May 2022 – Hematopathology

KIT D816V

Systemic mastocytosis is a rare disorder characterized by a clonal proliferation of morphologically and immunophenotypically atypical mast cells. There is a wide range of clinical presentation with an estimated prevalence of approximately 1 in 10,000 persons.¹ In the pediatric population, mastocytosis is frequently a cutaneous-limited disease that may regress, whereas in adults, mastocytosis will often manifest as a systemic disease, affecting one or more organs infiltrated by mast cells.^2,3 Organ involvement may include, but is not limited to the liver, spleen, gastrointestinal tract, and bone marrow, which contributes to the variability in patient presentation.^1,3

Systemic mastocytosis is classified into several subtypes according to the World Health Organization (WHO): 1. Indolent systemic mastocytosis; 2. Smoldering systemic mastocytosis; 3. Systemic mastocytosis with an associated hematological neoplasm; 4. Aggressive systemic mastocytosis; 5. Mast cell leukemia. The most recent diagnostic criteria, set by the WHO in 2016, includes a combination of major and minor criteria encompassing histopathologic, molecular, and chemical analysis.⁴

Histopathologic evaluation includes identifying the atypical mast cells. The morphologic features of the atypical mast cells include round to fusiform-shaped cells with long polar cytoplasmic processes, irregular lobulated nuclei, and decreased cytoplasmic granules that are often unevenly distributed.⁵ Immunohistochemical staining of the atypical cells demonstrates expression of tryptase, CD43, and KIT (CD117) with aberrant coexpression of CD25. Occasional aberrant coexpression of CD2 and CD30 has also been reported.³ Interestingly, CD30 expression occurs more frequently and in increasing intensity with more aggressive forms of the disease. Although tryptase is expressed in most cases, its expression level may be low, leading to an incorrect diagnosis.⁵

Mutations in KIT, which encodes for the receptor tyrosine kinase KIT (CD117), occurs in greater than 90% of cases, with the D816V mutation being the most notable mutation. This gain in function mutation results in uncontrolled proliferation, autonomous growth, and enhanced survival of mast cells.⁷ Additional associated mutations include the tumor suppressor gene TET2 and N/K-RAS.⁸

References

1. K. Brockow. Epidemiology, prognosis, and risk factors in mastocytosis. Immunol Allergy Clin. N. Am. 2014; 34:283–295.
2. R. Caplan. The natural course of urticaria pigmentosa: analysis and follow-up of 112 cases. Arch Dermatol. 1963;87(2):146–157.
3. A. Pardanani. Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management. Am J Hematol. 2019;94:363–377.
4. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–2405.
5. Stevens EC, Rosenthal NS. Bone marrow mast cell morphologic features and hematopoietic dyspoiesis in systemic mast cell disease. Am J Clin Pathol. 2001;116:177–182.
6. H Horny, K. Sotlar, P. Valent. Mastocytosis: immunophenotypical features of the transformed mast cells are unique among hematopoietic cells. Immunol Allergy Clin North Am. 2014;34(2):315–321.
7. Piao X, Bernstein A. A point mutation in the catalytic domain of c-kit induces growth factor independence, tumorigenicity, and differentiation of mast cells. Blood. 1996;87:3117–3123.
8. Komi DEA, Rambasek T, Wöhrl S. Mastocytosis: from a molecular point of view. Clin Rev Allergy Immunol. 2018 Jun;54(3):397–411.