Q. If you have a blood smear that shows a lymphocytosis, and all the lymphocytes look pretty mature, how do you know whether it’s chronic lymphocytic leukemia (CLL) or just a plain old benign lymphocytosis?

A. Good question.

There are several things you can do.
1. Look at the patient’s age. If your patient is a child, and you’re seeing a ton of mature-looking lymphocytes, it’s probably one of two things: infectious lymphocytosis (a viral infection of childhood in which you can see a huge lymphocytosis, anywhere from 35-100) or Bordetella pertussis (in which the count is usually between 10 and 55).  One curious thing about Bordetella is that the lymphocytes often have little nuclear notches. Not clefts (which are big creases or cleavings in the cell nucleus that are indicative of follicular small cleaved cell lymphoma), but notches. Bordetella is usually a disease of childhood – but adults can get it too. Children never get CLL, by the way – CLL is a disease of grown-ups only.

2. If your patient is an adult, and you’re seeing a ton of mature-looking lymphocytes, the thing you worry about is CLL. The lymphocytosis could potentially be due to Bordetella infection (though that’s unlikely in adults) or to stress (though with stress lymphocytosis, the counts only get up to about 8 or so – not very high), but you need to make sure you’re not dealing with CLL. To rule out CLL, you really need to do flow cytometry (immunophenotyping). If it’s a benign lymphocytosis, the lymphocytes will be a mixture of T and B cells (with a greater proportion of T cells). If it’s CLL, all the cells will mark as B cells, but they will also express CD5, a marker that is normally associated with the T cell lineage. Weird.

3. Finally, look around and see if you see some reactive lymphocytes in addition to the normal ones. In certain infections – particularly viral infections, like infectious mononucleosis – you can get a whopping lymphocyte count, and when you look at the cells, they’ll look “reactive” – meaning, “weird.” Sometimes they have abundant cytoplasm, sometimes they’re very large and look like immunoblasts. If you see cells like that, particularly if the patient is a child or young adult, infectious mononucleosis should be in your differential.

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