Objective
To evaluate the incidence of posttransplant lymphoproliferative disease (PTLD) and the risk factors and the impact of this complication on survival outcomes in a large cohort of liver transplant recipients at a single institution.

Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience.

Monoclonal gammopathies are disorders characterized by the proliferation of a single clone of plasma cells producing a homogeneous monoclonal protein (M-protein, M-component, paraprotein). Each M-protein consists of two heavy polypeptide chains of the same class and two light polypeptide chains of the same type. The heavy polypeptide chains are gamma (γ) in immunoglobulin G (IgG), alpha (α) in immunoglobulin A (IgA), mu (μ) in immunoglobulin M (IgM), delta (δ) in immunoglobulin D (IgD), and epsilon (e) in immunoglobulin E (IgE). The two light-chain types are kappa (κ) and lambda (λ). A polyclonal gammopathy is characterized by an increase in one or more heavy chains and in both types of light chain. One must differentiate between a monoclonal and a polyclonal increase in immunoglobulins, because a monoclonal increase is associated with a clonal process that is malignant or potentially malignant, whereas a polyclonal increase of immunoglobulins is caused by a reactive or inflammatory process. A sensitive, rapid, and dependable screening method is needed to detect the presence of an M-protein, and a specific assay is used to identify its heavy-chain type and light-chain class. 61 High-resolution agarose gel electrophoresis is the recommended method for detection of an M-protein. 54 Immunofixation or immunosubtraction with capillary electrophoresis must be done to confirm the presence and type of M-protein. Serum protein electrophoresis should be done whenever multiple myeloma (MM), Waldenstrom's macroglobulinemia (WM), primary amyloidosis (AL), or a related disorder is suspected. Serum protein electrophoresis also is indicated for patients with anemia, unexplained back pain, weakness or fatigue, osteolytic lesions or fractures, osteopenia, hypercalcemia, renal insufficiency, presence of Bence Jones proteinuria, or a history of recurrent bacterial infections. Serum protein electrophoresis should be performed for patients with unexplained sensorimotor peripheral neuropathy, carpal tunnel syndrome, nephrotic syndrome or renal insufficiency, cardiomyopathy or refractory congestive heart failure, orthostatic hypotension, or malabsorption, because these conditions are common in AL. Severe weight loss, change in the tongue or voice, paresthesias, numbness, increased bruising, bleeding, and steatorrhea are additional indications for the performance of serum protein electrophoresis. Even when the serum protein electrophoretic pattern is nondiagnostic, immunofixation should be performed whenever MM, WM, AL, or related disorders are suspected. An M-protein usually is visible as a discrete band on the agarose gel electrophoretic strip or as a tall, narrow spike or peak in the γ or β regions, or, rarely, in the α 2 area of the densitometer tracing (Fig. 1). A polyclonal increase in immunoglobulins produces a broad band or a broad-based peak and is limited to the γ region (Fig. 2). Two M-proteins (biclonal gammopathy) occur in 3% to 4% of sera containing an M-protein (Fig. 3). 63 A small M-protein may be present even when the total protein, α, β, and γ components, and quantitative immunoglobulins are all within normal limits. Such an M-protein may be concealed in the normal β or γ components. Monoclonal κ or λ light chains (Bence Jones proteinemia) usually are present in a concentration too low to be visible as a spike in the agarose gel. The type of M-protein is best determined by immunofixation. Immunofixation should be performed whenever a sharp peak or band is found in the agarose gel or when MM, WM, AL, solitary or extramedullary plasmacytoma, or a related disorder is suspected. Immunofixation is critical for the differentiation of a monoclonal from a polyclonal increase in immunoglobulins. It may be performed with commercial kits, or laboratory personnel can pour their own plates and cut the appropriate troughs. Immunoelectrophoresis also may be used to detect an M-protein, but it is less sensitive than immunofixation and is not recommended. Capillary zone electrophoresis measures protein on-line by absorbance, so protein stains are not necessary and, thus, no point of application is seen. After electrophoresis, immunotyping can be performed by an immunosubtraction procedure in which the serum sample is incubated with sepharose beads coupled with anti-γ, anti-α, anti-μ, anti-κ, and anti-λ antisera. After incubation, the supernatants are reanalyzed to determine which reagents removed the electrophoretic abnormality. 45 This procedure is technically less demanding, is automated, and is a useful procedure for immunotyping M-proteins. The use of a rate nephelometer is best for the quantitation of immunoglobulins. This method is not affected by molecular size, so it measures monomers, polymers, and aggregates of the M-protein. The levels of IgM may be 1000 to 2000 mg/dL more than the size of the M-spike in the densitometer tracing. Immunoglobulin G and IgA may also be spuriously increased. 93 Obviously, the clinician must use the same technique to measure the M-protein on subsequent visits. Electrophoresis and immunofixation of an aliquot from a 24-hour urine specimen should be done initially in all patients with MM, WM, or AL. The amount of M-protein is best measured by multiplying the percentage of the M-spike in the densitometer tracing by the total protein in the 24-hour specimen. The amount of M-protein in the urine provides an index of the patient's tumor mass. It is useful for monitoring the disease. 84 The differential diagnosis of monoclonal gammopathies is outlined in the following box. 
				Classification of Monoclonal Gammopathies
									 IMonoclonal gammopathy of undetermined significance (MGUS)
												 ABenign (IgG, IgA, IgM, IgD) BAssociated with neoplasms of cell types not known to produce monoclonal proteins CIdiopathic Bence Jones proteinuria DBiclonal gammopathies ETriclonal gammopathies II
												 AMalignant monoclonal gammopathies
															 1Symptomatic multiple myeloma 2Smoldering multiple myeloma 3Plasma cell leukemia 4Nonsecretory myeloma 5Osteosclerotic myeloma (POEMS)*
																		*POEMS = polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes BPlasmacytoma
															 1Solitary plasmacytoma of bone 2Extramedullary plasmacytoma IIIWaldenstrom's macroglobulinemia IVHeavy-chain diseases (HCD)
												 Aγ-HCD Bα-HCD Cμ-HCD VPrimary amyloidosis (AL) During 1998, 1149 newly recognized cases of monoclonal gammopathy were identified at Mayo Clinic, Rochester, Minnesota (Fig. 4). The term monoclonal gammopathy of undetermined significance denotes the presence of an M-protein in persons without evidence of MM, WM, AL, lymphoproliferative disorders, plasmacytoma, or related conditions. The previously used term benign monoclonal gammopathy is misleading, because a proportion of patients will develop MM or related disorders during long-term follow-up. It is impossible to tell at the time of diagnosis whether the process producing an M-protein will remain stable and benign or will progress to a serious disease. Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of a serum M-protein value less than 3 g/dL, less than 5% plasma cells in the bone marrow, no or only small amounts of Bence Jones protein in the urine, absence of lytic bone lesions, and no related anemia, hypercalcemia, or renal failure. The proliferative rate of the plasma cells (plasma cell labeling index) is low. The finding of MGUS is an unexpected event in the laboratory tests of an apparently normal person or during the evaluation of an unrelated disorder. Monoclonal gammopathy of undetermined significance has been found in approximately 3% of persons older than 70 years in Sweden, 5 the United States, 57 and France. 97 In 6995 persons older than 25 years from Sweden, an M-protein was found in 1%. 5 In a cluster of cases of MM in a small Minnesota community, 57 M-protein was detected in 15 of 1200 persons 50 years or older (1.25%), and in France, 303 of 17,968 persons 50 years or older (1.7%) had an M-protein. 97 The incidence of MGUS is higher in older patients. Crawford et al 21 reported that 10% of 111 persons older than 80 years had an M-protein. In another report, 23% of 439 persons aged 75 to 84 years had an M-protein. 68 Cohen et al 20 found that 3.6% of 816 persons 70 years or older had an M-protein. As in MM, the incidence of M-proteins is higher in African-Americans than in whites. 98 In a recent study, the prevalence of an M-protein was 8.4% in 916 African-Americans. 20 In contrast, the incidence of monoclonal gammopathies was less (4 of 146 [2.7%]) in elderly Japanese patients. 14 Because the prevalence of MGUS is relatively high, and patients are seen by physicians in different fields of clinical practice, it is important to know whether the disorder is benign or whether MM, WM, AL, or a related disorder will develop.

https://www.hemonc.theclinics.com/article/S0889-8588(05)70120-9/pdf

Monoclonal gammopathies of undetermined significance

The term ‘monoclonal gammopathy of undetermined significance’ denotes the presence of a monoclonal protein in patients without evidence of multiple myeloma, macroglobulinemia, amyloidosis or related plasma cell proliferative disorders. The disorder has been found in approximately 3% of persons older than 70 years and in approximately 1% of persons older than 50 years. A population-based study included 1384 patients from south-eastern Minnesota who had the disorder diagnosed at the Mayo Clinic from 1960 through 1994. Risk of progression was about 1% per year, but patients were at risk of progression even after 25 years or more of stable monoclonal gammopathy of undetermined significance. The risk for development of multiple myeloma was increased 25-fold; the risk of macroglobulinemia, 46-fold; and the risk of primary amyloidosis, 8.4-fold. Concentration and type of monoclonal protein were the only independent predictors of progression. The presence of a urine monoclonal protein and the reduction of one or more uninvolved immunoglobulins were not risk factors for progression. Monoclonal gammopathy of undetermined significance may be associated with various disorders, including lymphoproliferative diseases, leukemia, von Willebrand disease, connective tissue diseases and neurologic disorders.

Monoclonal gammopathies of undetermined significance.

Post-transplant lymphoproliferative disorder is the most common malignancy, with the exception of skin cancer, after solid organ transplantation in adults. The incidence varies according to the transplanted organ and is often associated with Epstein-Barr virus. Prognosis is variable, due in part to the heterogeneity of the disease, which ranges from reactive plasmacytic hyperplasia to aggressive monoclonal disease.

https://theoncologist.onlinelibrary.wiley.com/doi/pdf/10.1634/theoncologist.11-6-674

Post-transplant lymphoproliferative disorders.

Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of a serum monoclonal (M) protein level less than 3 g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of hypercalcemia, renal insufficiency, anemia, or bone lesions attributable to a clonal plasma cell disorder. Patients may be tested for a monoclonal gammopathy by serum protein electrophoresis, immunofixation, and the free light chain (FLC) assay. The prevalence of MGUS is 3% for persons more than 50 years of age and 5% in those more than 70 years of age. The risk of progression to multiple myeloma or a related disorder is 1% per year. The size and type of M protein, the number of bone marrow plasma cells, and the results of the FLC ratio are independent risk factors for progression. Smoldering multiple myeloma (SMM) is a more advanced premalignant phase than MGUS and is characterized by more than 3 g/dL of serum M protein, more than 10% clonal plasma cells in the bone marrow, or both, with no evidence of end-organ damage.

/pdf/monoclonal-gammopathy-of-undetermined-significance-and-54xu8mzeqs.pdf

Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

Background. A high incidence of serum monoclonal immunoglobulins (mIgs) has been described after solid organ transplantation. For transplant recipients, the prevalence of posttransplant lymphoproliferative disorders (PTLDs) has been reported to be between 2% and 6%. The relationship between the finding of serum mIg in transplant recipients and the subsequent development of PTLDs is not clearly documented. Methods. We retrospectively analyzed all cases of mIg and PTLD that occurred in 86 liver transplant recipients who survived more than 3 months. Patients were characterized by protein electrophoresis, immunofixation electrophoresis, pre- and post-liver transplantation Epstein-Barr virus (EBV) serology, EBV presence in lymphoproliferative tissues by in situ hybridization, type of infection episodes, rejection episodes, and immunosuppressive treatment. Results. Thirty-eight patients (44%) had abnormal immunofixation electrophoresis with an electrophoretic Ig peak. Twelve patients had a polyclonal Ig peak, and 26 patients had mIgs (30%). These 26 patients were divided into two groups: 13 patients had a transient mIg peak with a mean delay for normalization of electrophoresis of 2 months, and 13 patients had a permanent mIg peak. No correlation could be demonstrated between the appearance of abnormal banding and indications for transplantation, age of patients, and acute rejection rate. There was a strong correlation between occurrence of viral infections and presence of permanent mIg. Three patients with permanent mIg (23%) developed PTLD and died. Conclusions. We concluded that the prevalence of mIg after liver transplantation was 30%. Viral infections increase the risk of developing mIg. Persistence of mIg beyond 7 months may be regarded as prelymphomas necessitating a careful follow-up in these patients.

Prevalence of monoclonal immunoglobulins after liver transplantation: relationship with posttransplant lymphoproliferative disorders.

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Prevalence of monoclonal immunoglobulins after liver transplantation: relationship with posttransplant lymphoproliferative disorders.