Submitting Author: Song, Liping, MD, PhD
Institution: The University of Texas Health Science Center at Houston
Additional authors:Lei Chen, Robert Brown, Amer Wahed
Session: Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1

This is a 28 year old male with progressive diffuse lymphadenopathy, night sweat, poor appetite, weight loss and fatigue for several months.

Specimen 1:

Site: Left posterior neck lymph node

Specimen type: Core needle biopsy and superficial fine needle biopsy

Method of fixation: Formalin

Gross description: Two core biopsies were prepared: 1 cm×0.2 cm and 1.2 cm×0.2 cm

Microscopic description: Core biopsy shows diffuse infiltration with malignant lymphocytes of medium size with vesicular nuclei and one to several nucleoli. Frequent mitotic figures are seen. The malignant cells are admixed with increased number of eosinophils, mature lymphocyte and moderate number of tangible-body macrophages .

Specimen 2:

Site: Left posterior iliac crest

Specimen type: bone marrow trephine biopsy and aspiration specimen

Method of fixation: Formalin

Gross description: decalcified; one core measuring 0.7 cm in length; Wright-Giemsa stain of smear

Microscopic description: The bone marrow aspirate smears contain numerous marrow particles, which are moderately cellular and adequate for evaluation. Granulocytic precursors increased with normal maturation. Erythroid precursors are decreased in proportion and show complete and progressive maturation. Occasional lymphocytes with atypical morphology are present. Megakaryocytes appear adequate in number and normal in morphology. No overtly dysplastic features are noted. A 500 cell differential count on the aspirate smears demonstrates: 1% blasts, 5.0% promyelocytes, 9 % myelocytes, 9% metamyelocytes, 35% neutrophils, 20% eosinophil, 0% plasma cells, 0% basophils, 15% lymphocytes, and 5% erythroid precursors.

The trephine biopsy is adequate for evaluation. The clot sections contain numerous marrow particles, which are adequate for evaluation. The most prominent finding is eosinophilia (20%). The overall cellularity is 90% with M: E ratio of 13:1. A few atypical mast cells were seen. Granulopoiesis are increased and shows progressive maturation. Erythrocytic precursors show progressive maturation in erythroid islands. The trabecular bone is normal. No lymphoid aggregates, granuloma, or other focal lesions are identified. Megakaryocytes are normal in number and morphology.

Specimen 3:

Time: one month after one cycle of hyperCVD

Site: Right posterior iliac crest

Specimen type: bone marrow trephine biopsy and aspiration specimen

Method of fixation: Formalin

Gross description: decalcified; one core measuring 0.6 cm in length; Wright-Giemsa stain of smear

Microscopic description: The bone marrow aspirate smears contain numerous marrow particles, which are moderately cellular and adequate for evaluation with M/E ratio 2.2:1. Granulocytic precursors increased with left shift and demonstrate progressive maturation. Erythroid precursors are normal in quantity and show complete and progressive maturation. Megakaryocytes are increased and display dysplastic features. A 500 cell differential count on the aspirate smears demonstrates: 1% blasts, 5.0% promyelocytes, 12 % myelocytes, 9% metamyelocytes, 33% neutrophils, 1% plasma cells, 3% eosinophils, 1% monocytes, 0% basophils, 3% lymphocytes, 29% erythroid precursors and 3% mast cells.

The trephine biopsy is adequate for evaluation. The clot sections contain numerous marrow particles, which are adequate for evaluation. The cardinal feature is the increased atypical spindle shaped mast cells with focal cluster formation. The overall cellularity is 90%. Megakaryocytes are increased with dysplastic features. There are increased eosinophils. Granulopoiesis are increased with left shift and shows progressive maturation. Erythrocytic precursors show progressive maturation. The trabecular bone is normal. No lymphoid aggregates, granuloma, or other focal lesions are identified.

Specimen 1

Immunohistochemical stains, with adequate controls, are performed. The malignant cells are positive for CD2, CD3, CD4, CD5, CD45, CD56, BCL2 and TdT (90% of cells) and negative for CD8, CD10, CD15, CD20, CD23, CD30, ALK1 and cyclin D1. EBV in situ hybridization is also negative. 47% T-lymphoblasts are identified by flow cytometric analysis with expression of CD2, CD3 (cytoplasmic), CD5, TdT, with aberrant loss of surface CD3 and CD7. These blasts are predominantly CD4+/CD8- (83%) with small subset of double positive for CD4+/CD8+ (12%). They are small to medium in size, and they are negative for CD34 and HLA-DR.

Specimen 2

Immunostains with appropriate controls were performed for CD3, CD4, CD8 and TdT. CD3 and CD8 positive cells are sparse. However there are disproportionately increased CD4 positive cells. The flow cytometry study shows 41.7% of lymphocytes are T cells with a CD4/CD8 ratio of 1.14, without loss of pan T-cell markers in contrast to lymph node specimen. TdT show scattered focal positive cells.

Specimen 3

Immunostains with appropriate controls were performed for CD2, CD3, and CD117. The atypical spindled mast cells are highlighted with CD117 immunochemistry staining. CD3 and CD2 positive cells are sparse. However there are disproportionately increased CD4 positive cells. The flow cytometer study shows 41.7% of lymphocytes are T cells with a CD4/CD8 ratio of 1.14, without loss of pan T-cell markers as shown in lymph node specimen. TdT show scattered focal positive cells.

Specimen 1:

47, XY, t (8; 13) (p11; q12), +21[20][ Fig 4]. An abnormal clone was noted in all GTG banded metaphases analyzed. The clone is characterized by trisomy 21 and an 8; 13 translocation that has been specifically correlated with the 8p11 myeloproliferative syndrome (EMS).

53% of nuclei positive for FGFR1 Gene Rearrangement by FISH .Trisomy 21 was also noted. Normal PDGFRA/B MPN Related regions. No BCR or ABL Gene Rerrangment.

Specimen 2:

47, XY, t (8; 13) (p11; q12), +21[20]. An abnormal clone was noted in all GTG banded metaphases analyzed. The clone is characterized by trisomy 21 and an 8; 13 translocation that has been specifically correlated with the 8p11 myeloproliferative syndrome (EMS).

87% of nuclei positive for FGFR1 gene rearrangement by FISH; Negative for SCFD2/FIP1L1, LNX/CHIC2 and PDGFRA, PDGFRB, BCR/ABL by FISH.

Specimen 3:

46,XY,t(8;13)(p11;q12)[5]/47,idem,+21[5]/46,XY[10]. An abnormal clone was noted in all GTG banded metaphases analyzed. The clone is characterized by trisomy 21 and an 8; 13 translocation that has been specifically correlated with the 8p11 myeloproliferative syndrome (EMS). The cells with secondary trisomy 21 evolution have decreased in this analysis.

9% of nuclei positive for FGFR1 gene rearrangement, no c-KIT mutation was identified.

On diagnosis, the patient was presented with diffuse T lymphoblastic lymphoma and bone marrow showed minimal involvement of T-ALL by morphology and flowcytometric analysis. However, 87% of nuclei are positive for FGFR mutation with concurrent trisomy 21, which may be explained by pluripotent (lymphoid/myeloid) stem cell nature of bone marrow neoplastic cells. One month later with one cycle hyperCVD, the patient’s lymphanopathy had improved dramatically and bone marrow biopsy showed 9% of the cells FGFR1 gene rearrangement by FISH. Trisomy 21 evolution decreased as well. Interestingly, many atypical mast cells (spindle-shaped) marked by CD117 with focal aggregates were also identified on core biopsy. Serum tryptase level was 38.9 µg/L (reference level: 2.2 µg/L to 13.2 µg/L) and c-kit mutation is negative. The patient had completed 5 cycle of hyperCVD and his lymphanopathy has diminished and his peripheral eosinophil counts returned to normal. The patient developed cardiomyopathy, anemia secondary to chemotherapy. The patient also complained headache, however multiple CSF cytology displays negativity for malignancy.

The 8p11 stem cell myeloproliferative disorder, involving lymphoid (T- and B-cell) and myeloid lineages, may have variable presentations reportedly (e.g. PV evolving to an atypical MPN, or a T-cell lymphoblastic lymphoma relapsing as AML, as in this case, atypical mastocytosis ). The MPN syndrome transforms rapidly into myelomonocytic leukemia, and is refractory to current chemotherapies with poor prognosis. The patient will be monitored closely for transformation.

Myeloid and lymphoid neoplasm with eosinophilia and FGFR1 abnormality by WHO Classification, akin “8p11 Myeloproliferative syndrome”

Myeloid and lymphoid neoplasm with FGFR1 rearrangement, t(8;13)(p11.2;q12), presenting with T lymphoblastic lymphoma, myeloproliferative neoplasm, and eosinophilia

Case 433