Discussion:
The “others” (14.2%) on peripheral blood smear were atypical lymphoid cells with ovoid to irregular nuclear contours, condensed chromatin, occasional prominent nucleoli, and abundant pale cytoplasm with irregular circumferential hair-like projections. These morphologic findings combined with the patient’s history of low-grade B-cell lymphoma and splenomegaly, raised suspicion for Hairy Cell Leukemia (HCL). The patient’s CBC showed monocytopenia, which also favored the diagnosis of HCL. However, it is important to consider other splenic B-cell lymphomas/leukemias (SBLs) that present with similar features. High on the differential diagnoses is Hairy Cell leukemia Variant (HCL-v), followed by Splenic Diffuse Red Pulp Small B-cell Lymphoma (SDRPL) and Splenic Marginal Zone Lymphoma (SMZL). Flow cytometric analysis is essential to distinguish between these entities. In this patient, flow cytometry revealed an aberrant B-cell population (14.7% of total) with the following immunophenotype: CD5- CD10- CD20(bright)+ CD103+ CD11c(bright)+ CD25- CD123- CD200- CD1d-. The presence of bright CD11c and CD103 expression, but absence of CD25, CD123, CD200, and CD1d, suggested a diagnosis of HCL-v over classic HCL. Subsequent bone marrow biopsy demonstrated aspirable marrow with an interstitial pattern of involvement (10%), similar to flow cytometric findings, and absence of BRAF V600E mutation on next-generation sequencing (NGS), supporting the diagnosis of HCL-v. NGS also showed TP53 mutation, potentially indicated a poor prognosis.
 
Hairy Cell Leukemia Variant (HCL-v) is a rare small CD5- CD10- monoclonal B-cell neoplasm of splenic origin that resembles classic HCL (hence the name), but exhibits variant cytological and hematological features. It presents clinically with leukocytosis, lymphocytosis, and normal absolute monocyte and neutrophil counts, features atypical lymphoid cells with variably prominent nucleoli, and lacks expression of CD25, CD123, CD200, CD1d, annexin A1, and TRAP. Notably, HCL-v has wildtype BRAF, whereas classic HCL has BRAF V600E somatic mutations in >95% of cases. A subset of HCL-v cases has activating mutations in MAP2K1, a gene that encodes MEK1, a downstream component of the BRAF-MEK-ERK signaling cascade. KMT2C, CCND3, and U2AF1 pathogenic variants have also been described in a subset of cases. Reflecting this biological distinction, the 2022 WHO 5th edition renamed the entity as Splenic B-cell Lymphoma/Leukemia with Prominent Nucleoli (SBLPN), while the 2022 ICC retained the name of HCL-v.
 
Correct diagnosis of HCL-v is critical as its prognosis and treatment differ significantly from those of classic HCL and other SBLs. Although both HCL-v and classic HCL typically follow an indolent course, HCL-v is associated with poorer outcomes, shorter survival times, higher rates of histologic transformation, and resistance to conventional HCL therapies, including BRAF inhibitors. The first-line treatment for HCL-v includes ibrutinib or cladribine-rituximab, whereas treatment for classic HCL typically involves cladribine or pentostatin.
 
As a take-home lesson, recognizing the morphologic feature of cytoplasmic hair-like or villous projections in atypical lymphoid cells is useful, as it raises suspicion for HCL. However, it is crucial to note that this morphologic finding is not pathognomonic for HCL, necessitating a broad differential diagnosis, including HCL-v. A complete evaluation involving peripheral blood smear, flow cytometry, bone marrow biopsy, genetic studies, and, if applicable, histopathologic evaluation of a splenectomy specimen, is strongly recommended for making an accurate diagnosis and ruling out other entities.