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This relatively uncommon lymphoma began to be described in mid 1970s, under a variety of names. Some of the other terms used in the past: centrocytic lymphoma, diffuse follicular small cleaved cell lymphoma, mantle zone lymphoma, intermediate lymphocytic lymphoma. The current term, mantle cell lymphoma, was coined in 1991. Because this lymphoma is a latecomer on the scene, little is known about it compared to the more common types. Most studies so far have focused on retrospective analyses of cases.
This cancer is described as "atypical (with slightly irregular or cleaved nuclei) small lymphoid cells in wide mantles around benign germinal centers." It is typically observed as a mixture of small lymphoid cells, some like CLL and some like small cleaved cells. It is assumed that the malignant cells correspond to newly made normal lymphocytes that travel from the bone marrow and reside in primary lymphoid follicles, and in the mantle zones of secondary follicles in the lymph nodes and spleen. The cancerous cells, however, are arrested at this stage of development and do not differentiate (mature properly) as normal cells would.
There are three subsets of the cells: mantle zone architecture, nodular or diffuse architecture, and blastic or blastoid architecture. These various patterns often occur together to some degree; researchers try to distinguish between the three variants on the basis of frequency of occurrence of these various cells. About 30% of diagnoses show nodularity, and some of these show a mantle zone pattern. Some studies have reported that small diffuse areas were seen in the mantle zone pattern as well, in about 40% of the cases.
Later in the course of the disease, invasion and obliteration of the germinal centers by cancerous cells results in a diffuse pattern of growth. In about 20% of cases, the cells are (or become) larger, with finely dispersed chromatin and small nucleoli. These cells are the blastic variants, and they are regarded by some as the histologic transformation of MCL. Abrupt transformation to large cell lymphoma does not seem to take place. Mitotic rate is low in the small variant, but increases in the mixed and blastic variants, and recurrences are often accompanied by gradual increase of cell size and cell proliferative fraction (speed of proliferation). The nodular types may also progress to a diffuse pattern. Please note that there is no definite agreement at present regarding the precise distinguishing characteristics of the above variants and exactly how they affect survival.
MCL is very similar to several other disease types: follicular small cleaved cell NHL, CLL, MALToma, mantle zone hyperplasia, and Castleman’s disease. Therefore, extra care must be taken with the diagnosis. It should not be made from blood or bone marrow sample alone because of lack of precise criteria. Immunologic studies are key in making the correct diagnosis. It is recommended that several opinions are sought as to the accurateness of the diagnosis, one of these from a recognized mantle cell expert in your area.
MCL cells are of the monoclonal B-cell phenotype, and typically express CD5 and CD43 antigens, and lack CD10 and CD23. (Rarely, MCL occurs in a CD5 negative form, but its significance is at present not understood.) Staining for the cyclin D1 protein is useful in distinguishing this NHL from other low grade types.
The tumor grade is currently surrounded by controversy. European classification identified it as low grade, based on its initially slow growing, small cell histology. American classification considered it intermediate based on patients’ shorter median survival. With the advent of combined European-American classification (REAL), the status of MCL is still being debated. One source suggests that the zonal and nodular variants be classed as low grade, and the diffuse variant as intermediate. But will the intermediate category continue to be used? Also, the intermediate placement suggests a faster growing disease that is potentially curable, which is not the case with MCL. Some have likened the blastic variant to high grade NHL because its proliferative fraction is closer to lymphomas placed in that category, and median survival tends to be shorter than other MCLs (but not as short as unresponsive high grade lymphomas of other types). While studies of cellular proliferation in MCL have generally found low rates in the lymphocytic forms and higher rates in the blastic variants, there is considerable overlap which complicates the picture. Only time will tell how these issues will sort out. Further studies will better elucidate the nature of these cells.
This lymphoma, unlike its other NHL cousins, is refractory (resistant) to initial treatment. The reason for its refractoriness is at present not known.
Mantle cell lymphoma is usually widespread at diagnosis into the lymph nodes, spleen, bone marrow (up to 90%), peripheral blood, and extranodal sites, particularly the Waldeyer’s ring (the ring of adenoid, palatine and lingual tonsils at the back of the mouth) or the gastrointestinal tract. Sometimes there is a diffuse infiltration in the colon, known as multiple lymphomatous polyposis. Spleen enlargement is often seen (about 60-80%), particularly in the nodular variant. Occasionally, the liver is involved.
Typically at diagnosis patients show small disseminated swollen lymph nodes, their health is good (known as "good performance status"), and there are few or no clinical symptoms. Mild anemia is fairly common, but thrombocytopenia (low platelets) is rare. A number of patients have reported lower back pain, and burning pain in legs and testicles for several months to a couple of years prior to diagnosis. Sometimes, diagnosis is preceded by recurrent infections. As in other slow-growing lymphomas, spontaneous remission sometimes occurs (the one instance mentioned on the mantle cell list was partial and lasted about a year).
With time, lymph nodes increase in volume, there is increasing infiltration into the blood, and into extranodal sites. Eventually, performance status worsens, B symptoms appear, weight loss being the most common, and high LDH or high beta2-microglobulin levels are seen in more than 50% of patients. Sometimes (20-40%), there is lymphocytosis (high lymphocyte count of greater than 4000 µL).
The disease has low grade characteristics initially -- there are slowly growing peripheral and abdominal nodes without symptoms. Most patients present with grade III or VI. Two studies reported the following break-down:
| First study | ..... | Second study |
|---|---|---|
| 0% stage I | 2% stage I | |
| 13% stage II | 2% stage II | |
| 23% stage III | 45% stage III | |
| 64% stage IV | 50% stage IV |
Signs predictive of survival have varied among various studies, The bad signs that seem most corroborated are: poor health, absolute lymphocytosis, and high mitotic rate. To a lesser extent, these are also worrisome: B symptoms, advancing age, male sex, elevated LDH and beta2-microglobulin, proliferation of blastic cells, and low platelets (under 100,000).
CNS involvement with neurologic changes sometimes occurs in the end stage of the disease.
Mantle cell lymphoma is currently incurable. Some studies use ambiguous language, but there has been no evidence of a curable subset in studies, and there are no case reports of cured patients in the literature.
Many of the problems associated with MCL are shared by other lymphomas as well.
For detailed information on these problems, go to page called "Health
problems associated with NHL."
More often seen in males aged 50-70 years, but may occur in younger people (some studies mention a few people in their 30s, and one study found a 27 year old). It is rare under the age of 50. The ratio of males to females ranges from 2:1 to 4:1, depending on the study.
This disease has the shortest median survival of all lymphoma subtypes. Median survival is 3-5 years regardless of treatment. Maximum survival (I have seen) recorded: about 16-18 years from diagnosis.
Roughly, about 5% of patients with B-cell lymphomas have MCL. This type of cancer is increasing in incidence along with other lymphomas. Median age at diagnosis: about 60 years.
Very few trials have addressed the needs of people with MCL because the subtype emerged clearly only recently. Patients have been treated with surgery, radiation, and single agent or combination chemotherapy, with CHOP and similar regimens being common. A small portion of patients may benefit from observation only. This is known as "watch and wait."
Some patients have a misapprehension regarding this modality. The following was posted recently on the mantle cell list by one of the resident oncologists (Roda, PI). "Watching and waiting, under appropriate circumstances is NOT sticking one's head in the sand. It's more like waiting out a rainstorm -- and trying to decide whether waiting under a bough where you are getting a little wet is better or worse than running across the field and getting soaked. In some cases, the toxicities of action are worth it, in other patients (based on their age OR stage of disease) action is best deferred. In either case, this should be an informed, well thought out decision. An informed patient makes the best decisions -- but don't be led into the trap of acting because not acting is akin to surrendering -- it's not! One can run away to fight another day -- in some oncologic situations it's best to defer heavy duty therapy."
No standard treatment has been recommended for MCL patients. CHOP and CVP have shown similar results, and patients treated with aggressive regimens have not shown an advantage. There seems to be some evidence that the inclusion of doxorubicin may produce "longer event-free survival" -- but how much longer? The study did not say. Other studies have noted similar response rates to regimens that contain or lack doxorubicin.
Complete response has been reported to be around 30%, and is associated with longer time to progression. (One study reported a CR rate of 56% with CHOP.) Most patients only get a partial regression of the lymphoma for 6-18 months, then progress and die. A few patients have been reported to have long-term remissions. A CHOP-B study reported a CR of 52% and possibly improved survival (but did not say by how much). A CVP regimen is recommended for elder patients over CHOP.
Interferon may improve slightly the time to progression, but there is not enough data so far. Dr. Coiffier (a noted authority on MCL) has written recently: "Purine analogs (fludarabine and cladribine) have not shown better results and will not change the outcome of these patients." One new study reported that MCL responds slower than other lymphomas to therapy, and suggested that lower dose long term treatment be tried (for example, with oral etoposide).
BMTs may increase response rates of salvage therapies, but are neither curative nor life-extending. Some sources say that the time to progression was also not improved by BMTs. These are not recommended for patients in later stages of the disease, but may help some patients who are diagnosed early, are relatively young and in good health. More research on this is ongoing.
Although one source recommended high dose chemotherapy for the blastic variant in 1996, Dr Coiffier notes in 1998: "Outside randomized trials, high dose therapy is not recommended for MCL patients."
Salvage therapies are used once the disease recurs, but none is associated with a good response rate or a long time to progression.
All experts agree: Long term prognosis of MCL patients receiving conventional treatment is poor, and new and better therapies are badly needed.
There are several trials going on in the U.S. specifically for mantle cell. Some other trials accepting patients with low grade or intermediate lymphomas may accept mantle cell as well. The following protocols are of interest:
The MD Anderson Protocol is high dose chemotherapy with or without stem cell transplant. It is available at MD Anderson Cancer Center in Texas. The regimen consists of the following sequence: HyperCVAD (Cytoxan, Vincristine, Adriamycin and Decadron) with high dose ARA-C and methotrexate. If well tolerated, and in younger patients, it is then followed by high dose cyclophosphamide, total body irradiation and stem cell transplant. Each one of these two cycles is delivered four times, so it is an eight month commitment. This is a trial that has the patient community very interested, and their results so far have been encouraging. However, until a comparison study is run, it will not be known if the results are truly an improvement. Dr Roda the MCL list remarked: "Until MD Anderson's data cover five year survival and are reproduced elsewhere, their approach must be considered experimental. Without being critical of any one center, it's well recognized that many pilot programs at major centers don't turn out as good when larger comparative studies are performed. Thus, I would encourage patients to participate in research trials, particularly innovative trials including stem cell or conventional chemo plus Rituxan, interferon, etc. But I can't say that any one approach should be standard of care until randomized trials are completed." A similar protocol is followed by Dr Julie Vose at Nebraska, with good results. Also, the MD Anderson doctors will help local oncologists implement the protocol if a patient selects it -- the patient need not be part of the trial to obtain this treatment.
Rituxan is a cold monoclonal antibody that was approved in 1997. It can be administered by any oncologist locally. It is approved for low grade relapsed NHL, but is widely used off label. It is given in 4-8 infusions at weekly intervals. The drug has low toxicity and is very well tolerated by most patients. Usually, however, the regression effected by Rituxan is not long lasting (about 8 mos. in low grade relapsed NHL). For that reason, trials are underway in combination with CHOP. Excellent response rates have been reported for this combination, with CR reported in the patient community to be as high as 80%. Dr Orion Howard at Dana Farber is running the trial for MCL.
Bexxar is a radiolabeled monoclonal antibody, coupled with radioactive iodine. Dr Kaminski at the U of Wisconsin has been running trials with low radioactive Bexxar, but they have had no luck with MCL. The word is that they treated 5 patients with MCL and they only obtained a partial response in three patients, of a very brief duration (3 months). They are not accepting MCL patients into the current trial for previously untreated patients. Dr Press in Washington state has been using high radioactive Bexxar with high dose chemotherapy followed by stem cell rescue. He has reported 74% of patients progression-free after a year and a half.
Oncolym is another iodine radiolabeled antibody. Trials for relapsed intermediate lymphomas are being run at many cancer centers around the country (MD Anderson, U of New Mexico, George Washington U, Sylvester Cancer Center in Miami, Iowa City VA, U of Illinois in Chicago).
LL2 is yet another antibody, available in both cold and radiolabeled versions, effective against CD22 antigen. Trials for relapsed intermediate NHL are being run at Sloan Kettering, Buffalo, U of Nebraska, and Garden State Cancer Center in NJ.
Flavopiridol is a drug that was thought to have a particular promise against MCL, and may still find its niche. Flavopiridol is reported to induce apoptosis of normal lymphoid cells, causes immunosuppression, and has shown antitumor activity. It is active against cyclin D, and in mice with transplanted lymphoma tumors, this drug was very effective. There are recently started trials at Dana Farber and Chicago. Unfortunately, the first 3 patients in Chicago failed to respond.
Phenylacetate is being tested at Mayo. This is a low toxicity treatment based on the ideas of the alternative cancer researcher Dr Burzynski. It is a peptide that depletes a certain amino acid. One disadvantage of the treatment is a temporary unpleasant body odor the drug causes. The Mayo clinic has not publicly disclosed any results yet though the trial has been going on for 2-3 years now. They will disclose information to patients seriously interested in joining the trial.
Purine analogs (fludarabine and cladribine) have not shown good results with MCL though several trials remain open and a new one is planned. Some of the trials use the analogs with other drugs, for example interferon and cyclophosphamide. According to a report by Lawrence Piro, M.D. of Cedars Sinai Medical Center that he presented at the Pan Pacific Lymphoma Conference, "fifteen patients with mantle cell lymphoma were treated with Fludarabine achieving an overall remission rate of 27% with one complete remission and three partial remissions reported. Dr Weisenburger, a noted expert, has recently written: "Therapeutic experience with the purine analogues, fludarabine and 2-CDA, and interferon has been disappointing." I was puzzled why trials for a treatment with disappointing results are continued. Dr Roda on the mantle cell list furnished the following explanation: "1. The trial could be for patients with refractory disease (ie failed adriamycin containing therapy and are not a candidate for anything else). 2. There is data suggesting that purine analogues might be additive to adriamycin and/or alkylating agents. These trials would still be legitimate. 3. While I personally don't think that purine analogues are very helpful in MCL, I don't know this for a medical fact. Thus while I wouldn't use fludarabine or cladribine as a single agent in this disease, a trial that was started (a few years ago) and has yet to include enough patients to have a statistically meaningful result should be continued. Once an older trial has reached enough patients to show a statistical benefit to any arm, the trial is usually stopped."
Which treatment for mantle-cell lymphoma patients in 1998? Coiffier, B. J Clin Oncol. 1998 Jan; 16(1): 3-5.
Mantle cell lymphoma -- an entity comes of age. Weisenburger, D.D. and Armitage, J.O. Blood. June 1, 1996. Vol. 87, no. 11, 4483-4494.
Mantle cell lymphoma: a retrospective study of 27 patients. Clinical features and natural history. Bertini, M. et al. Haematologica. 1998 Apr; 83(4): 312-316.
Meusers P, Hense J, Brittinger G. Mantle cell lymphoma: diagnostic criteria, clinical aspects and therapeutic problems. Leukemia 1997; 11 (Suppl. 2):S60-S64.
Before you do anything else, you must understand exactly what "median survival" means. I cannot stress this enough! Please see the unsurpassed file written on this topic by Steven Jay Gould (http://cancerguide.org/median_not_msg.html) when he was diagnosed some years back with a cancer with a far worse prognosis than MCL. Then review the statistics once again. Remember that long tail? It's there in MCL!
Keep in mind that many good minds are focusing on MCL now that it has been clearly identified -- especially since it presents a particular challenge to researchers with its puzzling qualities. When people become intrigued, good ideas often follow.
Brand new agents (immunotherapies) are becoming available for the treatment of lymphoma that may considerably improve the odds.
The integrative approach to lymphoma has not been studied, but it is common sense that patients in any chronic disease who undertake steps to a healthier lifestyle and who take good care of themselves will likely do better in the long run than those who do not. What is true for heart disease and diabetes is likely true for cancer as well.
Joining a support group will link you with other people with MCL, as well as with professionals with special interest in this form of cancer. Local groups may only be possible in large metropolitan areas but the mantle cell list is open day and night and one need not travel anywhere. There you will hear about the newest therapies and how patients experience them from first person accounts. You will be able to draw strength from others in the same situation and share your own strengths as you learn to cope. This single step can make a big difference in your cancer experience and your survival.
Keep in mind that uppity patients have been shown to do better than passive patients over time. Question and fight: it is your life!
Look for the gifts that the cancer brings you, despite itself. Use it to bring good things into your life. Cancer is an adventure. Not one we would have chosen, I know. But an adventure nevertheless... Live it creatively, live it to the full.
This is important: you may not be able to heal the cancer, but you CAN heal you life.
Researched and compiled by Vera Bradova © 1998
Updated 7-15-1998
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