Which FDG/PET parameters of the primary tumors in colon or
sigmoidcancer provide the best correlation with the pathological findings?
1. IntroductionColorectal cancer (CRC) is a frequently occurring malignancy[1]. Over the last 2 decades, multimodality
treatment has resultedin crucial improvements for the treatment of this disease. Preop-erative chemoradiotherapy
followed by total mesorectal excisionhas become the standard procedure for rectal cancer patientsbecause of various
anatomical locations [2]. For resectable colon or sigmoid cancer (CSC), the first treatment option is colectomy withen bloc
removal of the regional lymph nodes [3]. Following surgi-cal treatment, adjuvant chemotherapy is typically recommendedfor
patients with the American Joint Committee on Cancer (AJCC)stage III (T1–4, N1–2, M0) or high-risk stage II (T3–4, N0, M0)
dis-ease [4]. Recently, despite imaging techniques being highly criticalin the preoperative workup for treatment decision, a
paucity of cor-relation studies exists between pretreatment image findings andpathological results in this patient
setting.Currently,18F-fluoro-2-deoxdeoxyglucose positron emissiontomography (FDG–PET) imaging is widely used for diagnosis,
mon-itoring treatment response, surveillance, and prognostication forCRC. However, the underlying pathological implication
behindthe clinical observations of FDG accumulation has rarely beenelucidated. In rectal cancer, the correlation between
PET-basedparameters and pathology has been detailed in 2 previous studies[5,6]. When compared to magnetic resonance
imaging (MRI) andcomputed tomography (CT), one study indicated that automatically generated PET/CT-based contours show
the most suitable matchwith surgical specimens [6]. Because of the variation in anatomi-cal structure between rectal cancer
and CSC, it is questionable thatrectal cancer results could be applied consistently to CSC. Addi-tionally, rectal cancer also differs
from colon and sigmoid tumorsin tumor biology [7]. It is necessary to identify which approachacross various FDG–PET
parameters provides the best correlationwith pathological findings.A unique advantage of FDG–PET scanning is the ability to use
thequantitative information of the glucose uptake within the tumor toautomatically create a contour around the tumor. In
contrast withCT- or MRI-based tumor delineations, this auto-contouring processsignificantly reduces the inter-observer
variability in the interpre-tation of Images [8–11]. Consequently, FDG–PET scanning increasesconsistency, diminishes
inter-observer variability, and is time-efficient. Because of a research gap of matching PET-parameters andpathological findings
in CSC patients, we compared various auto-segmentation methods to determine the most suitable match withthe tumor size on
pathological specimen, as well as pathologicalstaging.2. Materials and methods2.1. Patient populationBetween January
2009 and December 2010, 77 newly diagnosedCSC patients scheduled to undergo curative surgical procedures atChina Medical
University Hospital were enrolled in this retrospec-tive study (certificate number of local institutional review
board:DMR99-IRB-010-1). Tumor locations were colon (35 patients) andsigmoid colon (42 patients). The median age was 57
years (range:26–90 years). Forty-six patients were men, and 31 were women. Allpatients received PET/CT for pretreatment
staging and underwentprimary tumor resection thereafter (median: 7 days; range: 1–26days). No patient received preoperative
chemotherapy or had a his-tory of diabetes. All patients had a normal serum glucose level priorto obtaining PET/CT images. The
characteristics of the 77 patientsare shown in Table 1.2.2. PET/CT image acquisitionAll patients fasted for at least 4 h prior
to18F-FDG PET/CT imag-ing. The images were captured using a PET/CT scanner (PET/CT-16slice, Discovery STE, GE Medical
System, Milwaukee, WisconsinUSA) approximately 60 min after administering 370 MBq of18F-FDG. Patients were requested to
rest during the uptake period. ThePET/CT workstation provided a quantification of FDG uptake forSUV. One nuclear medicine
physician identified the locations andSUVmaxvalues for all primary tumors. Thereafter, another physicianreconfirmed the
allocated point of the SUVmaxwithin the tumors.This procedure has been detailed in our previous report [12].2.3.
Measurement of PET-based maximum tumor length andwidthThe PET-based maximum tumor length (TL) and tumor
width(TW) were measured from attenuation-corrected FDG–PET imagesby using an SUV-based automated contouring program
(AdvantageWorkstation Volume Share version 2, GE Health). The FDG–PETdata in DICOM format were inputted into the
workstation, and theimages were reviewed to localize the target lesions, as confirmedby 2 nuclear medicine physicians. They
were unaware of the infor-mation on preoperative image or pathological findings. To definethe maximum TL and TW around the
tumor, we used the measureddistance above 20% of SUVmax(TL20% and TW20%), 30% of SUVmax(TL30% and TW30%), 40% of
SUVmax(TL40% and TW40%), and 50% of SUVmax(TL50% and TW50%). Using this tool, the calculated unitfor the analyses was
mm. Fig. 1 shows the contours of different TLand TW thresholds of a patient with sigmoid colon cancer.2.4. Measurement of
MTV and TLGThe MTVs were also measured from attenuation-correctedFDG–PET images. The MTV was defined as the sum of
metabolic vol-umes of the primary tumors. The volume boundaries were drawnsufficiently wide to incorporate each target
lesion in the axial, coro-nal, and sagittal FDG–PET images. To define the contouring marginsaround the tumor, we used SUVmaxof
2.5 (MTV2.5) and SUVmaxof3.0 (MTV3.0), as previously reported [12]. Furthermore, volumesabove 20% of SUVmax(MTV20%),
30% of SUVmax(MTV30%), 40% ofSUVmax(MTV40%), and 50% of SUVmax(MTV50%) were analyzed.The contour around the target
lesions within the boundaries wasautomatically produced, and the voxels presenting an SUV inten-sity of SUVmax≥ 2.5 or ≥3.0
and ≥20%, ≥30%, ≥40% or ≥50% ofSUVmaxwithin the contouring margin were incorporated to definethe tumor volumes. The
MTVs for the primary tumors includedadjacent lymph nodes with small volumes. The small lymph nodesadjacent to the primary
tumor cannot be segmented from the pri-mary tumor by PET/CT when they appear similar to a part of theprimary lesion.
However, large lymph nodes neighboring the pri-mary tumor can be segmented using an automatic VOI tool onPET/CT, even if
they are partially contiguous to the primary tumor.Although visual interpretation can be used to evaluate MTV [13],our study
does not include this method because it is susceptible tovariations caused by window level settings, and is highly
operator-dependent [14]. These influences may result in wide variabilityamong institutions.The TLGs were also measured from
attenuation-correctedFDG–PET images using a SUV-based automated contouring pro-gram (Advantage Workstation Volume
Share version 2, GE Health),as discussed. The TLG was calculated according to the followingformula: TLG = mean SUV × MTV
[15]. We used the same thresholdlevels as the MTVs, namely, TLG2.5, TLG20%, TLG30%, TLG40%, andTLG50%. 2.5. PathologyA
routine pathology preparation was performed followingtumor resection. The examination was conducted by a
patholo-gist who specialized in gastrointestinal treatment. The maximumlength and width of the primary tumors
(abbreviated as pTL andpTW) were carefully measured macroscopically on formalin fixedspecimens using a ruler prior
to slicing. The measurements wereconfirmed by another pathologist. The pathologists were blindedfrom any
information on the image-based tumor measurements.2.6. Statistical analysisAll values discussed in this section are
expressed asmeans ± standard deviation (SD). Tumor diameters as measuredwith the TL and TW on PET/CT at
various thresholds were comparedwith maximum pathological pTL and pTW using linear regression,including the
Pearson correlation coefficient. The predictive valuesof PET-related parameters for the pathological stage were
exam-ined using the Chi-square test and multivariate logistic regressionanalysis. In addition, the analyses were tested
by receiver-operatingcharacteristic (ROC) curve analysis. All analyses were 2-sided withP values < 0.05 considered
statistically significant. Statistical anal-yses were performed using SPSS, version 13.0 (SPSS Inc, Chicago,IL).3.
Results3.1. Correlation between pTL/pTW and PET-related parameterspTL varied from 2.0 to 11.0 cm on pathology
examination(mean 4.8 ± 2.0 cm), and pTW ranged from 1.5 to 7.0 cm (mean3.4 ± 1.2 cm). Different threshold
approaches of PET/CT-based max-imum TL and TW are shown in Table 2. TL30% and TW 30% achievedthe best
match for pTL (R = 0.81, p < 0.001) and pTW (R = 0.70,p < 0.001), respectively. The association for TL30% relative to
pTL isshown in Fig. 2, whereas that for TW30% to pTW is shown in Fig. 3.Compared with TW30% and pTW, the
relation between TL30% andpTL shows greater linear association. 3.2. Correlation between pathological stage and
PET-relatedparametersBased on the pathological T stage of primary tumors, patientswere divided into 2 groups: patients
with pT1–2 (n = 11) and thosewith pT3–4 (n = 66). As shown in Table 3, several MTVs with thresh-old settings
between 20% and 50%, as well as various TWs, wereassociated with pT3–4 in the univariate analysis. In the
multivari-ate analysis, only TW30% remained significantly associated withpT3–4 (odds ratio = 1.26; 95% CI =
1.07–1.47; p = 0.01). The meanvalues of the TW30% for pT1–2 and pT3–4 patients are 2.2 ± 0.6 cmand 3.3 ± 1.0
cm, respectively. Similarly, based on the pathologicalN stage, patients were divided into 2 groups: patients with pN0(n
= 33) and those with pN1–2 (n = 44). However, no significantdifferences were observed across all the PET-related
parametersfor primary tumors. Conversely, only 20 of the 44 node-positivepatients (45.5%) were observed to have
positive nodes in the pre-operative PET/CT. There was no association of the epidermoidgrowth factor receptor status
on PET-parameters or pathologicalfinding.ROC curve analyses showed that MTV40% and TW30% achievedbetter
correlation with an advanced pathological T stage. Fig. 4 illus-trates quantitative factors between pT1–2 and pT3–4 for
SUVmax,MTV40%, and TW30%. Using the median value for TW30% (2.8 cm)as a threshold, the sensitivity and
specificity for the prediction ofpT3–4 were 56% and 82%, respectively (PPV = 95%, NPV = 24%, accu-racy = 60%).
When patients were divided with the median MTV40%value (25.4 ml), the sensitivity and specificity were 58% and
91%,respectively (PPV = 97%, NPV = 26%, accuracy = 62%). These resultsindicate that TW30% and MTV40% could
provide a higher specificityand PPV for predicting pT3–4. 4. DiscussionCSC is typically staged after pathologic
examination of the surgi-cal specimen. Some criteria should be included in the report of thepathologic evaluation, such
as grade of the cancer, depth of pene-tration, and extension to adjacent structures (T stage), number ofpositive
regional lymph nodes (N stage), and the presence of distantmetastases to other organs or the peritoneum [16,17].
Althoughthere is a developing interest in the role of FDG–PET in stagingor monitoring response, FDG–PET for CSC
has not been definedin mapping tumor size or assessing local invasion. This is the firststudy that shows a strong
correlation between the TL or TW mea-sured using an automated approach with PET/CT and pathology as areference.
In addition, our study showed that TW30% and MTV40%could predict a higher specificity and PPV for pT3–4 diseases
andshould be treated more aggressively or surrogated further closely.On the other hand, a plausible explanation for
the unsatisfactorysensitivity or NPV shown could be attributable to the imbalancedsample size between the 2 groups.
Thus, further research is requiredfor validation.Previous research has reported that a disadvantage of using
PETimaging in CRC is that PET has low sensitivity for nodal disease[18]. This research shows that PET-parameters of
primary tumorswere also unable to effectively predict the presence of pathologi-cal nodes. This may be attributable to
the low spatial resolution inPET or that small lymph nodes adjacent to primary lesions cannotbe segmented separately
from primary tumors when they appearsimilar to a part of the primary lesion. Conversely, Vliegen et al.indicated that
PET/CT cannot reliably predict the involvement ofthe mesorectal fascia for advanced rectal cancer [19]. Thus,
PETmay be expected to be unable to detect microscopic tumor exten-sion because of the limited spatial resolution.
Although MRI withphase-arrayed coils has excellent sensitivity for detecting trans-mural penetration of rectal cancer
[20], evidence that indicates asimilar effect in labeling the local invasion for CSC tumors is lack-ing. More recently,
Maffione et al. investigated 15 different PET/CTparameters in a cohort of 69 patients with locally advanced rec-tal
cancer as pathological response predictors after neoadjuvantchemoradiotherapy (CRT) [21]. They found several
parameters afterCRT (SUVmax, MTV, TLG), and difference between two scans weresignificantly correlated with
pathological response. Among thesefactors, SUVmaxafter CRT had the highest ROC with a sensitiv-ity of 86% and a
specificity of 80%. In contrast, our study showedhigher preoperative TW30% or MTV40% values can alert
physiciansof the risk of higher pathological T-stage in CSC. Based on variousstrategies in treating CRC; therefore,
PET/CT-related parameters indifferent period of treatment course can be applied for predictingtreatment results.This
research has several limitations. First, the macroscopictumor diameters were measured after formalin fixation
insteadof mapping immediately in the original dimension followingresection. This may have resulted in various
degrees of shrinkageof the surgical specimen. Jonmarke et al. reported linear correc-tion factors for tumor shrinkage
between 1.04 and 1.14 in prostatecancer [22], indicating that the influence of shrinkage, althoughlimited, might occur.
Assuming that the composition of the tumorstroma of colorectal tumors may be more compact than the fibro-muscular
stroma of the prostate, we infer that the shrinkage effectin CSC tumors by formalin would be even less than in the
prostate[6]. Second, we were unable to reliably measure the 3D tumor vol-ume in the surgical specimen. Particularly,
the lumen in CSC mightbe not in a straight line as rectal cancer. In addition, uncertain-ties might also exist when
measuring a hollow organ. These factorswould influence the accuracy of the correlation. For optimizing afuture
research, an innovative method for accurate 3D volume mea-surements should be developed. As described by
Wigmore et al. [23], the resected volume can be estimated by comparing withthe specimen weight measured on spring
balance scales after sur-gical resection. It could be assumed that 1 g of tumor tissue hasa volume of 1 ml. Third, because the
scope of our study was todetermine the most effective PET/CT approach matching with thepathology, the PET/CT data were not
compared with other diagnos-tic images, such as CT or MRI. The question addressed in our ongoingstudy will compare PET/CT
markers with CT or MRI images. Finally,the ROC curve analysis might be biased due to the low numberof pT1–2. Future
auto-segmentation studies should include moreparticipants prospectively and consecutively, and use standardizedprotocols for
FDG–PET acquisition and PVE correction [24]. Further-more, other algorithms like background-based tumor
delineationapproaches should be correlated with current methods.As mentioned, manual delineation is well known to be
largelyoperator-dependent [11]. The use of auto-contours can dimin-ish inter-observer differences. Therefore, our study
represents anovel approach for institutions considering preoperative PET/CT tosupplement CT or MRI for staging workup of CSC
in addition toexclude disseminated disease. In the future, it is crucial to adjustfor further confounders, such as tumor location,
to determine theoptimal threshold value. Also, studies should include more patientsand long-term patient outcome using these
parameters shouldbe investigated to optimize their predictive value. Based on ourmethods, we recommend that CSC patients
with a large TW30% orMTV40% be considered for higher possibilities of advanced T stage.5. ConclusionFor CSC patients
requiring surgical procedures, pretreatmentPET/CT can be a useful tool for predicting the final pathologicalfindings. The TL30%
and TW30% are associated with pathological TLand TW, respectively. In addition, the TW30% and MTV40% couldprovide higher
specificity and PPV in predicting
_pathological T3or T4.Contribution1. Pretreatment FDG PET/CT is a useful tool for predicting
thefinal pathological findings for colon or sigmoid cancer patientsrequiring surgical procedures.2. Using a 30% threshold level
for maximum uptake oftumor length and tumor width in FDG PET/CT yield results thatprovide an optimal match with maximum
pathological length andwidth.Disclosure statementAll authors declare they encountered no actual or potential con-flicts of
interest in conducting this study.