Molecular An Immunophenotypic Prognostic Factors In Follicular Lymphoma

As with DLBCL, many molecular, cytogenetic, and immunohistochemical factors have been shown to have prognostic significance in small series of patients with FL.38-40 Some of these are summarized in Table 66.7. The variability in the prognostic factors identified across many of these studies reflects selection bias into the various studies, heterogeneity of treatment

Table 66.6 Five year and 10 year overall survival rates for patients with FL according to FLIPI risk group

Number of Distribution of 5 year 10 year

Risk group adverse factorsa patients (%) OS (%) OS (%)

Intermediate 2 37 77.6 50.9

high >3 27 52.5 30.5 OS, overall survival.

aAdverse risk factors for FLIPI are age > 60 years, Ann Arbor stage III or IV, hemoglobin <12 g/dL, serum LDH > upper limit of normal, number of nodal sites > 4.

regimens, and the lack of consistency in the diagnosis and grading of FLs, which has been documented in many previous studies.

As with aggressive NHL, the use of GEP has recently been applied to the study of FLs in an attempt to refine prognostic groups identified by the FLIPI and IPI. The largest GEP study to date has been reported from the Leukemia and Lymphoma Molecular Profiling Project (LLMPP).41 In this study, cDNA microarrays were performed on 191 biopsies from patients with FL for which clinical follow-up data were available. This study identified two gene expression signatures, both with high levels of genes characteristic of immune response functions. One of these signatures was associated with favorable and the other with adverse prognosis. Many of the immune response genes identified in both signatures are typically expressed in macrophages, and further studies demonstrated that the signatures with prognostic significance were expressed in cells other than the germinal center derived malignant B-cells. This study demonstrated the potential prognostic significance of the immune response in this disease, especially since the gene

Table 66.7 Examples of morphologic, immunohisto-chemical, and molecular markers with prognostic significance in FL

Marker

Impact on prognosis

Histologic grade

Higher grade carries adverse prognosis

Ki-67 (proliferation marker)

Higher proliferation rate carries adverse prognosis

Diffuse areas

Adverse

Loss of p53

Adverse

Loss of p16

Adverse

Gain of c-myc

Adverse

bcl-6

Variable in different series

bcl-2

Variable—site of breakpoint in rearranged bcl-2 gene has prognostic significance

expression signatures had predictive value independent of the IPI.

Consistent with these observations, a recent study from British Columbia has examined the potential prognostic significance of lymphoma-associated macrophage (LAM) content in low-grade FL, using routine immuno-histochemical staining for a macrophage marker (CD68) in routinely processed and fixed clinical specimens.42 Out of 99 evaluable patients with FL, all uniformly treated between 1987 and 1993, 87 were classified as having low LAM content and 12 as having high LAM. The median overall survival for each group was 16.3 years versus 5.0 years, respectively (p = 0.0003). In multivariate analysis, LAM and IPI retained independent predictive value. TMA studies are in progress for patients with FL at present and are likely to identify candidate immunohistochemical markers which will be used to construct refined prognostic models in the future.

In the meantime, clinical prognostic factors such as the FLIPI or IPI will remain the standard tool for clinical practice and clinical trials.

Few studies of functional imaging have been conducted in FL, and most suggest that the PPV and NPV of FDG-PET are relatively low, suggesting that this is unlikely to provide a useful prognostic tool in these diseases.

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