PATIENT: 40-year-old male with 2-years history of CML (BCR-ABL p210 b2a2 positive).  
 
MEDICAL HISTORY: The initial treatment with Imatinib in 2019 showed no positive effect and was changed to Nilotinib. Due to the lost response to treatment and clonal evolution (L248V mutation+), Nilotinib was changed to Dasatinib with little and only temporary effect. After two years since the primary diagnosis of CML, the disease progressed to accelerated phase. Treatment with Dasatinib was changed to Bosutinib. However, patient developed extensive papular rash and 21% of myeloblast was detected in bone marrow aspirate by flow cytometry; also detected were 2,4 % of CD117+ cells with mast cells phenotype. Subsequently, trisomy 8 and 17q duplication was discovered by SNP-A. Transcript of PML-RARA/ RUNX1-RUNX1T1/ CBFB-MYH11/DEK-NUP214 and mutations of NPM1/ FLT3 ITD and TKD/ KIT D816V/IDH1/IDH2 were all negative.  
 
1st SKIN PUNCH BIOPSY was done and revealed interstitial and perivascular infiltrate, composed of large and medium sized blastoid cells with admixture of immature-looking eosinophils (Fig 1-5). Some cells showed deep-purple metachromatic granules on Giemsa stain, while eosinophils had lighter/more eosinophilic granules (Fig. 6-7). Immunoprofile (Fig. 8-24):  
• MPO+ heterogenous reaction 100%;  
• WT1+ (including cells with granular cytoplasm) 90%;  
• CD43+ 100%;  
• CD117+ 60%;  
• Mast cell tryptase+ 60%;  
• CD25+ 60%;  
• CD30+ 5%;  
• CD123+ 20%;  
• Bcl2+ 100%;  
• CD4+ 100%;  
• CD7+ 15%;  
• Lysozyme+ 60%;  
• HLA-DR+ scattered cells;  
• CD34/CD2/CD99/CD163/CD14(-)  
• Ki67 proliferation index up to 90%.  
 
Patient then received treatment with the HAM protocol. After the treatment, bone marrow aspirate showed 0,1% of aberrant myeloblast (CD45+ faint, CD117+ faint, CD11a-/+ faint, CD11b+, CD33+, CD38-/+ faint, CD123+het, CD2-, CD4-, CD7-, CD13-, CD14-, CD15-, CD34-, CD36-, CD56-, CD64-, CD99-, CD133-, HLA-DR-) and 0,33% cells of mast cell lineage, with similar immunophenotype to myeloblast exept for bright CD117+ expression.  
 
2nd SKIN PUNCH BIOPSY (done 4 days after the treatment with HAM protocol) showed perivascular dermal infiltrate of small cells with minimal cytoplasm and bland nuclei with condensed chromatin (Fig.25-26), without metachromatic granules on Giemsa stain (Fig.27). Immunophenotype (Fig.28-32): CD117/MCT+(bright); CD25+(bright); WT+/- (faint, focal), CD34/TdT/CD7/CD3/CD20/CD2/CD30/Lesozyme(-); Ki67 proliferation index up to 1 %.  
 
3rd SKIN PUNCH BIOPSY (Fig.33) was done after 20 days since the 2nd and showed changes analogous to 1st biopsy, except for scattered blastoid CD34+ cells (Fig.34). Also, KIT D816V mutation was not detected in this skin sample.  
The patient is currently stable and waiting for allogeneic bone marrow transplant.  
 
PROPOSED DIAGNOSIS:  
• CML blast phase with myelomastocytic differentiation?  
• CML blast phase (with myeloblasts) and systemic mastocytosis (aka SH-AHN, KIT D816V negative)  
• Other?  
 
Any opinion on the matter would be of great value!  

tzankov 2021-05-21 14:02

Very impressive case. Since CKIT is not mutant and there is a clear mixture of myeloblasts and atypical mast cells and because of the specific clinical history I would favor here blast-phase variant of chronic myeloid leukemia (CML), BCR-ABL1–positive, with features of myelomastocytic differentiation. To formally prove the diagnosis (or the clonal relatioship of the masct cells and the CML) you may perform a FISH on the skin biopsy and look for fusions in the mast cells. I would probably stain the case for TP53/p53.     The case is reminsicent to case 40 of our paper: Am J Clin Pathol 2021;155:239-266 (Figure 8)

ugnius 2021-05-21 16:29

Thanks a lot! By the way, this is Ugnius' apprentice Gintarė.   To make it more clear - cKIT was performed on the 3rd biopsy with atypical mast cell population, it was not performed on the 2nd, with bland looking mast cells. There might be two separate populations of mast cells - one as a component of exCML blasts and another one as a separate mature mast cells/mastocytosis?   I believe we don't have BCR-ABL FISH, only PCR. Althougt, we could perform BCR-ABL PCR and cKIT on the 2nd biopsy...   Thank You again for the great ideas and a reference!