All patients with symptomatic cryoglobulinemia are advised to avoid, or protect their extremities, from exposure to cold temperatures. Refrigerators, freezers, and air-conditioning represent dangers of such exposure.

Individuals found to have circulating cryoglobulins but no signs or symptoms of cryoglobulinemic diseases should be evaluated for the possibility that their cryoglobulinemia is a transient response to a recent or resolving infection. Those with a history of recent infection that also have a spontaneous and full resolution of their cryoglobulinemia need no further treatment. Individuals without a history of infection and not showing resolution of their cryoglobulinemia need to be further evaluated. Their cryoglobulins should be analyzed for their composition of immunoglobulin type(s) and complement component(s) and examined for the presence of the premalignant and malignant diseases associated with Type I disease as well as the infectious and autoimmune diseases associated with type II and type III disease. A study conducted in Italy on >140 asymptomatic individuals found five cases of hepatitis C-related and one case of hepatitis b-related cryoglobulinemia indicating that a complete clinical examination of asymptomatic individuals with cryoglobulinemia offers a means for finding people with serious but potentially treatable and even curable diseases. Individuals who show no evidence of a disease underlying their cryoglobulinemia and who remain asymptomatic should be followed closely for any changes that may indicate development of cryoglobulinemic disease.

Several other illnesses can present with a monoclonal gammopathy, and the monoclonal protein may be the first discovery before a formal diagnosis is made:

The protein electrophoresis test should be repeated annually, and if there is any concern for a rise in the level of monoclonal protein, then prompt referral to a hematologist is required. The hematologist, when first evaluating a case of MGUS, will usually perform a skeletal survey (X-rays of the proximal skeleton), check the blood for hypercalcemia and deterioration in renal function, check the urine for Bence Jones protein and perform a bone marrow biopsy. If none of these tests are abnormal, a patient with MGUS is followed up once every 6 months to a year with a blood test (serum protein electrophoresis). Although patients with MGUS have sometimes been reported to suffer from Small Fiber Neuropathy in monoclonal gammopathy of undetermined significance:a debilitating condition which causes bizarre sensory problems to painful sensory problems. peripheral neuropathy, no treatment is indicated.

A diagnosis of Waldenström's macroglobulinemia depends on a significant monoclonal IgM spike evident in blood tests and malignant cells consistent with the disease in bone marrow biopsy samples. Blood tests show the level of IgM in the blood and the presence of proteins, or tumor markers, that are the key symptoms of WM. A bone marrow biopsy provides a sample of bone marrow, usually from the back of the pelvis bone. The sample is extracted through a needle and examined under a microscope. A pathologist identifies the particular lymphocytes that indicate WM. Flow cytometry may be used to examine markers on the cell surface or inside the lymphocytes.

Additional tests such as computed tomography (CT or CAT) scan may be used to evaluate the chest, abdomen, and pelvis, particularly swelling of the lymph nodes, liver, and spleen. A skeletal survey can help distinguish between WM and multiple myeloma. Anemia is typically found in 80% of patients with WM. A low white blood cell count, and low platelet count in the blood may be observed. A low level of neutrophils (a specific type of white blood cell) may also be found in some individuals with WM.

Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), kidney and liver function, total protein levels, and an albumin-to-globulin ratio. The ESR and uric acid level may be elevated. Creatinine is occasionally elevated and electrolytes are occasionally abnormal. A high blood calcium level is noted in approximately 4% of patients. The LDH level is frequently elevated, indicating the extent of Waldenström's macroglobulinemia–related tissue involvement. Rheumatoid factor, cryoglobulins, direct antiglobulin test and cold agglutinin titre results can be positive. Beta-2 microglobulin and C-reactive protein test results are not specific for Waldenström's macroglobulinemia. Beta-2 microglobulin is elevated in proportion to tumor mass. Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional. Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish the spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenström's macroglobulinemia. Immunoelectrophoresis and immunofixation studies help identify the type of immunoglobulin, the clonality of the light chain, and the monoclonality and quantitation of the paraprotein. High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and characterize the monoclonal IgM paraprotein.

The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenström's macroglobulinemia may exhibit more than one M protein. Plasma viscosity must be measured. Results from characterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually of the kappa type, are found in the urine. Urine collections should be concentrated.

Bence Jones proteinuria is observed in approximately 40% of patients and exceeds 1 g/d in approximately 3% of patients. Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin associated glycoprotein serology.

Criteria for diagnosis of Waldenström's macroglobulinemia include:

1. IgM monoclonal gammopathy that excludes chronic lymphocytic leukemia and Mantle cell lymphoma

2. Evidence of anemia, constitutional symptoms, hyperviscosity, swollen lymph nodes, or enlargement of the liver and spleen that can be attributed to an underlying lymphoproliferative disorder.

In the absence of symptoms, many clinicians will recommend simply monitoring the patient; Waldenström himself stated "let well do" for such patients. These asymptomatic cases are now classified as two successively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance (i.e. IgM MGUS) and smoldering Waldenström's macroglobulinemia.

But on occasion, the disease can be fatal, as it was to the French president Georges Pompidou, who died in office in 1974. Mohammad Reza Shah Pahlavi, the Shah of Iran, also suffered from Waldenström's macroglobulinemia, which resulted in his ill-fated trip to the United States for therapy in 1979, leading to the Iran hostage crisis.

Paraproteinemias may be categorized according to the type of monoclonal protein found in blood:

- Light chains only (or Bence Jones protein). This may be associated with multiple myeloma or AL amyloidosis.

- Heavy chains only (also known as "heavy chain disease");

- Whole immunoglobulins. In this case, the paraprotein goes under the name of "M-protein" ("M" for monoclonal). If immunoglobulins tend to precipitate within blood vessels with cold, that phenomenon takes the name of cryoglobulinaemia.

The three types of paraproteins may occur alone or in combination in a given individual. Note that while most heavy chains or whole immunoglobulins remain within blood vessels, light chains frequently escape and are excreted by the kidneys into urine, where they take the name of Bence Jones protein.

It is also possible for paraproteins (usually whole immunoglobulins) to form polymers by aggregating with each other; this takes the name of macroglobulinemia and may lead to further complications. For example, certain macroglobulins tend to precipitate within blood vessel with cold, a phenomenon known as cryoglobulinemia. Others may make blood too viscous to flow smoothly (usually with IgM pentamer macroglobulins), a phenomenon known as Waldenström macroglobulinemia.

Diagnosis is confirmed histologically by tissue biopsy. Hematoxylin-eosin stain of biopsy slide will show features of Langerhans Cell e.g. distinct cell margin, pink granular cytoplasm. Presence of Birbeck granules on electron microscopy and immuno-cytochemical features e. g. CD1 positivity are more specific. Initially routine blood tests e.g. full blood count, liver function test, U&Es, bone profile are done to determine disease extent and rule out other causes. Radiology will show osteolytic bone lesions and damage to the lung. The latter may be evident in chest X-rays with micronodular and interstitial infiltrate in the mid and lower zone of lung, with sparing of the Costophrenic angle or honeycomb appearance in older lesions. MRI and CT may show infiltration in sella turcica. Assessment of endocrine function and bonemarrow biopsy are also performed when indicated.

- S-100 protein is expressed in a cytoplasmic pattern

- peanut agglutinin (PNA) is expressed on the cell surface and perinuclearly

- major histocompatibility (MHC) class II is expressed (because histiocytes are macrophages)

- CD1a

- langerin (CD207), a Langerhans Cell–restricted protein that induces the formation of Birbeck granules and is constitutively associated with them, is a highly specific marker.

In the heart, there are two forms of the hypereosinophilic syndrome, endomyocardial fibrosis and Loeffler's endocarditis.

- Endomyocardial fibrosis (also known as Davies disease) is seen in tropical areas.

- Loeffler's endocarditis does not have any geographic predisposition.

Numerous techniques are used to diagnose hypereosinophilic syndrome, of which the most important is blood testing. In HES, the eosinophil count is greater than 1.5 × 10/L. On some smears the eosinophils may appear normal in appearance, but morphologic abnormalities, such as a lowering of granule numbers and size, can be observed. Roughly 50% of patients with HES also have anaemia.

Secondly, various imaging and diagnostic technological methods are utilised to detect defects to the heart and other organs, such as valvular dysfunction and arrhythmias by usage of echocardiography. Chest radiographs may indicate pleural effusions and/or fibrosis, and neurological tests such as CT scans can show strokes and increased cerebrospinal fluid pressure.

A proportion of patients have a mutation involving the "PDGFRA" and "FIP1L1" genes on the fourth chromosome, leading to a tyrosine kinase fusion protein. Testing for this mutation is now routine practice, as its presence indicates response to imatinib, a tyrosine kinase inhibitor.

Although elevated whole blood viscosity is a better measure of hyperviscosity and more common and clinically important, serum viscosity and plasma viscosity are more frequently measured. Normal plasma viscosity is between 1.4 and 1.8 centipoise while symptoms from hyperviscosity typically occur greater than 4 centipoise (about 4 times more viscous than water) and require emergency treatment.

Patients will also have evidence of their underlying disorder. Those with myeloma will typically display a rouleaux formation on a peripheral smear and a large globulin gap, indicative of a significant paraprotein load. While viscosity can be directly measured, results can take a few days to return and thus a high index of suspicion is required to make the diagnosis in a timely manner. If hyperviscosity is suspected, treatment may need to be started prior to obtaining the official viscosity level.

In addition to tests corresponding to the above findings (such as EMG for neuropathy, CT scan, bone marrow biopsy to detect clonal plasma cells, plasma or serum protein electrophoresis to myeloma proteins, other tests can give abnormal results supporting the diagnosis of POEMS syndrome. These included raised blood levels of VEGF, thrombocytes, and/or erythrocyte parameters.

Patients diagnosed as having Castleman disease but also exhibiting many of the symptoms and signs of POEMS syndrome but lacking evidence of a peripheral neuropathy and/or clonal plasma cells should not be diagnosed as having POEMS syndrome. They are better classified as having Castleman disease variant of POEMS syndrome. These patients may exhibit high blood levels of the interleukin-6 cytokine and have an inferior overall survival compared to POEMS syndrome patients. Treatment of patients with this POEMS syndrome variant who have evidence of bone lesions and/or myeloma proteins are the same as those for POEMS syndrome patients. In the absence of these features, treatment with rituximab, a monoclonal antibody preparation directed against B cells bearing the CD20 antigen, or siltuximab, a monoclonal antibody preparation directed against interleukin-6, may be justified.

Paraproteinemia, also known as monoclonal gammopathy, is the presence of excessive amounts of paraprotein or single monoclonal gammaglobulin in the blood. It is usually due to an underlying immunoproliferative disorder or hematologic neoplasms, especially multiple myeloma. It is sometimes considered equivalent to plasma cell dyscrasia.

Castleman disease is diagnosed when a lymph node biopsy reveals regression of germinal centers, abnormal vascularity, and a range of hyaline vascular changes and/or polytypic plasma cell proliferation. These features can also be seen in other disorders involving excessive cytokine release, so they must be excluded before a Castleman disease diagnosis should be made.

It is essential for the biopsy sample to be tested for HHV-8 with latent associated nuclear antigen (LANA) by immunohistochemistry or PCR for HHV-8 in the blood.

The pathogenesis of Langerhans cell histiocytosis (LCH) is a matter of debate. There are ongoing investigations to determine whether LCH is a reactive (non-cancerous) or neoplastic (cancerous) process. Arguments supporting the reactive nature of LCH include the occurrence of spontaneous remissions, the extensive secretion of multiple cytokines by dendritic cells and bystander-cells (a phenomenon known as cytokine storm) in the lesional tissue, favorable prognosis and relatively good survival rate in patients without organ dysfunction or risk organ involvement.

On the other hand, the infiltration of organs by monoclonal population of pathologic cells, and the successful treatment of subset of disseminated disease using chemotherapeutic regimens are all consistent with a neoplastic process. In addition, a demonstration, using X chromosome–linked DNA probes, of LCH as a monoclonal proliferation provided additional support for the neoplastic origin of this disease. While clonality is an important attribute of cancer, its presence does not prove that a proliferative process is neoplastic. Recurrent cytogenetic or genomic abnormalities would also be required to demonstrate convincingly that LCH is a malignancy.

Activating mutation of a protooncogen in the Raf family, the BRAF gene, was detected in 35 of 61 (57%) LCH biopsy samples with mutations being more common in patients younger than 10 years (76%) than in patients aged 10 years and older (44%). This study documented the first recurrent mutation in LCH samples. Two independent studies have confirmed this finding. Presence of this activating mutation could support the notion to characterize LCH as myeloproliferative disorder.

Plasmapheresis may be used to decrease viscosity in the case of myeloma, whereas leukapheresis or phlebotomy may be employed in a leukemic or polycythemic crisis, respectively. Blood transfusions should be used with caution as they can increase serum viscosity. Hydration is a temporizing measure to employ while preparing pheresis. Even after treatment, the condition will recur unless the underlying disorder is treated.

The International Myeloma Working Group has defined the diagnostic criteria for plasma cell leukemia as the presence in blood of >2x10 plasma cells per liter or, alternatively, >20% of nucleated blood cells being plasma cells. More recently, the Group has suggested that values of 0.5x10 or 5%, respectively, may be more appropriate from a therapeutic viewpoint and therefore should be studied as a definitive criterion for the disease. A recent study supported this suggestion in finding that multiple myeloma patients with >5% circulating plasma cells had a prognosis much worse than that for multiple myeloma and similar to that for plasma cell leukemia. Flow cytometry immunophenotyping of blood cells to detect clonal phenotypes of plasma cells seen in multiple myeloma (e.g. the CD138, CD38, CD19, CD45 phenotype) may be a more sensitive method to enumerate circulating clonal plasma cells and diagnose plasma cell leukemia.

PTLD may spontaneously regress on reduction or cessation of immunosuppressant medication, and can also be treated with addition of anti-viral therapy. In some cases it will progress to non-Hodgkin's lymphoma and may be fatal. A phase 2 study of adoptively transferred EBV-specific T cells demonstrated high efficacy with minimal toxicity.

Evidence is conflicting on the prognostic significance of chloromas in patients with acute myeloid leukemia. In general, they are felt to augur a poorer prognosis, with a poorer response to treatment and worse survival; however, others have reported chloromas associate, as a biologic marker, with other poor prognostic factors, and therefore do not have independent prognostic significance.

There are three sub-types of Castleman disease.

- Unicentric Castleman disease

- HHV-8-associated multicentric Castleman disease

- HHV-8-negative multicentric Castleman disease

Some myeloma centers now employ genetic testing, which they call a “gene array.” By examining DNA, oncologists can determine if patients are high risk or low risk of the cancer returning quickly following treatment.

Cytogenetic analysis of myeloma cells may be of prognostic value, with deletion of chromosome 13, non-hyperdiploidy and the balanced translocations t(4;14) and t(14;16) conferring a poorer prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis.

Prognostic markers such as these are always generated by retrospective analyses, and it is likely that new treatment developments will improve the outlook for those with traditionally "poor-risk" disease.

SNP array karyotyping can detect copy number alterations of prognostic significance that may be missed by a targeted FISH panel. In MM, lack of a proliferative clone makes conventional cytogenetics informative in only ~30% of cases.

1. Virtual karyotyping identified chromosomal abnormalities in 98% of MM cases

2. del(12p13.31) is an independent adverse marker

3. amp(5q31.1) is a favorable marker

4. The prognostic impact of amp(5q31.1) over-rides that of hyperdiploidy and also identifies patients who greatly benefit from high-dose therapy.

Array-based karyotyping cannot detect balanced translocations, such as t(4;14) seen in ~15% of MM. Therefore, FISH for this translocation should also be performed if using SNP arrays to detect genome-wide copy number alterations of prognostic significance in MM.

Definitive diagnosis of a chloroma usually requires a biopsy of the lesion in question. Historically, even with a tissue biopsy, pathologic misdiagnosis was an important problem, particularly in patients without a clear pre-existing diagnosis of acute myeloid leukemia to guide the pathologist. In one published series on chloroma, the authors stated that 47% of the patients were initially misdiagnosed, most often as having a malignant lymphoma.

However, with advances in diagnostic techniques, the diagnosis of chloromas can be made more reliable. Traweek et al. described the use of a commercially available panel of monoclonal antibodies, against myeloperoxidase, CD68, CD43, and CD20, to accurately diagnose chloroma via immunohistochemistry and differentiate it from lymphoma. Nowadays, immunohistochemical staining using monoclonal antibodies against CD33 and CD117 would be the mainstay of diagnosis. The increasingly refined use of flow cytometry has also facilitated more accurate diagnosis of these lesions.

Flow cytometry with monoclonal antibodies is used to screen for deficiencies of CD18.

The disease is an uncontrolled proliferation of B cell lymphocytes latently infected with Epstein-Barr virus. Production of an interleukin-10, an endogenous, pro-regulatory cytokine, has also been implicated.

In immunocompetent patients, Epstein-Barr virus can cause infectious mononucleosis in adolescents, which is otherwise asymptomatic in children during their childhood. However, in immunosuppressed transplant patients, the lack of T-cell immunosurveillance can lead to the proliferation of these EBV-infected of B-lymphocytes.

However, calcineurin inhibitors (tacrolimus and ciclosporin), used as immunosuppressants in organ transplantation inhibit T cell function, and can prevent the control of the B cell proliferation.

Depletion of T cells by use of anti-T cell antibodies in the prevention or treatment of transplant rejection further increases the risk of developing post-transplant lymphoproliferative disorder. Such antibodies include ATG, ALG and OKT3.

Polyclonal PTLD may form tumor masses and present with symptoms due to a mass effect, e.g. symptoms of bowel obstruction. Monoclonal forms of PTLD tend to form a disseminated malignant lymphoma.