Routine laboratory investigation revealed normocytic normochromic anemia [hemoglobin (Hb), 60 g/L; mean corpuscular volume (MCV), 88 fL], leukopenia (leucocyte count, 2×109/L) with relative lymphocytic prominence (30% neutrophil, 60% lymphocytes, 4% eosinophils, 6% monocytes), and adequate platelet count (350×109/L). Peripheral smears revealed scattered suspicious lymphoid cells constituting 10% of all lymphoid cells (Fig. 1). A review of bone marrow aspiration (BMA) slides performed at the referring hospital for evaluation of his cytopenia(s) revealed hemodilution with suppressed trilineage hematopoiesis and no abnormal cells, indicating a suspicion of marrow hypoplasia. Trephine core sections showed a variably cellular marrow with suppressed trilineage hematopoiesis with near-total replacement by diffuse sheets of a monotonous population of small to intermediate-sized atypical lymphoid cells with round to mildly irregular nuclear contours, dense chromatin, and inconspicuous nucleoli. In places, these cells exhibited perinuclear clear zones with a fried egg appearance. There was no evidence of increased mitosis, granuloma, necrosis, or any large cell transformation. Reticulin staining showed myelofibrosis (MF) grade 0–1 condensation [World Health Organization (WHO) classification]. Immunohistochemical investigation revealed lymphoid cells with strong and diffuse positivity for CD20, CD11c, and BCl2; weak immunopositivity for CD10 and kappa light chain; and negativity for CD3, CD5, CD23, BCl6, CD138, cyclin D1, CD30, ALK1, CD34, CD117, and lambda light chain, consistent with a low-grade B cell lymphoproliferative neoplasm (LPN) of hairy cell phenotype (Fig. 2). The results of serum immunofixation electrophoresis and Coomb test were within normal limits. A repeat BMA sample was subjected to multiparametric flow cytometric immunophenotyping, which showed bright CD200, CD25, CD11c, CD19, and CD20 expression, consistent with hairy cell leukemia (HCL). Dim to moderate CD23 expression was also noted in a subset of these gated lymphoid cells (Fig. 3). The patient was referred to a specialized tertiary care cancer institute for further management; he was started on cladribine treatment and achieved a complete response and is presently under follow-up. Molecular testing for BRAF was not done as per the clinician's decision.
HCL is a rare, clinically indolent, mature small B cell lymphoproliferative neoplasm (LPN) that accounts for 2% of all lymphoid leukemias. It is characterized by the proliferation of small lymphoid cells with abundant cytoplasm with circumferential fine hairy projections involving the peripheral blood, bone marrow, and expanding splenic red pulp. The hallmark features are marked splenomegaly, peripheral blood cytopenia(s), monocytopenia, and circulating CD19+, bright CD20+/CD22+/CD200+, CD25+, CD103+, and CD11c+ hairy cells demonstrated classically by flowcytometric analysis. Annexin A1 is the most specific marker for HCL, which helps in differentiating HCL mimics such as variant HCL (vHCL) and splenic marginal zone lymphoma, which are both annexin A1-negative .
Atypical or unusual presentation in HCL (aHCL) is uncommonly reported in the literature (1990 to 2018), which may pose a significant diagnostic challenge in routine practice (Table 1) [2-10]. Splenohepatomegaly is conspicuously absent which, in the presence of peripheral blood cytopenia(s), resembled hypoplastic anemias. Significant lymphadenopathy; skeletal manifestation in the form of arthralgia, multifocal lytic to sclerotic bone lesions; neurological manifestations; isolated epidural, skull base, or breast lesions have dominated the clinical presentations in other reports [2,4-9]. HCs were conspicuously absent to very sparse; both in peripheral blood smear (PBS) and scant bone marrow aspirate (BMA) smears requiring tartrate-resistant acid phosphatase (TRAP) cytochemistry. The trephine sections resembled hypoplastic marrow with atypical lymphoid cells forming discrete or nodular aggregates unlike those of classical HCL. Diffuse infiltration by low-grade LPN gave a typical ‘fried egg’ appearance in others. Others showed classic histomorphology in extramedullary sites without evidence of marrow involvement. Flowcytometric and/or IHC analysis demonstrated classical HCL phenotypes with bright CD200 coexpression in all cases reported in the literature [11, 12]. Immunophenotypic aberrancies such as heterogenous CD10 and CD23 coexpression are reported in up to 15% cases; whereas CD5+ and CD103/CD25- were sporadically reported and were not associated with any specific laboratory abnormalities. Atypical presentations or immunophenotypic aberrancies did not alter the favorable response to purine analogs such as cladribine [7, 11].
In summary, unusual or atypical clinical presentation is not uncommon in HCL. Furthermore, rare immunophenotypic aberrancies in HCL should be considered when interpreting flow cytometric/immunohistochemical patterns in such cases to avoid misdiagnosis.
No potential conflicts of interest relevant to this article were reported.