Prolymphocytic transformation

Prolymphocytic transformation was a concept introduced by David Galton in
the 1970s. People often attach a more sinister interpretation to it than is
warranted. While some cases undoubtedly are true transformations to a more
malignant form of CLL, in many cases the transformation is transient and in some
cases there has always been a high percentage of prolymphocytes, especially in
the lymph nodes, but the condition is stable.

Here is a recent article I wrote about it:


Prolymphocytoid transformation.
Definition
Prolymphocytes are large lymphocytes some 10-15 m in diameter compared to
7-10 m for CLL cells. They have round or indented nuclei with chromatin that
is less dense than that of CLL cells, but more dense than that of
lymphoblasts. They possess a single prominent nucleolus. The cytoplasm is more abundant
than that of a typical CLL cell and in Romanowsky stained specimens is pale
blue and agranular. Although small numbers of prolymphocytes are usually found
in CLL, there is a distinct B-cell prolymphocytic leukemia (PLL) that is
completely unrelated to CLL. Clinically splenomegaly without lymphadenopathy is
the rule, but it is defined by the presence of >55% circulating
prolymphocytes39. It is immunophenotypically distinct, with strong positivity for surface
immunoglobulin, CD20, CD22, CD79b and FMC7, while it is negative for CD23 and
mouse rosettes. The reaction with CD5 is controversial. Most cases are CD5
negative but perhaps 20% are CD5 positive. This may be explained by the
discovery of a splenomegalic form of mantle cell lymphoma with t(11;14) that
morphologically resembles PLL40, 41.
Prolymphocytoid transformation of CLL was first reported by David Galton’s
group at the Royal Postgraduate Medical School in London42. It was
specifically noted that the cells retained the immunophenotype of CLL cells. In a series
of papers43-46 the Galton group defined typical CLL as having <10%
prolymphocytes and CLL/PLL as those cases with between 10 and 55% prolymphocytes.
Although as a group patients with CLL/PLL had more surface immunoglobulin than
those with typical CLL there was no sudden transition from a lower density at
an earlier stage of the disease, and the immunophenotype of small and large
cells was indistinguishable.
Contrary to the common perception, in a study of 55 cases of CLL/PLL44 half
showed a stable picture without a progressive increase in prolymphocytes. The
prognosis of this group was similar to that of stable CLL without
prolymphocytes. In one third of cases the increase in prolymphocytes was unsustained
and in only 18% was there a definite progression towards a more malignant
phase of the disease. In a multivariate analysis of prognostic factors in CLL/PLL
only an absolute number of prolymphocytes and spleen size were of
independent prognostic significance. The median survival for patients with >15 x 109/L
was three years.39.
Karyotype
Cellular morphology seems to be closely related to karyotype. In a study of
544 patients, Matutes et al47 found trisomy 12 in 18%. 31% of these had
CLL/PLL compared to 10% of the whole series. Subsequent studies have shown that
such atypical morphology is also associated with deletions at 6q2148 and
t(14;19) translocations49, both of which are associated with an adverse prognosis.
Even more significantly 80% of patients with p53 abnormalities have CLL/PLL
morphology50.
Oscier et al found evidence of karyotypic evolution in 16% of 112 patients
with CLL studied by sequential cytogenetic studies51. Finn et al found a
higher incidence of 43% in 51 patients52. The most common extra abnormality was a
structural abnormality of 6q21. Bea et al found sequential increases in
chromosomal abnormalities in six out of ten patients with Richter’s
transformation of other types of clinical progression53.
Treatment may induce evolution. It may be thought of as a selective pressure
inducing change. Just as antibiotics can select for drug resistant bacteria,
so chemotherapy may kill only the susceptible cells, allowing drug resistant
cells to regrow. These may be morphologically more extreme, karyotypically
different and express greater amounts of CD3854.
Implications for management
Merely finding increased numbers of prolymphocytes in the blood is not
necessarily an indication of transformation of CLL. The increase may be transient,
indicative of a recent infection or other unknown event. Some karyotypic
abnormalities (such as trisomy 12) are associated with >15% circulating
prolymphocytes, yet these patients may remain stable for many years. Increasing
numbers of prolymphocytes and karyotypic evolution usually have a malign
prognosis. Most authors have been unable to attach an independent prognostic effect to
deletions at 6q21, but acquisition of p53 abnormalities at 17p13 carries the
worse possible prognosis55-57. This is often associated with morphological
change (prolymphocytoid transformation50 or Richter’s syndrome53) and drug
resistance58.
The indications for treatment in CLL/PLL are the same as those CLL itself:
systemic symptoms and bone marrow failure. The presence of prolymphocytes
should raise the possibility of abnormalities of the p53 pathway which mean drug
resistance and might indicate non-standard therapy such as alemtuzumab or
high-dose methylprednisolone is needed.

Dear Antonina

The markers are characteristic of CLL not PLL. There is a condition known as
CLL/PLL which can only be diagnosed from the blood film. Prolymphocytes are
larger than lymphocytes. The nucleus of the cell tends to be slightly to one
side, and to contain a single nucleolus (a clear ring in the middle of the
nucleus). CLL/PLL requires there to be between 10% and 55% prolymphocytes, and
the cell markers are those of CLL.

It is often thought of as a transformation of CLL, but this is true in only
a minority of cases. In some, the appearance of prolymphocytes is temporary -
they disappear after a while, while in others there is a constant number of
prolymphocytes that doesn't change over time. This is usually associated with
trisomy 12 by FISH.

If there are >55% prolymphocytes and the markers are those of CLL then it is
probably a true transformation from CLL to PLL, though I have to say that
this is a very rare phenomenon.

In cases of CLL/PLL the markers tend to be a bit atypical. Surface Ig is
denser thabn usual for CLL, though not as dense as in PLL or SLVL. FMC7 may be
positive and CD20 denser than usual. CD22 and CD79b may also come up a bit
positive.

CD22 is something that can fool flow cytometrists. It is present in all B
cells, but not on the surface of CLL cells, only within the cytoplasm. CD23
can also be a catch. It disappears if the cells are frozen and thawed before
testing.

I wrote the following in a recent book about PLL


Prolymphocytes are large lymphocytes some 10-15 mm in diameter compared to
7-10 mm for CLL cells. They have round or indented nuclei with chromatin that
is less dense than that of CLL cells, but more dense than that of
lymphoblasts. They possess a single prominent nucleolus. The cytoplasm is more abundant
than that of a typical CLL cell and in Romanowsky stained specimens is pale
blue and agranular. Although small numbers of prolymphocytes are usually
found in CLL, there is a distinct B-cell prolymphocytic leukemia (PLL) that is
completely unrelated to CLL. Clinically splenomegaly without lymphadenopathy is
the rule, but it is defined by the presence of >55% circulating
prolymphocytes39. It is immunophenotypically distinct, with strong positivity for surface
immunoglobulin, CD20, CD22, CD79b and FMC7, while it is negative for CD23
and mouse rosettes. The reaction with CD5 is controversial. Most cases are CD5
negative but perhaps 20% are CD5 positive. This may be explained by the
discovery of a splenomegalic form of mantle cell lymphoma with t(11;14) that
morphologically resembles PLL40, 41.
Prolymphocytoid transformation of CLL was first reported by David Galton’s
group at the Royal Postgraduate Medical School in London42. It was
specifically noted that the cells retained the immunophenotype of CLL cells. In a series
of papers43-46 the Galton group defined typical CLL as having <10%
prolymphocytes and CLL/PLL as those cases with between 10 and 55% prolymphocytes.
Although as a group patients with CLL/PLL had more surface immunoglobulin than
those with typical CLL there was no sudden transition from a lower density at
an earlier stage of the disease, and the immunophenotype of small and large
cells was indistinguishable.


Contrary to the common perception, in a study of 55 cases of CLL/PLL44 half
showed a stable picture without a progressive increase in prolymphocytes. The
prognosis of this group was similar to that of stable CLL without
prolymphocytes. In one third of cases the increase in prolymphocytes was unsustained
and in only 18% was there a definite progression towards a more malignant
phase of the disease. In a multivariate analysis of prognostic factors in CLL/PLL
only an absolute number of prolymphocytes and spleen size were of
independent prognostic significance. The median survival for patients with
prolymphocytes >15 x 109/L was three years.39.
Implications for management
Merely finding increased numbers of prolymphocytes in the blood is not
necessarily an indication of transformation of CLL. The increase may be transient,
indicative of a recent infection or other unknown event. Some karyotypic
abnormalities (such as trisomy 12) are associated with >15% circulating
prolymphocytes, yet these patients may remain stable for many years. Increasing
numbers of prolymphocytes and karyotypic evolution usually have a malign
prognosis. Most authors have been unable to attach an independent prognostic effect to
deletions at 6q21, but acquisition of p53 abnormalities at 17p13 carries the
worse possible prognosis55-57. This is often associated with morphological
change (prolymphocytoid transformation50 or Richter’s syndrome53) and drug
resistance58.
The indications for treatment in CLL/PLL are the same as those CLL itself:
systemic symptoms and bone marrow failure. The presence of prolymphocytes
should raise the possibility of abnormalities of the p53 pathway which mean drug
resistance and might indicate non-standard therapy such as alemtuzumab or
high-dose methylprednisolone is needed.