Results: detection of distant metastases by metastatic site No data were identified for the detection of metastatic disease according to metastatic site in participants undergoing imaging for primary staging of melanoma.
In three of six studies, scan coverage was reported to include the skull (Arrangoiz 2012;Kang 2011;Maubec 2007), but the detec- tion of brain metastases was not separately documented.
Re-staging
Three studies recruited participants undergoing imaging for re- staging of disease following a clinical indication of recurrence
(Iagaru 2007;Rubaltelli 2011;Strobel 2007a). One study included any participant having imaging for re-staging purposes (Iagaru 2007), and two included clinically node negative participants ei- ther undergoing ultrasound of the regional lymph nodes as part of a follow-up program (Rubaltelli 2011), or with raised serum S100 (> 0.2 µg/L) during follow-up (Strobel 2007a).
Forest plots of all available study data are presented inFigure 9. Summary estimates of sensitivity and specificity are presented in
Table 2. Summary details of all studies in this section are presented alphabetically inAppendix 9.
Figure 9. Forest plot of imaging for re-staging of melanoma, for the detection of any metastases or nodal metastases (per patient and per lesion data).
Results: detection of any metastases
Two studies provided per patient data for the detection of any metastasis in 153 participants with 95 cases of metastatic disease (Figure 9); the prevalence of any metastasis was 53% inIagaru 2007and 83% inStrobel 2007a.
CT. In one study, the sensitivity of CT for detection of any metas-
tasis on a per patient basis was 68% (95% CI 54% to 80%) and specificity 94% (95% CI 83% to 99%) (106 participants; 56 cases of metastatic disease) (Iagaru 2007).
MRI. No data on MRI were identified for participants undergoing
re-staging of melanoma.
PET-CT. Two studies evaluated PET-CT on a per-patient ba-
sis in 153 participants, 95 of whom had confirmed metastases (Iagaru 2007; Strobel 2007a); summary sensitivity was 92.6% (95% CI 85.3% to 96.4%) and specificity 89.7% (95% CI 78.8% to 95.3%) (Table 2).
Comparison of PET-CT with CT inIagaru 2007demonstrated PET-CT to be more sensitive (89%, 95% CI 78% to 96%) than CT alone (increase of 21%), with similar specificity (88%, 95% 33 Ultrasound, CT, MRI, or PET-CT for staging and re-staging of adults with cutaneous melanoma (Review)
CI 76% to 95%). Similar results were observed on a per lesion ba- sis (Figure 9). Although numbers were small, PET-CT was more sensitive in the subgroup with stage IIIc to IV disease who under- went PET-CT for re-staging after therapy (100%, 95% CI 81% to 100%) (n = 32; 18 with metastatic disease) than in those with less advanced disease (84%, 95% CI 69% to 94%).
Results: detection of nodal metastases
One study presented per patient data for the detection of nodal re- currence after primary treatment in 460 participants with 37 cases of nodal metastases (prevalence 8%) (Rubaltelli 2011) (Figure 9).
Ultrasound. Considering participants with ’common signs of ma-
lignancy’ or with focal hypoechoic cortical thickening as positive for metastases detected all participants with nodal metastases (sen- sitivity 100%, 95% CI 91% to 100%) with a specificity of 93% (95% CI 90% to 95%) (460 participants, 37 with nodal metas- tases) (Rubaltelli 2011). The combination of contrast-enhanced ultrasound with B-mode ultrasound for participants with focal cortical thickening (presence of perfusion defects corresponding to the cortical focal thickening required for a positive test result) increased specificity to 100% (95% CI 98% to 100%).
Other imaging tests. No data on CT, MRI, or PET-CT for the
detection of nodal metastases were identified for participants un- dergoing re-staging for recurrence of melanoma.
Results: detection of distant metastases
No data were identified for the detection of distant metastases in participants undergoing re-staging for disease recurrence.
Results: detection of distant metastases by metastatic site Two of three studies conducted in participants undergoing imag- ing for re-staging of melanoma included imaging of the brain and documented some results for the detection of brain metastases. InIagaru 2007, one of the nine lesions classified as a false negative on PET-CT was a brain lesion that was identified by MRI during follow-up; the total number of brain metastases identified in the study was not reported.
InStrobel 2007a, two brain metastases were identified on PET- CT, both of which were confirmed to be malignant on the reference standard.
3. Staging in mixed or not clearly described populations
Studies in mixed and not clearly described populations have been considered together on the basis that we would be unable to make clear statements regarding the expected accuracy of imaging at any particular point on the clinical pathway for either subset of studies.Table 3describes variability in the clinical pathway and
indications for imaging, inclusion criteria, and stage of disease of participants included in these studies.
Fifteen studies were conducted in mixed population groups (n = 11), including participants undergoing primary staging, re-stag- ing, and follow-up imaging (i.e. at more than one point in the clin- ical pathway) (Abbott 2011;Aukema 2010a;Bastiaannet 2009;
Cachin 2014;Dellestable 2011;Klebl 2003;Pfannenberg 2007;
Pfluger 2011;Reinhardt 2006;van den Brekel 1998;van Wissen 2016), or did not clearly describe the clinical pathway in included participants (n = 4) (Aukema 2010b; Hausmann 2011;Jouvet 2014;Strobel 2007b).
Stage of disease on recruitment was not reported in four stud- ies (Aukema 2010a;Cachin 2014;Klebl 2003;Strobel 2007b), two studies included any stage of disease (with 56% (Reinhardt 2006) and 73% (Dellestable 2011) at stage III or stage IV), six included only stage III melanoma (Abbott 2011;Aukema 2010b;
Bastiaannet 2009;Pfluger 2011;van den Brekel 1998;van Wissen 2016), one included stage IV only (Jouvet 2014), and two in- cluded either stage III or IV melanoma (both with just under 40% with stage III disease) (Hausmann 2011;Pfannenberg 2007). Nine of the fifteen studies reported accuracy data only on a per patient basis (Abbott 2011;Aukema 2010a;Aukema 2010b;
Bastiaannet 2009; Klebl 2003;Reinhardt 2006;Strobel 2007b;
van den Brekel 1998; van Wissen 2016), five reported data per lesion (Dellestable 2011; Hausmann 2011; Jouvet 2014;
Pfannenberg 2007;Pfluger 2011), and one reported both per pa- tient and per lesion data (Cachin 2014). Of those reporting per lesion data, two studies reported accuracy data only for those imaging abnormalities identified by each test (Dellestable 2011;
Jouvet 2014), such that comparative studies reported different numbers of lesions and confirmed metastases per index test eval- uated (Dellestable 2011; Jouvet 2014). Three studies included all lesions detected by any index test so that the number of le- sions included in each 2×2 contingency table was the same for every test (Hausmann 2011;Pfannenberg 2007;Pfluger 2011); two included all lesions considered suspicious by any one index test (Hausmann 2011;Pfannenberg 2007); and one reported in- cluding only lesions considered positive for melanoma on at least one index test (Pfluger 2011). Variation in lesion inclusion has the potential to reduce sensitivity in studies that included all lesions detected by any index test, as any metastases missed by any one test would count as false negative results in the contingency table; any missed benign lesions would be considered true negative results, but a large number of lesions would need to be missed to have any detectable effect on specificity.
The considerable clinical heterogeneity between studies in terms of population groups, stages of disease, lesion selection, differences between tests, and definitions of target conditions (either including or excluding imaging of the brain) means that no conclusions can be drawn from studies in mixed and not clearly described populations (Table 3; Appendix 9). Study results are therefore described narratively inAppendix 12.
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