The true incidence of histologic transformation is difficult to determine for a wide variety of reasons.1 As noted above, there are a number of differences in the way in which transformation is defined. It may also be difficult to distinguish patients with histologic transformation from those with unrecognized discordant pathology at diagnosis. Most authors suggest that patients with evidence of transformation within 6 months of diagnosis have discordant pathology, rather than transformation.5-7 There is also a lack of uniformity regarding patient follow-up in many series. Long-term follow-up of large cohorts is necessary to determine the true frequency of transformation, since transformation may be a late event. Many studies cite crude incidence rates instead of actuarial risk. In addition, the risk of transformation includes all patients in some series, while other reports restrict calculations to patients who have progressed and received biopsies. Accurate statistics on the risk of transformation are also impaired by a lack of standardized criteria for biopsy of suspected sites of relapse.1 For example, peripheral nodes are more likely to be biopsied than less accessible nodes. Infrequent biopsies of suspected sites of relapse will underestimate the risk of transformation. A single biopsy of only one site of relapse may fail to identify transformation that has occurred in another location. In addition, autopsy findings may not be included in some series. Finally, results from older series may not be applicable to patients managed more recently because of refinements in lymphoma classification, ease of detecting relapse and performing biopsies, and possible influences of newer treatments.

A wide variety of situations have been described, in which changes in the histology of lymphoma occur over time.8 Examples include progression of CLL/small lymphocytic lymphoma to diffuse large B-cell lymphoma and Hodgkin's lymphoma, progression of follicular lymphoma to diffuse large B-cell lymphoma, progression of marginal zone lymphoma to diffuse large B-cell lymphoma, and progression of mycosis fungoides to peripheral T-cell lymphoma. This chapter will focus mainly on transformation of follicular lymphomas and, to a lesser extent, on Richter's syndrome.

The frequency of NHL transformation has been examined in several series (Table 67.1). It is impossible to compare the different results due to variations in the way calculations are performed. The true rate of transformation may be overestimated, since many series perform calculations on the basis of only those patients who progress and undergo a repeat biopsy. Conversely, true rates of transformation may be underestimated, since many patients do not have repeat biopsies and few patients are examined at autopsy.

Some studies have shown a risk of transformation that plateaus after 6 or 7 years.1621 Other reports have shown a continuous risk of transformation without evidence of a plateau.6 717 The median time to documentation of histologic transformation was 57 months for a group of low-grade lymphoma patients (follicular small cleaved cell, follicular mixed small cleaved cell and large cell, and small lymphocytic) managed with initial observation.17 Other investigators have reported a median time from diagnosis to transformation ranging from 26 to 66 months.6151619'22

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