Leukemia & Lymphoma, 2014; Early Online: 1–6 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.919635
ORIGINAL ARTICLE: CLINICAL
Comparison of positron emission tomography/computed tomography with classical contrast-enhanced computed tomography in the initial staging of Hodgkin lymphoma Ewa Bednaruk-Młyński1, Joanna Pieńkowska2, Adam Skórzak3, Bogdan Małkowski4, Waldemar Kulikowski5, Edyta Subocz6, Justyna Dzietczenia7, Marta Zalewska8, Krzysztof Leśniewski-Kmak3,9, Renata Zaucha1, Tomasz Wróbel7 & Jan M. Zaucha3,9 Leuk Lymphoma Downloaded from informahealthcare.com by Tulane University on 10/12/14 For personal use only.
1Department
of Oncology and Radiotherapy, 2Department of Radiology and 9Department of Propadeutic Oncology, Medical University of Gdansk, Gdansk, Poland, 3Department of Oncology, Gdynia Oncology Center, Maritime Polish Red Cross Memorial Hospital Gdynia, Gdynia, Poland, 4Department of Nuclear Medicine, Oncology Center, Bydgoszcz, Poland, 5Department of Hematology, Regional Oncology Center, Olsztyn, Poland, 6Department of Hematology and Internal Medicine, Military Institute of Medicine, Warsaw, Poland, 7Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland and 8Department of Prevention of Environmental Hazards and Allergology, Medical University of Warsaw, Warsaw, Poland
aspect [1]. This is overcome, however, by combining CT with positron emission tomography (PET). HL has been shown to be highly PET-avid for fluorodeoxyglucose (18F-FDG) [2], with a sensitivity of 88–93.2% [3,4]. Early publications assessing the impact of PET on lymphoma staging usually involved mixed populations of non-HL (NHL) and HL, with patients with NHL being the majority [5]. There are reports in the literature comparing PET with conventional CT staging in larger series of patients with HL [3,6]. However, some of those studies used older-generation PET scanners not always combined with CT imaging. Therefore, the reported percentage of stage migration and treatment modification varies to some extent in different series. In both PET and PET/CT series reported to date (patients with HL and NHL), 8–40% of patients were upstaged (13–40% of patients with HL) and 1–15% were downstaged, leading to treatment modification in 5–25% [3,4,6–8,9,10]. These clear discrepancies encouraged us to perform a reanalysis of baseline scans in patients previously included in the clinical trial PLRG-11 conducted by the allied centers of the Polish Lymphoma Research Group (PLRG) [11]. We performed detailed analysis of nodal and extranodal disease manifestations, assessing stage migration and its impact on treatment selection. We aimed at defining a group of patients who would benefit the most from the incorporation of PET/CT into initial staging.
Abstract We compared initial computed tomography (CT) and positron emission tomography (PET)/CT in 96 patients with Hodgkin lymphoma (HL), assessing the role of baseline PET/CT in stage migration and treatment selection. The number of patients with stage I, II, III and IV disease based on CT versus PET/CT was: 5 vs. 7, 49 vs. 37, 28 vs. 22 and 14 vs. 30, respectively. In 33 (34%) patients, PET/CT changed HL stage: 27 (28%) were upstaged and six (6.3%) downstaged. Upstaging was caused by detection of new extranodal involvements (47 sites in 26 patients): bone marrow (10 patients), spleen (five patients) and lung (two patients). In nine patients ⱖ 2 further coexisting locations were detected. Downstaging resulted from the absence of fluorodeoxyglucose (18F-FDG) uptake in enlarged nodes (⬎ 15 mm) in the abdomen and pelvis. PET/CT modified HL stage in 34% of patients leading to treatment modification in the majority. Our results indicate that PET/CT should be mandatory in the initial staging of HL. Keywords: Hodgkin lymphoma, staging, PET/CT
Introduction Disease stage remains the most powerful prognostic factor in Hodgkin lymphoma (HL). Accurate detection of all nodal and extranodal lymphoma manifestations is critical to selecting optimal treatment strategy, avoiding under- or overtreatment and minimizing treatment-related morbidity. The important limitation of computed tomography (CT) is the interpretation of nodal involvement based solely on anatomic criteria of size and lack of any functional
Materials and methods Between January 2008 and September 2011, 96 consecutive patients with newly diagnosed HL were referred to four
Correspondence: J. M. Zaucha, Department of Propadeutic Oncology, Medical University of Gdan´sk, Ul. Powstania Styczniowego 1, 81-519 Gdynia, Poland. Tel: ⫹48587260438. Fax: ⫹48587260156. E-mail: [email protected] Received 10 February 2014; revised 21 April 2014; accepted 24 April 2014
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E. Bednaruk-Młyński et al.
Polish onco-hematological centers. The histological subtypes included: 78 patients (81%) with nodular sclerosis, 13 (14%) with mixed cellularity, four (4%) with lymphocyte rich and one patient with unclassified subtype. In all cases CT (usually performed by the referring center) and PET/ CT were done at diagnosis. Bone marrow biopsy (BMB) was performed if B symptoms or at least disease stage III was present. The original CT and PET/CT images were reviewed afresh by a dedicated radiologist and nuclear medicine specialist. They were blinded to the original local-center assessment and were not aware of their mutual staging. The number of nodal areas and extranodal sites involved, detected by each imaging modality, was scored, and the final CT and PET/CT stage of each patient established and compared. Discordant cases were reviewed and discussed with the local center until a consensus was reached. The study was approved by the Ethics Committee at the Medical University of Gdansk.
data were acquired for 2–5 min per bed position, starting 60–90 min after intravenous injection of 18F-FDG. Glucose levels were tested for all patients, and diazepam or a similar muscle relaxant was given orally to some patients before 18FFDG administration to avoid muscular uptake of the tracer. PET/CT scans were judged by visual assessment, and standardized uptake values (SUVs) were also reported. Sites of non-physiological 18F-FDG uptake above background were reported as HL involved. Diffuse uptake in the spleen was assumed to be indicative of HL involvement, providing the SUV was greater than in the liver. In contrast, diffuse uptake in the BM even if higher than in the liver was conservatively not treated as HL involvement.
Results The study included 51 males and 45 females; median age was 36 years (19–78). The median time interval between CT and PET/CT scanning was 19 days (1–77).
CT imaging CT scans covered the neck, thorax, abdomen and pelvis and included both unenhanced and enhanced scanning after administration of contrast medium (80–120 mL). Slice thickness was 1.25–5 mm in most (83%) cases and in the remainder 5–8 mm, which was standard in older CT studies when the observational study was launched. For CT staging classical radiologic criteria were used. Lymph nodes ⬎ 15 mm in longest dimension were considered pathological (CT⫹). In contrast, those smaller than 10 mm were considered as negative (CT⫺) and those in between were considered as “equivocal” (CT?). We distinguished 34 lymph node areas. CT and PET/CT scans were reassessed by a dedicated radiologist and nuclear medicine specialist independently of the initial examination result, and the results were matched and compared with regard to size and location of lymph nodes. Discrepancies were reviewed and discussed after completion of the study. Special attention was drawn to atypically located lymph nodes. We defined five extranodal sites of interest: lungs, bones and bone marrow (BM), liver, spleen and a group of other locations (nasopharynx, thyroid, thoracic wall, Waldeyer’s ring). Spleen and liver scans were regarded as positive for HL when any focal lesion (small nodule) was detected, excluding cystic and vascular changes. Diffuse lung parenchyma infiltration without clinical manifestation of inflammation or other possible etiology, and multiple nodules regardless of their size were considered as indicative for lymphoma. Single parenchymal nodules or subpleural nodules were considered benign when ⬍ 10 mm, equivocal when their size was 11–15 mm and pathologic at ⬎ 15 mm. Osteolytic, osteosclerotic or mixed bone changes if present were considered indicative for lymphoma.
PET/CT imaging PET/CT scans were performed with GE Discovery ST 16, GE Discovery STE and Siemens mCT 128 scanners at four centers. All PET centers took part in the PLRG audit to ensure that PET scanning standardization and adequate quality interpretation was achieved at each center [12,13]. Emission
Nodal areas CT detected 807 involved nodal areas, whereas PET/CT detected 100 more. Both methods identified 1012 nodal areas that were classified into five categories (Table I). The distribution of each category within anatomical regions is shown in Table II. Nodes positive for HL by both imaging modalities accounted for 53.9% of all nodes detected. Lymph nodes ⬎ 15 mm that were PET-negative represented only 4.6% of all lymph nodes (mainly abdominal). Within lymph nodes that were considered as “equivocal” in classical CT (CT?), about half (57%) were PET-positive (Figure 1). Some 20% of all PET/CT-positive nodes were ⱕ 10 mm.
Extranodal areas CT identified 26 extranodal HL manifestations in 21 patients, whereas PET/CT identified 73 in 52 patients. All 26 CT⫹ lesions were also PET/CT⫹. PET/CT identified 47 new extranodal lesions (Table III), one in the thyroid that turned out to be synchronous thyroid cancer.
Spleen PET/CT demonstrated spleen involvement in 27 patients. Only in nine patients did pathologic 18F-FDG-avid foci correspond to focal lesions on CT scans. Among the remaining 18 patients, PET/CT revealed focal 18F-FDG uptake in 12
Table I. Classification of five lymph node categories based on combined CT and PET/CT assessment. No. 1 2 3 4 5
Lymph node category
CT assessment (size)*
PET/CT assessment†
CT(⫹)‡PET/CT(⫹) CT(⫹)PET/CT(⫺)§ CT(⫺)PET/CT(⫹) CT(?)PET/CT(⫹) CT(?)PET/CT(⫺)
⬎ 15 mm ⬎ 15 mm ⬍ 11 mm or not detected 11–15 mm 11–15 mm
Positive Negative Positive Positive Negative
CT, computed tomography; PET, positron emission tomography; SUV, standardized uptake value; HL, Hodgkin lymphoma. *Longest node dimension. †Positive if SUV higher than background. ‡Positive for HL. §Negative for HL.
Initial staging of Hodgkin lymphoma
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Table II. Distribution of lymph nodes according to categories defined by combined CT and PET/CT assessment within each main anatomical region. Lymph node categories Anatomical region
1: CT(⫹) PET/CT(⫹) (%)
2: CT(⫹) PET/CT(⫺) (%)
3: CT(⫺) PET/CT(⫹) (%)
4: CT(?) PET/CT(⫹) (%)
5: CT(?) PET/CT(⫺) (%)
No. of all nodes detected
Cervical Thoracic Abdominal Pelvic All
54.3 62 51.2 48.2 53.9%
2.9 3.6 9.3 2.7 4.6%
16.7 20.7 17.4 27.3 20.5%
17.4 9.3 10.5 10.9 12.0%
8.7 4.4 11.6 10.9 8.9%
137 678 87 110 1012
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CT, computed tomography; PET, positron emission tomography.
patients, and diffuse with SUVmax greater than in the liver in six. The median difference between spleen and liver SUV was 4.5 (0.9–21.4). The spleen was the only subdiaphragmatic localization in two out of 12 patients with focal and in all six patients with diffuse spleen uptake.
Liver There were two cases of focal liver involvement coexisting with spleen involvement identified on CT. In both cases the lesions were 18F-FDG avid.
Bones and BM Foci of increased BM 18F-FDG uptake were seen in 20 (21%) patients. Almost all patients except one had B symptoms. The uptake was solitary in six (with SUVmax 7.5–23.4) and multiple in 14 patients. Only in four of 20 patients did 18F-FDG-avid foci correspond to bone lesions seen in classical CT. Of note, blind BMB was negative in all these cases. Diffuse BM uptake was seen in 21 patients; 14 (66%) of them had B symptoms. Most patients (n ⫽ 19) had bone SUVmax above the liver. Interestingly, BMB was positive in three of these patients; in two of them SUVmax was around 4.0, not much above the liver uptake, and in one 12.9, with unclassified type of HL that later progressed to diffuse large B-cell lymphoma.
described in four, three, two and one patients, respectively. In all cases but one (the patient with a subpleural nodule 17 ⫻ 10 mm), increased 18F-FDG uptake was found on PET/ CT. In the latter case the patient after treatment is still in complete remission and the lesion remains unchanged. In three patients CT scans were inconclusive, but highly suspicious for lung involvement. Multiple subpleural nodules 11–15 mm were seen in two and a single nodule in one patient. In PET/CT the multiple subpleural nodules were not active, in contrast to a single nodule (14 ⫻ 10 mm, SUVmax 2.6) in the remaining case. This single nodule lost its metabolic activity at interim PET/CT, and regressed completely after systemic treatment. In six patients CT findings were classified as not related to lymphoma: in two patients small single parenchymal nodules ⬍ 10 mm and in four cases small multiple subpleural nodules. In all six cases PET/CT was negative. PET/CT suggested lung involvement in 12 patients. In 10 cases 18F-FDG uptake (median SUV 6.5, range 2.6–15.5) corresponded to morphological changes detected by conventional CT (evident pathologic findings in nine patients, suspicious in one); in two cases increased 18F-FDG uptake seen as peribronchial thickening was not detected by conventional CT.
Staging
Lungs CT abnormalities within the lungs were detected in 19 patients; in 10 cases findings were classified as clearly indicative of HL: multiple nodules in lung parenchyma, single parenchymal nodule ⬎ 15 mm, diffuse infiltration of lung parenchyma and subpleural nodule 17 ⫻ 10 mm were
CT(?) PET/CT(+)
% 100
CT(?) PET/CT(–)
80
The results of staging based on independent assessments with conventional contrast-enhanced CT and PET/CT are shown in Table IV. CT and PET/CT were concordant in disease stage evaluation in 63 patients (66%); 27 (28%) patients were upstaged and six (6%) were downstaged by PET/CT (Table V). The reasons for disease upstaging were BM involvement (focal) in 10 (10.5%), spleen in five (5%) and lung in two (2%) patients, in one case an increase in the number of nodal Table III. Extranodal lesions detected by CT and PET/CT according to localization.
60 40 20 0 Cervix
Thorax
Abdomen
Pelvis
All
Figure 1. Percentage of PET(⫹) lymph nodes among “equivocal” nodes (10–15 mm) detected by classical CT.
Thoracic wall Lung Spleen Liver Bone/bone marrow focal Other* All
CT
PET/CT
1 10 9 2 4 0 26 in 21 patients
4 12 27 2 23 5 73 in 52 patients
CT, computed tomography; PET, positron emission tomography. *Nasopharynx, Waldeyer’s ring, thyroid.
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E. Bednaruk-Młyński et al. Table IV. Results of contrast-enhanced CT and independent PET/CT based staging including presence of B symptoms. Clinical stage IA IB IIA IIB IIIA IIIB IVA IVB Total
CT stage (%)
Bulky
PET/CT stage (%)
Bulky
All CT (%)
All PET/CT (%)
4 (4) 1 (1) 19 (20) 30 (31) 9 (9) 19 (20) 0 (0) 14 (15) 96
0 0 5 10 0 3 0 2 20
6 (6) 1 (1) 16 (17) 21 (22) 8 (8) 14 (15) 3 (3) 27 (28) 96
0 0 3 6 0 2 2 7 20
5 (5)
7 (7)
49 (51)
37 (39)
28 (29)
22 (23)
14 (15)
30 (31)
96 (100)
96 (100)
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CT, computed tomography; PET, positron emission tomography.
groups involved, and in nine (9.4%) patients there was more than one reason. Spleen involvement (two focal, three diffuse with SUVmax higher than in the liver) was the only reason for upstaging in five patients, all CT stage II; B symptoms were present in four of them. Lung involvement resulted in disease upstaging in two patients (CT stage II and III). In nine patients with more than one reason for upstaging, four had BM and spleen involvement, four spleen and subdiapragmatic lymph nodes, and one had lung and BM involvement. Change in the number of lymph nodes resulted in upstaging in only one patient with CT stage IA, who was upstaged to IIA since PET/CT identified another lymph node in the mediastinum. In five cases downstaging resulted from the absence of 18F-FDG uptake in enlarged (⬎ 15 mm) lymph nodes. In four cases stage III CT was reduced: in two to stage II and in the other two to stage I. One patient with CT stage II was downstaged to stage I. B symptoms were present in one patient. One patient initially staged as IV because of a single subpleural nodule 17 ⫻ 10 mm (coexisting with extensive mediastinal and hilar involvement) was finally downstaged to stage III because the pleural lesion was not 18F-FDG avid.
Potential change of treatment Inclusion of PET/CT staging would modify treatment (based on National Comprehensive Cancer Network [NCCN] or European Organisation for Research and Treatment of Cancer [EORTC] criteria) in 20 (21%) of patients. In 16 patients treatment would be extended: in three patients for focal bone/BM involvement (II→IV), five patients for spleen infiltration (II→III), one for lung involvement (II→IV) and two for more involved lymph nodes regions requiring radiotherapy. In five other patients there was more than one reason for treatment intensification. In four patients Table V. Disease stage migration using independent CT and PET/CT evaluation. PET/CT CT I II 6 III IV
I
II
III
IV
4 1 2 —
1 34 2 —
— 9 12 1
— 5 27 12 13
CT, computed tomography; PET, positron emission tomography.
with lymph nodes ⬎ 15 mm that were PET negative, treatment would be shortened (III→II).
Discussion Our study revisited the standards of HL staging in the era of modern PET/CT scanners. It confirms that PET/CT staging is more accurate for patients with HL compared with contrastenhanced CT, and provides strong arguments for PET/CT to be obligatory at diagnosis even in less developed countries. In almost one-third of patients, PET/CT changed their CTbased stage, and most of them were upstaged. PET/CT was more accurate in the detection of extranodal HL manifestations. This was clearly evident for the spleen, which was shown to be involved in 27 (28%) patients compared to only nine (9%) in CT. Our findings corroborate a previous report of occult subdiaphragmatic involvement of HL leading to treatment extension in 14% of patients [14]. A second important finding, however more difficult to interpret, refers to BM changes detected by PET/CT. They present as either focal or diffuse increase of 18F-FDG uptake. Focal uptake [15], especially with multiple sites, is considered indicative of HL. Many authors have confirmed the focal pattern of BM infiltration in HL, either seen on magnetic resonance imaging (MRI) [16], or by histopathology during guided biopsies [15,17,18]. Some clinical data also suggest that focal 18F-FDG uptake in the skeleton is consistent with HL infiltration [19]. We have confirmed the results of earlier reports [18,20] that PET/CT detects at least one-third more focal lesions than classical CT. However, none of our patients with focal BM uptake had a positive BMB; this supports the limited diagnostic accuracy of blind BMB [21]. Therefore, some authors have suggested that PET/CT should be used to guide bone biopsies if needed [6,15,17,18]. In contrast, the clinical significance of diffuse increased 18F-FDG uptake in the BM, which is observed even more frequently [17], is far less clear. In our study, we found 21 cases with diffuse increased 18F-FDG, with a SUV higher than in the liver in most cases (90%). In eight cases diffuse uptake in the BM coexisted with homogeneous diffuse uptake in the spleen. One may hypothesize that this phenomenon is related to cytokine activity rather than indicative of lymphoma, as postulated by others [22,23]. We did not find (data not shown) any difference between patients with focal and diffuse uptake with regard to white blood cell and neutrophil counts, erythrocyte sedimentation rate, activity of lactate dehydrogenase and alkaline
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Initial staging of Hodgkin lymphoma phosphatase and C-reactive protein, whereas both groups differed in these parameters from patients without bone lesions. Therefore, the interpretation of diffuse 18F-FDG uptake as negative for lymphoma should not be taken for granted, and needs further research. Although we conservatively did not change the stage of the disease based solely on diffuse 18F-FDG BM uptake, three of our patients had biopsy-proven presence of BM infiltration. The third argument for routine usage of PET/CT concerns pulmonary assessment. Pulmonary nodules are not an uncommon finding on classical CT. In a meta-analysis of more than 50 000 patients undergoing low-dose CT for lung cancer screening, any pulmonary changes requiring follow-up were observed in approximately 20% of the examined population [24]. Although patients with HL are often younger, the exact occurrence of benign lesions may be smaller, but accurate data are lacking. On the other hand, initial pulmonary involvement in HL is suspected in 10–20% of patients with pulmonary nodules, and infiltrative changes are the most predominant findings [25]. Therefore, differential diagnosis of lung lesions based solely on CT may be difficult. In this series of patients, classical CT revealed different pulmonary findings in 19 cases, of which 10 were indicative of lymphoma. In nine of these patients, pathological CT findings were metabolically active in PET and thus were highly suggestive of HL involvement. In six cases, changes that were regarded as not related to lymphoma were not metabolically active. In three patients CT scans were inconclusive due to the size of lesions (11–15 mm). Only in one of these cases was slightly increased SUV (2.6) noted on PET/CT, but by our criteria was classified as HL related. This points to the limitation of our study: the lack of biopsy-confirmed metabolically active lung lesions as involved by HL. Helpful and highly suggestive of HL involvement is the assessment of responses to treatment. Follow-up data showed that all metabolically active lesions regressed at the end of systemic treatment, whereas inactive lesions remained stable. However, it should be kept in mind that an FDG-avid pulmonary lesion potentially may be caused by inflammatory processes, which can also resolve after completion of therapy. The above results suggested that the criteria for lung involvement in classical CT were well chosen; however, three inconclusive cases in classical CT confirmed the utility of PET/CT assessment. Multiple parenchymal lesions in classical CT were metabolically active irrespective of size. None of the subpleural lesions (mostly multiple) of any size appeared to be positive by PET/CT. All solitary pulmonary nodules (14–26 mm) were 18F-FDG-avid, and resolved as a result of treatment. In contrast to the extranodal disease assessment, the detailed and careful analysis of 34 lymph node areas performed by an independent radiologist/nuclear medicine specialist did not translate to better staging by PET/CT, despite more lymph nodes detected. We were particularly interested in this analysis, since earlier reports concerning site-to-site nodal comparison reported smaller groups of patients, mixed HL and NHL populations, and often used PET and CT as separate imaging modalities [3]. Although the detection of more lymph nodes by PET/CT compared to
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CT rarely resulted in disease upstaging, it might influence treatment planning in patients referred for radiotherapy after systemic treatment. In our patients (data not shown), an increase in the number of nodal areas involved was seen in five potential candidates for radiotherapy. We also noted some atypically located nodes in seven other patients with early-stage disease, who were candidates for combined treatment. Thus, PET/CT results could have prevented a topographic omission in radiotherapy planning in these patients. The second new aspect of lymph node assessment was the question of HL involvement of slightly increased (11–15 mm) nodes. Half of them were metabolically active. This suggests that a safer threshold for the definition of negative lymph node for classical CT should be 10 mm rather than 15 mm, although 20% of all PET/CT positive nodes were 10 mm or smaller in size, which again highlights the value of PET/CT in the initial staging of HL. Finally, PET/ CT showed no 18F-FDG activity in some nodes ⬎ 15 mm that, by CT definition, were HL involved. We found five cases with enlarged lymph nodes, usually single in the abdomen, that were 18F-FDG negative. This allowed safe downstaging of these patients. It is true that enlargement of single abdominal lymph node in the pre-PET era was not always clinically treated as indicative of lymphoma; however, from the clinician’s point of view, the presence or lack of metabolic activity is very helpful in deciding whether an enlarged lymph node is HL related. The nodes in our study were usually single and remained stable during treatment. B symptoms were present in only one patient. Our study shows that the addition of PET/CT would result in treatment modification (mainly intensification) in 21% of patients. Patients with CT stage II seem to benefit the most from PET/CT staging. In the literature, treatment modification has been reported in 7.7–25% of patients [3,6,8–10,26,27]. Although bulky IIA or IIB disease is treated by some investigations as advanced stage [28], the incorporation of PET/ CT into initial staging enables tailoring the treatment to the needs of the individual patient and may significantly increase the effectiveness of the treatment. To conclude, the final argument for obligatory initial PET/ CT in HL is the increasing evidence for the utility of early PET response assessment. The detection of synchronous cancers should not be neglected either. The routine use of PET/CT does not obviate the diagnostic role of contrast-enhanced CT. In early stages of HL, CT is helpful for accurate radiotherapy planning. Therefore it has been proposed that contrastenhanced CT should be performed during a single PET/CT session if possible [29]. Alternatively PET/CT should be done first, and based on this, the decision whether to perform fulldose or low-dose regional contrast-enhanced CT or targeted BMB should be made.
Acknowledgements The authors are deeply grateful to Dr. Alberto Biggi and Dr. Stefan Chauvie from Cuneo PET Center, Italy, for nuclear medicine training of the Polish PET centers before project initiation and Professor Andrea Gallamini for help and constant support.
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Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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cycles of anthracycline-containing chemotherapy and consolidation radiation of spleen. Ann Oncol 2011;22:671–680. [15] Pelosi E, Penna D, Deandreis D, et al. FDG-PET in the detection of bone marrow disease in Hodgkin’s disease and aggressive non-Hodgkin’s lymphoma and its impact on clinical management. Q J Nucl Med Mol Imaging 2008;52:9–16. [16] Tardivon AA , Munck JN, Shapeero LG, et al. Can clinical data help to screen patients with lymphoma for MR imaging of bone marrow? Ann Oncol 1995;6:795–800. [17] 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. [18] Schaefer NG, Strobel K, Taverna C, et al. Bone involvement in patients with lymphoma: the role of FDG-PET/CT. Eur J Nucl Med Mol Imaging 2007;34:60–67. [19] El-Galaly TC, d’Amore F, Mylam KJ, et al. Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol 2012;30:4508–4514. [20] Nakamoto Y, Cohade C, Tatsumi M, et al. CT appearance of bone metastases detected with FDG PET as part of the same PET/CT examination. Radiology 2005;237:627–634. [21] Purz S, Mauz-Korholz C, Korholz D, et al. [18F]Fluorodeoxyglucose positron emission tomography for detection of bone marrow involvement in children and adolescents with Hodgkin’s lymphoma. J Clin Oncol 2011;29:3523–3528. [22] Elstrom RL, Tsai DE, Vergilio JA , et al. Enhanced marrow [18F] fluorodeoxyglucose uptake related to myeloid hyperplasia in Hodgkin’s lymphoma can simulate lymphoma involvement in marrow. Clin Lymphoma 2004;5:62–64. [23] Moulin-Romsee G, Hindie E, Cuenca X, et al. (18)F-FDG PET/CT bone/bone marrow findings in Hodgkin’s lymphoma may circumvent the use of bone marrow trephine biopsy at diagnosis staging. Eur J Nucl Med Mol Imaging 2010;37:1095–1105. [24] Bach PB, Mirkin JN, Oliver TK , et al. Benefits and harms of CT screening for lung cancer: a systematic review. JAMA 2012;307: 2418–2429. [25] Diederich S, Link TM, Zuhlsdorf H, et al. Pulmonary manifestations of Hodgkin’s disease: radiographic and CT findings. Eur Radiol 2001;11:2295–2305. [26] Pelosi E, Pregno P, Penna D, et al. Role of whole-body [18F] fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and conventional techniques in the staging of patients with Hodgkin and aggressive non Hodgkin lymphoma. Radiol Med 2008;113:578–590. [27] Schaefer NG, Hany TF, Taverna C, et al. Non-Hodgkin lymphoma and Hodgkin disease:coregistered FDG PET and CT at staging and restaging—do we need contrast-enhanced CT? Radiology 2004;232: 823–829. [28] Connors JM, Gascoyne RD, Hoskins P, et al. Hodgkin lymphoma patients with stage II B or stage II bulky disease have advanced disease and should not be included in limited stage trials. Blood 2010;116(Suppl. 1): Abstract 417. [29] Barrington SF, Mikhaeel NG. When should FDG-PET be used in the modern management of lymphoma? Br J Haematol 2014; 164:315–328.
ORIGINAL ARTICLE: CLINICAL
Comparison of positron emission tomography/computed tomography with classical contrast-enhanced computed tomography in the initial staging of Hodgkin lymphoma Ewa Bednaruk-Młyński1, Joanna Pieńkowska2, Adam Skórzak3, Bogdan Małkowski4, Waldemar Kulikowski5, Edyta Subocz6, Justyna Dzietczenia7, Marta Zalewska8, Krzysztof Leśniewski-Kmak3,9, Renata Zaucha1, Tomasz Wróbel7 & Jan M. Zaucha3,9 Leuk Lymphoma Downloaded from informahealthcare.com by Tulane University on 10/12/14 For personal use only.
1Department
of Oncology and Radiotherapy, 2Department of Radiology and 9Department of Propadeutic Oncology, Medical University of Gdansk, Gdansk, Poland, 3Department of Oncology, Gdynia Oncology Center, Maritime Polish Red Cross Memorial Hospital Gdynia, Gdynia, Poland, 4Department of Nuclear Medicine, Oncology Center, Bydgoszcz, Poland, 5Department of Hematology, Regional Oncology Center, Olsztyn, Poland, 6Department of Hematology and Internal Medicine, Military Institute of Medicine, Warsaw, Poland, 7Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland and 8Department of Prevention of Environmental Hazards and Allergology, Medical University of Warsaw, Warsaw, Poland
aspect [1]. This is overcome, however, by combining CT with positron emission tomography (PET). HL has been shown to be highly PET-avid for fluorodeoxyglucose (18F-FDG) [2], with a sensitivity of 88–93.2% [3,4]. Early publications assessing the impact of PET on lymphoma staging usually involved mixed populations of non-HL (NHL) and HL, with patients with NHL being the majority [5]. There are reports in the literature comparing PET with conventional CT staging in larger series of patients with HL [3,6]. However, some of those studies used older-generation PET scanners not always combined with CT imaging. Therefore, the reported percentage of stage migration and treatment modification varies to some extent in different series. In both PET and PET/CT series reported to date (patients with HL and NHL), 8–40% of patients were upstaged (13–40% of patients with HL) and 1–15% were downstaged, leading to treatment modification in 5–25% [3,4,6–8,9,10]. These clear discrepancies encouraged us to perform a reanalysis of baseline scans in patients previously included in the clinical trial PLRG-11 conducted by the allied centers of the Polish Lymphoma Research Group (PLRG) [11]. We performed detailed analysis of nodal and extranodal disease manifestations, assessing stage migration and its impact on treatment selection. We aimed at defining a group of patients who would benefit the most from the incorporation of PET/CT into initial staging.
Abstract We compared initial computed tomography (CT) and positron emission tomography (PET)/CT in 96 patients with Hodgkin lymphoma (HL), assessing the role of baseline PET/CT in stage migration and treatment selection. The number of patients with stage I, II, III and IV disease based on CT versus PET/CT was: 5 vs. 7, 49 vs. 37, 28 vs. 22 and 14 vs. 30, respectively. In 33 (34%) patients, PET/CT changed HL stage: 27 (28%) were upstaged and six (6.3%) downstaged. Upstaging was caused by detection of new extranodal involvements (47 sites in 26 patients): bone marrow (10 patients), spleen (five patients) and lung (two patients). In nine patients ⱖ 2 further coexisting locations were detected. Downstaging resulted from the absence of fluorodeoxyglucose (18F-FDG) uptake in enlarged nodes (⬎ 15 mm) in the abdomen and pelvis. PET/CT modified HL stage in 34% of patients leading to treatment modification in the majority. Our results indicate that PET/CT should be mandatory in the initial staging of HL. Keywords: Hodgkin lymphoma, staging, PET/CT
Introduction Disease stage remains the most powerful prognostic factor in Hodgkin lymphoma (HL). Accurate detection of all nodal and extranodal lymphoma manifestations is critical to selecting optimal treatment strategy, avoiding under- or overtreatment and minimizing treatment-related morbidity. The important limitation of computed tomography (CT) is the interpretation of nodal involvement based solely on anatomic criteria of size and lack of any functional
Materials and methods Between January 2008 and September 2011, 96 consecutive patients with newly diagnosed HL were referred to four
Correspondence: J. M. Zaucha, Department of Propadeutic Oncology, Medical University of Gdan´sk, Ul. Powstania Styczniowego 1, 81-519 Gdynia, Poland. Tel: ⫹48587260438. Fax: ⫹48587260156. E-mail: [email protected] Received 10 February 2014; revised 21 April 2014; accepted 24 April 2014
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E. Bednaruk-Młyński et al.
Polish onco-hematological centers. The histological subtypes included: 78 patients (81%) with nodular sclerosis, 13 (14%) with mixed cellularity, four (4%) with lymphocyte rich and one patient with unclassified subtype. In all cases CT (usually performed by the referring center) and PET/ CT were done at diagnosis. Bone marrow biopsy (BMB) was performed if B symptoms or at least disease stage III was present. The original CT and PET/CT images were reviewed afresh by a dedicated radiologist and nuclear medicine specialist. They were blinded to the original local-center assessment and were not aware of their mutual staging. The number of nodal areas and extranodal sites involved, detected by each imaging modality, was scored, and the final CT and PET/CT stage of each patient established and compared. Discordant cases were reviewed and discussed with the local center until a consensus was reached. The study was approved by the Ethics Committee at the Medical University of Gdansk.
data were acquired for 2–5 min per bed position, starting 60–90 min after intravenous injection of 18F-FDG. Glucose levels were tested for all patients, and diazepam or a similar muscle relaxant was given orally to some patients before 18FFDG administration to avoid muscular uptake of the tracer. PET/CT scans were judged by visual assessment, and standardized uptake values (SUVs) were also reported. Sites of non-physiological 18F-FDG uptake above background were reported as HL involved. Diffuse uptake in the spleen was assumed to be indicative of HL involvement, providing the SUV was greater than in the liver. In contrast, diffuse uptake in the BM even if higher than in the liver was conservatively not treated as HL involvement.
Results The study included 51 males and 45 females; median age was 36 years (19–78). The median time interval between CT and PET/CT scanning was 19 days (1–77).
CT imaging CT scans covered the neck, thorax, abdomen and pelvis and included both unenhanced and enhanced scanning after administration of contrast medium (80–120 mL). Slice thickness was 1.25–5 mm in most (83%) cases and in the remainder 5–8 mm, which was standard in older CT studies when the observational study was launched. For CT staging classical radiologic criteria were used. Lymph nodes ⬎ 15 mm in longest dimension were considered pathological (CT⫹). In contrast, those smaller than 10 mm were considered as negative (CT⫺) and those in between were considered as “equivocal” (CT?). We distinguished 34 lymph node areas. CT and PET/CT scans were reassessed by a dedicated radiologist and nuclear medicine specialist independently of the initial examination result, and the results were matched and compared with regard to size and location of lymph nodes. Discrepancies were reviewed and discussed after completion of the study. Special attention was drawn to atypically located lymph nodes. We defined five extranodal sites of interest: lungs, bones and bone marrow (BM), liver, spleen and a group of other locations (nasopharynx, thyroid, thoracic wall, Waldeyer’s ring). Spleen and liver scans were regarded as positive for HL when any focal lesion (small nodule) was detected, excluding cystic and vascular changes. Diffuse lung parenchyma infiltration without clinical manifestation of inflammation or other possible etiology, and multiple nodules regardless of their size were considered as indicative for lymphoma. Single parenchymal nodules or subpleural nodules were considered benign when ⬍ 10 mm, equivocal when their size was 11–15 mm and pathologic at ⬎ 15 mm. Osteolytic, osteosclerotic or mixed bone changes if present were considered indicative for lymphoma.
PET/CT imaging PET/CT scans were performed with GE Discovery ST 16, GE Discovery STE and Siemens mCT 128 scanners at four centers. All PET centers took part in the PLRG audit to ensure that PET scanning standardization and adequate quality interpretation was achieved at each center [12,13]. Emission
Nodal areas CT detected 807 involved nodal areas, whereas PET/CT detected 100 more. Both methods identified 1012 nodal areas that were classified into five categories (Table I). The distribution of each category within anatomical regions is shown in Table II. Nodes positive for HL by both imaging modalities accounted for 53.9% of all nodes detected. Lymph nodes ⬎ 15 mm that were PET-negative represented only 4.6% of all lymph nodes (mainly abdominal). Within lymph nodes that were considered as “equivocal” in classical CT (CT?), about half (57%) were PET-positive (Figure 1). Some 20% of all PET/CT-positive nodes were ⱕ 10 mm.
Extranodal areas CT identified 26 extranodal HL manifestations in 21 patients, whereas PET/CT identified 73 in 52 patients. All 26 CT⫹ lesions were also PET/CT⫹. PET/CT identified 47 new extranodal lesions (Table III), one in the thyroid that turned out to be synchronous thyroid cancer.
Spleen PET/CT demonstrated spleen involvement in 27 patients. Only in nine patients did pathologic 18F-FDG-avid foci correspond to focal lesions on CT scans. Among the remaining 18 patients, PET/CT revealed focal 18F-FDG uptake in 12
Table I. Classification of five lymph node categories based on combined CT and PET/CT assessment. No. 1 2 3 4 5
Lymph node category
CT assessment (size)*
PET/CT assessment†
CT(⫹)‡PET/CT(⫹) CT(⫹)PET/CT(⫺)§ CT(⫺)PET/CT(⫹) CT(?)PET/CT(⫹) CT(?)PET/CT(⫺)
⬎ 15 mm ⬎ 15 mm ⬍ 11 mm or not detected 11–15 mm 11–15 mm
Positive Negative Positive Positive Negative
CT, computed tomography; PET, positron emission tomography; SUV, standardized uptake value; HL, Hodgkin lymphoma. *Longest node dimension. †Positive if SUV higher than background. ‡Positive for HL. §Negative for HL.
Initial staging of Hodgkin lymphoma
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Table II. Distribution of lymph nodes according to categories defined by combined CT and PET/CT assessment within each main anatomical region. Lymph node categories Anatomical region
1: CT(⫹) PET/CT(⫹) (%)
2: CT(⫹) PET/CT(⫺) (%)
3: CT(⫺) PET/CT(⫹) (%)
4: CT(?) PET/CT(⫹) (%)
5: CT(?) PET/CT(⫺) (%)
No. of all nodes detected
Cervical Thoracic Abdominal Pelvic All
54.3 62 51.2 48.2 53.9%
2.9 3.6 9.3 2.7 4.6%
16.7 20.7 17.4 27.3 20.5%
17.4 9.3 10.5 10.9 12.0%
8.7 4.4 11.6 10.9 8.9%
137 678 87 110 1012
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CT, computed tomography; PET, positron emission tomography.
patients, and diffuse with SUVmax greater than in the liver in six. The median difference between spleen and liver SUV was 4.5 (0.9–21.4). The spleen was the only subdiaphragmatic localization in two out of 12 patients with focal and in all six patients with diffuse spleen uptake.
Liver There were two cases of focal liver involvement coexisting with spleen involvement identified on CT. In both cases the lesions were 18F-FDG avid.
Bones and BM Foci of increased BM 18F-FDG uptake were seen in 20 (21%) patients. Almost all patients except one had B symptoms. The uptake was solitary in six (with SUVmax 7.5–23.4) and multiple in 14 patients. Only in four of 20 patients did 18F-FDG-avid foci correspond to bone lesions seen in classical CT. Of note, blind BMB was negative in all these cases. Diffuse BM uptake was seen in 21 patients; 14 (66%) of them had B symptoms. Most patients (n ⫽ 19) had bone SUVmax above the liver. Interestingly, BMB was positive in three of these patients; in two of them SUVmax was around 4.0, not much above the liver uptake, and in one 12.9, with unclassified type of HL that later progressed to diffuse large B-cell lymphoma.
described in four, three, two and one patients, respectively. In all cases but one (the patient with a subpleural nodule 17 ⫻ 10 mm), increased 18F-FDG uptake was found on PET/ CT. In the latter case the patient after treatment is still in complete remission and the lesion remains unchanged. In three patients CT scans were inconclusive, but highly suspicious for lung involvement. Multiple subpleural nodules 11–15 mm were seen in two and a single nodule in one patient. In PET/CT the multiple subpleural nodules were not active, in contrast to a single nodule (14 ⫻ 10 mm, SUVmax 2.6) in the remaining case. This single nodule lost its metabolic activity at interim PET/CT, and regressed completely after systemic treatment. In six patients CT findings were classified as not related to lymphoma: in two patients small single parenchymal nodules ⬍ 10 mm and in four cases small multiple subpleural nodules. In all six cases PET/CT was negative. PET/CT suggested lung involvement in 12 patients. In 10 cases 18F-FDG uptake (median SUV 6.5, range 2.6–15.5) corresponded to morphological changes detected by conventional CT (evident pathologic findings in nine patients, suspicious in one); in two cases increased 18F-FDG uptake seen as peribronchial thickening was not detected by conventional CT.
Staging
Lungs CT abnormalities within the lungs were detected in 19 patients; in 10 cases findings were classified as clearly indicative of HL: multiple nodules in lung parenchyma, single parenchymal nodule ⬎ 15 mm, diffuse infiltration of lung parenchyma and subpleural nodule 17 ⫻ 10 mm were
CT(?) PET/CT(+)
% 100
CT(?) PET/CT(–)
80
The results of staging based on independent assessments with conventional contrast-enhanced CT and PET/CT are shown in Table IV. CT and PET/CT were concordant in disease stage evaluation in 63 patients (66%); 27 (28%) patients were upstaged and six (6%) were downstaged by PET/CT (Table V). The reasons for disease upstaging were BM involvement (focal) in 10 (10.5%), spleen in five (5%) and lung in two (2%) patients, in one case an increase in the number of nodal Table III. Extranodal lesions detected by CT and PET/CT according to localization.
60 40 20 0 Cervix
Thorax
Abdomen
Pelvis
All
Figure 1. Percentage of PET(⫹) lymph nodes among “equivocal” nodes (10–15 mm) detected by classical CT.
Thoracic wall Lung Spleen Liver Bone/bone marrow focal Other* All
CT
PET/CT
1 10 9 2 4 0 26 in 21 patients
4 12 27 2 23 5 73 in 52 patients
CT, computed tomography; PET, positron emission tomography. *Nasopharynx, Waldeyer’s ring, thyroid.
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E. Bednaruk-Młyński et al. Table IV. Results of contrast-enhanced CT and independent PET/CT based staging including presence of B symptoms. Clinical stage IA IB IIA IIB IIIA IIIB IVA IVB Total
CT stage (%)
Bulky
PET/CT stage (%)
Bulky
All CT (%)
All PET/CT (%)
4 (4) 1 (1) 19 (20) 30 (31) 9 (9) 19 (20) 0 (0) 14 (15) 96
0 0 5 10 0 3 0 2 20
6 (6) 1 (1) 16 (17) 21 (22) 8 (8) 14 (15) 3 (3) 27 (28) 96
0 0 3 6 0 2 2 7 20
5 (5)
7 (7)
49 (51)
37 (39)
28 (29)
22 (23)
14 (15)
30 (31)
96 (100)
96 (100)
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CT, computed tomography; PET, positron emission tomography.
groups involved, and in nine (9.4%) patients there was more than one reason. Spleen involvement (two focal, three diffuse with SUVmax higher than in the liver) was the only reason for upstaging in five patients, all CT stage II; B symptoms were present in four of them. Lung involvement resulted in disease upstaging in two patients (CT stage II and III). In nine patients with more than one reason for upstaging, four had BM and spleen involvement, four spleen and subdiapragmatic lymph nodes, and one had lung and BM involvement. Change in the number of lymph nodes resulted in upstaging in only one patient with CT stage IA, who was upstaged to IIA since PET/CT identified another lymph node in the mediastinum. In five cases downstaging resulted from the absence of 18F-FDG uptake in enlarged (⬎ 15 mm) lymph nodes. In four cases stage III CT was reduced: in two to stage II and in the other two to stage I. One patient with CT stage II was downstaged to stage I. B symptoms were present in one patient. One patient initially staged as IV because of a single subpleural nodule 17 ⫻ 10 mm (coexisting with extensive mediastinal and hilar involvement) was finally downstaged to stage III because the pleural lesion was not 18F-FDG avid.
Potential change of treatment Inclusion of PET/CT staging would modify treatment (based on National Comprehensive Cancer Network [NCCN] or European Organisation for Research and Treatment of Cancer [EORTC] criteria) in 20 (21%) of patients. In 16 patients treatment would be extended: in three patients for focal bone/BM involvement (II→IV), five patients for spleen infiltration (II→III), one for lung involvement (II→IV) and two for more involved lymph nodes regions requiring radiotherapy. In five other patients there was more than one reason for treatment intensification. In four patients Table V. Disease stage migration using independent CT and PET/CT evaluation. PET/CT CT I II 6 III IV
I
II
III
IV
4 1 2 —
1 34 2 —
— 9 12 1
— 5 27 12 13
CT, computed tomography; PET, positron emission tomography.
with lymph nodes ⬎ 15 mm that were PET negative, treatment would be shortened (III→II).
Discussion Our study revisited the standards of HL staging in the era of modern PET/CT scanners. It confirms that PET/CT staging is more accurate for patients with HL compared with contrastenhanced CT, and provides strong arguments for PET/CT to be obligatory at diagnosis even in less developed countries. In almost one-third of patients, PET/CT changed their CTbased stage, and most of them were upstaged. PET/CT was more accurate in the detection of extranodal HL manifestations. This was clearly evident for the spleen, which was shown to be involved in 27 (28%) patients compared to only nine (9%) in CT. Our findings corroborate a previous report of occult subdiaphragmatic involvement of HL leading to treatment extension in 14% of patients [14]. A second important finding, however more difficult to interpret, refers to BM changes detected by PET/CT. They present as either focal or diffuse increase of 18F-FDG uptake. Focal uptake [15], especially with multiple sites, is considered indicative of HL. Many authors have confirmed the focal pattern of BM infiltration in HL, either seen on magnetic resonance imaging (MRI) [16], or by histopathology during guided biopsies [15,17,18]. Some clinical data also suggest that focal 18F-FDG uptake in the skeleton is consistent with HL infiltration [19]. We have confirmed the results of earlier reports [18,20] that PET/CT detects at least one-third more focal lesions than classical CT. However, none of our patients with focal BM uptake had a positive BMB; this supports the limited diagnostic accuracy of blind BMB [21]. Therefore, some authors have suggested that PET/CT should be used to guide bone biopsies if needed [6,15,17,18]. In contrast, the clinical significance of diffuse increased 18F-FDG uptake in the BM, which is observed even more frequently [17], is far less clear. In our study, we found 21 cases with diffuse increased 18F-FDG, with a SUV higher than in the liver in most cases (90%). In eight cases diffuse uptake in the BM coexisted with homogeneous diffuse uptake in the spleen. One may hypothesize that this phenomenon is related to cytokine activity rather than indicative of lymphoma, as postulated by others [22,23]. We did not find (data not shown) any difference between patients with focal and diffuse uptake with regard to white blood cell and neutrophil counts, erythrocyte sedimentation rate, activity of lactate dehydrogenase and alkaline
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Initial staging of Hodgkin lymphoma phosphatase and C-reactive protein, whereas both groups differed in these parameters from patients without bone lesions. Therefore, the interpretation of diffuse 18F-FDG uptake as negative for lymphoma should not be taken for granted, and needs further research. Although we conservatively did not change the stage of the disease based solely on diffuse 18F-FDG BM uptake, three of our patients had biopsy-proven presence of BM infiltration. The third argument for routine usage of PET/CT concerns pulmonary assessment. Pulmonary nodules are not an uncommon finding on classical CT. In a meta-analysis of more than 50 000 patients undergoing low-dose CT for lung cancer screening, any pulmonary changes requiring follow-up were observed in approximately 20% of the examined population [24]. Although patients with HL are often younger, the exact occurrence of benign lesions may be smaller, but accurate data are lacking. On the other hand, initial pulmonary involvement in HL is suspected in 10–20% of patients with pulmonary nodules, and infiltrative changes are the most predominant findings [25]. Therefore, differential diagnosis of lung lesions based solely on CT may be difficult. In this series of patients, classical CT revealed different pulmonary findings in 19 cases, of which 10 were indicative of lymphoma. In nine of these patients, pathological CT findings were metabolically active in PET and thus were highly suggestive of HL involvement. In six cases, changes that were regarded as not related to lymphoma were not metabolically active. In three patients CT scans were inconclusive due to the size of lesions (11–15 mm). Only in one of these cases was slightly increased SUV (2.6) noted on PET/CT, but by our criteria was classified as HL related. This points to the limitation of our study: the lack of biopsy-confirmed metabolically active lung lesions as involved by HL. Helpful and highly suggestive of HL involvement is the assessment of responses to treatment. Follow-up data showed that all metabolically active lesions regressed at the end of systemic treatment, whereas inactive lesions remained stable. However, it should be kept in mind that an FDG-avid pulmonary lesion potentially may be caused by inflammatory processes, which can also resolve after completion of therapy. The above results suggested that the criteria for lung involvement in classical CT were well chosen; however, three inconclusive cases in classical CT confirmed the utility of PET/CT assessment. Multiple parenchymal lesions in classical CT were metabolically active irrespective of size. None of the subpleural lesions (mostly multiple) of any size appeared to be positive by PET/CT. All solitary pulmonary nodules (14–26 mm) were 18F-FDG-avid, and resolved as a result of treatment. In contrast to the extranodal disease assessment, the detailed and careful analysis of 34 lymph node areas performed by an independent radiologist/nuclear medicine specialist did not translate to better staging by PET/CT, despite more lymph nodes detected. We were particularly interested in this analysis, since earlier reports concerning site-to-site nodal comparison reported smaller groups of patients, mixed HL and NHL populations, and often used PET and CT as separate imaging modalities [3]. Although the detection of more lymph nodes by PET/CT compared to
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CT rarely resulted in disease upstaging, it might influence treatment planning in patients referred for radiotherapy after systemic treatment. In our patients (data not shown), an increase in the number of nodal areas involved was seen in five potential candidates for radiotherapy. We also noted some atypically located nodes in seven other patients with early-stage disease, who were candidates for combined treatment. Thus, PET/CT results could have prevented a topographic omission in radiotherapy planning in these patients. The second new aspect of lymph node assessment was the question of HL involvement of slightly increased (11–15 mm) nodes. Half of them were metabolically active. This suggests that a safer threshold for the definition of negative lymph node for classical CT should be 10 mm rather than 15 mm, although 20% of all PET/CT positive nodes were 10 mm or smaller in size, which again highlights the value of PET/CT in the initial staging of HL. Finally, PET/ CT showed no 18F-FDG activity in some nodes ⬎ 15 mm that, by CT definition, were HL involved. We found five cases with enlarged lymph nodes, usually single in the abdomen, that were 18F-FDG negative. This allowed safe downstaging of these patients. It is true that enlargement of single abdominal lymph node in the pre-PET era was not always clinically treated as indicative of lymphoma; however, from the clinician’s point of view, the presence or lack of metabolic activity is very helpful in deciding whether an enlarged lymph node is HL related. The nodes in our study were usually single and remained stable during treatment. B symptoms were present in only one patient. Our study shows that the addition of PET/CT would result in treatment modification (mainly intensification) in 21% of patients. Patients with CT stage II seem to benefit the most from PET/CT staging. In the literature, treatment modification has been reported in 7.7–25% of patients [3,6,8–10,26,27]. Although bulky IIA or IIB disease is treated by some investigations as advanced stage [28], the incorporation of PET/ CT into initial staging enables tailoring the treatment to the needs of the individual patient and may significantly increase the effectiveness of the treatment. To conclude, the final argument for obligatory initial PET/ CT in HL is the increasing evidence for the utility of early PET response assessment. The detection of synchronous cancers should not be neglected either. The routine use of PET/CT does not obviate the diagnostic role of contrast-enhanced CT. In early stages of HL, CT is helpful for accurate radiotherapy planning. Therefore it has been proposed that contrastenhanced CT should be performed during a single PET/CT session if possible [29]. Alternatively PET/CT should be done first, and based on this, the decision whether to perform fulldose or low-dose regional contrast-enhanced CT or targeted BMB should be made.
Acknowledgements The authors are deeply grateful to Dr. Alberto Biggi and Dr. Stefan Chauvie from Cuneo PET Center, Italy, for nuclear medicine training of the Polish PET centers before project initiation and Professor Andrea Gallamini for help and constant support.
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