Case 95-3

History/Physical Findings:

A cachectic 78 year old woman presented with hepatosplenomegaly, axillary lymphadenopathy and a 20-30 pound weight loss over a one year period. She was anemic and thrombocytopenic. There was a leukocytosis with an absolute monocytosis, and neutrophilia. Qualitative peripheral blood abnormalities included: dysmyelopoiesis, slight hypersegmentation, slight micro- and macro-cytosis, NRBCs in the peripheral blood, and large platelets.

The past medical history included a bone marrow aspirate/biopsy performed at an outside hospital which demonstrated 90% cellularity with an increased M:E ratio due to increased immature myeloid elements. The marrow was suspicious for CML vs. myelofibrosis. At this time, the WBC was 33.5; Hct 32; Plt 125K. Despite a LAP of 23, CML was considered the working diagnosis. No treatment was required. Shortly before diagnostic bone marrow biopsy was performed FNA of an axillary LN showed extramedullary hematopoiesis.

Laboratory Findings:

Qualitative PB Abnormalities: WBC: Moderate left shift with increased bands, metamyelocytes, myelocytes, rare promyelocyte, and dysmyelopoiesis. RBC: Marked anisocytosis and occasional schistocytes.

Microscopic:

A diagnostic bone marrow biopsy was performed:

Discussion:

The bone marrow cellularity was 100% with a predominance of Leder-positive granulocytic elements and several abnormal paratrabecular aggregates of mast cells. The myeloid:erythroid ratio was greatly increased due to the extensive proliferation of myeloid elements demonstrating a full range of maturation. Prominent nuclear sticks suggested mild dysmyelopoiesis. Scattered normal-appearing erythroid and megakaryocytic elements were present.

Most striking were the multiple paratrabecular aggregates of Leder-positive oval and spindle-shaped mast cells, many with atypical folded or indented nuclei. Toluidine blue staining showed metachromatic granulation. Fibrosis within these aggregates was demonstrated by reticulin and trichrome staining. Some aggregates were partially surrounded at the periphery by lymphocytes and eosinophils. Only small numbers of lymphocytes, plasma cells, and eosinophils were present within the mast cell aggregates. The findings of a hypercellular marrow with a predominance of myeloid elements, minimal dysmyelopoiesis, and dyserythropoiesis, and abnormal paratrabecular mast cell aggregates, support the morphologic impression of a chronic myeloproliferative disorder involving mast cells.

As reported in the literature, this patient presents with a classical picture of systemic mast cell disease*. The bone marrow findings are consistent with systemic mast cell disease type 2, also known as malignant mastocytosis*. The systemic mast cell disorders are clinically defined by some or all of the following: anemia, thrombocytopenia, monocytosis, leukocytosis with increased neutrophils, qualitative peripheral smear changes, increased serum alkaline phosphatase, LDH, and histamine, and the physical findings of hepatosplenomegaly and lymphadenopathy.

Based on bone marrow histopathology, systemic mast cell diseases have been divided into three types*.

Type 1 (Benign Systemic Mastocytosis) generally involves the skin as well as the reticuloendothelial system. Type 1 is characterized by paratrabecular aggregates of mast cells accompanied by dense reticulin, thickening of the adjacent bony trabeculae, and increased lymphocytes and plasma cells within the aggregates. A rim of increased eosinophils often surrounds the aggregates. The non-infiltrated marrow fat and hematopoeisis are normal. The clinical outcome of Type 1 mast cell disease is generally favorable with survival averaging 10 years or more.

Type 2 disease (Malignant Mastocytosis) typically demonstrates in addition to the marrow findings seen with Type 1 disease, marked fibrosis and osteosclerosis, but does not usually demonstrate increased lymphocytes and plasma cells within the mast cell aggregates. The non-mast cell infiltrated marrow shows decreased fat content and increased granulocytopoiesis or myeloid blast cells.

Type 3 disease (Malignant Mastocytosis) is characterized by diffuse marrow infiltration with atypical mast cells, hypoplasia of the marrow hematopoietic cells, and may demonstrate mast cell leukemia. The prognosis of type 2 and type 3 disease is poor with survival periods usually no more than 1-2 years.

Although flow cytometric immunotyping was not available for this case, a recent report shows that multiparametric flow cytometry of bone marrow can be useful in distinguishing indolent systemic mast cell disease (CD2+; CD 25+; CD 35+; CD 71-) from reactive mastocytosis (CD2-; CD 25-; CD 35-; CD 71+).

Diagnosis:

Systemic Mast Cell Disease, Type 2 (Malignant Mastocytosis)

References:

Escribano, L, et. al. Indolent Systemic Mast Cell Disease in Adults: Immunophenotypic Characterization of Bone Marrow Mast Cells and Its Diagnostic Implications. Blood 91(8):2731-2736, 1998.

*Horny, H.P., Parwaresch, M.R., and Lennert, K. Bone Marrow Findings in Systemic Mastocytosis. Hum. Path. 16(8):808-814, 1985.

Horny, H.P., et. al. Immunoreactivity of Normal and Neoplastic Tissue Mast Cells. A.J.C.P. 89(3):335-340, 1988.

Horny, H.P. et. al. Immunoreactivity of Normal and Neoplastic Human Tissue Mast Cells with Macrophage-Associated Antibodies, with Special Reference to the Recently Developed Monoclonal Antibody PG-M1. Hum. Path. 24(4):355-358, 1993.

Lawrence, J.B. et. al. Hematological Manifestations of Systemic Mast Cell Disease: A Prospective Study of Laboratory and Morphologic Features and Their Relation to Prognosis. Am. J.Med., 91:612-624, 1991.

Torrey, E. et. al. Malignant Mastocytosis With Circulating Mast Cells. Am. J. Hematology. 34:283-286, 1990.

Travis, WD, et.al. Systemic Mast Cell Disease: Analysis of 58 Cases and Literature Review. Medicine (Baltimore). 67:345-368, 1988.

Travis, W.D. and Li, C.Y. Pathology of Lymph Node and Spleen in Systemic Mast Cell Disease. Mod. Path. 1(1):4-14, 1988.

Contributors:

William E. Field II, M.D.
Department of Pathology
University of Virginia Health System.

Donald J. Innes, Jr., M.D.
Department of Pathology
University of Virginia Health System

Questions should be addressed to dji@virginia.edu