Plasma cell myeloma

Definition

A multifocal bone marrow based plasma cell neoplasm characterised by a serum monoclonal protein (M-component) and skeletal destruction. There is a spectrum from localised indolent disease to aggressively disseminated infiltration of multiple organs and plasma cell leukaemia.

Synonyms

Epidemiology

Plasma cell myeloma represents 15% of all haematological malignancies. It is predominantly a disease of the elderly.

Clinical features

The most common sites of bone involvement are the vertebrae, ribs, skull, pelvis, femur, clavicles and scapulae. Bone destruction results in bone pain, pathological fractures, hypercalcaemia and anaemia. There may be renal failure due to tubular damage by light chain proteinuria. Recurrent infections result from depressed normal immunoglobulin synthesis. 99% of patients show an M-component in serum or urine.

Variants

• non-secretory myeloma: 1% of cases fail to secrete an M-component and very rare cases fail to synthesis immunoglobulin.

• smoldering myeloma: these patients fulfill the minimum requirements for the diagnosis of plasma cell myeloma. However, the patients are asymptomatic and lack lytic bone lesions, anaemia, renal failure or hypercalcaemia.

• indolent myeloma: as for smoldering myeloma, but there may be up to three lytic bone lesions.

• plasma cell leukaemia (PCL): 2% of cases show circulating neoplastic plasma cells exceeding 2.10⁹/l or 20% of peripheral blood cells. PCL may be primary or a terminal complication. Lymphadenopathy and organomegaly are more common.

• Plasmacytoma of bone. There is a localised bone lesion composed of plasma cells. A skeletal survey shows no further lesions and there is no evidence of bone marrow plasmacytosis elsewhere. 5% of plasma cell neoplasms fall into this category. There may be a low level gammopathy.

• Extraosseous plasmacytoma. There is a solitary extraosseous plasma cell tumour. 3-5% of all plasma cell neoplasms fall into this category. 80% occur in the upper respiratory tract but they may be found at a wide range of sites. Some gastrointestinal cases may represent MALT lymphoma with extreme plasmacytic differentiation.

• monoclonal immunoglobulin deposition diseases (MIDD): these conditions are characterised by Ig deposition compromising organ function, prior to the development of a large tumour burden.

  • primary amyloidosis; a fibrillary protein is deposited as a b-pleated sheet which binds Congo Red to produce apple-green birefringence. 20% of patients presenting with primary amyloid have an overt plasma cell myeloma and 15% of patients with plasma cell myeloma will develop amyloidosis. Although antibodies to kappa and lambda can be useful, excessive background staining often prevents interpretation of staining of the amyloid; the plasma cells should also show light chain restriction. Lambda light chain is more common than kappa. The P component can also be demonstrated by Immunohistochemistry.

  • monoclonal light and heavy chain disease; protein is deposited as non-fibrillary amorphous material which odes not form a b-pleated sheet and bind Congo Red and does not contain P component. There is a prevalence of kappa light chain (80% of cases).

• osteosclerotic myeloma (POEMS syndrome): this is a rare syndrome consisting of polyneuropathy (sensorimotor), organomegaly (hepatosplenomegaly), endocrinopathy (diabetes, gynaecomastia, testicular atrophy, impotence), monoclonal gammopathy and skin changes (hyperpigmentation, hypertrichosis). The plasma cell infiltrate in the bone marrow is accompanied by thickened bone trabeculae. Lymph node changes resemble multicentric Castleman disease. The plasma cells contain monoclonal Ig (IgG or IgA). The light chain is lambda in over 90% of cases.

• heavy chain diseases: These are rare B cell neoplasms (but are not true plasma cell neoplasms) that produce pure heavy chains. The heavy chain is often truncated.

  • gamma heavy chain disease; this is a variant of lymphoplasmacytic lymphoma.

  • mu heavy chain disease; this is a variant of CLL.

  • alpha heavy chain disease; this is a variant of extranodal marginal zone lymphoma.

• Precursor lesion: monoclonal gammopathy of undetermined significance (MGUS): the presence of a monoclonal protein in a person without evidence of plasma cell myeloma or other lymphoma. MGUS affects 2% of those over the age of 50 years, 3% of those over 70 years. It is the most common cause of a monoclonal gammopathy. A proportion will evolve to symptomatic plasma cell myeloma or amyloidosis, the risk being 1-2% per annum, with the risk persisting even after 25 years of a stable MGUS.

• CD20+/pax-5 positive myelomas tend to show small mature morphology or plasma cell leukaemia and T(11;14) translocation^8,9

Histopathology

The bone marrow shows an excess of plasma cells, frequently in large nodules or sheets, displacing normal marrow elements. Although in many cases typical plasma cells are easily recognised, the morphology may make this very difficult:

• extreme dysplasia with blasts containing vesicular nuclei and prominent nucleoli, resembling DLBCL.

• bi-nucleation, multinucleation and bizarre giant cells.

• small cell

• cytoplasmic vacuoles or inclusions (Russell bodies: multiple inclusion give rise to Mott cells, grape cells or morular cells), nuclear invaginations giving rise to apparent nuclear inclusions (Dutcher bodies). Cells with small nuclei and voluminous cytoplasm are known as thesaurocytes. Cells rich in carbohydrate-containing IgA may have flame-pink cytoplasm (flame cells). The cytoplasmic inclusions may resemble erythrophagocytosis⁶ (as seen in association with some T-cell lymphomas).

Diagnostic criteria

For the diagnosis of plasma cell myeloma, one major and one minor criteria or three minor criteria are required a symptomatic patient

• Major criteria:

  • marrow plasmacytosis >30%
    
  • plasmacytoma on marrow biopsy
    
  • M-component;
    • serum IgG >3.5 g/dl, IgA >2 g/dl
      
    • urine >1g/24hr of Bence-Jones protein
• Minor criteria:
  • marrow plasmacytosis 10-30%
    
  • M-component present but less than above
    
  • lytic bone lesions
    
  • reduced normal immunoglobulin (<50% normal);
    • IgG <600mg/dl, IgA <100 mg/dl, IgM <50mg/dl

Immunohistochemistry

cytoplasmic Ig	positive (most often IgG, occasionally IgA, rarely IgD, IgE or IgM). 15% express light chain only.
surface Ig	negative
CD5	negative
CD10	usually negative
CD19†	most negative
CD20	most negative, 12/668: CD20 positive myelomas also tend to be positive for Pax-57
CD22	-
CD38	most positive5
CD45	var
CD56 / CD58	usually positive, negative in PCL
CD79a	most positive
CD117	43/85 (24 cases positive in more than 20% of cells, 29 cases positive in less than 20% of cells.)12
CD138	most positive4
cyclin D1	25%3
VS38c	most positive

†: fresh frozen tissue only

CD56 may be useful in differentiating myeloma from MGUS and polyclonal plasmacytosis:

†A case was considered to be CD56+ if > 50% of the CD138+ plasma cells showed expression of CD56 at a level comparable to that of the osteoblast layer (used as an internal positive control).¹¹

The expression of CD56 by myeloma cells may inhibit osteoid production: both myeloma cells and osteoblasts express CD56 and the inhibition may be mediated by homophilic binding.¹¹.

There is increasing evidence that neoplastic plasma cells express various haemopoietic and non-haemopoietic antigens. Since this issue could raise problems in diagnostic histopathology, Petruch et al investigated 51 cases of multiple myeloma (plasmacytoma) systematically with a broad panel of antibodies applicable on paraffin-embedded and mildly decalcified tissue. In approximately 90% of the cases the neoplastic plasma cells reacted with at least one antibody detecting haemopoietic antigens:

MB2	75%
DF-T1/CD 43	59%
UCHL1/CD 45RO	47%
Ki-B3	41%
anti-LCA/CD 45	40%
L26/CD 20	26%
4KB5/CD 45RA	18%
Ber H2/CD 30	10%
Leu-7/CD 57	8%
neutrophil elastase	4%
Dako-M1/CD 15	2%
KP1/CD 68	2%
glycoprotein IIIa	2%

In approximately 70% of the cases the cells reacted with antibodies against non-haemopoietic antigens:

epithelial membrane antigen	65% - 85%2 (mainly membrane)
BMA120	53%
vimentin	44%
pan-cytokeratin/KL1	8%
carcino-embryonic antigen	6%
HMB45	6%

Lack of awareness of the frequent expression of both haemopoietic and non- haemopoietic antigens by neoplastic plasma cells could lead to mis-diagnosis of plasmacytomas as malignant lymphomas or even as carcinomas or sarcomas.

Parathyroid hormone related protein may be produced by myelomas and contribute to osteolysis and hypercalcaemia. The use of mercury-based fixation and decalcification procedures may prevent immunostaining for PTHrP in bone marrow specimens; detection of PTHrP mRNA may therefore be more sensitive¹.

Differential diagnosis

• plasmacytoid lymphoma: plasmacytomas are composed of pure plasma cells without lymphocytes or plasmacytoid lymphocytes

• the plasmablastic variant of plasma cell myeloma may mimic immunoblastic diffuse large B-cell lymphoma

	CD19	CD20	CD22	CD38	CD45	EMA	PCA-1
lymphoplasmacytoid lymphoma	+	+	+	-	+	-	-
diffuse large B cell lymphoma	+	+	+	-	+	-	-
plasmacytoma	-	-	-	+	var	+	+

Prognosis

• Plasma cell myeloma is usually incurable with a median survival of three years.

• Solitary plasmacytoma of bone shows 35% cure at 10 years, with 55% of patients developing plasma cell myeloma and 10% having a recurrent solitary plasmacytoma at the same or a new site.

• Solitary extraosseous plasmacytoma 25% regional recurrence but only 15% of patients developing plasma cell myeloma.

References

World Health Organization Classification of Tumours, Tumours of the haematopoietic and lymphoid tissues, IARC Press 2001.

Petruch, U. R., Horny, H. P., Kaiserling, E. Frequent expression of haemopoietic and non-haemopoietic antigens by neoplastic plasma cells: an immunohistochemical study using formalin- fixed, paraffin-embedded tissue. Histopathology 1992;20:35-40.

¹ Zeimer H et al. Assessment of cellular expression of parathyroid hormone-related protein mRNA and protein in multiple myeloma. J Pathol 2000;192:336-341.

² ten Berge, R. L., Snijdewint, F. G., von Mensdorff-Pouilly, S. MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma, in the normally glycosylated or only partly hypoglycosylated form. J Clin Pathol 2001;54:933-939.

³ Swerdlow, S. H., Williams, M. E. From centrocytic to mantle cell lymphoma: a clinicopathologic and molecular review of 3 decades. Human Pathol 2002;33;7-20.

⁴ Costes V, Magen V, Legouffe E et al. The Mi15 monoclonal antibody (anti-syndecan-1) is a reliable marker for quantifying plasma cells in paraffin-embedded bone marrow biopsy specimens. Human Pathology 1999;30:1405-11.

⁵ Vallario A, Chilosi M, Adami F et al. Human myeloma cells express the CD38 ligand CD31. British Journal of Haematology 1999;105:441-4.

⁶ Pillai, G., K. Lwin, et al. (2002). "Malignant plasmacytosis mimicking erythrophagocytosis." Histopathology 41(5): 468-70.

⁷ Lin, P., M. Mahdavy, et al. (2004). "Expression of PAX5 in CD20-positive multiple myeloma assessed by immunohistochemistry and oligonucleotide microarray." Mod Pathol 17(10): 1217-22.

⁸ Robillard, N., H. Avet-Loiseau, et al. (2003). "CD20 is associated with a small mature plasma cell morphology and t(11;14) in multiple myeloma." Blood 102(3): 1070-1. FULL TEXT

⁹ Garcia-Sanz, R., A. Orfao, et al. (1999). "Primary plasma cell leukemia: clinical, immunophenotypic, DNA ploidy, and cytogenetic characteristics." Blood 93(3): 1032-7.

¹⁰ Martin, P., A. Santon, et al. (2004). "Neural cell adhesion molecule expression in plasma cells in bone marrow biopsies and aspirates allows discrimination between multiple myeloma, monoclonal gammopathy of uncertain significance and polyclonal plasmacytosis." Histopathology 44(4): 375-80.

¹¹ Ely, S. A. and D. M. Knowles (2002). "Expression of CD56/neural cell adhesion molecule correlates with the presence of lytic bone lesions in multiple myeloma and distinguishes myeloma from monoclonal gammopathy of undetermined significance and lymphomas with plasmacytoid differentiation." Am J Pathol 160(4): 1293-9. FULL TEXT

¹² Pruneri G, Ponzoni M, Ferreri AJ, et al. The prevalence and clinical implications of c-kit expression in plasma cell myeloma. Histopathology 2006; 48:529-35

This page last revised 3.5.2006.

©SMUHT/PW Bishop