Chronic lymphocytic leukemia with atypical features

Author:  Mir Alikhan, MD, 09/29/2021
Category: Lymphoma: Mature B-cell and Plasma cell Neoplasms > Low-grade B-cell lymphoma > Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Published Date: 10/19/2021

A 71-year-old man presents with fatigue. He was found to be anemic with a hemoglobin of 10.7 g/dL. A complete blood count also revealed a white blood cell count of 51,000 k/uL, with 80% of circulating cells being lymphocytes by the differential. A peripheral blood smear showed atypical lymphocytes. Some were small with round nuclei and clumped nuclear chromatin. However, many are enlarged with irregular nuclear contours and more abundant cytoplasm.

Flow cytometry was performed on the peripheral blood and showed a monotypic B-cell population with dim co-expression of CD20, CD5, CD23, dim kappa light-chain, and CD200. CD79b expression was absent.

A bone marrow study showed extensive infiltration by small to medium-sized lymphocytes in a rather diffuse manner. A diagnosis of chronic lymphocytic leukemia with atypical morphologic features was made. Cytogenetic studies showed trisomy 12 and deletion of 13q14. IGH sequencing analysis detected a B-cell clone with mutational analysis showing unmutated IGHV.


Learning Points:

- Chronic lymphocytic leukemia (CLL) is a neoplasm of mature B-cells occurring in the peripheral blood and bone marrow. It is essentially the same neoplasm as its nodal counterpart, small lymphocytic lymphoma (SLL). SLL can occur without significant peripheral blood involvement.

- The diagnosis of CLL requires a monoclonal B-cell count of 5X109/L or greater. Monoclonal B-cell levels less than this would be classified as monoclonal B-cell lymphocytosis (MBL), but only in the absence of nodal/extranodal or medullary disease, in which case SLL or CLL would be the most appropriate diagnosis, respectively.

- CLL/SLL is the most common mature leukemia/lymphoma in the Western world. Patients are often asymptomatic or may present with cytopenias related to marrow infiltration. Some patients present with autoimmune manifestations.

- The characteristic CLL cell is small with a round nucleus, scant cytoplasm, clumped nuclear chromatin, and inconspicuous nucleoli. The chromatin can appear like “cracked-earth” on smears and “chocolate-chip cookie” or “soccer ball”-like in tissue sections. Prolymphocytes are larger cells with a more visible nucleolus that can be observed in peripheral blood and tissue section. Often in tissue sections, larger cells with a central eosinophilic nucleolus can be seen, consistent with immunoblasts.

- CLL/SLL shows a characteristic immunophenotype. The B-cells show reduced expression of surface immunoglobulin and associated antigens, such as lights chains (kappa or lambda), CD20 and CD79b. Most cases are positive for CD200 by flow cytometry and LEF1 by immunohistochemical stain; CD23 is also often positive, but is not entirely sensitive or specific for CLL. There is aberrant co-expression of CD5, which is also seen in mantle cell lymphoma. However, cyclin D1 and the t(11;14) translocation are consistently negative.

- CLL-like cells with more abundant cytoplasm are associated with trisomy 12, seen in about 20% of cases. About half of cases show deletions of 13q14 and are associated with favorable prognosis. Less commonly, there is deletion of 11q23 (locus of ATM and BIRC3) or 17p (locus of TP53), both associated with poor prognosis.

- Also important for prognostication is whether the neoplastic cells are derived from a B-cell with unmutated IGHV (mostly naïve) B-cell or mutated IGHV (memory-like) B-cell. Unmutated IGHV refers to the IGH gene (on chromosome 14) being in germline configuration, prior to antigen exposure. Once exposed to antigen, IGH rearranges and undergoes somatic hypermutation. Mutated IGHV is recognized as having greater than 2% mutation rate compared to the germline configuration. This can be assessed by sequencing the IGH gene and comparing the sequences to the reference genome.

- Although the majority of CLL/SLL cases are indolent, about 5% undergo transformation to diffuse large B-cell lymphoma (termed “Richter transformation”). Rarely, there is transformation to classical Hodgkin lymphoma

Chronic lymphocytic leukemia - Peripheral blood

Peripheral blood smear shows prominent lymphocytosis. Some smudge cells (arrows) can be identified. The atypical lymphocytes show both small forms with clumped nuclear chromatin as well as some larger forms with more abundant cytoplasm.

Chronic lymphocytic leukemia - Bone marrow

The bone marrow exhibits increased atypical lymphocytes with similar cytologic features as those seen in the peripheral blood (A). These are present in a diffuse pattern (B) infiltrating between normal hematopoiesis (C).

Chronic lymphocytic leukemia - IHC

Immunohistochemical stains show the lymphocytes are mostly CD20-positive B-cells with just a few background T-cells. There is aberrant expression of CD5, without cyclin D1 positivity.

Chronic lymphocytic leukemia - Flow cytometry

Flow cytometry shows a population of CD19+ cells with aberrant CD5 co-expression (black arrow). These have dim kappa expression (red arrow), dim CD20 expression (curved arrow), and positivity for CD23 (yellow arrow) and CD200 (green circle). CD10 and CD79b are both negative.

Chronic lymphocytic leukemia - Cytogenetics

Conventional karyotype shows trisomy 12 (arrow). FISH studies (not pictured) showed deletion of 13q14.