People Places Policies Program Patient Care & Education Professional Development
Places
HMC
UWMC
VA PSHCS
Clinic Block Overview
Continuity Clinics
Ambulatory Clinics
Thematic Clinics
BOISE
WWAMI
International Rotations

Ecase #15-B

Lisanne Gauer, M.D.

September 24-28, 2001

An 80-year-old man with no acute complaints presents for routine physical exam. You plan to do an exam and order routine labs.

  • PMH: prostate CA (s/p prostatectomy), HTN, GERD.

  • Meds:Lasix, ECASA, Moduretic

  • Social: no TOB, occ EtOH.  Married with three daughters.  Previously worked as a commercial fisherman.

  • PE: BP 158/67 HR 61, T 97.3

  • HEENT: no scleral icterus.  OP without erythema/exudate

  • Neck: supple, NT, no LAD

  • Heart: RRR S1, S2 no m,g,r

  • Lungs: CTA bilat.

  • Back: no spinal, no CVA TTP. 

  • Abd: normal BS, NT, ND.  no HSM.

  • Ext: no c/c/e 1+ distal pulses.

  • Labs: WBC 10.3, Hb/HCT 14.6/43 plt 243.  Diff shows 15% neutrophils, 4% monocytes, 1% eosinophils, 30% normal/reactive lymphocytes and 47% abnormal lymphocytes as well as 3% prolymphocytes.

  • Chem: WNL; LFTs WNL.

Because the differential is abnormal you request that the laboratory staff review it, and they then call to report the presence of "smudge cells".

What do you do with this information?

Smudge cells are a well-recognized and typical feature of chronic lymphocytic leukemia (CLL), a condition you considered given the wbc differential.  Together with a hematology consultant you decide to order immunophenotyping.  Immunophenotyping is used for the diagnosis and classification of chronic lymphoproliferative disorders, and is also an important prognostic tool in CLL.  It can be used to assess if minimal residual disease is present in a patient who has received treatment.

This patient's immunophenotype demonstrates low to intermediate level CD20, co-expression of CD5, and positivity for CD23.  He also has a small population of prolymphocytes, which falls short of meeting the criteria required for classification of prolymphocytic leukemia. (Criteria is > 10% and less than 55% prolymphocytes.)  CLL-prolymphocytic leukemia has a poorer prognosis than classic CLL.  Poor prognosis is also associated with expression of FMC7, and high expression of CD38 is associated with more aggressive disease regardless of clinical stage.

Since more patients are getting routine CBCs, the proportion of patients in whom CLL is diagnosed in an asymptomatic phase has increased from about 30-40% in the 1970's, to about 60% today.  The most common presenting features in symptomatic patients are lymphadenopathy, fatigue, and weight loss (this patient reported none of these).

CLL is a disease of older patients with 90% of cases occurring after age 50 and a median age of presentation of 65. CLL usually pursues an indolent course but occasionally will present as a rapidly progressivedisease.  When this is the case, these patients usually have larger, less mature appearing lymphocytes and are said to have prolymphocytic leukemia.

Staging: please see reference 1 for staging system(Table 3).

Major complications and disorders associated with CLL:- autoimmune (hemolytic anemia, thrombocytopenia)- hypogammaglobulinemia- infections- disease transformation- second cancers (most frequent sites skin, lung, GItract)

Treatment:  Patients with early, stable CLL should not be treated unless sx develop or the disease progresses.  A number of indications justify tx in CLL - constitutional sx, bulky lymphadenopathy, and splenomegaly causing compressive problems. 

This patient was seen by hematology, and given the fact that he was asymptomatic without adenopathy or splenomegaly, it was decided to follow his CBC and exam serially.  Treatment would not be considered unless there was a rapid rise of his WBC or if the patient became symptomatic.  He was told about the risks of infection and asked to return sooner if he noticed increasing size of lymph nodes or abdominal fullness.

References

  • Rozman, C; Motserrat, E.  Chronic Lymphocytic Leukemia.  NEJM , vol 333, No. 16. 1052-10572.

  • Dighiero, Guillaume.  When and how to treat chronic lymphocytic leukemia. NEJM. Vol 343:1799-1801.

Dear Chris:

Thanks for the nice case summary and literature review on CLL. I didn't know that FMC7 and CD-38 were associated with more aggressive pattern of disease. This would make cytometry an especially useful lab modality for workup. The finding of pro-lymphocytes in your patient at time of diagnosis suggests aggressive disease just as you have pointed out.

I also liked your point about the shift in diagnosis to early, pre-symptomatic cases on account of the wide availability of automated blood counting. Most of these patients now come to us for confirmatory consultation after the primary care physician has already made the diagnosis.

In my own practice I try to determine over the first one  to two years of follow up what the tumor doubling time, (the time it takes to double the absolute lymphocyte count) of that particular patients leukemia might be. This is readily obtainable from the routine CBC and is another indicator of disease kinetics. For the usual patient, doubling is often in the range of 2-3-5 years. For patients with doubling times of one year or less I know that they patients are going to require intervention sooner.

The NEJM study mentioned in the accompanying editorial comparing Chlorambucil to Fludarabine was interesting and serves to underscore a dilemma that we encounter when we recommend treatment. Despite the availability of new and more active agents such as the nucleosides (Fludarabine, Cladiribine, Deoxycoformycin) we probably are not changing the overall survival of patients with this illness compared to what physicians could achieve with Chlorambucil a generation earlier.

One new agent that has just come into practice this past month and which may be able to change this is the new immunotherapeutic Campath. This is a mouse monoclonal antibody directed at CD-52, a ubiquitous antigen found on all lymphocytes and particularly B-cell CLL This antibody has been shown to be capable of producing remissions in patients who have failed prior therapy with Chemo including the above named drugs. Only time will tell if this antibody will improve survival in CLL similar to what we are now seeing in other B-cell malignancies treated for example with Rituxamab (another anti-lymphoma monoclonal antibody).

Jim Cunningham