Plasma cell dyscrasias are a common group of disorders having the proliferation of a single clone of immunoglobin secreting cells as a common feature. The incidence of various PCD is as follows: (i) MGUS—60 to 70%; (ii) MM—15%; (iii) Amyloidosis—9%; (iv) B cell lymphoproliferative disorders: non-Hodgkin’s lymphoma—5%, Waldenstrom’s macroglobinuria—2%, Chronic lymphocytic leukemia—2%; (v) Solitary plasmacytoma 1%; and (iv) Plasma cell leukemia—Rare [14
Because of the low frequency of PCL, most of the data has come from case reports or small series of cases [2
]. In almost all the series median age ranged between 53 and 57 years. However, Castello et al. [15
] and Raj et al. [16
] reported PCL in patients who were 30 and 21 years old respectively. In our patients the median age was 57 years, in accordance to that reported by others.
Primary PCL has a more aggressive course—high frequency of extramedullary involvement (liver, spleen, lymph nodes, extra osseous plasmacytomas etc.), thrombocytopenia, anemia, hypercalcemia and impaired renal function. A large study by Gracia-Sanz et al. [2
] analyzing the clinic-biologic characteristics of 26 cases of PCL, together with the immunophenotype, DNA cell content, proliferative index, and numeric chromosomal aberrations of the neoplastic PC with 664 MM patients at diagnosis showed that the median age, sex ratio, and bone lesion extension were similar to MM, but PCL cases displayed a higher prevalence of clinical stage III disease and extramedullary involvement.
Patients with PCL in addition to having symptoms of typical myeloma have more frequent extra-osseous disease commonly involving the spleen, lymph nodes, liver and skin. Our 4 of the 5 patients had extra-medullary involvement, spleen and liver was involved in 3 of them and thyroid in 1. Other sites which may be involved are kidney, heart, pleura, testes, skeletal muscle and the CNS. In a recent report by Madhvan et al. [17
] 53 year old patient with PCL presented with features of restrictive cardiomyopathy.
Radiographic bone lesions appear not to be more frequent in PCL compared to nonleukemic phase myeloma [18
The cytologic characteristics of leukemic plasma cells in PCL span much of the morphologic spectrum found in MM [6
]. The bone marrow is usually infiltrated heavily with plasma cells showing the same morphological features as those in the peripheral blood [19
]. The cases of PCL analyzed in this study also showed similar morphological features in peripheral blood and bone marrow.
Well differentiated plasma cells have a characteristic phenotype: Strong expression of CD38 and CD19 and weak expression of CD56. In contrast to normal plasma cells, myeloma cells are often immature and may have the plasmablastic appearance [21
]. While the expression of CD19 is usually negative, myeloma cells express CD56 antigen strongly along with CD38 [22
Plasma cells from PCL display a more immature phenotype than MM as assessed by expression of CD20 antigen, which is usually absent in MM [23
]. In addition plasma cells from PCL frequently lack CD56 antigen, which has been considered important in anchoring plasma cells to bone marrow stroma [24
]. Immunophenotypic expression is similar in PCL as MM for CD38, CD138, CD2, CD3, CD6, CD10, CD13 and CD15. Immunophenotyping of plasma cells in our patients where it was carried out was compatible with these literature findings.
The phenotypic differences do not allow a complete discrimination between PCL and MM, but help to explain the differences in survival, since CD56 expression has been associated with good prognosis while CD20 expression has been associated with a shorter survival [2
Cytogenetic aberrations are detected more frequently in PCL than in MM, the percentage of abnormal cases varies in different series but seems to be more than 50%. The overall pattern of cytogenetic changes is very similar to the pattern observed in MM, numerical changes and/or structural aberrations are seen. Monosomy 13 and trisomy 9 are the most frequent numerical abnormalities. Up to 90% may show chromosome 13 monosomy. Hypodiploidy is more common in PCL than in myeloma. Apart from chromosome 9, gains also involve chromosomes 3, 5, 7, 11, 15, and 19, whereas losses also involve chromosome X and Y; structural aberrations mainly involve chromosome 14, with 14q+ resulting from translocation t(11;14)(q13;q32) or other changes (e.g. Burkitt’s translocations); chromosomes 16 (p or q), 1 (p or q), 19 (p or q), 6q, 17q, 2p and 7q might also be involved. Chromosomal changes are detectable by conventional cytogenetic techniques or by FISH; in addition, comparative genomic hybridization showed to be a useful tool in PCL, allowing assessment of regions showing copy number changes [26
Chromosomal changes are detectable by conventional cytogenetic techniques or by FISH; in addition, comparative genomic hybridization is a useful tool in PCL, allowing assessment of regions showing copy number changes.
PCL is a rare aggressive variant of MM, characterized by a fulminant course and poor prognosis. Compared to MM, patients usually present with advanced disease, have more extra-medullary involvement, thrombocytopenia, anemia, raised LDH levels and impaired renal function. These findings can be explained not only by the presence at presentation of more extensive disease in PCL versus MM, but also by the presence of high proliferative ratio of neoplastic versus adverse cytogenetic data, which represents a unique array of adverse prognostic factors that explain the poor outcome described for patients with PCL. The survival of patients with PCL is therefore shorter then that of comparable patients with advanced myeloma, primarily because of early death due to irreversible disease complications. Clonal plasma cells from primary PCL display a higher proliferative capacity (S-phase cells) versus MM, thus explaining frequent association of high LDH and aggressive behavior in PCL [2
]. Residual bone marrow function is poorer in PCL versus MM, as assessed by both the hemoglobin level and platelet count. This is because proliferation of normal bone marrow cells (residual cells in S-phase) is markedly blunted. Therefore degree of anemia and thrombocytopenia is much higher in PCL versus MM which is difficult to explain based only on the tumor burden.
The outcome of plasma cell leukemia treated with the first-line myeloma regimen melphalan, prednisolone is usually disappointing, with medial survival of two months. There have been clinical trials with various drug combinations for PCL. Few to mention are VAD regimen (vincristine, doxorubicin, dexamethasone), cyclophosphamide–etoposide regime etc. Maximum survival benefit was observed with high dose chemotherapy with autologous bone marrow or stem cell support, especially in younger patients.
Since the prognosis is so poor, intensification of high dose chemotherapy followed by allogenic/autologous stem cell rescue should be tried [27
]. However, in un-affording patients induction with combination chemotherapy, followed by high dose chemotherapy is the current recommended approach for eligible patients [28
]. PCL requires such aggressive management so as to provide any survival advantage.
Of our 4 patients with primary PCL, 3 died within a week of diagnosis and start of chemotherapy and 1 patient did not take treatment and was discharged on request. Patient who had developed secondary PCL after 7 years of diagnosis of MM, treatment was started with Arsenic trioxide, 4 cycles were instituted but before treatment could be completed he died because of multi-organ failure and disseminated intra-vascular coagulation.
The prognosis in patients with PCL is poor. Median survival is less than 1 year [4
]. The longest survival reported is 28 months [5
]. Secondary PCL represents a terminal event for a refractory/relapsed MM and is usually not responsive to any treatment modality.