland Clinic)

Figure 41.3 Bone marrow finding in AA. (a) Peripheral blood smear from a patient with aplastic anemia demonstrates severe pancytopenia with normocytic to slightly macrocytic anemia, neutropenia, and thrombocytopenia (peripheral blood, Wright-Giemsa stain, original magnification X 100). (b) Bone marrow touch imprints may be helpful in excluding mimics of aplastic anemia, such as hairy cell leukemia, which can result in a dry tap. This low-power image of a touch imprint reflects the overall hypocellularity encountered in aplastic anemia (bone marrow biopsy touch imprint, Wright-Giemsa stain, original magnification X 10). (c) Bone marrow biopsy in aplastic anemia illustrates severe panhypoplasia with only rare scattered lymphocytes and plasma cells (bone marrow core biopsy, hematoxylin-eosin stain, original magnification X40). (d) Because marrow cellularity may vary geographically within the biopsy, with the area immediately subjacent to the cortex often being hypocellular, it is essential to obtain an adequately sized core biopsy when evaluating for possible aplastic anemia (bone marrow core biopsy, hematoxylin-eosin stain, original magnification X 10). (e) Hypocellular MDS can mimic aplastic anemia. In this biopsy, mature myeloid elements are reduced, and the presence of occasional mononuclear cells consistent with blasts (arrow) can be a subtle feature. Marrow aspirate smear (inset) showed 9% myeloid blasts with dysplastic changes in erythroid precursors (bone marrow core biopsy, hematoxylin-eosin stain, original magnification X40; inset: bone marrow aspirate, Wright-Giemsa stain, original magnification X 100) (courtesy of Dr. Karl Theil, Cleveland Clinic)

Diagnostic procedures

Diagnostic procedures include blood counts and a differential, and a bone marrow aspiration and biopsy (Figure 41.5). A reticulocyte count should always be obtained to assess severity and establish that anemia is related to the deficient marrow red blood cell production. The marrow exam should include cytoge-netic evaluation. The presence of even small numbers of blasts strongly questions the correctness of the AA diagnosis. The residual erythropoiesis may be mega-

loblastic; overt dysplasia of the myeloid series should not be seen in typical AA. Megakaryocytes are most typically absent or severely decreased in number. Routine flow cytometry of blood is not indicated, but may be helpful in excluding T-cell lymphoprolifera-tive syndromes and B-cell malignancies, especially hairy cell leukemia. Due to a common association and possible prognostic considerations, the presence of PNH should be investigated by flow cytometry on both red blood cells and granulocytes, which provide

Hypocellular bone marrow

Acquired aplastic anemia Fanconi anemia Aleukemic AML (rare) Hairy cell leukemia Hypocellular MDS

Myelofibrosis

Pacytopenia

Hypercellular bone marrow

Hematologic diseases MDS PNH

Myelofibrosis

Lymphoma

Myeloma

Hypothyrodism Anorexia nervosa Infections e.g.

Tuberculosis Q fever

Systemic diseases SLE

Hypersplenism

Sepsis

Alcohol

Brucellosis

Ehrlichiosis

Figure 41.4 Differential diagnosis of idiopathic aplastic anemia and pancytopenia a much more sensitive and, unlike erythrocytes, transfusion-independent assessment of the size of the PNH clone. In younger patients, Fanconi anemia should be excluded by diaminobenzidine (DAB) testing. Splenomegaly and lymphadenopathy are atypi-

Blood Counts

Pancytopenia

Bone Marrow Exam

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