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Plasma Cell Neoplasms: an overview

Written2017-11Elijah Buon, Matthew Ho Zhi Guang, Giada Bianchi
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115. EB, MHZG: these authors contribute equally. elijah_buon@dfci.harvard.edu; matthew_ho@dfci.harvard.edu; giada_bianchi@dfci.harvard.edu

Abstract Plasma Cell Neoplasms are a family of disorders characterized by clonal proliferation of a plasma cell. These include: Multiple Myeloma (MM) and its precursor states MGUS and SMM, solitary osseous or non-osseous plasmacytoma, POEMS syndrome, heavy chain disease, and systemic AL amyloidosis. The hallmark characteristics of plasma cell neoplasms are: (1) histopathologic confirmation of excess clonal plasma cells; and (2) excessive production and secretion of an intact monoclonal protein (M spike) or free light chains (FLC; not in association with heavy chains) in the serum and/or urines. Plasma cell neoplasms can be premalignant (e.g. MGUS) or malignant (e.g. MM).

Keywords Plasma cell neoplasia, multiple myeloma, plasmacytoma

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Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9732/3:
ICD-Morpho 9731/3:
ICD-Morpho 9762/3:
Atlas_Id 1793
 

Clinics and Pathology

Disease Plasma Cell Neoplasia is an umbrella term for diseases resulting from the excessive proliferation of plasma cells. These include: Multiple Myeloma (MM) and its precursor statesmonoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), solitary osseous or non-osseous plasmacytoma, POEMS syndrome, heavy chain disease, andsystemic AL amyloidosis. The hallmark characteristics of plasma cell neoplasms are: (1) histopathologic confirmation of excess clonal plasma cells; and (2) excessive production and secretion of an intact monoclonal protein (M spike) or free light chains (FLC; not in association with heavy chains) in the serum and/or urines. Plasma cell neoplasms can be premalignant (e.g. MGUS) or malignant (e.g. MM).
Phenotype / cell stem origin
MGUS, SMM, MMAntigen-selected, post-germinal center, terminally differentiated plasma cell (Anderson and Carrasco 2011)
PlasmacytomaWell defined, monoclonal proliferation of plasma cells that occurs either (1) inside (solitary bone plasmacytoma) or (2) outside (extramedullary plasmacytoma) the bone (Chang et al, 2014).
Heavy chain disease (HCD)Group of three rare and clinically distinct B-cell neoplasms (alpha, gamma, mu HCD) that result in the excessive production of abnormal immunoglobulin heavy chain incapable of binding light chains (Bianchi et al 2014). Alpha HCD is associated with immunoproliferative small intestinal disease with features resembling MALT lymphoma. Gamma HCD has features resembling Waldenstrom macroglobulinemia (WM) while Mu HCD has features resembling CLL (Bianchi et al 2014).
POEMS syndromeRare paraneoplastic syndrome caused by underlying plasma cell neoplasm. Characterized by polyradiculoneuropathy, the presence of clonal plasma cells, sclerotic bone lesions, elevated vascular endothelial growth factor, and Castleman disease. Other minor features include: organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis (Dispenzieri A, 2014).
Etiology Etiology not known. Possible (unconfirmed and controversial) risk factors include:
  • Environmental factors such as radiation exposure, occupational exposure (agricultural, chemical, metallurgical, rubber plant, pulp, wood, paper), and chemical exposure (formaldehyde, epichlorohydrin, Agent orange, hair dyes, paint sprays, asbestos).
  • Viral infection: Herpesvirus 8 infection noted in some patients with MM, but there are no data to substantiate a causative link;
  • Genetic predisposition: Patients with a siblings or other first-degree relatives who have one of these diseases are more likely to develop it as well.
    MGUS, SMM, MM

    Transformation of normal plasma cells into myeloma cells thought to result from one of two primary genetic events: either (1) hyperdiploidy or (2) aberrant class switch recombination (CSR). Secondary cytogenetic abnormalities result in progression of MGUS to SMM, MM, and plasma cell leukemia (Ho et al, 2017).

    Plasmacytoma

    Similar to MM in that cell of origin is plasma cell; expresses antigens associated with myelomonocytes (CD33), megakaryocytes (GpIIb/IIIa), erythroid cells (glycophorin) (Nikhil Sangle, 2011).

    Heavy chain disease

    Deletions, insertions or point mutations in the constant 1 (CH1) domain of the IgH are acquired during the process of somatic hypermutation. These mutations typically result in: (1) inability to bind and reach a stable quaternary structure with IgL chain; (2) inability to bind to the chaperone heat shock protein 78 (HSP 78), which mediates proteasomal degradation of free IgH (Goossens et al., 1998). As a result, free IgH can be detected in both serum and urine. Pathogenesis is unknown. Autoimmune disease is present in ~25% of patients and typically precedes by many years the onset of gamma HCD (Wahner-Roedler et al., 2003).

    POEMS syndrome

    Etiology unknown. Major feature of POEMS syndrome is the chronic overproduction of pro-inflammatory cytokines (e.g. VEGF; IL6). Thought to be a paraneoplastic syndrome caused by an underlying plasma cell disorder (Zou et al 2015).

  • Epidemiology
    DiseaseMGUSSMMMMPlasmacytomaPOEMS syndromeHeavy-chain disease
    Incidence3.76 per 100,000 persons; Progresses to MM at rate of ~1.4% per year0.9 per 100,000 persons~30,280 new cases/year; 6.6 per 100,000 persons (US)~1,543 new cases/year; 0.3 per 100,000 persons (US) ~700 new cases/year (US)A: Most common; G: Intermediate; M: Least common
    Prevalence> 50y: 3.2%; M: 3.7%; F: 2.9%Unknown118,539 (US)N/AN/AA: >400; G: ~130; M: ~35
    Overall survival5 yr: 78.3%Median OS: 54.8 months (2003-2007); 67.1% (2008-2011)5 yr: 49.6%SBP: 71.9% (5y); EMP: 88.2% (5y)5 yr: 60%A: ~67% (5yr); G: 7.4yr (median); M: ~2yr (median)
    Median age at diagnosis70y (<2% younger than 40y)67y69y55-65y48y (men); 59y (women)?: 20-30y; G: 51-68y; M: 58y
    EthnicityTwice as common in African Americans as in the Caucasian population; low in Asian countriesBlack > Asian/pacific islander> white Twice as common in African Americans as in the Caucasian population; low in Asian countries30% higher incidence rate in African Americans; Also seen in Caucasians and low in Asian countries.No known racial connection.A: Mediterranean, North African, Middle Eastern; G: Worldwide distribution; M: Mostly Caucasian
    GenderM > F M> FM > F (1.6:1)M > F (2-3:1)M > F (2.5:1)A: M > F; G: F > M; M: M > F
    Clinics

    Plasma Cell Neoplasm

    Clinical Features

    MGUS, SMM, MM

    MGUS: Asymptomatic
    SMM: Asymptomatic
    MM: Hypercalcemia, renal failure, anemia, bone disease (CRAB criteria)

    Plasmacytoma

    As space occupying lesions, the symptoms of plasmacytoma vary based on the location of the tumor. Plasmacytomas located in the brain (e.g. solitary craniocerebral plasmacytoma or EMP of the brain) can cause headaches, seizures, and paralysis, while plasmacytomas in the rib may cause non-cardiac chest pain that is pleuritic in nature.

    Generally speaking, a common yet nonspecific clinical symptom of SBP is pain. Motor and sensory deficits can also occur, secondary to nerve impingement from compression fractures (Guo et al, 2013). Complications of SBP include pathological fractures due to lytic bone disease.

    EMP, on the other hand, usually manifests itself in the upper respiratory tract and oral cavity, symptoms often include epistaxis, sore throat, rhinorrhea, and hemoptysis (Chang et al, 2014)(Galieni et al, 2000)

    HCD

    A: Digestive, lymphomatous, or respiratory forms
    G: Disseminated (generalized lymphadenopathy); localized (either isolated BM involvement or localized extra-nodal disease); minority with only autoimmune disease
    M: Splenomegaly, hepatomegaly, lymphadenopathy

    POEMS syndrome

    Polyneuropathy:

    • Symmetric distal weakness and paraesthesia
    • Impotence
    • Raynaud's phenomenon
    • Painful Diarrhea

    Organomegaly:

    • Hepatomegaly
    • Splenomegaly,
    • Lymphadenopathy, castleman disease

    Endocrinopathy:

    • Hypothyroidism##
    • Gonadal axis abnormality (e.g. amenorrhea)
    • Adrenal axis abnormality
    • Gynecomastia/ galactorrhea
    • Diabetes mellitus
    • Peripheral edema
    • Hyperhidrosis

    M-protein (sign)

    Skin changes:

    • Hyperpigmentation
    • Acrocyanosis and plethora
    • Hemangioma/ telangiectasia
    • Hypertrichosis
    • Thickening

    International Myeloma Working Group (IMWG) diagnostic criteria (Rajkumar, et al 2014):
    CLINICS
    Plasma Cell Disorder DefinitionProgression ratePrimary progression events
    Multiple myeloma
    (MM)

    (1) Clonal bone marrow plasma cells ? 10%
    OR
    (2) Biopsy proven bony or extramedullary plasmacytoma
    AND
    Any one or more of the following myeloma-defining events:
    End organ damage (CRAB)
    ï Hypercalcemia: Ca > 2.75 mmol/L (>11mg/dL)
    ï Renal insufficiency: Cr > 177 mol/L (>2mg/dL)
    ï Anemia: Hb < 100g/L or >20g/L below normal
    ï Bone lesions: One or more osteolytic lesion on skeletal radiography, CT, or PET/CT (if BM <10% clonal plasma cells, more than one bone lesion required to distinguish from solitary plasmacytoma with minimal marrow involvement)
    OR
    Biomarkers of malignancy
    ï ?60% clonal plasma cells on bone marrow examination
    ï Serum involved/uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100mg/L
    ï More than one focal lesion on MRI ?5mm in size
    NA

    At the terminal stage of disease, evolution to secondary plasma cell leukemia is common
    Smoldering multiple myeloma
    (SMM)

    Both criteria must be met:
    (1) Serum monoclonal protein (IgG or IgA) ?30g/L or urinary monoclonal protein ?500mg per 24h and/or clonal bone marrow plasma cells 10-60%
    AND
    (2) Absence of myeloma defining events or amyloidosis
    10%/year in the first 5 yearsMM
    Non-IgM monoclonal gammopathy of undetermined significance
    (non-IgM MGUS)

    All criteria must be met:
    (1) Serum monoclonal protein (non-IgM type) <30 g/L
    AND
    (2) Clonal bone marrow plasma cells <10%
    AND
    (3) Absence of end-organ damage such as hypercalcaemia, renal insu?ciency, anaemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
    1%/year

    MM, solitary plasmacytoma, immunoglobulin-related amyloidosis (AL, AHL, AH)
    IgM monoclonal gammopathy of undetermined significance
    (IgM MGUS)

    All criteria must be met:
    (1) Serum IgM monoclonal protein <30 g/L
    AND
    (2) Bone marrow lymphoplasmacytic in?ltration <10%
    AND
    (3) No evidence of anaemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly, or other end-organ damage that can be attributed to the underlying lymphoproliferative disorder
    1.5% per year

    Waldenstrom macroglobulinemia (WM), IgM MM, immunoglobulin-related amyloidosis (AL, AHL, AH)
    Light-chain monoclonal gammopathy of undetermined significance
    (Light chain MGUS)

    All criteria must be met:
    (1) Abnormal FLC ratio (<026 or >165) Increased level of the appropriate involved light chain (increased ? FLC in patients with ratio >165 and increased ? FLC in patients with ratio <026) and  no immunoglobulin heavy chain expression on immuno?xation
    AND
    (2) Clonal bone marrow plasma cells <10%
    AND
    (3) Urinary monoclonal protein <500 mg/24 h
    AND
    (4) Absence of end-organ damage such as hypercalcaemia, renal insu?ciency, anaemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
    0.3% per year

    Light chain MM, immunoglobulin light-chain amyloidosis
    Solitary plasmacytoma

    All criteria must be met:
    (1) Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
    AND
    (2) Normal bone marrow with no evidence of clonal plasma cells
    AND
    (3) Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
    AND
    (4) Absence of end-organ damage such as hypercalcaemia, renal insu?ciency, anaemia, or bone lesions (CRAB) that can be attributed to a lymphoplasma cell proliferative disorder

    About 10% within 3 yearsMM
    Solitary plasmacytoma with minimal marrow involvement

    All criteria must be met:
    (1) Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
    AND
    (2) Clonal bone marrow plasma cells <10%
    AND
    (3)Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
    AND
    (4) Absence of end-organ damage such as hypercalcaemia, renal insu?ciency, anaemia, or bone lesions (CRAB) that can be attributed to a lymphoplasma cell proliferative disorder

    60% (bone) or 20% (soft tissue) within 3 yearsMM
    POEMS syndrome

    Both #1 and #2 must be present plus
    (1) Polyneuropathy
    AND
    (2) Monoclonal plasma cell proliferative disorder (almost always ?)
    AND
    (3) Any one of the following three other major criteria:
    ï Sclerotic bone lesions
    ï Castleman's disease
    ï Elevated levels of VEGFA
    AND
    (4)Any one of the following six minor criteria:
    ï Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
    ï Extravascular volume overload (oedema, pleural e?usion, or ascites)
    ï Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)
    ï Skin changes (hyperpigmentation, hypertrichosis, glomeruloid haemangiomata, plethora, acrocyanosis, ?ushing, white nails)
    ï Papilloedema
    ï Thrombocytosis/polycythaemia
    NANA
    Systemic AL amyloidosis

    All criteria must be met:
    (1) Presence of an amyloid-related organ damage (eg, renal, liver, heart, gastrointestinal tract, soft tissue, lung or peripheral nerve involvement)
    AND
    (2) Positive amyloid staining by Congo red in any tissue (eg, fat aspirate, bone marrow, or organ biopsy)
    AND
    (3) Evidence that amyloid is light-chain-related established by direct examination of the amyloid using mass spectrometry-based proteomic analysis, or immunoelectronmicroscopy, and
    AND
    (4) Evidence of a monoclonal plasma cell proliferative disorder (serum or urine monoclonal protein, abnormal free light-chain ratio, or clonal plasma cells in the bone marrow)
    NA

    Some patients might develop MM
     
    Multiple myeloma: Left: Normal bone marrow; Right: Multiple Myeloma bone marrow (note: ? 10% clonal bone marrow plasma cells). Image taken from: http://www.keatslab.org/multiple-myeloma-info
     
    Plasmacytoma: Left: X-ray showing solitary bone plasmacytoma located in right shoulder complicated by pathological fracture of the head of humerus. Right: PET/CT showing extramedullary plasmacytoma located in the anterior clivus
     
    Waldenstrom macroglobulinemia: Bone marrow aspirate showing increased lymphoplasmacytoid lymphocytes. Image taken from: https://imagebank.hematology.org/image/1178/waldenstroumlmrsquos-macroglobulinemia-bone-marrow-aspirate--1?type=upload
     
    Heavy chain disease: In HCD, non-contiguous deletions in CH1 prevent binding of heavy chain to light chain and degradation in proteasome, and free heavy chains are secreted. Variably sized deletions also occur in the heavy chain diversity region, heavy chain joining region, and heavy chain variable region (Bianchi et al 2014). Image taken from: http://www.cancernetwork.com/oncology-journal/heavy-chain-diseases-clinical-and-pathologic-features
     
    Treatment Types of Treatment Available (in Italic: FDA approved in MM; otherwise: clinical development):
    Note: Specific treatment for each disease can be found in the various chapters in the Atlas
    1. Immunotherapy
      1. Immunomodulation
        1. Pembrolizumab
        2. Pidilizumab
        3. Nivolumab
      2. T cell-based therapies
        1. PVX-410
        2. MM-DC vaccine
        3. Anti-BCMA CAR-T cells
      3. Monoclonal antibodies
        1. Daratumumab
        2. Elotuzumab
        3. SAR
        4. BT062
        5. GSK2857916
    2. Chemotherapy
      1. Conventional chemotherapy (alkylating agents)
        1. Melphalan
        2. Carmustine
        3. Cyclophosphamide
        4. Doxorubicin
      2. Novel agents
        1. Proteasome inhibitors
          1. Bortezomib
          2. Carfilzomib
          3. Ixazomib
          4. Marizomib
          5. Oprozomib
        2. IMiDs
          1. Thalidomide
          2. Lenalidomide
          3. Pomalidomide
        3. Histone deacetylase inhibitors
          1. Panobinostat</li>
          2. Vorinostat
          3. Ricolinostat
          4. ACY-241
        4. Tyrosine kinase inhibitors
          1. Ibrutinib 
      3. Supportive agents
        1. Zoledronic acid
    3. Bone marrow transplantation
      1. Autologous stem cell transplantation
      2. Allogeneic stem cell transplantation
      3. Stem cell Mobilization
        1. Plerixafor
        2. Cyclophosphamide
    4. Radiation therapy
      1. Indications
        1. Pre-transplantation
        2. Palliation of symptoms (i.e.: pain)
        3. Plasmacytoma
    5. Surgery
      1. Indications
        1. Plasmacytoma
        2. Pathological fractures
        3. Compression fractures
    Prognosis The prognosis varies substantially depending on:
  • Stage of disease
  • Proliferation rates
  • LDH levels
  • Treatment availability: Conventional therapy / Targeted Therapy / High-dose chemotherapy
  • M protein concentration
  • Age
  • Treatment response
  • Plasmablastic histology
    Poor prognosticators include:
  • High LDH levels
  • Hypercalcemia
  • Renal impairment
  • Large tumor burden
  • Bence-Jones proteinuria
  • Low hemoglobin value
  • Genes involved and Proteins

    Gene Name

    Bibliography

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    Oncology (Williston Park) 2014 Jan;28(1):45-53
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    Extramedullary plasmacytoma of the nasopharynx: A case report and review of the literature
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    Oncol Lett 2014 Feb;7(2):458-460
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    PMID 22931316
     
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    Medicine (Baltimore) 2003 Jul;82(4):236-50
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    T-cell lymphoma with POEMS syndrome
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    Citation

    This paper should be referenced as such :
    Elijah Buon, Matthew Ho Zhi Guang, Giada Bianchi
    Plasma Cell Neoplasms: an overview
    Atlas Genet Cytogenet Oncol Haematol. 2018;22(12):497-506.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Anomalies/PlasmaCellNeoplasmsID1793.html


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