TO THE EDITOR: Abnormalities of chromosome 6q involving deletion of the regions 6q16-q27 have been reported in a variety of hematologic malignancies, most frequently in multiple myeloma [1, 2, 3]. The 8q isochromosome is also an uncommon clonal abnormality found primarily in T-prolymphocytic leukemia [4, 5]. Concurrent chromosome 6q- and i(8) are extremely rare in patients with hematologic malignancies and have never been reported as chromosomal abnormalities preceding evidence of malignancy.

Several case reports suggested that chromosomal abnormalities can provide evidence for hematologic malignancies before they develop [1, 2, 3]. We describe a patient with bone marrow hypoplasia and persistent unexplained chromosomal abnormalities of del(6)(q16) and i(8)(q10) who subsequently developed B-cell lymphoma 8 months after his initial presentation.

A 50-year-old man was admitted to our hospital in December 2009 with persistent fever. Peripheral blood counts showed hemoglobin 9.0 g/dL, white blood cell (WBC) count 6.2×10⁹/L (65% neutrophils, 15% lymphocytes, 10% monocytes, 8% atypical lymphocytes, 2% eosinophils), and platelets 201×10⁹/L. The reticulocyte count, iron, folate, and vitamin B12 levels were within the normal range.

The bone marrow showed a 1.2:1 myeloid:erythroid (M:E) ratio, no evident dysplasia and decreased cellularity (20%) (Fig. 1A). Cytogenetic analysis performed on bone marrow using a 24-hour unstimulated culture revealed the following distinct abnormal clone: 46,XY,del(6)(q16),i(8)(q10)[8]/46, XY[12] (Fig. 2). To evaluate his fever of unknown origin, brain magnetic resonance imaging (MRI), whole-body positron emission tomography/computerized tomography (PET/CT) and thoracic and abdominal CT were performed. These studies revealed only moderate hepatosplenomegaly with no evidence of malignancy. In addition, markers for viral infection and autoimmune disease showed negative results.

In August 2010, peripheral blood counts showed hemoglobin 9.1 g/dL, WBC count 4.45×10⁹/L (73% neutrophils, 11% lymphocytes, 9% monocytes, 6% atypical lymphocytes, 1% eosinophils), and platelets 154×10⁹/L. The bone marrow showed 1.7:1 M:E ratio, no evident infiltration of abnormal lymphoid cells, and hypocellular marrow. However, bone marrow biopsy showed relatively increased cellularity (40-60%) than before, with focal infiltration of atypical lymphoid cells that were positive for CD20 and CD79a, but negative for CD3, myeloperoxidase (MPO) and terminal deoxynucleotidyl transferase (TdT) on immunohistochemical stain (Fig. 1B and 1C). The results of chromosomal analysis were 46,XY,del(6)(q16),i(8)(q10)[7]/46,XY[5], showing the same abnormal clone as 8 months previously. Repeat brain MRI showed focal enhancements in the frontal and parietal skull bones suggestive of hematologic malignancy such as lymphoma or myeloma. Repeat whole-body PET/CT showed increased patchy uptake in multiple levels of the thoracic and lumbar spine suspicious of bone marrow infiltration. Cerebrospinal fluid analysis showed many atypical lymphoid cells. Together, these findings were consistent with lymphoma involving the central nervous system (CNS) and the patient was diagnosed as having B-cell lymphoma confined to the bone marrow and CNS (stage IV).

There were no accessible lymph nodes to perform a diagnostic biopsy. Treatment was immediately initiated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Bone marrow analysis showed complete hematologic remission after 2 cycles of CHOP and the bone marrow karyotype after chemotherapy was normal (46,XY[20]). In May 2011, he underwent autologous peripheral blood stem cell transplantation (PBSCT). Two years after PBSCT, in October 2013, the patient showed no morphologic evidence of residual lymphoma and no suspicious findings on follow-up whole-body PET/CT.

Deletion of 6q is frequently described in lymphoid malignancies. In lymphoid malignancies, a range of deleted sub-regions has been identified within the chromosomal region 6q14-q21. Interestingly, the most proximal region has been identified in adult T-cell leukemia, whereas the more distal regions have been linked to childhood B-ALL and, rarely, chronic lymphocytic leukemia [6]. The detection of a 6q deletion in several malignancies suggests that this region contains an unidentified tumor-suppressor gene that deserves further investigation of its role in the malignant process [7]. Del(6q) has been shown to be a prognostic factor associated with longer event-free survival in adult T-ALL [5]. In our case, the patient had a favorable clinical course without relapse during 4 years of follow-up, even with CNS involvement. Accordingly, this case supports an association between del(6q) and favorable prognosis.

There have been 182 cases of i(8)(q10) in hematologic malignancies published, with the majority (166 cases, 91.2%) exhibiting complex karyotypes [5], suggesting that i(8)(q10) is a secondary chromosomal abnormality. However, reports of i(8)(q10) in acute B-cell lymphoblastic leukemia/lymphoma have rarely been reported with only 5 cases published to date [5]. Several reports have suggested that the gain of 8q, but not the loss of 8p, is important in leukemogenesis [4, 8].

It can be difficult to distinguish bone marrow hypoplasia preceding lymphoma from aplastic anemia. In our case, persistent anemia and bone marrow hypoplasia were prominent, although neutropenia or thrombocytopenia was not evident. In adults, the major causes of pancytopenia involving bone marrow are clonal disorders such as acute myeloid leukemia (26%), myelodysplastic syndrome (17%) and non-Hodgkin lymphoma (NHL, 6%) [9]. In this case, persistent bone marrow hypoplasia was suspected as a rare manifestation of NHL. The most likely cause for the patient's bone marrow hypoplasia was a clonal disorder that suppressed hematopoietic stem cell proliferation and eventually resulted in lymphoma by selection of an abnormal clone [10, 11]. We suspected that the patient had lymphoma at the initial presentation, with the aplastic phase caused by the clonal cells' direct inhibition of normal bone marrow stem cells.

Hematologic malignancies preceded by chromosomal abnormalities have rarely been reported [1, 3]. However, in these cases the preceding chromosomal abnormalities may have signaled disease progression rather than the hematologic malignancy itself. This report describes the first case of B-cell lymphoma preceded by bone marrow hypoplasia with del(6)(q16) and i(8)(q10) prior to morphologic evidence of hematologic malignancy, followed by a favorable and persistent complete remission for nearly 4 years from the initial detection of the chromosomal abnormalities. Close follow-up in patients with abnormal karyotypes, even without morphologic evidence of hematologic malignancy, could uncover hidden hematologic malignancies and allow initiation of early and proper treatment.

Initial bone marrow biopsy showed (A) aplastic marrow (hematoxylin and eosin stain, ×100). In August 2010, repeat biopsy showed (B) increased cellularity with abnormal lymphoid infiltration that was (C) positive for CD20 on immunohistochemical stain (×100).

Giemsa-banded karyotype showing 46,XY,del(6)(q16),i(8)(q10) 9 months before evidence of B-cell lymphoma in the bone marrow. The abnormal chromosomes are marked by arrows.