Plasma cell disorder

Plasma cell disorders

Overview

Classification

Monoclonal gammopathy of undetermined significance (MGUS)
Malignant monoclonal gammopathies

Multiple myeloma
Malignant lymphoproliferative disorders
Chronic lymphocytic leukemia
Heavy-chain diseases
Cryoglobulinemia
Primary amyloidosis

Differentiating Plasma Cell Disorder

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Nazia Fuad M.D.,  Anmol Pitliya, M.B.B.S. M.D.[2]

Synonyms and keywords: Plasma cell dyscrasia

## Overview[edit | edit source]

Plasma cell disorders are a diverse type of blood disorders characterized by proliferation of a single clone of plasma cells that produces a homogeneous monoclonal (M) protein. These monoclonal paraprotein are seen in the serum or urine. Monoclonal plasma cells are present in the bone marrow or, rarely, in other tissues. Plasma cell disorders include monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia (LPL/WM), lymphoproliferative disorders, smoldering multiple myeloma (SMM); solitary or extramedullary plasmacytoma, amyloidosis, and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). These disorders have been defined by the International Myeloma Working Group in 2006.

## Classification[edit | edit source]

| Plasma cell disorder|

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Primary amyloidosis|

| Malignant monoclonal gammopathy|

| Chronic lymphocytic leukemia|

| Heavy chain diseases (HCD)|

| Cryoglobulinemia|

| Monoclonal gammopathy of undetermined significance (MGUS)|

| Multiple myeloma|

| Malignant lymphoproliferative disorders|

| γHCD|

| αHCD|

| μHCD|

| Benign
(IgG, IgA, IgD, IgM, and,
rarely, free light chains)|

| Associated neoplasms
or other diseases not known to
produce monoclonal proteins|

| Biclonal and triclonal
gammopathies|

| Idiopathic
(Bence Jones
proteinuria)|

| Waldenstrom macroglobulinemia|

| Malignant lymphoma|

Symptomatic multiple myeloma|

| Smoldering multiple myeloma|

| Plasma-cell leukemia|

| Non-secretory myeloma|

| IgD myeloma|

| Osteosclerotic myeloma|

| Solitary plasmacytoma of bone|

| Extramedullary plasmacytoma|

##  Differential Diagnosis[edit | edit source]

Disease  | IgM  | IgG  | IgA  | IgE  | IgD  | Monoclonal Ig level  | SFLC  | Bone marrow plasma cells  | Other criteria

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IgM MGUS | \+  | −  | −  | −  | −  | < 3gm/dl  | N/A  | <10%  |

* No end-organ damage

Non igM MGUS | \+  | −  | \+  | −  | −  | < 3gm/dl  | N/A  | <10%  |

* No end-organ damage

Smoldering MM  | −  | \+  | \+  | −  | −  | > 3gm/dl  | N/A  | 10-60%  |

* No myeloma-defining event
* No CRAB features

Light chain MGUS | −  | −  | −  | −  | −  | <500 mg/24 hrs (urine)  | Free kappa or lambda light chain
Abnormal ratio (<0.26 or >1.65)
Increase in involved light chain concentration  | <10%  |

* No end-organ damage

Active symptomatic Multiple myeloma | −  | \+  | \+  | \+  | \+  | >3gm/dl  | >100  | >60%  |

* ≥1 myeloma-defining event
* CRAB features

Waldenstrom macroglobulinemia | \+  | −  | −  | −  | −  | Variable  | N/A  | >10%  |

* Evidence of organ/tissue damage
* Anemia
* Hepatosplenomegaly

Solitary Plasmacytoma  | \+  | −  | −  | −  | −  | <3mg/dl  | Abnormal in 47% cases  | Normal  |

* Solitory bone lesion due to plasma cell tumor
* Preserved levels of uninvolved immunoglobulins
* No anemia, hypercalcemia or renal disease

Primary amyloidosis | −  | −  | −  | −  | −  | <3md/dl  | Light chains of immunoglobulines | <10%  |

* No bone lesions
* Nephrotic syndrome
* Restrictive cardiomyopathy
* Peripheral neuropathy
* Hepatomegaly with elevated liver enzymes
* Macroglossia
* Purpura and an unexplained bleeding diathesis

* Myeloma defining events: >60% clonal plasma cells on B.M exam; serum involved: uninvolved FLC ratio >100; >1 focal lesion on MRI >5mm
* CRAB features: elevated calcium >11mg/dl, renal insufficiency, anemia Hb <10 g/dL , bone disease ≥1 lytic lesions on skeletal radiography, CT, or PET-CT , SFLC: serum free light chains, kappa and lambda immunoglobulin light chains.
* The normal κ:λ ratio is 0.26 to 1.65 (17,18). A κ:λ ratio of <0.26 strongly suggests the presence of a of plasma cells that are producing clonal λ free light chains. Ratio >1.65 suggests production of clonal κ free light chains.

## Monoclonal gammopathies of undetermined significance (MGUS)[edit | edit source]

* Monoclonal gammopathy of undetermined significance is a condition in which a low or non-quantifiable level of a monoclonal paraprotein is detected in the blood by means of protein electrophoresis.[1][2][3]
* In addition, some patients develop a polyneuropathy or other problems related to the secreted antibody.
* MGUS is a premalignant condition and is distinct from multiple myeloma.
* Pathologically, the lesion in Monoclonal gammopathy of undetermined significance is in fact very similar to that in multiple myeloma.

For more information about monoclonal gammopathies of undetermined significance click here.

## Malignant monoclonal gammopathies[edit | edit source]

### Multiple myeloma[edit | edit source]

#### Symptomatic multiple myeloma[edit | edit source]

* People with multiple myeloma with symptoms are categorized to have active multiple myeloma and will exhibit any of the following features:[4]
* M protein in blood or urine
* Bone marrow plasma cells constitute more than 10% of the blood cells
* Presence of solitary plasmacytoma in bone
* ≥ 1 myeloma-defining event
* CRAB features ( explained above)
* Osteolytic lesions on bone x-ray

* Patients with active multiple myeloma usually require treatment to prevent progression of disease which can lead to death.

#### Smoldering multiple myeloma[edit | edit source]

* It is asymptomatic type of multiple myeloma.[5]
* Shows presence of M-spike that quantitates > 3 g/dl on protein electrophoresis.

* Presence of bone marrow plasma cell burden of > 10% but < 60%.

* Absence of end-organ damage such as anemia, hypercalcemia, renal dysfunction, or osseous lesions.

* Patients with smoldering (asymptomatic) multiple myeloma are managed by observation and undergoing follow up tests every 3 to 6 months.
* There is high risk of developing active multiple myeloma.

#### Plasma-cell leukemia[edit | edit source]

* Characterized by large number of plasma cells circulating in the blood.[6]
* Rare condition, can develop in to most aggressive form of multiple myeloma.
* Can occur as a secondary type in a patient with multiple myeloma.
* Treatment options for plasma cell leukemia is chemotherapy or stem cell transplant.

#### Non-secretory myeloma[edit | edit source]

* Type of multiple myeloma with less amount of M proteins secretion in blood or urine.[6]
* M protein is not detected by serum protein electrophoresis.
* Bone marrow exibit myeloma cells.
* Osteolytic bone lesions are seen on X-ray.

#### IgD myeloma[edit | edit source]

* IgD type constitues 2% of multiple myeloma.[6]
* IgD multiple myeloma has similar signs and symptoms as other types of multiple myeloma.

* IgD myeloma mostly affect people of younger age.

#### Osteosclerotic myeloma[edit | edit source]

* It is a rare disorder affecting multiple systems of the body.[6]

* It is called POEMS syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes.
* Treatment option for osteoclastic myeloma include:
* Chemotherapy
* Radiation therapy
* Stem cell transplant

#### Solitary plasmacytoma of bone[edit | edit source]

* Plasmacytoma is collection of abnormal plasma cells forming a single tumor.[7]
* Solitary plasmacytoma is occurrence of single bone tumor made up of myeloma cells.
* X-ray shows an osteolytic lesion at the site of the tumor.
* Bone marrow plasma population remains less than 10%.
* One third of patients with solitary plasmacytoma will develop multiple myeloma.

#### Extramedullary plasmacytoma[edit | edit source]

* It is developed outside the bone marrow in soft tissues of the body[6]
* Most commonly seen in throat, paranasal sinuses, nasal cavity, larynx, GI tract, breast, and brain.
* Diagnosis is confirmed by biopsy of the tumor.
* X-rays and bone marrow biopsy is normal.
* Treatment is done with either radiation therapy or surgery.

For more information about multiple myeloma, click here.

### Malignant lymphoproliferative disorders[edit | edit source]

#### Waldenstrom macroglobulinemia[edit | edit source]

* Waldenstrom macroglobulinemia is a cancer involving lymphocytes.[8]
* The main attributing antibody is IgM.
* It is a type of lymphoproliferative disease.
* It shares clinical characteristics with the indolent non-Hodgkin lymphomas.
* Waldenstrom macroglobulinemia represents 1% of all hematological cancers.
* Common causes of Waldenström's macroglobulinemia include genetic, environmental, and autoimmune factors.
* Common risk factors in the development of Waldenström's macroglobulinemia are monoclonal gammopathies of undetermined significance.

For more information about Waldenström's macroglobulinemia, click here.

#### Malignant lymphoma[edit | edit source]

* Type of cancer that originates in lymphocytes.[9]
* Also called hematological neoplasms.
* Primary types include Hodgkin lymphoma and non-Hodgkin lymphoma.

For more information about malignant lymphoma, click here.

### Chronic lymphocytic leukemia[edit | edit source]

* Chronic lymphocytic leukemia arises from pre-follicular center B cells, normally involved in immunoglobulins production.[10]
* Development of chronic lymphocytic leukemia is the result of multiple genetic mutations that promote both malignant leukemic proliferation and apoptotic resistance of mature B cells.
* Chronic lymphocytic leukemia must be differentiated from hairy cell leukaemia, prolymphocytic leukaemia, follicular lymphoma, and mantle cell lymphoma.
* Prognosis is generally good, and the 5-year survival rate of patients with chronic lymphocytic leukemia is approximately 81.7%.
* The mainstay of therapy for symptomatic chronic lymphocytic leukemia patients is immunochemotherapy.

For more information about chronic lymphocytic leukemia, click here

## Heavy-chain diseases (HCD)[edit | edit source]

* Heavy chain diseases are plasma cell neoplasia featuring overproduction of immunoglobulin heavy chains.[11]

### γHCD[edit | edit source]

* Also known as gamma chain or IgG heavy chain disease.
* Primarily seen in elderly men but can occur in children.
* High levels of IgG with reduction of normal immunoglobulin level.
* Lymphadenopathy, hepatosplenomegaly, and recurrent infections are common features.
* Vincristine, corticosteroids and radiation therapy may produce remission.

### αHCD[edit | edit source]

* Also known as alpha chain or IgA heavy chain.
* Appears between age 10-30 as an immune response to a microorganism.
* Patients present with diffuse abdominal lymphoma and malabsorption.
* Course is variable, some patients die in 1-2 yrs, others go in to remission lasting for many years.
* Serum protein electrophoresis detect increased α & β fraction.
* Treatment is corticosteroids, cytotoxic drugs and broadspectrum antibiotics

### μHCD[edit | edit source]

* Also known as mu chain or IGM heavy chain disease.
* Mainly affects individuals > 50 yrs.
* Spleen, liver and abdominal lymph nodes involvement is more common than peripheral lymphadenopathy.
* Serum protein electrophoresis exibit hypogammaglobulinemia.
* Vacuolated plasma cells are pathognomic on bone marrow exam.
* Treatment consists of alkylating agents and corticosteroids.

## Cryoglobulinemia[edit | edit source]

* Cryoglobulinemia is the presence of high amount of heavy globulins (e.g. IgM) in the bloodstream which thicken on exposure to cold.[12][13][14][15]
* Cryoglobulins are circulating immunoglobulins or proteins that become insoluble at less than 4 degrees celsius.
* Cryoglobulinemia can lead to a medium-sized vessel vasculitis due to vascular deposition of circulating immune complexes.
* This leads to the triad of palpable purpura, arthralgias and peripheral neuropathy.
* Common causes of cryoglobulinemia are primarily hematologic, oncologic, and rheumatic

For more information on cryoglobulinemia, click here.

## Primary amyloidosis[edit | edit source]

* The "AL" refers to amyloid light chain.[16][17]
* AL amyloidosis is the most common form of systemic amyloidosis in the US.
* Occurs in 5 to 15% of people with multiple myeloma.
* Treatment can involve application of chemotherapy similar to that used in multiple myeloma

For more information on primary amyloidosis, click here.

## References[edit | edit source]

1. ↑ Jego G, Bataille R, Geffroy-Luseau A, Descamps G, Pellat-Deceunynck C (June 2006). "Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors". Leukemia. 20 (6): 1130–7. doi:10.1038/sj.leu.2404226. PMID 16628189.
2. ↑ Dinarello CA (February 2009). "Targeting the pathogenic role of interleukin 1{beta} in the progression of smoldering/indolent myeloma to active disease". Mayo Clin. Proc. 84 (2): 105–7. doi:10.4065/84.2.105. PMC 2664579. PMID 19181642.
3. ↑ Merlini G, Palladini G (2012). "Differential diagnosis of monoclonal gammopathy of undetermined significance". Hematology Am Soc Hematol Educ Program. 2012: 595–603. doi:10.1182/asheducation-2012.1.595. PMID 23233640.
4. ↑ Sergentanis, Theodoros N.; Zagouri, Flora; Tsilimidos, Gerasimos; Tsagianni, Anastasia; Tseliou, Melina; Dimopoulos, Meletios A.; Psaltopoulou, Theodora (2015). "Risk Factors for Multiple Myeloma: A Systematic Review of Meta-Analyses". Clinical Lymphoma Myeloma and Leukemia. 15 (10): 563–577.e3. doi:10.1016/j.clml.2015.06.003. ISSN 2152-2650.
5. ↑ Rajkumar SV (July 2016). "Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management". Am. J. Hematol. 91 (7): 719–34. doi:10.1002/ajh.24402. PMC 5291298. PMID 27291302.
6. ↑ 6.0 6.1 6.2 6.3 6.4 Rajkumar, S. Vincent (2016). "Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management". American Journal of Hematology. 91 (7): 719–734. doi:10.1002/ajh.24402. ISSN 0361-8609.
7. ↑ Caers, J.; Paiva, B.; Zamagni, E.; Leleu, X.; Bladé, J.; Kristinsson, S. Y.; Touzeau, C.; Abildgaard, N.; Terpos, E.; Heusschen, R.; Ocio, E.; Delforge, M.; Sezer, O.; Beksac, M.; Ludwig, H.; Merlini, G.; Moreau, P.; Zweegman, S.; Engelhardt, M.; Rosiñol, L. (2018). "Diagnosis, treatment, and response assessment in solitary plasmacytoma: updated recommendations from a European Expert Panel". Journal of Hematology & Oncology. 11 (1). doi:10.1186/s13045-017-0549-1. ISSN 1756-8722.
8. ↑ Braggio E, Philipsborn C, Novak A, Hodge L, Ansell S, Fonseca R (September 2012). "Molecular pathogenesis of Waldenstrom's macroglobulinemia". Haematologica. 97 (9): 1281–90. doi:10.3324/haematol.2012.068478. PMC 3436227. PMID 22773606.
9. ↑ Pathology and Genetics of Haemo (World Health Organization Classification of Tumours S.). Oxford Univ Pr. ISBN 92-832-2411-6.
10. ↑ Hallek, Michael (2015). "Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment". American Journal of Hematology. 90 (5): 446–460. doi:10.1002/ajh.23979. ISSN 0361-8609.
11. ↑ Munshi, Nikhil C.; Cabot, Richard C.; Harris, Nancy Lee; Shepard, Jo-Anne O.; Rosenberg, Eric S.; Cort, Alice M.; Ebeling, Sally H.; Peters, Christine C.; Digumarthy, Subba; Rahemtullah, Aliyah (2008). "Case 13-2008". New England Journal of Medicine. 358 (17): 1838–1848. doi:10.1056/NEJMcpc0800959. ISSN 0028-4793.
12. ↑ Scotto G, Cibelli DC, Saracino A, Prato R, Palumbo E, Fazio V; et al. (2006). "Cryoglobulinemia in subjects with HCV infection alone, HIV infection and HCV/HIV coinfection". J Infect. 52 (4): 294–9. doi:10.1016/j.jinf.2005.05.025. PMID 16026843.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
13. ↑ Suszek D, Majdan M (2018). "[Cryoglobulins and cryoglobulinemic vasculitis]". Wiad Lek. 71 (1 pt 1): 59–63. PMID 29558353.
14. ↑ Blank N, Lorenz HM (2016). "[Cryoglobulinemic vasculitis]". Z Rheumatol. 75 (3): 303–15. doi:10.1007/s00393-016-0076-4. PMID 27034078.
15. ↑ Ramos-Casals M, Trejo O, García-Carrasco M, Cervera R, Font J (2000). "Mixed cryoglobulinemia: new concepts". Lupus. 9 (2): 83–91. doi:10.1191/096120300678828127. PMID 10787003.CS1 maint: Multiple names: authors list (link)
16. ↑ Gertz MA (2004). "The classification and typing of amyloid deposits". Am. J. Clin. Pathol. 121 (6): 787–9. doi:10.1309/TR4L-GLVR-JKAM-V5QT. PMID 15198347. Unknown parameter `|month=` ignored (help)
17. ↑ "Amyloidosis Causes, Diagnosis, Symptoms, and Treatment on MedicineNet.com".

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