All Lymphomas are now sub-classified into T-Cell, B-Cell or Hodgkin’s disease
CUTANEOUS
T-CELL LYMPHOMAS
MERKEL CELL
CARCINOMA
NON HODGKIN'S
LYMPHOMA
Cutaneous T-Cell Lymphomas
Lymphomas that affect the skin are usually two different types called Mycosis Fungoides (MF) and Sezary’s Syndrome (SS). A mutated population of cutaneous Helper T-Lymphocytes (CD-4 positive) is the cause of this disease. They infiltrate the skin and cause a local reaction; the skin becomes thickened and the abnormal cells release lymphokines that may contribute to the symptoms of itching, pain and redness. T-Lymphocytes hone to different tissues as part of their normal functions. In this instance, it is the hone cutaneous T-Lymphocytes that become malignant and because they are honed to the skin, the disease tends to remain localized to the skin for a long time.
The causative factor is unknown. It may be a spontaneous mutation or a viral or chemical induced cause that occurs in the T-Lymphocytes.
Mycosis
Fungoides
Sezary's Syndrome
There are other variants of Cutaneous T-Cell lymphomas, which I will not discuss here.
Mycosis Fungoides
Mycosis Fungoides is a very slowly evolving disease. The abnormal clone of T-Lymphocytes may remain localized in one area of the skin and go undiagnosed for years. The disease is frequently thought to be eczema or confused with other skin diseases, such as lymphomatoid papulosis, or alopecia mucinosa/follicular mucinosis or pagetoid reticulosis.
The disease does progress slowly, either spreading locally or erupting, sequentially in different parts of the trunk, arms or legs. Once the T- Lymphocytes leave the skin, they will spread to the local lymph nodes which become progressively larger. As time passes, these cells will spread around the whole body and become very like a regular lymphoma.
Treatment
Since this is a slow growing disease, aggressive treatments should be avoided.
Initially, topical treatments with nitrogen mustard, psoralen plus ultraviolet-A irradiation, local steroids, are all that is needed. These treatments will keep the disease controlled for many years. As the disease progresses, Electron Beam Radiation ought to be considered. Centers that specialize in this treatment can keep the disease contained for many years.
Immunotherapy
A modification of Immunotherapy is used. The patients are treated with Psoralen, a chemical that becomes attached to the patient's DNA. Then the phoresed white cells are radiated with Ultra-violet-light; this treatment kills the malignant T-lymphocytes. The re-infused lymphocytes stimulate the patients’ immune systems to produce antibodies and cytotoxic cells which kills the remaining malignant cells and by so doing can keep the disease controlled for months to years.
Monoclonal Antibodies
Monoclonal antibodies against the different T-Lymphocyte antigens, including CD-4, have been used successfully. I anticipate that there will be other antibodies coming along shortly that may be of help.
Hybrid molecules, composed of part of the Diphtheria toxin combined with Interferon 2 receptor have been used to treat this disease with some success.
Interferon
The different Interferons have been used with some success. They are frequently combined with Psoralen and UV-light or with chemotherapy.
Chemotherapy
Ultimately the disease usually progresses. When it involves lymph nodes or is obviously progressing in the skin, despite the effects of local control, then chemotherapy must be considered. Fludaramine, Pentostatin and Leukstatin have all been tried with some success. The response is usually short. Combinations have also been tried and so far the results have not been great.
The Retinoids
A new group of drugs called the Retinoic Acid Receptor Inhibitors may contribute to the control of this disease. Retinoid A Receptor (RAR) and Retinoid X Receptor (RXR) are receptors in the cell wall and in the nucleus of cells that regulate the expression of many genes. Retinoids reduce the expression of BCL-2 in the lymphocytes and high levels of BCL-2 prevent Apoptosis from happening. So any drugs that can actively reduce the production of BCL-2 should be therapeutic and one such drug is Bexarotene. It inhibits RXR and inhibits tumor cell proliferation. It has been used in patients with Mycosis Fungoides with some success at doses of 300mg per day. It does cause headaches, lowers thyroid function, interferes with liver chemistries and can affect lipid and cholesterol metabolism. In the future it may be used, combined with other medications, like interferon or chemotherapy drugs, in the hope that it will improve treatment for this slow-growing, malingering and ultimately fatal disease.
Other drugs, now in the pipeline, that down regulate BCL-2, should be of help in treatment of this disease.
If you wish to know more about this disease or the drugs used to treat it, then contact my office for an appointment and I will be happy to discuss further, clarify and manage your disease.
Szeary's Syndrome
This is a disease caused by the infiltration of abnormal T Lymphocytes into the skin and subcutaneous lymph nodes. It is postulated that the cutaneous T-Lymphocytes either mutate spontaneously to the malignant state, or a virus or the sun’s rays cause the mutation. Whatever the reason, these T-lymphocytes begin a slow, progressive proliferation and infiltration.
Initially the skin is involved and becomes diffusely red and itchy. Nodules can appear on the skin in a sporadic fashion. The lymph nodes become involved when the T-Cells continue their migration and proliferation.
The diagnosis is often delayed because this disease is slow to progress and mimics other diseases as it progresses. It takes an experienced pathologist to diagnose it.
The T-Lymphocytes are the CD-4 Helper cells. They can stimulate B-Lymphocytes to produces gamma globulins so patients may have elevations of these proteins. They also express antigen-BE-2, CD-45 (the memory cell antigen) and CLA. These cell wall antigens help to classify this abnormal population of cells. A flow cytometry evaluation of lymphocytes will show an increased percentage of CD-4 cells over CD-8 which may help making a definite diagnosis.
Treatments
The treatments for this disease are similar to those used to treat Mycosis Fungoides, described above.
If you wish to know more about this disease or the drugs used to treat it, then contact my office for an appointment and I will be happy to discuss further, clarify and manage your disease.
Merkel Cell Carcinoma
This is a rear cancer of the skin. The cell of origin is hypothesized to be one of the nerve endings in the skin.
It is a cancer composed of small cells that stain positive for neural tissue and is classified as a neuroendocrine tumor arising in the skin. It is grouped together with other small cell cancers that arise in other parts of the body, like the lung, the thyroid, the pancreas or the prostate.
All these cancers grow and spread rapidly and need to be treated aggressively if there is to be any hope of survival.
Merkel Cell carcinoma arises in the skin. It presents as a rapidly growing, painless, firm, shiny bluish-red, raised thickening of the skin. It is the pathologist, who recognizes the small characteristic, neuro-secretery-staining cells that usually makes the diagnosis at biopsy.
The cancer is thought to start in the dermis and extends into the subcutaneous tissues. Merkel’s cell is located in the hair follicle and is the receptor nerve that recognizes the mechanical stimulation of the hair follicles. Eighty percent of these tumors are localized to the skin; the rest may have metastasized to the local lymph nodes before they are diagnosed. Sometimes, the primary site is missed or spontaneously regresses and the cancers show up in the lymph nodes as the first sign of the disease. If this occurs in either arm pith, it can be misdiagnosed as breast cancer.
Merkel Cell carcinoma occurs amongst the elderly and in the sun exposed areas of the body. It seldom occurs amongst the young.
Treatment
The skin lesion is widely excised and if a diagnosis is made as being a Merkel Cell, then the sentinel technique should be used to see if the tumor has spread to the lymph nodes. If it has not, then no further therapy is needed.
If the tumor presents as enlarged lymph nodes in the arm pith or the neck, then a wide surgical excision should be done. Since this is a rapidly growing disease, attempts to stage the tumor should be done prior to any surgery. A PET scan or Cat Scan of the lungs and abdomen should be done, prior to surgery.
Patients with large primaries or positive sentinel nodes have a high risk of reoccurrence either locally or distantly so prophylactic treatment with radiation therapy or chemotherapy need to be considered.
This is a rear skin cancer and not many studies have been done to show which treatment is better. Having seen many cases, it is a tumor that must be treated with great respect for it can and will threaten life.
If you wish to know more about this tumor or the drugs used to treat it, call my office for an appointment and I will be happy to discuss, clarify or manage your case.
THIS IS A CANCER THAT STARTS IN THE LYMPH NODES.
Lymphoma is the term applied to malignancies that start in lymph nodes. The lymph nodes are the small kernels we feel around the groin. In the body, they form part of the body's immune system which protects us from infections, either bacterial, viral or fungal. The immune system also protects us from getting malignancies. These lymph nodes, together with the liver, spleen and the small white cells in the blood, call lymphocytes, make up the immune system. The lymphocytes are subdivided into two types; B-cells and T-cells. The B-cells produce antibodies called gamma-globulins and their function is to attach onto foreign substances, either bacteria, viruses or fungi, and help the body get rid of them. The T-cells control the production of B-cell proliferation.
The immune system is a complex system and malignancies of this system are complex diseases and are difficult to understand. To take away the complexity, physicians subdivide all lymphomas into three broad categories.
1. Low Grade Lymphomas: These present as slowly enlarging lymph nodes that can be found in the neck, the arm pit or the groin. The spleen may also be enlarged and may be palpable.
These tumors grow slowly and initially may not need to be treated at all. As they cause no symptoms, a period of observation is reasonable. If the lymph nodes begin to get larger, then it is not unreasonable to start treatment with chemotherapy using ...
Fludaramine, Pentostatin or Leustatin ... these are new drugs that have few side effects and get good long term responses.
2. Intermediate Lymphomas: These are similar type diseases, to the ones described above, but they tend to appear more rapidly and grow more quickly. They usually need to be treated immediately.
Drugs and drug combinations used to treat these are CHOP. (This is a combination of Cytoxan, Oncovin. Prednisone and Adriamycin ) This is a very good combination and frequently obtains complete remissions. Fludaramine and Cytoxan or Fludaramine and Leukeran can also be used.
3. High Grade Lymphomas: These are rapidly growing lymph nodes that can show up anywhere. Fever, lack of energy, pain and night sweats may be associated. These tumors are bad and need to be treated quickly.
CHOP is frequently used in the early stages and quite successfully. Relapses after CHOP may have to consider receiving High Dose Chemotherapy with Bone Marrow Rescue. This is a very aggressive treatment for a very aggressive disease. Sometimes these diseases must be treated aggressively if a remission is to be achieved.
There are other ways to sub-classify lymphomas. For instance, one of the sub-types of the intermediate lymphomas is call mantle cell lymphoma. Other lymphomas are called MALT cell lymphomas and others still are called Lymphomas with big spleens and villus lymphocytes. These are sub-types of the above.
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