Hodgkin's Disease | Non-Hodgkin's Lymphoma | AIDS-related Lymphoma |
Cutaneous T-cell Lymphoma
Role of Pathologist

The Anatomy

Lymphomas are cancers that develop in the lymph system, part of the body's immune system. The lymph system is made up of thin tubes that branch, like blood vessels, into all parts of the body. Lymph vessels carry lymph, a colorless, watery fluid that contains white blood cells called lymphocytes.

Along the network of vessels are groups of small, bean-shaped organs called lymph nodes. Clusters of lymph nodes are found in the underarm, pelvis, neck, and abdomen. The lymph nodes make and store infection-fighting cells. The spleen (an organ in the upper abdomen that makes lymphocytes and filters old blood cells from the blood), the thymus (a small organ beneath the breastbone), and the tonsils (an organ in the throat) are also part of the lymph system.
The most common types of lymphomas are Hodgkin's disease and non-Hodgkin's lymphoma. These usually start in the lymph nodes and the spleen. A less common lymphoma, cutaneous T-cell lymphoma, develops on the skin. AIDS-related lymphoma can be either Hodgkin's disease or non-Hodgkin's lymphoma and affects patients who have acquired immunodeficiency syndrome.

HODGKIN'S DISEASE

Hodgkin's disease can occur in children or adults. Adult Hodgkin's disease most commonly affects young adults or people older than 55 years of age. It may also be found in patients with acquired immunodeficiency syndrome (AIDS).

The chance of recovery (prognosis) and choice of treatment depend on the stage of the cancer. The stage depends on the number of involved areas, the size of the swollen nodes, the presence of disease outside the nodes, and whether any symptoms like night sweats, weight loss, or fever are present. Prognosis also depends on the type of Hodgkin's disease diagnosed. A pathologist examines the cancer cells and may perform additional molecular tests on the cells to arrive at a diagnosis.

Staging Tests
Once Hodgkin's disease is found, more tests will be done to find out if the cancer has spread from where it started to other parts of the body. This testing is called staging. A doctor needs to know the stage of the disease to plan treatment.

A doctor will determine the stage of the disease by conducting a thorough history and physical examination and by doing a chest x-ray and CT scan of the chest, abdomen, and pelvis. Other imaging that may be done includes gallium scanning or MRI. A bone marrow biopsy is also done, although bone marrow involvement is relatively uncommon. Blood tests include a complete blood count, Erythrocyte sedimentation rate, liver and kidney function, and determination of alkaline phosphatase and lactate dehydrogenase. This type of staging is called clinical staging.

In some cases, the doctor may need to perform an operation called a laparotomy to determine the stage of the cancer. During this operation, the doctor cuts into the abdomen. The doctor will remove the entire spleen and small pieces of tissue from abdominal lymph nodes and the liver. The tissue will be under a microscope to see whether it contains cancer. This type of staging is called pathologic staging. Pathologic staging is usually done only when it is needed to help the doctor plan treatment such as when a patient appears to have early disease involving only the lymph nodes above the diaphragm. In such a case, pathologic staging may be ordered after clinical staging if the treatment regimen being considered consists of radiation alone.

Symptoms
Each stage for Hodgkin's disease is further divided by an "A" or "B" designation based on whether certain symptoms called "B Symptoms" are present. B symptoms include the following: loss of more than 10% of weight in the previous 6 months, fever without any known cause other than Hodgkin's disease, and night sweats that leave the body soaked. Generalized itching is no longer considered a B symptom even though it can be a complaint. For example, if a patient had stage III disease without any B symptoms, the patient would have stage IIIA disease; if the patient had stage III disease with B symptoms, then the patient would have stage IIIB disease.

Staging

The following stages are used for Hodgkin's disease:

• Stage I A,B: Cancer is found in only one lymph node area or in only one lymphoid structure like the spleen or thymus
• Stage II A,B: Cancer is found in two or more lymph node areas on the same side of the diaphragm.
• Stage III A,B: Cancer is found in lymph nodes or lymphoid structures like the spleen or thymus on both sides of the diaphragm.
• Stage IV A,B: Cancer is found in areas which are not lymph nodes or lymphoid structures nor is it connected to nodal disease.
• Recurrent: Cancer has come back after it has been treated. It may come back in the area where it first started or in another part of the body.

When you see an "E" next to a stage designation
One other caveat exists which may be confusing when determining the stage. There can be involvement of an area that is not lymphoid in stages I, II, and III. However, it must be connected to or very close to the involved lymph node. This is noted by adding the letter E (extranodal) to the stage number, just as B is added when symptoms are present. If there is an extranodal site involved which is not contiguous with or in very close proximity to nodal disease then the disease is stage IV.

NON-HODGKIN'S LYMPHOMA

Non-Hodgkin's lymphoma is a disease in which cancerous (malignant) cells usually arise in the body's lymph system. However, it can arise in almost any tissue. About a quarter of adult lymphomas diagnosed find disease outside the lymph nodes. The most common sites for this extranodal involvement are the stomach, skin, mouth, small intestine and central nervous system. Non-Hodgkin's lymphoma that occurs in children is typically more widespread and aggressive than most adult lymphomas.

What is Histology?

There are many types of non-Hodgkin's lymphomas. Furthermore, some types spread more quickly than others and are referred to as high-grade (spreading faster), intermediate-grade, or low-grade (spreading slower). The specific type is determined by how the cancer cells look under a microscope. This determination is called the histology.

The histologies for adult non-Hodgkin's lymphoma are divided into two groups:

• Indolent(low grade) lymphomas, which are slower growing and have fewer symptoms;
• Aggressive ( intermediate and high grade) lymphomas, which grow more quickly.

Interestingly, although the indolent lymphomas are slower growing, they are harder to actually cure than the more aggressive types.

The most common types of indolent non-Hodgkin's lymphoma include:

• follicular small cleaved cell lymphoma
• follicular mixed cell lymphoma
• small lymphocytic (marginal zone)
• Other types of indolent non-Hodgkin's lymphoma are lymphoplasmacytoid lymphoma, monocytoid B-cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, splenic marginal zone lymphoma, hairy cell leukemia, and cutaneous T-cell lymphoma (Mycosis fungoides/Sezary syndrome).

The most common types of aggressive non-Hodgkin's lymphoma include:

• follicular, large cell
• diffuse small cleaved cell
• diffuse mixed cell lymphoma
• diffuse large cell lymphoma
• immunoblastic large cell lymphoma
• lymphoblastic lymphoma
• small noncleaved cell lymphoma
• Other types of aggressive non-Hodgkin's lymphoma are anaplastic large-cell lymphoma, adult T-cell lymphoma/leukemia, mantle cell lymphoma, intravascular lymphomatosis, angioimmunoblastic T-cell lymphoma, angiocentric lymphoma, intestinal T-cell lymphoma, primary mediastinal B-cell lymphoma, peripheral T- cell lymphoma, lymphoblastic lymphoma, post-transplantation lymphoproliferative disorder, true histiocytic lymphoma, primary central nervous system lymphoma, and primary effusion lymphoma.

Aggressive lymphomas are also seen more frequently in patients who are HIV-positive (AIDS-related lymphoma).

Childhood non-Hodgkin's Lymphoma

Children usually present with aggressive lymphomas. The three major types of childhood non-Hodgkin's lymphomas are:

• lymphoblastic lymphoma;
• small noncleaved cell lymphoma (either Burkitt's lymphoma or non-Burkitt's lymphoma);
• large cell lymphoma.

The classification of lymphoma can be a complicated issue. The older method which divides the lymphomas into low, intermediate, and high grade based only on what the cells look like under the microscope, is clinically useful, but incomplete. More specific classification using advanced immunologic and genetic testing can now be done to fully diagnose the type of lymphoma present. The chance of recovery (prognosis) and choice of treatment depend on the stage of the cancer (whether it is just in one area or has spread throughout the body), the exact type of the lymphoma, and the patient's age and overall condition.

Staging Tests

Once non-Hodgkin's lymphoma is found, more tests will be done to find out if the cancer has spread from where it started to other parts of the body. This testing is called staging.

A doctor determines the stage of the disease by examining the patient, taking a thorough history, and doing blood tests including a complete blood count, liver and kidney function, and lactate dehydrogenase level. A bone marrow biopsy is important and more commonly can show cancer cells than in Hodgkin's Disease. Imaging studies include doing a chest x-ray and a CT or CAT scan of the abdomen and pelvis that produce an image of the inside of the body. A CT of the chest is also done if the chest x-ray looks abnormal. A CT scan or MRI of the brain is needed if any symptoms suggest central nervous system involvement. Many patients will also need a spinal tap to examine the spinal fluid for cancerous cells. Additionally, a gallium scan is usually done, because it can sometimes detect disease that was not seen on CT scan. A gallium scan involves the injection of a small amount of radioactive tracer into the patient and then scanning the body to examine the way the different tissues took up the tracer. This type of staging is called clinical staging.

After determining the stage of disease, the particular type of lymphoma, and considering the patients age and overall condition, the prognosis and treatment plan can be formulated.

Staging for Adults

The following stages are used for adult non-Hodgkin's lymphoma:

• Stage I: Cancer is found in only one lymph node area or in only one area or organ outside the lymph nodes.
• Stage II: Either of the following may be true:
  • Cancer is found in two or more lymph node areas on the same side of the diaphragm.
  • Cancer is found in only one area or organ outside the lymph nodes and in the lymph nodes around it.
  • Other lymph node areas on the same side of the diaphragm may also have cancer.
  • In contiguous stage II cancer, the positive lymph node areas are next to one another.
  • In non-contiguous stage II, the positive lymph nodes are not next to each other, but are still on the same side of the diaphragm.
• Stage III: Cancer is found in lymph node areas on both sides of the diaphragm. The cancer may also have spread to an area or organ near the lymph node areas and/or to the spleen.
• Stage IV: Cancer has spread to more than one organ or organs outside the lymph system. Cancer cells may or may not be found in the lymph nodes near these organs. OR cancer has spread to only one organ outside the lymph system, but lymph nodes far away from that organ are involved.
• Recurrent: Cancer has come back after it has been treated. It may come back in the area where it first started or in another part of the body.

Staging for Children

The following stages are used for childhood non-Hodgkin's lymphoma:

• Stage I: Cancer is found in only one area outside of the abdomen or chest.
• Stage II: Any of the following mean the disease is stage II:
  • Cancer is found in only one area and in the lymph nodes around it.
  • Cancer is found in two or more lymph nodes or other areas on the same side of the diaphragm.
  • Cancer is found to have started in the digestive tract. The lymph nodes in the area may or may not have cancer.
• Stage III: Any one of the following mean the disease is stage III:
  • Cancer is found in lymph node areas on both sides of the diaphragm.
  • Cancer is found to have started in the chest.
  • Cancer is found in many places in the abdomen.
  • Cancer is found in the area around the spine, around the outermost covering of the brain, or on the outermost covering of the brain (epidural tumors).
• Stage IV: Cancer has spread to the bone marrow or to the brain, its inner coverings, or the spinal cord.
• Recurrent: Cancer has come back after it has been treated. It may come back in the area where it first started or in another part of the body.

AIDS-RELATED LYMPHOMA

AIDS-related lymphoma is a disease in which cancerous (malignant) cells are found in the lymph system in patients who have AIDS (acquired immunodeficiency syndrome). AIDS is caused by the human immunodeficiency virus (HIV), which attacks and weakens the immune system. Infections and other diseases can then invade the body, and the immune system cannot fight against them.
Both major types of lymphoma, Hodgkin's disease and non-Hodgkin's lymphoma, may occur in AIDS patients. However, AIDS is a definite risk factor for non-Hodgkin's lymphoma and AIDS patients develop non-Hodgkin's lymphoma at a much higher rate than the general population. Hodgkin's Disease may occur more frequently in AIDS patients, but this is not as clear-cut as non-Hodgkin's lymphoma. Therefore, AIDS related lymphoma is generally considered to be non-Hodgkin's lymphoma.

Intermediate-and high-grade (faster growing) types of non-Hodgkin's lymphoma are more commonly found in AIDS patients.

In general, patients with AIDS-related lymphoma respond to treatment differently than patients with lymphoma who do not have AIDS. AIDS-related lymphoma usually grows faster and spreads outside the lymph nodes to other parts of the body more often than lymphoma that is not related to AIDS. Because therapy can damage weak immune systems even further, patients who have AIDS-related lymphoma are generally treated with lower doses of drugs than patients who do not have AIDS.

Staging

Once AIDS-related lymphoma is found, more tests will be done to find out if the cancer has spread from where it started to other parts of the body. This testing is called staging. To plan treatment, a doctor needs to know the stage of the disease. The staging procedures for AIDS related lymphoma are the same as a non AIDS patient with lymphoma. The actual stages are also the same for patients with and without AIDS.

The following stages are used for AIDS related lymphoma : (note they are the same as in patients without AIDS)

• Stage I: Cancer is found in only one lymph node area or in only one area or organ outside of the lymph nodes.
• Stage II: Either of the following may be true:
  • Cancer is found in two or more lymph node areas on the same side of the diaphragm.
  • Cancer is found in only one area or organ outside of the lymph nodes and in the lymph nodes around it.
  • Other lymph node areas on the same side of the diaphragm may also have cancer.
• Stage III: Cancer is found in lymph node areas on both sides of the diaphragm. The cancer may also have spread to an area or organ near the lymph node areas and/or to the spleen.
• Stage IV: Either of the following may be true:
  • Cancer has spread in more than one spot to an organ or organs outside the lymph system. Cancer cells may or may not be found in the lymph nodes near these organs.
  • Cancer has spread to only one organ outside the lymph system, but lymph nodes far away from that organ are involved.
• Recurrent: Cancer has come back after it has been treated. It may come back in the area where it first started or in another part of the body.

In addition, AIDS-related lymphomas are grouped based on where they started, as follows:

• Systemic/peripheral lymphoma: Lymphoma that has started in lymph nodes or other organs of the lymph system. The lymphoma may have spread from where it started throughout the body, including to the brain or bone marrow.
• Primary central nervous system lymphoma: Lymphoma that has started in the brain or spinal cord, both of which are part of the central nervous system (CNS). This type of lymphoma is called a "primary CNS lymphoma" because it starts in the CNS rather than starting somewhere else in the body and spreading to the CNS.

CUTANEOUS T-CELL LYMPHOMA

Cutaneous T-cell lymphoma is a disease in which certain cells of the lymph system (called T-lymphocytes) become cancerous (malignant) and affect the skin. Lymphocytes are infection-fighting white blood cells that are made in the bone marrow and by other organs of the lymph system. T-cells are special lymphocytes that help the body's immune system kill bacteria and other harmful things in the body. The most common lymphoma of the skin is mycosis fungoides, which is a T-cell lymphoma. It has an indolent course and often patients exhibit nonspecific skin patches for several years before the diagnosis is made. The skin lesions can progress and become more numerous. Some patients present differently and have generalized erythroderma (red skin) sometimes with plaques and tumors of the skin as well.
The chance of recovery (prognosis) and choice of treatment depend on the stage of the cancer (whether it is just in the skin or has spread to other places in the body) and the patient's general state of health.

Staging

Once cutaneous T-cell lymphoma is found, more tests will be done to find out if cancer cells have spread to other parts of the body. This is called staging. A doctor needs to know the stage of the disease to plan treatment.

The following stages are used for cutaneous T-cell lymphoma:

• Stage I: The cancer only affects parts of the skin, which has red, dry, scaly patches, but no tumors. The lymph nodes are not larger than normal.
• Stage II: Either of the following may be true:
  The skin has red, dry, scaly patches, but no tumors. Lymph nodes are larger than normal, but do not contain cancer cells.
  There are tumors on the skin. The lymph nodes are either normal or are larger than normal, but do not contain cancer cells.
• Stage III: Nearly all of the skin is red, dry and scaly. The lymph nodes are either normal or are larger than normal, but do not contain cancer cells.
• Stage IV: The skin is involved, in addition to either of the following:
  Cancer cells are found in the lymph nodes.
  Cancer has spread to other organs, such as the liver or lung.
• Recurrent: Cancer has come back after it has been treated. It may come back where it started or in another part of the body.

The Role of the Pathologist

“Lymphoma” and “leukemia” are general categories that represent at least 30 types of cancer of the blood forming cells. The diagnosis is usually made by sampling a lymph node, bone marrow aspirate or biopsy or peripheral blood smear. Advances in research have determined that many types of lymphoma and leukemia respond best to specific treatment protocols. If the cancer gets an incorrect or inaccurate diagnosis, it is possible that the patient will receive inappropriate therapy. A number of sophisticated tests can be performed on the tissues to assist in determining the most accurate diagnosis. Tissue samples (biopsy) taken for the evaluation of lymphoma or leukemia should be examined by a hematopathologist, a pathologist with special training and expertise in these cancers.

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