Monday, April 06, 2009

Diagnosing CLL

The diagnosis of CLL is easy, but the criteria for the diagnosis have recently changed. The first thing that is necessary is a raised lymphocyte count. Back in the days when I started in CLL you needed 15,000 lymphocytes per microlitre for the diagnosis. Gradually this was reduced, first to 10,000 and then to 5000. In fact the upper limit of normal for lymphocytes is either 3,500 or 4000, depending on which set of normal values you go by, so we might have suspected CLL even if the lymphocyte count were less than 5000.

The second requirement is the peculiar immunophenotype of CLL. The cells must be positive for CD5, CD19 and CD23, have low levels of surface immunoglobulin and CD79b and be FMC7 negative. There is actually a CLL scoring system that gives 1 point for each of these (except CD19 which is present on all B cells tumors). A score of 4 or 5 is required for the diagnosis of CLL. Very occasionally a true CLL will only score 3, but these really are exceptional cases that require an expert eye over them.

I will say more about this when we talk about the differential diagnosis (that just means answering the question, "If it's not CLL, what else could it be?").

It is also necessary to demonstrate monoclonality. To be accurate, we don't actually demonstrate monoclonality, but instead take advantage of the fact that the immunoglobulin molecules can have one of two possible types of light chains, called kappa or lambda (those are just the Greek letters that stand for 'K' or 'L'). Normal B cell sometimes have kappa light chains and sometimes lambda light chains; usually the ration is 2 kappa for each lambda. Since CLL cells are derived from a single cells, in any individual all the CLL cells have a single light chain, either kappa or lambda.

The thing that has changed has been the threshold count. Instead of 5000 lymphocytes per microlitre, now you must have 5000 B-cells per microlitre. Since many cases of CLL have well in excess of 4000 T-cells per microlitre, this equates to a lymphocyte count of at least 8000 and sometimes as much as 15,000 per microlitre.

This all sounds like a circular route back to 1975. But the reason for the redefinition is clear. I have been saying for some time now that many cases of stage 0 CLL live out a normal life span and never require treatment - to label such patients as having leukemia is unnecessarily frightening. Especially since Andy Rawstron discovered monoclonal B cell lymphocytosis, which I will write about tomorrow.


Anonymous said...

Dear Dr.Hamblin,
can monoclonality be also a benign condition, like in the article posted? Do you know of any other cases?
Thank you!

Ian said...

Dr Hamblin - I found your blog as I was searching for information regarding my recent diagnosis of CLL.

In early March I went to my doctor as I'd been feeling lethargic and achy for a while. I am 50 years old. She ordered a full blood count.

With elevated leucoocytes of 11,500 cells/uL and 13,400 three weeks later, my GP ordered a Flow Cytometry where results were apparently consistent with B Cell CLL:

CD5 and CD19 coexpression - 81.7%
CD10 - 0.1%
CD20 - 60.9%
CD23 - 72%
KAPPA - 75.7%
LAMBDA - 67.8%

I was referred to a haemotologist, who saw me on the 1st May, confirming me at Stage 0 CLL. He plans to take regular blood tests over the next 12 months to determine the progression (if any) in my WBC.

Your blog talks about monoclonality rather than having Kappa and Lambda dually expressed - I'm puzzled?

Terry Hamblin said...

That is a very strange case in a very young child. I have never seen or heard of a similar case.
Something strange here. Either it is a laboratory error (most likely) or you have polyclonal B cell lymphocytosis, a quite distinct and benign condition. However this is almost confined to female smokers. If you have binucleate cells then that is the diagnosis.

Anonymous said...

Dear Mr. Hamblin,

I came across your blog three days ago by searching and trying to understand about CLL. Since then, I didn’t stop reading your postings. Many of my own questions have been answered by reading your blog. Your are a great inspiration to all who come across your path and those who read your blog. I wish your fast recovery and give us the pleasure of having you as our inspiration for many years to come.

My husband which is 42 years old has been recently (three weeks ago) diagnosed with CLL with no symptoms. We live in Dubai and the analyses have been done by an hematologic & oncology hospital and some other in Mumbai at Religare SRL Diagnostics.

The Dr here consider as being CLL 0 and we are now on w&w for the next six months. We are in a lot of distress to find out of this diagnosis for such a young person. For the moment we don’t know where to go and who to ask for second opinion and it will be of a great help for us if you can find the strength and time to give us one.
The results are :
WBC 15.000with lymphocytes, 37% neutrophils, platelet count 165.000, hemoglobin 13.56g/dl. C-reactive protein is normal at 0.24. Liver and renal functions are normal. Vitamin B12 normal. Sedimentation rate 13 mm after one hour. Then other tests : SmlgG – 03, SmlgM – 01, SmlgD – 00, HLA DR – 83. ZAP-70- Cll zap index – 0.28. Total IgG – L 1.20, Total IgA – H 8.56, Total IgM – 0.65. CHR Lymphoproliferative Disorders: * Peripheral Blood : WBC Count – H 16.6, Lymphoid Cells – 85. IMMUNOPHENOTYPIC MARKERS: CD45 – 99, CD5 – 95, CD19 – 84, CD5/CD19 (expression) – 83, CD20 – 71. CD11c – 13, CD23 – 83, CD25 – 01, CD10 – 00, CD22 – 79, CD11c/CD25 (expression) – 06, FMC7 24, CD38 – 08, CD103 – 00, KAPPA – 93, LAMBDA – 01. B2- Microglobulin – H 1872.0, LDH – 133, CRP – 0.2. CT Scan : multiple groups of slightly enlarged lymph nodes involving the upper and lower deep cervical, mediastinal,axillar as well as the mesenteric lymph nodes, all of which appear about 1.0 – 1.5 cm in size. Normal salivary glands and the thyroid. Bilateral pulmonary subpleural apical reticulo-nodular infiltrates, more evident on the left side, likely attributed to previous granulomatous infection. Clear rest of both lung fields. Normal CT appearance of the heart and great vessels, liver, spleen, pancreas, both kidneys, suprarenals.aorta and IVC. No ascites. Normal pelvic organs apart from subtile mural thickening of the small bowel loops.
Awaiting for your trustworthy opinion. Thank you very much, praying for your best health, Dora Mills