,· :'·' MOLECULAR
`. ': .-
`IMAGING
`AND BIOLOGY
`•
`
`B Academy of Molecular Imaging 2005
`Published Online: 23 July 2005
`
`Mol Imaging Biol (2005) 7:304-308
`DOI: 10.1007/s11307-005-0002-7
`
`RESEARCH ARTICLE
`
`Impact of 2-Deoxy-2[F-18]Fluoro-D-Glucose
`Positron Emission Tomography on the
`Management of Patients with
`Advanced Melanoma
`
`Marion T. Harris, FRACP,1,2 Salvatore U. Berlangieri, FRACP,1,2 Jonathan S. Cebon,
`FRACP,2,3 Ian D. Davis, FRACP,2,3 Andrew M. Scott, FRACP1,2,3
`1Centre for Positron Emission Tomography, Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia
`2Ludwig Institute for Cancer Research, Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia
`3Department of Medicine, Austin Hospital, University of Melbourne, Studley Road, Heidelberg, Victoria 3084, Australia
`
`Abstract
`Purpose: Accurate staging of patients with melanoma is vital to guide appropriate treatment.
`2-Deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET) has been
`reported to be a sensitive and specific technique for the staging of advanced melanoma,
`however, few studies provide information regarding its impact on patient management.
`Procedures: We retrospectively reviewed the FDG-PET scan results of 92 patients with
`melanoma who had 126 scans performed over a six-year period. These patients were seen at
`the specialist melanoma clinic at our Institution, and 84 patients (92%) had stage III or IV
`disease. FDG-PET scan results were correlated with computed tomography (CT) scans and
`other imaging when available, and with clinical follow-up of a minimum of three to six months.
`The impact of FDG-PET scans on patient management was also assessed.
`Results: On a lesion-by-lesion analysis, FDG-PET had a sensitivity of 92%, a specificity of 88%,
`and an accuracy of 91%. FDG-PET correctly affected the clinical decision-making process in 40
`of 126 patient studies (32%), particularly assisting in the selection of patients for surgery.
`Conclusion: FDG-PET has an important role in guiding the management of patients with
`advanced melanoma, particularly when surgery is contemplated.
`
`Key words: Melanoma, Positron emission tomography, Clinical management
`
`Introduction
`A ccurate disease staging of melanoma is important to
`
`guide the use of potentially curative surgery or radio-
`therapy in patients with stage III or IV disease. Conven-
`tional staging investigations have limited sensitivity and
`specificity for the detection of melanoma metastases [1].
`The reported accuracy of 2-deoxy-2-[F-18]fluoro-D-glucose
`(FDG)-positron emission tomography (PET) in detecting
`melanoma metastases ranges from 80% to 100%, and FDG-
`PET has particular sensitivity and specificity in the de-
`
`Correspondence to: Andrew M. Scott; e-mail: andrew.scott@ludwig.edu.au
`
`tection of metastases in soft tissue and lymph nodes that are
`not assessable by clinical examination and have not been
`demonstrated by computed tomography (CT) [2Y6]. How-
`ever, FDG-PET was found to be an insensitive indicator of
`microscopic lymph node metastases compared with sentinel
`lymph node biopsy in patients with early stage disease
`because of the small
`tumor volumes involved [7, 8].
`Information on the direct impact of FDG-PET on the clin-
`ical management of patients with melanoma is relatively
`limited. Retrospective studies of patients with predominant-
`ly stage III and IV disease suggested that the FDG-PET
`result influences the management of 22Y49% of patients
`[4, 9, 10]. In two prospective studies, the FDG-PET result
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`M.T. Harris et al.: Management Impact of FDG-PET in Melanoma Patients
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`305
`
`changed patient management 15% of the time in one series
`of 95 patients with stage III disease, and contributed to a
`change in therapy in 40% of a second series of 58 patients
`with suspected recurrent melanoma [11, 12]. We undertook
`to examine the accuracy of FDG-PET in the staging of
`patients with melanoma at our institution and to determine
`the impact of FDG-PET on the clinical management of
`patients with this disease.
`
`Methods
`
`Patients
`
`Between February 1994 and November 2000, 278 FDG-PET scans
`were performed on patients with melanoma at our institution. Of
`this group, 92 patients who had 126 scans were selected for
`retrospective review as they had an adequate period of clinical
`follow-up, which was defined as three months, unless death from
`progressive metastatic melanoma occurred prior to this.
`
`uptake. Abnormal foci of FDG uptake were classified as being in-
`volved by melanoma if reported as definitely, probably, or possibly
`involved, but not if reported as being equivocal.
`FDG-PET reports were compared with clinical examination
`findings over the follow-up period in which patients were followed
`by medical oncologists in the melanoma clinic at our institution.
`FDG-PET reports were also compared with CT reports as well as a
`limited number of plain X-rays, bone scans, and magnetic reso-
`nance imaging (MRI) scan reports if these were performed within
`six weeks of the FDG-PET scan. The conventional diagnostic im-
`aging tests were all performed and reported as part of a standard
`assessment under normal clinical circumstances. In most cases,
`this consisted of a CT scan of the chest, abdomen, and pelvis with
`or without a CT scan of the brain. In our Melanoma Unit all pa-
`tients with stage III and stage IV melanoma have a cerebral CT
`scan performed as part of routine staging. A CT scan was per-
`formed within six weeks of the FDG-PET for 116 of the 126 scans.
`False positive and negative FDG-PET scans were reviewed by a
`single reviewer (AMS) to verify the FDG-PET result. Eight FDG-
`PET reports were amended after review.
`
`FDG-PET Scans
`
`Analysis of FDG-PET Results
`
`All PET images were acquired using a Siemens ECAT 951/31R
`whole body PET scanner (CTI PET Systems, Knoxville, TN, USA).
`This scanner produces a 31-slice image per bed position, with a slice
`thickness of 3.37 mm, pixel size of 2.26  2.26 mm, with an
`effective in-plane spatial resolution of 6.5 mm (full-width half-
`maximum). FDG was synthesized using fluorine-18 produced by an
`in-house medical 10 MeV cyclotron (Ion Beam Applications,
`Belgium). Samples of FDG were subjected to radiopharmaceutical
`quality control as specified by US Pharmacopoeia.
`All patients fasted for four hours before the FDG-PET study
`and any patient with elevated blood glucose levels (i.e., 912Y15
`mmol/l) did proceed with an FDG-PET scan. Emission scans
`(eight to 10 bed positions, 7Y9 min per position) were acquired 45
`min after intravenous administration of 370 MBq (10 mCi) of FDG
`(normalized to 70 kg body weight). The majority of patients had
`whole-body scans acquired without attenuation correction, which
`did not involve routine brain imaging as part of the acquisition
`protocol. Only four patients had a focused FDG-PET scan of the
`brain performed. All images were reconstructed using a standard
`filtered back projection algorithm (Hamming filter with a cutoff
`frequency of 0.3 cycles/pixel).
`
`FDG-PET Image Analysis
`
`FDG-PET scans were reported as part of routine diagnostic imag-
`ing performed in the nuclear medicine department of the hospital.
`Reconstructed FDG-PET images were qualitatively analyzed by
`experienced PET nuclear physicians who had access to the patient’s
`clinical history and CT scans when these were available for
`correlation. The FDG uptake within the lesion relative to compa-
`rable normal tissue was the basis of analysis. Images were viewed
`on a computer workstation with the capability of multiple color
`scales and image orientations, including 3D rotational whole-body
`views. The reporting physicians paid special attention to the
`intensity of FDG accumulation within each lesion relative to normal
`background, the relative distribution of FDG within the defined
`lesion and the general extent of the regions of abnormal FDG
`
`FDG-PET results were described on a lesion by lesion basis as
`follows:
`
`True positive ( TP ): if the lesion seen on FDG-PET was shown to
`be metastatic melanoma or another tumor (benign or malignant) by
`standard imaging, clinical examination, or tissue biopsy during the
`three-month follow-up period.
`True negative ( TN ): if the lesion was seen on standard imaging,
`negative on FDG-PET, and shown to be neither a benign or a
`malignant tumor by biopsy, serial imaging, or clinical examination
`over the three-month follow-up period.
`False positive ( FP ): if the lesion was seen on FDG-PET and
`reported to be a benign or malignant tumor but was not apparent
`on targeted imaging performed at a minimum of three months
`post-FDG-PET.
`False negative ( FN ): if a benign or malignant tumor was not
`identified by FDG-PET but was identified on standard imaging
`performed e six weeks before or after FDG-PET (with growth seen
`during serial assessments or biopsy) or apparent on clinical
`examination within two months of the FDG-PET scan.
`Indeterminate ( I ): if follow-up was inconclusive such that the na-
`ture of a lesion identified by FDG-PET or standard imaging was un-
`able to be satisfactorily identified at the end of the follow-up period.
`
`One lesion was defined per organ. For example, the detection
`of multiple liver lesions or subcutaneous deposits was recorded as
`one disease site/lesion each. Where there was discordance within
`an organ, such as one lung metastasis detected and another missed
`by FDG-PET, one lesion was deemed true positive and one lesion
`deemed false negative. This definition was adopted as several
`patients had multiple lesions of skin, soft tissues, liver, or lungs.
`
`Analysis of CT Scan Results
`
`Standard imaging and CT scan results were not independently
`analyzed as some CT scans were not performed within six weeks
`of the FDG-PET scans and some scans were not available for
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`306
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`M.T. Harris et al.: Management Impact of FDG-PET in Melanoma Patients
`
`retrospective review. Lesions were identified from the standard
`reports, with the criteria of one lesion per organ (as defined for
`FDG-PET above).
`True positive and true negative CT results were defined by the
`presence or absence of lesions on CT scans. Apparent CT false
`positive and false negative results were defined as:
`
`False positive: if the lesion was reported to be present on CT but
`not on FDG-PET, and neither a benign or malignant tumor was
`identified on tissue biopsy, serial CT, alternative imaging (MRI,
`ultrasound), or clinical examination over the follow-up period.
`False negative: If the lesion was seen on FDG-PET but not
`reported to be present on CT performed within six weeks of FDG-
`PET, and was confirmed to be a benign or malignant tumor by
`tissue biopsy, later detection by CT, or clinical examination within
`two months of the CT scan.
`
`Impact of FDG-PET on Patient Management
`
`Only those patients with adequate clinical follow-up were included
`in this study. This was defined as a three-month minimum follow-
`up unless patient death occurred prior to three months because of
`progressive metastatic melanoma. All 92 patient records were
`reviewed by a single reviewer (MTH) to determine the impact of
`the FDG-PET scan result on patient management. A rigorous
`approach to impact on clinical management was taken, such that
`the FDG-PET scan was deemed not to have affected decision
`making if it confirmed the CT or clinical impression of multiple
`metastatic sites even if showing extra disease sites (unless the site
`was of particular clinical significance), or if it confirmed the CT
`and clinical impression of no active disease.
`
`Results
`
`Patients
`
`Of the 92 patients, 60 were male. The age range was 21Y77
`years with a median of 54 years. As determined clinically
`and by conventional imaging, three patients had stage I
`disease, five had stage II disease, 29 stage III disease, and 55
`stage IV disease (92% of patients had stage III or IV disease).
`The FDG-PET scans were requested by medical oncol-
`ogists in our melanoma clinic. The indications for FDG-
`PET scanning were for staging for 107 scans, and assessment
`of response to investigational treatment (a monoclonal anti-
`body) for 19 scans [13]. A total of 126 FDG-PET scans
`were performed in 92 patients. The median number of FDG-
`PET scans was one with a range of 1Y7.
`Clinical follow-up was obtained for a six-month mini-
`mum after 92 scans, a three- to six-month follow-up after 26
`scans (15 due to patient deaths), and less than three months
`follow-up after eight scans (all due to patient deaths).
`
`FDG-PET Scan Results
`
`The FDG-PET results by individual lesions were: TP 222,
`FP 2, TN 15, FN 20, and Indeterminate 31. False positives
`
`were attributable to a retrosternal goitre and a case of me-
`diastinal sarcoidosis (see Table 1). Analysis of FDG-PET
`results showed no evidence of false positive results in scans
`performed after investigational
`treatment. False negative
`sites included: lung 6, liver 8, brain 2, skin 3, and orbit 1.
`Fifteen false negative lesions were less than 1 cm in size
`and five lesions were 1, 1.5, 1.8, 2, and 4 cm each. No
`patients with false negative FDG-PET scans had received
`chemotherapy or radiotherapy within six weeks of the FDG-
`PET scan. Indeterminate lesions were excluded from sub-
`sequent analysis.
`Other tumors identified by FDG-PET (n = 7) included a
`case each of non-Hodgkin’s lymphoma, multiple myeloma,
`bowel cancer, breast cancer, pancreatic cancer, thyroid ade-
`noma, and a neurofibroma. The overall FDG-PET sensitiv-
`ity was 92%, specificity 88%, and accuracy 91%.
`
`CT Scan Results
`
`Fourteen CT false positive sites were identified, and in-
`cluded: liver 5, brain 2, mediastinal lymph nodes 3, ovary 2,
`lung 1, and axillary lymph node 1. The two false positive
`brain lesions were confirmed as small infarcts on MRI. Eight-
`een CT false negative sites were identified, and included: pan-
`creas 3, liver 1, small bowel/omentum 4, abdominal nodes 3,
`skin nodules 4, adrenal 1, axillary nodes 1, and groin nodes 1.
`
`Impact of FDG-PET on Patient Management
`
`FDG-PET affected the clinical decision making process
`after 43 out of 126 patient studies (34%). This influence was
`correct in 40 out of 43 of these clinical decisions (32% of
`total patient studies) as determined by observation during
`the period of clinical follow-up. The principal impact of
`FDG-PET was in determining suitability of patients for
`surgery (Figs. 1 and 2). The cases where FDG-PET scan
`result correctly impacted on the clinical management of
`patients are summarized in Table 2. The FDG-PET scan
`
`Table 1. False positives (FP) and false negatives (FN) FDG-PET and CT
`scans
`
`FDG-PET FP
`(n = 2)
`
`FDG-PET FN
`(n = 20)
`
`CT FP
`(n = 14)
`
`CT FN
`(n = 18)
`
`Retrosternal
`goitre (1)
`Mediastinal
`sarcoidosis (1)
`
`Lung (6)
`
`Liver (5)
`
`Pancreas (3)
`
`Liver (8)
`
`Brain (2)
`
`Liver (1)
`
`Brain (2)
`
`Skin (3)
`Orbit (1)
`
`Mediastinal
`nodes (3)
`Ovary (2)
`Lung (1)
`Axillary
`nodes (1)
`
`Small bowel/
`omentum (4)
`Abdominal nodes (3)
`Skin (4)
`Adrenal gland (1)
`
`Axillary nodes (1)
`Groin nodes (1)
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`M.T. Harris et al.: Management Impact of FDG-PET in Melanoma Patients
`
`307
`
`Table 2. Patients where FDG-PET had direct
`management of patients
`
`impact on the clinical
`
`Scan result
`
`Number of
`patients
`
`Clinical management
`outcome (n)
`
`Confirmed limited disease
`
`27
`
`Confirmed metastatic disease
`Confirmed nonmalignant
`lesion
`
`Confirmed malignant lesion
`
`New primary identified
`requiring treatment
`Identified tumor response to
`therapy
`
`4
`4
`
`3
`
`1
`
`1
`
`Surgery (22)
`Radiotherapy (2)
`Observation (3)
`Surgery cancelled (4)
`No treatment or
`further investigation
`required (4)
`Palliative chemotherapy
`(1) or palliative
`radiotherapy (2)
`Surgery immediately
`performed (1)
`Treatment continued (1)
`
`createctomy, porta hepatis, and a small bowel resection), as
`well as lymph node dissections of different sites (n = 16).
`Surgery was performed on 12 patients with stage III disease
`and nine patients with stage IV disease; one other patient
`with a past history of melanoma had multiple myeloma
`discovered on pathology following surgery to remove what
`was thought to have been a metastatic deposit in a rib. Six
`patients progressed within six months of the surgery and
`four of these subsequently underwent resections for stage
`IV disease.
`
`Discussion
`
`Our results show the accuracy of FDG-PET in the staging of
`advanced melanoma and confirm the conclusions of earlier
`studies. Our study also represents the largest series of
`patients with stage IV melanoma studied with FDG-PET
`where rigorous criteria for assessing management change
`resulting from FDG-PET scans have been applied. Most
`FDG-PET false negatives were less than 1 cm in diameter,
`and were mainly pulmonary and hepatic in location. The
`majority of these false negatives were detected by CT
`scanning,
`indicating that FDG-PET should complement
`rather than replace CT scanning in this group of patients.
`Twelve of eighteen CT false negatives were located in the
`abdomen, suggesting that FDG-PET can especially assist in
`the staging of this region. The advent of routine attenuation
`correction in whole-body FDG-PET scans and recent
`developments in PET/CT scanners should improve this
`false negative rate [6]. Our FDG-PET false positive rate was
`low, quite possibly due to the lack of clinical or imaging
`follow-up for all
`lesions, which in turn increased the
`number of
`lesions in the indeterminate category.
`In
`addition, an assessment of FDG-PET sensitivity for detec-
`tion of cerebral metastases was not possible as most patients
`did not have a focused FDG-PET scan of the brain
`performed. Previous studies suggest that FDG-PET may
`be insensitive in the detection of small metastases in the
`cerebral cortex [14].
`
`Fig. 1. Coronal FDG-PET image of a patient with a known
`melanoma lesion in the left lung base. FDG-PET showed the
`left lung lesion (open arrow), and in addition an unsuspected
`metastasis in the left side of the abdomen (black arrow) was
`also identified and subsequently confirmed histologically to
`be a small bowel metastasis. Surgery for resection of the left
`lung lesion did not proceed on the basis of the FDG-PET
`scan result.
`
`result did not affect the clinical decision making process for
`any patient with stage I or II disease.
`The three scans where FDG-PET incorrectly guided
`management included a case where cancer was thought to
`be localized to lymph nodes in a man who presented a few
`weeks after the scan with clinical symptoms from multiple
`small (G0.5 cm) brain metastases (shown by MRI but not by
`FDG-PET). These developed before we could proceed to
`node dissection. In two other cases, FDG-PET falsely
`reassured that lesions of uncertain significance were not
`malignant; however, subsequent follow-up identified pro-
`gressive disease at these sites. In neither case was patient
`management adversely affected.
`Surgery undertaken after FDG-PET scanning in 22
`patients included neurosurgery (n = 1), major abdominal
`surgery (n = 5) (which included hepatic resections, pan-
`
`A
`
`B
`
`(A) 3D coronal FDG-PET image of a patient with a
`Fig. 2.
`history of melanoma and a new solitary rib lesion believed to
`be a metastasis. FDG-PET showed increased uptake in a left
`anterior rib (arrow) [also seen in (B), transaxial image], but
`with no other focal metastases identified. Increased FDG
`uptake in humeri, ribs and pelvis was also evident. On the
`basis of the FDG-PET scan result, the rib lesion was re-
`sected and found to be a plasmacytoma. The patient sub-
`sequently received treatment for multiple myeloma.
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`308
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`M.T. Harris et al.: Management Impact of FDG-PET in Melanoma Patients
`
`The use of standard imaging (mainly CT scanning), as
`well as clinical examination and biopsy as the method of
`validation of disease presence, biased the results against
`FDG-PET scanning. In addition, the definition of one lesion
`being any number of metastatic deposits within an organ
`also removed the inherent advantage of FDG-PET in
`detecting additional sites of disease at various sites, which
`was observed in our study and has been reported by other
`groups. Nevertheless, the sensitivity, specificity, and accu-
`racy of FDG-PET in our series was high and comparable to
`the best results in the literature [2Y6, 15Y17]. The require-
`ment for adequate clinical follow-up in the patient popula-
`tion to confirm the presence or absence of disease increased
`the accuracy of the data in our series. It is also noteworthy
`that seven other tumor types were detected by FDG-PET in
`this patient group (Fig. 2), emphasizing the importance of
`considering differential diagnoses and obtaining a tissue
`diagnosis particularly at the time of the first relapse.
`By comparison, conventional diagnostic procedures (CT
`chest, abdomen, brain MRI with or without bone scan) have
`been estimated in studies of patients with stage IIYIV
`melanoma to have a sensitivity of 57Y81% and a specificity
`of 45Y87%, respectively, on the basis of single melanoma
`lesions [2Y4]. In a further study of 347 patients with clinical
`stage III melanoma, CT scans identified twice as many false
`positives as true positive melanoma lesions [1].
`Importantly, in our study FDG-PET had an impact on
`clinical decision making in one of three patient studies. Its
`most
`important role was to assist
`in the appropriate
`selection of patients for surgery. Surgery can be curative
`for stage III disease and is the only therapy that influences
`survival in patients with stage IV disease [18]. Up to one
`quarter of patients with metastatic disease are candidates for
`potentially curative surgical resection and 20% of patients
`who achieve a curative resection become long-term survi-
`vors [19]. However, FDG-PET can miss small volume
`disease and/or micrometastatic disease, as evidenced by our
`false negative rate and by the number of patients who
`relapsed soon after surgery. As such, FDG-PET can help to
`guide the appropriate use of surgery in this patient
`population, but may not guarantee a long-term favorable
`outcome postoperatively.
`
`Conclusion
`
`We conclude that FDG-PET is accurate in staging advanced
`melanoma and complements the results provided by CT
`scanning. This is particularly the case in patients with stage
`III and stage IV disease, and for the assessment of nodal,
`omental, and cutaneous lesions. FDG-PET has a role to play
`
`in the clinical management of melanoma patients, particu-
`larly by guiding the appropriate use of surgery.
`
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