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p53 mutation is associated with progression in follicular lymphomas
CA Sander, T Yano, HM Clark, C Harris, DL Longo, ES Jaffe and M Raffeld
Hematopathology Section, National Cancer Institute, National Institutes of
Health, Bethesda, MD 20892.
The majority of low-grade follicular lymphomas will eventually transform to
an aggressive intermediate, or high-grade lymphoma. The molecular
mechanisms responsible for this transformation have not been determined. We
studied serial biopsies from 34 patients with follicular lymphomas that
underwent histologic transformation, for abnormalities of the p53 tumor
suppressor gene by a combination of immunohistochemistry, single strand
conformation polymorphism analysis (SSCP), and sequencing. We found
overexpression of p53 in 10 of the 34 transformed aggressive lymphomas, 9
of which contained mutations identified by SSCP analysis and subsequent
sequencing. Matched pretransformation low-grade follicular lymphoma
biopsies were available for 7 of the 10 cases. None of six studied by
immunohistochemistry showed overexpression of p53 and only 1 of 4 studied
by SSCP/sequencing showed the presence of mutation in the pretransformation
biopsy. Interestingly, an eighth p53 positive transformed lymphoma recurred
with a clonally related, p53 negative low-grade lymphoma 5 years after the
patient had achieved a complete remission. Immunohistochemistry also showed
that several pretransformation biopsies from p53 positive transformed cases
showed rare p53 positive cells and in one case we could document an
increase in their number over time. Twenty-five additional low-grade
follicular lymphoma biopsies were also examined. Three patients had
lymphomas positive for p53 mutation. One of the three subsequently
transformed within a year of the biopsy studied; the second patient had an
earlier (unavailable) biopsy at a different site that showed transformed
histology. The third patient was treated with ProMACE-MOPP combination
chemotherapy and attained a complete remission. We conclude that (1)
mutations of p53 are associated with histologic transformation in
approximately 25% to 30% of follicular lymphomas and (2) p53 positive cells
can be detected before histologic transformation, but do not comprise a
significant percentage of the neoplastic cell population (identifiable by
SSCP) until late in the disease, just before or after histologic
progression. Finally, the data also suggest that p53 positive low-grade
lymphomas are at risk for progression and that in this subset, aggressive
therapy may be warranted.
Volume 82,
Issue 7,
pp. 1994-2004,
10/01/1993
Copyright © 1993 by The American Society of Hematology
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