Primary plasma cell leukemia with light chain secretion and multiple chromosomal abnormalities: How successfully treated? – A case report with review of literature

patients with multiple myeloma (MM). [1-4


INTRODUCTION
,7] The primary form occurs in the individuals without a preceding MM, whereas the secondary form is a leukemic transformation in individuals with MM. [1][2][3]5,7] Primary PCL (PPCL) has been estimated to occur in less than one case in a million. We rport a case of PPCL occurring in a 40-year-old female, with light chain secretion, flow cytometry revealing an unusual CD117 expression and multiple karyotypic abnormalities detected on fluorescent in-situ hybridization (FISH).

CASE REPORT
A 40-year-old female had presented with conjunctival hemorrhage.She had giddiness, fatigue, loss of appetite

A B S T R A C T
Primary plasma cell leukemia is a rare form of plasma cell dyscrasia.We present a case which had leukocytosis with numerous circulating plasma cells in the peripheral blood.Flow cytometry revealed an unusual CD117 expression.Free light chain analysis in the serum showed a markedly elevated level of free lambda light chains.Radiography did not reveal any lytic lesions.Fluorescent in-situ hybridization analysis revealed deletion of 13q14.3 and t(4;14)/t (11;14), while the cytogenetic analysis was normal.The patient was given chemotherapy and was subjected to autologous stem cell transplant, after which she is in complete remission till date.
Figure 2: Flow cytometry on the peripheral blood showed the plasma cells (painted red) in the monocytoid region in the forward scatter/side scatter plot.These cells expressed CD38, CD117 and cytoplasmic lambda light chain.These were negative for CD45, HLA-DR, CD20, CD19, CD56, cytoplasmic kappa, surface light chains, CD5, CD22, CD10, and CD23.Normal lymphocytes are painted green population with high forward scatter and a slightly high side scatter (corresponding to the monocytoid region) was gated.These cells were negative for CD45 and CD19 and expressed bright surface CD38, CD138, moderate CD117 and showed cytoplasmic lambda light chain restriction [Figure 2].These cells were negative for CD56, HLA-DR, CD20, cytoplasmic kappa and surface light chains.
Radiographs of the skull, dorsal spine, lumbar spine and both femora did not reveal any lytic lesions.The patient was diagnosed as PPCL with aberrant CD117 expression, light chain type and complex translocations involving del 13q and translocation 14q.She thereafter received chemotherapy with the RVd regimen comprising lenalidomide(R), bortezomib(V), and dexamethasone(d) for four cycles at 21 day intervals.After four cycles, she achieved a complete remission (CR), i.e., immunofixation negative CR, absence of plasma cells in the peripheral blood and marrow with 2% plasma cells.Serum free light chain assay revealed normal kappa (8.1 mg/L) and lambda (5.5 mg/L) levels with a normal kappa-lambda ratio (1.47).She underwent high dose chemotherapy with Melphalan 200 mg/m 2 , followed by autologous stem cell transplantation.She continues to be in complete remission, i.e., 9 months since the time of diagnosis.

DISCUSSION
PPCL is a distinct clinicopathological entity because its presenting features, response to chemotherapy, and prognosis are different from those of typical MM. [5] The development of MM is known to be a result of a multiple step transformation process. [5]The constellation of adverse prognostic factors in patients with advanced aggressive myeloma is already present at diagnosis in patients with PPCL. [5],7] These patients have a lower incidence of bone lesions as compared to secondary PCL. [1,2,5,7],7] What could not be explained was the cause for skin rash and itching, whether it was related to the disease or not or was there any skin infiltration.
The immunophenotypic profile is known to be different in MM and PCL. [6,7]Plasma cells usually express CD38 and CD138 both in MM and PCL. [6,7]However, the CD20 displayed a higher reactivity in PCL as compared to MM. [6,7] In addition, the expressions of CD56, CD117, HLA-DR and CD9 were higher in MM than in PCL. [6,7]However, there was no difference noted in the primary and secondary forms of PCL in clinical practice. [6,7]CD28, a research molecule, was known to be expressed more frequently in secondary than in PPCL. [5]The present case expressed CD117, which is uncommon.
A higher proportion of myeloma with light chain only, IgD, or IgE present as PCL as compared to those with IgG or IgA. [6,7][7] Due to markedly raised β 2 -microglobulin levels, the present case was categorized in stage III according to the International Staging System for Multiple Myeloma, which corroborated with other studies. [6,7]e molecular abnormalities are known to be commonly occurring in MM and PCL. [6,7]In PPCL, there was a very high incidence of chromosome 13 monosomy, as compared to MM. [1,7] This abnormality was associated with a short survival in MM treated with either conventional chemotherapy or high dose therapy. [7]Amongst the structural abnormalities, studies show a high incidence of chromosome 14q32 translocations with various rearrangements -t(6;14)(p21.1;q32.3),t(11;14)(q13;q32.3),t(14;18)(q32.3;q21.3)[10] The 14q32 translocations were associated with leukemic transformation and elevated LDH, indicating high myeloma cell mass and advanced disease. [8]Our patient showed both these abnormalities.][9] However, these were detected in association with 14q32 translocation, indicating secondary karyotypic evolution rather than a primary event. [8]Evaluation of chromosome 1 was not available in our study because of lack of suitable probes.
Presence of abnormal cytogenetic abnormalities in plasma cell dyscrasias is 30-65%. [10,11]The reasons for lack of abnormalities detected on karyotyping could be low proliferation rate of malignant cells, difficulty in obtaining good quality spreads, blurred and contracted chromosomes, resistance of plasma cells to G-banding and possibly the cells examined cytogenetically were not plasma cells. [11]In our case, any one of the above could be the reason for the failure to detect the karyotypic abnormalities, which were detected by FISH, and also an additional factor would have been the use of peripheral blood rather than bone marrow.
As PPCL is a rare malignancy, there is no universal treatment strategy. [5,12]However, due to a dismal prognosis, these need to be treated aggressively as acute leukemias. [12]he principle of treating is achievement of CR with induction chemotherapy followed by stem cell transplant. [12]Various regimens have been tried with a variable degree of success. [3,5,13,14]Recently, the combination of lenalidomide with bortezomib and dexamethasone has shown to be very active in newly diagnosed, refractory and relapsed cases of MM patients, with high response rates and manageable toxicity. [14,15]Although use of this regimen in PPCL has not been documented, we used this combination and the patient attained CR.Autologous stem cell transplantation is the standard transplant option. [12,13]The patient was alive and in CR without any complaints at the time of documentation.
The prognosis for primary and secondary PCL is poor with a median survival of about 6-8 months. [12]The survival is slightly more than 1 year in patients who respond to treatment as compared to less than a month for the non-responders. [5]] PPCL is a rare disorder associated with numerous chromosomal and molecular abnormalities.How these abnormalities contribute to the pathogenesis is yet to be understood.Possibly in future, this understanding would be utilized to develop targeted therapies that would result in better outcome.

Figure 1 :
Figure 1: Peripheral smear showing marked prominence of plasma cells having abundant basophilic cytoplasm and eccentrically placed nucleus with clumped chromatin (Leishman, ×1000) Goyal, et al.: Primary plasma cell leukemia