Wednesday, June 10, 2009

More of the CLL Chapter

I have been gradually improving since the weekend and I have put some work in on the chapter that is due next month.

The diagnosis of CLL is superficially very easy. For most patients the only abnormality is in the blood count, which shows a lymphocytosis comprising small round cells consisting of mainly nucleus with very little cytoplasm. The nuclear chromatin is coarsely condensed and nucleoli are not usually visible. Cytoplasm appears as a pale blue rim in Romanowsky stained blood films. Characteristically there are cells present on the blood film that appear to have burst or disintegrated; these are known as ‘smudge’, ‘smear’ or ‘basket’ cells. An admixture of larger cells is usually seen. Typically, prolymphocytes are present with larger nuclei with less condensed chromatin and a single prominent nucleolus. The nucleus is often eccentric set in rather more abundant pale cytoplasm.

Very rarely cells with a nuclear cleft are seen leading to confusion with follicular lymphoma. The term ‘atypical CLL’ has been applied to cases of CLL where the number of prolymphocytes exceeds 10% or where the total of atypical cells including prolymphocytes, clefted cells and plasmacytoid cells exceeds 15%. Although it is a commonly used term it has no basis as a different disease entity and the term is just as often used to describe cases of CLL with atypical cell markers. Atypical cell morphology is often associated with the presence of certain chromosomal abnormalities, particularly trisomy 12.

The definitive diagnosis of CLL relies not on the cellular morphology, but on the immunophenotype. The cells are monoclonal. Clonality is assumed by the finding of a single immunoglobulin light chain type (either kappa or lambda) on the surface of the CLL cells, but the quantity of surface immunoglobulin is only about 10% of that on normal B cells. The cells are typically positive for CD5, CD19 and CD23 and negative for FMC7 and surface CD22. The immunoglobulin associated molecule CD79b is only weakly positive. The Matutes score utilizes these markers to differentiate CLL from other lymphoid tumors. In its latest guise it allocates one point each for positive staining for CD5 and CD23, one point for negative staining with FMC7 and one point each for weak or negative staining for surface Ig and either CD79b or CD22. Most cases of CLL have scores or 4 or 5; those scoring 3 often have ‘atypical’ CLL and those scoring 0-2 have other lymphoid tumors.

The monoclonal antibody FMC7 detects and epitope of CD20 which is obscured by changes in membrane cholesterol metabolism. CD20 is also only relatively weakly expressed on CLL cells compared to other B cells. There are other antigens that are differentially expressed on CLL cells, including CD43, CD11c, CD25, and very low levels of CD45, but these markers are of less value in distinguishing CLL from other B cells malignancies than those used in the Matutes score. Flow cytometric examination of CLL cells usually includes CD20 and CD52 in the examining panel since antibodies to these antigens are part of the therapeutic armory.

Clinical features
Apart from the lymphocytosis, patients may have accumulations of lymphocytes elsewhere. Peripheral lymphadenopathy in cervical, axillary and inguinal regions must be looked for since lymph node enlargement in these areas form the basis of the clinical staging systems as do enlargement of the spleen and liver. More comprehensive lymphadenopathy may be detected by imaging techniques such as abdominal ultrasound (US) and computerized tomography (CT), but these techniques play no part in clinical staging. It should be emphasized that there is usually no place for CT scanning in the initial examination of most patients with CLL and staging based on CT findings can lead to serious mistreatment of patients.

The other area of lymphocytic infiltration that is clinically important is the bone marrow. This is assessed by measurement of the haemoglobin and platelet count and there is usually no need for bone marrow examination in the initial assessment of patients with CLL. Of course, there are other reasons than bone marrow infiltration for anemia and thrombocytopenia in CLL, such as autoimmunity, iron deficiency and hypersplenism. It is important to exclude these when clinical staging is assessed.

Two forms of clinical staging are currently used; Rai staging in America and Binet staging in Europe. Details of these systems are given in Table 1. Although they differ in detail they both in effect measure tumor mass, and neither measures the pace of disease. Both have prognostic value and both suffer from the same defects (such as using the same threshold haemoglobin value for males and females). Both have stood the test of time and both remain valuable despite the appearance


Burke said...

Dr. Hamblin,

Some things I've wondered about.

Are all of a cll patient's B cells malignant, or does he usually retain some healthy ones, at least for a while?

When a BMBx states that a certain percentage of the "cells tested" are malignant, does that mean that the rest are not malignant?

As I understand it, smaller cells are shown further to the left side on a flow histogram. So does the "left-shifted" terminology sometimes seen in BMBx reports refer to them? (as cll cells are small)

As I understand it, some docs are claiming (or hoping)to get cures with FCR. Are these docs relying on having some healthy B cells surviving the cancer and the treatment to attack residual disease as the graft does in an allograft?

(Glad you are feeling better. You made me feel a lot better once with some good advice at a difficult time.)

H Paul Garland said...

I am so glad that you are feeling a bit better Dr. Hamblin!

Shari said...

Dr. Hamblin, my husband and his mother both have CLL. Recently my sister in law had was diagnosed with throat cancer. She ignored the lump in her neck for many months and therefore the surgery to remove all the affected areas was quite extensive. My mother in law is with her and in a recent phone conversation told me that they tested for CLL. My mother in law was told that her daughter did not have CLL, but had the markers as if she did. If I had been there, I would have asked more questions but my mother in law does not have the same level of CLL comprehension that I do and it left her very confused. She thought I would understand the information, but it left me puzzled and wondering if my mother in law just misunderstood. However, I thought I would ask you if this makes any sense to your educated mind. : )

I enjoy your blog and have great admiration for you both spiritually and medically.

Terry Hamblin said...

Shari, this sounds like MBL, which I will write about in the next section of the chapter, but if you serach the blog on MBL you will find out quite a lot about it.

Terry Hamblin said...

There are always some B cells that are not part of the malignant clone, though even in normals, the B cells in the blood are far outnumbered by the T cells. In a BMBx the lymphocytes are not normally differentiated into T and B, so the non-malignant cells are mostly T cells. After FCR most B cells (normal and malignant) as well as most T cells are eliminated. Lymphocytes take a long time to return after FCR so there is no GVL effect as in a BMT.

'Left-shifted' is not applied to lymphocyes, only to the myeloid series.

Anonymous said...

Dr. Hamblin-

On a BMB under the Bone Marrow Clot, is CLL seen as "a single large lymphocyte"? I always thought CLL was all about small lymphocytes.

Jenny Lou Park

Anonymous said...

In an asymptomatic CLL patient, is having a FISH analysis always a matter of personal choice or does it ever have medical value regarding future tx. In this case the individual is an asymptomatic 55 year-old male with a WBC of 22.4, but all other counts normal, who has had CLL confirmed by flow cytometry, IgVH mutational status (unmutated), ZAP-70 (low, 4) and CT-scan (some minimal node involvement)? This individual's last normal WBC done 2 years prior to the elevated count and was a 9.
Your blog is greatly appreciated!

Terry Hamblin said...

Jenny Lou

Occasional large lymphocytes are normal in CLL


FISH is useful for picking up del 11q and del 17p, both of which carry a poor prognosis. Other FISH findings are less critical.