Answer: CML in blast crisis

Histology: The lymph node architecture is notable for widely-spaced cortical follicles surrounded by an abnormal paracortical expansion. Cytologically, the paracortex is composed of elements of extramedullary hematopoiesis in a background of small, mature lymphocytes. The hematopoietic cells include a predominance of blasts and myeloid elements, as well as several megakaryocytes and nucleated red cell precursors. The myeloid elements show a marked left shift in maturation. Frequent mitoses are identified.

By immunohistochemistry, the mature and immature myeloid elements, including many cells that are morphologically consistent with blasts, are positive for myeloperoxidase (MPO). The MPO-positive blasts are also positive for CD117 (c-kit) and CD34. The Ki-67 proliferation index (not shown) is abnormally increased in the paracortex. Moreover, flow cytometric analysis of the lymph node biopsy reveals an immature myeloid population with relatively frequent blasts.

The accompanying peripheral blood smear is notable for a marked leukocytosis with a left-shifted myeloid predominance. Though occasional blasts are circulating, they account for less than 5% of the nucleated cellularity. The more differentiated myeloid elements are morphologically within normal limits. In addition, frequent nucleated red cells and giant atypical platelets are identified. Basophils and eosinophils are not appreciably increased.

Discussion: The morphologic and immunophenotypic data are consistent with blastic transformation of a chronic myeloproliferative disorder. Moreover, despite the lack of apparent basophilia, cytogenetic analysis performed on a peripheral blood specimen from this patient demonstrated the t(9;22), diagnostic of chronic myelogenous leukemia. Furthermore, despite the absence of increased blasts in the periphery, the presence of extramedullary disease with a blast proliferation meets conventional criteria for blastic transformation.

Blastic transformation of CML is generally defined as 30% or more blasts in the blood or bone marrow smears, or focally increased blasts in a bone marrow biopsy or extramedullary tissue. Extramedullary sites most commonly involved are the lymph nodes, skin, cortical bone and spleen, but tumors with numerous blasts may occur in almost any location. Though an extramedullary tumor may resemble a malignant lymphoma, the nature of the myeloid lineage can be determined with monoclonal antibodies to MPO, lysozyme, c-kit, or other cytologic constituents of myeloid elements. In some patients, the extramedullary transformation of CML may precede changes in the blood and bone marrow by several months. Lastly, the blasts in the extramedullary sites may manifest additional chromosomal alterations that are characteristic of blast crisis occurring in the bone marrow. The most common cytogenetic abnormalities that strongly suggest blastic transformation include a second Philadelphia chromosome, trisomy 8, and isochromosome for the long arm of chromosome 17.

Acute myeloid leukemias, including those with megakaryoblastic differentiation, may present as extramedullary myeloid tumors, which may even precede hematological manifestations of acute leukemia. However, extramedullary myeloid tumors associated with AML are characterized as abnormal proliferations of the granulocytic or monocytic lineages. Tumors with trilineage hematopoiesis that includes erythroid precursors and mature megakaryocytes are typically associated with chronic myeloproliferative disorders. In addition, megakaryoblastic leukemias are negative for MPO and are often negative for CD34 and c-kit.

Though evidence of trilineage hematopoiesis in a lymph node is compatible with extramedullary manifestations of essential thrombocythemia, as well as CML and other myeloproliferative disorders, the presence of a blastic proliferation in this case suggests an aggressive transformation of the disease and not an indolent chronic phase. Obviously, the expression of myeloid antigens in this patient’s tumor excludes a diagnosis of lymphoma.