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==== Monoclonal gammopathy of renal significance ====
==== Monoclonal gammopathy of renal significance ====
Monoclonal gammopathey of renal significance or MGRS designates MGUS disease that has a clinically significant impact on renal function. The diagnosis of MGRS is made based on the presence of increased levels of urinary monoclonal light chains (typically > 0.5 gram/day), decreased kidney function as evidence by, e.g. a [[Renal function#Glomerular filtration rate|Glomerular filtration rate]] of <40, and biopsy confirmed or suspicion of [[Myeloma cast nephropathy|cast nephropathy]] due to the presence in kidney tubules of monoclonal light chain casts.<ref name="pmid27249749">{{cite journal | vauthors = Rajkumar SV | title = Updated Diagnostic Criteria and Staging System for Multiple Myeloma | journal = American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology. Meeting | volume = 35 | issue = | pages = e418–23 | year = 2016 | pmid = 27249749 | doi = 10.14694/EDBK_159009 | url = }}</ref>
Monoclonal gammopathey of renal significance or MGRS designates MGUS disease that has a clinically significant impact on renal function. The diagnosis of MGRS is made based on the presence of increased levels of urinary monoclonal light chains (typically > 0.5 gram/day), decreased kidney function as evidence by, e.g. a [[Renal function#Glomerular filtration rate|Glomerular filtration rate]] of <40, and biopsy confirmed or suspicion of [[Myeloma cast nephropathy|cast nephropathy]] due to the presence in kidney tubules of monoclonal light chain casts.<ref name="pmid27249749">{{cite journal | vauthors = Rajkumar SV | title = Updated Diagnostic Criteria and Staging System for Multiple Myeloma | journal = American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology. Meeting | volume = 35 | issue = | pages = e418–23 | year = 2016 | pmid = 27249749 | doi = 10.14694/EDBK_159009 | url = }}</ref>

=== Solitary plasmacytoma ===
Solitary plasmacytoma is an early stage malignancy with a clinical course that lies between MGUS and multiple myeloma in the spectrum of plasma cell dyscrasias.<ref name="pmid27249749"/> Solitary plasmacytomas typically present with local symptoms due to the growing mass of plasma cells such as bone pain or [[Pathologic fracture|pathologic bone fractures]] in solitary plasmacytomas of bone and headache, focal neurological deficits, or cranial nerve palsies in extramedullary plasmacytomas of [[Cavernous sinus|sellar and parasellar compartments]] of the brain.<ref name="pmid28251542">{{cite journal | vauthors = Lee J, Kulubya E, Pressman BD, Mamelak A, Bannykh S, Zada G, Cooper O | title = Sellar and clival plasmacytomas: case series of 5 patients with systematic review of 65 published cases | journal = Pituitary | volume = 20 | issue = 3 | pages = 381–392 | year = 2017 | pmid = 28251542 | doi = 10.1007/s11102-017-0799-5 | url = }}</ref> Its diagnoses must meet all four of the following criteria: biopsy-proven tumor consisting of clonal plasma cells; no evidence of any other plasmacytomas based on [[Skeletal survey|bone survey]] and [[Magnetic resonance imaging|MRI]] (or in place of MRI, [[CT scan]]); normal bone marrow examination; and absence end organ damage, CRAB features, or other signs or symptoms of systemic disease attributable to a plasma cell dyscrasia.<ref name="pmid27249749"/>. Blood or urine myeloma proteins are usually undetectable or low in solitary plasmacytomas. Solitary plasmacytoma is a rare disease with an incidence in the USA of <450 cases per year. In a review of 1,691 cases in the USA, the median age at diagnosis was 63 with males representing ~60% of all cases. The most common site of plasmacytoma involvement was bone (~58%) followed by upper or lower airway tract (~16%), soft tissue or connective tissue (~5%), [[central nervous system]] (~3%), [[gastrointestinal tract (~3%), skin (~1%), and all other sites (~3%). Overall median survival was 8.12 years with survival decreasing with age from 12.4 years for patients <40 to 5.2 years for patients of 60 years or older.<ref name="pmid28056880">{{cite journal | vauthors = Thumallapally N, Meshref A, Mousa M, Terjanian T | title = Solitary plasmacytoma: population-based analysis of survival trends and effect of various treatment modalities in the USA | journal = BMC Cancer | volume = 17 | issue = 1 | pages = 13 | year = 2017 | pmid = 28056880 | pmc = 5216567 | doi = 10.1186/s12885-016-3015-5 | url = }}</ref>


==Classification==
==Classification==

Revision as of 14:44, 19 June 2017

Plasma cell dyscrasias
SpecialtyHematology

Plasma cell dyscrasias (also termed plasma cell disorders) are a spectrum of progressively more severe conditions all of which involve the formation of a clone of pre-malignant or malignant plasma cells that over-produce a clonal antibody or portion thereof. At one end of this spectrum of hematological disorders, detection of one of these plasma cell-secreted myeloma proteins in an individual's blood or urine indicates the presence of a clinically silent disorder termed MGUS, i.e. monoclonal gammopathy of undetermined significance. At the other end of this spectrum, detection of the myeloid protein indicates the presence of malignant hematological diseases to which MGUS may progress viz., multiple myeloma or Waldenström's macroglobulinemia.[1][2] The clinical importance of understanding this spectrum of diseases is that individuals diagnosed in the early stages of the plasma cell dyscrasia spectrum require careful clinical monitoring to detect and thereby treat disease progression to malignancy (as well as any disease complications) as early as possible.[3]

Plasma cell malignancy

Main article: Humoral immunity
Main article: Antibody

Plasma cells are key effector elements of the adaptive immune system. They contribute to immunity by making antibodies that bind with and thereby initiate the process of neutralizing specific antigens that usually are found on the surface of invading pathogens and foreign substances. Plasma cells develop from B lymphocytes when they are stimulated to do so by T lymphocytes during the processing of these antigens. Developing plasma cells refashion parts of their genome in efforts to create a new gene that encodes an antibody that targets the instigating antigen. An intact antibody is composed of two identical heavy and two identical light chains. Formation of this new gene requires somatic hypermutations to create point mutations at a) the immunoglobulin heavy chain antigen-binding locus on the short or "q" arm of human chromosome 14 at position 32.33 (site notated as 14q32.33); b) the immunoglobulin light chain antigen binding locus located on the short or "q" arm of chromosome 22 at position 11.22; and c) other nearby sites. These point mutations are made in an effort to make a gene that encodes a protein that binds the instigating antigen. The next steps to form a functional gene involve V(D)J recombinations and class switch recombinations, i.e. the deletion and subsequent recombination of genetic material in order that the new gene encodes either an IgG, IgD, IgA, IgM, or IgE antibody isotype. These genetic changes can go awry by, for example, placing a gene that ordinarily controls cell growth next to highly active antibody gene promotors to create and oncogene or by forming extra chromosomes (see trisomy) or chromosomes with deleted or repetitive sections.[4][5][6] As a consequence of these aberrations, a malignant clone of rapidly proliferating plasma cells may become established most commonly in the bone marrow but sometimes in other tissues. This clone overproduces either intact IgG, IgD, IgA, IgM, or IgE antibodies; the respective gamma (γ), delta (δ), alpha (α), mu (μ), or epsilon (ε) heavy chains or these antibodies; or kappa (κ) or lambda (λ) light chains. The overproduced clonal globulins are detected as myeloma protein spikes on gel electrophoresis analyses of serum and/or urine and are the critical indicators for the presence of MGUS.[4]

Further genetic mutations in the plasma cells or, in IgM MGUS, lymphoplasmacytoid cells may establish other pre-malignant clones at the time of or after establishment of the initial clone. That is, plasma cell dyscrasias commonly involve more than one clone of pre-malignant or malignant cells and this may underlie the progression of plasma cell dyscrasias through its initial stage of the clinically silent presence of a myeloma protein in blood or urine to an overt malignancy, either multiple myeloma[4] or, in the case of IgM myeloid protein production, Waldenström's macroglobulinemia or other type of lymphoid neoplasm.[4][5]

Stages of plasma cell dyscrasias

MGUS

MGUS, i.e. monoclonal gammopathy of undetermined significance, is defined as the presence in the blood or urine of a monoclonal antibody, antibody heavy chain, or antibody light chain in a person lacking symptoms or signs of more serious plasma cell dyscrasia. The condition is typically discovered as an incidental finding when protein electrophoresis is done for various reasons unrelated to plasma cell dyscrasias. Protein electrophoresis generally detects on of the following pattern of monoclonal myeloma protein spikes representing: a) intact IgG, IgA, igD, or IgE; b) intact IgG, IgA, igD, or IgE plus high concentrations of a free (i.e. unbound to a heavy chain) κ or λ light chain; c) a free κ chain in great excess of a λ chain or a free λ chain in great excess of a κ chain; and d) free γ, δ, or μ heavy chains unbound to a light chain (free α and ε heavy chain myeloma protein spikes have not been reported). Among MGUS cases expressing an intact antibody, 70%, 15%, 12%, and 3% express either IgG, IgM, IgA, or two of these M proteins, respectively, with or without excessive levels of a light chain; these cases represent ~80% of all MGUS. About 20% of MGUS cases express either κ or λ light chains. As a group, these MGUS findings occur more commonly in men and are ~2-fold more common in individuals of African decent than Caucasians.[2][7] MGUS cases expressing free γ, δ, or μ heavy chains are extremely rare.[7][8] MGUS is categorized into the following sub-types based upon the identity and levels of the myeloma proteins detected as well as the prognoses for progressive disease indicated by these myeloma protein findings.

Non-IgM MGUS

Main article: Monoclonal gammopathy of undetermined significance

Non-IgM MGUS, commonly termed MGUS, is diagnosed in individuals who have serum levels of intact IgG, IgD, IgA, IgE below 30 gram/liter with or without increased levels of blood or urine free κ or λ light chains. Further requirements for the diagnosis of non-IgM MGUS are those that, if present, indicate a more advanced stage of plasma cell dyscrasia, There must be: a) bone marrow clonal plasma cells less than 10% of total nucleated cells; b) absence of any one of the CRAB critera (CRAB criteria are C = Calcium blood levels elevated, R = Renal failure, A = Anemia, B = Bone lesions, e.g. bone plasmacytomas); c) no evidence of a plasmacytoma(s) in bone or soft tissues, amyloidosis, or other plasma cell disorders; and d) a ratio of free light chains (i.e. a serum free κ/λ or λ/κ light chain ratio that is less than 100, providing that the higher light chain concentration is >100 mg/liter.[2]

Non-IgM MGUS is a relatively stable condition afflicting 3% of people aged 50 and 5% of people aged 70; on average, it progresses to multiple myeloma at a rate of 0.5-1% cases per year, as defined in studies following patients over a 25 year period. A study conducted by the Mayo Clinic found that MGUS associated with non-IgG myeloma proteins or with serum myeloma protein levels greater than 15 gram/liter had a greater risk per year of progression to multiple myeloma. A Spanish study group found that MGUS patients demonstrating aneuploidy (i.e. abnormal number of chromosomes) in bone marrow cells or >95% of resident bone marrow plasma cells that are clonal in nature also have a greater risk per year of progression to myeloma.[4] In a more recent study, MGUS patients that had the presence of none, 1, 2, or 3 of the three following risk factors, serum M protein levels >15 gram/liter, a non-IgG isotype, and abnormal free light chain ratios, had 5, 32, 37, and 58% chances, respectively, of progressing to multiple myeloma within 20 years; in another study MGUS patients with none, 1, or 2 of the following risk factors, >95% of bone marrow plasma cells that are clonal in nature and a 10% or greater rise in the levels of theri monoclonal proteins within 3 years, had 2, 16, and 72% risks, respectively, of progression within 7 years.[3] However, estimates on the risks of progression for some of these parameters are tentative and subject to change. For example, the IgA form of MGUS, while once considered to have a poorer prognosis than IgG MGUS, was found to have a prognosis similar to IgG MGUS in a more recent study.[9]

IgM MGUS

Main article: Waldenström's macroglobulinemia

While traditionally classified as such, it is not clear that IgM MGUS is a clonal plasma cell dyscrasia. IgM MGUS involves an increase in a B cell derivative with morphological features of both plasma cells and lymphocytes viz., lymphoplasmacytic cells. Studies indicate that both plasma cells and lymphoblastic cells infiltrate involved tissues and that one or perhaps both cell types harbor mutations in a) the MYD88 gene (~20% in IgM MGUS, >90% in IgM-related malignancies almost all of which are L265P mutations that continuously activate the same cell-activating pathways as Toll-like receptors; b the CXCR4 gene (8% in IgM MGUS, 25% in IgM-related malignancies); and c) increased gene copy number due to chromosomal rearrangements (36% in IgM MGUS, 82% in IgM-related malignancies).[7] It is clear that each cell type contributes to different features of IgM malignancies but not clear that clonal plasma cells are critical to the development or progression of IgM MGUS.[7] In all events, IgM MGUS is diagnosed in individuals who have serum IgM levels less that 30 gram/liter; have less than 10% of nucleated bone marrow cells with the lymphoplasmacytic morphology, and have no symptoms or findings of end organ dysfunction attributed to Waldenström's macroglobulinemia such as anemia, cold agglutinin disease, decreases in any white blood cell count, hyperviscosity of blood, lymphadenopathy, hepatomegaly, splenomegaly, peripheral neuropathy, cryoglobulinemia, or constitutional symptoms.[2][6][7]

There may be a modest increase in the incidence of IgM MGUS in people of African descent. A study of 213 individuals diagnosed with IgM MGUS found that 10% at 5 years and 24% in 15 years progressed to more serious IgM-related diseases including non-Hodgkin lymphoma, Waldenstorm's macroglobulinemia, systemic amyloidosis, and chronic lymphocytic leukemia. A second long-term study of 116 individuals with IgM MGUS found a 15-fold increased risk of progressing to a lymphoid malignancy, mostly to Waldenstorm's macroglobulinemia. In general, progression to one of these malignant outcomes occurs at a rate of 2% to 3% per year. Individuals with higher serum IgM or lower serum albumin levels progress at faster rates than those with normal levels of these parameters.[7]

Light chain MGUS

Individuals diagnosed with light chain MGUS lack detectable IgG, IgA, IgD, IgE, or IgM myeloma proteins while overexpressing a free κ/λ or λ/κ light chain ratio in their serum that is outside the range which includes 99% of normal reference ratios, i.e. 0.26 to 1.65. However, this ratio must be less than 100 and individuals' bone marrow plasma cell must be less than 10% of total nucleated cells, urinary monoclonal protein levels must be less than 0.5 gram/day, and CRAB criteria as well as evidence of amyloidosis or end organ damage attributable to the myeloma proteins or plasma cells must be absent. As so defined, light chain MGUS comprises ~19% of all MGUS cases, occurs in ~0.8% of the general population, and progresses to light chain multiple myeloma at the very slow rate of 0.3 cases per 100 years.[2][4][3]

A very different rate of progress occurs in light chain MGUS patients who have light chain ratios equal to or greater than 100. About 80% of these light chain MGUS patients were initially found to progress to light chain multiple myeloma within 2 years and therefore were recommended for being diagnosed and treated as having multiple myeloma.[3] However, two more recent studies reported a 2 year progression rate for these patients of 64 and 30% and therefore suggested that a light chain multiple myeloma diagnosis based solely on a free light chain ratio equal to or greater than 100 may be premature.[9]

Monoclonal gammopathy of renal significance

Monoclonal gammopathey of renal significance or MGRS designates MGUS disease that has a clinically significant impact on renal function. The diagnosis of MGRS is made based on the presence of increased levels of urinary monoclonal light chains (typically > 0.5 gram/day), decreased kidney function as evidence by, e.g. a Glomerular filtration rate of <40, and biopsy confirmed or suspicion of cast nephropathy due to the presence in kidney tubules of monoclonal light chain casts.[10]

Solitary plasmacytoma

Solitary plasmacytoma is an early stage malignancy with a clinical course that lies between MGUS and multiple myeloma in the spectrum of plasma cell dyscrasias.[10] Solitary plasmacytomas typically present with local symptoms due to the growing mass of plasma cells such as bone pain or pathologic bone fractures in solitary plasmacytomas of bone and headache, focal neurological deficits, or cranial nerve palsies in extramedullary plasmacytomas of sellar and parasellar compartments of the brain.[11] Its diagnoses must meet all four of the following criteria: biopsy-proven tumor consisting of clonal plasma cells; no evidence of any other plasmacytomas based on bone survey and MRI (or in place of MRI, CT scan); normal bone marrow examination; and absence end organ damage, CRAB features, or other signs or symptoms of systemic disease attributable to a plasma cell dyscrasia.[10]. Blood or urine myeloma proteins are usually undetectable or low in solitary plasmacytomas. Solitary plasmacytoma is a rare disease with an incidence in the USA of <450 cases per year. In a review of 1,691 cases in the USA, the median age at diagnosis was 63 with males representing ~60% of all cases. The most common site of plasmacytoma involvement was bone (~58%) followed by upper or lower airway tract (~16%), soft tissue or connective tissue (~5%), central nervous system (~3%), [[gastrointestinal tract (~3%), skin (~1%), and all other sites (~3%). Overall median survival was 8.12 years with survival decreasing with age from 12.4 years for patients <40 to 5.2 years for patients of 60 years or older.[12]

Classification

References

  1. ^ Castillo JJ (2016). "Plasma Cell Disorders". Primary Care. 43 (4): 677–691. doi:10.1016/j.pop.2016.07.002. PMID 27866585.
  2. ^ a b c d e Willrich M, Murray DL, Kyle RA (2017). "Laboratory testing for monoclonal gammopathies: Focus on monoclonal gammopathy of undetermined significance and smoldering multiple myeloma". Clinical Biochemistry. doi:10.1016/j.clinbiochem.2017.05.001. PMID 28479151. {{cite journal}}: Vancouver style error: initials in name 1 (help)
  3. ^ a b c d van de Donk NW, Mutis T, Poddighe PJ, Lokhorst HM, Zweegman S (2016). "Diagnosis, risk stratification and management of monoclonal gammopathy of undetermined significance and smoldering multiple myeloma". International Journal of Laboratory Hematology. 38 Suppl 1: 110–22. doi:10.1111/ijlh.12504. PMID 27161311.
  4. ^ a b c d e f Dutta AK, Hewett DR, Fink JL, Grady JP, Zannettino A (2017). "Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma". British Journal of Haematology. doi:10.1111/bjh.14649. PMID 28466550. {{cite journal}}: Vancouver style error: initials in name 5 (help)
  5. ^ a b El-Ayoubi A, Wang JQ, Hein N, Talaulikar D (2017). "Role of plasma cells in Waldenström macroglobulinaemia". Pathology. 49 (4): 337–345. doi:10.1016/j.pathol.2017.02.004. PMID 28483372.
  6. ^ a b Abeykoon JP, Yanamandra U, Kapoor P (2017). "New developments in the management of Waldenström macroglobulinemia". Cancer Management and Research. 9: 73–83. doi:10.2147/CMAR.S94059. PMC 5354523. PMID 28331368.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ a b c d e f Mailankody S, Landgren O (2016). "Monoclonal gammopathy of undetermined significance and Waldenström's macroglobulinemia". Best Practice & Research. Clinical Haematology. 29 (2): 187–193. doi:10.1016/j.beha.2016.08.015. PMID 27825465.
  8. ^ Bianchi G, Anderson KC, Harris NL, Sohani AR (2014). "The heavy chain diseases: clinical and pathologic features". Oncology (Williston Park, N.Y.). 28 (1): 45–53. PMID 24683718.
  9. ^ a b Muchtar E, Kumar SK, Magen H, Gertz MA (2017). "Diagnosis and management of smoldering multiple myeloma: the razor's edge between clonality and cancer". Leukemia & Lymphoma: 1–12. doi:10.1080/10428194.2017.1334124. PMID 28592156.
  10. ^ a b c Rajkumar SV (2016). "Updated Diagnostic Criteria and Staging System for Multiple Myeloma". American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology. Meeting. 35: e418–23. doi:10.14694/EDBK_159009. PMID 27249749.
  11. ^ Lee J, Kulubya E, Pressman BD, Mamelak A, Bannykh S, Zada G, Cooper O (2017). "Sellar and clival plasmacytomas: case series of 5 patients with systematic review of 65 published cases". Pituitary. 20 (3): 381–392. doi:10.1007/s11102-017-0799-5. PMID 28251542.
  12. ^ Thumallapally N, Meshref A, Mousa M, Terjanian T (2017). "Solitary plasmacytoma: population-based analysis of survival trends and effect of various treatment modalities in the USA". BMC Cancer. 17 (1): 13. doi:10.1186/s12885-016-3015-5. PMC 5216567. PMID 28056880.{{cite journal}}: CS1 maint: unflagged free DOI (link)

External links

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