Hairy cell leukemia pathophysiology

	Hairy cell leukemia Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Hairy cell leukemia from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Study of Choice
Staging
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
Chest X Ray
CT
MRI
Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Hairy cell leukemia pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hairy cell leukemia pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hairy cell leukemia pathophysiology
CDC on Hairy cell leukemia pathophysiology
Hairy cell leukemia pathophysiology in the news
Blogs on Hairy cell leukemia pathophysiology
Directions to Hospitals Treating Hairy cell leukemia
Risk calculators and risk factors for Hairy cell leukemia pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2], Haytham Allaham, M.D. [3], James Nasr [4]; Grammar Reviewer: Natalie Harpenau, B.S.[5]

Overview

Hairy cell leukemia arises from B cells that are normally involved in the process of human immunoglobulins production. It is thought to originate from a peripheral, antigen-experienced mature B cell with features resembling post–germinal center memory B cells. The most common gene involved in the pathogenesis of hairy cell leukemia is BRAF V600E mutation. On microscopic histopathological analysis, characteristic findings of hairy cell leukemia include small cells with "fried egg" like appearance, well-demarcated thread-like cytoplasmic extensions, and a clear cytoplasm. Hairy cell leukemia is driven by constitutive activation of the RAF–MEK–ERK signalling pathway which inhibits apoptosis and drives survival.

Pathogenesis

Hairy cell leukemia arises from B cells, which are normally involved in the process of human immunoglobulins production.^[1]
Hairy cell leukemia is thought to originate from a peripheral, antigen-experienced mature B cell with features resembling post–germinal center memory B cells.^[2]
Bone marrow failure may develop among hairy cell leukemia patients due to:

Malignant cells infiltration of the bone marrow, resulting in bone marrow failure or pancytopenia
Reticulin fibrosis of the bone marrow
Dysregulated cytokine production

The development of bone marrow failure interferes with the normal production of red blood cells and platelets among hairy cell leukemia patients.
Leukemic cells may also infiltrate both the spleen and liver and leads to organomegaly.
Extravascular hemolysis may develop due to splenic sequestration of the circulating red blood cells.
Lymph nodes involvement is unusual, and more often seen in relapse.^[3]^[4]
Hairy cell leukemia is driven by constitutive activation of the RAF–MEK–ERK signalling pathway, most commonly due to the BRAF V600E mutation.^[5]
Aberrant RAF–MEK–ERK signalling in hairy cell leukemia inhibits apoptosis, and BRAF inhibition can trim hairy projections and then induce apoptosis.^[6]
In approximately 40% of hairy cell leukemia cases, malignant cells co-express multiple clonally-related IgG, IgA, and IgM isotypes.

Genetics

The most common gene involved in the pathogenesis of hairy cell leukemia is BRAF V600E mutation.^[7]^[8]^[9]^[10]^[11]
The MEK-ERK cascade is activated which will amplify the cytoprotective survival pathways.^[12]

Associated Conditions

Hairy cell leukemia has been found to be associated with trisomy 5 in a number of reported cases.

Microscopic Pathology

On microscopic histopathological analysis, characteristic findings of hairy cell leukemia include:

Small cells with "fried egg" like appearance
Well-demarcated thread-like cytoplasmic extensions
Clear cytoplasm
Round to oval nuclei with inconspicuous nucleoli
Perinuclear clearing ("water-clear rim" appearance)

A positive tartrate-resistant acid phosphatase (TRAP) stain is a key diagnostic feature for hairy cell leukemia.^[13]
On immunohistochemistry, characteristic findings of hairy cell leukemia include:^[14]^[15]

Annexin A1 +ve
CD20 +ve
CD25 +ve
CD103 +ve
Cyclin D1 +ve
BRAF V600E +ve

On flow cytometry, characteristic findings of hairy cell leukemia include:^[16]

CD19 +ve
CD20 +ve
CD11c +ve
CD25 +ve
CD103 +ve
CD123 +ve
FMC7 +ve

Illustrated below is a series of microscopic images observed in hairy cell leukemia:

Hairy cell leukemia illustrated on a blood film^[17]
Hairy cell leukemia illustrated on high magnification^[17]
Hairy cell leukemia illustrated on very high magnification^[17]

References

↑ Tiacci E, Liso A, Piris M, Falini B (June 2006). "Evolving concepts in the pathogenesis of hairy-cell leukaemia". Nat. Rev. Cancer. 6 (6): 437–48. doi:10.1038/nrc1888. PMID 16723990.
↑ Basso K, Liso A, Tiacci E, Benedetti R, Pulsoni A, Foa R, Di Raimondo F, Ambrosetti A, Califano A, Klein U, Dalla Favera R, Falini B. Gene expression profiling of hairy cell leukemia reveals a phenotype related to memory B cells with altered expression of chemokine and adhesion receptors. J Exp Med. 2004 Jan 5;199(1):59-68. doi: 10.1084/jem.20031175. PMID: 14707115; PMCID: PMC1887727.
↑ Tadmor T, Polliack A. Hairy cell leukemia: Uncommon clinical features, unusual sites of involvement and some rare associations. Best Pract Res Clin Haematol. 2015 Dec;28(4):193-9. doi: 10.1016/j.beha.2015.10.020. Epub 2015 Nov 11. PMID: 26614897.
↑ Falini B, De Carolis L, Tiacci E. How I treat refractory/relapsed hairy cell leukemia with BRAF inhibitors. Blood. 2022 Apr 14;139(15):2294-2305. doi: 10.1182/blood.2021013502. PMID: 35143639; PMCID: PMC11022828.
↑ Tiacci E, Schiavoni G, Martelli MP, Boveri E, Pacini R, Tabarrini A, Zibellini S, Santi A, Pettirossi V, Fortini E, Ascani S, Arcaini L, Inghirami G, Paulli M, Falini B. Constant activation of the RAF-MEK-ERK pathway as a diagnostic and therapeutic target in hairy cell leukemia. Haematologica. 2013 Apr;98(4):635-9. doi: 10.3324/haematol.2012.078071. Epub 2013 Jan 24. PMID: 23349307; PMCID: PMC3659996.
↑ Pettirossi V, Santi A, Imperi E, Russo G, Pucciarini A, Bigerna B, Schiavoni G, Fortini E, Spanhol-Rosseto A, Sportoletti P, Mannucci R, Martelli MP, Klein-Hitpass L, Falini B, Tiacci E. BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity. Blood. 2015 Feb 19;125(8):1207-16. doi: 10.1182/blood-2014-10-603100. Epub 2014 Dec 5. PMID: 25480661; PMCID: PMC4366655.
↑ Wanko SO, de Castro C (2006). "Hairy cell leukemia: an elusive but treatable disease". Oncologist. 11 (7): 780–9. doi:10.1634/theoncologist.11-7-780. PMID 16880237.
↑ Ng PC, Levy S, Huang J, Stockwell TB, Walenz BP, Li K, Axelrod N, Busam DA, Strausberg RL, Venter JC (August 2008). "Genetic variation in an individual human exome". PLoS Genet. 4 (8): e1000160. doi:10.1371/journal.pgen.1000160. PMC 2493042. PMID 18704161.
↑ Shao H, Calvo KR, Grönborg M, Tembhare PR, Kreitman RJ, Stetler-Stevenson M, Yuan CM (April 2013). "Distinguishing hairy cell leukemia variant from hairy cell leukemia: development and validation of diagnostic criteria". Leuk. Res. 37 (4): 401–409. doi:10.1016/j.leukres.2012.11.021. PMC 5575750. PMID 23347903.
↑ Tiacci E, Schiavoni G, Forconi F, Santi A, Trentin L, Ambrosetti A, Cecchini D, Sozzi E, Francia di Celle P, Di Bello C, Pulsoni A, Foà R, Inghirami G, Falini B (January 2012). "Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation". Blood. 119 (1): 192–5. doi:10.1182/blood-2011-08-371179. PMID 22028477.
↑ Schnittger S, Bacher U, Haferlach T, Wendland N, Ulke M, Dicker F, Grossmann V, Haferlach C, Kern W (March 2012). "Development and validation of a real-time quantification assay to detect and monitor BRAFV600E mutations in hairy cell leukemia". Blood. 119 (13): 3151–4. doi:10.1182/blood-2011-10-383323. PMID 22331186.
↑ Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, Pucciarini A, Bigerna B, Pacini R, Wells VA, Sportoletti P, Pettirossi V, Mannucci R, Elliott O, Liso A, Ambrosetti A, Pulsoni A, Forconi F, Trentin L, Semenzato G, Inghirami G, Capponi M, Di Raimondo F, Patti C, Arcaini L, Musto P, Pileri S, Haferlach C, Schnittger S, Pizzolo G, Foà R, Farinelli L, Haferlach T, Pasqualucci L, Rabadan R, Falini B (June 2011). "BRAF mutations in hairy-cell leukemia". N. Engl. J. Med. 364 (24): 2305–15. doi:10.1056/NEJMoa1014209. PMC 3689585. PMID 21663470.
↑ Cawley JC (October 2006). "The pathophysiology of the hairy cell". Hematol. Oncol. Clin. North Am. 20 (5): 1011–21. doi:10.1016/j.hoc.2006.06.002. PMID 16990104.
↑ Matutes E, Wotherspoon A, Catovsky D (March 2003). "The variant form of hairy-cell leukaemia". Best Pract Res Clin Haematol. 16 (1): 41–56. PMID 12670464.
↑ Forconi F, Raspadori D, Lenoci M, Lauria F (February 2005). "Absence of surface CD27 distinguishes hairy cell leukemia from other leukemic B-cell malignancies". Haematologica. 90 (2): 266–8. PMID 15710587.
↑ Shao H, Calvo KR, Grönborg M, Tembhare PR, Kreitman RJ, Stetler-Stevenson M, Yuan CM (April 2013). "Distinguishing hairy cell leukemia variant from hairy cell leukemia: development and validation of diagnostic criteria". Leuk. Res. 37 (4): 401–409. doi:10.1016/j.leukres.2012.11.021. PMC 5575750. PMID 23347903.
↑ ^17.0 ^17.1 ^17.2 Small cell lymphoma. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Small_cell_lymphomas#Hairy_cell_leukemia Accessed on October, 8 2015

Template:WikiDoc Sources

[pmid167239902-1] Tiacci E, Liso A, Piris M, Falini B (June 2006). "Evolving concepts in the pathogenesis of hairy-cell leukaemia". Nat. Rev. Cancer. 6 (6): 437–48. doi:10.1038/nrc1888. PMID 16723990.

[2] Basso K, Liso A, Tiacci E, Benedetti R, Pulsoni A, Foa R, Di Raimondo F, Ambrosetti A, Califano A, Klein U, Dalla Favera R, Falini B. Gene expression profiling of hairy cell leukemia reveals a phenotype related to memory B cells with altered expression of chemokine and adhesion receptors. J Exp Med. 2004 Jan 5;199(1):59-68. doi: 10.1084/jem.20031175. PMID: 14707115; PMCID: PMC1887727.

[3] Tadmor T, Polliack A. Hairy cell leukemia: Uncommon clinical features, unusual sites of involvement and some rare associations. Best Pract Res Clin Haematol. 2015 Dec;28(4):193-9. doi: 10.1016/j.beha.2015.10.020. Epub 2015 Nov 11. PMID: 26614897.

[4] Falini B, De Carolis L, Tiacci E. How I treat refractory/relapsed hairy cell leukemia with BRAF inhibitors. Blood. 2022 Apr 14;139(15):2294-2305. doi: 10.1182/blood.2021013502. PMID: 35143639; PMCID: PMC11022828.

[5] Tiacci E, Schiavoni G, Martelli MP, Boveri E, Pacini R, Tabarrini A, Zibellini S, Santi A, Pettirossi V, Fortini E, Ascani S, Arcaini L, Inghirami G, Paulli M, Falini B. Constant activation of the RAF-MEK-ERK pathway as a diagnostic and therapeutic target in hairy cell leukemia. Haematologica. 2013 Apr;98(4):635-9. doi: 10.3324/haematol.2012.078071. Epub 2013 Jan 24. PMID: 23349307; PMCID: PMC3659996.

[6] Pettirossi V, Santi A, Imperi E, Russo G, Pucciarini A, Bigerna B, Schiavoni G, Fortini E, Spanhol-Rosseto A, Sportoletti P, Mannucci R, Martelli MP, Klein-Hitpass L, Falini B, Tiacci E. BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity. Blood. 2015 Feb 19;125(8):1207-16. doi: 10.1182/blood-2014-10-603100. Epub 2014 Dec 5. PMID: 25480661; PMCID: PMC4366655.

[pmid16880237-7] Wanko SO, de Castro C (2006). "Hairy cell leukemia: an elusive but treatable disease". Oncologist. 11 (7): 780–9. doi:10.1634/theoncologist.11-7-780. PMID 16880237.

[pmid18704161-8] Ng PC, Levy S, Huang J, Stockwell TB, Walenz BP, Li K, Axelrod N, Busam DA, Strausberg RL, Venter JC (August 2008). "Genetic variation in an individual human exome". PLoS Genet. 4 (8): e1000160. doi:10.1371/journal.pgen.1000160. PMC 2493042. PMID 18704161.

[pmid233479032-9] Shao H, Calvo KR, Grönborg M, Tembhare PR, Kreitman RJ, Stetler-Stevenson M, Yuan CM (April 2013). "Distinguishing hairy cell leukemia variant from hairy cell leukemia: development and validation of diagnostic criteria". Leuk. Res. 37 (4): 401–409. doi:10.1016/j.leukres.2012.11.021. PMC 5575750. PMID 23347903.

[pmid22028477-10] Tiacci E, Schiavoni G, Forconi F, Santi A, Trentin L, Ambrosetti A, Cecchini D, Sozzi E, Francia di Celle P, Di Bello C, Pulsoni A, Foà R, Inghirami G, Falini B (January 2012). "Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation". Blood. 119 (1): 192–5. doi:10.1182/blood-2011-08-371179. PMID 22028477.

[pmid22331186-11] Schnittger S, Bacher U, Haferlach T, Wendland N, Ulke M, Dicker F, Grossmann V, Haferlach C, Kern W (March 2012). "Development and validation of a real-time quantification assay to detect and monitor BRAFV600E mutations in hairy cell leukemia". Blood. 119 (13): 3151–4. doi:10.1182/blood-2011-10-383323. PMID 22331186.

[pmid21663470-12] Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, Pucciarini A, Bigerna B, Pacini R, Wells VA, Sportoletti P, Pettirossi V, Mannucci R, Elliott O, Liso A, Ambrosetti A, Pulsoni A, Forconi F, Trentin L, Semenzato G, Inghirami G, Capponi M, Di Raimondo F, Patti C, Arcaini L, Musto P, Pileri S, Haferlach C, Schnittger S, Pizzolo G, Foà R, Farinelli L, Haferlach T, Pasqualucci L, Rabadan R, Falini B (June 2011). "BRAF mutations in hairy-cell leukemia". N. Engl. J. Med. 364 (24): 2305–15. doi:10.1056/NEJMoa1014209. PMC 3689585. PMID 21663470.

[pmid16990104-13] Cawley JC (October 2006). "The pathophysiology of the hairy cell". Hematol. Oncol. Clin. North Am. 20 (5): 1011–21. doi:10.1016/j.hoc.2006.06.002. PMID 16990104.

[pmid12670464-14] Matutes E, Wotherspoon A, Catovsky D (March 2003). "The variant form of hairy-cell leukaemia". Best Pract Res Clin Haematol. 16 (1): 41–56. PMID 12670464.

[pmid15710587-15] Forconi F, Raspadori D, Lenoci M, Lauria F (February 2005). "Absence of surface CD27 distinguishes hairy cell leukemia from other leukemic B-cell malignancies". Haematologica. 90 (2): 266–8. PMID 15710587.

[pmid23347903-16] Shao H, Calvo KR, Grönborg M, Tembhare PR, Kreitman RJ, Stetler-Stevenson M, Yuan CM (April 2013). "Distinguishing hairy cell leukemia variant from hairy cell leukemia: development and validation of diagnostic criteria". Leuk. Res. 37 (4): 401–409. doi:10.1016/j.leukres.2012.11.021. PMC 5575750. PMID 23347903.

[patho-17] 17.0 ^17.1 ^17.2 Small cell lymphoma. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Small_cell_lymphomas#Hairy_cell_leukemia Accessed on October, 8 2015

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]