| Abstract|| |
Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma accounting for 2-3% of all plasma cell dyscrasias characterized by the presence of circulating plasma cells. The diagnosis is based on the % (≥20%) and absolute number (≥2x10 9 /L) of plasma cells in the peripheral blood. The incidence of primary PCL (pPCL) is very rare and reported to occur in <1 in a million. It is classified as either pPCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. pPCL is a distinct clinicopathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. We report two cases of pPCL, both having acute onset of illness, varied clinical presentation with one of them showing "hairy cell morphology," with rapidly progressing renal failure, and was not suspected to be plasma cell dyscrasia clinically. A detailed hematopathological evaluation clinched the diagnosis in this case. It is recommended that techniques such as immunophenotyping by flow cytometry and protein electrophoresis must be performed for confirmatory diagnosis. A detailed report of two cases and a review of PCL are presented here.
Keywords: Immunophenotyping, plasma cell dyscrasias, plasma cell leukemia
|How to cite this article:|
Gangadhar P, Ahmed Z, Pai MR, Sandhya I. Primary plasma cell leukemia: A report of two cases of a rare and aggressive variant of plasma cell myeloma with the review of literature. Indian J Pathol Microbiol 2016;59:541-4
|How to cite this URL:|
Gangadhar P, Ahmed Z, Pai MR, Sandhya I. Primary plasma cell leukemia: A report of two cases of a rare and aggressive variant of plasma cell myeloma with the review of literature. Indian J Pathol Microbiol [serial online] 2016 [cited 2020 Nov 27];59:541-4. Available from: https://www.ijpmonline.org/text.asp?2016/59/4/541/191818
| Introduction|| |
More than a century ago, the first case of plasma cell leukemia (PCL) was recognized by Gluzinski and Reichentein.  Traditionally, PCL has been diagnosed based on Kyle's criteria, which requires circulating plasma cells to account for 20% of the peripheral blood leukocytes and/or an absolute circulating plasma cell count of 2.0 10 9 /L, with evidence of monoclonal gammopathy.  The incidence of PCL ranges between 2% and 4% of patients with multiple myeloma (MM). PCL is classified as primary when it presents "de novo" in patients with no evidence of previous MM and as secondary when it is observed as a leukemic transformation of relapsed or refractory disease in patients with previously recognized MM. Of them, 60-70% of PCL is primary and the remaining 30-40% is secondary. 
The control mechanisms by which plasma cells initially remain predominantly confined to the bone marrow, only rarely entering the blood stream, are poorly understood. In fact, a low proportion of plasma cells can be detected in peripheral blood in patients within the entire spectrum of plasma cell dyscrasias, including newly diagnosed MM, smoldering MM, and exceptionally, in MGUS (monoclonal gammopathy of undetermined significance).  PCL patients usually have accompanying anemia, hypercalcemia, renal insufficiency, and organomegaly. Two types of PCL are seen: Secretory and nonsecretory. No M-protein is detected in the nonsecretory type of PCL. Compared with classic MM, primary PCL (pPCL) has both a different biologic background as well as distinct clinical and laboratory features. PCL is more frequent in light chain only, IgE and IgD myeloma and is less frequently seen in IgG or IgA myeloma.  PCL is derived from terminally differentiated B-cells and the malignant cells stain positive for mature B-cell markers (CD38 and PCA-1). 
According to several prognostic indicators (β2- microglobulin serum level, proportion of S-phase plasma cells, proteinuria, calcium serum level, lactate dehydrogenase [LDH], and renal function), the incidence of adverse prognostic factors was significantly higher in PCL when compared with MM.  Immunophenotypic expression was similar for CD38, CD138, CD2, CD3, CD16, CD10, CD13, and CD15, but PCL differed from MM in the expression of CD56, CD9, HLA-DR, CD117, and CD20 antigens. PCL is an extremely aggressive disease with no standard treatment regime so far due to the rarity of the disease. Prognosis is very poor with a median survival of 2-8 months. It is very important to recognize this entity sufficiently early so that one can offer combination chemotherapy at the earliest followed by stem cell transplant which can prolong the survival. 
| Case Reports|| |
Case report 1
A 48-year-old male presented with a history of fever for 2 weeks, vomiting, abdominal pain, and yellowish discoloration of the skin for 1 week, easy fatigability, and significant weight loss of >10% over the past 6 months. He reported no significant past medical history. He was afebrile and had mild hepatosplenomegaly. Hemogram revealed anemia (hemoglobin [Hb] 6.8 g/dl), thrombocytopenia (75,000/cumm), and leukocytosis with total leukocyte count (TLC) of 19,370/cumm. Preliminary biochemical evaluation was suggestive of azotemia with blood urea of 195 mg/dl, serum creatinine of 7.8 mg/dl, uric acid of 7.6 mg/dl, and elevated calcium levels of 13 mg/dl. Serum electrolytes were normal and liver function tests were normal except for mild elevation in alkaline phosphatase. Routine urine test showed proteinuria (3+). Ultrasound revealed hepatosplenomegaly with moderate ascitis. Peripheral smear showed a dimorphic anemia with thrombocytopenia and leukocytosis with differential count showing abnormal cells having Central to eccentrically placed nucleus, prominent nucleoli with abundant bluish cytoplasm displaying circumferential cytoplasmic projections giving the characteristic "hairy cell" morphology [Figure 1]a. The size of the cells was about 2-2.5 times the size of a small lymphocyte. Few cells exhibited cleaved and bilobed nuclei. Occasional typical plasma cells were also noted. The abnormal cells accounted for 28% of the differential count (neutrophils 36%,lymphocytes 29%, eosinophils 04%,monocytes 03%and atypical cells 28%), and absolute count on peripheral smear was 5423cells/cumm of TLC. The patient appeared acutely ill on admission. Erythrocyte sedimentation rate (ESR) was high - 141 mm/h. Urine Bence Jones protein was negative. Serum protein electrophoresis and immunofixation were negative. Free light chain assays were not performed due to financial constraints. Bony pains were absent, and a skeletal survey was also normal. His renal function further deteriorated on consequent days with creatinine of 8.8 mg/dl, thus requiring hemodialysis. Bone marrow aspiration examination revealed hypercellular marrow with good cellular trails and replacement of the normal marrow elements by sheets of plasma cells (83%), immature plasma cells, and plasmablasts with diminished myeloid, erythroid, and megakaryocytic series [Figure 1]b. Peripheral blood was sent for immunophenotyping by flow cytometric analysis as the bone marrow aspiration yield was insufficient for flowcytometry. Immunophenotyping showed 27% of atypical cells expressing CD38 (+), CD138 (+), Cykappa (+), and CD56 (-) [Figure 1]c, and serum immunoassay showed an increase in IgE (170 IU/ml). Based on the findings of peripheral smear, bone marrow, flow cytometric analysis, and immunoassays, the patient was diagnosed to have pPCL. He was treated with melphalan/prednisolone regime along with supportive care. However, the patient was lost to follow-up.
|Figure 1: (a) Atypical cells with centrally to eccentrally placed nucleus, prominent nucleoli with abundant bluish cytoplasm displaying circumferential cytoplasmic projections (hairy cell morphology -inset) (×1000, Leishman stain). (b) Bone marrow aspiration showing sheets of plasma cells, immature plasma cells, and plasmablasts (×1000, Leishman stain). (c) Flow cytometry shows 27% of atypical cells expressing CD38 (+), CD138 (+), Cykappa (+), and CD56 (?)|
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Case report 2
A 72-year-old male presented with a history of generalized weakness and fever for 1 month. He reported no significant past medical history. Initial blood investigations revealed anemia (Hb: 5.3 g/dl), leukocytosis 15,700 cells/cumm, and thrombocytopenia (platelet count: 62,000/cumm). ESR was high at 144 mm/1 h. Peripheral smear examination showed increased rouleax formation of red blood cells with a dimorphic picture, and 8 nucleated RBCs/100 white blood cells were noted. Differential count showed neutrophils of 45% with shift to the left up to myelocytes, lymphocytes 25%, eosinophils 4%, and monocytes 6%, with 20% plasma cells and few abnormal cells having centrally placed nucleus with gray-blue cytoplasm [Figure 2]a. A dimorphic anemia with a leukoerythroblastic blood picture and plasmacytosis (20% plasma cells) (absolute plasma cell count of 3140cells/cumm) was reported. Bone marrow examination revealed hypercellularity with replacement of the normal marrow elements by sheets of plasma cells (78%) with diminished myeloid, erythroid, and megakaryocytic series [Figure 2]b. Ultrasonography revealed mild hepatosplenomegaly. Serum protein electrophoresis revealed a thick M band. Serum LDH was elevated at 813 IU/l. Other biochemical parameters including calcium levels were within normal limits. Bone scan was normal. Flow cytometry showed atypical cells expressing CD38, Cylambda, CD20, and negative for CD56 [Figure 2]c. Immunoassays showed an increase in IgA (630 mg/dl).
|Figure 2: (a) Peripheral smears showing >20% of atypical plasma cells (×1000, Leishman stain). (b) Bone marrow aspiration showing proliferation of plasma cells and immature plasma cells and few plasmablasts (×1000, Leishman stain). (d) Flow cytometry shows atypical cells expressing CD38+, CD138 + Cylambda+, CD20, and rest of the markers are negative|
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| Discussion|| |
PCL is characterized by the presence of >20% of plasma cells in peripheral blood or absolute plasma cell count >2 10 9 /L.  A recent publication suggests that if the diagnostic criteria were reduced to 5% plasma cells and/or an absolute count of >0.5x10 9 /L while incorporating anciliary techniques, patients could be diagnosed earlier and have a better prognosis.  By definition, both our patients had pPCL.
Because of the relative low incidence and prevalence of this entity, most clinical data come from isolated case reports and small retrospective studies. No prospective series have been published and only seven reports including >20 patients have been identified. The median age ranged between 52 and 65 years, about 10 years younger than the median age of 65-70 years were observed in the general myeloma population and in secondary PCL (sPCL).  Our patients were aged 48 years and 72 years. This shows the wide range of presentation of pPCL.
pPCL has a more aggressive clinical presentation than MM, including a higher tumor burden. Patients may present with symptoms due to profound anemia, hypercalcemia, or bleeding diathesis, owing to thrombocytopenia. On physical examination, patients may exhibit a higher prevalence of organomegaly with involvement of the liver, spleen, lymph nodes, pulmonary findings associated with pleural effusions, neurological deficits due to central nervous system involvement, pallor, petechiae, and palpable extramedullary soft tissue plasmacytomas.  Both our cases had profound anemia, leukocytosis, thrombocytopenia, mild hepatosplenomegaly, and elevated serum LDH, but only one case had hypercalcemia and acute renal failure with elevated creatinine and blood urea. Similar features were also seen in a case series by Rajeshwari et al and Kumar TN et al.  The incidence of several adverse prognostic indicators (serum beta-2 microglobulin, proportion of S-phase plasma cells, protienuria, serum calcium levels, LDH, and renal function derangement) has been found to be significantly higher in PCL Versus MM. In contrast, the presence of lytic bone lesions is lower than that observed in MM. [5.6] One of our patients had lytic lesions in the frontal bone of the skull.
Two types of pPCLs are seen: Secretory and nonsecretory. No M-protein is detected in the nonsecretory type of PCL.  One of our cases was a secretory type of PCL showing a thick M band in serum electrophoresis and other case was a nonsecretory type of PCL with serum electrophoresis studies, including immunofixation being negative.
Serum-free light chain assay in such cases would suggest the majority of patients with conventional nonsecretory PCM do have evidence of clonal immunoglobulin production.  However, serum-free light chain assay was not done in our case due to financial constraints.
A monoclonal protein is absent in the serum and urine of patients with nonsecretory PCL due to (i) low synthetic capacity for immunoglobin (nonproducers) (ii) an inability to excrete immunoglobin (nonsecretors) (iii) or rapid extracellular degradation of abnormal immunoglobins (iv) increased intracellular degradation. The molecular basis of nonseceretory myeloma could be due to loss of light chain production (in nonproducers) or mutations that cause an absence of cysteines required for disulfide bonds. This results in abnormal misfolded light chains, which gets retained in the plasma cells and are lysed.
These intracytoplasmic immunoglobulin could be detected by immunohistochemical staining or flow cytometry method.  Our case belonged to the "nonsecretors type" as flowcytometry showed expression of CD138+, CD38+, and cytoplasmic Kappa positivity with CD56 negativity. In other words, our patient was able to synthesize immunoglobulin, but was unable to secrete them out of the cells.
PCL is more frequent in light chain only, IgE and IgD myeloma and is less frequently seen in IgG or IgA myeloma.  Both of our cases showed an increase in IgE (170 IU/ml) levels in serum immunoassay. Increased frequency of urine Bence Jones protein has been reported by García-Sanz et al.,  unlike in our cases.
Peripheral blood plasma cells range from mature forms with characteristic "clock-face" chromatin and perinuclear hof to immature blastic forms with loose reticular chromatin, high nucleo-cytoplasmic ratio, and prominent nucleoli. Immature neoplastic cells may be indistinguishable from myeloblasts. In some instances, plasma cell displays lymphoplasmacytoid morphology. ,
The presence of neoplastic cells resembling hairy cells in the peripheral smear was seen in one of our cases. Bone marrow in this case was hypercellular with replacement of the normal marrow elements by sheets of plasma cells (83%) with diminished myeloid, erythroid, and megakaryocytic series. Immunophenotyping by flowcytometry showed 27% of atypical cells expressing CD38 (+), CD138 (+), Cykappa (+), and CD56 (-) and were negative for B-cell lineage. These features were also seen in a case series by Rajeshwari et al.  and another study by Kumar et al., where the plasma cells were masquerading as hairy cells. However, these cells were negative for tartarate-resistant acid phosphatase stain, B lineage, and hairy cell markers and positive for plasma cell markers CD38 and CD138. Other case was also positive for CD38 and negative for CD56. CD56 antigen plays an important role in anchoring plasma cells to the marrow stroma. It has been reported that the malignant plasma cells of PCL (pPCL or sPCL) do not or weakly express CD56. 
Genomic and clinical differences between PCL and myeloma have been recognized. The presence of p53 deletions, 13q deletions, karyotypic complexity, hypodiploidy, and 1q gains could confer an advanced stage on PCL disease progression characterized by therapy resistance and a dismal prognosis. 
| Conclusion|| |
PCL belongs to a unique subset of plasma cell dyscrasias and has both a different biologic background as well as distinct clinical and laboratory features. The prognosis of pPCL is very poor, with a median overall survival of only 7 months with standard chemotherapy, and therefore, requires innovative treatment approaches incorporating various modalities to improve the outcome.
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Department of Pathology, A J Institute of Medical Sciences and Research Centre, Mangalore - 575 004, Karnataka
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]