Chicago Medical School

MYELOPROLIFERATIVE SYNDROMES AND PLASMA CELL DISORDERS Arthur S. Schneider, M.D. 2012 Department of Pathology Chicago Medical School at Rosalind Franklin University of Medicine and Science

DISORDERS OF WHITE BLOOD CELLS myeloproliferative syndromes chronic myelogenous leukemia polycythemia (rubra) vera (PRV) agnogenic myeloid metaplasia essential thrombocythemia

JAK2V617F mutations Most, if not all, patients with polycytheia rubra vera and a significant number of patients with agnogenic myeloid metaplasia and essential thrombocythemia are JAK2V617F positive

POLYCYTHEMIA RUBRA VERA RBC 8-10 million rubor due to increased absolute red cell mass pruritus (itching)

POLYCYTHEMIA RUBRA VERA splenomegaly WBC and platelets moderately increased hyperviscosity causes thrombotic phenomena and hemorrhage erythropoietin decreased

POLYCYTHEMIA RUBRA VERA treat with phlebotomy late phase clinically resembles CML blastic transformation into acute leukemia most often associated with chemotherapy or P32 therapy

SECONDARY POLYCYTHEMIA chronic hypoxia pulmonary pathology congenital heart disease high altitude inappropriate production of erythropoietin renal cell carcinoma and adult polycystic disease hepatocellular carcinoma cerebellar hemangioma

SECONDARY POLYCYTHEMIA endocrine abnormalities pheochromocytoma hypercorticism (Cushing syndrome) exogenous androgens

Fibrotic marrow in fully developed agnogenic myeloid metaplasia

Hypercellular marrow with positive reticulin stain in early agnogenic myeloid metaplasia

Agnogenic myeloid metaplasia (teardrop cells)

AGNOGENIC MYELOID METAPLASIA extensive extramedullary hematopoiesis in spleen, liver, and lymph nodes massive splenomegaly non-neoplastic myelofibrosis megakaryocytosis and thrombocytosis may be primary abnormality PDGF and TGF-ß from platelets and megakaryocytes may be cause of fibroblastic proliferation

AGNOGENIC MYELOID METAPLASIA anemia, teardrop-shaped erythrocytes scattered late granulocytic precursors occasional blasts scattered nucleated red cells can mimic CML

Agnogenic myeloid metaplasia (teardrop cell, nucleated RBC, and a myelocyte in peripheral blood

Agnogenic myeloid metaplasia (teardrop cells)

Agnogenic myeloid metaplasia (teardrop cell and a basophil)

Agnogenic myeloid metaplasia (nucleated RBC)

PLASMA CELL DISORDERS multiple myeloma Waldenström macroglobulinemia

Plasma cells

PLASMA CELL DISORDERS neoplastic clonal proliferations of well- differentiated immunoglobulin-producing cells multiple myeloma solitary plasmacytoma Waldenström macroglobulinemia benign monoclonal gammopathy (monoclonal gammopathy of undetermined significance) heavy chain (Franklin) disease primary amyloidosis

Multiple myeloma

MULTIPLE MYELOMA malignant multifocal plasma cell tumor characteristically involves bone protein abnormalities in serum and urine lytic lesions in bone, especially in skull and axial skeleton "punched-out" lesions osteoclast activating factor secreted by neoplastic plasma cells

Multiple myeloma (punched out lesions)

Multiple myeloma (punched out lesions)

Multiple myeloma (punched out lesions)

Multiple myeloma (punched out lesions

PROTEIN ABNORMALITIES proliferation of large quantities of monoclonal identical immunoglobulin molecules results in serum M spike M protein most often IgG of either kappa or lambda specificity IgA myeloma also common IgM and IgE very rare

PROTEIN ABNORMALITIES Bence Jones protein in urine (isolated free light chains, either kappa or lambda) heat test: precipitation of B.J. protein at 60 C, with redissolution 97 C

“M” protein

“M” protein

IgA kappa

IgG kappa

Multiple myeloma

CLINICAL FEATURES OF MULTIPLE MYELOMA bone lesions often associated with severe bone pain and spontaneous fractures anemia rouleaux formation of RBC on blood smear susceptibility to infection due to deficiency of normal immunoglobulins hypercalcemia secondary to bone destruction

CLINICAL FEATURES OF MULTIPLE MYELOMA amyloidosis of primary amyloidosis type renal insufficiency due to myeloma kidney (myeloma nephrosis) interstitial infiltrates of myeloma cells tubular casts of Bence Jones protein multinucleated macrophage-derived giant cells metastatic calcification

WALDENSTRÖM MACROGLOBULINEMIA generalized lymphadenopathy and mild anemia lymphoplasmacytic lymphoma infiltration of blood, bone marrow, lymph nodes, and spleen with mature-appearing plasmacytoid lymphocytes

WALDENSTRÖM MACROGLOBULINEMIA plasmacytoid lymphocytes are intermediate stage between B lymphocytes and immunoglobulin- producing plasma cells Dutcher bodies are round PAS-positive inclusions of immunoglobulin

Waldenström macroglobulinemia

Waldenström macroglobulinemia

Dutcher bodies in Waldenström macroglobulinemia

CLINICAL FEATURES serum protein IgM spike of either kappa or lambda specificity Bence Jones protein in 10% of cases no bone lesions slowly progressive course most frequent in males over age 50 bleeding related to platelet dysfunction secondary to abnormal protein

CLINICAL FEATURES hyperviscosity syndrome retinal vascular dilatation, sometimes with hemorrhage, confusion, and other CNS changes emergency plasmapheresis to prevent blindness

CASE FOURTEEN A 67-year-old woman is referred because of bone pain, spontaneous fractures, and anemia. Significant laboratory abnormalities include a normochromic normocytic anemia with a hemoglobin of 8.5 gm, a "spike" protein on serum protein electrophoresis, Bence Jones proteinuria, and increased serum calcium.

CASE FOURTEEN 1. What single further diagnostic procedure is necessary to confirm the diagnosis? Describe the anticipated findings. 2. What procedures are used to further define the nature of the "spike" protein?

CASE FOURTEEN 3. What would you expect to find on roentgenographic examination of the bones? Why does the patient have hypercalcemia? 4. What are some of the problems you might anticipate in the management of this patient?

Thank you for your attention.