A Puzzling Case of Hyperviscosity Syndrome

An 81-year-old female admitted to the hospital for coronary angiography had an accompanying finding of viscous blood. Her past medical history was significant for moderate coronary artery disease, hyperlipidemia, gastroesophageal reflux disease, hypothyroidism, and a remote history of Lyme disease. She was being treated with bisoprolol, aspirin, pantoprazole, eltroxin, furosemide, and fluvastatin. She presented with symptoms of hyperviscosity syndrome including exertional dyspnea, syncope, tinnitus, vertigo, blurring vision, tingling in the hands and feet, and cold-induced central cyanosis. To investigate her hyperviscosity, initial laboratory investigations indicated a monoclonal protein concentration of 20g/L on serum protein electrophoresis (SPE),4 which was identified as a monoclonal IgM κ on immunofixation electrophoresis. This was correlated with increased total IgM (35.71 g/L; reference range, 0.4–2.3 g/L), increased free κ light chain (86.9 mg/L; reference range, 3.3–19.4 mg/L) with increased serum free light–chain ratio of 8.12 (reference range, 0.3–1.6), presence of urinary Bence Jones κ light chain (0.1 g/CP), and increased β2-microglobulin (4.3 mg/L; reference range, 0.6–2.3 mg/L). Although her hemoglobin was initially within the reference range at 12.1g/dL (121 g/L; reference range, 120–160 g/L), she later developed a mild normocytic anemia of 10.0 g/dL (100.1 g/L). There was no evidence for polycythemia vera, thrombocytosis, and leukemia as potential causes of hyperviscosity, which was supported by an otherwise unremarkable complete blood count (CBC). The increased monoclonal IgM inferred the possibility of a plasma cell or lymphoproliferative disorder, with the primary differential diagnoses of Waldenström macroglobulinemia (WM; lymphoplasmacytic lymphoma), marginal zone lymphoma, or less likely multiple myeloma. The patient did not display hypercalcemia or bony disease associated with multiple myeloma, although evidence of renal insufficiency (creatinine clearance of 29 mL/min/1.73 m2) without significant proteinuria was observed. WM and multiple myeloma are associated with ≥10% lymphoplasmacytic or plasma cell infiltration in the bone marrow, respectively (1, 2). However, the patient's bone marrow showed only minimal disease as indicated by bone marrow biopsy and flow cytometry of the aspirate. The bone marrow biopsy showed 3% infiltration with monoclonal B cells and 4% infiltration with plasma cells. The aspirate, as demonstrated by flow cytometry, showed only 1.2% of monoclonal B cells and no plasma cells. The immunophenotype of the cells were as follows: CD19+, CD20+, CD5−, CD10−, CD23−, CD38dim+, sIGK+, sIG− for the B cells and CD20−, cIGK+, cIGL−, cIGM+, cIGG−, cIGA− for the plasma cells. In view of the results showing both a small B cell and a plasma cell population, these results were consistent with either WM or marginal zone lymphoma. There was no evidence of an extramedullary disease, making the diagnosis of marginal zone lymphoma unlikely and resulting in a working diagnosis of WM. However, the MYD88 L265P mutation could not be demonstrated, which is identified in over 90% of patients with WM (2). One potential explanation could be the lack of sufficient cells in the bone aspirate, as only 1.2% was determined by flow cytometry, and the detection limit of the test as established in our laboratory is 2.5%. Alternatively, MYD88 mutation may in fact be absent in this patient and we did not test for the CXCR4 mutation also commonly found in WM (3). The diagnostic search continued with assessing the presence of rheumatoid factor (RF) and cryoglobulins, because IgM-RF could present with hyperviscosity in mixed cryoglobulinemia. RF concentrations were >20000 IU/mL (reference range, <14 IU/mL) as assessed on 2 different instrument platforms (The Binding Site's Optilite and Roche Cobas), and cryoglobulins were negative on 2 separate samples. An IgM-RF complex was confirmed by size-exclusion chromatography displaying increased RF in the IgM fraction, and precipitation using polyethylene glycol reduced both IgM and RF concentrations simultaneously. Moreover, chronic infections and rheumatological diseases associated with increased RF were ruled out by unremarkable antinuclear antibodies (ANA) and an array of infectious disease testing that included HIV, hepatitis C, hepatitis B, Epstein–Barr, syphilis, mononucleosis, and Lyme disease. The patient underwent 3 rounds of therapeutic plasma exchange (TPE), which normalized blood viscosity and reduced IgM and RF concentrations 10-fold, although RF remained significantly increased above 2400 IU/mL. TPE resulted in minimal symptomatic improvements and both viscosity and IgM concentrations continued to increase post-TPE treatment. The patient went on to receive treatment with Rituximab with a working diagnosis of an atypical presentation of WM. The differential diagnosis of hyperviscosity syndrome encompasses disorders associated with increased paraproteins, immune complexes, or cellular components. Monoclonal gammopathy of undetermined significance (MGUS) is the most common disease associated with increased IgM; however, diagnostic criteria exclude the presence of hyperviscosity. Similarly, IgM myeloma presents with increased monoclonal IgM; however, it also rarely presents with hyperviscosity. As defined by the International Myeloma Working Group, multiple myeloma must include clonal bone marrow plasma cells ≥10% or biopsy-proven bony or soft tissue plasmacytoma (1). In the current case, the patient did not display significant bone marrow plasma cell infiltration, did not have an extramedullary plasmacytoma, and did not fit the secondary diagnostic criteria for evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia, and bone lytic lesions) (1). In addition, the presence of a monoclonal B cell population with similar immunoglobulin light chain restriction and surface expression of IgM suggests that it is clonally related to the plasma cells in the marrow. The presence of both populations is inconsistent with a diagnosis of a plasma cell neoplasm. WM is a B-cell lymphoproliferative disorder that accounts for 1%–2% of all hematologic cancers and up to 30% of patients display symptomatic hyperviscosity (4). Diagnostic criteria for WM as defined by the 2016 Mayo Clinic consensus include the following: IgM monoclonal gammopathy of any size, ≥10% bone marrow infiltration by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation, and an atypical immunophenotype (surface IgM+, CD5-, CD10-, CD19+, CD20+, CD23-) (2). The MYD88 gene mutation is found in >90% of all WM patients and rarely presents in multiple myeloma or marginal zone lymphoma (2). Less commonly cited recommendations from the 2003 International Workshop on WM do not endorse the need for ≥10% bone marrow infiltration to establish a diagnosis and suggest any level of bone marrow involvement is sufficient to differentiate WM from IgM MGUS (5). Furthermore, they propose a category of patients with “IgM related disorders” that have IgM monoclonal protein without overt evidence of lymphoma but display clinical features attributable to the IgM (cryoglobulinemia, amyloidosis or autoimmune phenomena) (5). According to these more historical recommendations, the patient may better fit the criteria of WM. An IgM concentration of 30–40g/L, as observed in this patient, has been associated with symptomatic hyperviscosity in only 3% of patients with WM as indicated in a retrospective study (6). In the current case, the patient had viscosity levels that were beyond the measuring range and capacity of the laboratory's rotational viscometer (>10 cP; reference range, 1.6–2.4 cP), thereby hindering all initial laboratory investigations. However, warming the sample allowed all laboratory tests to be performed except SPE (Fig. 1). Increased IgM is particularly challenging for SPE analysis owing to aggregation and precipitation of the paraprotein at the loading site (7). The use of a reducing agent (e.g., β-mercaptoethanol, dithiothreitol) can be used to break disulfide bonds and convert IgM from a pentameric to monomeric form (7). In the present study, β-mercaptoethanol was used to allow migration through the gel and provide a reliable monoclonal protein measurement (Fig. 1). Addition of the reducing agent β-mercaptoethanol allowed for quantitation of an M spike on SPE from a highly viscous sample. Failure of paraprotein migration on SPE is an indication to investigate for cryoglobulins (8). Cryoglobulins are immunoglobulins that precipitate at temperatures below 37°C and redissolve upon warming. There are 3 types of cryoglobulins: Type 1 containing a monoclonal immunoglobulin (usually IgM), Type 2 containing a monoclonal RF-IgM + polyclonal IgG, and Type 3 containing a polyclonal RF-IgM + polyclonal IgG (8). Type 1 is associated with monoclonal paraproteinemia, whereas Type 2 and 3 are associated with chronic infections, such as HIV, and autoimmune/connective tissue diseases. The current case was particularly thought-provoking given that the patient's monoclonal paraproteinemia would suggest type 1 cryoglobulins; however, the unexpected finding of increased RF would fit more with type 2 and 3 cryoglobulins. Surprisingly, the patient was negative for cryoglobulins and thus the potential of a false-negative result was investigated. Lack of standardization and widespread differences in the methodology of cryoglobulin assessment result in variable sampling conditions and false-negative results due to loss of cryoprecipitate (8). To exclude the possibility of a false negative, we ensured appropriate sampling conditions as proposed by Ravishankar et al. (8) on 2 separate occasions, which consistently provided a negative result. Hyperviscosity in patients with autoimmune or connective tissue disorders is rare, with only a few case reports published (9). In these patients, increased viscosity is most commonly attributed to intermediate IgG complexes with RF activity (10), although other monoclonal paraprotein complexes with RF activity have been reported in the absence of connective tissue or immunoproliferative disease (11). Extremely increased concentrations of RF or immune complexes have been shown to mask the detection of autoantibodies in patients with hyperviscosity and result in false negative ANA (9). In the current case, the patient did not present with IgG intermediate complexes as indicated by size-exclusion chromatography. The patient also did not display symptoms associated with rheumatic disease and had negative ANA both before and after TPE. WM and IgM multiple myeloma may not always be easily differentiated, though MYD88 mutation and criteria established by less commonly cited guidelines may be helpful. Uncommonly, hyperviscosity can present in connective tissue diseases including rheumatoid arthritis; however, ANA can be falsely negative with increased RF or immune complexes. Variable sampling conditions may lead to false-negative cryoglobulin assessments that can be addressed by following proposed standardized protocols. Viscous samples may require warming to 37°C or treatment with reducing agents to achieve reliable laboratory measurements. A laboratory protocol can be developed when receiving viscous samples into the laboratory to ensure appropriate sample handling and accurate analysis. The present case is unique given that the patient did not clearly fit the diagnostic criteria for common causes hyperviscosity syndrome and monoclonal IgM. Our study shows that unclear cases of hyperviscosity syndrome may fit less commonly known classifications of IgM-related disorders (5) or may be idiopathic, as previously reported (11). The laboratory can assist in determining an underlying diagnosis by ensuring steps that provide appropriate and reliable test results. A laboratory protocol for handling viscous samples may include the following: (a) adding reducing agent or warming viscous samples before analytical measurements, (b) ensuring appropriate preanalytical conditions for cryoglobulin assessment, (c) investigating presence of RF activity and immunoglobulin complexes, and (d) investigating possibilities of false negative and positive results (i.e., cryoglobulins, ANA, RF). serum protein electrophoresis complete blood count Waldenström macroglobulinemia rheumatoid factor anti-nuclear antibody therapeutic plasma exchange monoclonal gammopathy of undetermined significance. Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. C. Chen, provision of study material or patients. Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: V. Kulasingam, The Journal of Applied Laboratory Medicine, AACC. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: None declared. Research Funding: None declared. Expert Testimony: None declared. Patents: None declared. The authors acknowledge Dr. Jan Delabie, Megan Spencer, Nadine Singh, Kam Tin, and Antoninus Soosaipillai for their assistance.

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