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© 2001 American Society for Clinical Oncology Comparison of Positron Emission Tomography Scanning and Sentinel Node Biopsy in the Detection of Micrometastases of Primary Cutaneous Malignant MelanomaFrom the Skin Tumour Unit, Department of Dermatopathology, St John’s Institute of Dermatology; Departments of Plastic Surgery and Nuclear Medicine, Guys & St Thomas’ Hospital; and Department of Dermatology, King’s College Hospital, London, United Kingdom. Address reprint requests to K.M. Acland, Skin Tumour Unit, St John’s Institute of Dermatology, St Thomas’ Hospital, Lambeth Palace Rd, London SE1 7EH, United Kingdom.
PURPOSE: Sentinel node biopsy (SNB) is a surgical technique for detecting micrometastatic disease in the regional draining nodes. 2-fluorine-18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scanning is an imaging technique that can detect clinically undetectable metastases. This prospective study was undertaken to compare the sensitivity of FDG-PET scanning with SNB in the detection of micromatastatic malignant melanoma. PATIENTS AND METHODS: Fifty consecutive patients (23 women, 27 men; mean age, 53 years) with primary melanoma >1 mm thick or lymphatic invasion were recruited (mean, 2.41 mm). Primary lesions had been narrowly excised (<1 cm). Patients underwent PET scanning followed by SNB, using a dual technique. Preoperative lymphoscintigraphy was used to identify the draining basin. Lymph nodes were examined histologically and immunostained for S100 and HMB 45. RESULTS: The sentinel node (SN) was identified in all patients. Fourteen patients (28%) had positive SNBs, including eight patients with melanoma <1.5 mm thick. In none of these 14 patients did PET scans identify metastatic disease in the SN or draining basin. In seven patients, the PET scans were positive in other locations, and in four cases, this was suspicious of metastatic disease. However, no patient has developed recurrent melanoma (mean follow-up, 15 months). All patients with positive SNBs underwent therapeutic lymph node dissection. Further lymph node involvement was found in two patients (primary lesions, 1.3 mm and 3.5 mm thick). CONCLUSION: This study demonstrates the limitations of FDG-PET scanning in staging patients with primary melanoma. SNB is the only reliable method for identifying micrometastatic disease in the regional draining node.
IN THE United Kingdom, the incidence of malignant melanoma has increased by 4% per annum since 1973. Over the past decade, it has increased faster than any other cancer, except lung cancer in women. Although mortality has not risen as fast as incidence, there were 1,370 deaths from melanoma in the United Kingdom in 1997. The prognosis for primary cutaneous melanoma worsens with increasing Breslow thickness. This is probably because of micrometastatic spread of the disease before excision of the primary lesion. Metastatic spread within the regional draining basin has been shown to progress in an orderly fashion, and the first draining node (sentinel node [SN]) is the most likely to show metastatic disease. If this SN is histologically free from disease, then it is rare for other nodes to contain any melanoma cells. The technique of sentinel node biopsy (SNB) was developed by Morton et al1 who demonstrated a false-negative rate of less than 1%. SNB allows accurate staging at the time of diagnosis and identification of those patients who have microscopic stage 3 disease and are liable to relapse.2-4 A positive SNB has been found to carry greater prognostic significance than the Breslow thickness, and in addition, it identifies those patients who might benefit from early therapeutic intervention, whether this be early surgical intervention, adjuvant therapy with interferon, or vaccine treatment. However, SNB is an invasive procedure that may require general anesthesia as well as preoperative investigations to determine the regional draining basins. In addition, SNB will not demonstrate evidence of distant disease if present. Positron emission tomography (PET) is used for in vivo diagnosis of metastases in a number of malignancies. It relies on the increased tumor metabolism of glucose, thought to be caused by increased glycolysis and an increased hexokinase-glucose-6-phosphatase enzyme ratio. The increased glucose consumption has been shown to correlate with proliferation rate in some tumors.5 Thus a radioactive glucose moiety (2-fluorine-18-fluoro-2-deoxy-D-glucose [FDG]) is most commonly used. FDG-PET scanning has been reported to detect melanoma metastases as small as 3 mm in size and is, therefore, one of the most sensitive noninvasive imaging techniques available.6 The purpose of this study was to compare FDG-PET with SNB for identifying regional metastases in patients with primary cutaneous melanoma of Breslow thickness 1 mm or greater and to establish whether FDG-PET scanning provided any additional information in this group of patients.
Approval was obtained from the Institutional Ethics Committee. Fifty consecutive patients with a histologic diagnosis of malignant melanoma with Breslow thickness greater than 1 mm were recruited from the Dermatology Departments at St Thomas’ Hospital, Guy’s Hospital, and King’s College Hospital, London. Patients with primary lesions less than 1 mm were included if there was evidence of lymphatic invasion on histology. All were clinically examined to confirm that they had primary cutaneous melanoma. Exclusion criteria included pregnancy, diabetes, prior surgery to the draining basin, or a past history of hypersensitivity to the infusion materials. Patients who had had wide excision (greater than 1 cm margins) of the primary melanoma were also excluded because of potential disruption of lymphatic drainage patterns. Informed consent was obtained from all patients. All patients underwent PET scans and SNB, which was preceded by lymphoscintigraphy to establish the regional draining basin or basins. Baseline blood investigations, including full blood count, urea, and electrolytes and liver function tests, were also performed.
FDG-PET Scan Protocol All scans were evaluated qualitatively by visual inspection. Qualitative assessment was made by two nuclear medicine consultant physicians experienced in PET (M.O’D. and T.N.) with the specific aim of establishing whether there was evidence of metastatic disease or local recurrence. Low-grade uptake equivalent to, or just above, surrounding tissue was regarded as no evidence of malignancy; higher uptake was reported as suggestive of metastatic disease.
Lymphoscintigraphy Protocol Delayed images of the SN site were acquired at 3 hours to determine whether the SN was still visualized and also to investigate any drainage further along the lymphatic channel. Some patients had further static images at 24 hours to assess whether the SN could still be detected because the use of a hand-held gamma probe (in the operating theater) to localize the SN was dependent on radioactivity still being present in the node at this time.
SNB
Histology
Statistics
Fifty patients were included in the study, 23 women and 27 men. Ages ranged from 26 to 89 years (mean, 53 years). Primary lesions were 1 mm or greater, except for one patient with a lesion of 0.8 mm in which there was histologic evidence of lymphatic invasion. The mean thickness of the primary lesions was 2.41 mm, with a range of 0.8 mm to 10 mm. All lesions were in vertical growth phase; two lesions (Breslow thickness, 1.13 and 3.15) showed evidence of regression and two (Breslow thickness, 3.51 and 3.15) were ulcerated. One further acral lesion of 2.7 mm showed both lymphatic and vascular invasion. The primary lesions were predominantly on the limbs (n = 25) and on the trunk (n = 17), with the remainder (n = 8) on the head and neck. SNs were identified in all patients. The mean number of nodes removed in each patient was 2.8 (range, one to nine nodes). In all but three patients, there was only one draining basin identified on lymphoscintigraphy; and in these three patients, the primary lesions were on the nasal bridge, mid posterior thorax, and leg (popliteal and inguinal SNs). The mean follow-up time was 13 months (range, 5 to 26 months). Fourteen patients had positive SNBs. The Breslow thickness of these primary lesions ranged from 1.0 mm to 4.2 mm (mean, 1.93 mm). However eight primary lesions with positive nodes (57%) were less than 1.5 mm thick. All of these eight primary tumors showed vertical growth phase histologically, however only one lesion of 1.13 mm showed regression. Positive nodes were identified microscopically on hematoxylin and eosin staining as well as immunostaining in all but one patient, in whom there was one small nest of metastatic melanocytes initially identified by immunostaining alone. In none of these 14 patients did PET scanning identify metastatic disease in the same location, giving PET scanning a sensitivity of 0% (95% confidence interval, 0% to 23%). However, in seven patients, PET scans were positive in other sites. Three of these cases were felt to be due to causes other than malignant melanoma; these were physiologic uptake in the neck in two patients and increased gut uptake in the third patient. The remaining four cases were felt to represent malignant melanoma, and of these four patients, three had positive SNBs. The patient whose SN was negative had suspicious areas in the neck but is clinically free from disease and has had a normal computed tomography scan and repeat PET scan at 1 year. One of the three remaining patients had a papillary carcinoma of the thyroid on further investigation. In one other patient, the PET scan was suspicious of an intransit metastasis, but there is no clinical evidence of this after 15 months of follow-up. The final patient had a mediastinal focus, but a computed tomography scan was normal postoperatively, and there is no evidence of disease recurrence at 12 months follow-up. Therefore, we regard none of these four suspicious PET scans as representing melanoma metastasis. All 14 patients who had positive SNBs underwent therapeutic lymph node dissection. Further lymph node involvement was found in only two patients (14%), with primary lesions 1.3 mm and 3.5 mm thick. In both cases, only one additional lymph node was found to be involved histologically out of 18 and 16 nodes, respectively.
Relapse after wide excision of a primary melanoma is usually distant from the site of excision, most commonly in the regional nodes and less commonly in transit metastases or distant spread. This relapse is attributable to micrometastatic spread of disease before the primary excision. Melanoma in regional lymph nodes has been shown to spread in an orderly fashion, progressing first to a sentinel lymph node, which drains the area of skin on which the melanoma arose. Initially these small deposits are not clinically apparent but are the most likely cause of the decreased survival in those patients with primary lesions and no clinical evidence of extracutaneous spread. The assessment of patients with apparent cutaneous disease alone has proved difficult historically, and there is no worldwide consensus with regard to screening and staging investigations. Some authors recommend blood tests (full blood count and liver function tests) alone for American Joint Committee on Cancer stage 1 and 2,7 whereas others maintain that there is insufficient evidence that any investigations are worthwhile in patients with primary lesions less than 1 mm.8,9 Blood tests performed as a baseline investigation are relatively cheap and easy, but there is little evidence to suggest that they increase the detection of occult metastases,10 although elevated lactate dehydrogenase has been shown to be a sensitive marker for hepatic metastases.11 Many authors also perform a baseline chest x-ray for primary lesions more than 1 mm.12,13 However, the detection rate in asymptomatic patients is low and false-positive results are frequent, as demonstrated by one study that found that only 0.1% of routine chest x-rays were true positives but that 15% showed abnormalities that required further investigation.14 Similarly, scans of brain and bone in stage 1 melanoma using radiopharmaceuticals have also been shown to be unproductive.15-17 The role of computed tomography scans seems more controversial, its sensitivity has been found to be low and false-positive rates have been reported as high as 17%.18 However, some authors recommend its use because occasional occult lesions are detected.19 The development of SNB offers a staging procedure that seems to be highly sensitive with a low false-negative rate. Although minute deposits may be missed using conventional histology and immunostaining,20 the presence or absence of a positive SN has been shown to be the strongest predictor of survival.4,21,22 It does, however, have the disadvantage of being an invasive surgical procedure with documented complications. Recent interest has focused on PET scanning in the detection of metastatic disease. PET is potentially an ideal imaging modality for malignancy. It allows quick simultaneous assessment of both local and distant sites and, as a result of avid uptake of the glucose moiety, may potentially identify small tumor loads. Previous studies have demonstrated that it can routinely detect lesions 5 mm in diameter and report sensitivities from 88% to 100%.23-26 Some reports suggest it is capable of detecting metastases in clinically normal nodes as small as 3 mm in diameter.27-29 This study was designed to compare the sensitivity and specificity of PET scanning with SNB in the detection of micrometastatic disease in the regional nodes. In addition, it was hoped that the study would establish whether FDG-PET scanning provides any additional information on spread to distant sites in patients with or without a positive SNB. Our data clearly demonstrates that PET is not sufficiently sensitive to detect small deposits within clinically normal lymph nodes. No patients had nodal tumor detected by PET, even those cases in which more than one node contained micrometastases. PET cannot, therefore, be used as a sensitive staging investigation in primary cutaneous malignant melanoma. This result is, perhaps, unsurprising because one might predict that there would be a minimum volume of tumor that a dynamic scanning procedure would be able to detect. Thus, one would not expect a small collection of melanoma cells, 30 µm in diameter, to be detected by an imaging technique with a reported lower limit of 3 mm, which is two orders of magnitude greater in diameter. Although, in this study, the tumor volume of the positive nodes was not calculated in all cases, it was microscopic and sometimes only a few cells in diameter. A recent study by Wagner et al30 found that the average tumor volume in lymph nodes was 4.3 mm3 in patients with primary cutaneous disease undergoing SNB. The same study also concluded that PET scanning had a low sensitivity for the detection of occult lymph node disease, with only two out of 18 positive SNB found to be positive, yielding a sensitivity of 11%. This same study reported as many as 12 possible false positives at distant sites in 10 patients. The mean Breslow thickness in our study was 1.9 mm, and 28% of patients (14 of 50) had micrometastatic disease detected by SNB. This is higher than other trials, which have reported overall rates of 15%, 18%, and 20%.31-33 In our study, the percentage of positive SNBs was higher in those patients with thinner lesions, 36% for melanomas less than 1.5 mm and 23% in those with thicker lesions. We feel that this is likely to be due to the small sample size because most other studies report rates of 10% or less with melanomas of Breslow thickness less than 1.5 mm.34 It does, however, emphasize the value of SNB in patients with stage I disease. Our study was also notable in that SNs were identified in 100% of patients in this study. This emphasizes the important role of using a dual technique employing both blue dye and radiolabeled colloid accompanied by preoperative lymphoscintigraphy for operative localization.35,36 In conclusion, our study demonstrates a high incidence of positive SNB, even in patients with thin lesions. Detection of these metastases can only be achieved reliably by SNB. We believe this should be the routine staging procedure in all patients with cutaneous malignant melanoma greater than 1 mm thick and in all melanomas showing a vertical growth phase or evidence of lymphatic invasion histologically. FDG-PET has little to contribute as a staging procedure in this group of patients.
We thank P. Seed for statistical analysis.
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Gershenwald JE, Thompson W, Mansfield PF, et al: Multi-institutional melanoma lymphatic mapping experience: The prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17: 976-983, 1999 22. Shivers SC, Wang X, Li W, et al: Molecular staging of malignant melanoma: Correlation with clinical outcome. JAMA 280: 1410-1415, 1998 23. Macfarlane DJ, Sandak V, Johnson T, et al: Prospective evaluation of 2-(18F)-2-deoxy-D-glucose positron emission tomography in staging of regional lymph nodes in patients with cutaneous malignant melanoma. J Clin Oncol 16: 1770-1776, 1998[Abstract] 24. Boni R, Huch Boni RA, Steinert H, et al: Staging of malignant melanoma by whole body positron emission tomography using 2-fluorine-18-fluoro-2-Deoxy-D-glucose. Br J Dermatol 132: 556-562, 1995[Medline] 25. Holder WD, White RL, Zuger JH, et al: Effectiveness of positron emission tomography for the detection of melanoma metastases. Ann Surg 227: 764-771, 1998[Medline] 26. Rinne D, Baum RP, Hor G, et al: Primary staging and follow up of high risk melanoma patients with whole body 18F-fluorodeoxyglucose positron emission tomography. Cancer 82: 1664-71, 1998[Medline]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
10 MBq of 99Tcm-labeled nanocolloid (particle size: > 95% is < 80 nm) were injected around the melanoma site. Dynamic images of 1 minute per frame were acquired over the suspected draining site to identify draining lymphatic channels and continued until the first node(s) was visualized (the SN). This region varied according to the melanoma site being either inguinal or axillary and sometimes included the injection site within the imaging field-of-view. Static images of the SN were acquired in both anterior/posterior and lateral projections with the position of the SN being marked on the skin surface. 
