For ceCT, standard CT criteria for individual lymph node groups (when >10 mm in short axis), lung, liver, and spleen were used to determine the site of suspect HD localization.27 For bone marrow involvement, any lytic area that usually appears as a region of soft-tissue attenuation with irregular margins that usually breach the cortex or any sclerotic lesions that appear hyperdense and irregular has been considered pathologic (Figure 2).
For nodal involvement, a datasheet indicating the nodal stations was filled for PET/ldCT and ceCT results. As far as the extranodal site is concerned, the physicians were required to sign the presence or absence of disease (regardless of diffuse or focal) in lung, liver, spleen, bone marrow, skin, and brain. A third datasheet was then generated, including functional (PET) and ceCT data. The clinical stage of the patients was assessed in agreement with Ann Arbor classification.11
Follow-up Data as the Reference Standard
Any area of residual 18F FDG uptake in interim PET has been evaluated by 2 experienced nuclear medicine physicians (AC and OS) by means of qualitative analysis according to the Deauville 5 point score.22 All the positive findings in interim PET have been confirmed by means of mediastinum or upper cervical lymph node(s) biopsy (because these were the sites of no-therapy response or recurrence detected in PET/CT).
All the findings detected in staging PET/ldCT, ceCT, and PET/ceCT were compared with those obtained after CHT: the absence or decrease of 18F FDG uptake and the decrease of lesion size and pathologic shape for ceCT data has been used for further confirmation of the pathological findings in the first scan (Table 1).
Agreement among techniques has been studied with the κ-statistic. In order to assess the statistical significance on extranodal findings by different imaging methods, we performed P calculation by means of Fisher’s exact test. In order to evaluate the impact of different imaging modalities on staging, we performed a two-way analysis of variance test. A hypothesis was considered valid when P value was ≤0.05.
There is a good agreement between PET/ldCT and PET/ceCT (95.14% of the observations, κ = 0.939). By means of PET/ceCT, 212 sites of both nodal and extranodal illness localization were found; 210 were detected by PET/ldCT and 204 by ceCT alone. As far as nodal involvement is concerned (184 lymph nodes, 40 patients), there was complete concordance among the 3 imaging modalities (Table 1). We did not find any difference between ldCT and ceCT in supra- and subdiaphragmatic lymph node sites (regional analysis), lung, skin, and bone marrow involvement, whereas liver and spleen sites were not detectable in ldCT.
PET/ldCT detected 26 extranodal lesions, ceCT alone detected 20 lesions and 28 were detected by PET/ceCT (Table 1, Figure 1). No statistically significant difference has been found comparing PET/ldCT and ceCT in the detection of extranodal involvement (P = 0.0776). One patient presented a spleen lesion detectable only with ceCT, whereas another presented a spleen lesion detectable only with PET/ldCT (Figure 1). While comparing PET/ldCT and PET/ceCT results, no differences have been found for extranodal disease involvement (P = 1). PET/ceCT detect more extranodal lesions than ceCT alone (28 vs 20 lesions, P = 0.0044) as shown in Table 1.
Eight patients (20% of the entire population) presented bone marrow involvement. All these patients presented positive findings in PET/ldCT and PET/ceCT, whereas only 2 of them (5% of the entire population, 25% of the patients with bone marrow involvement) were positive in ceCT (P = 0.007) (examples are shown in Figure 2). Both brain PET/ldCT and ceCT were negative for HD, and superior mediastinum was the most frequent localization of HD in our series (34 patients, 85%).
Regarding the staging, 6 patients (15%) were stage I, 15 patients (37.5%) stage II, 3 patients (7.5%) stage III, and 13 patients (40%) stage IV in PET/ceCT (Table 2).
As outlined in Table 2, there were no statistically significant differences between the imaging modalities at staging (F = 0, P = 1). Disagreement about the stage of the disease between PET/ldCT and ceCT was found in 3/40 patients (7.5%), which showed bone marrow involvement. According to ceCT results, 2 of these 3 patients were stage II and 1 was stage III, whereas they were stage IV in PET/ldCT and PET/ceCT. As a collateral finding, 1 patient (man, 23 years old) showed a lesion in the left kidney that was consistent with a clear renal cell carcinoma (CCRCC, Figure 3).
One of the main findings of our study is a good concordance at staging between PET/ldCT and PET/ceCT in the detection of nodal and extranodal HD involvement. As outlined in Table 1, the main differences with ceCT are due to bone marrow sites where intravenous contrast administration cover a minor role.13 Hence, the lack of differences between PET/ldCT and PET/ceCT is rather a result of PET than CT-imaging protocols. During image evaluation, the radiologist did not report any difference between the number of regions of supra- and subdiaphragmatic lymph node sites in ldCT and ceCT, respectively. However, if one considers the number of lymph node sites, in our experience, ceCT is able to detect a larger number of lymph nodes as compared to ldCT.
An issue recently outlined is the opportunity of using oral and intravenous contrast agents during a PET/CT study, as they may lead to misinterpret PET/CT examinations, while providing better anatomical details and showing contrast-enhancing lesions.28 Intravenous contrast agents have been reported to provoke artifacts at PET/CT scans due to the transient bolus passage of undiluted intravenous contrast agent,29 and some authors proved that PET/ldCT (without oral or iv contrast agents) is feasible to stage HD and non-Hodgkin lymphoma (NHL) as well.18 To date, several PET/ceCT protocols have been proposed.30 In particular, Brix et al30 investigated a biphasic injection of intravenous contrast (90 and 50 mL at 3 and 1.5 mL/s, respectively) versus a triple-phase injection (90, 40, and 40 mL at 3, 2, and 1.5 mL/s, respectively) in the craniocaudal direction with a 50-second delay and a dual-phase injection (80 and 60 mL at 3 and 1.5 mL/s, respectively) in the caudocranial direction with a 50-second delay. The authors concluded that a dual-phase intravenous contrast injection and a CT in the caudocranial direction with a 50-second delay yields the best high image quality in absence of contrast-related artifacts on CT images with reproducible high levels of PET image quality after CT-based attenuation correction using the ceCT images.30 In another report of Pfannenberg et al,31 a ceCT consisting of a multiphase CT protocol including a low-dose nonenhanced attenuation scan and an arterial and portal–venous ceCT scan followed by a whole body PET was of additional value in 52/100 patients (85 total lesions) and changed the PET/CT interpretation in 42% of the patients. To note, only 6 patients were affected by lymphoma in this study, whereas most of the patients examined were affected by a large variety of cancer (gastrointestinal, bronchial, neuroendocrine, head-neck cancer, and so on).31 In these patients, the incremental benefit of diagnostic CT is due to the correct localization of gastrointestinal and peritoneal lesions (due to the improved delineation of the bowel wall by oral and rectal negative contrast agents in combination with standard CT dose acquisition) or in differentiating malignant FDG uptake from nonmalignant and physiological uptake in infectious lesions, splenosis, postoperative changes, and sites of physiological FDG uptake in the bowel and bladder by the typical CT morphology.31
During the execution of a PET/ceCT examination, the patients incur an increased exposure compared with an individual ceCT or PET/ldCT examination.32 Our study was not designed to estimate the radiation exposure in the different imaging modalities used; nevertheless, some conclusions can be drawn from the different protocols used in our study. In fact, the PET/ceCT protocol used is similar to 3 of the 4 PET/CT protocols investigated by Brix et al30 where separate ldCT scans were acquired for attenuation correction of emission data in addition to a ceCT; this study shows a higher radiation exposure in these patients, mainly due to higher milliampere and kilovolts of ceCT, with an effective dose of 26.4, 24.4, and 23.7 mSv, respectively, that is higher as compared to a PET/ldCT (effective dose 8.5 mSv).30
In a previous published study, Picardi et al17 compared the role of PET/ceCT and PET/ldCT in 2 different populations of patients affected by HD. 18F FDG PET/ceCT significantly improved the diagnostic accuracy and directly affected therapeutic treatment as compared to a pool of patients staged with separate procedures.17
As far as spleen and liver illness sites are concerned, our findings are in partial disagreement with those of the previously mentioned studies. We did not find significant differences while comparing ceCT, PET/ldCT, and PET/ceCT results in organs with the exception of 2 patients with spleen lesions. In particular, a patient presented a hypodense lesion with no focal uptake in the 18F FDG PET/CT scan whereas another, with no abnormalities in ceCT, showed a focal FDG uptake (Figure 1, Table 1). The detection of a non-FDG avid lesion is not surprising considering that HD lesions of the spleen usually present a focal or diffuse 18F FDG uptake.17,19,20 In the already cited paper by Picardi et al,17 the authors found that diagnostic CT identified at least 1 focal lesion in 17 patients whereas only 7 patients were positive at PET/ldCT. The authors concluded that the detection of subdiaphragmatic lesions by means of PET/ldCT is affected by dimensions and positions.17 Especially for the liver and spleen, respiration may affect image evaluation (as in our case study, where the non-FDG avid lesion is located in the upper pole of the spleen as shown in Figure 1).
As compared to the paper of Picardi et al,17 our study shows a different number of patients examined (lower in our study) and a different methodology. The relatively small patient cohort would explain why ceCT was not useful in our study.
As for nodal sites, our findings are in partial disagreement with a previous report on a population of patients with HD and NHL.33 Despite a good concordance for supradiaphragmatic lymph nodes at staging,33 PET/ceCT showed a more accurate nodal status detection for external iliac lymph nodes, internal iliac lymph nodes, and common iliac lymph nodes compared with PET/ldCT.33 This is mainly due to the efficacy of ceCT at providing details on lesion locations, morphology, size, and structural changes to adjacent tissues,34 especially for small-sized lymph nodes and retroperitoneal lymphatic pathways.35 In our study and in the previous cited report of Rodriguez-Vigil et al20 (in which only 34% of the entire population was affected by HD), the conjunction of PET/ldCT with ceCT did not improve the diagnostic accuracy at a nodal level. A possible explanation of these discrepancies can be sought in the different lymphoproliferative disorders examined. In the cited study of Morimoto et al,33 only 24% of the patients were affected by HD. Aggressive NHL and HD generally show a significantly higher 18F FDG uptake than indolent lymphomas35; for example, HD and aggressive NHL types have a high uptake of FDG and, given the potentially lower sensitivity for detecting lymphoma deposits, the use of 18F FDG-PET for indolent-type lymphomas has been questioned.35
Our results show that both PET/ldCT and PET/ceCT are able to detect a larger number of extranodal sites in bone marrow (that is of utmost importance for staging11) as compared with ceCT alone. In our study, bone marrow involvement has been described in 8 patients in PET/ldCT and PET/ceCT and only 2 of them presented positive ceCT findings. This last aspect confirms the limitations of ceCT to identify limited skeletal involvement.36 Interestingly, in the already cited paper of Pinilla et al,19 the authors did not find significant differences while comparing bone marrow sites as detectable by means of ceCT alone with PET/ldCT and PET/ceCT. These results could be explained by the high portion of low-grade histology NHL in the population examined by Pinilla et al19; the authors concluded that PET was suboptimal to evaluate the bone marrow in this subgroup of patients.
All the discordant findings in staging HD (3/40 patients, 7.5%) are due to bone marrow sites. It is of interest to note that both PET/ceCT and PET/ldCT mostly upstaged disease when compared with ceCT alone, especially in the early stages of the disease as previously reported.18 Further studies are necessary in the more advanced stages of HD in order to confirm the added value of PET at staging.
ceCT allowed the detection of a CCRCC (non-18F FDG avid, Figure 3) that could be misdiagnosed in PET/ldCT. In agreement with the results of Pinilla et al,19 ceCT could cover a minor role in staging HD due to the incidental findings in PET/ceCT examination.
The results of our study suggest that the conjunction of PET/ldCT with ceCT does not impact the staging in patients with HD. PET leads to a higher diagnostic accuracy in staging HD, especially for bone marrow lesions as compared with ceCT alone. The higher radiation exposure because of a ceCT scan could be avoided while staging patients with HD or reserved for selected cases.
1. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.
2. Campbell BA, Voss N, Pickles T, et al. Involved-nodal radiation therapy as a component of combination therapy for limited-stage Hodgkin’s lymphoma: a question of field size. J Clin Oncol. 2008;26:5170–5174.
3. Johnson PW. Management of early-stage Hodgkin lymphoma: is there still a role for radiation? Hematology Am Soc Hematol Educ Program. 2013;400.
4. Borchmann P. Early intensification treatment approach in advanced-stage Hodgkin lymphoma. Hematol Oncol Clin North Am. 2014;28:65–74.
5. Borchmann P, Andreas EA. The past: what we have learned in the last decade. Hematology Am Soc Hematol Educ Program. 2010;2010:101–107.
6. Domınguez AR, Marquez A, Guma J, et al. Treatment of stage I and II Hodgkin’s lymphoma with ABVD chemotherapy: results after 7 years of a prospective study. Ann Oncol. 2004;15:1798–1804.
7. Enger A, Plütschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363:640–652.
8. Boleti E, Mead GM. ABVD for Hodgkin’s lymphoma: full-dose chemotherapy without dose reductions or growth factors. Ann Oncol. 2007;18:376–380.
9. Owadally WS, Sydes MR, Radford JA, et al. Initial dose intensity has limited impact on the outcome of ABVD chemotherapy for advanced Hodgkin lymphoma (HL): data from UKLG LY09 (ISRCTN97144519). Ann Oncol. 2010;21:568–573.
10. Chiaravalloti A, Pagani M, Di Pietro B, et al. Is cerebral glucose metabolism affected by chemotherapy in patients with Hodgkin’s lymphoma? Nucl Med Commun. 2013;34:57–63.
11. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol. 1989;7:1630–1636.
12. Bednaruk-Mlynski E, Pienkowska J, Skorzak A, et al. The comparison of PET/CT with classical contrast-enhanced CT in the initial staging of Hodgkin lymphoma. Leuk Lymphoma. 2014;2:2.
13. Di Paul S, Townsend DW. Di Paul S, Townsend DW. PET-CT imaging of lymphoma. Clinical PET-CT in Radiology: Integrated Imaging in Oncology. Springer; 2011:267–295.
14. Haerle SK, Strobel K, Ahmad N, et al. Contrast-enhanced 18
F-FDG-PET/CT for the assessment of necrotic lymph node metastases. Head Neck. 2011;33:324–329.
15. Tateishi U, Maeda T, Morimoto T, et al. Non-enhanced CT versus contrast-enhanced CT in integrated PET/CT studies for nodal staging of rectal cancer. Eur J Nucl Med Mol Imaging. 2007;34:1627–1634.
16. Chu MM, Kositwattanarerk A, Lee DJ, et al. FDG PET with contrast-enhanced CT: a critical imaging tool for laryngeal carcinoma. Radiographics. 2010;30:1353–1372.
17. Picardi M, Soricelli A, Grimaldi F, et al. Fused FDG-PET/contrast-enhanced CT detects occult subdiaphragmatic involvement of Hodgkin’s lymphoma thereby identifying patients requiring six cycles of anthracycline-containing chemotherapy and consolidation radiation of spleen. Ann Oncol. 2011;22:671–680.
18. Kasamon YL, Jones RJ, Wahl RL. Integrating PET and PET/CT into the risk-adapted therapy of lymphoma. J Nucl Med. 2007;48:19–27.
19. Pinilla I, Gomez-Leon N, Del Campo-Del Val L, et al. Diagnostic value of CT, PET and combined PET/CT performed with low-dose unenhanced CT and full-dose enhanced CT in the initial staging of lymphoma. Q J Nucl Med Mol Imaging. 2011;55:567–575.
20. Rodriguez-Vigil B, Gomez-Leon N, Pinilla I, et al. PET/CT in lymphoma: prospective study of enhanced full-dose PET/CT versus unenhanced low-dose PET/CT. J Nucl Med. 2006;47:1643–1648.
21. Harris NL, Jaffe ES, Diebold J, et al. Lymphoma classification—from controversy to consensus: the R.E.A.L. and WHO Classification of lymphoid neoplasms. Ann Oncol. 2000;11(Suppl 1):3–10.
22. Biggi A, Gallamini A, Chauvie S, et al. International validation study for interim PET in ABVD-treated, advanced-stage Hodgkin lymphoma: interpretation criteria and concordance rate among reviewers. J Nucl Med. 2013;20:20.
23. Werko L. [Ethics committees bear a responsibility for patient information. Informed consent implies that the patient understands what he has consented to]. Lakartidningen. 2002;99:1552–1555.
24. Chiaravalloti A, Danieli R, Abbatiello P, et al. Factors affecting intrapatient liver and mediastinal blood pool F-FDG standardized uptake value changes during ABVD chemotherapy in Hodgkin’s lymphoma. Eur J Nucl Med Mol Imaging. 2014;22:22.
25. Alessandrini M, Pagani M, Napolitano B, et al. Early and phasic cortical metabolic changes in vestibular neuritis onset. PLoS One. 2013;8:7.
26. Schillaci O, Travascio L, Bolacchi F, et al. Accuracy of early and delayed FDG PET-CT and of contrast-enhanced CT in the evaluation of lung nodules: a preliminary study on 30 patients. Radiol Med. 2009;114:890–906.
27. Gossmann A, Eich HT, Engert A, et al. CT and MR imaging in Hodgkin’s disease—present and future. Eur J Haematol Suppl. 2005;66:83–89.
28. Cook GJ, Wegner EA, Fogelman I. Pitfalls and artifacts in 18FDG PET and PET/CT oncologic imaging. Semin Nucl Med. 2004;34:122–133.
29. Antoch G, Jentzen W, Freudenberg LS, et al. Effect of oral contrast agents on computed tomography-based positron emission tomography attenuation correction in dual-modality positron emission tomography/computed tomography imaging. Invest Radiol. 2003;38:784–789.
30. Brix G, Lechel U, Glatting G, et al. Radiation exposure of patients undergoing whole-body dual-modality 18F-FDG PET/CT examinations. J Nucl Med. 2005;46:608–613.
31. Pfannenberg AC, Aschoff P, Brechtel K, et al. Value of contrast-enhanced multiphase CT in combined PET/CT protocols for oncological imaging. Br J Radiol. 2007;80:437–445.
32. Wu TH, Huang YH, Lee JJ, et al. Radiation exposure during transmission measurements: comparison between CT- and germanium-based techniques with a current PET scanner. Eur J Nucl Med Mol Imaging. 2004;31:38–43.
33. Morimoto T, Tateishi U, Maeda T, et al. Nodal status of malignant lymphoma in pelvic and retroperitoneal lymphatic pathways: comparison of integrated PET/CT with or without contrast enhancement. Eur J Radiol. 2008;67:508–513.
34. Histed SN, Lindenberg ML, Mena E, et al. Review of functional/anatomical imaging in oncology. Nucl Med Comm. 2012;33:349–361.
35. Schoder H, Noy A, Gonen M, et al. Intensity of 18fluorodeoxyglucose uptake in positron emission tomography distinguishes between indolent and aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 20 2005;23:4643–4651.
© 2014 by Lippincott Williams & Wilkins, Inc.
36. Carr R, Barrington SF, Madan B, et al. Detection of lymphoma in bone marrow by whole-body positron emission tomography. Blood. 1998;91:3340–3346.