Lymphoma lymphoplasmocytaire / disease of Waldenstrom
DEFINITION.
Lymphoma lymphoplasmocytaire's lymphoma non Hodgkin (NHL) rare in mature B cells characterised by the presence of lymphoplasmocytaires cells in the bone marrow. The presence in addition to a monoclonal IgM protein in the serum defines disease of Waldenstrom (MW) [classification who 2016]
The serum IgM is also called macroglobulin (ability to polymerize in pentamerous), explaining that the MW is still called "Waldenstrom Macroglobulinemia"
Rare disease (1-2% of malignant hematologic diseases; impact = 0.5 new cases per 100,000 people per year) that predominates in humans (sex ratio = 2 to 2.5), with a median age of presentation = 63 impact of 3.5 / 100 000 H to 75 years and more).
It seems that in the majority (if not all) cases the MW is preceded by a phase of asymptomatic with peak serum IgM, called MGUS to IgM (Monoclonal Gammopathy of Unknown Significance), with a pace of transformation of 1.5% per year.
1. clinical signs
GENERAL SIGNS:
Weight loss, weakness, fatigue.
SIGNS OF INFILTRATION TUMOUR IN 30-40% OF THE POINTS.
* Lymphadenopathy (20% of cases): often neck-axillary, then inguino-femoral. Painless bilateral, symmetric, closed. Deep lymph will be searched (visualized by CT or scanner)
* Splenomegaly rare and of low volume (found only in 15% of cases); hepatomegaly moderate in 10% of cases
* Visceral locations in 10% of cases (mainly gastrointestinal, rarely bone).
* Signs of spinal cord failure (20% of cases): pallor, fatigue, dyspnea.
SIGNS RELATED TO SERUM IGM.
* Hyperviscosity syndrome. Observed in 20% of patients.
IgM increases plasma viscosity (which goes from 1.5 - 1.8 to 4 cp centipoise in the MW).
Observed:
basically skin-mucosal hemorrhagic syndrome (spontaneous bleeding: epistaxis, gingivorragies); sometimes hematemeses (thrombopathie related to the Ig that surrounds the pads and limits their efficiency);
Retinopathy with Visual disorders: a review of the fundus is necessary before any sign of hyperviscosity. (congestion of the retinal veins, retinal hemorrhages, papilledema);
Neurological syndrome: central (with headache, fatal, confounding syndrome) and/or device (neuropathy). (then do an EMG).
Requires rapid treatment (plasmaphereses).
* Signs related to a cryoglobulinique activity.
15% of the pts have a cryoglobuline, asymptomatic in 2/3 of cases.
Clinical manifestations: weakness, purpura, mucosal bleeding, arthralgias, Acrocyanosis (Raynaud's phenomenon, peripheral vascular occlusions).
The cryoglobuline is of type I or II (see below).
During hepatitis C infection is associated with a B lymphoproliferative response that often results in 10% of cases to NHL, a MW.
* Disease of cold agglutinins.
Cold agglutinins are not the cryoglobulins.
Cold agglutinins represent 30% of the immune hemolytic anemias.
Patients present an Acrocyanosis (Raynaud's phenomenon) or hemolysis after exposure to cold.
The presence of antibodies anti MAG.
The presence of an IgM peak can be associated with a peripheral neuropathy with or without the classic signs of the MW.
MMI has an antibody against a protein of neural activity, primarily the Myelin Associated Glycoprotein or MAG.
2 pathogenesis.
The cell responsible for the MW is a B IgM + or IgM + D + cell arrested after somatic hypermutation in the germinal Center and before terminal differentiation into plasma. There is no switching isotypique: it is probably a cell "memory-like" of the splenic marginal zone or the lymphoid follicle, that has:
acquired a secretory capacity of IgM.
a likely origin for antigenic stimulation chronic, infectious (+ / ditto MALT lymphomas).
acquired a morphology + / lymphoplasmocytaire,.
has kept an expression of the CD20 and the surface IgM.
Tumor cells release the soluble CD27, which activates the spinal cord mast cells, which in turn produce cell activators B as APRIL and CD40L, which stimulate the differentiation of the clone lymphoplasmocytaire.
About 20% of the MW have in their family of individuals showing the quantitative changes of serum proteins (G, A, or M). Hypo gamma found in half of the MW would be a preliminary step to malignancy.
A mutation of the MYD88 gene, which codes for a protein of the trandsuction of the signal of the toll-like receptors like activating NK Kappa B is found in > 90% of the points.
3 biology.
3.1 SEDIMENTATION SPEED
Accelerated, usually > 70-100 mm for the 1st time.
(unless cryoglobuline type I, which can cause the gelling of the blood)
3.2 COMPLETE BLOOD COUNT
* Anemia.
Variable importance: Hb = 6-14 g/dL.
It may be true by medullar insufficiency, or distorted by hemodilution sometimes very important (oncotic important plasma pressure related to the IgM).
Most often: macrocytic normocytic aregenerative.
Sometimes there are hemolysis with test positive direct Coombs (10% of cases), often mixed M + G + it + it, or M type with cold agglutinins.
On the blood smear: phenomenon of rollers = crowding in piles of plates of the g of the fact of the monoclonal IgM.
Remarks.
There are abnormal reactions between reagents of the Automatons of blood picture and monoclonal Ig in great excess, resulting in a falsely high Hb.
It has been described (rare) a falsely anemia, macrocytic, by pseudo - agglutination of because of the excess of IgM: after incubation at 37 ° C and fast reanalysis this pseudo macrocytose disappears;
* Leukocytes.
The number most often normal. There is a moderate Lymphocytosis (> 4 G/L) in 30% of cases. Sometimes neutropenia, most often by distribution anomaly.
* Thrombocytopenia moderate in 40% of cases.
3.3 MYELOGRAM AND BIOPSY MEDULLAR OSTEO (BOM)
Puncture and BOM are essential
Rich marrow. Polymorphic lymphoid infiltration, representing 20 to 60% (or more) of the total cell, with mixture of lymphocytes, lympho-plasma cells, and often a small number of plasma cells.
Macroglobulinemia
The rounded, gray inclusions or dews are often observed (small or large) in the cells lymphoplasmocytaires = Mott cells ("grape cells").
Sometimes there is large and translucent, the bodies of Dutcher intranuclear inclusions.
Frequent presence of mast cells [non-specific, because sometimes observed in: LLC;] Hodgkin M, SMD]. Opposite of the normal mast cells, they express the CD 154 (= CD40 ligand) as in anaphylaxis. The Ly of the MW express the CD40, and the interaction of CD40-CD40L in the MW could encourage tumor lymphoid proliferation (Tournilhac et al, Ann histopathology 2006)
Other lineages quantitatively reduced in number, without morphological peculiarity.
Always look for a potential associated with myelodysplasia (age in favor, preferential association with the low grade lymphoproliferations).
The BOM will specify the nature of the infiltration, often diffuse (discreet Myelofibrosis in 1/2 of the cases).
Remarks:
-sometimes failure of sprawl by hyperviscosity of aspirated product or aspiration (Myelofibrosis).
3.4 IMMUNOPHENOTYPE OF LYMPHOID CELLS
-Lymphoid mature B cells: + CD19, CD20 +, CD22 + (but weak), CD79a +; often IgM + D membrane (normal or increased expression).
-Usually: lack of CD5 and CD23 (difference with cells of LLC), lack of CD10 (difference with centrofolliculaires cells), and of CD138 (difference with plasma cells).
-score of Matutes = < 2.
Remarks:
-Sometimes delicate Phenotyping because several stages of maturation of the lymphoid cells are possible, with mixture of CD45RA (less differentiated) cells and CD45RO (late stages), cells with and without surface Ig.
-Membrane IgM has the same light chain (and possibly the same antibody activity) than serum IgM (intracytoplasmic IgM is present in the more mature cells)
-Membrane RMI presents the same type of light chain than IgM.
-When there are abnormal lymphocytes in the blood, they belong to the same clone as the Medullary cells.
3.5 BIOCHEMICAL EXAMINATIONS
Serum and urinary proteins.
Protidemie: 80 to 120 g/L
Electrophoresis of serum proteins: narrow and symmetrical area gamma or beta monoclonal spike fast. The peak is > 5g / L (5-30 g/L in 60% of cases), sometimes > 100 g/L.
In 50% of cases, there is a drop of IgG and IgA.
Immunoelectrophoresis or immunofixation: IgM, with Kappa chain in 80% of cases.
The weight (nephelometry) dosage of the IgM is often imprecise and the value of the peak measured on the route of the electrophoresis is used in practice.
Proteinuria: present in 50% of cases, moderate, rarely > 1 g / 24 h), corresponding to the monotypic light chain (Bence Jones proteinuria =)
Activity cryoglobulinique in 15% of cases.
Most type I (= monoclonal Ig M), more rarely mixed type II (monoclonal IgM to anti-IgG Polyclonal [anti IgG IgM] activity). The association to the hepatitis C virus is not rare in the latter case.
Remarks:
-the MW without pic IgM (= no excretantes) are much rarer than in the MM
-for an appropriate biochemical study it may be necessary to depolymerize the IgM with reducing agents (2-mercaptoethanol, dithiothreitol).
3.6. OTHER
Beta2 microglobulin: > 3 mg/L in 50% of cases [marker of tumor mass]
Cold agglutinin in 10% of cases.
Almost always M kappa, specificity anti I or anti i, with titles often exceeding 1/1000. In some of the cases, it causes hemolysis cold (dose = haptoglobine, bilirubin, LDH)
Sometimes: abnormalities of hemostasis.
In practice we realize a balance of hemostasis in the MW.
Adhesion and platelet aggregation can be disrupted.
Coagulation inhibitors are sometimes detected (circulating anticoagulants)
The factors I, II, VII, VIII and X are sometimes lowered.
Serology of hepatitis C.
Other laboratory tests:
Positivity for rheumatoid factor (Waaler Rose), related to the presence of cryoglobuline in the majority of cases.
Anti-nuclear antibodies and syphilitic serology may be falsely positive. Exceptionally lower C1 esterase inhibitor.
LDH is increased in the case of hemolytic anemia and in some aggressive forms.
Resting plasma: not carried out in practice. Can reach 2 to 3 times normal values. (isotopic method with GR marked chromium 51).
Measurement of plasma viscosity (centiPoise) is sometimes performed. It may exceed 3 times normal (N = 1,5-1,8 cp) and increases much more quickly than the concentration of IgM.
NB: the hepatic and renal functions must be appreciated in any patient to deal with.
3.7 GANGLIONIC BIOPSY
Diffuse invasion with disappearance of normal architecture: tumor cells are lymphocytes or lympho-plasma (with often mast cells).
The differential diagnosis with autresLNH low grade is not always easy: Lymphoma gastrointestinal MALT that spreads, the splenic marginal zone Lymphoma (30% were IgM > 5 g/L, some of them have an AHAI), LLC with differentiation Lympho-pododermatitis.
3.8 STUDY CYTOGENETIC AND MOLECULAR.
Molecular study of the IgVH sequence: somatic hypermutation without diversity intraclonale (no switch)
Karyotype: diagnostic no interest. The absence of t (11;14) t(14;18) can be used for difficult differential diagnosis.) 20% of cases have a Trisomy 4, and Trisomy 3 / + 3q is absent.
Point mutation of the gene MYD88 L265P in 90% of the MW. This mutation, accessible to the PCR study, is also present in 87% of the IgM MGUS (but absent from sMGUS IgG/A), and approximately 20% of the NHL the splenic marginal zone and the NHL at large not germinal Center B cells. Can be used as a marker of the disease (Jimenez et al. Leukemia 2013)
Mutation of CXCR4 in 30% of the LPL and 20% of MGUS IgM but absent of the IgG/A MGUS.
4.2 (BIOLOGICAL) DIFFERENTIAL DIAGNOSIS: OTHER SITUATIONS WITH PEAK IGM
NHL edge zone: peak IgM (till 30-40 G/L) in 1/3 of cases.
Often splenomegaly notable, rare and discreet in the MW.
Frequent blood Lymphocytosis (sometimes with villeuses cells or monocytoides).
LLC, NHL Burkitt and diffuse large cell: sometimes peak IgM moderate (< 5 g/L).
Cryoglobulinemies, diseases of the cold agglutinins: biological and clinical symptomatology may precede an authentic MW for several years.
Exceptional multiple myelomas in IgM. Correspond to MM that the switch has been altered: the clinical monkeys are those of the MM, and tumor proliferation is made up of plasma cells CD138 +.
Other situations presenting an IgM pic: see corresponding document.
5. Evolution, complications and treatment.
LITTLE AGGRESSIVE SPONTANEOUS EVOLUTION
Close to that of the LLC, with a near 10-year survival expectancy
Treatment is limited to symptomatic patients, knowing that the average time between the diagnosis of a purely biological shape and the appearance of a symptomatic disease is 7 years.
Clinical and biological monitoring is performed 2-3 times per year, to specify the appearance of anaemia (< 11.5 g/dL), the increase of the B2M > 3 mg/L, or the peak increase > 30 g/L (from the electrophoretic trace).
THERE ARE 5 MAJOR PROGNOSTIC FACTORS IN THE INTERNATIONAL STAGING SYSTEM:
-age > 65 years
-Hb = < 11.5 g/dL
-Inserts < 100 G/L - β2 M > 3 mg/L
-Serum IgM > 70 g/L
What defines a prognostic score (see the SFH 2009 repository for the treatment of the MW).
COMPLICATIONS
Emphasis to the neurological disorders; renal failure; infiltration Lymphoma (lung, digestive, skin)
Hematological complications: accentuation of the hemolysis of Cytopenias, effects of cryoglobulinemia, Richter syndrome, appearance of a transformation the secondary to chemotherapy (1-2% of the pts).
Excessive increase of the total plasma volume: risk of Cardiac decompensation.
TREATMENT
-Plasmaphereses: to quickly reduce the monoclonal component in case of hyperviscosity syndrome.
Act without delay.
We decrease the IgM concentration below the symptomatic if the hyperviscosity syndrome is isolated and we're back to a normal rate if there are neurological or other abuses of bodies, or that there is a hemolytic anemia or a cryoglobulinemia.
-Symptomatic treatment of infections as appropriate.
-Monochimiotherapie with a (Chlorambucil) alkylating agent or an analogue of the purines (Fludarabine, 2CDA)
-Combination chemotherapy combining any of the previous drugs and a monoclonal antibody (including an anti-CD20).
-Intensive chemotherapy is available to some patients.
The repository published by the SFH in November 2009 said the therapeutic modalities (see SFH site).
Complete remission is achieved with total disappearance of the pic is rare: most often the remission is partial with improvement of clinical signs and the peak of 50 to 75% reduction. The prognosis is generally good since the average survival after starting treatment is 8 years old.
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