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Flower‐like/clover leaf lymphocytes appear in various diseases: Cerebrospinal fluid cytology case with review of the literature

Dear Dr. Bedrossian: In the literature, cytological findings of flower-like/clover leaf lymphocytes of B-cell lineage are rare. We herein report an interesting case of primary central nervous system lymphoma (PCNSL) of B-cell origin showing flowerlike/clover leaf lymphocytes in the cerebrospinal fluid (CSF). A 55-year-old Japanese woman was admitted to our hospital with amaurosis fugax and transient walking difficulty. Magnetic resonance imaging of her brain showed a well-circumscribed mass 29 mm in diameter in the right temporal occipital lobe. There were no other physical abnormalities. Whole-body positron emission tomography with 18F-fluorodeoxyglucose imaging showed no other lesions. Her laboratory data revealed a white blood cell count of 5.66 3 10/lL (73.4% neutrophils, 21.6% lymphocytes, and no abnormal cells), lactate dehydrogenase level of 160 IU/L, and soluble IL-2 receptor level of 132 U/mL. Enzyme-linked immunosorbent assay was negative for human T-cell lymphotropic virus 1. CSF examination revealed pleocytosis (128/mm, 100% mononuclear cells) with high protein and low glucose levels. Microscopic examination of the CSF (cytospin preparation with air-dried May–Giemsa staining) revealed so-called flower-like/clover leaf lymphocytes (Fig. 1A) with small lymphocytes. The flower-like/clover leaf cells were immunocytochemically positive for CD20 (Fig. 1B). Neither heavy chain rearrangement nor T-cell receptor gene rearrangement of the CSF was observed. Flow cytometric immunophenotyping of the CSF revealed the following: 93% CD3, 96% CD2, 92% CD5, 0% CD10, 3% CD19, 10% CD20, 2% j, and 1% k. A biopsied specimen from the brain mass showed diffuse infiltration of large mononuclear cells. Large cells in the biopsied specimen were immunohistochemically positive for CD20 and MUM1 and negative for CD3, CD10, CD5, bcl-6, and CK AE1/AE3. These cells were also negative for Epstein-Barr virus by in situ hybridization. The biopsied specimen was diagnosed as diffuse large B-cell lymphoma (non-germinal center type). Bone marrow aspiration showed no lymphoma cell involvement. More than 95% of PCNSLs are diffuse large B-cell lymphoma (DLBCL) and are highly aggressive. Thus, early diagnosis is essential. Although biopsy is the standard diagnostic procedure for patients with suspected PCNSL, the risks of brain biopsy may outweigh the benefits. The usefulness of a combination of CSF diagnostic techniques including identification of heavy chain rearrangement, flow cytometry, and cytology has been reported. In this case, although the biopsy specimens from the brain mass showed typical DLBCL, heavy chain rearrangement of the CSF was not observed. In addition, flow cytometric immunophenotyping of the CSF showed that most lymphocytes were T-cells. The cause of this discrepancy was the number of lymphoma cells in the CSF. Most lymphocytes in the CSF were considered to be reactive T-cells. Therefore, cytology is useful when the number of lymphoma cells is small, and immunocytochemical examination is useful for determination of the origin of lymphocytes, as in the present case. However, morphological evaluation of reactive “atypical” lymphocytes and lymphoma cells is difficult. The presence of flower-like/clover leaf lymphocytes is a well-known morphologic feature in the peripheral blood of patients with adult T-cell leukemia/lymphoma (ATLL). They *Correspondence to: Takeshi Uehara, MD, PhD, Department of Laboratory Medicine, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan. E-mail: tuehara@shinshu-u.ac.jp Received 16 October 2013; revised 22 January 2014; Accepted 24 February 2014 DOI: 10.1002/dc.23147 Published online 8 March 2014 in Wiley Online Library (wileyonlinelibrary.com).