Final Diagnosis -- Systemic Mastocytosis

FINAL DIAGNOSIS:

1. Systemic Mastocytosis
2. Hypercellular marrow with trilineage hematopoiesis, myeloid hyperplasia, reticulin fibrosis, and bony changes
3. Mild plasmacytosis with excess kappa immunoglobulin light chain staining

DISCUSSION:

Mast cells are thought to be a unique type of myeloid derived cell having effects on a diverse range of cell types including vascular and perivascular cells, GI tract epithelium, endothelium, fibroblasts, and leukocytes. The effector molecules contained within mast cells granules include Histamine, prostaglandins, leukotrienes, tryptases, tissue plasminogen activator, heparin, and tumor necrosis factor - alpha. Stemming from the unique function and phenotype of mast cells it has been recognized that mast cell disease is a distinct hematopoietic myeloid lineage neoplasm with a unique set of clinicopathologic characteristics that have been summarized in the WHO classification of tumors of hematopoietic and lymphoid tissues. Patients with mast cell disease represent a heterogenous group of clinical disorders with all being morphologically characterized by cytologic atypia and aggregation of mast cells in one or more organ system. The broad classification of mast cell disease includes the following entities: cutaneous mastocytosis (CM), indolent systemic mastocytosis(ISM), systemic mastocytosis with an associated clonal non-mast-cell lineage disease (SM-AHNMD), aggressive systemic mastocytosis(ASM), mast cell leukemia(MCL), mast cell sarcoma (MCS) and, extracutaneous mastocytoma.

The disease manifests most commonly in the skin as it did in the current case and often will remain confined entirely to the skin (80%). In the remaining 20% of patients with suspected systemic disease bone marrow biopsy is essential as it almost always will provide diagnostic material. Our patient showed signs of a primary lesion in the marrow (leukoerythroblastosis, cytopenias) and thus clinical suspicion was high for marrow involvement. The strict diagnosis of systemic mastocytosis(SM) has major and minor criteria which are summarized in Table1 and modified form the WHO. In order to make the diagnosis one must demonstrate one major and one minor or alternatively three minor criteria.

Table 1. WHO Criteria for the diagnosis of systemic mastocytosis

Major Criteria	Minor Criteria
Multifocal dense aggregates (15 or more mast cells) in sections of bone or other extracutaneous organs confirmed by tryptase IHC	a)   >25% of identified mast cells are immature or have spindle-shaped or atypical morphology b)   ckit point mutation at codon 816 is detected at any extracutaneous site with infiltrate of mast cells c)   extracutaneous infilatrate of mast cells that co-express CD117 with CD2 and/orCD25 d)   serum total tryptase >20ng/ml (assuming there is no associated clonal myeloid disorder)

Table 2 Mast cell morphology in systemic mastocytosis (SM)
Modified from Valent et al (2001); Sperr et al (2001)

Cell Type	Criteria	Proposed Normal Counterpart
Typical Mast Cell	Round Cells, Well granulated, Central Round nucleus	Mature tissue mast cell
Atypical Mast Cell Type 1	a)      Elongated surface projections, often spindle-shaped cells b)      Hypogranulated with focal granule accumulations c)      Oval decentralized nucleus             Out of a,b,and c at least   two must be present	Unknown: tissue mast cells often found lining tissue elements but usually not on bone marrow smears in absence of SM
Atypical Mast Cell Type 2 (promastocyte)	Mostly immature with bi- or multi-lobed nuclei	Immature mast cell
Metachromatic Blast	Myeloblast with a few metachromatic granules	Immature mast cell-committed progenitor

The current case demonstrated the major criteria and 2 minor criteria namely, >25 of mast cells with atypical morphology (Table 2) and co-expression of CD117 with CD2 and CD25, thus fulfilling the WHO criteria for systemic mastocytosis.

In fact both type 1 and type 2 atypical mast cells were identifiable in the current case along with both CD25 and CD2 expression (Figues 1, 2 and 3, Figure 9, Figure 10).

It has recently been demonstrated that CD25 expression correlated extremely well with the presence of ckit point mutation in mast cell disease and can be used reliably as an immunohistochemical stain on paraffin-embedded tissue.

Further classification of this patient's systemic mastocytosis into either the indolent or aggressive forms mentioned above requires knowledge of more morphologic, clinical, and laboratory parameters shown in Table 3.

Table 3 Criteria for variants of systemic mastocytosis

“B”findings	“C” findings
1)      BM >30% infiltration of mast cells and/or serum total tryptase >200ng/ml 2)      Signs of dysplasia or myeloproliferation in non-mast cell lineage cells but insufficient for the WHO criteria for other clonal hematologic malignancies 3)      Hepatomegaly without impairment of liver function, and/or palpable splenomegaly without hypersplenism, and/orpalpable visceral lymphadenopathy	1)      Bone marrow dysfunction manifested by one or more cytopenia but no frank non-mast cell malignancy 2)      Palpable hepatomegaly with impairment of liver function, ascites, or portal hypertension 3)      Skeletal involvement with large sized osteolysis and/or fractures 4)      Palpable splenomegaly with hypersplenism 5)      Malabsorption with weight loss due to GI mast cell infiltrates

Although not all laboratory and clinical information regarding the criteria in Table 3 were available, attention must be brought to the abnormal bone marrow findings in the current case. Specifically, the reticulin fibrosis, osteosclerosis, myeloid hyperplasia, combined with a hypercellular marrow raised the possibility of an associated myeloproliferative disorder although the strict WHO criteria for any single disorder was not met. Furthermore, our patient presented with bone marrow dysfunction as manifested by the thrombocytopenia. These features automatically remove the patient from a diagnosis of ISM where no "B" or "C" findings are allowable and place them into the more aggressive ASM category which requires at least one "C" finding.

Though regarded as worse prognosis, no significant data-base exists to judge clinical responsiveness and accurately predicts behavior in these ASM variants and clinical behavior from case to case is quite heterogenous. Should the disease transform into a non-mast-cell lineage clonal hematopoietic disorder diagnosable by strict WHO criteria, the clinical course would be expected to mimic the non-mast-cell lineage disease.

The clinical significance of the excess kappa plasmacytosis and the MGUS remains uncertain. However, there is one report in the literature of a patient with bone marrow mastocytosis with MGUS who later went on to develop multiple myeloma and a few reports of polyclonal plasmacytosis in the marrow associated with SM and a serum dysglobulinemia thus confirming plasmacytosis co-existing with SM to be a rarely reported phenomenon in the literature the significance of which is uncertain.

REFERENCES:

1. WHO Classification of Tumors of the Haematopoietic and Lymphoid tissues. IARC Press, Lyon France (2001)
2. Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol. 2003 Sep;122(5):695-717. Review
3. CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol. 2004 Oct;28(10):1319-25.
4. A case of bone marrow mastocytosis associated with multiple myeloma. Ann Hematol. 1998 Mar-Apr;76(3-4):167-74.
5. Bone marrow pathology in 5 cases of systemic mastocytosis. Pseudomyelomatous forms with dysglobulinemia and benign polyclonal bone marrow plasmacytosis. Hamazaki-Wesenberg bodies associated with mast cell granulomas] Arch Anat Cytol Pathol. 1983;31(1):11-8. French.

Contributed by Sourav Ray, MD