Hairy cell leukemia (HZL)

As for all mature B-cell neoplasms, the methods of cytomorphology and histology guide downstream diagnosis.

In smears of peripheral blood or bone marrow in HZL, neoplastic cells are small to medium-sized, with oval to indented, "kidney-shaped" nuclei with pale, glassy chromatin that is less clumped than that of normal lymphocytes. The nucleoli are inconspicuous or absent. The cytoplasm is variably abundant and pale blue. It exhibits the namesake conspicuous and fine villous (hairy) projections, which are circumferential and may have small vacuoles (Alaggio et al. 2022).

Examination of the bone marrow aspirate and especially the -biopsy specimen is essential to determine the extent of bone marrow infiltration and to validate the diagnosis (Grever et al. 2017). In HZL, this often results in a dry puncture ("punctio sicca"), due to the reticulin fibrosis that accompanies the disease (Alaggio et al. 2022).

Specific to hairy cell leukemia is the immunohistochemically detectable expression of annexin A1 (ANXA1), this is not found in any other mature B cell neoplasia. In addition, the expression of CD103, CD11c and CD25 is observed in immunophenotyping. This very specific expression pattern can be used very well and with high sensitivity to measure minimal/measurable residual disease (MRD).

Chromosomal analysis is not obligatory in the diagnosis of hairy cell leukemia. Due to the low in vitro proliferation of HZL cells, there are also only few data on cytogenetic changes so far.

A broad spectrum of non-specific chromosomal aberrations has been described for hairy cell leukemia, affecting chromosomes 1, 2, 5, 6, 7, 11, 13, 14, 19, 20. Among these, deletions and inversions seem to occur more frequently than numerical aberrations or translocations. Cytogenetic alterations may also affect the IGH locus on 14q32 (Haglund et al. 1994, Kluin-Nelemans et al. 1994, Hockley et al. 2011, Durham et al. 2017).

Like chromosomal analysis, this test is not mandatory for the diagnosis of HZL.

In hairy cell leukemia, the V600E mutation in the BRAF gene occurs in over 95% of patients, but extremely rarely in other mature B-cell neoplasms (Tiacci et al. 2011, Blombery et al. 2012, Alaggio et al. 2022). This can greatly facilitate the differentiation of hairy cell leukemia from other lymphomas. In addition, quantification of BRAF V600E mutation by real-time PCR can be used very well and with high sensitivity as a marker of progression (MRD) (Schnittger et al. 2012). For the majority of patients (>90%), somatic hypermutations of the IGHV locus are also detectable (Alaggio et al. 2022).

For cases without a detectable BRAF mutation but with a classic HZL immunophenotype, there appears to be an association with the IGHV4-34 gene (Maitre et al. 2019) and there is evidence that IGHV4-34 expression and BRAF mutation are mutually exclusive (Xi et al. 2012, Waterfall et al. 2014). IGHV4-34-positive classic hairy cell leukemia is associated with an unmutated IGHV status, a less favorable prognosis, and a reduced response to therapy with purine analogues (Arons et al. 2009, Forconi et al. 2009, Xi et al. 2012). In a subset of these cases, mutations in the MAP2K1 gene have also been described (Waterfall et al. 2014, Maitre et al. 2018). However, because these cases show overlap with SBLPN cases, it is not clear whether MAPK1-mutated HCL cases exist (Alaggio et al. 2022).

Additional genetic alterations that have been clustered in hairy cell leukemia include mutations in the transcription factor KLF2 (16%) (Piva et al. 2015, Falini et al. 2016).