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  Table of Contents    
CASE REPORT  
Year : 2012  |  Volume : 55  |  Issue : 3  |  Page : 409-412
Systemic mastocytosis with associated acute myeloid leukemia with t (8; 21) (q22; q22)


1 Hematopathology Laboratory, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Cancer Cytogenetic Laboratory, Tata Memorial Hospital, Mumbai, Maharashtra, India

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Date of Web Publication29-Sep-2012
 

   Abstract 

Systemic mastocytosis with associated clonal hematological nonmast cell lineage disease (SM-AHNMD) is a subtype of mastocytosis associated commonly with myeloid neoplasms, Non-Hodgkin's lymphoma, or other hematological neoplasms. In these conditions, mastocytosis needs to be differentiated from mast cell hyperplasia or mast cell activation states. Neoplastic nature of mastocytosis is proved either by morphology, aberrant immunophenotype, or detection of point mutation at codon-816 of c-kit gene. This is a rare entity, even more so in pediatric population. Herein, we report a case of 14-year-old girl with SM associated with acute myeloid leukemia with maturation with t(8;21). Multifocal dense infiltrate of spindle-shaped mast cells on bone marrow aspirate and biopsy with coexpression of CD2 and CD25 by flow cytometric analysis proved the SM component at the time of diagnosis and persistence at post induction status also.

Keywords: Acute leukemia, acute myeloid leukemia, mastocytosis

How to cite this article:
Gadage V S, Kadam Amare P S, Galani K S, Mittal N. Systemic mastocytosis with associated acute myeloid leukemia with t (8; 21) (q22; q22). Indian J Pathol Microbiol 2012;55:409-12

How to cite this URL:
Gadage V S, Kadam Amare P S, Galani K S, Mittal N. Systemic mastocytosis with associated acute myeloid leukemia with t (8; 21) (q22; q22). Indian J Pathol Microbiol [serial online] 2012 [cited 2019 Jun 25];55:409-12. Available from: http://www.ijpmonline.org/text.asp?2012/55/3/409/101761



   Introduction Top


Systemic mastocytosis with associated clonal hematological nonmast cell lineage disease (SM-AHNMD) is a distinct variant of systemic mastocytosis (SM). The hematological disorder may vary from a myeloid neoplasm to a non-Hodgkin lymphoma. [1],[2] Of these, SM with acute myeloid leukemia (AML) with t(8;21) is mentioned only as few case reports or as a part of small series. [2],[3],[4],[5],[6] Also, SM is extremely rare in pediatric population. [1],[3],[4],[7] A thorough bone marrow (BM) evaluation is must to note mastocytosis as it may be masked or missed at the time of diagnosis. [2],[3],[4],[6],[7] An aberrant immunophenotype, i.e. coexpression of CD2 and CD25 defines the neoplastic nature of mast cells. [1],[2],[7],[8],[9] We report a case of 14-year-old girl with SM-AHNMD with myeloid component represented by AML-M2 with t(8;21). The neoplastic nature of mast cells was confirmed by flow cytometry (FCM) evaluation which demonstrated a coexpression of CD2 and CD25 at the time of diagnosis and even at the post induction stage. Post induction BM showed no excess of blasts with persistence of mast cells with partial cytogenetic response.


   Case Report Top


A 14-year-old girl presented with a dull aching type of abdominal pain, low grade fever, generalized weakness, and numbness in both lower limbs for 2 weeks. Magnetic resonance imaging (MRI) of the spinal cord showed irregular soft tissue densities within sacral canal from the level of S1 to S5 vertebrae, invading the sacral foramina and encasing the sacral nerve roots. She had no complaints of itching or any skin lesions. A complete blood count (CBC) revealed a hemoglobin (Hb) of 4 g/dl, a total leucocyte count (TLC) of 11,000/mm 3 , and a platelet count of 5000/mm 3 . Peripheral blood smear (PBS) examination showed 66% blasts with myeloperoxidase (MPO) positivity. She underwent a BM aspiration and biopsy for morphology, immunophenotyping, and cytogenetic studies. BM aspiration stained with Wright's stain showed a hypercellular marrow with the absence of megakaryocytes and erythroid cells. At scanner view, there were striking focal aggregates (>15 cells in clusters) of spindle-shaped mast cells within the BM particles [Figure 1]a-d. BM aspirate smears showed 68% blasts with occasional blast showing an Auer rod. Maturing myeloid cell series comprised more than 10% of all cells with 8% eosinophils. Differential diagnosis considered were AML-M2 with mast cell hyperplasia and SM with AML-M2. With review of PBS, 2% circulating hypogranulated mast cells were noted [Figure 1]e.
Figure 1: BM aspirate [(a– e): Wright's stain] at the �� me of diagnosis, (a) clusters of mast cells and myeloid blasts – scanner (×40) view; (b) spindleshaped mast cells – low power (×100) view; (c and d) myeloid blasts with diff eren�� ating myeloid cells and spindle-shaped mast cell – oil immersion (×1000) view, and (e) PBS showing circulating hypogranular mast cell at the tail end of smear (×1000)

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Immunophenotyping analysis by multicolor-FCM was performed by standard protocol of lyse-wash-stain technique using a CD45-gating strategy [Figure 2]a. The aim was to define immunophenotype of myeloid blasts and in specific of mast cells, namely normal versus neoplastic nature. Various fluorochrome-conjugated (FITC/PE/PerCP.Cy5.5/PE-Cy5/APC/APC-H7) monoclonal antibodies were used in the following combinations: CD38/CD19/CD10/CD20/CD34/CD45, CD64/CD33/HLA-DR/CD14/CD117/CD45, CD7/CD13/CD3/CD16/CD56/CD45, and anti-MPO/cyto-CD79a/-/cyto-CD3/CD34/CD45. Additional panels, i.e. CD2/CD33/CD117/CD5/CD25/CD45 and HLA-DR/CD68/CD123/CD117/CD45, were added to study the nature of mast cells. Blasts were positive for CD45 (moderate), CD34 (heterogenous), CD19 [Figure 2]b, CD117, CD13, and MPO while negative for all other markers. Mast cells coexpressed CD117, CD2, and CD25 along with CD45 (moderate), CD33 [Figure 2]c and d, CD68 and were negative for HLA-DR, CD123, CD5, and CD14. Coexpression of CD2 and CD25 proved the neoplastic nature of mast cells. Diagnosis of SM-AHNMD, i.e. SM with AML-M2 was offered based on multifocal, dense infiltrates of mast cells (≥15 mast cells in aggregates) in BM aspirate (major criterion) with spindle-shaped morphology (>25% of mast cells in infiltrate) and coexpression of CD2 and CD25 along with CD117 by FCM (two minor criteria). [1]
Figure 2: FCM analysis: the red color represents blast population and the green color represents neoplastic mast cell; (a-d) at time of diagnosis: (a) CD45 versus SSC gating of the BM sample, (b) blasts are positive for CD19 and eterogeneously positive for CD34, (c) strong CD117 and CD33 cells represent mast cells (P5 gate); and (d) the same mast cells express CD2 and CD25, neoplastic in nature. (e and f) Post induction BM samples show persistence of neoplastic mast cells expressing (e) CD2 and CD25 and (f) CD117, but negative for CD34

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BM biopsy showed hypercellular marrow spaces with increase in blast cells which were CD34 positive. CD117 highlighted blasts as well as collection of spindle-shaped mast cells [Figure 3]a-c.
Figure 3: BM biopsy (a-c): at the time of diagnosis, (a) clusters of mast cells around blood vessels, (b) CD34 highlighting blasts and not the mast cells, and (c) CD117 highlighting clustering of mast cells. BM biopsy (d-f): at the time of post induction, (d): persistence of mast cells around blood vessels, (e) CD34 highlighting only endothelial cells and not the blasts, and (f) CD117 highlighting mast cells

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Fluorescent in situ hybridization (FISH) using a dual color reciprocal fusion probe (Vysis, Abbott Molecular, Germany) showed >90% cells with 1R1G2Y signal of AML1-ETO. The patient received 3 + 7 induction chemotherapy (cytarabine 100 mg/m 2 for 7 days and daunorubicin 60 mg/m 2 for 3 days). Her day 28 CBC revealed anemia (Hb: 9.3 g/dl) with normal TLC and platelet count. Post induction day 28, BM aspirate revealed no excess of blasts; however, there was persistence of mastocytosis with coexpression of CD2, CD25, and CD117 by FCM [Figure 2]e and f. Biopsy showed clusters of mast cell around blood vessels, highlighted by CD117 while CD34 was negative [Figure 3]e and f. She had partial cytogenetic response with persistence of AML1-ETO in 8% interphase cells by FISH. However, it was difficult to comment whether persistence of AML-ETO was in mast cells or blast/other hematopoietic cells on DAPI stain even with an expert observer. She was not subjected to allogenic stem cell transplant due to financial constraints.


   Discussion Top


SM is subdivided into six variants among which SM-AHNMD is the second most common variant. [1] In SM-AHNMD, AHNMD may be diagnosed before; simultaneously with/after the diagnosis of SM. In some cases, diagnosis of SM was missed/masked at the time of diagnosis, mainly due to excess number of blasts and tendency of mast cells to localize within stroma of BM particles. [1] However, persistence of mastocytosis at the time of post induction BM evaluation with reduction in blast percentage helps us to diagnose SM at that time/even retrospectively. [2],[3],[4],[6],[7]

The most frequently associated myeloid neoplasms include AML and chronic myelomonocytic leukemia (CMML). [1],[2],[6],[7] Although all FAB subtypes of AML have been reported with SM, M2 and M5 are the most common subtypes. [6],[7] Of these, only few cases show the presence of t(8;21). [2],[3],[4],[5],[6] SM-AHNMD is extremely rare in pediatric population, usually lacks skin lesions like urticaria pigmentosa and extramedullary mast cell involvement. Also, patients rarely present with symptoms related to mast cell mediator release. [1],[3],[4],[10] Hence, it is not suspected clinically, but morphology associated with immunophenotyping and/or molecular testing clinches the diagnosis. [6]

The differential diagnosis of SM-AML is AML with mast cell hyperplasia or myelomastocytic leukemia [1],[5] , wherein there is a substantial increase in immature atypical mast cells without fulfilling diagnostic criteria for SM. [5] Our case showed spindle-shaped mast cells infiltrate opposite to the endosteal surface, or to blood vessels [1],[6] [Figure 3]a and d. Aberrant immunophenotype with expression of CD2 and/or CD25 defined neoplastic nature of mast cells. [1],[2],[6],[7],[8],[9],[10] Both antigens are consistently absent in normal mast cells, in mast cells in reactive BM and BM from different hematological or nonhematological diseases. [9] In our case, we were able to define the neoplastic mast cells based on FCM. Valent et al. [7] and Escribano et al. [9] mentioned FCM evaluation as the most sensitive and a very specific method for detection of neoplastic mast cells than histology and immunohistochemistry. Mast cells share a common progenitor and differentiation antigens with myelomonocytic cells such as CD33 and CD68 as in our case. [7],[9] In addition, myeloblasts are known to express CD19, as in our case. [3],[4] In our case, the tryptase level and KIT mutation were not done due to lack of facility of these tests at our center.

AML with t(8;21) is usually associated with good response to chemotherapy and high complete remission with long-term disease-free survival rate. However, certain factors such as CD56 expression, the presence of KIT mutation, associated SM adversely affect prognosis as in our case. [1],[3],[4] With standard chemotherapy, these cases showed persistence of mastocytosis as in our case. [2]

Diagnosis of SM with AML with differentiation (M2) helps in assessing the treatment strategy, prognosis, and also helps in monitoring of treatment response. FCM has a definite role in defining neoplastic nature of mast cells where there is a lack of molecular diagnosis or unavailability of antibodies by immunohistochemistry.

 
   References Top

1.Horny HP, Metcalfe DD, Bennett JM, Bain BJ, Akin C., Escribano L. et al. Mastocytosis. In: Swerdlow SH, Campo E. editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4 th ed.. Lyon: International Agency for Research on Cancer; 2008. p. 54-63.  Back to cited text no. 1
    
2.Bernd HW, Sotlar K, Lorenzen J, Osieka R, Fabry U, Valent P, et al. Acute myeloid leukemia with t(8; 21) associated systemic mastocytosis. Report of an unusual case and review of the literature. J Clin Pathol 2004;57:324-8.  Back to cited text no. 2
[PUBMED]    
3.Mahadeo KM, Wolgast L, McMahon C, Cole PD. Systemic mastocytosis in a child with t(8;21) acute myeloid leukemia. Pediatr Blood Cancer 2011;57:684-7.  Back to cited text no. 3
[PUBMED]    
4.Pullarkat ST, Pullarkat V, Kroft SH, Wilson CS, Ahsanuddin AN, Mann KP, et al. Systemic mastocytosis associated with t(8;21)(q22;q22) acute myeloid leukemia. J Hematopathol 2009;2:27-33.  Back to cited text no. 4
    
5.Sperr WR, Drach J, Hauswrirth AW, Ackermann J, Mitterbauer M, Mitterbauer G, et al. Myelomastocytic leukemia: Evidence for the origin of mast cells from the leukemic clone and eradication by allogeneic stem cell transplant. Clin Cancer Res 2005;11:6787-92.  Back to cited text no. 5
    
6.Horney HP, Sotlar K, Sperr WR, Valent P. Systemic mastocytosis with associated Clonal haematological non-mast cell lineage diseases: A histopathological challenge. J Clin Pathol 2005;57:604-8.  Back to cited text no. 6
    
7.Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic criteria and classification of mastocytosis: Aconsensus proposal. Leuk Res 2001;25:603-25.  Back to cited text no. 7
[PUBMED]    
8.Pardanani A, Kimlinger T, Reeder T, Li CY, Tefferi A. Bone marrow mast cell immunophenotyoping in adults with mast cell disease: A prospective study of 33 patients. Leuk Res 2004;28:777-83.  Back to cited text no. 8
[PUBMED]    
9.Escribano L, Díaz-Agustín B, Bellas C, Navalon R, Nuñez R, Sperr WR, et al. Utility of flow cytometric analysis of mast cells in the diagnosis and classification of adult mastocytosis. Leuk Res 2001;25:563-70.  Back to cited text no. 9
    
10.Valent P, Sperr WR, Schwartz LB, Horney HP. Diagnosis and classification of mast cell proliferative disorders: Delineation from immunologic diseases and non-mast cell hematopoietic neoplasms. J Allergy Clin Immunol 2004;114:3-11.  Back to cited text no. 10
    

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Correspondence Address:
V S Gadage
Hematopathology Laboratory, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.101761

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