This study demonstrates the potential utility of PET body imaging in the assessment of patients with a presumptive diagnosis of PCNSL. Seven percent of patients were found to have systemic NHL by staging FDG body PET when body CT scans and bone marrow biopsies were negative. The yield was even higher in the setting of restaging for recurrent disease, where positive body PET imaging led to a confirmed diagnosis of a systemic site of NHL in 27% of patients.
The current recommended staging evaluation for PCNSL includes a CT CAP and bone marrow biopsy; careful testicular examination is recommended in older men.10
Our results suggest that PET may be more sensitive than a conventional staging evaluation in the detection of systemic lymphoma. Three of the FDG-avid foci identified in this study were outside the thoracic, abdominal, and pelvic cavities, underscoring a major limitation of CT CAP: its inability to image outside the torso. This is particularly important considering that PCNSL patients are at higher risk for extranodal NHL.13
FDG PET has been found to add incremental information to conventional CT in various systemic lymphomas,14
and may also be helpful in the assessment of abnormal body CT scans obtained in PCNSL patients. The superior sensitivity of FDG PET compared to bone marrow biopsy has been previously described in aggressive NHL and Hodgkin’s disease;15
further work will be necessary to determine if FDG PET is a reasonable alternative to this invasive test in staging PCNSL. In our own practice, FDG PET is already emerging as an important option in the subset of patients with renal dysfunction, for whom contrast dye used with CT CAP is best avoided. This is critical to prevent nephrotoxicity and allow subsequent safe delivery of high-dose methotrexate. FDG PET may be an important adjunct to our conventional staging evaluation for PCNSL because it can uncover foci not seen on anatomic imaging, it can visualize the entire body, and it is safe and noninvasive.
We found a higher incidence of systemic lymphoma in our PCNSL patients than reported in prior series,11,16,17
suggesting that occult systemic lymphoma may be more common than recognized previously. In a recent study, Jahnke et al.12
described subclinical systemic disease that was not evident on conventional staging by looking for clonally rearranged immunoglobulin in the peripheral blood and bone marrow of PCNSL patients. Their work suggests that the malignant clone may be present systemically at diagnosis but, for reasons yet to be understood, grows preferentially in the CNS. It may be that the systemic clone is controlled by the immune system but grows unchecked in the relatively immune-privileged CNS. One could hypothesize that the uncommon diagnosis of systemic disease may be related to the inadequacy of conventional staging examinations to uncover small foci of disease. A more informative staging evaluation may not only reveal those patients with systemic lymphoma, but also help further our understanding of the biologic origin of PCNSL.
The identification of a systemic focus of lymphoma or second malignancy is critical, as this alters patient management. Patients with concomitant systemic and CNS lymphoma require treatment with a chemotherapy regimen that addresses both disease compartments, typically one that includes both high-dose methotrexate and doxorubicin. Response assessment also requires careful evaluation of both CNS and systemic disease. Second malignancies may require additional therapy. Because FDG PET lacks the precision necessary to distinguish discrete histologies, the presence of an FDG-avid lesion may be associated with an unexpected malignancy and highlights the importance of confirmation with tissue biopsy.18
SUV in this study was variable and not informative beyond the identification of an abnormality. Values ranged from 3.8 to 30.5 in patients with histologic confirmation of systemic lymphoma. In systemic NHL, lesions with SUV > 2.5 or 3 are often considered to be malignant with good sensitivity and specificity.19,20
However, four of our patients had lesions with a high SUV (3.0, 3.5, 4.0, and 4.3) and an indeterminate biopsy or no clinical evidence of systemic NHL at last follow-up. These foci may represent systemic NHL that responded to chemotherapy administered for the CNS disease. Current recommendations for use of FDG PET in lymphoma depend on visual assessment of PET abnormality rather than on any quantitative measures and are likely the most appropriate guideline to use in PCNSL.5
Further evaluation of PET in PCNSL should incorporate other radiotracers, such as 18
F-fluorothymidine, a marker of cellular proliferation that has successfully identified foci of disease and predicted higher tumor grade in preliminary studies of systemic lymphoma.21
This may be particularly useful in identifying aggressive subsets of PCNSL.
This is the first study to evaluate the role of body FDG PET in the staging evaluation of PCNSL. Although it reflects a relatively large collection of patients, it is inherently limited by its retrospective nature. In particular, there may have been clinical suspicions in the patients selected for FDG PET that were not evident by record review. Therefore, our findings need to be confirmed and validated in prospective studies in which FDG PET is employed in the staging of PCNSL patients and compared to the yield of CT CAP and bone marrow biopsy. An emerging role for FDG PET in staging could have important implications for the management of PCNSL as well as our understanding of this disease.