29. High grade B cell lymphomas (BL, DLBCL). Plasma cell neoplasms

From greek.doctor

Burkitt lymphoma

Burkitt lymphoma (BL) is an aggressive, mature non-Hodgkin B cell lymphoma. A lymphoma is always present; leukaemia is uncommon but may occur. Three subtypes exist, each of which have different etiology and clinical manifestations.

Endemic Burkitt lymphoma is associated with EBV infection and is most commonly seen in children and young adults in equatorial Africa and South America. The lymphoma is typically located in the head and neck area.

Sporadic Burkitt lymphoma is associated with EBV in only 30% of cases. It can occur anywhere in the world but is most commonly seen in western countries. It mostly affects children and young adults, and the typical manifestation is a lymphoma in the abdomen, forming an abdominal mass.

Immunocompromised-related Burkitt lymphoma is associated with HIV/AIDS and other immunocompromised states. EBV infection is present in around 30% of cases. It has no typical manifestation.

All three forms of BL are highly associated with translocations of the C-MYC gene, which is located on chromosome 8. The most common translocations is t(8;14) with IgH/MYC.

The tumor cells have very high rate of proliferation, and apoptosis is widespread. This causes the characteristic “starry sky” pattern on histology.

Burkitt lymphoma is one of the fastest-growing neoplasms with a doubling time of <24 hours.

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive, mature non-Hodgkin B-cell lymphoma. It’s the most common non-Hodgkin lymphoma. It mostly affects older adults in the 60-70 years range. Immunodeficiency is a strong risk factor, especially together with EBV.

DLBCL forms rapidly growing tumors. Approximately 60% of them are extranodal. Extranodal tumors are usually found in the CNS, GI tract, mediastinum or skin.

The name comes from that the tumor cells are very large on histology. The tumors show a diffuse “blastic” infiltrate.

There is no one gene or translocation that is always implicated in DLBCL, however one or more of the three genes Myc, BCL2 and BCL6 are commonly mutated or translocated. The more of these genes that are mutated, the worse the prognosis.

DLBCL may develop de novo or secondary to transformation from an indolent B-cell NHL, often CLL/SLL (in which case it’s called Richter transformation) or follicular lymphoma.

Plasma cell dyscrasias

Introduction

Plasma cell dyscrasias or plasma cell neoplasms are mature non-Hodgkin B-cell lymphomas that belongs to the “other” group. The neoplastic cells are plasma cells, leading to them usually producing immunoglobulins, either complete ones or just fragments of them. Because the neoplasm originates from one plasma cell the proliferation is monoclonal, which in practice means that all the tumor cells produce the exact same immunoglobulin, which can be detected in the serum.

Due to the presence of large amounts of a monoclonal immunoglobulin in the serum these disorders can also be called monoclonal gammopathies.

AL amyloidosis is a possible complication of these diseases due to the high level of immunoglobulin light chains in the blood.

Diagnosis

Diagnosis is based on the presence of these monoclonal immunoglobulins in the serum, where they’re known as “M proteins”. Immunoglobulin light chains can also be detected in the urine, where they’re known as Bence-Jones proteins.

Types

These are the most important plasma cell dyscrasias:

  • Multiple myeloma (= plasma cell myeloma)
  • Smouldering myeloma
  • Monoclonal gammopathy of unknown significance (MGUS)
  • Solitary plasmacytoma
  • Waldenström macroglobulinaemia

Multiple myeloma

Introduction and epidemiology

Multiple myeloma (MM), sometimes called plasma cell myeloma, is the most important of the plasma cell dyscrasias. It is characterised by proliferation of genetically abnormal monoclonal plasma cells in the bone marrow, which produce monoclonal paraprotein which leads to organ damage and which can be detected in blood and urine.

It’s the second most common haematological malignancy. It mostly affects elderly. Its prognosis used to be poor but nowadays the expected overall survival is >5 years. However, it is still considered incurable.

Sometimes multiple myeloma presents as a solitary tumour, in which case it’s called plasmacytoma.

Pathology

Multiple myeloma infiltrates the bone marrow of many bones in the body and frequently produces lytic lesions anywhere in the skeletal system. The lytic lesions develop as a consequence of cytokines produced by the tumor cells promoting osteoclast activity. The complications of multiple myeloma which lead to organ damage can be remembered with the mnemonic CRAB:

  • Calcium elevation– due to osteolysis
  • Renal failure – as the tubules are damaged following filtering of Bence-Jones proteins
  • Anaemia – due to the infiltrated bone marrow
  • Bone lesions – localized osteolytic lesions

Patients with multiple myeloma become immunosuppressed as the cancer interferes with the function of normal plasma cells. This increases the risk of bacterial infections.

The word “myeloma” means “malignant tumor of the bone marrow” and is not related to the myeloid cell line.

Other plasma cell dyscrasias

Monoclonal gammopathy of unknown significance

Monoclonal gammopathy of unknown significance (MGUS) is a precursor stage to multiple myeloma. MGUS can be found in 3% of healthy adults over 50. There are no symptoms or organ damage, only a laboratory abnormality (mildly elevated M-protein).

MGUS carries a 1-2% risk per year to progress to multiple myeloma. Regular follow-up allows early detection of progression.

Smouldering myeloma

Smouldering myeloma is the next precursor stage to multiple myeloma, a form of middle stage between MGUS and MM. It’s characterised by higher level of M-protein than MGUS as well as >10% of the bone marrow being occupied by plasma cells. There is still no organ damage.

As smouldering myeloma is “closer” to multiple myeloma than MGUS, the yearly risk of progression to MM is higher, 10%/year. Regular follow-up allows early detection of progression.

Waldenström macroglobulinaemia

Waldenström macroglobulinaemia or lymphoplasmacytic lymphoma is a form of plasma cell dyscrasia characterised by proliferation of lymphoplasmocytic cell and monoclonal IgM protein in the blood.