Chronic Neutrophilic Leukemia (CNL)

Diagnostic Criteria

Activating CSF3R mutation (usually T618I or T615A)
WBC ≥ 25,000 (at least 80% neutrophils + bands, <10% neutrophil precursors)
- No dysgranulopoiesis or monocytosis (<1,000/μL)
Bone marrow hypercellularity
- <5% blasts
- Increased granulopoiesis
- No evidence of dysgranulopoiesis
No molecular abnormalities or diagnostic characteristics of another MPN or MPN/MDS

If a CSF3R mutation is NOT identified, the diagnosis of CNL can still be made if other reactive causes are excluded or other evidence of clonality is identified (persistent for at least 3 months).

CSF3R mutations were identified in 59% of cases of CNL or atypical CML.
Patient with CSF3R mutations have shown excellent response to JAK1/2 inhibitor ruxolitinib.
CSF3R mutations may be seen in combination with other mutations (e.g. SETBP1 and ASXL1)

Photomicrographs

Chronic Neutrophilic Leukemia (CNL) with granulocytic hyperplasia

Immunohistochemistry

The use of immunohistochemistry (IHC) in many of the myeloproliferative neoplasms is limited. Identifying an increased blast population is one of the most useful, and may indicate a more aggressive course or transformation to acute leukemia. Helpful IHC markers may include:

Stain	Comment
CD34	CD34 marks immature cells including myeloblasts. In the setting of AML, it is ~70% sensitive. A subset of lymphoblasts may express CD34.
CD117	CD117 is a specific myeloid marker, and marks a subset of myeloblasts. The expression is dim, and one often must look at 20-40X to clearly see expression. Mast cells (fried egg looking cell) will have very strong expression.
CD71	CD71 marks nucleated erythroid cells. This may be helpful in quantitating and differentiating erythroid cells from myeloid cells. This marker may be set-up as a double stain with CD34.
E_Cadherin	In the setting of hematopoietic cells, E-Cadherin marks immature erythroid cells. Like CD71, E-Cadherin may be useful to differentiate immature erythroid cells from immature myeloid cells.
TdT	TdT is a sensitive lymphoblast (~95%) marker. It is not entirely specific for lymphoblasts, but other markers can help clarify diagnostic difficulties (B and T-cell markers).

References

Swerdlow SH, Campo E, Harris, NL, Jaffe ES, Pileri SA, Stein H, Thiele J (Eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition). IARC: Lyon 2017

Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127: 2391–2405. doi:10.1182/blood-2016-03-643544

Maxson JE, Gotlib J, Pollyea DA, Fleischman AG, Agarwal A, Eide CA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013;368: 1781–1790. doi:10.1056/NEJMoa1214514