1. NRAS Q61R Mutation in Erdheim-Chester Disease Accompanying by Myeloid Neoplasia: Evidence for a Possible Clonal Relationship
Neval Ozkaya M.D.1, Benjamin Durham M.D.1, Omar Abdel-Wahab M.D.2, Eli Diamond M.D.3, Ahmet Dogan M.D., Ph.D.1
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

2. Clinical History
66/M several months of progressive cognitive impairment, deterioration of gait, fatigue, and urinary incontinence in the summer of 2012 (In 09/2012; WBC: 9400, Hb: 11, Plt: , Abs Mono: 2500)
Outside laboratory studies significant for abnormal endocrine labs and elevated inflammatory markers (CRP: 7.5)
MRI multifocal contrast-enhancing lesions of the cerebral meninges.
CT and PET scan of the chest, abdomen, and pelvis paravertebral, pleural, presacral, and renal masses, as well as widespread lytic osseous lesions.

3. Clinical History
Biopsy results of both renal and presacral masses foamy CD68+/CD1a−/S100- histiocytic infiltrate
Nuclear bone scintigraphy abnormal tracer uptake in the long bones of the lower extremities.
The presence of a non-Langerhans histiocytic infiltrate and the distribution of bone lesions in the long bones of the legs essentially confirmed a diagnosis of Erdheim-Chester Disease (ECD)

4. Imaging
Contrast-enhanced sagittal magnetic resonance imaging scan demonstrates lobulated enhancing masses arising from the cerebral meninges
Fluorodeoxyglucose-avid lesions in the abdomen, pelvis, and long bones
The classic scintigraphic uptake in the long bones

5. Presacral Mass Biopsy
CD163
S100

6. Clinical History
At presentation, patient’s blood level has led to a bone marrow biopsy on December 2012
At that time CMML-1 couldn’t be entirely excluded
IFN therapy was started in 02/2013
He has tolerated treatment well, but monocytosis has persisted since patient’s presentation as stable (>1 × 109/l)
On 10/ severe cytopenias, IFN was come off
(WBC: 9100, Hb: 7.1, Plt: , Mono: 17%, Abs Mono: 1700)
Repeat bone marrow biopsy CMML-1

7. Bone Marrow Aspiration
Myeloid lineage: Markedly increase and left-shifted, monocytosis
Megakaryocytes: Several dysplastic forms (mononucleation, hypolobation)

8. Bone Marrow Biopsy CD117 Hypercellular bone marrow (95%)
Myeloid lineage: Markedly increase and left-shifted
Erythroid lineage: Markedly increased with megaloblastic maturation
Megakaryocytes: Several dysplastic forms (mononucleation, hypolobation)
Other: Plasmacytosis and minute foci of histiocytic aggregates

9. Cytogenetic Normal karyotype. FISH : EVI (3q26) gene (-)
Deletion 7q (-)
Monosomy 7 (-)
Translocation of the MLL (11q23) gene (-)
Trisomy 8 (-)
Deletion 20q (-)
Loss of TP53 gene (-)

10. Molecular Studies:
Presacral mass and bone marrow biopsies were interrogated for hotspot mutations in 8 commonly mutated oncogenes (EGFR, KRAS, BRAF, PIK3CA, NRAS, AKT1, ERBB2, and MAP2K1) using the Sequenom MassARRAY system
NRAS Q61R mutation (+) Presacral mass and bone marrow biopsies
BRAF V600E (-) Presacral mass and bone marrow biopsies
Proposed Diagnosis: NRAS Q61R mutated ECD accompanying by clonally linked myeloid neoplasia

11. Interesting Features
ECD is a rare type of non-Langerhans histiocytosis
Recent identification of the clonal nature of the ECD with recurrent somatic mutations have made progress in redefining the pathogenesis of this disorder and establishing molecularly and immunologically based targeted therapeutics1,2
However, the cell of origin for ECD is still enigmatic
Haroche et al. (2012) High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood. 120(13):2700–2703
Emile et al. (2014) Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease. Blood Nov 6;124(19):3016-9

12. Interesting Features
Historically, ECD has been presumed to arise from transformed or pathologically activated dermal dendritic cells
However, new evidence supports a model in which ECD occurs as a consequence of a misguided differentiation programme of myeloid dendritic cell precursor1
This is, to our knowledge, the first report demonstrating association of ECD with a myeloid neoplasia and both neoplastic populations displayed the same molecular abnormality that is NRAS Q61R mutation in the absence of BRAF mutation
Haroche et al. (2015) The histiocytosis Erdheim–Chester disease is an inflammatory myeloid neoplasm. Expert Rev Clin Immunol. 2015;11(9):