Annals of Clinical & Laboratory Science 36:479-484 (2006)
© 2006 Association of Clinical Scientists
Polyclonal Plasma Cell Proliferation with Marked Hypergammaglobulinemia and Multiple Autoantibodies
Lin Li1,*,
Peihong Hsu2,*,
Keyur Patel2,
Yasi Saffari2,
Ida Ashley3 and
Judith Brody1
1 Department of Pathology and Laboratory Medicine, North Shore University Hospital, Manhasset, NY, 2 Department of Pathology and Laboratory Medicine, Long Island Jewish Medical Center, New Hyde Park, NY, and 3 Great Neck Hematology and Oncology, Great Neck, NY
Address correspondence to Judith Brody, M.D., Department of Pathology, North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030, USA; tel 516 562 4180; fax 516 562 4591; e-mail jbrody{at}nshs.edu.
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Abstract
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A 77-yr-old man presented with marked peripheral blood and bone marrow plasmacytosis, marked hypergammaglobulinemia, and multiple autoantibodies. Serum protein immunofixation and immunophenotyping of bone marrow plasma cells by flow cytometry and immunohistochemistry disclosed polyclonal proliferation of plasma cells at various stages of differentiation. The presence of multiple autoantibodies in the patient’s serum suggests that an autoimmune disease underlies the polyclonal proliferation of plasma cells.
Keywords: polyclonal plasmacytosis, hypergammaglobulinemia, autoantibodies, immunoelectrophoresis, flow cytometry, immunohistochemistry
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Introduction
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Benign polyclonal plasmacytosis (BPP) in peripheral blood and bone marrow is rare with only a few reported cases [1–5]. BPP has been associated with polyclonal hypergammaglobulinemia, autoimmune disorders, chronic infection, and malignancies [2–6]. Frequently, florid plasmacytosis precipitates an investigation to exclude a malignant process, such as multiple myeloma or plasma cell leukemia.
We report the occurrence of marked plasmacytosis in peripheral blood and bone marrow of an elderly man with marked hypergamma-globulinemia and multiple autoantibodies. Plasma cell leukemia was a strong consideration initially, but serum protein electrophoresis and immunophenotypic analysis of the plasma cells demonstrated polyclonality.
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Case History
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A 77-yr-old man with a medical history of cardiomyopathy and arrhythmia was admitted to the hospital because of chest pain. His medical history included hospitalization for possible pneumonia a year previously. Prior to the present admission, the patient developed ataxia and difficulty in walking. An MRI of the brain revealed focal C7 to T1 disc space edema with enhancement suggesting traumatic or infectious discitis. Physical examination on admission showed a blood pressure of 128/45 mmHg, a pulse of 82 beats/min, and body temperature of 96.1°F. The patient was lethargic, confused, and occasionally disoriented. A generalized erythematous skin rash was present, which was most severe on the face and legs, and less severe on the chest and back. A few basilar rales were detected in the lungs. Results of hematological studies were: hemoglobin concentration, 12.7 g/dl; platelet count, 199 x 109/L, and leukocyte count, 17.8 x 109/L, with 2% monocytes, 16% lymphocytes, 17% plasma cells, and 34% immature plasma cells. Rouleux formation was present. Urinalysis revealed 3+ hematuria (50–75 RBC/high power field); positive bilirubin test; trace proteinuria; urobilinogenuria (4 mg/dl); and positive nitrite test. Urine microscopy showed moderate bacteriuria and amorphous sediment. Other laboratory results included: low serum albumin, 1.8 g/dl; high serum total protein, 9.8 g/dl; normal serum AST and ALT activities; elevated serum bilirubin, 2.7 mg/dl; elevated serum alkaline phosphatase activity, 159 U/L (reference range, 39–117 U/L); and elevated serum GGT activity, 146 U/L (reference range 8–61 U/L). Other abnormal laboratory tests included decreased serum sodium (128 mmol/L) and elevated serum urea nitrogen (28 mg/dl). The blood partial thromboplastin time (PTT) was 46.9 sec on the first hospital day, 75.4 sec on the second day, and 81.6 sec on the third day. The erythrocyte sedimentation rate was 122 mm/hr. Bone marrow aspiration and core biopsy were performed. The results of immunologic studies, serum and urine protein electrophoresis, and immunofixation are listed in Table 1
. The patient died despite complete resolution of his peripheral plasmacytosis following the administration of steroids. Autopsy was not performed.
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Pathologic Findings
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Morphology.
Stained slides of peripheral blood cells showed a prominent increase of plasmacytoid cells of varying size and maturity. The bone marrow aspirate had no cellular spicules, but showed a cellular composition similar to the peripheral blood with more than 50% mature and immature plasma cells. The bone marrow core biopsy, performed at the same time, displayed hypercellularity (50–70%) with nearly complete replacement of normal cells by perivascular and interstitial plasmacytoid cells. Rare myeloid and erythroid precursors were present. Megakaryocytes appeared normal in number.
The morphology of the plasmacytoid cells in a peripheral blood smear (Fig. 1A), bone marrow aspirate (Fig. 1B, inset), and core biopsy (Fig. 1B) showed a broad spectrum of plasma cell differentiation. The plasmablasts appeared large with prominent nuclei, dispersed fine chromatin, conspicuous nucleoli, and scant basophilic cytoplasm. Immature plasma cells had round nuclei with condensed chromatin and abundant basophilic cytoplasm. These early plasma cells further differentiated into mature plasma cells with eccentric nuclei and basophilic cytoplasm with perinuclear halos.
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Fig. 1. Peripheral blood smear (A, Giemsa, x1000) and bone marrow biopsy (B, H&E, x1000) display plasma cells at various stages of plasma cell differentiation (plasmablast: dark arrow; early plasma cells: dark arrow head; mature plasma cell: open arrow). Marrow aspirate (B inset, Giemsa, x1000) shows plasmablasts (dark arrow head) and an early plasma cell (dark arrow).
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Immunophenotyping.
The bone marrow immunophenotype obtained by flow cytometry and immunohistochemistry (IHC) reflected a full spectrum of B cell to plasma cell differentiation. Flow cytometry showed the mature plasma cells to be positive for bright CD38, CD19, cytoplasmic kappa and lambda light chains, dim CD45, and partial HLA-DR (Fig. 2). By IHC, the mature plasma cells stained strongly positive for membranous CD138, nuclear MUM-1, and cytoplasmic CD79a, and negative for Ki-67 (Fig. 3) In contrast, flow cytometry of the immature plasma cells (including plasmablasts and early plasma cells) stained positive for bright HLA-DR, CD19, dim CD45, and negative for cytoplasmic kappa and lambda (Fig. 2). By IHC, the immature plasma cells displayed weak to negative staining for membranous CD138, weak positivity for CD79a, and strong nuclear positivity for Ki-67 and MUM-1 (Fig. 3). Neither plasmablasts nor mature plasma cells stained with CD56, CD16, or CD20 by flow cytometry. Cytogenetic analysis by conventional G-band analysis revealed a normal karyotype (46, XY) in 19 metaphase cells and trisomy 21 in one metaphase cell.
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Fig. 2. Flow cytometric analysis of plasma cells in bone marrow specimen. Forward-scatter (FSC) and side-scatter (SSC) show the plasmacytoid cells larger than lymphocytes with a dimmer CD45 intensity (a–b). Plasma cells exhibit negative CD20 with increasing intensity of HLA-DR (c), positive CD19 (d), and bright CD38 with polyclonal cytoplasmic kappa and lambda (e–f). Surface kappa and lambda and CD56 are negative (not shown). A small portion (~20%) of brighter, larger HLA-DR+ cells represent plasmablasts and/or early plasma cells, while the smaller, dim HLA-DR+ cells represent mature plasma cells (c).
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Fig. 3. The differentiation of the mature plasma cells vs the plasma blasts and early plasma cells is illustrated immunohistochemically using MUM1, CD138, CD79a, and Ki-67. The mature plasma cells are positive with MUM1, CD138, and cytoplasmic CD79a, and are negative for Ki-67. The plasma blasts and early plasma cells are positive with MUM1 and Ki-67, and are weak or negative for CD138 and cytoplasmic CD79a.
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Discussion
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The appearance of plasmablasts and plasma cells in a smear of peripheral blood is a worrisome finding that requires diagnostic investigation. While a monoclonal population of plasma cells in peripheral blood is seen in plasma cell leukemia, a polyclonal population of plasma cells in peripheral blood suggests a benign reactive process.
In our patient, the florid increase of plasmablasts and mature plasma cells in the peripheral blood and bone marrow was initially suggestive of a plasma cell malignancy. However, despite the high percentage of plasmacytoid cells, the morphologic heterogeneity was atypical of a plasma cell dyscrasia. Immunophenotyping by flow cytometry and immunohistochemistry identified the plasma cells as CD19+/CD56– with polyclonal cytoplasmic light chain staining in addition to bright CD38+ and dim CD45+. This phenotype suggested reactive polyclonal plasma cell proliferation rather than malignant, monoclonal process that is characteristically CD19–/CD56+ [7] in addition to bright CD38+ and dim CD45+. The polyclonality in our patient was further supported by immunoelectrophoresis of serum proteins that showed a prominent polyclonal gammapathy without an M-spike (Table 1
). Non-neoplastic reactive conditions rarely show >20% plasma cells [8]. Our patient showed >50% plasma cells in bone marrow, which is extremely unusual in reactive polyclonal plasmacytosis.
Pellat-Deceunynck and Bataille [7] and Jego et al [8] investigated circulating plasma cells in 10 cases of reactive plasmacytosis and found that reactive plasma cells are a mixture of (i) plasma cell progenitors (plasmablasts) and precursors (early plasma cells) that retain the capacity to differentiate into plasma cells, and (ii) nonproliferative, immunoglobulin-secreting mature plasma cells. Generally, plasmablasts and early plasma cells are generated from naïve or memory B cells in secondary lymphoid organs upon contact with antigens. Both migrate to bone marrow and differentiate into plasma cells. Normally, in a controlled immune reaction, plasmablasts comprise <0.1% of peripheral blood cells. The immunoprofile of the infiltrating plasma cells in bone marrow sections of our patient disclosed a full spectrum of plasma cells at different stages of differentiation [7–11]. Ki-67 staining revealed approximately 5–10% plasmablasts, which were MUM-1+, and gave weak to negative reactions with both CD79a and CD138.
Benign polyclonal plasmacytosis (BPP) was first described in 1988 by Peterson et al [1] as benign polyclonal immunoblast proliferation. BPP is a rare entity with only 8 previously reported cases. As listed in Table 2, the most common clinical presentations have been fever with leukocytosis and skin rash. Other presenting signs include lymphadenopathy, dyspnea, hepatosplenomegaly, jaundice, and autoantibodies. The BPP cases showed an association with bacterial sepsis (Staphylococcus aureus, Pseudomonas aeruginosa), viral infection (hepatitis C, infectious mononucleosis), serum sickness-like syndrome (streptokinase therapy), and immunological disorders. The frequent association of BPP with bacterial sepsis, viral infection, and autoimmune antibodies can be interpreted as a dysregulated hyperactive immune response.
Our patient presented with chest pain, skin rash, and leukocytosis, without fever or lymphadenopathy. Immunologic studies revealed a high titer of homogeneous anti-nuclear autoantibody (ANA), positive anti-dsDNA and anti-RNP, and both IgG and IgM anti-cardiolipin antibodies. Although the prevalence of autoantibodies increases progressively with aging [12], the titers tend to be lower than the level of overt autoimmune disease and are of IgM isotype [12–14]. Therefore the high titer autoantibodies detected in our patient are most suggestive of an autoimmune process. The patient had a history of sepsis with methicillin-resistant Staphylococcus aureus (MRSA) one year previously, so concomitant infection cannot be ruled out in the current hospitalization.
Monoclonal plasma cell proliferation is the most important differential diagnosis for patients with benign polyclonal plasmacytosis. Once diagnosed, the treatment of BPP patients is mainly symptomatic and supportive [1–3]. Although several of the reported cases showed resolution of peripheral plasmacytosis with steroid administration [1–3], deaths from associated co-morbid conditions such as sepsis have been reported (Table 2). Therefore, it is important to be cautious in following these patients and to identify any malignant clone by integration of morphologic, immunophenotypic, immunofixation, radiologic, and cytogenetic findings.
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Footnotes
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* Both authors contributed equally to this study. 
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References
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- Peterson LC, Kueck B, Arthur DC, Dedeker K, Brunning RD. Systemic polyclonal immunoblastic proliferations. Cancer 1988;61:1350–1358.[Medline]
- Poje EJ, Soori GS, Weisenburger DD. Systemic polyclonal B-immunoblastic proliferation with marked peripheral blood and bone marrow plasmacytosis. Am J Clin Pathol 1992;98:222–226.[Medline]
- Shtalrid M, Shvidel L, Vorst E. Polyclonal reactive peripheral blood plasmacytosis mimicking plasma cell leukemia in a patient with Staphylococcal sepsis. Leuk Lymphoma 2003;44:379–380.[Medline]
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- Nosanchuk JS, Schnitzer B. Follicular hyperplasia in lymph nodes from patients with rheumatoid arthritis. Cancer 1969;24:304–314.
- Pellat-Deceunynck C, Bataille R. Normal and malignant human plasma cells: proliferation, differentiation, and expansions in relation to CD45 expression. Blood Cells Mol Dis 2004;32:293–301.[Medline]
- Jego G, Robillard N, Puthier D, et al. Reactive plasmacytosis are expansions of plasmablasts retaining the capacity to differentiate into plasma cells. Blood 1999;94:701–712.[Abstract/Free Full Text]
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- Falini B, Fizzotti M, Pucciarini A, Bigema B et al. A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells. Blood 2000; 95:2084–2092.[Abstract/Free Full Text]
- Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nat Rev Immunol 2005;5:230–242.[Medline]
- Andersen-Ranberg K, Hoier-Madsen M, Wiik A, Jeune B, Hegedus L. High prevalence of autoantibodies among Danish centenarians. Clin Exp Immunol 2004; 138:158–163.[Medline]
- Tan EM, Feltkamp TE, Smolen JS, Butcher B, Dawkins R, et al. Range of antinuclear antibodies in "healthy" individuals. Arthritis Rheum 1997;40:1601–1611.[Medline]
- Ayed K. Anti-DNA antibodies: structure and pathogenic role. Arch Inst Pasteur Tunis 2000;77:3–9.[Medline]
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Abstract
Introduction
