Of all cancers involving the lymphocytes, 1% of cases are WM.

WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually. The median age of onset of WM is between 60 and 65 years, with some cases occurring in late teens.

Current medical treatments result in survival of some longer than 10 years; in part this is because better diagnostic testing means early diagnosis and treatments. Older diagnosis and treatments resulted in published reports of median survival of approximately 5 years from time of diagnosis. Currently, median survival is 6.5 years. In rare instances, WM progresses to multiple myeloma.

The International Prognostic Scoring System for Waldenström’s Macroglobulinemia (IPSSWM) is a predictive model to characterise long-term outcomes. According to the model, factors predicting reduced survival are:

- Age > 65 years

- Hemoglobin ≤ 11.5 g/dL

- Platelet count ≤ 100×10/L

- B2-microglobulin > 3 mg/L

- Serum monoclonal protein concentration > 70 g/L

The risk categories are:

- Low: ≤ 1 adverse variable except age

- Intermediate: 2 adverse characteristics or age > 65 years

- High: > 2 adverse characteristics

Five-year survival rates for these categories are 87%, 68% and 36%, respectively. The corresponding median survival rates are 12, 8, and 3.5 years.

The IPSSWM has been shown to be reliable. It is also applicable to patients on a rituximab-based treatment regimen. An additional predictive factor is elevated serum lactate dehydrogenase (LDH).

This is a rare disease, with less than 100 cases reported. Of these cases, an equal male:female ratio was observed,

with cases typically seen in older adults.

Plasma cells, also called plasma B cells, plasmocytes, plasmacytes, or effector B cells, are white blood cells that secrete large volumes of antibodies. They are transported by the blood plasma and the lymphatic system. Plasma cells originate in the bone marrow; B cells differentiate into plasma cells that produce antibody molecules closely modelled after the receptors of the precursor B cell. Once released into the blood and lymph, these antibody molecules bind to the target antigen (foreign substance) and initiate its neutralization or destruction.

Plasmacytoid dendritic cells (pDCs) are innate immune cells that circulate in the blood and are found in peripheral lymphoid organs. They develop from bone marrow hematopoietic stem cells and constitute < 0.4% of peripheral blood mononuclear cells (PBMC).

In humans they exhibit plasma cell morphology and express CD4, HLA-DR, CD123, blood-derived dendritic cell antigen-2 (BDCA-2), Toll-like receptor (TLR) 7 and TLR9 within endosomal compartments, but do not express high levels of CD11c or CD14, which distinguishes them from conventional dendritic cells or monocytes, respectively. Mouse pDC express CD11c, B220, BST-2/Tetherin (mPDCA) and Siglec-H and are negative for CD11b.

As components of the innate immune system, these cells express intracellular Toll-like receptors 7 and 9 which detect ssRNA and unmethylated CpG DNA sequences, respectively. Upon stimulation and subsequent activation, these cells produce large amounts (up to 1,000 times more than other cell type) of type I interferon (mainly IFN-α (alpha) and IFN-β (beta)), which are critical pleiotropic anti-viral compounds mediating a wide range of effects.

The number of circulating pDCs are found to be decreased during chronic HIV infection as well as HCV infection.

Plasma cell leukemia (PCL) is a plasma cell dyscrasia, i.e. a disease involving the malignant degeneration of a subtype of white blood cells called plasma cells. It is the terminal stage and most aggressive form of these dyscrasias, constituting 2% to 4% of all cases of plasma cell malignancies. PCL may present as primary plasma cell leukemia, i.e. in patients without prior history of a plasma cell dyscrasia or as secondary plasma cell dyscrasia, i.e. in patients previously diagnosed with a history of its predecessor dyscrasia, multiple myeloma. The two forms of PCL appear to be at least partially distinct from each other. In all cases, however, PCL is an extremely serious, life-threatening, and therapeutically challenging disease.

The majority (90%) of cases have not had detectable cytogenetic abnormalities. Most importantly, the Philadelphia chromosome and other BCR/ABL fusion genes are not detected.

Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.

The typical patient with angioimmunoblastic T-cell lymphoma (AITL) is either middle-aged or elderly, and no gender preference for this disease has been observed. AITL comprises 15–20% of peripheral T-cell lymphomas and 1–2% of all non-Hodgkin lymphomas.

Secondary PCL (sPCL) is diagnosed in 1-4% of patients known to have had multiple myeloma for a median time of ~21 months. It is the terminal phase of these patients myeloma disease. sPCL patients typically are highly symptomatic due to extensive disease with malignant plasma cell infiltrations in, and failures of, not only the bone marrow but also other organs. They have failed or broke through one or more treatment regimens and therefore may also show some of the toxic effects of these treatments.

At the Mayo Clinic, MGUS transformed into multiple myeloma or similar lymphoproliferative disorder at the rate of about 1-2% a year, or 17%, 34%, and 39% at 10, 20, and 25 years, respectively, of follow-up—among surviving patients. However, because they were elderly, most patients with MGUS died of something else and did not go on to develop multiple myeloma. When this was taken into account, only 11.2% developed lymphoproliferative disorders.

Kyle studied the prevalence of myeloma in the population as a whole (not clinic patients) in Olmsted County, Minnesota. They found that the prevalence of MGUS was 3.2% in people above 50, with a slight male predominance (4.0% vs. 2.7%). Prevalence increased with age: of people over 70 up to 5.3% had MGUS, while in the over-85 age group the prevalence was 7.5%. In the majority of cases (63.5%), the paraprotein level was <1 g/dl, while only a very small group had levels over 2 g/dl. A study of monoclonal protein levels conducted in Ghana showed a prevalence of MGUS of approximately 5.9% in African men over the age of 50.

In 2009, prospective data demonstrated that all or almost all cases of multiple myeloma are preceded by MGUS. In addition to multiple myeloma, MGUS may also progress to Waldenström's macroglobulinemia, primary amyloidosis, B-cell lymphoma, or chronic lymphocytic leukemia.

Acute mast cell leukemia is extremely aggressive and has a grave prognosis. In most cases, multi-organ failure including bone marrow failure develops over weeks to months. Median survival after diagnosis is only about 6 months.

Memory B cells are a B cell sub-type that are formed within germinal centers following primary infection and are important in generating an accelerated and more robust antibody-mediated immune response in the case of re-infection (also known as a "secondary immune response").

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.

Autoimmune lymphoproliferative syndrome (ALPS), also known as Canale-Smith syndrome, is a form of lymphoproliferative disorder (LPDs). It affects lymphocyte apoptosis. It is a RASopathy.

It is a rare genetic disorder of abnormal lymphocyte survival caused by defective Fas mediated apoptosis. Normally, after infectious insult, the immune system down-regulates by increasing Fas expression on activated B and T lymphocytes and Fas-ligand on activated T lymphocytes. Fas and Fas-ligand interact to trigger the caspase cascade, leading to cell apoptosis. Patients with ALPS have a defect in this apoptotic pathway, leading to chronic non-malignant lymphoproliferation, autoimmune disease, and secondary cancers.

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system by secreting antibodies. Additionally, B cells present antigen (they are also classified as professional antigen-presenting cells (APCs)) and secrete cytokines.

In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ. (The "B" from B cells comes from the name of this organ, where it was first discovered by Chang and Glick, and not from bone marrow as commonly believed).

B cells, unlike the other two classes of lymphocytes, T cells and natural killer cells, express B cell receptors (BCRs) on their cell membrane. BCRs allow the B cell to bind a specific antigen, against which it will initiate an antibody response.

Angioimmunoblastic T-cell lymphoma (AITL, sometimes misspelled AILT) (formerly known as "angioimmunoblastic lymphadenopathy with dysproteinemia") is a mature T-cell lymphoma of blood or lymph vessel immunoblasts characterized by a polymorphous lymph node infiltrate showing a marked increase in follicular dendritic cells (FDCs) and high endothelial venules (HEVs) and systemic involvement.

Post-transplant lymphoproliferative disorder (PTLD) is the name given to a B-cell proliferation due to therapeutic immunosuppression after organ transplantation. These patients may develop infectious mononucleosis-like lesions or polyclonal polymorphic B-cell hyperplasia. Some of these B-cells may undergo mutations which will render them malignant, giving rise to a lymphoma.

In some patients, the malignant cell clone can become the dominant proliferating cell type, leading to frank lymphoma, a group of B cell lymphomas occurring in immunosuppressed patients following organ transplant.

Xanthogranulomatous osteomyelitis (XO) is a peculiar aspect of osteomyelitis characterized by prevalent histiocytic infiltrate and foamy macrophage clustering.

Mast cell leukemia is an extremely aggressive subtype of acute myeloid leukemia that usually occurs "de novo" but can, rarely, evolve from transformation of chronic myeloid leukemia into the more aggressive acute myeloid leukemia. In a small proportion of cases, acute mast cell leukemia may evolve from a more progressive form of systemic mastocytosis. The diagnosis of acute mast cell leukemia by the WHO criteria includes the requirement for a prevalence of 20% neoplastic mast cells in marrow and 10% in blood. If the mast cells represent less than 10% of blood cells, the tumor is called "aleukemic" mast cell leukemia.

Apoptosis is one of the major mechanisms of cell death targeted by cancer therapies. Reduced susceptibility to apoptosis increases the resistance of cancer cells to radiation and cytotoxic agents. B-cell lymphoma-2 (Bcl-2) family members create a balance between pro and anti-apoptotic proteins. Pro-apoptotic proteins include Bax and Bak. Anti-apoptotic proteins include Bcl-2, Bcl-X, Bcl-w, Mcl-1. When anti-apoptotic family members are overexpressed, apoptotic cell death becomes less likely.

- Oblimersen sodium (G3139, Genasense) targets BCL-2 mRNA

- ABT-737 (oral form navitoclax, ABT-263). A small molecule that targets anti-apoptotic Bcl-2 family proteins (Bcl-2, Bcl-X and Bcl-w). ABT-737 binds anti-apoptotic Bcl-2 proteins with an affinity two or three orders of magnitude more potent than previously reported compounds. High basal levels of Mcl-1 expression are associated with resistance to ABT-737. Combining ABT-737 with second agents that inactivate Mcl-1 may reduce this effect. ABT-737 has demonstrated single-agent efficacy against cell lines from lymphoid malignancies known to express high levels of Bcl-2, including DLBCL. It has also been found to be synergistic with proteasome inhibitors.

- Fenretinide. A synthetic retinoid that induces apoptosis of cancer cells and acts synergistically with chemotherapeutic drugs by triggering the activation of 12-Lox (12-lipoxygenase) leading to oxidative stress and apoptosis via the induction of the transcription factor Gadd153 and the Bcl-2-family member protein Bak.

Plasmacytoma, multiple myeloma, Waldenström macroglobulinemia and plasma cell leukemia are malignant neoplasms ("cancer") of the plasma cells. Multiple myeloma is frequently identified because malignant plasma cells continue producing an antibody, which can be detected as a paraprotein.

Common variable immunodeficiency is thought to be due to a problem in the differentiation from lymphocytes to plasma cells. The result is a low serum antibody level and risk of infections.

Primary amyloidosis (AL) is caused by the deposition of excess immunoglobulin light chains which are secreted from plasma cells.

Pathologically, the lesion in MGUS is in fact very similar to that in multiple myeloma. There is a predominance of clonal plasma cells in the bone marrow with an abnormal immunophenotype (CD38+ CD56+ CD19−) mixed in with cells of a normal phenotype (CD38+ CD56− CD19+); in MGUS, on average more than 3% of the clonal plasma cells have the normal phenotype, whereas in multiple myeloma, less than 3% of the cells have the normal phenotype. What causes MGUS to transform into multiple myeloma is as yet unknown.

Treatment is most commonly directed at autoimmune disease and may be needed to treat bulky lymphoproliferation. First line therapies include corticosteroids (very active but toxic with chronic use), and IVIgG, which are not as effective as in other immune cytopenia syndromes.

Second line therapies include: mycophenolate mofetil (cellcept) which inactivates inosine monophosphate, most studied in clinical trials with responses varying (relapse, resolution, partial response). It does not affect lymphoproliferation or reduce DNTs, with no drug-drug interactions. This treatment is commonly used agent in patients who require chronic treatment based on tolerance and efficacy. It may cause hypogammaglobulinemia (transient) requiring IVIgG replacement.

Sirolimus (rapamycin, rapamune) which is a mTOR (mammalian target of rapamycin) inhibitor can be active in most patients and can in some cases lead to complete or near-complete resolution of autoimmune disease (>90%) With this treatment most patients have complete resolution of lymphoproliferation, including lymphadenopathy and splenomegaly (>90%) and have elimination of peripheral blood DNTs. Sirolimus may not be as immune suppressive in normal lymphocytes as other agents. Some patients have had improvement in immune function with transition from cellcept to rapamycin and it has not been reported to cause hypogammaglobulinemia. Hypothetically, Sirolimus may have lower risk of secondary cancers as opposed to other immune suppressants and requires therapeutic drug monitoring. It is the second most commonly used agent in patients that require chronic therapy. It is mostly well tolerated (though side effects include mucositis, diarrhea, hyperlipidemia, delayed wound healing) with drug-drug interactions. It has better activity against autoimmune disease and lymphoproliferation than mycophenolate mofetil and other drugs; however, sirolimus requires therapeutic drug monitoring and can cause mucositis. A risk with any agent in pre-cancerous syndrome as immune suppression can decreased tumor immunosurvellence. Its mTOR inhibitors active against lymphomas, especially EBV+ lymphomas. The Goal serum trough is 5-15 ng/ml and can consider PCP prophylaxis but usually not needed.

Other treatments may include drugs like Fansidar, mercaptopurine: More commonly used in Europe. Another is rituximab but this can cause lifelong hypogammaglobulinemia and a splenectomy but there is a >30% risk of pneumococcal sepsis even with vaccination and antibiotic prophylaxis

The granulomatous tissue largely comprises foam cells of monocyte/macrophage origin positive for KP1, HAM56, CD11b and CD68. Neutrophils, hemorrhagic foci and numerous plasma cells are additional findings. Staphylococcus aureus was isolated in the case reported by Kamat et al. A delayed type hypersensitivity reaction in cell-mediated immunity has been suggested in this type of infiltrate that is composed of macrophages and T cells. T cells are represented by a mixture of CD4+ and CD8+ lymphocytes. Macrophages and lymphocytes show marked expression of HLA-DR antigen.

Arguably XO is the bone localization of the xanthogranulomatous process occurring in several other locations.