At one time_ positron emission tomography _PET_ was

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					                    Oncologic positron emission tomography:
                             a surgical perspective
                                  TODD O. MOORE, MD, AND LANDIS K. GRIFFETH, MD, PHD

         t one time, positron emission tomography (PET) was                                                      Figure 1. A normal PET scan. Notice the
         used only in academic research. Now it is increasingly                                                  organs with high glucose consumption,
                                                                                                                 such as the brain and kidneys. The blad-
         being used in clinical practice. This article reviews the                                               der fills as FDG is eliminated. The liver
background of PET in surgical oncology, its approved indications,                                                and heart are somewhat less intense.
and its uses in the diagnosis and management of different types                                                  Notice the uptake in the laryngeal re-
of cancer.                                                                                                       gion on this patient. This can easily rep-
                                                                                                                 resent the movement of the vocal cords
                                                                                                                 as his arytenoids consume glucose.
    In the vast majority of current clinical applications, PET uses
a glucose analog tracer, 18F-fluorodeoxyglucose (FDG), which has
a half-life of 110 minutes. Because of this, PET scanners previ-
ously had to be located relatively closely to a cyclotron, the type
of accelerator utilized for 18F production. In recent years, local
and regional distribution centers have increased the availability
of FDG in most major cities. The principle of using FDG in PET
lies in the usefulness of identifying metabolically active cells
(Figure 1). Just as chemotherapy utilizes metabolic analogues to
treat cancer by exploiting cancer cells’ increased metabolism and
nucleic acid synthesis, FDG tends to accumulate in cells that are
consuming the most glucose. While quantitative analysis is pos-
sible, qualitative standardized uptake value analysis of localized    high clinical suspicion, PET may be appropriate. Second, PET
consumption is most commonly used for clinical interpretation.        helps to classify a radiographic abnormality as benign or malig-
                                                                      nant; the solitary pulmonary nodule is the classic example. When
INDICATIONS FOR PET                                                   anatomic studies are equivocal, such as when postsurgical scars
    In 1998, Medicare first began to approve reimbursement for        or radiation necrosis must be distinguished from viable tumor,
PET for several oncologic conditions. In general, Medicare will       PET often provides such differentiation. Finally, serial PET ex-
cover PET for diagnosis, staging, and restaging of a solitary pul-    aminations can be used to monitor the efficacy of a given treat-
monary nodule, non–small cell lung cancer, melanoma, head and         ment regimen. The results may facilitate a change in treatment
neck cancer, colorectal cancer, esophageal cancer, and lymphoma.      plan by providing early physiologic evidence showing whether
Medicare also began to cover PET for breast cancer (staging and       the initial therapy is working. This helps to avoid wasted time,
restaging of locoregional disease or distant metastases, and treat-   morbidity, and expense. Physicians can then offer the patient
ment follow-up) in October 2002. In addition, Medicare will           more effective and efficient treatment.
approve PET costs for the following nononcologic conditions:              Overall, PET has been shown to change treatment plans in
myocardial perfusion (utilizing a different tracer, Rubidium-82,      many patients, including 45% of the colorectal cancer patients
an analog of potassium), myocardial viability, and refractory epi-    treated at Baylor University Medical Center (1). However, this
lepsy. Although Medicare will not cover PET costs for sarcoma         statistic does not translate into 45% fewer operations. Although
or for primary brain, pancreatic, hepatocellular, testicular, ova-    occult, distant metastases usually preclude curative resection,
rian, and cervical cancer, PET should be considered for these and     PET may show that a patient who was deemed to have dissemi-
other tumors under special circumstances.
    As specific conditions are considered with regard to PET          From the Departments of Surgery (Moore) and Radiology (Griffeth), Baylor Uni-
scanning, several themes emerge. First, as a functional scan, PET     versity Medical Center, Dallas, Texas.
assesses metabolic changes that are usually detectable earlier than   Presented at surgical grand rounds, Baylor University Medical Center, June 19, 2002.
anatomic changes. Thus, if an anatomic image like computed            Corresponding author: Todd O. Moore, MD, Department of Surgery, Baylor Uni-
tomography (CT) does not show a pancreatic mass but there is          versity Medical Center, 3500 Gaston Avenue, Dallas, Texas 75246.

BUMC PROCEEDINGS 2003;16:13–20                                                                                                                          13
                                                                       Table 1. Sensitivity and specificity of positron emission tomography
                                                                                   in assessing the solitary pulmonary nodule*

                                                                      Researcher                       n      Sensitivity (%)      Specificity (%)
                                                                      Kubota et al (1990)              32            83                     90
                                                                      Duhaylongsod et al (1995)        67            97                     81
                                                                      Bury et al (1996)                50           100                     88
                                                                      Knight et al (1996)              48           100                     63
                                                                      Gupta et al (1996)               61            93                     88
                                                                      Lowe et al (1997)                197           96                     77
                                                                      Lowe et al (1998)                90            92                     90
                                                                      Total                            555        83–100               63–90
                                                                      *Compiled from references 2–8.

Figure 2. (a) A chest CT reveals an
abnormal mass (arrow). (b) The PET
scan confirms a metabolically active
process (arrow), but the mediasti-
num is free of disease. The patient
went directly to surgery, where the
mass was found to be a resectable
adenocarcinoma of the lung.

nated disease is a candidate for curative resection. In the future,                Figure 3. PET scan demonstrating not only tumor and
even tumors considered inoperable, such as small-cell lung can-                    associated mediastinal metastases but also distant me-
cer, usually a nonsurgical disease at the time of diagnosis, may                   tastases.
eventually prove to be amenable to surgery in some cases if PET
can confirm very early, localized disease with sufficient confi-      Non–small cell lung cancer
dence. More importantly, the use of PET to diagnose limited               If a diagnosis of non–small cell lung cancer is made, PET can
metastases or recurrences earlier than anatomic imaging modali-       help surgeons determine which patients would benefit from re-
ties is likely to improve the surgical cure rate of such patients.    section. PET may be especially helpful when traditional anatomic
                                                                      imaging, such as CT or sonogram, is equivocal (Figure 3).
LUNG CANCER                                                               How good is PET at staging the mediastinum? In 339 patients
Solitary pulmonary nodule                                             in 8 different studies over the past decade, the sensitivity of PET
    A wealth of information has been published on the use of          ranged from 75% to 100%, while the sensitivity of CT ranged
PET to assess the solitary pulmonary nodule (Figure 2). Seven         only from 43% to 87%; the specificity of PET ranged from 81%
studies from 1990 to 1998 show that PET ranges in sensitivity         to 100%, whereas that of CT was lower, between 44% and 94%
from 83% to 100% in detecting malignancy, with specificity of         (9–16).
63% to 90% (2–8) (Table 1). The largest study to date, by Lowe            Based on an average sensitivity and specificity of 90%, if non–
et al in 1997, evaluated 197 patients and showed that PET has a       small cell lung cancer at stage N2 has a historical prevalence of
sensitivity of 96% and specificity of 77% (7). In most hands, the     30%, the negative predictive value of a negative PET scan of the
sensitivity and specificity approximate 95% and 85%, respec-          mediastinum is 95%. This suggests that no further evaluation is
tively. Due to the high glucose utilization of macrophages, nu-       required. Conversely, with the same assumptions for a positive
merous inflammatory processes such as granulomatous diseases,         PET scan, the positive predictive value falls to 79%. Because of
sarcoidosis, and aspergillosis can lead to false-positive results.    the lower predictive value, mediastinoscopy should still be per-

14                                           BAYLOR UNIVERSITY MEDICAL CENTER PROCEEDINGS                                    VOLUME 16, NUMBER 1


                                                                                           Figure 5. PET scan from a patient with melanoma of the leg who
                                                                                           has had a popliteal recurrence. Although PET may be accurate
                                                                                           in melanoma, its clinical utility in initial staging is limited.

                                                                                         The benefits of PET imaging in melanoma are more subtle.
                                                                                     Several early PET studies suggested staging “high-risk” melano-
                                                                                     mas—those >1.5 mm thick—with PET. Data supporting the use
Figure 4. (a) CT and (b) PET scans of a patient who had radiation therapy for lung
                                                                                     of PET in patients with high-risk melanoma tout its sensitivity,
cancer. The CT is indeterminate. On the PET scan, the posterior rim is avid and is   which ranges from 74% to 100%, and its specificity, which ranges
probably viable tumor.                                                               from 83% to 98% (21–26). There are few treatment and man-
                                                                                     agement options for melanoma, but patients who might other-
formed. More recent studies have shown unexpected distant                            wise have isolated limb perfusion or resection of a solitary
metastases in 13% to 17% of non–small cell lung cancer patients;                     metastasis may require a different approach if PET demonstrates
thus, PET results upstaged these patients who were not thought                       distant subclinical metastases (Figure 5).
to have mediastinal nodes or distant disease (17–19). Correct                            The sentinel lymph node biopsy has removed much of the
staging potentially avoids a noncurative thoracotomy.                                morbidity of staging intermediate-thickness melanomas; there-
    In patients who have undergone treatment for lung cancer,                        fore, although PET may be accurate, its clinical utility in initial
PET can help measure tumor response and assess for tumor re-                         staging of intermediate-thickness melanoma is rather limited.
currence (Figure 4).                                                                 PET currently should not be considered an alternative to senti-
    MacManus et al studied 153 patients with tumors that were                        nel node biopsy in the staging of regional lymph node basins due
deemed unresectable by conventional imaging (20). PET imag-                          to the higher accuracy of directed sampling and evaluation with
ing showed that, in fact, 6 of the patients (4%) had tumors that                     modern pathologic techniques. In a thick melanoma (>4.0 mm),
were resectable; two thirds (66%) needed external beam irradia-                      if physical examination and conventional imaging reveal no
tion, and 30% needed palliative treatment. After 2 years of                          metastasis, PET may help determine if systemic chemotherapy
follow-up, PET-assigned staging (P = 0.0041) correlated signifi-                     is needed, although the effect of PET on survival has not been
cantly better with survival than did conventional staging (P =                       studied.
    Increasingly, surgeons are beginning to appreciate PET scans                     HEAD AND NECK CANCER
as another tool to deal with lung cancer—for the workup of a                             Nonmelanoma cancers of the head and neck present a vari-
solitary nodule, for staging before surgery, or for postoperative                    ety of problems for which PET scans may be helpful. For staging
surveillance.                                                                        of head and neck cancer, PET can help identify both locoregional

JANUARY 2003                                ONCOLOGIC POSITRON EMISSION TOMOGRAPHY: A SURGICAL PERSPECTIVE                                                    15


           Figure 6. Another example from Baylor University Medi-
           cal Center. One patient had a right cervical node that
           was found to be squamous cell carcinoma. Thorough
           evaluation with physical exam, CTs of the neck and chest,
           and panendoscopy revealed no primary site. The primary
           site was identified and treated only after PET localized
           the area of uptake to the vallecula on the left.

and distant metastases, especially when CT scans are indetermi-
nate. During follow-up visits, PET can monitor the results of
treatment. For example, if a patient opted for irradiation but PET                      ➔
demonstrated poor tumor response, the patient’s treatment could                                   ➤
be altered and surgery performed earlier, when it may be more
successful.                                                                                         ➤

Synchronous primary lesion
     One phenomenon widely observed in head and neck cancer
is that of the synchronous primary lesion. PET is particularly well
suited for workup of the second primary lesion. A recent study
                                                                             Figure 7. Scans of a patient with colon cancer. (a) CT scan showing a metastasis
by Stokkel et al found a synchronous primary lesion in 9 of 54               (arrow) and a benign cyst (arrowhead), which were confirmed by sonography.
patients (17%) by using PET (27). For staging, PET was 96%                   (b) PET shows the metastasis (arrow), but not the benign cyst, and multiple me-
sensitive and 90% specific; this was superior to either CT or                tastases (arrowheads) not seen on the CT scan.
combined ultrasound/fine-needle aspiration.
                                                                             (38%). Though there are little hard data, a generally accepted
Unknown primary lesion                                                       phenomenon is that, as a tumor dedifferentiates, its ability to
     In the case of an unknown primary lesion, PET may not                   concentrate 131I decreases, while its glucose metabolism increases.
change the outcome dramatically, but it may guide treatment.                     Nevertheless, for medullary and anaplastic thyroid cancers,
Advanced head and neck cancer may respond well to aggressive                 published results for PET have been less consistent. PET sensi-
treatment, while a bronchogenic carcinoma metastatic to the                  tivity and specificity were 78% and 79%, respectively (30). Only
neck would require a different approach. A study by Bohuslavizki             magnetic resonance imaging had higher sensitivity at 82%. Both
et al looked at 53 patients with unknown primary lesions (28).               metaiodobenzylguanidine (MIBG) and 111In-Octreoscan studies,
Despite inconclusive conventional imaging, PET was able to iden-             however, had higher specificity than PET, at 100% and 92%,
tify the true primary site in 20 patients, including one patient with        respectively. A case report of insular cancer showed no uptake
breast cancer and another with cecal cancer (Figure 6).                      by PET (31). In general, optimal PET imaging of endocrine and
                                                                             neuroendocrine tumors probably awaits approval of positron-
Thyroid cancer                                                               emitting tracers other than FDG, such as 18F-dopa or labeled
    PET can also be used to follow up on treatment for papillary             somatostatin-receptor-binding peptides.
and follicular thyroid cancer. In 2001, Frilling et al studied 24
patients with differentiated thyroid cancer and a rising thyroglob-          COLORECTAL CANCER
ulin level but a negative 131I scan (29). PET was 95% sensitive                  The clearest indication for PET in colorectal cancer is a ris-
in detecting recurrences and distant metastases but was only 25%             ing carcinoembryonic antigen level with an inconclusive CT
specific. However, PET affected management in 9 of 24 patients               scan. However, almost half of all patients with recurrences will

16                                                    BAYLOR UNIVERSITY MEDICAL CENTER PROCEEDINGS                                  VOLUME 16, NUMBER 1
          Table 2. Sensitivity and specificity of positron emission tomography and computed tomography in recurrent colorectal cancer*

                                                               Liver                                      Pelvis                                  Abdomen
                                             Sensitivity (%)           Specificity (%)     Sensitivity (%)      Specificity (%)      Sensitivity (%)   Specificity (%)
Researcher                        n           PET       CT              PET       CT        PET       CT         PET       CT         PET       CT      PET       CT
Schiepers et al (1995)           76           94       85               100      99         93        60         97       72           —        —           —        —
Delbeke et al (1997)             52           91       81               96       60         100       74         50       40           —        —           —        —
Ogunbiyi et al (1997)            58           95       74               100      85         91        52         100      80           —        —           —        —
Valk et al (1999)                155          95       84               100      95         97        68          96       90          85       50         100       99
Hooker et al (2000)               52          100      79               100      93          86       70          96       93          86       57          93       93
Arulampalam et al (2001)          42          100      45               100      100        100       86         86       100          93       73         75        58
*Compiled from references 1, 32–36.
PET indicates positron emission tomography; CT, computed tomography.

not demonstrate an elevated carcinoembryonic antigen level.
Patients frequently benefit from PET if posttreatment conven-
tional imaging shows an indeterminate lesion. Finally, other
patients may be candidates for resection of metastases, and PET
can help assure the surgeon that the patient may be cured by
resection or ablation of isolated metastasis (Figure 7).
    Many reports have evaluated the effectiveness of PET in di-
agnosing recurrent colorectal cancer (1, 32–36) (Table 2). At the
North Texas Clinical PET Institute, PET was consistently more
sensitive than CT in the regions of the liver, pelvis, and abdo-
men (1). Findings on the 52 patients examined in that report
correlated well with the overall literature, which shows an overall
PET sensitivity ranging from 85% to 93%. Specificity of PET was
consistently better than that of CT, although it was more vari-
able among different centers. PET Institute data show >93%
specificity for all regions. With this information, PET scans ac-
tually changed the management of 35% to 56% of the patients,
including 45% of the patients at the North Texas Clinical PET
Institute. A recent prospective trial in Australia found that PET                        Figure 8. Kaplan-Meier plot demonstrating how survival differed in 100 consecu-
                                                                                         tive patients when based on PET findings alone. The solid line identifies patients
changed patient management in 59% of cases (37).                                         with localized disease by PET; the dashed line, the outcome of those patients
    What does the future hold for PET in colorectal cancer? A                            found to have distant metastasis after up to 36 months of follow-up. Reprinted
group in Ohio has reported using a modified handheld gamma                               from reference 41 with permission of Elsevier Science, Inc.
counter during surgery to guide the surgeon to the tumor, though
the short half-life and expense of FDG make this technique im-                               PET is limited in esophageal evaluation, however, because
practical at present (38). In addition, adenomatous polyps have                          esophagitis may lead to false-positive scans. To date, PET has not
been shown to be PET avid, especially those >13 mm (39). Fi-                             been shown to identify high-grade dysplasia or carcinoma in situ
nally, PET has been shown to surpass intraoperative sonography                           (43). Thus, patients with these conditions will still require up-
in the detection and management of colorectal cancer (40).                               per endoscopy.

ESOPHAGEAL CANCER                                                                        BREAST CANCER
    For esophageal cancer, PET is used during staging to improve                              Numerous studies have applied PET to the detection of breast
patient selection, thus avoiding radical surgery that would not                          cancer (44–50). Mammography has high sensitivity, but its speci-
be curative. The Kaplan-Meier plot in Figure 8 demonstrates how                          ficity is <30%. PET has also shown sensitivity ranging from 80%
survival differed in 100 consecutive patients when based only on                         to 100% and specificity ranging from 86% to 100%. PET may
PET findings of local vs distant disease. This study helps to vali-                      miss well-differentiated cancers such as tubular cancers or duc-
date PET as an independent staging tool (41).                                            tal carcinoma in situ because of their relatively normal metabo-
    Additional support comes from an article by Choi et al (42),                         lism, while inflammatory lesions may lead to false-positive results.
who found PET to consistently outperform CT at nodal staging                             Small, subcentimeter lesions may lie below the resolution of PET.
and identification of metastases, with sensitivity of 75% vs 18%,                        On the other hand, patients in whom the value of mammogra-
specificity of 99% vs 97%, and accuracy of 86% vs 78%, respec-                           phy might be limited may benefit from PET detection of breast
tively. PET even surpassed endoscopic ultrasound and CT at                               cancer. Young women who have dense breasts or women who
nodal staging, with rates of 83%, 58%, and 60%, respectively.                            have undergone breast augmentation are the ideal candidates.

JANUARY 2003                              ONCOLOGIC POSITRON EMISSION TOMOGRAPHY: A SURGICAL PERSPECTIVE                                                                17
     A recent report by Raylman et al evaluated the effectiveness       activated white cells are less avid, such as nucleic acid or amino
of PET in guiding percutaneous needle biopsy to tumor regions           acid analogs.
with the highest activity when imaging had revealed diffuse ab-
normalities (51). The potential value of PET lies in reducing           LIVER CANCER
sampling errors during needle biopsy and thus improving the                 PET is not as well suited for evaluating hepatocellular carci-
diagnostic accuracy of the procedure.                                   noma as it is for evaluating metastatic disease. Since cirrhotic
     In staging breast cancer, axillary dissection remains the gold     livers have been found to have irregular glucose-6-phosphatase
standard. However, PET has performed well. In over 278 patients,        activity, the PET scan can be misinterpreted. In contrast, me-
the sensitivity of PET varied from 57% to 100%, while specific-         tastases are more easily found against a background of normal,
ity ranged from 75% to 100% (44–46, 48, 52–54).                         relatively homogeneous hepatic parenchyma. Another source of
     Breast cancer is another process in which the standardized         error is the occasional intrahepatic abscess (69).
uptake value may reflect tumor metabolism and ultimate histo-               One potential role for PET is in the follow-up of tumor ab-
logic grading. Smith and colleagues used this grading informa-          lation. Chemoembolization efficacy has been considered (70).
tion from serial PET scans to identify responders to a given            To date, however, there are no reports on using PET to monitor
treatment and to change treatment modalities accordingly (55).          radiofrequency or ethanol ablation.
     In addition to treatment follow-up, PET’s largest role in breast
cancer currently is the assessment of suspected recurrence or dis-      SARCOMA
tant metastases. A 2001 study by Kim et al showed 93% accuracy              In sarcomas, PET can be used to guide the surgeon toward
in identifying recurrent breast cancer (56). Another report dem-        areas of most intense mitotic activity and away from areas of
onstrated that PET performed better at detecting metastases than        necrosis. Such use may improve the accuracy of biopsy in assess-
did bone scans (57). Because of the nature of osteocyte metabo-         ing maximum tumor grade. Treatment progress may be followed
lism, PET detects osteoclastic lesions better than osteoblastic le-     by serial PET scans if there is doubt as to its efficacy. Misleading
sions. Bone scans favor osteoblastic processes because they detect      results may be obtained in cases of infection or hypermetabolic
the reaction of the bone to the malignant lesion. PET provides          conditions such as Paget’s disease.
the additional benefit of imaging internal mammary nodes. Over-
all, Yap et al found that PET changed the mode of management            NONTHYROID ENDOCRINE CANCERS
in 28% of their patients (58).                                              Carcinoid endocrine tumors have been shown to be poorly
                                                                        imaged by PET; consensus is that 111In-Octreoscan is still the scan
PANCREATIC CANCER                                                       of choice in these conditions.
     Several studies have addressed whether PET is useful in iden-          Incidentally discovered adrenal masses may accurately be
tifying pancreatic cancer (59–63). In 434 patients, PET was 85%         classified as benign or malignant. According to a study by Boland
to 95% sensitive; however, specificity was 78% to 99% due to            et al, PET was 100% accurate, correctly classifying 14 malignant
false-positive FDG uptake in some inflammatory lesions. Over-           and 10 benign lesions (71). In patients who have a history of
all accuracy hovered between 85% and 93%.                               cancer, an adrenal mass represents metastasis in 27% to 36% of
     If a surgeon is willing to perform a pancreaticoduodenectomy       cases. PET is useful in such cases for identifying a distant me-
only in cases of potentially curable cancer, management may             tastasis, which may become a preferable target for a percutane-
change in up to 41% of cases (27% malignant and 14% distant             ous biopsy. The anticipated benefit of radical surgery would have
metastases) according to Rose et al (64). PET identified cancer         to be carefully evaluated.
in 18 of 60 patients who had indeterminate CT scans. Distant
metastases were identified at the outset in 7 patients. Sperti et       SUMMARY
al also reported how PET influenced their management of cys-                PET can be useful to the surgical oncologist in diagnosing
tic neoplasms of the pancreas (65). They were content to per-           tumors (particularly solitary pulmonary nodules), grading tumors
form limited excisions of the cysts or simple biopsy alone in those     (assessing baseline standardized uptake values and tumor metabo-
patients who had negative scans.                                        lism), guiding biopsies of highly active tumor regions, staging
     With special techniques for quantification, parameters such        tumors, monitoring treatment, and determining prognosis. PET
as the hexokinase activity of the cell may be assessed by PET.          may be an independent staging tool or be used for surveillance
Hexokinase may serve as an indication of proliferation, may be          and in recurrence or restaging. PET has been clinically available
found to be a factor related to tumor grade, or may even be seen        for a relatively short time. We certainly will gain more knowl-
as a target for chemotherapy (66). Researchers from Germany             edge regarding its appropriate role in the surgical management
recently tried to compare PET findings with those of CT, endo-          of oncologic patients as more experience is gained in a wide va-
scopic retrograde cholangiopancreatography, and intraoperative          riety of tumor types.
sonography (67). Inconsistency led the investigators to deem each
of the techniques as unreliable, and they warned about the pos-
sibility of PET ushering in a new spectrum of “misinterpretation.”      1.   Hooker G, Grossman S, Lichliter W, Griffeth L. Comparison of PET and
                                                                             CT for detection of recurrent or metastatic colorectal cancer. Presented at
One particular limitation of PET is a false-positive scan in the             the North Texas Chapter of the American College of Surgeons, February
setting of chronic pancreatitis (68). Again, optimal PET imag-               26, 2000.
ing of these tumors likely awaits approval of tracers for which         2.   Kubota K, Matsuzawa T, Fujiwara T, Ito M, Hatazawa J, Ishiwata K, Iwata

18                                            BAYLOR UNIVERSITY MEDICAL CENTER PROCEEDINGS                                     VOLUME 16, NUMBER 1
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20                                                      BAYLOR UNIVERSITY MEDICAL CENTER PROCEEDINGS                                         VOLUME 16, NUMBER 1

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