¹⁸F-FDG Avidity in Lymphoma Readdressed: A Study of 766 Patients

MATERIALS AND METHODS

RESULTS

At least one ¹⁸F-FDG–avid lymphoma site was detected in 718 patients (94%), including all 233 patients with Hodgkin disease (175 nodular sclerosis, 32 mixed cellularity, 4 lymphocyte-rich, 1 lymphocyte-depleted, 1 nodular lymphocyte-predominant, and 20 with unspecified classic Hodgkin disease) and all patients with Burkitt lymphoma (n = 18), mantle cell lymphoma (n = 14), anaplastic large T-cell lymphoma (n = 14), nodal marginal zone lymphoma (n = 8), lymphoblastic lymphoma (n = 6), angioimmunoblastic T-cell lymphoma (n = 4), plasmacytoma (n = 3), and natural killer/T-cell lymphoma (n = 2). An ¹⁸F-FDG avidity of 97% was found in patients with diffuse large B-cell lymphoma (216/222), 95% for patients with follicular lymphoma (133/140: 24/24 grade I, 47/48 grade II, 33/37 grade III, and 29/31 grade not specified), and 90% for patients with peripheral T-cell lymphoma (9/10) (Table 1).

¹⁸F-FDG avidity below 90% was found in small lymphocytic lymphoma (83%; 24/29), enteropathy type T-cell lymphoma (67%; 2/3), extranodal marginal zone lymphoma (55%; 29/53), lymphomatoid papulosis (50%; 1/2), and primary cutaneous anaplastic large T-cell lymphoma (40%; 2/5) (Table 1).

According to the clinical classification for NHL, 97% (285/293) of the aggressive NHL cases and 83% (200/240) of the indolent NHL cases were ¹⁸F-FDG–avid (Table 2).

There were 48 lymphoma patients with disease that was not ¹⁸F-FDG–avid, accounting for 6% of the total study population. All were over the age of 18 y. Six of the 222 patients (3%) with diffuse large B-cell lymphoma had disease that was not ¹⁸F-FDG–avid, including 2 patients with cutaneous lymphoma, 1 patient with a single site in the colon, 1 patient with disease confined to the bone marrow, 1 whose diagnosis was made from a pleural effusion, and 1 with disease involving the maxillary sinus. One of the 3 patients with enteropathy-type T-cell lymphoma showed no ¹⁸F-FDG uptake in the known site of disease in the small bowel. One of the 10 patients (10%) with peripheral T-cell lymphoma had disease that was not ¹⁸F-FDG–avid and involved the buccal mucosa. Seven of the 140 patients (5%) with follicular lymphoma had disease that was not ¹⁸F-FDG–avid, including 2 with disease confined to the bone marrow and 5 who had only skin lesions. Twenty-three of the 50 patients (46%) with MALT marginal zone lymphoma had nonavid disease, including 17 patients with involvement of the gastrointestinal tract (16 stomach, 1 colon), 3 with involvement of the skin, 1 with bone marrow and spleen involvement, 1 with involvement of the tracheal mucosa, and 1 with disease in the orbit. One of the 3 patients with splenic marginal zone lymphoma had nonavid disease. One of 2 patients with lymphomatoid papulosis of the skin had nonavid disease, as well as 3 of the 5 patients (60%) with primary cutaneous anaplastic large T-cell lymphoma involving the skin. Five of 29 cases (17%) of small lymphocytic lymphoma were not ¹⁸F-FDG–avid. All included nodal disease, with additional bone marrow involvement found in 4 of the 5 (Tables 1 and 3).

DISCUSSION

In the present study of 766 patients referred for staging of lymphoma,¹⁸F-FDG–avid disease was found in 94%—equal to (5) or similar to (92% (6)) the percentages reported in previous studies that included smaller and more heterogeneous populations (Table 3). A metaanalysis performed by Isasi et al. (15) including 20 studies with a cumulated number of 854 patients reported a median sensitivity of 90%.

The present results demonstrated that although NHL had an overall ¹⁸F-FDG avidity of 91%, the avidity was lower in indolent disease (83%) than in aggressive disease (97%). ¹⁸F-FDG avidity correlates better with the histopathologic subtype of NHL than with clinical characteristics, as previously noted (5,6). Indolent NHL subtypes such as plasmacytoma, nodular marginal zone lymphoma, and—regardless of grade—follicular lymphoma showed high ¹⁸F-FDG avidity, whereas the aggressive NHL-enteropathy type of T-cell lymphoma had low ¹⁸F-FDG avidity.

MALT marginal zone lymphoma demonstrated an ¹⁸F-FDG avidity of 54%, an incidence that is at the lower limit of the previously reported wide range of 55%−82% (10,16–19). These different results may be due both to the small number of studied patients that were included in most of the previous reports and to a possible difference in the location of disease in the various series. There is a known variability in ¹⁸F-FDG avidity between MALT marginal zone lymphoma of the gastrointestinal tract (mainly the stomach) and MALT marginal zone lymphoma involving other organs such as the orbit, skin, or lungs (10).

Small lymphocytic lymphoma exhibited a relatively low ¹⁸F-FDG avidity, 83%, in a group that, to the best of our knowledge, includes the largest number of newly diagnosed patients reported to date, 29. Previous studies including smaller patient series have reported a significantly lower ¹⁸F-FDG avidity, around 50% (Table 3) (6,9). Furthermore, of the total of 766 patients, small lymphocytic lymphoma was the only lymphoma subtype with nonavid nodal sites of disease.

The relatively low ¹⁸F-FDG avidity (67%) found in a small group of 3 patients with splenic marginal zone lymphoma is consistent with that of previous literature reports (Table 3) (6).

It is notable that one third of the cases that were not ¹⁸F-FDG–avid occurred in patients with disease confined to the skin, regardless of histologic subtype. Highly variable ¹⁸F-FDG avidity has previously been reported in small subsets of 1–24 patients with cutaneous lymphoma of B- and T-cell origin (Table 3) (5,6,8,20,21).

In addition to Hodgkin disease, which was ¹⁸F-FDG–avid in all 233 patients who had the disease, the commonly encountered aggressive diffuse large B-cell lymphoma-NHL subtype was also associated with a high ¹⁸F-FDG avidity rate of 97%. Less common aggressive NHL subtypes such as mantle cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, anaplastic large T-cell lymphoma, angioimmunoblastic T-cell lymphoma, and natural killer/T-cell lymphoma had an ¹⁸F-FDG avidity of 100%. Only 1 of 10 cases of peripheral T-cell lymphoma in the present series was not ¹⁸F-FDG–avid, in contrast to the results of Elstrom et al. (5), who reported a low ¹⁸F-FDG avidity of 40% in a small sample of 5 patients. The only aggressive lymphoma with a relatively low ¹⁸F-FDG avidity, 67%, was enteropathy-type T-cell lymphoma, contrary to previously reported higher uptake rates (22,23).

Although this study contributes to the growing body of evidence concerning the overall ¹⁸F-FDG avidity of lymphomas and defines the distinct histopathologic subtypes exhibiting a higher rate of nonavid cases, the study is subject to several relative limitations. The degree of ¹⁸F-FDG avidity was not assessed quantitatively; however, according to the International Harmonization Project, visual assessment of the presence and intensity of ¹⁸F-FDG uptake is considered sufficient and is recommended in the clinical setting. Despite the significant increase in the number of patients analyzed in all subtypes of lymphoma, compared with previous studies, many histologic subgroups still consist of few patients.

Further projects will pursue additional issues raised by the current results. These include a site- and location-based analysis of ¹⁸F-FDG avidity in various histologic subtypes of lymphoma to correlate the inherent metabolic characteristics related to histology with lesion size and pattern of distribution. Specifically, the present results suggest that lymphoma involving the skin and possibly disease in the mucosa or pleural fluid may be either less ¹⁸F-FDG–avid or more difficult to detect, and these preliminary findings warrant an in-depth analysis of larger patient groups.

CONCLUSION

In this large group of 766 patients with newly diagnosed lymphoma evaluated in a single institution, most of the lymphoma subtypes were ¹⁸F-FDG–avid. MALT marginal zone lymphoma and small lymphocytic lymphoma showed lower ¹⁸F-FDG avidity and therefore a lower detectability rate, and additional diagnostic modalities apart from ¹⁸F-FDG imaging may provide important clinical information on these specific histologic subtypes. The cumulating evidence consistently showing high ¹⁸F-FDG avidity in the potentially curable Burkitt lymphoma, natural killer/T-cell lymphoma, and anaplastic large T-cell lymphoma subtypes justifies further investigations of the utility of ¹⁸F-FDG PET in these diseases at presentation.