Epidemiology

• Median age at diagnosis of 66 years, incidence rates are as high as >15/100,000 in the older age group, and about 70% of all diagnoses of AML are in patients over 55 years of age.
• December and January as the two months with the highest number of new diagnoses, particularly for patients older than 65 years and men.

Clinical Manifestations

• Short history (1–8 weeks) of constitutional complaints (fatigue, lack of energy, malaise, profuse sweats), manifestations of bleeding (such as from gums, bruising in the skin, epistaxis, menorrhagia), or fevers.
• The white blood cell (WBC) count can vary from low to high and will range from 5000/µL to 100,000/µL in most patients.
  • The highest degrees of leukocytosis can be seen in AML with myelomonocytic differentiation.
  • Leukocytosis of 100,000/µL or higher is considered an emergency and requires immediate efforts to reduce the disease burden (e.g., leukapheresis, chemotherapy) because (1) leukostasis in some vascular beds may have catastrophic consequences (e.g., lung, brain), and (2) it may elicit a systemic inflammatory response with serious secondary organ damage (e.g., diffuse alveolar injury, hepatic failure).
  • There is not always a good correlation between the severity of leukocytosis and immediate adverse clinical effects, and far lower WBC levels may elicit life-threatening symptoms.
• Anemia and thrombocytopenia are universal.
  • Thrombocytosis is rarely identified and is characteristic of AML with abnormalities on the long arm of chromosome 3 involving the MDS1 and ecotropic viral integration site 1 (EVI1) complex locus protein EVI1 (MECOM gene, formerly called EVI1).
  • Platelet transfusions are needed to decrease the risk of hemorrhage, especially because the platelet count may be overestimated in the setting of hyperleukocytosis. Additionally, patients with hyperleukocytosis may have DIC, and leukapheresis acutely lowers the platelet count. An initial platelet count goal of 50000/μL is appropriate in the setting of hyperleukocytosis and/or DIC.
• Disseminated intravascular coagulation is often seen in patients with myelomonocytic AML, APL, and any high-WBC AML.
  • The cause of DIC is thought to be release of tissue factor-like procoagulants from the azurophilic granules within leukemia cells.
  • DIC is manifested clinically by bruising and, when severe, by bleeding from multiple sites.
  • Subclinical DIC is common in many forms of AML and can worsen with the institution of therapy.
• Extramedullary infiltrations of leukemia cells occur in the lymph nodes (11.5%), spleen (7.3%), liver (5.3%), skin (4.5%), gingivae (4.4%), and CNS (1.1%).
  • Leukemic skin infiltration, or leukemia cutis, occurs in approximately 10% of patients with AML, most commonly in those with monocytic subtypes. Skin lesions are often nodular and violaceous, are painless, and may be widespread or localized.
  • Biopsy distinguishes leukemia cutis from benign skin lesions associated with AML, including Sweet syndrome and pyoderma gangrenosum, which are typically painful and respond to corticosteroids.
  • Central nervous system (CNS) involvement (cranial nerve defects and other focal neurologic abnormalities, mental status changes, seizure activity) are rare, with the exception of AML with monocytic/monoblastic differentiation or in any AML with considerable leukocytosis (>100,000/µL).
• Hypokalemia may result from potassium uptake by rapidly proliferating AML cells or from proximal renal tubular damage caused by elevated levels of lysozyme, particularly in monocytic AML subtypes.
• Abnormalities of renal and hepatic values may represent infiltration of these organs, even in the absence of clinical symptoms.
• Bone pains are infrequent even with excessive leukocytosis and should raise the suspicion of an ALL, especially in children.

Diagnosis

Morphology

• Type 1 (A): agranular basophilic cytoplasm, nucleus with fine chromatin, and two to four distinct nucleoli.
• Type 2 (B): basophilic cytoplasm with ≤20 azurophilic granules and similar nuclear features as type 1 blasts.
• Type 3 (C): basophilic cytoplasm with >20 azurophilic granules.
• Promyelocytes have moderately basophilic cytoplasm with numerous azurophilic granules, and monoblasts and promonocytes usually exhibit folded/convoluted nuclei and may contain prominent acidophilic nucleoli.
• Cases with extensive fibrosis may represent a preceding myeloproliferative neoplasm or acute megakaryocytic leukemia.

Blast cells in acute myeloid leukemia (AML) exhibit a wide spectrum of morphologic features

The French–American–British classification described three types of blasts depending on the granule content (A–C). However, blasts with nuclear invagination (frequently associated with NPM1 and/or FLT3 mutations) (D); blasts with pseudopods (frequently shown to be megakaryoblasts) (E); and monoblasts (F) are also quite distinctive. Blast equivalents include granular or hypogranular promyelocytes (G and H) for acute promyelocytic leukemia, promonocytes (I) for AML with a monocytic component, and atypical pronormoblasts (frequently with cytoplasmic vacuoles) (J) for acute erythroleukemia of the pure erythroid type. Micromegakaryocytes (K) and pronormoblasts (L) are not considered blasts.

Immunophenotyping