CLINICAL/PATHOLOGIC CORRELATIONS IN MALIGNANT LYMPHOMAS AND PLASMA CELL MYELOMA
Dr. B. F. Burns, Dept of Pathology/Lab Medicine
TABLE OF CONTENTS
TYPES OF LYMPHOMAS:
HODGKINS LYMPHOMA (also called HODGKIN'S DISEASE):
PLASMA CELL MYELOMA
Students after this lecture should be able to discuss the following in general terms:
- The difference between a lymphoma and a leukemia and how each typically presents clinically.
- How the common lymphomas are classified and the differences in clinical presentation and prognosis between Hodgkins disease and the non-Hodgkins lymphomas.
- The typical genetic mechanisms involved in the development of lymphomas.
- What the common signs and symptoms of plasma cell myeloma are and how it is diagnosed.
Suggested Reading: Robbins Pathologic Basis of Disease, 6th Ed., Cotran, R. 1999, p 651-674.
Lymphomas - these are malignant neoplasms derived from lymphocytes that form "tumors", usually in lymph nodes but also in other organs or in soft tissue. Unlike the leukemias the tumor cells do not appear in the blood in detectable numbers.
Plasma cell myeloma- these are bone marrow based, monoclonal tumors of plasma cells. Symptoms are related to replacement of normal marrow hematopoietic elements (anemia, etc.) and weakening of the bones resulting in fractures.
TYPES OF LYMPHOMAS:
The lymphomas are broadly grouped into two types:
A. Non-Hodgkins lymphomas (60%)
B. Hodgkins lymhoma (also known as Hodgkin's disease) (40%)
Cells of origin: The non- Hodgkins lymphomas are derived from either B or T lymphocytes. The cell of origin in Hodgkins lymphoma is now known to be of B-cell origin also, but with "crippled" rearrangements of their immunoglobulin genes.
PATHOGENESIS OF LYMPHOMAS
All lymphomas, leukemias and plasma cell myeloma are derived from a single mutated cell and are thus "clonal" or "monoclonal" in origin. The specific mutations involved differ from one type of lymphoma/leukemia to the next but a large number of them involve chromosomal translocations, for example the t(9;22) translocation of chronic granulocytic leukemia or the t(14;18) translocation of follicular lymphomas (see below). Tumor progression, in the form of further mutations, typically occurs during the course of the patients disease and results in an increasingly aggressive form of the disease.
SPECIFIC TYPES OF LYMPHOMAS
HODGKINS LYMPHOMA (also called HODGKIN'S DISEASE):
Hodgkins lymphoma is a form of lymphoma that usually affects young people in their teens, 20s and early 30s, with a minor "bimodal" blip at around age 60. It most typically involves the cervical and mediastinal lymph node groups and spreads in a predictable pattern to contiguous lymph node groups (as opposed to "skipping" groups and arising in a more "random" pattern).
The diagnosis of Hodgkins lymphoma is made when "Reed-Sternberg cells" are seen in a lymph node along with other characteristic features. These cells are bi- or multi-nucleated tumor cells that have very large nucleoli, resembling viral inclusion bodies. These cells and other less diagnostic mononuclear forms of the tumor cell population appear to produce a number of lymphokines, such as IL-5, that attract other non-neoplastic lymphocytes, histiocytes, fibroblasts and often eosinophils into the affected node. This results in the very characteristic pathologic picture of a lymph node with large amounts of collagenous fibrous tissue (from the fibroblasts), numerous small lymphocytes, histiocytes and eosinophils with relatively few tumor cells. In fact, on occasion a pathologist will have to search through several slides before finding the diagnostic Reed-Sternberg cells.
Hodgkins lymphoma has traditionally been divided into 4 histologic sub-types (the Rye Classification):
1. Nodular sclerosis (most common form) 2. Lymphocyte predominant, nodular 3. Mixed cellularity 4. Lymphocyte depletion (this is very rare and it's existence is controversial)
The important thing in Hodgkins lymphoma however is not the histologic sub-type but the "stage" of the disease at the time of diagnosis. This will dictate the treatment and the prognosis of the disease.
Ann Arbor Lymphoma Staging Criteria (also applies to staging non-Hodgkins lymphomas)
Stage I - involving a single node or group of contiguous nodes on the same side of the diaphragm or a single extranodal site (called IE) Stage II - two or more lymph node groups on the same side of the diaphragm or limited contiguous extranodal involvement (IIE) Stage III - lymph node groups on both sides of the diaphragm, may include the spleen (IIIS) or limited extranodal involvement (IIIE) Stage IV - multiple or disseminated foci involving one or more extranodal sites
Each of these stages can be further divided into A (not affected) or B (affected) subcategories depending on whether the patient also has fever, night sweats or weight loss of >10%.
Practically speaking Stage IV involvement is usually diagnosed when the bone marrow is found to be involved, hence the importance of bilateral iliac crest bone marrow biopsies in staging.
The prognosis of patients with Hodgkins disease is now excellent, especially in those with stage I or II disease, who can often be treated with radiotherapy to only the affected areas.
In contrast to Hodgkins disease, the non-Hodgkins lymphomas have a range of clinical aggressiveness that depends much more on the specific histologic sub-type than on the stage of the disease. Thus the classification of the specific type of non-Hodgkins lymphoma is very important to the correct management of a patient. Non-Hodgkins lymphomas are also much more frequently found arising in organ sites other than lymph nodes, such as stomach, lung, salivary glands and even such unlikely sites as brain. Recent studies have shown that a chronic infection of the stomach by a bacteria (Helicobacter pylori) has been associated with lymphomas arising in the stomach.
As mentioned at the beginning of the handout the non-Hodgkins lymphomas may be derived from either B- or T-cells. In North America and Europe, between 90-95% of these lymphomas are derived from B-cells. T-cell lymphomas are rare here, but relatively common in Japan where they are strongly linked to an oncogenic retrovirus, HTLV 1.
The B-cell lymphomas may have either a follicular or a diffuse pattern of growth in the affected lymph node or tissue. In general, follicular lymphomas have a slower rate of growth and a less aggressive clinical course than their diffuse counterparts. The only exception is the "small lymphocytic" lymphoma, which has a very slow growth rate and is the lymph node equivalent of CLL. T cell lymphomas are always diffuse, never follicular.
The classification of the non-Hodgkins lymphomas is currently in a state of flux. The "N.I.H. Working Formulation" was devised in 1979 and is still in many textbooks currently. It is presented below in a somewhat simplified form. More recently a new classification scheme has been devised, based on the cell of origin (B or T) and reflecting specific diseases in terms of characteristic genetic mutations, . This is now referred to has the W.H.O. Classification .
N.I.H. Working Formulation of non-Hodgkin's Lymphomas: (slightly abridged)
LOW GRADE (clinically slowly growing, but poorly responsive to treatment)
1. Small lymphocytic (similar to chronic lymphocytic leukemia)
This lymphoma is slow growing and composed of small round lymphocytes with scant cytoplasm and very few mitoses. They almost all of B-cell origin and express pan B-cell markers, such as CD20, as well as CD5 and CD23. in time they may transform to more aggressive forms of large cell lymphoma.
2. Follicular lymphomas- further subdivided on the basis of the relative numbers small cleaved and large non-cleaved cells in the follicles, into (a) small cleaved, (b) mixed or (c) large cell (this latter form tending toward the intermediate grade in behavior)
INTERMEDIATE GRADE (more rapidly growing, treated aggressively)
3. Diffuse lymphomas- again subdivided on the same basis as the follicular lymphomas into (a) small cleaved cell, (b) mixed or (c) large cell
HIGH GRADE (very rapidly growing, treated very aggressively, often like acute leukemias)
4. Lymphoblastic 5. Small non-cleaved (Burkitts lymphoma)
PLASMA CELL MYELOMA
Plasma cell myelomas are derived from primitive stem cells in the bone marrow that differentiate into mature immunoglobulin secreting plasma cells. The genetic basis of this tumor development is not as consistent as many of the lymphomas and no characteristic translocations are known. The tumor cells gradually replace the bone marrow, especially in the vertebrae, ribs and skull, resulting in bone resorbtion and pathologic fractures (fractures of diseased, rather than normal, bone). Typically affecting older people in their 50s to 60s, this disease may present in a number of different ways relating either to (1) bone destruction (fractures), (2) the effects of marrow replacement (anemia, infections) or (3) excessive immunoglobulin production (producing kidney failure). Many students are surprised to learn that a tumor that produces large amounts of immunoglobulin should also be associated with an increased incidence of infections. It should be remembered that the immunoglobulin being produced is monoclonal and hence it is all the same in terms of it's antigen recognition capacity. In fact the serum concentrations of all other "normal" immunoglobulins is typically decreased and the monoclonal Ig is not an effective substitute in recognizing pathogens, especially bacteria like Strep pneumoniae and Staph aureus.
The diagnosis of myeloma can be suspected in patients who have the typical x-ray picture of "punched-out" lytic lesions in their vertebrae, ribs, skull or pelvis, etc and who have an increase in serum immunoglobulins. Confirmatory tests include bone marrow aspiration and biopsy (showing >10% plasma cells in the marrow) and serum or urine immunoelectrophoresis showing a monoclonal spike of immunoglobulin. Occasionally only the light chain of the immunoglobulin is found in the urine (Bence-Jones protein), without an increase in serum Ig.
A very characteristic feature of myeloma is its tendency to affect the kidneys, either directly from the effects of the immunoglobulin precipitating in the renal tubules (so-called "myeloma kidney") or more indirectly via hypercalcemia (from bone resorbtion) resulting in kidney stone (calculi) formation. Another form of bad news for the kidney is the development of amyloidosis, with the monoclonal Ig as substrate for the amyloid fibrils. This results in very heavy protein leakage (especially albumin) into the urine, producing the "nephrotic syndrome".
The prognosis in plasma cell myeloma is related to the extent of disease at the time of diagnosis (i.e., stage of disease). Most patients with extensive bony lesions live less than 1 year and the median survival is only 3 years overall.
Lymphoma lecture slides 184 Kb.
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