What is Non-Hodgkin's Lymphoma?

Lymphoma is a cancer of the white blood cells, starting in solid areas of immune cells. White Blood Cells ("WBC's") regulate the body's immune system, identifying, fighting and engulfing germs. This is an astoundingly complex process, involving many types of WBC's and supporting cells. It is also essential to life, since we are literally surrounded by bacteria, fungi, viruses and protozoa (all "germs") which would take over our bodies and kill us if we did not have an immune system to fight them off. To understand lymphoma, it helps to have some understanding of how the immune system works, and what type of cells normally do that work.

There are 3 basic types of blood cells in the body- WBC's to fight infection, Red Blood Cells ("RBC's") to carry oxygen, and Platelets to assist in blood clotting. All of these cells arise from a common cell in the bone marrow, called a "stem" cell or "pleuripotential" cell (meaning it gives rise to everything). The process by which the stem cell divides to form all the blood cells is called "differentiation", and is an elaborate, multi-step process for each type of cell. A cell may become cancerous at any point along it's development, accounting for the many types of blood cell cancers.

While there is ultimately just one type of RBC and platelet, there are normally several main types, and many subtypes, of WBC's. The main types are lymphocytes, neutrophils, monocytes, eosinophils, and basophils. The number of each of these per milliliter of blood is counted in the laboratory during the routine Complete Blood Count ("CBC") with "differential" . All of them participate in the immune system, and the lymphocyte is the crucial cell for identification of invading germs. The 2 main subtypes of lymphocytes are called "T-cells" (for Thymus) and "B-cells" (for Bone). The "T-cells" are involved in stimulating (T-helper) and suppressing (T-Suppressor) the immune system, while "B-cells" form the surface coating ("antibodies") sprayed onto foreign invaders, to allow them to be engulfed ("phagocytized") by the other WBC's. The system must stay in fine balance to function properly.

Now each of the body's cells has "surface proteins" (also called "immunoglobulins") coating their external membranes; these particular proteins are unique for each individual (except identical twins). When foreign tissue, such as a transplanted organ or some germ invades the body, it is quickly identified as foreign by it's different surface proteins, a process performed by T-helper cells. These T-cells then contact the nearby "B-cells", which receive information from the T-cells about exactly what the invader's surface coat looks like. The "B-cells" then make an antibody to attack this particular coat, leaving every other body cell alone. Once coated, the invader in quickly destroyed by other roaming WBC's. To keep the process from getting out of hand, "T-Suppressor" cells kick in and reduce the immune response. If this system doesn't work well, "auto-immune" diseases like rheumatoid arthritis or Lupus can develop.

Similarly, a strong immune response will cause the rejection of a transplanted organ, so "immunosuppressive" drugs will be needed to tone down the immune response. T-helper cells can recall for many years what a germ looks like, and then quickly activate an immune response if exposed to it again. This is the principle of vaccination. While T-helper cells can live many years, other WBC's only live for 8 to 12 hours, so must continuously be replaced to avoid infection. The "T" and "B" lymphocytes may be found circulating in the bloodstream, stuck in the bone marrow, or living in clusters in "lymph nodes". These lymph nodes, or "glands", are normally pea-sized filters which purify the blood. Lymph nodes are connected to each other via lymph channels which can act as conduits for spreading infection or cancer. Lymph nodes normally swell when working on fighting an invading germ, since more WBC's are being produced in them. This is seen in mumps and groin infections. They will also swell if invaded by cancer, whether it starts inside migrates from outside of the lymph node. There are also areas of "lymphoid tissue" containing the germ fighting WBC's in the tonsils, spleen, liver and intestines. Germs are usually quickly and effectively killed by the immune system, without us ever being aware of them! Thus the immune system is a dynamic process which normally saves our lives every day.

Lymphoma is actually a confusing myriad of diseases, the classification of which is still argued about today. Normally, the production of new WBC's is under strict control of the immune system, regulated by the "genes" inside of each cell. The genes determine whether more copies of the cell should be made to fight a particular infection, via sensing a particular stimulation (such as a piece of the germ) from the infecting agent. The common element in all lymphomas is that an alteration occurs in the genes of a single cell, leading to it's uncontrolled division. That is, it makes millions of copies, or "clones" of itself. Any WBC that has been exposed to an invader undergoes a change in it's genes ("rearrangement") which now will identify it. If it loses control of it's division processes, it also fails to perform it's regular functioning, which compromises the delicately balanced immune system. Ultimately, all cancers are diseases of the genetic material ("DNA") within the genes of the affected cell. Cancers have different names depending upon what type of cell is affected (i.e. lung, liver, prostate, myeloma) but the basic process remains the same - uncontrolled production of abnormal cells. These cells then have the capacity to spread to other body areas, which is the definition of "malignant". The actual process of spread is called "metastasis", and is what makes cancer so dangerous.

Lymphoma is divided into "B" and "T" cell types, and is simply when these cells, at some stage of their development, start dividing out of control, lose their ability to fight infections, and shunt nutrients away from normal cells. It is different from leukemia, another type of blood cancer, by the fact that it develops in lymph nodes, although it may spread to any body area. In fact, some chronic types of leukemia and lymphoma may be indistinguishable. Lymphoma may be aggressive or indolent; their are lots of types. Hodgkin's and Non-Hodgkin's lymphoma is the first distinction.

Hodgkin's versus Non-Hodgkin's Lymphoma

A particular type of lymphoma was first described in 1832 by Thomas Hodgkin, who saw swollen lymph nodes in patient's necks not attributable to inflammation. Some cells from these lymph nodes were seen to have 2 nuclei, called "Owl's Eyes" or "Reed-Sternberg" cells. This was the first identification of any lymphoma, and it was called "Hodgkin's Lymphoma" after it's discoverer. While Hodgkin's virtually always started in lymph nodes, spread continuously from one "chain" of nodes to another, and uncommonly involved bone marrow, it became obvious that some "lymphomas" did not follow these rules, and were different . Thus, the first major distinction was between "Hodgkin's" and "Non-Hodgkins" lymphomas. Over the ensuing century, finer distinctions were noted between these types, including that Hodgkin's rarely involved the liver or nervous system, while Non-Hodgkin's often did . While all Hodgkin's disease started in lymph nodes, only 45% of Non-Hodgkin's did, and those that started elsewhere were called "Extranodal" . Furthermore, it was very common for Non-Hodgkin's to "skip" to distant body areas, something very rare for Hodgkin's. Non-Hodgkin's was much more likely to involve body areas below the chest than Hodgkin's. In the 1950's when therapies became available for these diseases, it was seen that their response and curability were also much different. Although much finer classifications between lymphoma types are now available, the historic distinction between Hodgkin's and Non-Hodgkin's Lymphomas continues to be useful today.

How Common is Non-Hodgkin's Lymphoma?

Each year in there are about 45,000 new cases of Non-Hodgkin's Lymphoma in the U.S.A. (compared to 7500 new cases of Hodgkin's Disease). Lymphoma causes about 22,000 deaths annually. The incidence (number of new cases each year) of lymphoma has been steadily increasing over the past century. Some of this increase is due to better diagnosis, but the disease has definitely gotten more common . Reasons for this are appreciated when considering increases in the the "risk factors" below. As will be seen, different subtypes of Non-Hodgkin's lymphoma routinely affect different age groups. Thus, patients may be small children, adolescents, young adults, middle aged or elderly- the whole spectrum of human ages. Overall, the disease is more common in males than females, and Whites than Blacks.

What Causes, or Increases the Risk for Non-Hodgkin's Lymphoma?

As for any cancer, the precise reason why one person gets lymphoma and another does not remains unknown . However, by studying groups of patients, some things have been noted that seem to increase the risk, called "risk factors" :

Viruses - The Human Immunodeficiency Virus (HIV) which causes AIDS is strongly linked with increased "high-grade B-cell" lymphomas involving the brain. The Epstein-Barr Virus (EBV) which commonly causes infection mononucleosis ("mono") is linked to the "high- grade Burkitt's" lymphoma. Often both HIV and EBV are present.

"Immunodeficiency States" means the immune system is malfunctioning . Full-Blown AIDS decimates the immune system, and is associated with high-grade B-cell lymphomas of the brain (much more commonly than just having HIV alone). This is a prime reason for the increase in lymphoma seen in young adults. Other things that depress the immune system are medicines taken to prevent rejection of transplanted organs ("immunosuppressives"). If a person takes these drugs after a transplant, their risk of lymphoma will in- crease by about 100 times! Certain "Autoimmune" diseases (like Rheumatoid Arthritis, Hashimoto's disease, Lupus, Scleroderma) affect immune function and increase risk. Also, inborn "immunodeficiency syndromes", (e.g. ataxia- telangiectasia, Wiskott-Aldrich, SCIDS, agammaglobulinemia) while rare, will increase lymphoma risk. Finally, very poor nutrition and/or severe depression lower immune response, and may increase the risk over time.

Pre-existing Hodgkin's Disease or blood manufacturing ("myeloproliferative") disorder increases the risk, particularly after successful treatment! This has led to the idea that Chemotherapy and Radiation Therapy, and especially both together, increase risk. Recall that cancer is basically a malfunction of a gene which has become altered. Anything capable of changing ("mutating) the gene might lead to cancer, and Chemotherapy and Radiation do affect the DNA and the genes it forms. A chemical which causes cancer is called a "carcinogen". "Alkylating agent" chemotherapy (i.e. mustard gas derivatives like cytoxan) are known to increase the risk for "non-lymphocytic leukemias"; they may increase lymphoma risk also. For myeloproliferative diseases, like Polycythemia Vera, "Alkeran" (an alkylating agent) is often used to decrease high red blood cell counts- and these patients more commonly develop lymphoma. What is not yet settled is how much of the risk is attributable to the primary disease, and how much to it's subsequent therapy.

Geographic Area - Some lymphomas tend to occur in "clusters" in specific parts of the world, leading for clues to their causes. In America, a higher in- cadence of low-grade lymphomas the Midwest "grain belt" has led to the idea that pesticides used on crops raise the risk. In Africa the high rate of high- grade Burkitt's Lymphoma in children has led to a virus (EBV) being a risk factor, but in America EBV is more closely related to Hodgkin's Disease! Thus, the "genetic susceptibility" of the local population, in combination with the DNA disturbing agent(s) found there, together may ultimately foretell lymphoma risk.

What are the Types of Non-Hodgkin's Lymphoma?

This is a difficult question, for experts as well as laymen, since there are so many apparent types of lymphoma! Furthermore, more subdivisions are being discovered, and new classification systems proposed. It's almost as if "lymphoma" was a term to pidgeon-hole a whole spectrum of diseases, with different treatments and outcomes.

One useful distinction which has survived, as mentioned, is distinguishing "Hodgkin's" from "Non-Hodgkin's" lymphoma. It is in the sub-classification of the Non- Hodgkin's type that things become confusing. For instance, expert pathologists (doctors who specialize in diagnosing disease) has differed on whether classification should be based upon:

What the cells look like under the microscope?
What type of stains do the cells take up?
What kind of surface proteins ("markers") are on the cells?
What do their gene sequences look like?
Do the cells clump ("nodules") or are they scattered ("diffuse")?
What about clinical behavior? How aggressive is the disease?
How closely do the cells look like regular inflammatory cells?
Are the cancerous cells "T-cell" or "B-cell" lymphocytes?
How likely are the cells to spread, and to what areas?

What combination of the above factors should be used for a classification system remains in debate, but for some consistency, a "Working Formulation" has been developed (in the meantime!) to describe Non-Hodgkin's lymphoma. Combining this Formulation with added distinction for "B-cell" or "T-cell" origin leads to this schema:

B-Cell Non-Hodgkin's Lymphoma

Low Grade: (In general this means that disease smolders for a long periods (years) but that is it likely to be extensive when first diagnosed- having already gone to the bone marrow. It has the longest survival, but is ironically the hardest to cure, and more commonly effects the elderly than the young.)

Small Lymphocytic Lymphoma means the disease looks a lot (or is the same as!) Chronic Lymphocytic Leukemia ("CLL") - patients tend to be over 60 years old, most have extensive lymph node swelling and bone marrow is involved. Patients may go many years before diagnosis, and live about 7 - 10 years.

Follicular Lymphoma may be "Small Cleaved", "Large Cell", or "Mixed" . Follicular lymphoma usually presents isolated in lymph nodes, that is "nodular". Most of the patients have bone marrow involvement when diagnosed, but the disease usually progresses slowly and patients commonly survive 10 years. About 30% of patients even get a "spontaneous remission" without therapy. In fact, the effectiveness of any therapy for this disease has often been questioned. What is disturbing is that the disease can "transform" to a higher grade and very lethal lymphoma at any time.

MALT Lymphoma ("Mucosa Associated Lymphoma Tissue") start outside of the lymph nodes ("extranodal") in such areas as the lung, stomach, thyroid and breast. They are sometimes seen along with an autoimmune disease that affects the organ, and were sometimes not even considered true lymphoma in the past ("pseudolymphoma"). The tend to stay localized, and patients will usually survive many years even if the disease is unrecognized and untreated.

Mantle Cell Lymphomas arise from cells that surround the "germinal centers" within lymph nodes. Germinal centers are where new "B-Cells" are forming; as more cells form, they spread out to make "follicles" . Around the follicles are slightly different "B-Cells" which form the "Mantle Zone" . A "marginal zone" or "parafolliclular" zone then surrounds each mantle zone. Further toward the periphery inside a lymph node, "T-Cells" are found, and the whole node is then surrounded by a "capsule" that acts as it's protective coat. Mantle Cell lympho- ma often starts in the gastro-intestinal area. Although low grade, it does a bit worse, on average, than follicular lymphomas. If the mantle cells plump up and congregate to form a "nodular" type pattern, it is better than if the spread out into the lymph node (a "diffuse" pattern).

Monocytoid B-Cell Lymphomas begin in the "marginal zone" of B-lymphoctyes described above; the cells appear like those in hairy cell leukemia. The cells are called "monocytoid" since they superficially resemble monocytes, a large type of white blood cell. The elderly are mostly affected, and survival is similar to follicular lymphomas.

High Grade B-Cell Lymphomas: In the "Working Formulation", B-Cell lymphomas are separated into low, inter- mediate and high "grades" . Most researchers now feel that the "intermediate" and "high" grade categories can be lumped together, since their behavior is very similar or identical. Thus, newer proposals for classification simply state "low" or "high" grade, as is done here. An interesting paradox is that while high grade lymphomas have untreated survivals of only about one year, they are actually more curable than low grade lymphomas! High grade lymphomas are much more likely (80%) to be localized when first diagnosed, and so only about 20% of them have spread ("disseminated") to bone marrow. Over 80% of these localized lymphomas are curable with conventional therapy, and and about 40% of the disseminated ones are curable. This contrasts with the longer untreated survival (often 10 years) in low grade lymphomas- but the near impossibility of "curing" them with conventional treatment! Diffuse "Large Cell", "Mixed", and "Immunoblastic" Lymphoma are all high grade and demand urgent treatment.

Nodular Lymphomas come from "B-Cells", about 80% of diffuse, high grade lymphomas come from B-Cells and the remainder from "T-cells" (to be discussed) . The Diffuse lymphomas do not have the solid, compact "architecture" seen in lymph nodes (with a micro- scope) that the low-grade nodular type exhibit; instead the cancer cells pervade though the lymph node. This is the type of lymphoma seen most commonly in AIDS and Organ Transplant patients, it may be harder to treat because of the depressed immune function of these patients (they may not tolerate aggressive chemotherapy). The disease often involves the upper throat ("Waldeyer's Ring") gastro-intestinal tract, abdominal ("mesenteric") lymph nodes, bone and brain. Furthermore, involvement of the bone marrow and brain linings ("meninges") is commonplace at diagnosis. Both HIV and Epstein-Barr Virus (EBV) are often present together in these patients (see "risk factors"). In patients who's immune systems are suppressed by drugs to prevent transplanted organ rejection, sim- ply lowering the amount of "Immunosuppression" may cure the lymphoma!

Small Cell Non-Cleaved Lymphomas are another type of high grade disease, also seen in young patients and in the context of AIDS or immunosuppressive drugs. These lymphomas are extremely aggressive, and subdivided into "Burkitt's" and "Non-Burkitt's" types. This difference is currently academic, based upon microscopic appearance of the cells. Classical "Burkitt's" lymphoma is found as an "endemic" African type (i.e. common to that area) and a "sporadic" type that may arise anywhere, anytime. Again, these differences are academic, since any type of Small Cell Non-Cleaved Lymphoma is aggressive and demands immediate treatment if the patient is to have a chance of survival.

T-Cell Lymphomas make up a very diverse category, again not well described by the current "Working Formulation". Their spectrum of behavior is confusing for the medical student; some types seem to only involve the skin and be seldom fatal, while other types grow into large chest masses and are rapidly fatal. The most basic differ- fence is between the less aggressive, low grade "PERIPHERAL" T-Cell lymphomas, and the highly aggressive, high grade "IMMUNOBLASTIC" T-Cell lymphomas :

Mycosis Fungoides often only involves the skin, and was once not even thought of as a lymphoma. Patients may have the disease go unnoticed for years. While some patients with mycosis fungoides have rapid development of skin plaques (mycosis means "fungus like") and need intensive therapy (such as electron beam to their whole skin) others have very little disease that is easily cured in a dermatologist's office. The first stage of the disease is called the "pre-mycotic" phase, that may last for many years. Eventually skin "plaques" ("plaque phase") form, followed by the "tumor stage" - with involvement of lymph glands. When the "T-Cells" are fond in the circulating blood, this is "Cicero Syndrome" showing the disease is advanced. Ultimately, liver, spleen, lung and kidneys are affected.

Anaplastic (Kiwi) Large Cell Lymphoma may affect children or adults and often is initially diagnosed as skin cancer (i.e. melanoma). The disease is often limited to the skin, as mycosis fungoides (above), but can ultimately involve any organ. Happily, some cases spontaneously resolve, and others respond well to therapy. Angiocentric Immunoproliferative Disease, as the name implies, says that abhor- ma immune cells (in this case T-cells) are forming around blood vessels and destroying them. "Lethal Midline Granuloma" (often curable!) involves sinuses, while another type called "Lymphamatoid Granulomatosis" affects lung, digestive system, skin and nervous systems. The basic problem in both of these diseases is an overactive immune system spewing out abnormal T-cells bent on destruction. It historically was not considered a lymphoma, and may not be in the future.

Lennert's Lymphoma ("Lymphoepithelioid" lymphoma) is a more aggressive illness than standard Hodgkin's, which it used to be subclassified as. It is now considered a Non-Hodgkin's lymphoma which is seen to co-exist in some cases of advanced Hodgkin's disease. It involves sinuses, GI tract , lung and spleen, and this diffuse nature makes it harder to cure, with average survival of one year. Adult T-Cell Leukemia-Lymphoma is seen in association, or caused by, the HTLV-I virus which is related to the HIV ("AIDS") virus. It is rare in the UPS., but has the bad characteristics of both lymphoma and leukemia, with organ swelling, fevers, lower- ed immunity, brain and bone marrow involvement. It is difficult to cure because the immunosuppression makes infection likely- the virus lives in the same white cells that are necessary to fight infection! The disease may initially lie "dormant" (much like HIV) but once it manifests, life expectancy is only about 10 months. ***From the above spectrum of diseases, you can appreciate why T-Cell lymphomas are a confusing entity- with life expectancies ranging from a few months to normal!

Lymphoblastic Lymphoma are always aggressive, predominantly occurring in male adolescents. The disease is often first noticed as a large mass in the front ("anterior") portion of the middle of the chest ("mediastinum"). This mass grows and causes shortness of breath. It may cause fluid leakage into the lungs or about the heart ("effusions") and quickly spreads to bone marrow and brain linings. It is considered even more aggressive than B-Cell Immunoblastic lymphomas. If not treated, the disease is usually fatal in 6 months, but with proper therapy (similar to that used for childhood leukemias) it's often cured.

How is Non-Hodgkin's Lymphoma Detected and Evaluated?

As is evident from the above descriptions, there is a wide variety of "behaviors" that Non-Hodgkin's can follow, depending upon the particular subtype. If a patient comes to their doctor with "signs" (things measured) or "symptoms" (things felt) of lymphoma the following is standardly done:

Physical Examination should be completed, including a pelvic exam in women. Some particular items noted are skin paleness and texture, signs of jaundice (yellowing of eyes) showing liver problems, enlarged glands in the neck, groin or armpit region, and swelling of the liver or spleen on abdominal exam. Any swelling of a limb may be the result of blockage of draining lymph channels by enlarged lymph nodes. The patient is asked asked about night sweats and fatigue, and checked for bruising, fever, and signs of recent weight loss.

Routine Blood and Urine Tests include the standard Complete Blood Count (CBC) which documents anemia (shown as a hemoglobin under 12 grams) and the size and shape of the red blood cells. If the red blood cells are small ("micro cytic") it can indicate iron deficiency anemia from lack or iron or chronic bleeding; if they are too large ("megaloblastic") it indicates foliate or B-vitamin deficiency. The CBC also gives the number of platelets (normally 150,000 - 400,000) with under 100,000 indicating too few and under 50,000 being at high risk for spontaneous internal bleeding. Importantly, the CBC tells the number of white blood cells per milliliter of blood (normally 3,000 to 10,000). The cells are examined in a blood smear, called a "differential", describing the type of white cells present, along with abnormal sizes and shapes. The abnormal "clone" of B-cells or T-cells may be in the circulating blood, or it may not. Thus, "peripheral blood smear" alone does not diagnose lymphoma. The number of "reticulocytes", which are immature new red blood cells, is noted.

Another blood test which helps distinguish actual lymphoma from "leukemoid reactions" (increased white cells due to some other cause) is the LAP score This test, which measures an enzyme called "alkaline phosphatase" in white cells, is low in leukemia/lymphoma but normal or high in benign disease. It is routine to get a "Coomb's Anti globulin" Test (Direct Coomb's) if lymphoma is suspected, patients may develop an "auto-immune hemolytic anemia" meaning that their immune system is attacking their own red blood cells.

The next standard blood test is a Blood Chemistry Panel (SMA) which tells sodium, potassium, chloride and bicarbonate (together called "electrolytes") and blood sugar and cholesterol. It also measures liver and kidney function with enzyme tests, and suggests whether someone has had a recent heart attack. Uric acid is an important test included in the SMA, it is a by-product of numerous white cells being broken down; uric acid is excreted through the kidneys. Too high uric acid in the blood can crystallize in the tissues to cause gout, or in the kidneys to make painful kidney stones.

A Standard Urinalysis (UA) tells about blood, protein and sugar in urine, as well as urinary tract infection or crystals of uric acid or calcium. If infection is suspected, the sample can be "plated out" onto a growth media dish to let the germs grow, identify their specific type, and prescribe the right antibiotic. Overall kidney function ("creatinine clearance") and amounts of excreted uric acid and calcium can be calculated from a 24 hour collected urine sample.

Bone Marrow Biopsy is a crucial part of the evaluation of lymphoma. Frequently it is done under local anesthesia from the hip bone above each buttock. Boring needles are used to penetrate the hard outer "cortex" of the bone and remove a core of the soft marrow inside. The importance of bone marrow biopsy is that the white blood cells are actually being produced within the bone marrow prior to their delivery into the bloodstream. Only in the bone marrow can the actual types and numbers of new cells produced be accurately tallied. Recall that most low-grade lymphomas are present in the bone marrow at diagnosis. Bone marrow tests may be repeated during treatment to monitor response, confirming "remission" (clearing of all obvious lymphoma cells from the body).

Radiology Tests include standard Chest X-Ray looking for tumors and signs of pneumonia or lymphocytic infiltration of the pleural lining of the lungs. For a suspicious Chest X-Ray, a confirmatory Chest CT scan is ordered, it will provide much greater detail than plain X-Ray. To confirm the presence of an enlarged liver or spleen, or look for lymph gland swelling within the abdomen, an Abdominal CT scan is helpful. CT is basically a set of multiple X-ray slices fused together; if "contrast" is used the blood vessels are highlighted and the scan is more detailed. The contrast is injected into an arm vein; "omnipaque" brand (or equivalent) contrast is more expensive but less likely to cause an allergic reaction or kidney problems. If an area of bone becomes painful, Plain X-Rays of the bone can help tell if there is a destructive tumor present, and a "Bone Scan" (where radioactive dye is injected into a vein and preferentially taken up by cancer spread to bone) may show abnormalities even if a plain X-ray is normal. A scan is taken of the whole body after the dye is injected, so any suspicious area of bone may be examined. In general, more than 1/2 of the cortex of a bone area must be destroyed to show up on a plain X-ray; bone scan is more sensitive. Other exotic tests like Magnetic Resonance Imaging (MRI), liver-spleen scan, Gallium scan, Brain CT scan, IMP and Barium enema are only done if therapy changes justify their discomfort and high cost.

Lymphangiography is where dye is put into leg veins and plain X-rays are taken to image the lymph glands in the pelvis, it is justifiable for lymphoma if the radiologist is very experienced with it. The test is difficult to perform and to interpret; it shows if certain lymph nodes are swollen in the pelvis and in the abdomen ("paraaortic nodes") but fails to "opacify" (highlight) other important lymph nodes in the pelvis, and so may totally miss disease there. It used to be routine for Hodgkin's and Non-Hodgkin's, but is now done in select hospitals.

Specialized Pathology Tests include looking for the particular type of cell that has become cancerous by the process of "immunophenotyping". Basically, all blood cells start out from a common precursor "stem cell", and cells put out special protein markers on their surfaces as they mature, called antigens. By identifying these antigens, we can tell exactly the cell type we are dealing with. Also, the antibodies that the white cells excrete can be identified. There are certain well recognized gene abnormalities, called "translocation", often seen in lymphoma patients. A translocation means a piece of a chromosome (which contains many genes) has broken off, and somehow attaches to a different chromosome. For example, in many follicular lymphomas a piece of chromosome #14 has broken off and attaches to chromosome #18, while in Burkitt's lymphoma a piece of chromosome #8 attaches to chromosome #18. While classifying lymphomas is still based upon their appearance under the microscope, in the future classification may rely on the genetic abnormalities. The chromosome analysis is usually done on the bone-marrow biopsy cells, but can be done on a regular blood smear if the cancerous cells are present in sufficient numbers. The science jargon word for chromosome analysis is "karyotype" . The cells are stimulated to divide (so the chromosomes are visible) and photographed; the 23 pairs and 2 sex chromosomes are studied. Finer tests for gene rearrangements which can lead to cancer are done by specialized laboratories, and include tests such as "Southern Blotting" and "Polymerase Chain Reaction" to identify actual genes.

Lymph Node Biopsy is useful for making the diagnosis, especially if the bone marrow is not involved. If a group of lymph nodes is swollen,the largest one is removed (under local anesthesia) and sent to a "pathologist" for review. A pathologist is a physician who specializes in diagnosing disease from tissue samples. It usually takes several days (of anxious waiting) for results. For Peripheral T-Cell Lymphomas like mycosis fungoides, a skin biopsy may make the diagnosis (but alone will not define the extent of disease). 7) Laparotomy and Splenectomy means actually doing abdominal surgery to check the extent of the lymphoma; it is not done to make the initial diagnosis. Since this is considerable surgery under general anesthesia, it is only done if the results will change the patients therapy. Patients with large masses in the chest are a high anesthesia risk; it may be impossible to remove the ar- tificial ventilation after surgery. When "Laparotomy" is done for staging, the abdomen is opened and any obvious tumor biopsied. Lymph nodes are then samples, with any enlarged ones removed. The liver is biopsied, and the en- tire spleen is removed (for slicing into thin sections for examination). Partial spleen removal is inaccurate and not practical due to bleeding problems. A consequence of spleen removal, especially in children, is greater likelihood of infections with "encapsulated" bacteria (strep, hemophilus, salmonella).

While "staging Laparotomy" is often done in early Hodgkin's to "rule out" any disease below the diaphragm (so the patient can be treated with radiation only), the usually wide-spread nature of Non-Hodgkin's lymphoma makes it less likely that Laparotomy will change the planned therapy. That is, since chemotherapy will almost certainly be necessary, Laparotomy will seldom determine that the patient can get radiation only for Non-Hodgkin's disease. A possible exception to this is for very early lymphoma apparently localized to a single area, where radiation alone may be curative. Again, Laparotomy (and most all surgery for lymphoma) is DIAGNOSTIC, NOT THERAPEUTIC - that is it doesn't do anything to cure the disease, but merely says how to best treat it! Rarely, surgery can cure early, extremely localized lymphoma.

How Is the Extent of Lymphomas Gauged?

As for any cancer, the extent of lymphoma is described by the "Stage". Every major type of cancer has it's own staging system, and sometimes more than one system is in common usage. Some staging systems are more descriptive and accurate than others in predicting how well (or poorly) patients will do. For Non-Hodgkin's lymphoma the same system is used as for Hodgkin's Disease; it is called the Ann Arbor system. The problem is that staging is supposed to reflect survivals, but the particular subtype of Non-Hodgkin's lymphoma is more predictive for survival than the Ann Arbor stage. However, the staging does give some idea of how widespread the disease is in the body:

Stage I means a single lymph node "region" (i.e. axilla, cervical, inguinal) is involved (more than one lymph node may actually be involved)
Stage IE means a single "extralymphatic site" (i.e. bone, brain, stomach) is involved- the disease started somewhere besides a lymph node.
Stage II means two or more lymph node regions are involved and they are both either above or below the diaphragm .
Stage IIE means single lymph node "region" and a single "extralymphatic site" (i.e. cervical lymph nodes in neck, and Waldeyer's Ring in throat).
Stage III means two or more lymph node regions are involved, and are located above and below the diaphragm.
Stage IIIE means in addition to stage III, an "extralymphatic site" is involved, such as the spleen (stage IBIS) or lung (stage IIIE) or all (stage IVIES)
Stage IV means diffuse, or widespread involvement of nodes, organs, and other extralymphatic sites. For instance, bone marrow or central nervous system involvement are stage IV. In practice, stage IV means disseminaked disease to multiple body areas.

When the spleen is involved, the stage is followed by an "S". When another organ (besides spleen) is involved, the stage has an "E" . When both the spleen and another organ are involved, the stage is "ES" . When patients have greater than 10% weight loss, or night sweats, or chronic fevers, these are called "B-symptoms" and the stage is followed a "B" (when the symptoms are present) or "A" (when they are absent). Generally, "B symptoms" suggest spread to bone marrow.

What is the Survival from Lymphoma?

Survivals do not clearly follow the stages, as they do for Hodgkin's Disease. Instead they are closer related to the particular subtype of Non-Hodgkin's lymphoma. Overall:

Low Grade Lymphomas seem rarely curable, but the average life expectancy is 8 years for Follicular lymphomas and 5 years for Mantle Zone lymphomas. This will include demise from all causes (i.e. heart attack, a different cancer)- many of the patients are elderly and so have "co-morbid" conditions shortening lifespan. Many otherwise healthy patients do live over 10 years with these low grade lymphomas.

High Grade Lymphomas will kill quickly (within one year ) if untreated; those that were classified as "intermediate" grade in the Working Formulation may have two year untreated survivals. With treatment, some patients will be cured, and have normal life expectancies, and some will not, and so will succumb within a year or two. Ironically, the more aggressive disease is also the more curable!

What Determines Survival in Lymphomas?

Factors affecting survival are called "prognostic factors" which are elucidated by carefully studying groups of patients- how their disease presents and how they respond to particular therapies. This studying allows us to draw conclusions about what things are likely to be good ("favorable") or bad ("unfavorable") for a patient. While some things are controllable (type of therapy) other are not (type of cancer, age). Some general conclusions about what is favorable or unfavorable in lymphomas, and depend upon whether they are low or high grade:

Low Grade Lymphomas

-Early stage is better than late stage (just 20% of patients are early stage I & II).
-Follicular is better than Mantle Zone, Small (cleaved) Follicular better than Large.
-Rapid response to therapy is better than failure to respond.
-"B-Cell" types do better than the rare "T-Cell" type.
-A high lymphocyte count in the blood smear may foretell "transformation" to a
more aggressive grade (15% of patients) and is bad.
-"B-Symptoms" are worse than none present ("A").

High Grade Lymphomas

-Stage is important with early stage (I & II) doing better than later stage (III & IV).
-Smaller tumors (under 10 cm. ~ 4 inches) do better than larger tumors.
-Age is important with patients younger than 60 do better than older patients.
-Better "Performance Status" (general ability to take care of one's self) is better.
-Quick response to therapy better than slow response.
-"B-Cell" types do better than "T-Cell" types.
-AIDS or Organ Transplant associated types do worse than spontaneous types.

What is the Conventional Treatment for Non-Hodgkin's Lymphoma?

The conventional treatment for low grade lymphoma is observation, just alleviating symptoms as they arise. For high grade lymphoma, treatments have been Surgery, Radiation Therapy, and Chemotherapy . The purpose of each of these "modalities" is to remove or kill the cancerous cells, hopefully leading to cure of the disease. Surgery and Radiation Therapy are "local" treatments, they do nothing for disease which has spread outside their areas. Chemotherapy is a "systemic" treatment, meaning it goes throughout the body to (ideally) treat disease everywhere. Each of the conventional therapies has had significant advancements in the past 2 decades, and the use, side effects and results of each is now discussed in detail.

Surgery has a very limited role in lymphomas; the disease is often spread at initial diagnosis and surgery is only a local therapy. As mentioned, surgery is indispensable in making the diagnosis; usually by biopsy of the most suspiciously enlarged lymph node. Very localized high-grade lymphomas of the stomach, intestines or thyroid may be cured by surgery, it is crucial to do a complete "staging evaluation" to try and make sure the disease is truly localized. Surgery is preferred as the initial treatment for localized gastro-intestinal lymphomas, since we are worried that if chemotherapy is given, it may cause bleeding or even perforation (a hole through) the stomach as the lymphoma cells die. Also, surgery allows us to actually see how locally extensive the disease there is, to sample local lymph nodes that are normally inaccessible.

Obviously, any major surgery has risks of general anesthesia (1 in 10,000 death rate), infection (10%), wound splitting open ("dehiscence")(5%), blood clots or heart attack in the "perioperative" period (5%) and failure to get all the cancer (25%). The risks will of course vary with the overall condition of the patient, but recent heart attack (within past 6 months) is considered a "contra-indication" (reason not to do) anything except emergency surgery. Overall, the death rate ("mortality") from major surgery for lymphoma is 5%, and the complication rate ("morbidity") about 15%. Recovery time from abdominal surgery is about 3 weeks; it takes this long for tissue strength to return to 75% of normal. After 3 weeks weight can again be lifted. It is now considered important to get the patient out of bed within a couple days of surgery to reduce the risk of blood clots, and to do breathing exercises into an "incentive spirometer" at the bedside to reduce pneumonia risk.

Another surgical procedure sometimes done in lymphoma is spleen removal ("splenectomy") when this organ becomes grossly swollen ("splenomegaly"). When the spleen becomes enlarged, it can trap blood cells, causing anemia. When the spleen is removed, the risk of later infection with "encapsulated bacteria" (see "Diagnosis and Evaluation") is increased. Another option besides surgical removal of the spleen is to give it low dose Radiation Therapy to shrink it and raise the blood counts (see next section).

The results of surgery would be, obviously, complete cure if every lymphoma cell was removed. Unfortunately, even if the the disease appears entirely localized, there is often undetected local spread, or escaped distant disease ("micrometastasis") . Thus, surgery alone results in only a 35% or so cure even for "localized" extranodal lymphomas, and is usually combined with other treatment (i.e. radiation therapy) to raise the cure rate.

Radiation Therapy is a standard and important treatment for curing localized Non-Hodgkin's Lymphoma, or for relieving it's symptoms ("palliation") . It may be used "emergently" to shrink a large chest mass obstructing breathing, to alleviate compression on the spinal cord to prevent paralysis, to help prevent bone fracture, or as "definitive" (curative) treatment. Most lymphoma cells are easily killed by radiation.

Treatment is administered under a "Radiation Oncologist", a cancer doctor who specializes in utilizing radiation. Radiation kills cancer cells by damaging their DNA, they die when they try to divide. Thus, damaged cancer cells die even after the treatment is complete. Radiation will also kill normal cells, which limits the amount that can be given. However, it usually takes more radiation to kill normal cells than cancer cells, and normal cells can often repair the radiation damage, while cancer cells can not. Nevertheless, it is important to be as exacting as possible in the administration and dose of radiation, to minimize the injury to adjacent normal cells.

To receive therapy, a patient is first seen in "consult" by a radiation oncologist, who reviews the patient's medical record, complaints, and radiology films. After explaining the possible benefits and side-effects of radiation, the patient is scheduled for a "simulation" . This means the area to be treated is marked out on a replica treatment machine, and films are taken. Watercolor marks are painted on the patient to denote the treatment area, and eventually small, permanent tattoos are placed on the skin. If the area to be treated is in the head and neck, a plastic "mask" can be made and the marks placed upon this to avoid disfigurement. Sometimes the patient is sent for a CT scan along with the simulation, the whole process takes less than 2 hours, and is painless. Information from the simulation and relevant scans is placed into a "treatment planning computer", which generates a "plan" . This plan tells how much radiation is going to the tumor area, and how much to adjoining normal tissues.

For head and neck area radiation, such as the "Waldeyer's Ring" field, the dose to the brain, eye, and salivary glands is closely monitored. For chest area radiation, such as for a large mediastinal mass, limiting dose to heart, lung and spinal cord is crucial. For abdominal radiation, such as a stomach lymphoma, particular attention is paid for how much radiation is going to the liver, small intestine and spinal cord. For pelvic radiation, such as bladder lymphoma, dose to small intestine, bladder and rectum is monitored. The whole brain and spinal cord may be treated for fulminant central nervous system lymphoma. For all lymphomas, The beam may be aimed from 2 or 4 directions (front, back, right and left sides) to uniformly dose an area. Higher energy treatment machines (over 15 Megavolts) also help smooth out the dose to deep organs. The plan is reviewed by the radiation oncologist and also by a specially licensed Radiation Physicist prior to starting therapy. The patient then comes in for their "treatment start" . They are placed on a hard, flat table in a specially shielded room and aligned with laser lights. The actual treatments are given by "Radiation Therapists", or "R.T.T's", who are first certified for diagnostic X-rays and then get additional training to deliver therapy. For the first treatment, "verification films" are taken to ensure proper positioning; they do not tell anything about the cancer. The actual treatment only takes a couple of minutes and is given with a Linear Accelerator (or occasionally older Cobalt-60) which precisely aims a beam of photons at the treatment area. For superficial lymphomas, or those in the head and neck, electron beam gives a higher skin dose, while for deep tumors photons give a higher dose.

A mixture of photons, electrons, and beam energies may be used to optimally treat an area. For mycosis fungoides, the entire skin may be treated with electrons, but for most lymphomas smaller regions are treated with photons. The head of the machine can swivel about the patient, to give the treatment from different angles. The patient needs only to lie still. Areas that are not to be treated can be "blocked" with special lead-type blocks in the head of the treatment machine. Normally, patients area treated 5 days a week, Monday through Friday, taking only several minutes each day. The usual dose for lymphoma is 30 to 50 Gray (units of radiation) given at 10 Gray per week. If a treatment is missed, it is simply tacked on to the end so full prescribed dose it given. It is common to "cone down" after most of the treatments are given and shrink the field to treat the original tumor area only, to give it the highest dose. This is called a "boost."

Radiation to any area is painless, the patient does not become "radioactive", or get "radiation sickness". Side effects are normally only in the area of treatment, so scalp hair will only be lost if the scalp is being treated, and sterility will only result if the testicles or ovaries are treated. The patient can usually maintain normal activities, such as working, driving, and intake of alcoholic beverages. The side-effects of External Beam treatments are classified as "acute" (during treatment) or "late" (months to years after treatment). The most common acute symptoms are reddening of the skin in the treatment area, and mild fatigue. Specific side effects by area:

For brain irradiation, the scalp hair falls out after about 1 week of treatment but should eventually grow back. The scalp may get red, irritated and the skin may peel. The ears are especially likely to get irritated, and there may be some middle ear pain. The patient is usually quite tired and has less appetite from brain radiation. For late effects, hormone levels are reduced are may need to be artificially replaced. The patient may have a prolonged period (months) of fatigue, called "somnolence syndrome". The lens of the eye will probably develop cataracts after several years, but these can be removed surgically like other cataracts. Brain radiation is well tolerated.

For head and neck irradiation, the mouth will become dry ("xerostomia") as the salivary glands are treated, it is important that the teeth are checked by a dentist prior to starting therapy. Taste is less acute ("dysgeusia") and most patients prefer sweet foods. Acutely the inside of the mouth may become sore, and prone to treatable fungal infections. Unfortunately, the mouth dryness and taste loss tend to be permanent.

For chest area irradiation, there is usually progressive pain on swallowing as the esophagus (food tube) gets irritated, as well as the usual skin redness and fatigue. Rare but possible later effects are pneumonia caused by radiation damage to lung ("radiation pneumonitis") with cough, fever, and shortness of breath. This is usually treatable with steroids but may be fatal. The heart lining can become irritated and weep fluid ("pericardial effusion") requiring drainage to relieve pressure on the heart ("constrictive pericarditis"). Most fearsome is spinal cord damage, there is a 1% risk of paralysis with doses of 50 Gray to the "cord" ("transverse myelopathy"), irreversible.

For abdominal area irradiation there is often acute nausea or vomiting with high dose treatment that can be helped by lowering the dose per treatment and/or "anti-emetic" drugs (i.e. Compazine, Zofran, or Marijuana pills (Marinol). We want to avoid high doses to the liver (above 25 Gray) to prevent "radiation hepatitis", and to the stomach to reduce risk of gastric bleeding. Also, the kidney stops working after about 30 Gray, so both kidneys are never given high dose radiation. When giving spleen radiation, the dose is usually just 0.5 Gray or so twice per week with monitoring of blood counts. Substantial dietary modification during treatment may be necessary to prevent malnutrition. Late effects include intestinal malabsorption, and intestinal obstruction requiring surgery (5% of patients). Also, the spinal cord tolerance must be respected (45 Gray) to reduce the low but present risk of paralysis. In young women, the dose to sterilize the ovaries is about 12 Gray, but they won't get this much even if the stomach is given 40 Gray, with careful planning.

For pelvic area irradiation, it is common to develop frequent urination and diarrhea as the bladder and rectum (respectively) become irritated. The anal area can get itchy ("pruritis"). Prescription of soothing steroid suppositories and anti-diarrheal medicine is usually all that's necessary to treat these acute reactions. In men, the dose to the testicles from pelvic area irradiation is quite low (1% of the dose from scattered radiation) and so shouldn't cause sterility. On average, 5 Gray is necessary to the testicles for sterilization, but more (15 Gray) to stop male hormone production. Late effects include possible chronic diarrhea (5%), urethral obstruction (2%), impotence from male prostate radiation (40%), vaginal dryness in women (can be relieved with estrogen creams (20%) and bowel obstruction requiring surgery (5%).

The results of "definitive" (curative) radiation alone for localized high grade Non-Hodgkin's lymphoma are about 80% apparent cure rate at 5 years. This includes patients with single small skin involvement (~ 1 inch), bone, GI tract, thyroid, eye, breast and testes. For total-skin electrons for mycosis fungoides, about 40 - 50% of patients are apparently cured. The results are much poorer for brain lymphoma, especially in AIDS patients (5% at 5 years) but may be improved with combination chemotherapy in addition to radiation. Palliation (symptom relief) in advanced disease is over 90% with proper radiation. Patients should be carefully monitored for relapse after radiation alone, and if detected they will then be recommended chemotherapy, as described below.

Chemotherapy is the cornerstone of treatment for lymphoma, and has been for 40 years. Only chemotherapy goes throughout the body to treat lymphoma cells that have migrated to the bone marrow or distant organs. However, due to the "blood-brain" barrier, chemotherapy may poorly penetrate into the brain, spinal cord, and testicles. These areas are called "sanctuary sites" and may harbor malignant cells and require special treatment. This means disturbing the blood-brain barrier with chemicals or radiation, and/or giving drugs right into the spinal canal ("intrathecal chemotherapy") . As mentioned, Non-Hodgkin's lymphoma is usually a disseminated disease at diagnosis. For low grade lymphomas, like the Follicular type, just 25% of patients have disease on only one "side of the diaphragm (i.e. upper or lower body) and patients widespread disease, including to bone marrow, about 80% of the time. While for high-grade lymphomas local presentation and absence of bone marrow involvement is more common (25%), the disease may still have unrecognized spread at diagnosis and relapse elsewhere later. Furthermore, just because the disease is localized does not guarantee surgery or radiation alone is practical, since the area may be too sensitive to remove surgically or not encompassed in a safe radiation field (for the dose required). Moreover, if the patient relapses after surgery or radiation therapy, chemotherapy is only current effective treatment left.

The original effective chemotherapy for Non-Hodgkin's lymphomas, and still the "gold standard" by which other regimens are measured, is abbreviated as "CHOP". This is a modification of the therapy for Hodgkin's Disease ("MOPP"). The CHOP regimen is a 4 agent combination, that is "combination chemotherapy" . The specific drugs are Cyclophosphamide, Adriamycin, Vincristine and Prednisone . This is a very powerful combination that produces "complete response" (no apparent disease- full "remission") in about 70% of patients with aggressive lymphoma. The cure rate with CHOP is lower because of potential for relapse, and slightly above 50%. The side effects of CHOP can be formidable. They are a different for each of the 4 agents:

Cyclophosphamide is one of the first chemotherapy drugs developed, it is related to the "mustard gas" poison used in WWI. It comes as a pill, "cytoxan", and is taken daily during each "cycle" of chemotherapy. It's side-effects are a lowering of all blood counts (red cells, white cells, and platelets), hair loss ("alopecia") and irritation to the bladder, which can cause blood in the urine ("hematuria"). These effects abate after cyclophosphamide is stopped.

Adriamycin is a red liquid injected into the veins, it's also called "Doxorubicin". It is a very powerful drug used also for breast cancer. It damages the heart and lungs, and so must be limited to a dose of 500 mg. per square meter of body surface area (people are 1 to 2 square meters). It also lower blood counts and causes hair loss. Before starting adriamycin, most patients get a heart scan ("MUGA") to ensure they can tolerate the drug. If a patient gets radiation with or after receiving adriamycin, there is greater skin redness and peeling ("recall reaction").

Vincristine is another powerful drug given by injection, also called "Oncovin". It will damage the nerves and kidneys, causing eventual numbness in the extremities ("peripheral neuropathy") and hearing loss. These side effects may or may not reverse when vincristine is discontinued. It doesn't decrease blood counts much.

Prednisone is a form of the well known steroid hormone cortisone. It is usually given in pill form, and causes abnormal white blood cells to die by bursting. Short term, it has few side effects besides mood swings and increased appetite, but if given long term (months) it causes a "Cushenoid" appearance. This means the body fat gets redistributed from the limbs to the abdomen (so the limbs get thin), the face puffs up, the body gets hairier and a fat pad forms at the top of the back ("buffalo hump"). It is also easier to get bruising and internal bleeding, get infections, and break bones due to increased fragility. If one has been on steroids for months or years, and suddenly stops taking them, the body cannot produce it's own and can go into shock ("Addisonian Crises")- so they are tapered over time. The reason for giving aggressive "combination chemotherapy" instead of just one drug is because the combination is much more effective than any "single agent". Also, the side-effects ("toxicities") of the multiple drugs are specifically meant to be different, since if they have the same side-effects they are superadditive and yet more dangerous. However, modifications from CHOP have been looked at to see if we can get the same (or better) results with equal or less side-effects.

There are actually many modifications of CHOP, the first important one was to exclude adriamycin (which tends to cause the most severe side effects). Adjusting the Hodgkin's Disease MOPP therapy makes C-MOPP (Cyclophosphamide, Vincristine, Prednisone and Procarbazine) which gives about the same results as CHOP (60 - 80% remission), adriamycin can then be used later if relapse occurs. Another regimen uses lower dose adriamycin along with 6 other drugs- M-BACOD (Methotrexate, Leucovorin, Bleomycin, Adriamycin, Cyclophosphamide, Vincristine, Dexamethasone) but has a higher relapse rate and lower 5 year survival rate (30%) than CHOP, so isn't recommended. Interestingly, however, another multidrug regimen called MACOP-B (Methotrexate, Leucovorin, Adriamycin, Cyclophosphamide, Vincristine, Prednisone, Bleomycin, Ketoconazole) uses full strength adriamycin for 12 weeks and had resulted in 85% complete remission, with 75% of patients surviving 5 years! This is significantly better than CHOP . One more regimen worth mentioning is the popular ProMACE/cytaBOM (Prednisone, Methotrexate, Leucovorin, Adriamycin, Cyclophosphamide, Etoposide, Cytosine arabinoside, Bleomycin, Vincristine). It uses 1/2 strength adriamycin compared to CHOP, and results are in between CHOP and MACOP-B . Using 9 drugs obviously requires expert supervision.

If the Non-Hodgkin's lymphoma relapses after one of the above regiments, as it does 20 - 30% of the time, then SALVAGE CHEMOTHERAPY is prescribed. These usually use new drugs the patient hasn't received previously, since the lymphoma has already (presumably) developed resistance to the previous drugs. A popular salvage therapy is ESHAP (Etoposide, Solumedrol, High Dose Cytosine Arabinoside, Cisplatin) which produces new remission in about 40% of patients but only cures 10%. Another such regimen is MINE (Mesna, Ifosphamide, Novantrone, Etoposide) which gives similar results. Bone Marrow transplantation (below) should be considered for these relapsed patients, where survival may be as high as 50%.

What is the Latest, Effective Treatment?

As mentioned, low grade lymphomas are seldom cured. Lymphocytic and Follicular disease waxes and wanes and the patient usually succumbs to anemia, infection, debility, or other medical condition ("co-morbid factors"). As mentioned, these patients tend to be elderly and will not tolerate aggressive chemotherapy, which has not been shown to be curative anyway for this condition! Also, with the long course of the illness it isn't always possible to know if someone has been really "cured" or not. For the patient in otherwise good health who wishes to be aggressive, there is some indication that the disease may be put into prolonged remission, and occasionally cured, by a series of "total lymphoid" radiation treatments. This is similar to the treatment given for low grade Chronic Lymphocytic Leukemia ("CLL"), and these diseases may be indistinguishable. It has been known for many years that whole-body radiation quickly reduces the white blood cell count, and it has been used at low doses (less than 1 Gray) several times per week for a couple weeks to induce remission. Another new therapy is alpha-Interferon injection which may cure some of these patients.

The best treatment for localized high-grade Non-Hodgkin's lymphoma is regional radiation therapy, and combination chemotherapy. This has resulted in a remission rate of up to 99% and apparent cure in nearly 90% of patients, superior to radiation therapy alone. The radiation dose should be at least 40 Gray, and a chemotherapy regimen which has been studied for this scenario is PROMACE/MOPP, with radiation treatments to begin after the 4th dose of chemotherapy. This leads to 96% complete response. Poorer results are gotten for central nervous system lymphomas in AIDS or organ transplant patients; higher radiation doses are needed (55 Gray). Combination chemotherapy with radiation is definitely superior to radiation treatment alone.

For Cutaneous T-Cell lymphomas like mycosis fungoides, which involve more than one area, topical chemotherapy with nitrogen mustard or Psoralen with Ultraviolet light is useful for limited disease in the plaque stage. Another drug that seems to help in the plaque stage is Cis-Retinoic acid. For more advanced disease, total skin electron beam therapy may cure 40% - 50% of patients. Chemotherapy is only given if the disease has traveled beyond the skin, and alpha-Interferon is a new approach that shows a 50% response rate in these patients.

For Burkitt's lymphomas, survival used to be only about 30%. Now we use a combination approach of surgery to remove the main tumor, and combination chemotherapy (e.g. COMP - Cyclophosphamide, Vincristine, Methotrexate, Prednisone) along with local radiation therapy to residual disease after surgery. With this, survival for limited Burkitt's is over 90%, and 60% for widespread disease.

The very best treatment for widespread high grade relapsed Non-Hodgkin's lymphoma is bone-marrow transplant, started in patients under 55 years old, who have a suitably matched donor (often a sibling). It may also be appropriate in first remission for patients with bad prognostic factors (see that section). It is sometimes possible to clean ("purge") the patients own marrow, but this runs a higher relapse risk. Bone-marrow transplant involves puncturing the hips bones many times from the donor to remove marrow. This is done under general anesthesia, is not at all dangerous, but can leave puncture scars at the top surface of both buttocks. The marrow is specially prepared and stored, while the patient is prepared for transplant. The patients original marrow, which contains the lymphoma cells, must be totally destroyed. This is done with using high doses of chemotherapy just prior to the transplant. Also, whole-body radiation therapy (usually 6 sessions of 15 minutes each over 3 days) may be used to be sure all the lymphoma cells are killed before the transplant. The donor bone marrow is then "reinfused" (that is transplanted) into a regular vein in the patient, and finds it's own way into the bone while circulating in the bloodstream. The new marrow will hopefully "take" and start producing new blood cells, but until it does the patient is at very high risk for infection and must be hospitalized in a sterilized environment. It usually takes 2-4 weeks before the new marrow is functional. Once it is, the patient can be discharged with medications to prevent infection and rejection.

Side-effects of getting bone marrow from another individual ("allogeneic") are more than when a person donates their own marrow for later use ("autologous") . It may become possible to effectively clean a person's own marrow (purging) but this is difficult for lymphomas, since they permeate the marrow itself! Thus, while for breast cancer transplants are autologous, for lymphoma they are often allogeneic. However, progress is being made at more effective purging using Monoclonal Antibodies against the disease, which may even help for therapy if injected into the patient.

Expected side-effects arise from the preparation ("ablation") for the transplant, and then after the donor marrow is administered. Most common are nausea, diarrhea and fatigue. Also, temporary hair loss ("alopecia") and permanent loss of fertility ("sterility") are expected. If radiation is used as a part of the preparation, nausea is worse, glands temporarily swell, skin redness, mouth sores and sore throat is common. These are all temporary. After the new marrow is infused, the patient is at very high risk for any infection, so preventative ("prophylactic") antibiotics are given. Also, the patient will be anemic weak from lack of red blood cells (which live about 4 months), and have easy bruising from platelets (which last about 10 days). These problems will abate as the new marrow takes over and produces blood cells. A serious side-effect is "graft versus host disease " or "GVH" for short. This happens if the new marrow actually rejects the body it's put into. It is more likely if the previous marrow was not completely destroyed, or if the donor marrow is not a close enough match. Some degree of GVH is expected, is shown by skin splotches and blood tests, and is controlled with immune-suppressing anti-rejection drugs like prednisone and cyclosporine. This is a double-edged sword, however, since these drugs also lower the immune system's ability to fight infection. In severe cases GVH can be fatal, but today it is usually well controlled with medication (sometime for the rest of the patient's life). Other possible side effects are lung damage ("pneumonitis"), kidney damage ("nephritis") and liver damage ("hepatitis" and "veno-occlusive disease").

These may show up weeks to months after the transplant, and cataracts or second cancers may occur in long-term survivors. Overall, the death rate ("mortality") from transplant is down to about 10%, which is a major improvement over the past 10 years. There is even talk of doing the transplants at smaller community hospitals, instead of just big universities. Newer drugs which stimulate the newly infused marrow (erythropoeitin and neupogen) to produce red cells and white cells respectively have much improved success rates. The results of bone-marrow transplant for stage III or IV aggressive Non Hodgkin's lymphoma now show over 40% survival at 5 years, so it the best available treatment (albeit drastic) for this disease. Fortunately, it is becoming less drastic and more routine all the time. It can now be recommended for the patient with widespread high-grade lymphoma who wishes to be aggressive.

Conclusion:

The patient with newly diagnosed Non-Hodgkin's lymphoma should not rely on any one therapy, but instead should use a combination approach to maximize the chance for success Specifically, besides the conventional medical therapies mentioned above, consider the use of a non-toxic, not over-expensive alternative therapy that you believe in, a program of spiritual renewal, "mind over cancer', nutritional therapy and exercise . Keep the most positive attitude possible- research has shown this to be an important factor in survival. CancerAnswers has a transcript available on reasonable alternative treatments which you can order through our web-site . Using a true "multi-modality" approach will give the confidence that you have done everything possible for a happy outcome, and certainly improve the current quality of life.

New techniques utilizing radiation therapy, chemotherapy and bone-marrow transplant are showing better survival rates than ever before for aggressive Non-Hodgkin's lymphoma. If cure is the objective, consider getting treatments at a University Academic Center and joining ongoing research trials which offer the latest therapies. The National Cancer Institute keeps a listing of open cancer trials on their website (they change frequently). Especially look for ones listed as "Intergroup" studies, or in conjunction with the Radiation Oncology Therapy Group ("RTOG") . The Dana Farber Cancer Center is particularly involved with the latest research with transplants and monoclonal antibodies. The future has never looked brighter for lymphoma patients!