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© 1999 American Society for Clinical Oncology Prospective Study of Fluorodeoxyglucose–Positron Emission Tomography Imaging of Lymph Node Basins in Melanoma Patients Undergoing Sentinel Node BiopsyFrom the Departments of Surgery, Radiology, Pathology, Medicine, and Biostatistics, Indiana University School of Medicine, Indiana University–Purdue University at Indianapolis, Indianapolis, IN. Address reprint requests to Jeffrey D. Wagner, MD, RT 471, Cancer Pavilion Building, 535 Barnhill Dr, Indianapolis, IN 46202.
PURPOSE: To prospectively compare positron emission tomography (PET) imaging of regional lymph node basins to sentinel node biopsy (SNB) in patients with American Joint Committee on Cancer (AJCC) stage I, II, and III melanoma localized to the skin. METHODS: Patients with cutaneous melanoma with Breslow's depth greater than 1 mm (AJCC T2-4N0M0) or localized regional cutaneous recurrence (TxN2bM0) underwent whole-body imaging of glucose metabolism with fluorodeoxyglucose (FDG) PET followed by SNB. PET scans were interpreted in a blinded fashion and compared with histologic analyses of SNB specimens and clinical follow-up examination. Nodal tumor volumes were estimated. RESULTS: Eighty-nine lymph node basins were evaluated by FDG-PET and SNB in 70 assessable patients. Eighteen patients (25.7%) had lymph node metastases at the time of FDG-PET imaging: 17 proved by SNB (24.3%) and one by follow-up examination (1.4%). Median tumor volume in positive sentinel node basins was 4.3 mm3 (range, 0.07 to 523 mm3). Sensitivity of SNB for detection of occult regional lymph node metastases was 94.4%, specificity was 100%, positive predictive value (PPV) was 100%, and negative predictive value (NPV) was 98.6%. Sensitivity of FDG-PET was 16.7%, specificity was 95.8%, PPV was 50%, and NPV was 81.9%. At a median follow-up duration of 16.6 months, seven patients (10%) developed recurrent disease. PET predicted one recurrence (14.3%) in a node basin missed by SNB. CONCLUSION: FDG-PET is an insensitive indicator of occult regional lymph node metastases in patients with melanoma because of the minute tumor volumes in this population. FDG-PET does not have a primary role for staging regional nodes in patients with clinically localized melanoma.
CUTANEOUS MELANOMA is rapidly increasing in incidence in the United States and elsewhere.1-4 By virtue of its metastatic potential, melanoma easily accounts for the vast majority of deaths from cutaneous neoplasms. Early recognition and surgical excision is the treatment of choice for both primary lesions and clinically obvious regional lymph node metastases. Most patients with locoregional disease can be rendered clinically free of disease, but many with deep primary lesions or regional lymphatic metastases will later die from distant metastatic disease. Identification of the patient with occult melanoma metastases is important for accurate staging, treatment planning, and prognosis. Factors predictive of treatment failure in patients with melanoma have been identified, including increasing tumor thickness, axial tumor location, ulceration, male sex, and increased age.5-7 However, prognostic factors only identify the patient at increased risk for recurrence in a population, without identifying individuals who will actually experience recurrence. Improvements in staging of melanoma patients have been sought. The most clinically useful techniques rely on surgical interrogation of regional lymph node basins, which are the most common site of melanoma metastases. The recent development of sentinel node biopsy (SNB) technology by Morton and other investigators has been an important advance in the treatment of patients with melanoma.8-11 The histologic status of the sentinel node (SN) has been shown to be an important prognostic factor in melanoma.12,13 However, SNB still cannot directly identify patients with occult distant metastatic disease. Accurate noninvasive staging of the individual melanoma patient remains problematic. Anatomic imaging studies such as computed tomography (CT) and magnetic resonance imaging (MRI) rely on morphologic alterations at secondary tumor sites. They are inherently insensitive and nonspecific for locating small metastatic tumor deposits.14,15 Other efforts have focused on detecting distant metastases, including gallium scintigraphy and immunoscintigraphy using monoclonal antibodies against melanoma-associated antigens, without significant improvements in diagnostic sensitivity.16-18 Recent interest has been directed toward metabolic imaging with positron emission tomography (PET) using fluorodeoxyglucose (FDG), which theoretically can show smaller deposits of metastatic tumor. Retrospective and prospective studies have reported FDG-PET to be a sensitive indicator of metastatic melanoma compared with conventional diagnostic imaging modalities.19-27 The improved sensitivity and potential cost-effectiveness of FDG-PET are rational arguments for PET staging of patients with recurrent melanoma.28 Table 1 summarizes the literature pertaining to PET imaging for metastatic melanoma.
The role of FDG-PET in current clinical care algorithms for patients with clinically localized melanoma has not been defined. Although providing useful information on the ability of FDG-PET to detect metastatic melanoma, existing studies are flawed because they compare FDG-PET to clinical examination or to imaging studies, both of which are known to be inadequate for detection of occult metastatic melanoma. Prior studies are limited by inconsistent histologic confirmation or by confirmation of only positive PET results. No prospective studies exist that compare FDG-PET to histologic analysis of SN tissues, the current gold standard for staging of regional node basins in patients with clinically normal lymph nodes. The present prospective study was designed to provide definitive information on the ability of FDG-PET to detect occult regional lymph node metastases in patients with clinically localized cutaneous melanoma.
A prospective nonrandomized clinical research study of adult patients with cutaneous melanoma was conducted at Indiana University Medical Center and affiliated hospitals through the Indiana University Cancer Center Interdisciplinary Melanoma Program. The study protocol and informed consent statement were reviewed and approved by the Indiana University–Purdue University at Indianapolis Institutional Review Board. All subjects gave voluntary written informed consent to participate in the study. The study schema is shown in Fig 1. Adult patients (at least 18 years of age) with biopsy-proven primary cutaneous melanoma with Breslow's thickness greater than 1 mm (American Joint Committee on Cancer [AJCC] stage T2-4N0M0) or locally recurrent melanoma after prior excision (AJCC stage TxN2bM0) were eligible for participation.29 Criteria for exclusion were as follows: ocular or mucosal melanomas; any clinical evidence of regional lymph node basin metastases or distant metastatic (M1) disease; palpable lymphadenopathy; infection or inflammation in the regional node basin(s); prior wide excision greater than 4 cm in diameter; lymph node dissections; skin grafts, tissue transfers, or flaps that may alter the lymphatic drainage pattern from the primary tumor site to the regional nodal basin(s); pregnancy or breast feeding; prior malignancy (except in situ lesions, stage I basal and squamous cell skin malignancies, and patients without evidence of disease > 5 years after treatment); and allergy to isosulfan blue dye or FDG.
Prestudy Staging
PET Techniques During the latter portion of the study (subjects 25 to 74), a high-sensitivity scanning protocol for the regional lymph node basin(s) was used. The protocol was similar, but scanning began 60 minutes after injection. Multiple bed PET images were obtained over the lymph node basin(s) of interest, with scan duration of 10 minutes at each position. Depending on the location of the cutaneous melanoma tumor, the following lymph node basins were imaged: for melanomas of the face and scalp, bilateral parotids, cervical, and suboccipital basins; for melanomas of the neck, bilateral cervical basins; for melanomas of the shoulder and upper chest (above the level of the nipples), bilateral axillary and cervical basins; for melanomas of the upper extremity, ipsilateral axillary basin (including the epitrochlear region if below the elbow); for melanomas of the trunk, at or below the nipples, bilateral axillary and bilateral inguinal basins; for melanomas of the lower extremity, ipsilateral inguinal and pelvic basins (including the popliteal region if below the knee). Immediately after a 5-minute-per-bed position transmission study, the dose of FDG was injected. At 60 minutes after injection, emission scans were performed over the same regions of the body for 10 minutes at each bed position. Finally, a whole-body study was performed (without attenuation correction) as a screen for distant metastatic disease.
PET Data Interpretation PET images for research interpretation purposes were derived from an ordered subset expectation maximization (OSEM) data reconstruction algorithm, when possible. Knowing only the location of the melanoma tumor, a single nuclear medicine specialist experienced in FDG-PET melanoma imaging performed PET interpretations in a blinded fashion using a receiver operating characteristic (ROC). The researcher interpreted OSEM reconstruction images (or best FBP reconstruction images) and assigned each lymph node basin at risk for occult disease a reading of definitely positive, probably positive, uncertain, probably negative, or definitely negative. Standardized uptake values were calculated to obtain quantitative information on the FDG uptake. Strong focal hypermetabolic lesions (standardized uptake value > 2.5) were generally considered malignant. However, the definite decision for classifying a focus as a metastasis was based on the visual evaluation, with appropriate consideration to location, symmetry, and uptake pattern. The research interpretation also evaluated for possible foci of distant metastases using the original data set.
Lymphatic Mapping/SNB Procedures After the induction of anesthesia, 0.5 to 2.0 mL of Lymphazurin Blue (Zenith Parenterals, Rosemont, IL) was injected intradermally around the site of the cutaneous tumor just before skin preparation. All basins identified by lymphoscinitgraphy were explored through incisions directed by the use of a hand-held gamma probe (C-Track; Care Wise Medical Products, Morgan Hill, CA). All blue nodes were removed as SNs. Ex vivo SN to residual node basin radioactivity ratios were calculated. If necessary, additional hot nodes were removed until the ratio of the hottest ex vivo SN to residual node basin was at least 10:1. If frozen section or permanent section analysis of SN specimens showed evidence of metastatic melanoma, complete regional lymphadenectomy was performed on the involved basin(s).
Histologic Analysis of Surgical Specimens Nonsentinel nodes (NSN) and completion lymphadenectomy specimens were analyzed in routine fashion after formalin fixation, with one to three sections from the central region of the node(s) reserved for hematoxylin-eosin staining.
Determination of Lymph Node Tumor Volumes
Statistical Analysis
Seventy-four subjects signed informed consent and were enrolled onto the study. The patient population included 40 men (54%) and 34 women (46%) with an age range of 28 to 79 years (mean, 53.9 years). Seventy patients had primary cutaneous melanomas (T2-4N0M0) and four had locally recurrent melanoma in or near a prior wide excision scar (TxN2bM0). Location of the melanomas was truncal in 39 patients (53%), in the head/neck in 11 (15%), in the upper extremity in 12 (16%), and in the lower extremity in 12 (16%). The mean Breslow's depth was 2.64 mm (range, 1.0 to 14 mm). Ninety-five regional lymph node basins were subjected to SNB, as defined by the localization protocol. Four subjects with six lymph node basins were not assessable (three patients were unable to tolerate PET scanning because of claustrophobia, and one patient because of technical problems with the SNB procedure), leaving 89 assessable basins in 70 assessable subjects. Locations of the assessable basins were axillary (n = 52), inguinal (n = 19), cervical (n = 14), parotid (n = 2), and popliteal (n = 2). A total of 218 SNs were collected (mean, 2.4 SN/basin; range, one to eight SN/basin). Seventeen (24.3%) of 70 patients had a positive SN in at least one basin. One patient (1.4%) developed an isolated nodal recurrence in an SNB-negative basin. The sensitivity of SNB for detection of occult regional nodal metastases with a mean follow-up duration of 16.6 months was 94.4%. Eighteen (25.7%) of 70 subjects and 18 (20.2%) of 89 node basins harbored at least one tumor-containing lymph node at the time of PET imaging. The aggregate lymph node basin tumor volume in each of the tumor-containing node basins [total volume(s) of SN(s) plus additional tumor found in NSNs at completion lymphadenectomy] was estimated. Median aggregate tumor volume in tumor-containing basins was 4.3 mm3 (range, 0.07 to 523 mm3). Of 70 assessable patients, 65 had FBP and OSEM image reconstruction and five had FBP reconstruction only. The best available image was used for the blinded research interpretation (intent-to-treat analysis). PET efficacy for detection of occult regional lymph node metastases (compared with SNB and clinical follow-up examination) for three different PET scan interpretation scenarios is shown in Tables 2, 3, and 4. Table 2 shows sensitivity, specificity, positive predictive value, negative predictive value, and the limits of the corresponding 95% confidence intervals, assigning only the ROC reading of definitely positive to be positive, with all other readings considered negative. Table 3 shows the same statistical analysis using a more liberal interpretation threshold, assigning the ROC readings of definitely positive and probably positive to be positive, with all other readings considered negative. Table 4 shows statistical analysis using the most liberal interpretation threshold, assigning the ROC readings of definitely positive, probably positive, and uncertain to be positive, with other readings considered negative.
Tables 5 and 6 show subset analyses of FDG-PET performance stratified by prestudy AJCC stage (Table 5) and tumor ulceration (Table 6). For subset analyses, FDG-PET interpretation scenario 2 (Table 3) was used for comparison because this threshold was believed to be most clinically applicable.
Whole-body FDG-PET imaging showed findings suspicious for possible distant metastatic disease at 12 sites (six pulmonary/mediastinal, two liver, one abdominal, and three distant soft tissue/lymph node) in 10 patients (14.3%). Conventional imaging modalities (CT and/or ultrasound) showed a biopsy-proven hepatic adenoma in one patient and a probable pulmonary hamartoma in another. Ten sites in eight patients remained unconfirmed by conventional imaging and clinical follow-up examination (median duration, 16.6 months). No patients were correctly upstaged to AJCC stage IV (distant metastatic disease) by confirmed findings at the initial PET evaluation. At a median follow-up duration of 16.6 months, seven patients (10%) developed recurrence of disease after SNB. Recurrences involved the regional lymph node basin only in one SNB-negative patient (1.4%), intransit plus distant in three patients (4.3%), and distant site only in three patients (4.3%). The isolated recurrence in the SNB-negative lymph node basin was predicted correctly by FDG-PET (Fig 2).
Patients with melanoma localized to the skin (AJCC stages TxN0M0 and TxN2bM0) represent a heterogeneous population composed of at least four subgroups of pathologic disease status. Depending on primary tumor characteristics, 5% to 70% of patients with clinical stage I melanoma harbor occult metastatic disease. Patients with primary melanomas may have localized disease without regional lymph node or distant metastases. This group will be cured by excision of the cutaneous lesion and will not benefit from any other therapy. A second subgroup will have subclinical nodal metastases in the absence of distant disease. The most common site of initial appearance of melanoma metastases is the regional lymph nodes. This group of patients has been the focus of considerable attention because they are potentially curable. Patients with occult distant metastases with or without occult regional lymphatic metastases comprise the remainder of patients with localized cutaneous melanoma. These patients are generally considered incurable with current therapies. Improvements in the surgical staging of melanoma patients have recently come into common clinical use. Morton and other investigators have developed a surgical technique of lymphatic mapping and SNB that reliably identifies patients with occult regional metastatic disease.8-11 SNB is an important advance in the care of melanoma patients. Because of its high accuracy, low morbidity, and ability to select patients for therapies such as lymphadenectomy or adjuvant immunotherapy, SNB has become the staging technique of choice among surgeons who frequently treat melanoma patients. The most important limitation of SNB is that it cannot precisely identify patients who also have occult distant metastatic disease. Anatomic imaging techniques such as CT and MRI are inherently insensitive and nonspecific for locating small metastatic tumor deposits. Studies have shown them to be of no value in the routine staging of primary melanoma and of questionable value in locoregional recurrent melanoma.14,15,30-32 The ideal clinical test for screening melanoma patients before therapy would be a single noninvasive test capable of simultaneously identifying both regional lymphatic and distant metastatic disease with a high degree of sensitivity and specificity. Such a test would have the potential to eliminate morbidity and decrease cost due to unnecessary diagnostic and therapeutic procedures. FDG-PET is a rapid, single noninvasive imaging modality with the potential to simultaneously detect and localize metastatic melanoma in many organ systems. Clinical data on FDG-PET indicate that metastatic melanoma can be detected within normal-sized nodes. Gritters et al19 reported FDG-PET detection of metastatic melanoma in seven of seven lymph node basins in 13 patients, including three basins with normal-sized nodes, confirmed by biopsy or clinical progression. The report by Steinert et al22 included 17 patients with peripheral lymph node metastases observed with FDG-PET and confirmed by a combination of CT, MRI, or biopsy. The report by Boni et al20 included 19 positive FDG-PET foci in lymph nodes (16 were true positive) confirmed by a combination of CT, MRI, and biopsy. We recently reported a pilot study testing FDG-PET for detection of nonpalpable metastatic melanoma in regional lymph nodes and found 100% sensitivity and specificity for FDG-PET in 11 melanoma patients who underwent complete lymphadenectomy of 14 nonpalpable lymph node basins.21 In a similar study, Macfarlane et al27 reported 88% accuracy for FDG-PET prediction of residual/occult regional lymph node status in a heterogeneous group of 21 patients undergoing lymph node dissection for histologic confirmation. Although various studies support a potential role for FDG-PET in melanoma staging, further investigations are indicated. The value of FDG-PET in the surgical treatment of patients with primary melanoma will depend on the ability of the technique to detect small tumor burdens within lymph nodes and other organ systems. Previous studies are flawed by the comparison of FDG-PET to conventional imaging studies known to be inadequate for detection of metastatic melanoma. Most reports include only small numbers of patients. Many do not provide AJCC staging information or describe whether disease found by FDG-PET is palpable, nonpalpable, or microscopic. Histologic confirmation techniques were not consistently applied. The true sensitivity and specificity of FDG-PET for detection of metastatic melanoma, especially in lymph nodes, are unknown. Modern melanoma management incorporates surgical staging of regional lymph node basins to provide important prognostic information upon which clinical decisions are based. Because lymphatic mapping has not been used in prior PET studies, some regional node basins harboring subclinical metastases could have been missed. It is timely and clinically relevant to compare PET findings to histologic analysis of SNB specimens from all basins identified by lymphoscintigraphy as being at risk for metastatic disease. Peripheral lymph node basins in patients with melanoma represent the ideal testing ground for PET imaging. Regional lymph nodes are the most common site of melanoma metastases in patients with clinically localized melanoma. Detection of nodal metastases is highly relevant in the care of these patients. Palpably normal peripheral lymph node basins in clinical stage I melanoma patients have a low background use of glucose and should be ideally suited to sensitive and specific imaging with FDG-PET.21 Preliminary data suggest FDG-PET may be a sensitive indicator of regional lymph node metastases with potential to identify a subset of patients with occult stage IV disease. Current clinical care algorithms emphasize SNB and therefore allow PET findings in regional node basins to be histologically confirmed. Lastly, detailed studies on PET interpretation parameters are possible, particularly with respect to tumor burden necessary for detection by PET. The present study is the first to comprehensively evaluate PET staging of regional lymph node basins in a homogeneous group of patients with melanoma clinically localized to the skin. This report details a comparison of FDG-PET imaging of regional node basins to a clinical care protocol, which emphasized conventional staging, SNB, and clinical follow-up. The study shows that FDG-PET imaging of regional lymph node basins in patients with AJCC stage I, II, and III (T4N0 and TxN2bM0) melanoma is not sensitive for detection of the occult nodal metastases commonly demonstrated by SNB. The strength of these findings is enhanced by rigid adherence to a surgical and lymphatic mapping protocol, blinded PET interpretations, use of a single PET examiner, OSEM image reconstruction, and a high-sensitivity PET imaging protocol specifically designed to localize small tumor volumes. These findings can be generalized to the care of this population of melanoma patients in the usual clinical settings. Although these findings are contrary to prior studies, they are not surprising in view of the minute tumor volumes involved. A possible (likely) explanation for different results is that prior studies were probably successfully imaging larger foci of metastatic disease. FDG-PET is not as sensitive for detection of occult disease as histologic analysis of SNB specimens. The working hypothesis of our study presumed a substantial overlap in detectable tumor volumes would exist. The burden of regional lymph node disease encountered in the study population (4.3 mm3) was far below the expected spatial resolution of modern PET scanners (spatial resolution approximately 5 mm23 or a tumor volume of approximately 65 mm3). These minute tumor volumes have recently been shown to be characteristic of SNB in melanoma patients.33 Because melanoma vigorously accumulates FDG, metastatic foci smaller than the scanner's spatial resolution, particularly if multiple or adjacent, may be detected. Further work is needed in this area to define the limits of PET detection for small foci of melanoma. However, our data clearly show that FDG-PET imaging does not detect a large enough proportion of occult regional lymph node melanoma metastases to enable it to replace surgical staging of regional lymph node basins. We performed subset analyses in an attempt to identify a subgroup of patients more likely to have successful imaging of occult regional lymph node metastases by FDG-PET. In a previous study, we showed a marginally significant positive correlation between increasing tumor thickness and tumor volume.33 We hypothesized certain high-risk populations, such as patients with thick primary or ulcerated tumors, may demonstrate better performance with FDG-PET imaging for regional nodal metastases. The incidence of occult nodal metastases increased with increasing tumor stage (a correlate of thickness), as expected. Subset analysis by prestudy AJCC stage showed a weak trend toward better PET sensitivity for detection of occult N1 disease with increasing stage, with best sensitivity in patients already known to have stage III disease (T4N0M0 or TxN2bM0). Although detection of occult N1 disease in this subset of patients could potentially be of clinical importance, these patients were not actually upstaged by PET findings. Similarly, tumor ulceration correlated with SNB result, but not with PET result. The use of a ROC permitted clinically relevant flexibility in the scan interpretation and PET comparisons. The variations in sensitivity and specificity noted with liberalization of threshold for interpretation of metastatic disease show the expected relationship between sensitivity and specificity for any diagnostic test. Attempts to improve sensitivity by lowering the visual threshold for a positive interpretation were associated with increased false-positive readings and a decrease in specificity. The ROC interpretation most likely to be applied in a clinical setting is shown in Table 3 (definite and probably positive interpreted as positive). With a sensitivity of only approximately 17% and an overall accuracy of 82%, PET is clearly not useful as a screening test for occult regional lymph node metastases in this population. We noted a sensitivity of 94.4% for SNB in our study compared with clinical follow-up, a finding similar to other reported series. At a median follow-up duration of 16.6 months, one false-negative SNB procedure was identified in a patient who had a prior significant (1.5 cm) margin of excision before SNB. This basin was correctly identified as definitely positive by FDG-PET imaging, and the recurrence was predicted. It is possible that FDG-PET may have a secondary role in staging of regional node basins in patients who are not good candidates for SNB, such as patients with poor medical status and those who have had prior wide excision, flaps, or grafts that may interfere with lymphatic drainage from the primary site, rendering SNB less reliable. A detailed comparison of FDG-PET staging to the conventional staging protocol for occult distant metastases (stage IV disease) was a planned part of this study. Histologic sampling of all potential sites at risk for occult disease is not possible in this endeavor. Comparison must therefore rely on a combination of conventional imaging and adequate clinical follow-up for detection of occult metastases, which will manifest as recurrent disease. At this interim analysis, FDG-PET imaging has not prospectively upstaged any patient to stage IV, but several patients are being monitored for suspicious findings that have not yet been elucidated by conventional imaging or follow-up. The insensitivity of FDG-PET for detection of small tumor burdens in regional nodes raises skepticism on the ability of FDG-PET to detect similar minute foci of melanoma in other organs. At this time, our data do not support the routine use of FDG-PET imaging in the initial staging of melanoma patients with AJCC stage I, II, or III melanoma localized to the skin. In conclusion, PET imaging with intravenous FDG is an insensitive indicator of occult melanoma lymph node metastases because of the minute tumor volumes encountered in this population. PET imaging does not have a primary role in regional lymph node staging in patients who present with AJCC stage I, II, or III melanoma localized to the skin. Longer clinical follow-up of this series is necessary to determine whether routine FDG-PET staging will have a significant impact in the management of clinically localized melanoma.
Supported by grant no. R01 CA74389-01 from the National Cancer Institute.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
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ABSTRACT
INTRODUCTION
