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  Table of Contents    
CASE REPORT  
Year : 2017  |  Volume : 60  |  Issue : 4  |  Page : 593-595
Fibroblast growth factor receptor-1 associated myeloproliferative neoplasm and T-lymphoblastic lymphoma


1 Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
2 Department of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India

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Date of Web Publication12-Jan-2018
 

   Abstract 


Myeloid and lymphoid hematological malignancies with eosinophilia and abnormalities of fibroblast growth factor receptor-1 (FGFR1) result from the formation of abnormal fusion genes that encode constitutively activated tyrosine kinases. The WHO classification (2008) of hematolymphoid neoplasms recognizes a category of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of FGFR1. Here, we present the case of a 30-year-old-woman who was diagnosed with T-lymphoblastic lymphoma from lymph node biopsy and myeloproliferative neoplasm with eosinophilia from bone marrow studies. She was treated with combination chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD regimen) and is on maintenance chemotherapy for the past 2 months. We present this case to create awareness among physicians about this rare condition associated with dual malignancies.

Keywords: Fibroblast growth factor receptor-1, myeloproliferative neoplasm, T-lymphoblastic lymphoma

How to cite this article:
Gopan G, Anoop T M, Prakash N P, Nambiar R, Krishnachandran R. Fibroblast growth factor receptor-1 associated myeloproliferative neoplasm and T-lymphoblastic lymphoma. Indian J Pathol Microbiol 2017;60:593-5

How to cite this URL:
Gopan G, Anoop T M, Prakash N P, Nambiar R, Krishnachandran R. Fibroblast growth factor receptor-1 associated myeloproliferative neoplasm and T-lymphoblastic lymphoma. Indian J Pathol Microbiol [serial online] 2017 [cited 2019 Jun 20];60:593-5. Available from: http://www.ijpmonline.org/text.asp?2017/60/4/593/222972





   Introduction Top


The association of T-lymphoblastic lymphoma (T-LBL) with myeloid neoplasms with fibroblast growth factor receptor (FGFR) mutations is rare. The postulated cell of origin for FGFR1 rearranged disease is a pluripotent progenitor capable of giving rise to both myeloid and lymphoid neoplasms. Here, we present the case of a 30-year-old-woman who presented with generalized lymphadenopathy, tonsillar enlargement, and splenomegaly. Her lymph node biopsy was diagnostic of T-LBL, bone marrow (BM) studies confirmed myeloproliferative neoplasm with eosinophilia and mutational analysis revealed FGFR1 mutation.


   Case Report Top


A 30-year-old female presented with complaints of fever, loss of weight and appetite of 2 weeks duration. Physical examination demonstrated pallor, generalized lymphadenopathy, tonsillar enlargement, pedal edema, and moderate splenomegaly. Investigations showed anemia (9 g/dl), thrombocytosis (14 Lakhs/cumm) and hyperleukocytosis (65,000/cumm) with 30% eosinophils and lactate dehydrogenase 827 mg/dl. Peripheral smear demonstrated anisopoikilocytosis with evidence of erythroid regeneration, mild neutrophilia, moderate eosinophilia, and severe thrombocytosis. Computer tomography of neck, chest abdomen, and pelvis revealed generalized lymphadenopathy with bulky tonsils. BM biopsy showed clustering of erythroid and myeloid precursors with plenty of eosinophils [Figure 1]. Megakaryocytes appear proliferated with normal hypolobated forms and dysplastic forms. Reticulin staining showed grade 1 fibrosis confirming the diagnosis of myeloproliferative neoplasm with eosinophilia. Mutational analysis was negative for BCR-ABL fusion gene, inversion 16, t(8;21), JAK2, PDGFRb and FIP1L1-PDGFRa rearrangement. Inguinal lymph node biopsy showed atypical small lymphoid cells with clumped chromatin [Figure 2]. Immunohistochemistry was positive for CD 3, 5, 7, 10, and Terminal deoxynucleotidyl transferase confirming the diagnosis of T-LBL. With the BM demonstrating myeloproliferative disorder and the lymph node biopsy showing T-LBL, a possibility of FGFR1-related myeloproliferative neoplasms was considered, and further mutational studies were carried out. Cytogenetic evaluation revealed 46 XX, t(8;13), +mar [Figure 3]. Fluorescent in situ hybridization analysis revealed deletion of FGFR1 3' locus in 75% cells along with positivity for FGFR1 gene rearrangement or 8p12 in 15% cells. The final diagnosis was FGFR1 associated myeloproliferative neoplasm and T-LBL. She was treated with combination chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD regimen). She attained remission post chemotherapy but was still FGFR1 rearrangement positive. Prophylactic cranial radiation therapy was given. At present, she is on maintenance chemotherapy for the past 2 months.
Figure 1: Bone marrow biopsy showed clustering of erythroid and myeloid precursors with plenty of eosinophils (H and E, ×400)

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Figure 2: Inguinal lymph node biopsy showed atypical small lymphoid cells with clumped chromatin (H and E, ×400)

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Figure 3: GTG banded karyotype showing 46 XX, t(8;13), +mar

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   Discussion Top


The association of T-LBL with myeloid neoplasms with FGFR mutations is rare.[1],[2] The WHO classification (2008) of hematolymphoid neoplasms recognizes a category of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of FGFR1.[3] The postulated cell of origin for FGFR1 rearranged disease is a pluripotent progenitor capable of giving rise to myeloid neoplasms and to lymphoblastic leukemia/lymphoma.[4] FGFR1 plays a role in embryonic development and wound repair by controlling growth, differentiation, and cell migration.[4] The FGFR family is composed of 18 ligands that exert their actions through four highly conserved transmembrane tyrosine kinase receptors (FGFR1, FGFR2, FGFR3, and FGFR4). Activation of FGFR1 leads to downstream signaling through the PI3K/AKT and RAS/MAPK pathways, which are central to growth, survival migration, and angiogenesis in many cancers.[5] Dysregulation of FGFR family signaling due to various mechanisms, such as amplification, translocation, and point mutations, has been described in a broad range of tumor types, including various sarcomas, plasma cell myeloma, and cancers of the breast, prostate, urinary bladder, lung, and endometrium.

The FGFR1 gene at chromosome 8p11 is usually associated with myeloproliferative disorders, and these neoplasms have been referred to as 8p11 myeloproliferative syndrome.[5],[6] An association between the t(8;13) and the triad of T-LBL/leukemia, eosinophilia, and myeloid malignancy was first reported in 1992.[7] Gene fusion results in constitutive activation of FGFR1 tyrosine kinase. Hematolymphoid neoplasms associated with FGFR1 fusions are rare and aggressive tumors. Patients usually have B symptoms, lymphadenopathy, and hepatosplenomegaly. The BM is usually hypercellular with eosinophilia and features suggestive of myeloproliferative neoplasm. These tumors frequently progress to acute myeloid leukemia (AML) (around 15%). Most patients with hematolymphoid neoplasms associated with t(8;13)(p11;q12) develop T-LBL/leukemia involving nodal or extranodal sites.[7] The association with lymphoblastic lymphoma/leukemia of B lineage is rare. Cytogenetic studies showed that translocation involves the 8p11-12 breakpoint resulting in a variety of fusion genes involving a portion of the FGFR1 gene. The most common translocation is t(8;13)(p11;q12) resulting in a ZNF198-FGFR1 fusion gene.[7] Patients with t(8;22)(p11;q11)/BCR-FGFR1 often have neutrophilia and basophilia mimicking CML. Patients with t(6;8) (q27;p12)/FGFR10P-FGFR1 may present with a polycythemia vera-like picture.[8] Translocation t(8;9)(p11;q34) is the most likely finding in patients with tonsillar enlargement. Patients with t(8;13)(p11;q12) more often present with or develop lymphadenopathy secondary to T-LBL.

Myeloproliferative and lymphoid neoplasms with eosinophilia and specific tyrosine kinase gene fusions have got clinical significance due to varying responsiveness to tyrosine kinase inhibitors. Disorders with FGFR1 and JAK2 gene fusions are resistant to imatinib and other tyrosine kinase inhibitors. At present, there is no standard approved therapy for myeloid and lymphoid neoplasms with FGFR1 abnormalities. Currently, intense chemotherapeutic regimens including hyper-CVAD followed by allogeneic stem cell transplantation are recommended for patients. There is a report on one patient who responded partially to midostaurin.[9] A high index of suspicion is required to establish the diagnosis of these rare diseases. These neoplasms should be suspected in the presence of eosinophilia, a finding that is detected in >70% of cases. Suspicion is heightened if the BM is hypercellular with eosinophilia and if the patient has concomitant or subsequent T-LBL/leukemia or AML.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
JabbarAl-Obaidi M, Rymes N, White P, Pomfret M, Smith H, Starczynski J, et al. Afourth case of 8p11 myeloproliferative disorder transforming to B-lineage acute lymphoblastic leukaemia. A case report. Acta Haematol 2002;107:98-100.  Back to cited text no. 1
    
2.
Macdonald D, Aguiar RC, Mason PJ, Goldman JM, Cross NC. A new myeloproliferative disorder associated with chromosomal translocations involving 8p11: A review. Leukemia 1995;9:1628-30.  Back to cited text no. 2
    
3.
Bain BJ, Gilliland DG, Horny HP, Vardiman JW. Myeloid and lym- phoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR 1. In: Swerdlow S, Campo E, Harris N, Jaffe ES, Pileri SA, Stein H, et al. editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed., Vol. 1. IARC Press; Lyon: 2008. p. 68-9, 70-3.  Back to cited text no. 3
    
4.
Ondrejka SL, Jegalian AG, Kim AS, Chabot-Richards DS, Giltnane J, Czuchlewski DR, et al. PDGFRB-rearranged T-lymphoblastic leukemia/lymphoma occurring with myeloid neoplasms: The missing link supporting a stem cell origin. Haematologica 2014;99:e148-51.  Back to cited text no. 4
    
5.
Vega F, Medeiros LJ, Bueso-Ramos CE, Arboleda P, Miranda RN. Hematolymphoid neoplasms associated with rearrangements of PDGFRA, PDGFRB, and FGFR1. Am J Clin Pathol 2015;144:377-92.  Back to cited text no. 5
    
6.
Savage NM, Johnson RC, Gotlib J, George TI. Myeloid and lymphoid neoplasms with FGFR1 abnormalities: Diagnostic and therapeutic challenges. Am J Hematol 2013;88:427-30.  Back to cited text no. 6
    
7.
Inhorn RC, Aster JC, Roach SA, Slapak CA, Soiffer R, Tantravahi R, et al. Asyndrome of lymphoblastic lymphoma, eosinophilia, and myeloid hyperplasia/malignancy associated with t(8;13)(p11;q11): Description of a distinctive clinicopathologic entity. Blood 1995;85:1881-7.  Back to cited text no. 7
    
8.
Lourenco GJ, Ortega MM, Freitas LL, Bognone RA, Fattori A, Lorand-Metze I, et al. The rare t(6;8) (q27;p11) translocation in a case of chronic myeloid neoplasm mimicking polycythemia vera. Leuk Lymphoma 2008;49:1832-5.  Back to cited text no. 8
    
9.
Chase A, Grand FH, Cross NC. Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome. Blood 2007;110:3729-34.  Back to cited text no. 9
    

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Correspondence Address:
Rakul Nambiar
Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_357_17

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