Thursday, July 03, 2008

Is CLL a lymphoma?

This is one of the most frequently asked questions by patients, and the answer is yes and no. It depends on what you understand by the word 'lymphoma'. At its simplest a lymphoma is simply a cancer of the lymph nodes. Lymphomas were among the most easily treated of all cancers; they respond well to radiotherapy or chemotherapy compared to other types of cancer. Therefore the specialty of medical oncology grew up treating mainly lymphomas. It has to be recognised, of course, that not all cancers in the lymph nodes are cancers of the lymph nodes. The lymph nodes act as filters for cancer cells being shed from other types of cancer and so are a common site for secondary cancers. Enlarged lymph nodes full of secondary cancer are commonly seen in breast cancer, melanoma, lung cancer, bowel cancer and many other types. Oncologists began by treating lymphomas, but now treat lots of other types of tumors. An oncologist may spend most of his time now treating breast cancer, bowel cancer and lung cancer with chemotherapy.

At the same time that oncologists were learning to treat lymphomas, hematologists were learning to treat leukemias. The strategy adopted by hematologists was twofold. For acute leukemias the idea was to bash the patient as hard as possible with chemotherapy so that the bone marrow was destroyed, and then strive to keep the patient alive until the normal bone marrow recovered. This worked quite well, producing longish remissions. For chronic leukemias, the idea was to give enough of a drug continuously to keep the white count under control while not damaging the bone marrow too much. Rather arbitrarily two drugs derived from mustard gas were chosen to do this: chlorambucil (or Leukeran) for CLL and busulphan (or Myleran)for CML. Busulphan is not much used for this purpose any more though it is used in bone marrow transplantation, but some doctors still use chlorambucil in this old fashioned way though modern clinical trials have shown us better ways of using it.

CLL has been claimed by both hematologists and oncologists as both a leukemia and a lymphoma and, of course, it is both, though this is just semantics, and it doesn't help to draw conclusions as to who should treat it by which category you put it in.

Lymphoma is not just one disease. For more than a century it has been divided into Hodgkin's disease and non-Hodgkin's lymphoma, though in truth this is a bit of a false distinction. However, there are lots of ways of sub-classifying it. At one time oncologists preferred the 'Working Formulation' which made things very easy. This described three types of non-Hodgkin's lymphoma: high grade (which was rare and included conditions like acute lymphoblastic leukemia and Burkitt's Lymphoma), intermediate grade (which included about half the rest) and low grade (which included the other half, and notably CLL).

Because this was very simple it became very popular, and among some oncologists still is. However, the pathologists rather than lumping the lymphomas together insisted on splitting them apart. Chief among them was Karl Lennert from Kiel University in Germany. His classification was very complicated but criticised on the grounds that the distinctions that he made were clinically unimportant. Also he had to contend with the Rappaport classification which talked about lymphocytic lymphoma and histiocytic lymphoma (previously lymphosarcoma and reticulosarcoma). This seemed to suggest that the intermediate grade lymphomas were really tumors of macrophages not lymphocytes. This was so clearly wrong in Lennert's eyes (and mine, for what its worth - I was a mere junior during all this) that there emerged not only a dispute between pathologists and oncologists, but also between Europeans and Americans.

It wasn't until the REAL classification (Revised European and American Lymphoma) Classification emerged that agreement was possible, and soon afterwards a new comprehensive WHO classification was approved. It was the recognition of specific immunological and chromosomal abnormalities that allowed this to happen. In the WHO classification there are 40 different types of Non-Hodgkin's lymphoma, and one of the types of Hodgkin's disease is also now recognised as a non-Hodgkin's lymphoma.

CLL is known as CLL/SLL according to this classification, the SLL standing for small lymphocytic lymphoma. This recognises that rarely SLL can be a totally lymph node-based disease without a leukemia, and that when CLL lymph nodes are examined they have exactly the same histological picture (and indeed immunology and chromosomes) as SLL.

The importance of this comes from how lymphomas are managed by oncologists. So as to know how to treat a lymphoma, an oncologist will stage a patient according to Ann Arbor staging. Stage I is when the lymphoma is confined to a single group of glands; stage 2 can have more glands involved, but they are confined to one side of the diaphragm (either above or below); stage III can be both sides of the diaphragm, but is confined to lymph nodes and stage 4 means the disease has spread outside the lymph nodes into other tissue such as liver or bone marrow. (For this sort of staging the spleen is regarded as a big lymph node below the diaphragm).

CLL therefore presents a problem. Stage 4 lymphoma requires immediate treatment, but since CLL virtually always involves the bone marrow even in the most benign cases, it would seem that nearly all CLLs need treating as soon as they are seen, because they are Ann Arbor stage 4. We know from clinical trials that this is not so and therefore Ann Arbor staging must not be used in CLL. Instead either Rai or Binet staging must be used.

Knowing more precisely about individual lymphomas has become necessary, and will be more so in the future as treatment are targeted to specific molecular mistakes. No oncologist would now make the mistake of treating mantle cell lymphoma in the same way as diffuse large B cell lymphoma, even though they are both intermediate grade lymphomas. Similarly follicular lymphoma and CLL are different tumors and must be managed differently. Alas, we still see CLL patients getting CVP-R even though it has never been tested in CLL and CVP has been shown decades ago to hold no advantage over chlorambucil except that it causes numb feet and fingers (if you call that an advantage - it does allow you to pick op hot plates without feeling pain.)


Hugh L said...

Thank you for an excellent blog, a couple of years too late from my perspective. Having been diagnosed with CLL two years ago and been put through the CVP-R protocol, the leukemia is now in remission. However, I now have severe and debillitating peripheral neuropathy in my feet as a result of the Vincristine. A year on from my last chemo treatment there is still no sign of the condition improving. It is so frustrating to only now read about the "chlorambucil option" - the horse has bolted!

Wayne said...

This issue of CLL being a Lymphoma or a Leukemia has been baffling to me and others mostly as to WHY it should be important.
You wrote in part "CLL has been claimed by both hematologists and oncologists as both a leukemia and a lymphoma and, of course, it is both, though this is just semantics,......" I am curious to know if Dr. Richard Furman CLL Research Center Weill Cornell Medical College has, to your knowledge, any functional benefit in mind for reclassifying CLL as a Lymphoma based on the maturity of the cancer cells? It came to my mind that many drugs have potential crossover usage in the many related lymphomas/leukemias such as Rituximab. Because Rituximab was primarily designed for more highly expressed CD20 lymphomas it does not carry a labeled use for CLL and the "standard" dose of 375mg/m2 is, I believe, derived from work on FL. None the less "R" is widely used and valued in CLL tx protocols with varied dosages. Would the reclassification of CLL to a lymphoma have any practical, economic or drug development/application benefit for the patient? I never got to question Dr. Furman about whether his reclassification proposal was merely an academic exercise or if it had some tangible benefit that I still fail to grasp.

As usual your explanation uses common sense with a background of extensive knowledge to sort out a logical way of explaining this issue to the layman.

Thanks for your good works,

Terry Hamblin said...

Wayne, calling CLL a lymphoma may be a way of bamboozling insurers since CLL is not a licensed indication for rituximab and lymphoma is. It is dishonest but effetive.

Anonymous said...

A good and informative post.

I have also heard of cases where rituximab would not be covered by insurance for CLL, but it will be covered for a lymphoma.

Since CLL is both, whatever works, I guess.

Anonymous said...

Please help me out. 65 yr old mother was just diagnosed with CLL/SLL. CBC was normal, but had slightly enlarged nodes in neck. Scan showed the same for nodes under arms, chest and groin. Biopsy of node in neck/collar area confirmed CLL/SLL. Almost all info. I read on CLL/SLL is that it is first suspected due to high WBC. Are there studies that indicate it is better, worse, indifferent, that the initial dx was from enlarged nodes vs blood counts?

Terry Hamblin said...

The outcome will depend on the same prognostic factors as CLL that is mainly in the blood, and the indications for treatment should follow the same guidelines