Lymphoma & related disorders
Mature B cell neoplasms
Small B cell lymphomas with a circulating component
Hairy cell leukemia variant


Topic Completed: 22 September 2020

Minor changes: 22 September 2020

Copyright: 2001-2020, PathologyOutlines.com, Inc.

PubMed Search: hairy cell leukemia variant [title]

Pallavi Khattar, M.D.
Julie Teruya-Feldstein, M.D.
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Cite this page: Khattar P, Bedi P, Teruya-Feldstein J. Hairy cell leukemia variant. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lymphomahclvariant.html. Accessed October 28th, 2020.
Definition / general
  • Rare B cell chronic lymphoproliferative disorder
  • Not biologically related to classic hairy cell leukemia (cHCL)
  • Exhibits a heterogeneous spectrum of clinical, morphologic, immunophenotypic and genetic features
  • Overlap features with classic hairy cell leukemia and other hairy cell-like B cell neoplasms
  • Provisional entity within the category of splenic B cell lymphoma / leukemia, unclassifiable, along with splenic diffuse red pulp small B cell lymphoma
Essential features
  • First recognized by Cawley et al. in 1980 (Leuk Res 1980;4:547)
  • Clinical laboratory findings
    • Leukocytosis and presence of monocytes
  • Bone marrow biopsy / aspirate: aspirable (reticulin fibrosis is normal / not increased)
  • Morphological findings
    • Intermediate size cells with blastic or convoluted nuclei, prominent nucleoli and circumferential shaggy contours
    • Other morphologic subtypes include convoluted and blastoid variant (Best Pract Res Clin Haematol 2015;28:253)
  • Immunophenotypic findings
    • Absence of CD25, CD123, annexin A1 and tartrate resistant acid phosphatase (TRAP)
  • Wild type BRAF
  • Resistant to conventional HCL therapy (e.g. cladribine)
  • Poorer prognosis (median survival ~ 9 years) (Leukemia 2001;15:184)
Terminology
  • Prolymphocytic variant of hairy cell leukemia
  • Atypical hairy cell leukemia
  • Japanese variant (HCL JV): predominant in females and may respond better to treatment (Leukemia 1993;7:181)
  • Synonyms
    • HCL variant
ICD coding
  • ICD-O: 9591/3 - non-Hodgkin lymphoma, NOS
  • ICD-10: C85.17 - unspecified B cell lymphoma, spleen
Epidemiology
  • Incidence
    • Constitutes 0.4% of chronic lymphoid malignancies; ~ 10% of all HCL cases
  • Age (Cancer Treat Rev 2011;37:3)
    • Middle aged to elderly patients
    • Reported median age 71 years
  • Sex
Sites
  • Mainly spleen, bone marrow and peripheral blood
  • Liver: less than 33% of patients
  • Lymph node, other solid organs: uncommon
Pathophysiology
  • Activated B cell at a late stage of maturation
Diagrams / tables

Contributed by Pallavi Khattar, M.D.
Differential diagnosis

Differential diagnosis



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Therapeutic algorithm for HCL variant

Therapeutic algorithm for HCL variant

Clinical features
Diagnosis
  • Requires constellation of clinical features, peripheral blood smear, bone marrow, immunophenotyping and molecular studies
Laboratory
  • Clinical laboratory values
    • Leukocytosis (average WBC ~ 30 x 109/L) and lymphocytosis (versus splenic diffuse red pulp small B cell lymphoma (SDRPL) with low lymphocytosis and cHCL with pancytopenia and monocytopenia)
    • Anemia (~ half of the patients)
    • Thrombocytopenia (~ half of the patients)
    • Absolute monocyte count is typically within the normal range (versus classic hairy cell leukemia (cHCL) with monocytopenia) (Mod Pathol 2018;31:1717)
Radiology description
  • Abdominal CT scan
    • Splenomegaly
    • Hepatomegaly
Prognostic factors
  • Chronic clinical course with a tendency for more aggressive behavior than cHCL
  • Median survival 9 years with only 15% survival over 15 years (Leukemia 2001;15:184, Cancer Treat Rev 2011;37:3)
  • Reported complete remission (combined purine analog and rituximab treatment or immunotherapy alone)
  • Unfavorable prognostic factors: (Br J Haematol 2012;158:347)
    • Significant anemia
    • Older age
    • Mutations in TP53
Case reports
Treatment
  • Therapeutic algorithm for hairy cell leukemia variant (HCL variant; see Diagram 1) (Ann Oncol 2015;26:v100)
    • Observation and close monitoring: asymptomatic patients with moderate splenomegaly and no cytopenia
    • Symptomatic disease (progressive splenomegaly or elevated leukocyte counts with cytopenia)
    • Relapsed / refractory cases (Am J Hematol 2017;92:1382)
    • Interferon alpha and purine analogs alone are unsatisfactory and fail to achieve a high complete remission rate
Microscopic (histologic) description
  • Peripheral smear
    • Leukemic cells
      • Variable morphology
      • Exhibit hybrid features of prolymphocytic leukemia and cHCL
      • Morphological subtypes e.g. blastic and convoluted
      • Cells are intermediate size
      • Nuclear features range from condensed chromatin with the prominent central nucleoli of a prolymphocytic cell to dispersed chromatin with highly irregular nuclear contours (Blood 2016;128:1018)
      • Cytoplasm abundant basophilic cytoplasm, circumferential stellate / hairy projections
    • Bone marrow
      • Aspirable: no significant reticulin fibrosis (MF = 0) (versus hairy cell leukemia showing marked fibrosis and dry tap)
      • Infiltration may be subtle; usually interstitial and lesser intrasinusoidal distribution (Mod Pathol 2018;31:1717)
      • Immunohistochemical staining is helpful to highlight the pattern and extent of infiltration
    • Spleen
      • Red pulp: diffusely involved and expanded
      • White pulp: follicles atretic / absent
      • Leukemic cells are present in the dilated sinusoids
      • Blood lakes may be present
    • Liver
      • Leukemic cell infiltration involves both the portal tract and sinusoids
Microscopic (histologic) images

Contributed by Pallavi Khattar, M.D. and Case #437
Bone marrow biopsy Bone marrow biopsy

Bone marrow biopsy

CD20 immunostain CD20 immunostain

CD20 immunostain

Bone marrow aspirate Bone marrow aspirate

Bone marrow aspirate


Bone marrow aspirate Bone marrow aspirate

Bone marrow aspirate

Bone marrow biopsy Bone marrow biopsy

Bone marrow biopsy

Bone marrow aspirate Bone marrow aspirate

Bone marrow aspirate


Bone marrow aspirate

Bone marrow aspirate

CD20 immunostain

CD20 immunostain

CD3 immunostain

CD3 immunostain

DBA-44 immunostain

DBA-44 immunostain

Peripheral smear images

Contributed by Pallavi Khattar, M.D. and Case #437
Peripheral smear Peripheral smear Peripheral smear Peripheral smear

Peripheral smear

Positive stains
Negative stains
Flow cytometry description
Flow cytometry images

Contributed by Pallavi Khattar, M.D. and Case #437
Flow cytometry analysis Flow cytometry analysis

Flow cytometry analysis

Molecular / cytogenetics description
  • Negative for BRAF V600E mutation
  • No somatic mutations of IGHV: 33% of cases
    • Unmutated cases have a high frequency of TP53 dysfunction
  • VH gene family, IGHV4-34 (immunoglobulin heavy variable) overexpression (Blood 2012;119:3330)
  • Recurrent mutations in the gene MAP2K1 (15q22.31) (Nat Genet 2014;46:8)
  • Mutations in KMT2C, CCND3 and U2AF1 seen in a subset (Blood 2017;130:1644)
  • Large number of DNA copy number alterations
  • Most frequent gains on chromosome 5 and losses on 7q and 17p (Leukemia 2011;25:1189)
Sample pathology report
  • A - D: bone marrow, left posterior iliac crest, trephine biopsy, aspirate smears, peripheral blood and flow cytometry analysis:
    • CD103 positive / CD5 negative / CD10 negative B cell lymphoma (see comment)
    • Comment: Bone marrow biopsy demonstrates increased CD20+ atypical lymphoid cells in the interstitial distribution. Flow cytometry analysis exhibits monotypic lambda restricted CD5 negative / CD10 negative B cell population with bright CD20, CD11c, variable expression of CD103 and lack of CD25. Overall findings, in conjunction with morphologic, immunophenotypic features (lack of CD25 (on flow cytometry) and annexin A1 (by IHC)) are suggestive of splenic B cell lymphoma / leukemia, unclassifiable, favor hairy cell leukemia variant (HCL variant). However, the differential diagnosis includes splenic diffuse red pulp small B cell lymphoma (SDRPL). Additional cytogenetic and molecular studies are in progress and will be reported separately.
    • Peripheral smear: Manual review of the peripheral blood shows normochromic, normocytic anemia, thrombocytopenia and increased atypical mononuclear cells.
    • RBCs: Mild normochromic, normocytic anemia with anisopoikilocytosis.
    • WBCs: Increased atypical lymphocytes (~ 15%) on smear that are intermediate in size with cytoplasmic projections and occasional prominent nucleoli.
    • Platelets: Thrombocytopenia with unremarkable morphology.
    • Bone marrow biopsy: Quality: adequate. Cellularity: 30 - 40% (normocellular marrow for age). Hematopoiesis: trilineage maturation with increased interstitial lymphocytes (better highlighted on CD20 immunostain ~ 10 - 20% of biopsy cellularity).
    • Immunohistochemical stains: Show interstitial small lymphocytes that are positive for CD20 and PAX5, while negative for CD3, CD5, CD10, BCL6, BCL1, BRAF / VE1, CD25 and annexin A1.
    • Bone marrow clot section: Quality: adequate. Morphologic features are similar to those observed in the core biopsy.
    • Special stains: Reticulin stain: no increase in reticulin fibrosis (MF = 0).
    • Bone marrow aspirate: Quality: adequate. Increased atypical lymphocytes that are intermediate in size with cytoplasmic projections and occasional prominent nucleoli. Myeloid and erythroid lineage shows progressive maturation with no significant dysplastic features. Megakaryocytes are adequate in number with unremarkable morphology.
    • Iron stores (PERL stain): Yes positive stores, no ring sideroblasts.
    • Flow cytometry studies: Flow cytometry immunophenotypic studies: abnormal B cell population detected. Monotypic lambda restricted B cell population (40% of total, 72% of cells in lymphocyte gate) exhibiting the following immunophenotype: CD5-, CD10-, CD19+, CD20+ (bright), CD22+, CD25- and CD103+. Remaining antigens are negative or noncontributory.
Differential diagnosis
  • See Diagram 2
  • Hairy cell leukemia:
    • Pancytopenia and monocytopenia with characteristically few circulating cells
    • Reniform or oval nuclei, circumferential long villi, inconspicuous nucleoli
    • Spleen: diffuse infiltrate in red pulp cords, effaced white pulp, formation of blood lakes
    • Marked reticulin fibrosis (dry tap)
    • Immunophenotype: CD25+, CD103+, CD123+
    • Genetics: BRAF V600E (~ 100%)
    • Treatment: purine analogs, rituximab
  • Splenic diffuse red pulp small B cell lymphoma:
    • No monocytopenia
    • Broad based polar cytoplasmic extensions
    • Spleen: diffuse involvement of red pulp with cord and sinusoid infiltration, absence of white pulp involvement
    • Immunophenotype: CD25-, CD103-, CD123-
    • Genetic mutations: CCND3, NOTCH1, MAP2K1, TP53
    • Treatment: splenectomy
  • Splenic marginal zone lymphoma:
    • No monocytopenia
    • Smaller cells may have short cytoplasmic projections
    • Cells have clumpy chromatin, indistinct nucleoli, different staining pattern
    • Spleen: white pulp is infiltrated by the neoplastic cells, marginal zone differentiation
    • Immunophenotype: CD25+, CD103 variable, CD123-
    • Cytogenetic: deletion of 7q
    • Genetic: NOTCH2, VH1 / 2
    • Treatment: splenectomy, rituximab
Board review style question #1
Which of the following are bad prognostic markers in hairy cell leukemia variant?

  1. Asymptomatic patient with normal counts
  2. IGHV mutation status
  3. Mutation in TP53
  4. Young age
Board review answer #1
C. Mutation in TP53. Mutations in TP53 are associated with worse prognosis in HCL variant. Other adverse prognostic factors are significant anemia and older age. IGHV mutation status does not have prognostic impact. (Br J Haematol 2012;158:347)

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Reference: Hairy cell leukemia variant
Board review style question #2

Which of the following stains are most useful for differentiating classic hairy cell leukemia and hairy cell leukemia variant?

  1. CD21, CD23, CD35
  2. CD103, CD11c, CD25, annexin A1
  3. CD34, CD117, myeloperoxidase
  4. CD3, CD10, CD20, BCL2
Board review answer #2
B. CD103, CD11c, CD25, annexin A1. Hairy cell leukemia variant is positive for CD11c (bright) and CD103 (variable) while negative for annexin A1, CD25 and CD123.

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Reference: Hairy cell leukemia variant
Board review style question #3
Which one of the following is the most characteristic feature to differentiate hairy cell leukemia from hairy cell leukemia variant?

  1. Affects adult patients
  2. BRAF V600E mutation
  3. CD103 positivity
  4. Splenomegaly
Board review answer #3
B. BRAF V600E mutation. Classical hairy cell leukemia is almost always positive for BRAF V600E mutation (100%) but HCL variant is not.

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Board review style question #4
Which among the following splenic B cell neoplasms is associated with the worst prognosis?

  1. Classic hairy cell leukemia
  2. Hairy cell leukemia variant
  3. Splenic diffuse red pulp small B cell lymphoma
  4. Splenic marginal zone lymphoma
Board review answer #4
B. Hairy cell leukemia variant. It is associated with a worse prognosis than classic hairy cell leukemia and has been reported to show a median survival of ~ 9 years.

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