Editorial

The use of PET scanning in lymphoma: progress and problems

The medical community and oncologists in particular have enthusiastically embraced the use of PET scans, or more recently, scans combining both PET and computerized axial tomography. The adoption of the PET scan has been most notable in the treatment of lymphomas where its incorporation into the care of Hodgkin’s and non-Hodgkin’s lymphomas is now virtually universal. PET scans have clearly impacted the way lymphomas are staged and treated, particularly those types with the potential for cure, such as classical Hodgkin’s lymphoma and large cell and/or aggressive lymphoma. PET scans have also engendered some rethinking of our care of these diseases.

PET scans, because of their enhanced sensitivity and convenience, have almost totally replaced gallium scans. Unlike gallium scans, PET scans are routinely used in staging since the scans are able to reveal disease in normal sized lymph nodes (on CT scan) which would otherwise have been interpreted as unremarkable.

Morton Coleman, MD
Morton Coleman

PET scanning has altered treatment approaches as well. For instance, bulky masses, despite being sterilized of lymphoma, are often characterized by some residual mass or scar. Using conventional means, it has been difficult to determine whether the residual mass after treatment did or did not contain active disease. As a result, these masses had been routinely irradiated even if a biopsy showed scar (because of possible sampling error). Although many still advocate irradiating bulky masses, the advent of the PET scan has engendered a rethinking of this approach when no disease activity is apparent.

Today, a truly negative PET scan at the completion of therapy has become the sine qua non for a complete remission. Few relapses occur, usually in single–digit percentages. Data are also emerging that determination of a response early, after one, two or three cycles of chemotherapy, may be even more predictive of outcome for classical Hodgkin’s lymphoma and large cell lymphoma than that obtained at the end of therapy. This has prompted the initiation of trials to determine whether altering therapy early, based on interim PET scanning, may be beneficial.

Questions about PET

Data show that a positive PET scan obtained during or after chemotherapy predicts for a high probability of treatment failure. If that is true, should a positive PET scan obtained after interim chemotherapy, mandate alternative therapy be immediately pursued, particularly if the results are substantiated by biopsy? Would this spare unnecessary, ineffective therapy and/or would the initiation of different measures, for example, transplantation, still rescue the patient? It is possible that a strongly positive PET scan may simply be a doleful predictor of drug resistance, which may not be overridden by the ‘exponential’ doses of chemotherapy given in transplantation.

In the presence of an early interim negative PET scan, can therapy be shortened, since by convention, chemotherapy is given two cycles beyond complete remission? Treatment could then be stopped after three, four or five cycles of chemotherapy rather than the conventional six. If very few relapses occur after a negative PET scan, is there a need for serial follow-up scans because the likelihood of relapse would be small? There are no compelling data to indicate that a somewhat earlier detection of relapse by PET in these rare relapsing patients would alter subsequent therapy or ultimate outcome. Would the yield outweigh the cost, anxiety and radiation associated with serial monitoring?

The role of PET scans in low-grade lymphoma is less clear. In general, but not always, the semiquantitative standard uptake value (SUV) scores for low-grade lymphoma are low, usually seven or less, whereas those for large cell and/or aggressive lymphoma is twelve or higher. Scores between seven and twelve represent an intermediate zone and may often be seen with classical Hodgkin’s lymphoma. If a higher than expected SUV score in a node or nodal area in an apparent low-grade lymphoma is discovered, it should prompt and direct a biopsy to the area for the presence of aggressive disease. This is particularly useful at initial diagnosis where more than one type of lymphoma pathology may be present or later when transformation is suspected. This utility, however, does not warrant the routine, serial follow-up of low-grade lymphoma by PET scan.

Proceed with caution

Having described the exciting, brave new world of PET scans in lymphoma, words of caution are in order. All is not rosy. For starters, it isn’t always clear what constitutes a positive or negative study. Is the eyeball assessment more accurate than the semiquantitative SUV scores? If SUV scores are used, what low level of SUV activity represents negativity? What background determinants are being used? Further, data amongst machines are not readily transferable. The interval between injection of the radioisotope and subsequent measurement has been variable, not fully standardized, and can affect results. Conditions other than lymphoma may result in a positive PET scan and include infection, thymic rebound, late infiltration of inflammatory cells and/or post-therapy changes.

Perhaps most distressing are the preliminary reports of discordance among observers independently reviewing the same scans. This discordance is reminiscent of the discordance among lymphoma pathologists rendering independent reviews of the same slides. When the material is clear-cut, as with follicular lymphoma in pathology, an unequivocal negative or positive PET scan can be easily diagnosed and yield a high degree of concordance among reviewers. It is the subtle or gray areas that create difficulty. For instance, PET scans showing a major but not complete fall in the SUV scores can create difficulties in interpretation. Despite difficulties with ‘subtleties,’ no one would suggest discarding the use of PET scans any more than one would suggest discarding subclassifying lymphomas. PET scans are here to stay and clearly represent a major advance in the care of lymphoma.

Morton Coleman, MD, is Director of the Center for Myeloma and Lymphoma at Weill Cornell Medical College and the Section Editor of the Hematologic Malignancies section of the HemOnc Today Editorial Board.

The medical community and oncologists in particular have enthusiastically embraced the use of PET scans, or more recently, scans combining both PET and computerized axial tomography. The adoption of the PET scan has been most notable in the treatment of lymphomas where its incorporation into the care of Hodgkin’s and non-Hodgkin’s lymphomas is now virtually universal. PET scans have clearly impacted the way lymphomas are staged and treated, particularly those types with the potential for cure, such as classical Hodgkin’s lymphoma and large cell and/or aggressive lymphoma. PET scans have also engendered some rethinking of our care of these diseases.

PET scans, because of their enhanced sensitivity and convenience, have almost totally replaced gallium scans. Unlike gallium scans, PET scans are routinely used in staging since the scans are able to reveal disease in normal sized lymph nodes (on CT scan) which would otherwise have been interpreted as unremarkable.

Morton Coleman, MD
Morton Coleman

PET scanning has altered treatment approaches as well. For instance, bulky masses, despite being sterilized of lymphoma, are often characterized by some residual mass or scar. Using conventional means, it has been difficult to determine whether the residual mass after treatment did or did not contain active disease. As a result, these masses had been routinely irradiated even if a biopsy showed scar (because of possible sampling error). Although many still advocate irradiating bulky masses, the advent of the PET scan has engendered a rethinking of this approach when no disease activity is apparent.

Today, a truly negative PET scan at the completion of therapy has become the sine qua non for a complete remission. Few relapses occur, usually in single–digit percentages. Data are also emerging that determination of a response early, after one, two or three cycles of chemotherapy, may be even more predictive of outcome for classical Hodgkin’s lymphoma and large cell lymphoma than that obtained at the end of therapy. This has prompted the initiation of trials to determine whether altering therapy early, based on interim PET scanning, may be beneficial.

Questions about PET

Data show that a positive PET scan obtained during or after chemotherapy predicts for a high probability of treatment failure. If that is true, should a positive PET scan obtained after interim chemotherapy, mandate alternative therapy be immediately pursued, particularly if the results are substantiated by biopsy? Would this spare unnecessary, ineffective therapy and/or would the initiation of different measures, for example, transplantation, still rescue the patient? It is possible that a strongly positive PET scan may simply be a doleful predictor of drug resistance, which may not be overridden by the ‘exponential’ doses of chemotherapy given in transplantation.

In the presence of an early interim negative PET scan, can therapy be shortened, since by convention, chemotherapy is given two cycles beyond complete remission? Treatment could then be stopped after three, four or five cycles of chemotherapy rather than the conventional six. If very few relapses occur after a negative PET scan, is there a need for serial follow-up scans because the likelihood of relapse would be small? There are no compelling data to indicate that a somewhat earlier detection of relapse by PET in these rare relapsing patients would alter subsequent therapy or ultimate outcome. Would the yield outweigh the cost, anxiety and radiation associated with serial monitoring?

The role of PET scans in low-grade lymphoma is less clear. In general, but not always, the semiquantitative standard uptake value (SUV) scores for low-grade lymphoma are low, usually seven or less, whereas those for large cell and/or aggressive lymphoma is twelve or higher. Scores between seven and twelve represent an intermediate zone and may often be seen with classical Hodgkin’s lymphoma. If a higher than expected SUV score in a node or nodal area in an apparent low-grade lymphoma is discovered, it should prompt and direct a biopsy to the area for the presence of aggressive disease. This is particularly useful at initial diagnosis where more than one type of lymphoma pathology may be present or later when transformation is suspected. This utility, however, does not warrant the routine, serial follow-up of low-grade lymphoma by PET scan.

Proceed with caution

Having described the exciting, brave new world of PET scans in lymphoma, words of caution are in order. All is not rosy. For starters, it isn’t always clear what constitutes a positive or negative study. Is the eyeball assessment more accurate than the semiquantitative SUV scores? If SUV scores are used, what low level of SUV activity represents negativity? What background determinants are being used? Further, data amongst machines are not readily transferable. The interval between injection of the radioisotope and subsequent measurement has been variable, not fully standardized, and can affect results. Conditions other than lymphoma may result in a positive PET scan and include infection, thymic rebound, late infiltration of inflammatory cells and/or post-therapy changes.

Perhaps most distressing are the preliminary reports of discordance among observers independently reviewing the same scans. This discordance is reminiscent of the discordance among lymphoma pathologists rendering independent reviews of the same slides. When the material is clear-cut, as with follicular lymphoma in pathology, an unequivocal negative or positive PET scan can be easily diagnosed and yield a high degree of concordance among reviewers. It is the subtle or gray areas that create difficulty. For instance, PET scans showing a major but not complete fall in the SUV scores can create difficulties in interpretation. Despite difficulties with ‘subtleties,’ no one would suggest discarding the use of PET scans any more than one would suggest discarding subclassifying lymphomas. PET scans are here to stay and clearly represent a major advance in the care of lymphoma.

Morton Coleman, MD, is Director of the Center for Myeloma and Lymphoma at Weill Cornell Medical College and the Section Editor of the Hematologic Malignancies section of the HemOnc Today Editorial Board.