A rare case of B-lymphoproliferative disorder with villous lymphocytes harboring t(8;14)(q24;q32) translocation

Abstract

Splenic lymphoma with villous lymphocytes (SLVL) or splenic marginal zone lymphoma with circulating villous lymphocytes is rare, and prolymphocytic transformation of SLVL is rarer. At present, only one case of SLVL with t(8;14)(q24;q32) translocation has been reported. In this study, we report a case of B-lymphoproliferative disorder with villous lymphocytes harboring t(8;14)(q24;q32) chromosome translocation that we inclined to SLVL with a prolymphocytic transformation. A 73-year-old female showed marked hepatosplenomegaly and high lymphocytosis (lymphocytes>200×10⁹/L). The abnormal lymphocytes had short coarse villi and round nuclei with prominent nucleoli. The immunophenotypes showed CD19⁺, CD20⁺, HLA-DR⁺, CD22⁺, CD5⁺, Kappa⁺, CD25^dim, CD71^dim, Lambda⁻, CD7⁻, CD10⁻, CD23⁻, CD34⁻, CD33⁻, CD13⁻, CD14⁻, CD117⁻, CD64⁻, CD103⁻, and CD11c⁻. The karyotype showed complex abnormality: 46XX,+3,−10, t(8;14)(q24;q32)[11]/46XX[⁹]. The cytoplasmic projection, immunological characteristics, and trisomy 3 chromosome abnormality supported the diagnosis of SLVL. However, the presence of prominent nucleoli and high lymphocytosis suggested prolymphocytic transformation, probably as a result of t(8,14) chromosome translocation. In this report, we described an unusual case of B-lymphoproliferative disorder with villous lymphocytes harboring t(8;14)(q24;q32) translocation, which could provide help in the diagnosis and differential diagnosis of B-lymphocytic proliferative diseases.

Keywords

splenic lymphoma with villous lymphocytes / splenic marginal zone lymphoma / transformation / chromosome translocation

Introduction

Splenic lymphoma with villous lymphocytes (SLVL) or splenic marginal zone lymphoma (SMZL) with circulating villous lymphocytes is a rare disorder that comprises less than 1% of lymphoid neoplasms and is characterized by splenomegaly, inconspicuous adenopathy, moderate lymphocytosis, and villous lymphocytes on the peripheral blood. Some SLVL cases can transform to high-grade B cell proliferative disease, and the most usual transformation is the progression to diffuse large B cell lymphoma [¹,²]. To our knowledge, only one group had reported the transformation to prolymphocytic leukemia (PLL) in SLVL [³]. Cytogenetic abnormalities of SLVL included chromosome 14q32 (47%) [predominantly t(11;14)(q13;q32)], chromosome 3 (26%) [predominantly 3q], chromosome 17p (26%), and trisomy 12 (16%) [⁴,⁵]. However, Burkitt-like t(8,14) translocation in SLVL is rare with only one case reporting SLVL with t(8;14)(q24;q32) translocation [⁶]. In this study, we report a case of SLVL with t(8,14) translocation, which may cause prolymphocytic transformation.

Case report

A 73-year-old Chinese female was admitted to Affiliated Hospital of Jiangsu University with a 5-year history of gradual fatigue, night sweat, weight loss, and abdominal distention. When the patient visited the hospital, she was diagnosed with hepatosplenomegaly (3 cm below the costal margin for the liver and 6 cm for the spleen), whereas lymphadenopathy was inconspicuous. Seven years ago when she was involved in a traffic accident, she casually was found with splenomegaly and nearly normal whole blood cell count. Laboratory tests indicated elevated levels of alkaline phosphatase 254 U/L (35–136 U/L) and lactate dehydrogenase 343 U/L (135–225 U/L) and negative hepatitis C virus infection. Whole blood count was abnormal with 224.8 × 10⁹/L white blood cells, 10 g/dL hemoglobin, and 80 × 10⁹/L platelets. Peripheral blood smear revealed 2% lymphoblasts and 92% prolymphocytes, which had a diameter of 10–15 mm and round nuclei with prominent nucleoli and less abundant basophilic cytoplasm. About 84% of these immature lymphocytes had irregularly distributed short coarse cytoplasmic projections (Fig. 1A and 1B) and tested negative for peroxidase and specific esterase stain (Fig. 1 C and 1D) and tartrate-resistant acid phosphatase stain. In bone marrow smear, the characteristics of lymphatic lineage resembled that of the peripheral blood smear. Meanwhile, proliferation of myeloid lineage and erythroid lineage was very low with only 3% metagranulocytes, 1% segmented neutrophils, and 1% normoblasts. The mean number of megakaryocytes was 34 per slide of bone marrow smear. Flow cytometric immunophenotypes were performed using a direct immunofluorescence stain technique with a panel of phycoerythrin (PE) or fluorescein isothiocyanate (FITC)-conjugated monoclonal antibodies. Results showed that 96% leukocytes were abnormal and expressed CD19 (65%), CD20 (89%), HLA-DR (94%), CD22 (94%), CD5^high (97%), Kappa^high (99%), CD25^dim (41%), and CD71^dim (53%), but did not express Lambda, CD7, CD10, CD23, CD34, CD33, CD13, CD14, CD117, CD64, CD103, and CD11c (Fig. 2). The immunoglobulin (Ig) levels in serum, including IgA, IgG, IgM, Lambda light chain, and Kappa light chain, were normal. Cytogenetic analysis by R-banding demonstrated complex chromosomal abnormality involving 46XX, +3,−10, t(8;14)(q24;q32)[11]/46XX[⁹] (Fig. 3). The patient refused splenectomy because of old age, and spleen biopsy was unfortunately unavailable. The patient underwent chemotherapy of COP regimen (cyclophosphamide, vincristine, and prednisone), which decreased her WBC count. The patient suffered from severe pneumonia and died three months later.

Discussion

The patient in this report had villous projections in 84% of her lymphoid cell surfaces. Cytoplasmic projections in lymphocytes and marked splenomegaly have been described in three different kinds of indolent mature small B cell lymphoproliferative disorders, namely, SLVL, hairy cell leukemia (HCL), and hairy cell leukemia variant (HCL-v) [⁴]. These projections were also occasionally found in cell surface of other lymphoproliferative disorders, such as splenic red pulp lymphoma (SRPL), mantle cell lymphoma, and even PLL.

Immunological expression of CD103, CD11c, and CD25 can differentiate SLVL from HCL, HCL-v, and SRPL [⁷]. HCL expresses CD11c, CD25, and CD103. Whereas HCL-v expresses CD11c and CD103 at an expression rate of 100% for both CD11c and CD103 [⁸] or 87% for CD11c and 60% CD103 [⁹] according to the literature, but uniformly lack CD25. The expression of CD103 is rare in SLVL and can clearly distinguish HCL and HCL-v from SLVL [⁸]. The cellular phenotype of SRPL is quite close to HCL-v, with a strong CD11c expression, variable CD103 expression, and little or no CD25 expression [⁴,¹⁰]. In the present patient, the negative expression of CD103 and CD11c and dim expression of CD25 rule out the diagnosis of HCL, HCL-v, and SRPL.

Hence, the patient was suspected of SLVL. The immunophenotype fulfilled the diagnosis of SLVL, except for CD5. As the isolated surface marker characteristic for SLVL is absent, we used a complete panel of markers for the diagnosis. A large number of studies reported that SLVL cells express CD19, CD20, and CD22, but not CD5, CD23, and CD10 [¹¹,¹²]. However, the positive expression of CD5 also has been observed in some patients. Tierens et al. [¹³] reported that 5 out of 23 SLVL cases expressed CD5 and several other groups reported that about 20% [¹⁴,¹⁵] to 30% [⁴] cases of SLVL did. Although this case was CD5 positive, the immunological profile was different from that of chronic lymphocytic leukemia upon considering other B cell markers, such as CD23. Additionally, we did not consider follicular lymphoma because of negative expression of CD10. In spite of the shortage of CyclinD1 and SOX-11 data, the karyotype showed the absence of t(11;14) chromosomal translocation (see below). Meanwhile, the percent of villous lymphocytes in the present case is 84%, while even if some villous lymphocytes are present in the mantle cell lymphoma, the level is low [⁴]. Therefore, we also basically rule out mantle cell lymphoma. All clinicopathological evidences in this patient suggested the diagnosis of SLVL.

However, the lymphocytes in SLVL should be mature small B cells with condensed nuclei and without nucleoli. In the present case, the lymphocytes exhibited naive characteristics with loose chromatin and one or two predominant nucleoli. Additionally, lymphocytosis in SLVL is usually moderate and rarely exceeds 100 × 10⁹/L [¹⁶], whereas the lymphocytes in the present case reached more than 200 × 10⁹/L. The presence of prominent nucleoli and high lymphocytosis suggested PLL diagnosis, which is another rare sub-acute lymphoid leukemia. The prolymphocyte has a larger diameter and higher nuclear-to-cytoplasmic ratio than mature small B cell lymphocyte and has a moderately condensed chromatin and prominent nucleolus [¹⁷]. More than three-fourths of PLL have blood lymphocyte count greater than 100 × 10⁹/L [¹⁸]. Prominent nucleolus and high lymphocytosis can also be associated with HCL-v [⁹]. The HCL-v, especially rare ones without CD11c and CD103 expression, should also be considered. However, the cells in HCL-v have abundant and gray-blue cytoplasm with frayed margins exhibiting a similar texture to that in HCL. However, the cells in SLVL have less abundant and more basophilic cytoplasm with irregularly distributed coarse projections, resembling to that described in this case [¹⁹]. Therefore, we speculate that the lymphocytes were more probably derived from SLVL.

Diagnosis of primary PLL could not be completely excluded, but a five-year history and the typical lymphocytic villus in high level supported the diagnosis of secondary PLL that transformed from indolent SLVL rather than from aggressive primary PLL. Thus, we consider the possibility of transformed secondary PLL being larger than that of primary PLL. SLVL is a low-grade lymphoma and follows either a stable or a slowly progressive clinical course. Only few cases can transform to other diseases. Most common cases of transformation are progression to large B cell lymphoma [²], and very few arise from transformation to Burkitt lymphoma [²⁰]. At present, only one report on the prolymphocytic transformation in SLVL exists [³].

Cytogenetic abnormalities of SLVL include chromosome 14q32 (47%) [predominantly t(11;14)(q13;q32)], chromosome 3 (26%) [predominantly 3q], chromosome 17p (26%), and trisomy 12 (16%) [⁴,⁵]. In this patient, the karyotype showed complex abnormality including trisomy 3 and t(8;14)(q24;q32) translocation. One chromosome 10 was deleted and another was randomly lost. Trisomy 3 is more frequent in CD5⁺ groups than in CD5⁻ groups [¹⁴]. About 12% of SMZL cases carry a translocation involving the chromosome 14q32 region (IGH gene) [¹⁴]. Chromosomal abnormality of t(8;14)(q24;q32) translocation, involving the MYC gene on chromosome 8 and the immunoglobulin heavy chain gene (IGH) on chromosome 14, is recurrent for Burkitt lymphoma and is reportedly present in PLL [²¹]. To our knowledge, the study by Sonu et al. [⁶], who thought that chromosomal translocation is a progressing form of disease, is the only reported case of SLVL with t(8;14)(q24;q32) translocation. In the present case, we consider that t(8;14) (q24;q32) translocation may contribute to prolymphocytic transformation in SLVL. CLL and HCL arise from mutated precursors [²²,²³]. Therefore, we speculate this transformation might have originated from a mutated stem/progenitor cell.

This study has several limitations. The first limitation is the shortage of gene tests for SOX11, CCND1, BCL-2, IRF4, BRAF, TP53, and so on, which are required by the new WHO criteria [²⁴] for the differentiation of B-lymphoproliferative disorders, mainly because these tests are technologically difficult several years ago. The second limitation is the lack of spleen biopsy specimen because of the refusal of the patient and her family. If the splenic histology is available, then a definitive diagnosis can be obtained.

Conclusions

In this paper, we reported a rare case of B-lymphoproliferative disorder with villous lymphocytes harboring t(8;14)(q24;q32) translocation that we inclined to SLVL with prolymphocytic transformation. This study could provide help in the diagnosis and differential diagnosis of B-lymphocytic proliferative diseases.

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