Joint Program in Nuclear Medicine

Gallium-67 Imaging of Lymphoma

Jac D. Scheiner, MD 
Annick Van den Abbeele, MD

December 12, 1995

Presentation

A 39 year old female presented for evaluation of low grade non-Hodgkin's lymphoma. Thirteen years prior to presentation, the patient was diagnosed with stage IV low grade non-Hodgkin's lymphoma and treated with chemotherapy. She was in complete remission for 5 years when she relapsed with low grade non-Hodgkin's lymphoma, which was treated with splenectomy and chemotherapy. The lymphoma progressed, despite these interventions, and 6 years prior to presentation the patient received a bone marrow transplant.

The patient was in complete remission until 8 months prior to presentation when she relapsed with low grade non-Hodgkin's lymphoma. Gallium-67 and Thallium-201 imaging was performed 4 months prior to and at the time of presentation.

Imaging Technique

Gallium-67 imaging is performed at 72 hours to provide a favorable target to background ratio. A medium energy, high resolution, parallel hole collimator is used. Planar imaging is performed using a matrix size of 256 x 256. Images are obtained in anterior and posterior projections of the chest (2,000,000 counts per view) with arms up, abdomen/pelvis (with and without the liver in the field of view 1,500,000 counts per view), and the thighs (imaged for the same amount of time as the abdomen/pelvis). Lateral views of the head and neck are obtained as well (6000,000 counts per view on one side, followed by the same amount of time for the other side). Single photon emission computed tomography (SPECT) imaging is then performed using matrix size of 64 x 64 and 50-70 seconds per projection. Images are obtained from the nasopharynx to the lung bases, and then from the lung bases through the pelvis. The final data is reconstructed in axial, coronal, and sagital planes using parameters specific for each camera.

Imaging Findings

On the study 4 months prior to presentation, the Gallium-67 imaging (top) was negative, whereas Thallium-201 imaging (bottom) showed findings of active non-Hodgkin's lymphoma in the axillae and the left neck (shown by arrows). Bone marrow biopsy demonstrated low grade non-Hodgkin's lymphoma , with small cells and 10% large cells. The patient refused treatment at that time.

On presentation, Ga-67 imaging (top) showed new findings of active non-Hodgkin's lymphoma in the left axilla and left neck. Tl-201 imaging (bottom) showed findings of active non-Hodgkin's lymphoma in the left neck and bilateral axillae (shown by arrows) which were of increased intensity and extent than on prior exam. Bone marrow biopsy demonstrated low grade non-Hodgkin's lymphoma, with small cells and over 50% large cells. At this point, chemotherapy was initiated.

Followup

Four months after presentation, Ga-67 imaging (top) showed new findings of active non-Hodgkin's lymphoma in the right axilla (shown by arrow), with findings of active non-Hodgkin's lymphoma in the left axilla and left neck which were of increased extent and intensity than on prior exam. The Tl-201 scan also showed signs of active lymphoma in the left neck and axillae, increased in extent and intensity from prior examination.

Our experience is that non-Hodgkin's lymphoma Ga-67 avidity tends to be proportional to tumor grade, and that low grade non-Hodgkin's lymphomas tend to be more avid for Tl-201 than Ga-67. Thus, the interpretation of the imaging studies was that there was a mixed population of non-Hodgkin's lymphoma cells (regarding biological activity), and that both the higher and lower grade non- Hodgkin's lymphoma cells were proliferating in the axillae and left neck.

Discussion

Gallium-67 Mechanism of Uptake

Gallium-67 is a ferric ion analogue with at 78 hour half life, that has photopeaks at For tumor imaging, a dose of 10 mCi of Ga-67 - Citrate i.v. is recommended. Once injected, it binds to various plasma proteins, including transferrin and lactoferrin. It also binds to ferritin and siderophores. Live lymphoma cells express surface receptors for these plasma proteins, thus allowing this isotope bind to these cells and provide a physiologic assessment of viable tumor cells.

Comparison with Other Imaging Methods

A single morphologic image abnormality in time is not a reliable indicator of active disease. A retrospective view of the chest X- rays of 65 patients treated for mediastinal Hodgkin's lymphoma demonstrated residual abnormalities in 88%, mediastinal widening of greater than 6 cm in 42% (19% of these patients relapsed) and mediastinal widening of less than or equal to 6 cm in 58% (24% of these patients relapsed)(1).

A study performed on 25 patients with a history of Ga-67 avid lymphoma (2) showed that, of 21 patients in complete remission (assessed by long term follow-up), Ga-67 scans were negative in 20/21 patients, whereas computed tomography (CT) scans were negative on only 11/19 patients. In the 4 patients with active disease, both the Ga-67 and CT scans were positive. The higher false positive rate of CT was most likely due to a residual morphologic mass of dead tumor tissue. This study was useful in showing the excellent correlation of Ga-67 imaging with the presence of live tumor.

A SPECT Ga-67 study (8 mCi, 48-72 hour delay) of 43 patients treated for Hodgkin's lymphoma showed the positive and negative predictive values to be 80% and 84%, compared with 29% and 88% respectively for CT (3) . The same study also examined 56 patients treated for non-Hodgkin's lymphoma, showing the positive and negative predictive values of Ga-67 to be 73% and 84%, whereas those for CT were 35% and 80%. In both the Hodgkin's lymphoma and non-Hodgkin's lymphoma patients, the negative predictive values were similar. The dramatically lower positive predictive values for CT in both studies was most likely due to the previously mentioned problem of a residual mass due to non-viable tumor tissue. It is also interesting to note the lower positive predictive value in non-Hodgkin's lymphoma than Hodgkin's lymphoma patients on Ga-67 imaging, most likely due to difficulties in distinguishing normal Ga-67 secretion in bowel from active tumor.

The results of Gallium-67 imaging are better when the disease is localized above the diaphragm. In a study of 19 patients with mediastinal/neck lymphoma (5 mCi, 48 hour delay, planar images) (4), the false positive rate for residual active disease was 53% for CT, while it was only 5% for Ga-67. A SPECT Ga-67 study (5-7 mCi, 48-72 hour delay) of 34 patients treated for mediastinal Hodgkin's lymphoma showed the sensitivity, specificity, positive predictive value, and negative predictive value to be 86%, 100%, 100% and 94% for Ga-67, whereas the results for MRI were 93%, 81%, 68%, and 96%(5). MRI has been known to be one of the most sensitive methods to detect morphologic abnormalities. However, many of the abnormalities detected by MRI do not represent active disease, as shown by its much lower positive predictive value.

Mid-course Gallium Scintigraphy

Ga-67 ability to detect active lymphoma has been put to use in other clinical scenarios. A prospective planar Ga-67 study (7-10 mCi, 72 hour delay) of 37 patients with large cell non-Hodgkin's lymphoma was performed in which Ga-67 imaging was performed half way through the patient's chemotherapy course (6). Of the 17/37 patients what were Ga-67 positive at the half way point, 28 month follow-up revealed that 10 died and only 4 were in remission. Of the 20/37 patients that were Ga-67 negative at the half way point, 37 month follow-up revealed that only 5 had died and 14 were in remission.

Thus, Ga-67 imaging provides a useful index for assessing response to chemotherapy and overall survival in patients with non-Hodgkin's lymphoma. A positive Ga-67 scan midway through a patient's chemotherapy course suggests that different therapy options should be considered. Similarly, a positive Ga-67 scan in a patient post therapy for lymphoma should raise concern, even in the absence of confirmation by other tests. A SPECT Ga-67 study (8 mCi, 48 hour delay) of 32 patients treated for lymphoma showed that, of the 10 patients that eventually relapsed, sites of recurrence were first detected on Ga-67 imaging approximately 6.8 months before they were noticeable on physical exam, chest X-ray, or CT.

Tumor Avidity for Gallium

Further experience with Ga-67 imaging has shown that, in general, a lymphoma's avidity for Ga-67 is proportional to its histopathologic grade. High grade lymphomas, such as diffuse large cells non- Hodgkin's lymphoma, and most Hodgkin's lymphomas, typically demonstrate intense Ga-67 uptake, whereas low grade lymphomas, such as nodular, poorly differentiated lymphocytic non-Hodgkin's lymphoma, typically do not.

Thallium-201 Imaging

Imaging with Tl-201-Chloride or Technetium-99m - MIBI has shown promise in better imaging these low grade lymphomas. A prospective study performed on 33 patients with non-Hodgkin's lymphoma (23 low grade and 10 intermediate grade; 86 disease sites) imaged with both Ga-67 and Tl-201(8) showed that the Tl-201 scan was positive and the Ga-67 scan was negative in 26% of the disease sites, all in patients with low grade lymphoma. The Ga-67 scan was positive and the Tl-201 scan was negative for active tumor in 9% of disease sites, all in the abdomen.

Tl-201 is normally secreted into the small and large bowel, to a greater degree than Ga-67, rendering it of little usefulness in evaluating the abdomen. Low grade non-Hodgkin's lymphoma patients can be imaged with Tl-201 (to best detect low grade non- Hodgkin's lymphoma), Ga-67 (to detect change in tumor biology, such as conversion to a higher grade, which occurs in about 25% of cases), and possibly a CT of the abdomen and pelvis (to better evaluate for low grade non-Hodgkin's lymphoma which can not be easily distinguished from normal tracer in bowel on Tl-201 or Ga-67 scans).

Summary

Ga-67 imaging of lymphoma provides information regarding the presence or absence of active lymphoma. Using SPECT imaging, the literature quotes sensitivities mostly in the 85% - 95% range, and sensitivities greater than 98% (5,9,10,11). Most importantly, the positive predictive value for the presence of active disease has consistently been shown to be greater than that for morphologic imaging techniques (such as CT and MRI), primarily due to the presence of residual mass in treated lymphoma. Avidity of lymphoma for Ga-67 to usually be proportional to the histopathologic grade. Low grade lymphomas tend to be more avid for Tl-201 than Ga-67. A combined imaging approach, using Ga-67, Tl- 201, and sometimes CT, is the current imaging method of choice for low grade non-Hodgkin's lymphoma .

References

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2. Israel O, Front D, Lam M, et al. Gallium-67 imaging in monitoring lymphoma response to treatment. Cancer 1988;61:2439-43.

3. Front D, Ben-Haim S, Israel O, et al. Lymphoma: predictive value of Ga-67 scintigraphy after treatment. Radiology 1992;182:359-63.

4. Drossman SR, Schiff RG, Kronfeld GD, et al. Lymphoma of the mediastinum and neck: evaluation with Ga-67 imaging and CT correlation. Radiology 1990;174:171-5.

5. Gasparini MD, Balzarini L, Castellani MR, et al. Current role of gallium scan and magnetic resonance imaging in the management of mediastinal Hodgkin=s lymphoma. Cancer 1993;72: 577-82.

6. Kaplan WD, Jochelson MS, Herman TS, et al. Gallium-67 imaging: a predictor of residual tumor viability and clinical outcome in patients with diffuse large-cell lymphoma. J Clin Onc 1990;8:1966-70.

7. Front D, bar-Shalom R, Epelbaum R, et al. Early detection of lymphoma recurrence with gallium-67 scintigraphy. J Nucl Med 1993;34:2101-4.

8. Kaplan WD, Southee AE, Annese ML, Jochelson MS, Nadler LM. Evaluating low and intermediate grade NHL with Gallium-67 and Thallium-201. J Nucl Med 1990;31:793 (abstr).

9. Front D, Israel O, Epelbaum R, et al. Ga-67 SPECT before and after treatment of lymphoma. Radiology 1990;175(2):515-9.

10. Tumeh SS, Rosenthal DS, Kaplan WD, English RJ, Holman BL Lymphoma: evaluation with Ga-67 SPECT. Radiology 1987;167(1):111-4.

11. Front D, Israel O. The Role of Ga-67 Scintigraphy in Evaluating the results of Therapy of Lymphoma Patients. Sem Nucl Med 1995;25(1):60-71.

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J. Anthony Parker, MD PhD, Tony_Parker@bidmc.harvard.edu