AMP case report: Unexpected diagnosis of indolent systemic mastocytosis through evaluation of NGS data

Create PDF

Another interesting feature of our case, in addition to the unusual association of ISM and MGUS, is the presence of non-KIT mutations. Although KIT mutations are well described in the pathogenesis of mast cell neoplasms and represent a minor criterion for SM diagnosis, information regarding the importance of additional mutations detected in mast cell disease is emerging. Recent retrospective studies evaluating non-KIT mutations by NGS in patients with SM have demonstrated mutations that occur in SM with increased frequency and that may impact disease phenotype or prognosis. Schwaab and colleagues reported additional mutations in 3/12 (25 percent) of ISM patients, with CBL, SETBP1, U2AF1, JAK2, ASXL1, RUNX1, and ETV6 mutations reported in this group.¹⁵ This group also noted that in patients with advanced SM but no additional mutations, disease phenotype was less severe, overall survival was improved, and there were not significant cytopenias as compared with patients with one or more non-KIT mutations.¹⁵ Pardanani and colleagues evaluated 150 patients with SM, 29 percent of whom had ISM and 53 percent of whom had SM-AHN (nine percent of SM-AHN patients had either lymphoma or myeloma, not further specified).¹⁶ In this group, the most commonly mutated genes across all categories of SM were TET2, ASXL1, CBL, SF3B1, DNMT3A, JAK2, U2AF1, and RUNX1, with ASXL1 mutations associated with inferior overall survival and presence of ASXL1 mutations incorporated into a proposed prognostic scoring system for SM patients.¹⁶ Of relevance to our case, Pardanani, et al., identified non-KIT mutations (DNMT3A and TET2 only) in 14 percent of ISM patients, essentially identical to our reported case.¹⁶ The relationship of the DNMT3A mutation to SM is unclear, as this mutation could represent clonal hematopoiesis of indeterminate potential (CHIP), particularly in elderly individuals. In our case, the TET2 variant with near 50 percent variant allele fraction is likely to be a germline polymorphism. Naumann and colleagues reported another recent study of 109 SM patients (24 percent with ISM), of whom 24 percent had TET2 mutations and one percent had DNMT3A mutations.¹⁷ Previous studies looking only at the presence of TET2 and RAS family mutations in SM have suggested some impact on disease phenotype but no clear impact on disease prognosis from these mutations.^18,19 Further work is needed to fully characterize the mutational landscape of SM and the prognostic impact, if any, from non-KIT mutations in SM.

In our case, unexpected NGS findings led to an additional diagnosis that would have been missed by routine bone marrow evaluation alone. Our case illustrates the necessity of additional morphologic evaluation to explain and correlate unexpected molecular findings. The identification of unexpected ISM in this case did not prompt immediate treatment, but it contributes to the need for close clinical monitoring for disease progression in this case and will be important information should the patient develop mastocytosis-related symptoms in the future.

1. Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Rev. 4th ed. Lyon, France: IARC Press; 2017.
2. Ogg GS, Rosbotham JL, MacDonald DM. Urticaria pigmentosa coexisting with multiple myeloma. Clin Exp Dermatol. 1996;21(5):365–366.
3. Hagen W, Schwarzmeier J, Walchshofer S, et al. A case of bone marrow mastocytosis associated with multiple myeloma. Ann Hematol. 1998;76(3–4):167–174.
4. Stellmacher F, Sotlar K, Balleisen L, Valent P, Horny HP. Bone marrow mastocytosis associated with IgM kappa plasma cell myeloma. Leuk Lymphoma. 2004;45(4):801–805.
5. Sotlar K, Saeger W, Stellmacher F, et al. “Occult” mastocytosis with activating c-kit point mutation evolving into systemic mastocytosis associated with plasma cell myeloma and secondary amyloidosis. J Clin Pathol. 2006;59(8):875–878.
6. Pullarkat ST, Sedarat F, Paquette R, Said J. Systemic mastocytosis with plasma cell dyscrasia: report of a case. Leuk Res. 2008;32(7):1160–1163.
7. Kluin-Nelemans HC, Ferenc V, van Doormaal JJ, et al. Lenalidomide therapy in systemic mastocytosis. Leuk Res. 2009;33(3):e19–22.
8. Motwani P, Kocoglu M, Lorsbach RB. Systemic mastocytosis in association with plasma cell dyscrasias: report of a case and review of the literature. Leuk Res. 2009;33(6):856–859.
9. Filanovsky K, Lev S, Haran M, et al. Systemic mastocytosis associated with smoldering multiple myeloma: an unexpected diagnosis in a patient with a rash. Leuk Lymphoma. 2010;51(6):1152–1154.
10. Du S, Rashidi HH, Le DT, Kipps TJ, Broome HE, Wang HY. Systemic mastocytosis in association with chronic lymphocytic leukemia and plasma cell myeloma. Int J Clin Exp Pathol. 2010;3(4):448–457.
11. Jain P, Verstovsek S, Orlowski RZ, Yap E, Amin HM. An unusual case of aggressive systemic mastocytosis with associated refractory plasma cell myeloma. Clin Lymphoma Myeloma Leuk. 2012;12(6):459–462.
12. Butterfield JH, Weiler CR. Systemic mastocytosis in the elderly. Am J Hematol. 2013;88(5):406–408.
13. Ghanem S, Garcia G, Ying L, Hurford M, Odaimi M. Systemic mastocytosis with smoldering multiple myeloma: report of a case. Case Rep Oncol Med. 2016;2016:3161768.
14. Prabahran AA, Juneja SK. Systemic mastocytosis with concurrent multiple myeloma. Blood. 2018;131(13):1494.
15. Schwaab J, Schnittger S, Sotlar K, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood. 2013;122(14):2460–2466.
16. Pardanani A, Lasho T, Elala Y, et al. Next-generation sequencing in systemic mastocytosis: derivation of a mutation-augmented clinical prognostic model for survival. Am J Hematol. 2016;91(9):888–893.
17. Naumann N, Jawhar M, Schwaab J, et al. Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis. Genes Chromosomes Cancer. 2018;57(5):252–259.
18. Tefferi A, Levine RL, Lim KH, et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia. 2009;23(5):900–904.
19. Wilson TM, Maric I, Simakova O, et al. Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis. Haematologica. 2011;96(3):459–463.

Dr. Moser is assistant professor of pathology, Dr. George is professor of pathology, and Dr. Karner is assistant professor of pathology, University of Utah School of Medicine and ARUP Laboratories, Salt Lake City.

Test yourself