Primary isolated bone marrow diffuse large B-cell lymphoma with the initial presentation as severe thrombocytopenia, successfully treated with chemotherapy: a case report and review of the literature

Secondary bone marrow involvement of non-Hodgkin’s lymphoma (NHL) is relatively common. However, primary isolated bone marrow involvement in NHL, successfully treated without any relapse, is quite rare, except in several leukemia/ lymphoma cases which are considered to primarily involve the bone marrow. We here report a case of primary bone marrow diffuse large B cell lymphoma (PBML/DLBCL), in which the patient presented a prolonged high-grade fever and systemic purpura due to severe thrombocytopenia, which was successfully treated with systemic chemotherapy and remains in complete remission (CR) at 2.5 years after the initial diagnosis. Review of 53 cases of PBML/DLBCL presented in the literature suggests that the prognosis for this eternity is unfavorable, but rituximab-based therapeutic strategies, including autologous stem cell transplantation are promising for improving their outcomes.


Background
Secondary bone marrow involvement of non-Hodgkin's lymphoma (NHL) is relatively common. However, primary isolated bone marrow involvement in NHL, successfully treated without any relapse, is quite rare, except in several leukemia/lymphoma cases which are considered to primarily involve the bone marrow. We here report a case of primary bone marrow diffuse large B cell lymphoma (PBML/DLBCL), with the initial presentation as severe thrombocytopenia, which was successfully treated with systemic chemotherapy and remains in complete remission (CR) at 2.5 years after the initial diagnosis. We also reviewed 53 cases of PBML/DLBCL. PBML is a very uncommon lymphoma with particular clinical features and heterogeneous histology and its outcome is unfavorable. Its recognition is essential for establishing accurate diagnosis and adequate therapeutic strategy.

Discussion
Non-Hodgkin's Lymphoma (NHL) presenting with primary isolated bone marrow involvement is extremely rare, so a lack of uniform diagnostic criteria has made it difficult to define its clinical manifestation, histological findings, treatment and prognosis. Its diagnosis is currently based on bone marrow biopsy. The important points used to define primary bone lymphoma (PBML) are; (1) its confinement to the bone marrow; (2) the absence of bone trabeculae destruction in the bone marrow biopsy; (3) the exclusion of any other leukemia/lymphoma entity known to arise primarily in the bone marrow; and (4) no evidence of lymph node, spleen, liver or other extra bone marrow involvement [1]. Review of 53 PBML/DLBCL cases presented in the literature suggested that common features at the initial presentation include advanced lymphoma stage (CSIV), sole bone marrow involvement with cytogenetic abnormalities, fever of unknown origin, cytopenia, and elevated LDH levels and showed a poor prognosis [1][2][3][4][5][6][7] (Table 2). According to their histological features and immunohistochemical findings, several hematological malignancies arose primarily in the bone marrow. Kajiura et al., compared the asian variant of intravascular large B-cell  Table 2. Summary of studies describing PBML/DLBCL with thrombocytopenia at the initial presentation.
In our case, at the initial presentation, viral infections, such as EBV, CMV, HIV were considered to be some of the differential diagnosis or complications, as the cause of unknown fever, associated with thrombocytopenia. Especially, the diagnosis of EBV associated hemophagocytic syndrome or EBV positive diffuse large B-cell lymphoma of the elderly was highly suspected, however EBV DNA load in the peripheral blood was within normal limits and EBER in situ hybridization in the bone marrow tissue was negative (data now shown), so finally diagnosis, related to EBV infection was ruled out.
Recently, there have been significant advances in cancer imaging techniques. PET/CT becomes popular in the evaluation of patients with malignant lymphoma and has been shown to be more sensitive and specific than contrast-enhanced CT scan for the evaluation of nodal and extranodal involvements of lymphoma. Bone marrow involvement is one of the most important prognostic factors in patients with lymphoma, thus in patients with high grade lymphoma or intermediate grade lymphoma, like our case is associated with significantly shorter survival. Therefore, bone marrow biopsy is now included as a part of the essential evaluation for the initial staging in patients with malignant lymphoma. However, bone marrow biopsy is an invasive procedure with a restrictive reliability, as only a limited area of the bone marrow is investigated, shown as a false negativity in up to 80% in a unilateral iliac crest biopsy, compared to bilateral iliac biopsies. Some of discordant rate was reported between bone marrow biopsy and FDG-PET/ CT in detecting bone marrow involvement of DLBCL and although, there are no established guidelines to interpret bone marrow involvement by FDG-PET/CT in patients with newly diagnosed malignant lymphoma. However, patients with concordant bone marrow involvement had inferior survival compared to those with discordant marrow involvement, so additional results on the role of FDG-PET/CT in detecting bone marrow involvement may available and FDG-PET/CT may be used as a complementary rather than an alternative tool in detecting bone marrow involvement in patients with newly diagnosed DLBCL [9][10][11].
Review of 53 PBML/DLBCL cases presented in the literature suggests that most reported PBML cases have been diffuse large B cell lymphoma (DLBCL)( Table 1) Martinez et al., analyzed 21 PBML cases and found that 19 cases were B-cell lymphomas (4 cases; FCL, 15cases; DLBCL) and 2 cases were peripheral T cell lymphoma (PTCL) [8]. Furthermore, PBML/DLBCL cases that initially presented with severe thrombocytopenia, successfully treated without any relapse were extremely rare and had showed especially unfavorable outcomes, with a median overall survival (OS) of from 1 month to 2.4 years [1]. Changs et al., also reported these 12 cases and one of these cases reveals OS of 56months with CHOP therapy, however this case relapsed 2 . In previous reports, in most cases, the first therapeutic option is R-CHOP therapy, however considering their unfavorable prognosis, intensive chemotherapy, including dose-modified R-ESHAP (rituximab, etoposide, cisplatin, cytarabine, prednisolone) or dose-modified R-hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) may be one of the therapeutic options even in the elderly patients without any organ dysfunctions or complications. Also, especially in younger patients without any organ dysfunctions or complications, up-front autologous stem cell transplantation may be one of the therapeutic options. However in our case, chiefly due to bone marrow suppression after R-CHOP chemotherapy, it is impossible to repeat chemotherapy every 3 weeks. So, after confirming the recovery of neutrophil count in the peripheral blood, the next course of R-CHOP therapy was initiated, every 4 weeks. Our case also belong to high risk group, according to IPI score and the presence of chromosomal abnormalities. Despite these backgrounds, our case has been in CR until now without any relapse signs, 2.5 years after the initial presentation. Several previous cases eventually developed extranodal relapse, such as central nervous system (CNS) relapse, so we also continue to take care of CNS involvement with the administration of prophylactic intrathecal methotrexate [1][2][3].
In conclusion, we reported unique case of PBML/DLBCL initially presenting with severe thrombocytopenia was successfully treated with systemic chemotherapy and has remained in CR for 2.5 years in September 2012. In cases with unknown fever and thrombocytopenia, PBML/DLBCL may be included in the differential diagnosis, as well as viral infections, and it is important to establish the exact diagnosis as quickly as possible and immediately initiate adequate therapies.