Ann Surg Oncol DOI 10.1245/s10434-016-5142-2
ORIGINAL ARTICLE – MELANOMAS
The Diagnostic Value of PET/CT Imaging in Melanoma Groin Metastases Julia van Wissen, MD1, Bernies van der Hiel, MD2, Jos A. van der Hage, MD, PhD1, Bart A. van de Wiel, MD3, Michel W. J. M. Wouters, MD, PhD1, and Alexander C. J. van Akkooi, MD, PhD1 1
Department of Surgical Oncology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; 2Department of Nuclear Medicine, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; 3Department of Pathology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
ABSTRACT Background. Combined superficial (inguinal) and deep (iliac and obturator) groin dissection (CGD) is the standard treatment of patients with stage IIIB and IIIC melanoma groin metastases; however, the additional value of iliac lymphadenectomy is debated. In our institute, imaging with positron emission tomography/computed tomography (PET/CT) is part of the regular preoperative work-up. The aim of this study was to evaluate the diagnostic value of PET/CT in detecting iliac lymph node metastases. Patients and Methods. This retrospective study included 70 melanoma patients with stage IIIB or IIIC melanoma and an indication for therapeutic CGD, who were treated at our institution between 2003 and 2013. Median diseasefree survival (DFS) was 9 months and median follow-up time was 16 months. The results of PET/CT were compared with the results of pathological analysis after CGD. Additional quantitative analysis of PET/CT imaging was performed. Results. For superficial melanoma groin metastases, sensitivity of PET/CT was 97 %, specificity was 50 %, positive predictive value (PPV) was 90 %, and negative predictive value (NPV) was 71 %. For iliac lymph node metastases, sensitivity of PET/CT was 67 %, specificity was 91 %, PPV was 73 %, NPV was 81 %, and false negative rate was 33 %. Conclusions. The results of this retrospective study indicate that PET/CT imaging could be a valuable method in
Ó Society of Surgical Oncology 2016 First Received: 19 September 2015 J. van Wissen, MD e-mail:
[email protected]
preoperative work-up in this patient category; however, PET/CT alone should not be used as a tool to determine the extent of surgery, since one-third of patients with iliac lymph node involvement will be missed on PET/CT.
Since the introduction of the sentinel node (SN) procedure in melanoma, the number of patients presenting with palpable nodal (macroscopic) stage IIIB disease has dropped significantly. Nevertheless, a significant amount of patients either present with a synchronous palpable node at initial diagnosis or develop a regional or distant nodal recurrence during follow-up.1 Worldwide, there is consensus amongst surgeons that patients with resectable melanoma groin metastases, in the absence of disseminated disease, are eligible for potentially curative surgical treatment; however, there is ongoing debate on the extent of this curative surgical approach. Most centers propagate combined superficial and deep groin dissection (CGD) as the standard treatment for melanoma groin metastases. In CGD, both the superficial (the femoral and inguinal nodes) and deep nodes (the external iliac nodes up to the common iliac artery and the obturator nodes) are dissected. This technique provides additional prognostic information, optimal regional control, and longterm survival in approximately 20–25 % of patients.2–8 However, the additional therapeutic value of iliac lymph node dissection in patients with palpable melanoma groin metastases remains a topic of debate and some centers advocate to only perform a superficial groin dissection (SGD). Survival and local control depends more on the extent of the disease rather than on the extent of surgery, where iliac involvement is seen as a symptom of disseminated (stage IV) disease.2,9–12 Moreover, some have
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suggested that limiting the operation to the SGD has clear benefits to the patient with respect to a shorter operation time, shorter hospital stay, and a lower complication rate.13,14 The aim of this study was to evaluate the diagnostic accuracy of positron emission tomography/computed tomography (PET/CT) in detecting iliac lymph node metastases of the groin in patients with stage IIIB and IIIC melanoma by comparing the preoperative PET/CT images with the postoperative pathological analysis.
In addition to this visual assessment, semi-quantitative analysis was performed on all PET/CT scans, measuring the maximum standard uptake value (SUVmax) of the most FDG-avid lymph node in the iliac as well as inguinal region of the patient. Furthermore, we conducted additional analyses by investigating the SUVmax cut-off point for detecting lymph node metastases, based on the method described by Koolen et al.15 We observed that with an SUVmax cut-off point of 4.00, the false-negative and false-positive rate was optimal. Surgical Procedure
PATIENTS AND METHODS Patients All patients with stage IIIB or IIIC melanoma treated at The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital (NCI–AVL), Amsterdam, The Netherlands, between 2003 and 2013 were included in this study, and all patients were selected for therapeutic CGD. Patients who did not have fludeoxyglucose (FDG) PET/CT imaging prior to surgery or who underwent SGD only were excluded from this analysis. Patient and tumor characteristics, PET/CT imaging results, treatment characteristics, pathological analysis, and follow-up data were retrospectively collected in a database for this study.
CGD was performed either via two separate incisions or with one single longitudinal incision; this decision was based on the surgeon’s personal preference. In case of two separate incisions, the iliac groin dissection was performed through a transverse incision approximately 5 cm above the inguinal ligament and a second transverse incision approximately 2–3 cm below the inguinal ligament. In all cases, the following lymph nodes were dissected: the femoral–inguinal nodes (SGD), the external iliac nodes up to the common iliac artery, and the obturator nodes. The dissected lymph nodes and surrounding tissues were marked using a fixed pattern of colored beads and directly sent to the pathologist for further examination. Pathological Analysis
Positron Emission Tomography/Computed Tomography (PET/CT) PET/CT scans were performed using a hybrid PET/CT scanner (Gemini II; Philips, Eindhoven, The Netherlands). 18 F-FDG was intravenously administered at a dosage of 180–240 MBq after a fasting period of 6 h and adequate fluid intake. Whole-body acquisitions were performed according to standard acquisition protocols, and low-dose CT images (40 mAs, 2–5 mm slices) were acquired without intravenous contrast. PET was fused with the low-dose CT after correction for attenuation. PET/CT imaging characteristics, i.e. blood glucose levels, injected dose (MBq) and incubation period were documented, along with time interval between PET/CT and previous SN procedure or fine-needle aspiration prior to surgery. The generated images were displayed using an Osirix Dicom viewer in a UNIX-based operating system (MAC OS X, Apple, Cupertino, CA, USA). A single expert nuclear medicine physician (BvdH) reviewed all PET/CT scans. Characteristics on which a lymph node was diagnosed as negative, positive, or indeterminate were the intensity of FDG uptake with respect to the size of the lymph node, background, and other lymph nodes in the surrounding tissue or at the contralateral side.
Pathological analysis was performed by different pathologists at our institution during the period of this study. A single expert pathologist (BvdW) reviewed all pathology reports and, when necessary, the available macroscopic pictures/stored material for the purpose of the current study. The total number of excised lymph nodes and number of metastatic lymph nodes were evaluated. A distinction was made between superficial (femoral–inguinal), and deep (external iliac up-to the common iliac artery and obturator nodes) lymph nodes. In addition, extracapsular extension was evaluated. Statistics Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and false negative rate (FNR) of PET/CT imaging in detecting inguinal and/or iliac groin metastasis was calculated by comparing PET/ CT imaging results with the pathological results. Disease-free survival (DFS) was calculated from the date of CGD to the date of first recurrence (any site; local, regional and/or distant), while overall survival (OS) was calculated from the date of CGD to the date of death, regardless of the cause of death. DFS and OS were
The Diagnostic Value of PET/CT Imaging in Melanoma Groin Metastases TABLE 1 Baseline patient, tumor and surgery characteristics
TABLE 1 continued
Combined groin dissections [n = 70] Sex
Combined groin dissections [n = 70] 30-day complications
Female
35 (50)
Surgical site infection
13 (17)
Male
35 (50)
Postoperative hemorrhage
4 (6)
58 (24–83)
Cellulitis
2 (3)
Postoperative fever
1 (1)
Other
3 (4)
Age, years Location of primary tumour Leg
58 (83)
Arm Trunk
0 (0) 6 (9)
Missing/unknown
6 (9)
Breslow thickness, mm B1.00
6 (9)
B2.00
15 (21)
2.01 B 4.00
15 (21)
[4.00
12 (17)
Missing/unknown
22 (31)
Ulceration Absent
19 (27)
Present
11(16)
Missing/unknown
40 (57)
Mean number of dissected inguinal nodes
10 (3–27)
Mean number of positive inguinal nodes 0 1
10 (14) 32 (46)
2–3
15 (22)
C4
12 (17)
Missing/unknown
1 (1)
Mean number of dissected iliac nodes
6 (1–15)
Mean number of positive iliac nodes 0
47 (67)
1
10 (14)
2–3
5 (7)
C4
5 (7)
Missing/unknown
3 (4)
Mean number of dissected obturator nodes
6 (1–9)
Data are expressed as n (%) or median (range) TABLE 2 Results of positron emission tomography/computed tomography imaging compared with pathologic analysis for superficial and deep lymph node metastasis PA?
PA-
Missing/ unknown PA
Total
63
Superficial lymph node metastasis PET/CT?
57
5
1
PET/CT-
1
5
0
6
PET/CT±a
1
0
0
1
59
10
1
70
Total
Deep lymph node metastasis PET/CT?
16
4
2
22
PET/CT-
6
35
1
42
PET/CT±a
2
4
0
6
24
43
3
70
Total
Superficial lymph node metastasis: sensitivity = 57/59 = 97 %, specificity = 5/10 = 50 %, PPV = 57/63 = 90 %, NPV = 5/ 7 = 71 % Deep lymph node metastasis: sensitivity = 16/24 = 67 %, specificity = 39/43 = 91 %, PPV = 16/22 = 73 %, NPV = 39/ 48 = 81 % PET/CT positron emission tomography/computed tomography, PA pathologic analysis, PPV positive predictive value, NPV negative predictive value a
PET/CT marked with ± indicates doubtful scan results and was regarded as a negative result in order to calculate sensitivity, specificity, PPV, and NPV of PET/CT imaging
Mean number of positive obturator nodes 0
28 (40)
1
7 (10)
2–3 C4
2 (3) 1 (1)
Missing/unknown
32 (46)
visualized using Kaplan–Meier curves. All statistics were performed using SPSS version 22.0 (released 2013, IBM SPSS Statistics for Windows or Mac; IBM Corporation, Armonk, NY, USA). RESULTS
Extracapsular invasion Absent
56 (81)
Present
14 (19)
Missing/unknown
0 (0)
Operative time, min
156 (40–540)
Length of stay, days
6 (3–37)
Baseline Patient Characteristics In total, 179 patients presented with palpable nodal stage IIIB and IIIC melanoma and an indication for therapeutic lymph node dissection of the groin, 49 patients were
J. van Wissen et al. TABLE 3 Analysis of cut-off point for SUVmax
TABLE 4 Results of SUVmax and the largest node on computed tomography compared with pathologic analysis for deep lymph node metastasis
SUVmax
PA-
PA?
Missing/unknown PA
1.60
0
1
0
1.80
1
0
0
2.10
1
0
0
2.20
1
0
0
2.20
0
1
0
2.30
1
0
0
2.40
0
1
0
2.50
1
0
0
2.90
0
1
0
3.00
1
0
0
3.20 3.60
1 0
0 0
0 1
SUVmax: sensitivity = 11/15 = 73 %, specificity = 9/10 = 90 %, PPV = 11/12 = 92 %, NPV = 9/13 = 69 %
3.80
1
0
0
3.90
1
0
0
Largest node: sensitivity = 12/15 = 80 %, specificity = 8/ 12 = 67 %, PPV = 12/16 = 75 %, NPV = 8/11 = 73 %
4.00
0
1
0
4.90
0
1
0
5.20
1
0
0
6.90
0
1
0
10.00
0
1
0
11.00
0
1
0
11.10
0
1
0
12.10
0
1
0
13.00
0
0
1
13.20
0
1
0
16.60
0
1
0
20.40
0
1
0
44.40
0
1
0
SUVmax maximum standard uptake value, PA pathologic analysis
excluded because preoperative PET/CT was not performed, 30 patients were excluded because they only underwent SGD, 13 patients were excluded because they underwent a completion lymph node dissection after an SN, 5 patients were excluded because they only underwent iliac groin dissection, and 8 patients were excluded because PET/CT was not available for re-evaluation (performed at the referring centre). Finally, four patients were excluded for various other reasons. Thus, a total of 70 patients were included in this study. All operations were performed between 2003 and 2013 at the NCI–AVL, Amsterdam, The Netherlands. Median follow up was 16 months (range 0–71 months), and median age was 58 years (range 24–83 years) on the day of surgery. Baseline patient, tumor, and treatment characteristics are shown in Table 1.
PA?
PA-
Total
SUVmax C4
11
1
12
\4 Total
4 15
9 10
13 25 16
Size of largest node on CT, mm [10
12
4
\10
3
8
11
Total
15
12
27
SUVmax maximum standard uptake value, PA pathologic analysis, CT computed tomography, PPV positive predictive value, NPV negative predictive value
Preoperative PET/CT Imaging and Pathological Examination All included patients were staged with FDG PET/CT. With regard to the superficial lymph node involvement, 63 (90 %) patients showed superficial groin lymph node involvement (PET/CT-positive), 6 patients (9 %) showed no superficial groin lymph node involvement (PET/CTnegative), and in 1 (1 %) patient the PET/CT scan was indeterminate. With regard to iliac lymph node involvement, 22 patients (31 %) showed PET/CT-positive lesions, PET/CT was negative in 42 (60 %) patients, and PET/CT was indeterminate in 6 (9 %) patients. The diagnostic accuracy of PET/CT imaging for inguinal and iliac lymph node metastases is shown in Table 2. Of the 63 patients diagnosed with positive inguinal lymph node involvement by PET/CT imaging, 57 were confirmed by pathological examination. Of the 22 patients diagnosed with positive iliac lymph node involvement by PET/CT imaging, 16 were confirmed by pathological examination, 4 were confirmed as negative, and the pathological report was not available/missing in 2 patients. Of 42 patients with a negative PET/CT, 6 patients (14 %) had positive iliac lymph nodes after pathologic examination. Sensitivity of PET/CT for detection of inguinal lymph node metastases was 97 %, specificity was 50 %, PPV was 90 %, and NPV was 71 %. Sensitivity of PET/CT for detection of iliac lymph node metastases was 67 %, specificity was 91 %, PPV was 73 %, and NPV was 81 %, respectively.
The Diagnostic Value of PET/CT Imaging in Melanoma Groin Metastases
A
1,0
0,8 negative iliac nodes (PET/CT)
0,6 positive iliac nodes (PET/CT)
0,4
0,2
0,0 ,00
1,00
2,00
3,00
4,00
5,00
6,00
Disease Free Survival Rate (proportion)
Overall Survival Rate (proportion)
A
1,0
0,8
0,6
0,4
0,2
0,0
Time (years)
,00
1,00
2,00
3,00
4,00
5,00
6,00
5,00
6,00
Time (years) 1,0
B
0,8 negative iliac nodes (PA)
0,6
0,4 positive iliac nodes (PA)
0,2
0,0 ,00
1,00
2,00
3,00
4,00
5,00
6,00
Time (years)
Overall Survival Rate (proportion)
Overall Survival Rate (proportion)
B
1,0
0,8
0,6
0,4
0,2
0,0 ,00
1,00
2,00
3,00
4,00
Time (years)
FIG. 1 Survival curves comparing a positive and negative iliac nodes detected by PET/CT imaging and b positive and negative iliac nodes examined by PA. PET/CT positron emission tomography/computed tomography, PA pathologic analysis
FNR for inguinal nodal involvement was 3, and 33 % for iliac nodal involvement. The results of semi-quantitative analysis of PET/CT imaging, i.e. the SUVmax in patients with and without lymph node metastases and the cut-off point of 10 mm of the largest iliac node on CT, are shown in Tables 3 and 4, respectively. We found that when taking a cut-off point of 4.0, the sensitivity of SUVmax is higher than the standard visual assessment of PET/CT imaging (73 % with an SUVmax cut-off of 4.0 vs. 67 % with visual assessment) and the specificity is more or less the same (90 vs. 91 %). If we take the size of the largest node on CT with a cut-off point of 10 mm, the sensitivity is even higher but the specificity is lower compared with the standard visual assessment of PET/CT imaging and the SUVmax with a cutoff point of 4.0. These results suggest that the visual assessment of PET/CT is less accurate than semi-quantitative measures of PET/CT imaging, and that the standard evaluation should be reassessed.
FIG. 2 Survival curves of a disease-free survival and b overall survival
Recurrences The locoregional recurrence rate (i.e. lymph node metastasis, local recurrence, satellites, or in-transit metastasis) was 54 % (38/70), and 46 % (32/70) developed distant metastases. At the time of last follow-up, 20 of 70 patients had died (29 %). The median time to first locoregional recurrence was 6 months (range 0– 30 months), and median time to distant metastasis was 9 months (range 0–37 months). Survival Analyses The 5-year Kaplan–Meier estimated DFS and OS curves are shown in Fig. 1a and b. The 3- and 5-year DFS rates of the total group were 28 and 8 %, respectively, and the 3and 5-year OS rates of the total group were 66 and 45 %, respectively.
J. van Wissen et al.
The 5-year Kaplan–Meier estimated OS rates comparing patients with positive and negative iliac lymph node involvement detected by PET/CT are shown in Fig. 2a. PET-positive patients had 3- and 5-year estimated OS rates of 68 and 45 % versus 62 and 47 % for PET-negative patients (non-significant). The 5-year Kaplan–Meier estimated OS rates comparing patients with positive and negative iliac lymph node involvement detected by pathology are shown in Fig. 2b. Pathology-positive patients had 3- and 5-year estimated OS rates of 38 and 19 % versus 81 and 65 % for pathologicalnegative patients (p = 0.003). DISCUSSION In our study, sensitivity of visual assessment of PET/CT imaging for detecting inguinal lymph node metastases was 97 % and specificity was 50 %. Sensitivity of PET/CT imaging for the detection of iliac lymph node metastases was 67 % and specificity was 91 %. We expected the high sensitivity for detection of inguinal nodal metastases, but the low sensitivity (and high FNR) for inguinal nodal metastases does not allow us to safely exclude these patients from iliac lymphadenectomy. The high FNR for the detection of inguinal metastases is partially explained by the fact that seven of ten patients had a diagnostic resection of a lymph node prior to the lymph node dissection. The PET/CT is likely to have shown inflammation after this resection rather than residual disease in the groin. For this reason, the sensitivity we calculated is distorted. Semi-quantitative analysis with an SUVmax cut-off value of 4.0 showed a sensitivity of 73 %, with a specificity of 90 % in patients with iliac lymph node metastases. These results indicate that compared with visual assessment of PET/CT imaging, semi-quantitative analysis with an SUVmax cut-off value appears to be a more sensitive method for detecting lymph node metastases, but would still lead to an FNR of 27 %. We analyzed the false negative and false positive results regarding the semi-quantitative analysis with an SUVmax cut-off point of 4.0. In total, four false-negative results were observed, and the pathologic examination of one of these false-negatives showed focal necrosis. In addition, this scan was assessed as positive upon visual assessment of the PET/CT imaging. The other three false-negatives remained unexplained. Only one false-positive was noted in this analysis. This patient had an unknown primary tumor, and pathologic examination showed a necrotic inguinal node. Thus, it is conceivable that the iliac nodes were reactive to the necrotic inguinal node. We also analyzed the false-negative and false-positive results with regard to the size of the largest iliac node with a cut-off
point of 10 mm, which demonstrated similar results as above. Our results suggest that, in addition to the standard visual assessment of PET/CT imaging, the nuclear medicine physician should always measure the SUVmax and the size of the largest iliac node. Survival rates were significantly lower in patients with iliac lymph node involvement on pathological examination compared with patients with only superficial lymph node involvement. At the same time, survival curves according to PET/CT involvement were not significantly different, indicating that visual assessment alone of PET/CT is not reliable enough to differentiate between inguinal and iliac involvement. We acknowledge that our study has several limitations. First, in this retrospective study we only selected patients who had PET/CT imaging before surgery and who underwent a CGD. In this way, only a minority of stage IIIB and IIIC patients treated at our institute were included, which might introduce a bias. At the same time, it does not capture the value of PET/CT for the detection of distant metastases, which upstaged patients to stage IV. Second, we chose to merge patients with stage IIIB and IIIC disease. Although we recognize that patients with stage IIIB have a different tumor biology and prognosis compared with patients with IIIC disease, both groups are considered high risk and could have potential iliac involvement. Third, there is a large amount of primary tumor data missing/unknown. Our missing/unknown data is partially explained by the fact that a large proportion of our patients were initially treated for their primary tumor at other hospitals, and sometimes years prior to the current groin dissection. In addition, other cases related to unknown primary tumors. However, as the aim of our study was to evaluate the diagnostic value of PET/CT imaging in patients with palpable node (N1b, N2b, N3) stage IIIB and IIIC disease, we do not believe that this missing/unknown data will have much impact on the outcome; it could only change from stage IIIB to IIIC in case of ulceration. Fourth, because of the small number of patients with iliac lymph node involvement, the calculated sensitivity, specificity, PPV, and NPV rates could more or less easily be significantly influenced by a single event. Thus, the power of our small, single-center retrospective study is limited. Fifth, we used the initial pathologic examination as a gold standard; however, it is possible that if we examined the iliac nodes more extensively, by including immunohistochemical staining, we would have detected more positive nodes. Finally, some PET/CTs were performed elsewhere and were only seen for re-evaluation at our center. The quality of PET/CT equipment has improved and the new scanners might achieve a higher diagnostic accuracy than that seen during the period of this study.
The Diagnostic Value of PET/CT Imaging in Melanoma Groin Metastases
Our results are in line with a recent study by van der Ploeg et al.14, who investigated the accuracy of CT in detecting iliac lymph node involvement. These investigators found a sensitivity of 71.4 %, specificity of 85.1 %, PPV of 58.8 %, and NPV of 90.9 %; however, a limitation of this study was its limited power. Furthermore, they showed that survival and local control did not differ for patients with palpable groin metastasis treated with CGD or SGD.14 Shada and Slingluff16 showed that SGD provides good regional control in patients without iliac lymph node involvement on CT. There is a need for a larger prospective study to evaluate the diagnostic value of preoperative PET/CT imaging in the surgical management of melanoma groin metastases. CONCLUSIONS The current study demonstrated that preoperative PET/ CT could accurately demonstrate superficial groin melanoma metastases, although PET/CT cannot safely rule out deep groin (iliac/obturator) involvement. Although semiquantitative analysis of PET/CT imaging could be a valuable addition to standard assessment, at this moment PET/ CT alone is not yet useful for clinical decision making for the extent of surgery; however, the results of PET/CT imaging should be a part of the total risk analysis in patients with melanoma groin metastasis. DISCLOSURE Julia van Wissen, Bernies van der Hiel, Jos A. van der Hage, Bart A. van de Wiel, Michel W.J.M. Wouters, and Alexander C.J. van Akkooi have no relevant conflicts of interest to disclose.
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