Type 2 Cryoglobulinemia – When Polytypic Staining Can Mean Monoclonal Renal Disease
A variety of renal diseases have been described in association with monoclonal gammopathy. Most of these diseases result from the deposition of a monoclonal immunoglobulin (M-Ig) in the glomerular, tubulo-interstitial, and/or vascular compartments. The association between the renal disease and the circulating monoclonal immunoglobulin is then easily established by identifying the deposited monotypic Ig (as an entire Ig or as its light or heavy chain component) by immunofluorescence studies. In rare cases, M-Ig-associated renal disease manifests as glomerular deposits with a polytypic appearance by immunofluorescence studies, posing a real challenge for pathologists and clinicians. This situation is encountered in M-Ig-associated Type 2 cryoglobulinemia.
Cryoglobulinamias are classified into three types.
- Type 1 cryoglobulinemia is composed of a single M-Ig and is almost always associated with an underlying lymphoproliferative disorder.
- Type 2 cryoglobulinemia (T2Cryo) is composed of immunocomplexes formed of a monoclonal IgM associated to polyclonal IgG. T2Cryo is associated with viral infections (mostly hepatitis C), autoimmune diseases, and monoclonal gammopathy.
- Type 3 cryoglobulinemia is composed of polyclonal Ig (usually IgM and IgG), and is associated with autoimmune conditions or infectious diseases.
In the context of monoclonal gammopathy, T2Cryo is largely associated with IgM-secreting B-cell lymphoproliferative disorders such as Waldenström macroglobulinemia. Other IgM-secreting haematological conditions associated with T2Cryo include MGRS, monoclonal B-cell lymphocytosis, and non-Hodgkin B-cell lymphomas. In T2Cryo, circulating monoclonal IgM complexes with polyclonal IgG and precipitate in the glomeruli results in the classic membranoproliferative glomerulonephritis pattern (Figure 1) with intra-luminal PAS positive pseudo-thrombi (Figure 2).
By immunofluorescence, staining for IgM, IgG with both kappa and lambda is present (Figure 3), reflecting the composition of the cryoglobulins and resulting in a polytypic appearance. However, staining for the monoclonal component is usually more intense than the polyclonal component.This highlights the importance of meticulous and cautious interpretation of deposits with a polytypic appearance when a histological pattern of cryoglobulinemia is present. A correlation with the detection and typing of cryoglobulins in the serum by electrophoresis-immunofixation is helpful for definitive typing of cryoglobulinemia. Moreover, the presence of a T2Cryo should prompt clinical investigation for monoclonal gammopathy and underlying lymphoproliferative disorder, especially in patients without evidence of hepatitis C infection.
– Post prepared by Virginie Royal, AJKDBlog Contributor.
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