Hairy B-Cell Lymphoproliferative Disorder and its Differential Diagnosis: a Case with Long-Term Follow-Up
1 Department of Hematology and Oncology, Tokyo University Hospital, Japan.
2 Departments of Hematology and Laboratory Medicine, Aiseikai Yamashina Hospital, Japan.
3 Department of Infection Control and Laboratory Medicine, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Japan.
4 Division of Hematology and Oncology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Japan.
5 Center for Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Japan.
Received: July 26, 2017
Accepted: August 8, 2017
Mediterr J Hematol Infect Dis 2017, 9(1): e2017054 DOI 10.4084/MJHID.2017.054
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B-cell lymphoproliferative disorder (HBLD) is one of chronic polyclonal
B-cell lymphocytosis. We report a 47-year-old female Japanese patient
diagnosed as having HBLD based on lymphocytosis with hairy cell
appearance and characteristic phenotypes including CD11c+ and without
B-cell monoclonality. She was a non-smoker and possessed HLA-DR4. She
has been closely followed up without treatment and lymphoma development
for over five years. Although this disease is quite rare and has been
reported, to our knowledge, in only 13 Japanese cases, an accurate
diagnosis, particularly differential diagnosis from persistent
polyclonal B-cell lymphocytosis or hairy cell leukemia-Japanese variant
is essential for the prevention of unnecessary treatments.
For a right diagnosis of HBLD, distinguishing this disease from hairy cell leukemia-Japanese variant (HCL-Jv), an accurate workup is needed because of their morphological similarities including hairy cell appearance and a characteristic immunophenotype. The essential difference is whether B-cell monoclonality is detected or not.
This report concerns a female patient with HBLD. The absence of B-cell clonalities was confirmed regarding the lack of light chain restriction verified both using flow cytometric analysis and clonal immunoglobulin (Ig) gene rearrangement determined using Southern blotting analysis and multiplex polymerase chain reaction (PCR).
|Figure 1. Peripheral blood smears (A) and electron microscopic examination (B) show atypical lymphocytes with partially hairy projections and abundant irregularly shaped cytoplasms. No ribosome-lamella complex was found.|
No ribosome-lamella complex (RLC) was found, but rouleau formation was detected. The serum level of IgG was 6278 mg/dl, of IgA 359 mg/dl, and of IgM 283 mg/dl. Fractionation of serum protein showed no M-peak, and urine and serum immunoelectrophoretic studies showed no M-protein. Flow cytometric (FCM) analysis of the peripheral blood immunophenotype showed positivity for CD11c (38.9%), CD19 (64.3%), CD20 (62.5%), and CD22 (50.5%), and negativity for CD5 (16.6%), CD10 (0.9%), CD23 (0.1%), CD25 (1.0%), FMC-7 (3.7%), and ZAP-70 (4.4%). No light chain restriction was detected (k:lambda=33.9%:13.6%). Southern blotting analysis of peripheral blood cells showed no rearrangement band for either the clonal immunoglobulin heavy chain (IGH) gene (JH, Cµ) or the light chain gene (Jk, Ck, Clambda). Multiplex PCR analysis using the three sets of VH primers and one JH consensus primer as specified for the BIOMED-2 primer sets showed no monoclonal peak of IGH gene recombination (Figure 2). Cytogenetic analysis of bone marrow cells using G-banding revealed 46, XX [11/11]. Direct DNA sequencing showed no BRAF V600E mutation. Our patient possessed the HLA-DR4/DR5 histocompatibility complex. She was diagnosed as having HBLD based on the finding of a polyclonal proliferation of hairy B-cells with phenotypes such as CD5-, CD11c+, CD20+, and CD25-. Although she has been closely followed up without treatment, her WBC count has been stable (8.9 x 109/l) (atypical lymphocytes 31.0%), and her general status has remained fair over five years.
|Table 1. Comparison of previously reported cases of hairy B-cell lymphoproliferative disorder (HBLD), persistent polyclonal B-cell lymphocytosis (PPBL), and hairy cell leukemia-Japanese variant (HCL-Jv).|
According to a review of previous reports concerning 13 cases of HBLD, the median age for onset of HBLD was 57 years (range 29-80 years) and the male: female ratio was 3:10. These cases generally possessed HLA-DR4.[8,12,14] Cases of PPBL, on the other hand, usually are also young to middle-aged women, often smokers and HLA-DR7 positive.[5,6] HBLD and HCL-Jv17, are more prevalent in the elderly than PPBL.
As to the clinical features of our case, they showed splenomegaly but no definite signs of lymphadenopathy as mentioned in previous reports of HBLD,[8-11,13,14] PPBL and HCL-Jv.[17,18] Laboratory findings of the peripheral blood showed lymphocytosis and elevated serum IgG level without M-protein. The retinal hemorrhages of our case were thought to be due to hyperviscosity associated with her hypergammaglobulinemia. All the reported HBLD cases[7-14] and some of the HCL-Jv cases had elevated serum IgG levels with a polyclonal pattern but without M-protein. On the other hand, PPBL cases reportedly had elevated serum IgM levels. Although this IgM elevation is mostly polyclonal, Cornet et al. reported that 2 of 111 cases had IgM monoclonal gammopathy of undetermined significance at the time of PPBL diagnosis.
Morphologically, the atypical lymphocytes of our case had a hairy cell appearance and a round nucleus, but HBLD cases, including our case, did not have RLC. Although RLC is a specific electron microscopic finding of hairy cell leukemia, it had been found in only 4 of 26 (15%) HCL-Jv cases. The immunophenotype of our case was CD5-, CD11c+, CD20+, and CD25-, which corresponds to previously reported findings of HBLD as well as of HCL-Jv.[8,18] For these reasons, it might be impossible to distinguish HBLD from HCL-Jv regarding morphology and immunophenotype. Moreover, among the PPBL features the atypical lymphocytes are morphologically binucleated and not villous, and immunophenotypically CD11c-.
For these reasons, the clonality analyses are essential for distinguishing HBLD from HCL-Jv and morphology and immunophenotype from PPBL. No B-cell clonalities were detected in our case by FCM analysis for light chains, by Southern blotting and multiplex PCR for the rearrangements of Ig genes, by cytogenetic analysis using G-banding, and by immunoelectrophoretic studies for M-protein. Although proliferated B-cells of both HBLD and PPBL cases are polyclonal, some of the latter may have small numbers of clonal B-cells. In fact, PPBL can be associated with recurrent chromosomal abnormalities such as +i(3q)[4,6] or t(14;18) etc. and clonal Ig gene rearrangements.[3,6,20] Furthermore, while there have been no reports on the clonal evolution of HBLD, cases of PPBL can develop B-cell lymphoma.[5,6]
In conclusion, we reached the diagnosis of HBLD for our case on the basis of hairy cell appearance, the presence of a characteristic immunophenotype (CD5-, CD11c+, CD20+, and CD25-), and the absence of B-cell monoclonality. All previously reported cases of HBLD also satisfied these features. These findings are useful for the correct diagnosis of HBLD and for differentiating this disease from PPBL and HCL-Jv. Of the 14 reported HBLD cases including our case, 7 cases were from Osaka University,[8,9] and 2 from our Institute.
Until now and without therapy, our case has not shown any B-cell clonality nor any malignant development of HBLD. A wait-and-see approach without treatment can, therefore, be considered a potentially useful strategy for HBLD. Our case demonstrates that accurate diagnosis of this disease is essential for the prevention of unnecessary treatments.
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