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Original article
Incidental focal uptake in colorectal location on oncologic FDG PET and PET/CT studies: Histopathological findings and clinical significances夽 Jordi Fuertes a,∗ , Clara Montagut b , Santi Bullich c , Mar Iglesias Coma d , Antoni Mestre-Fusco e , e ˜ Marina Suárez-Pinera , Carlos Trampal c , Joaquim Bellmunt b a
Nuclear Medicine Department, Hospital Universitari Sant Joan, Reus, Tarragona, Spain Medical Oncology Department, University Hospital del Mar-IMIM, Universitat Pompeu Fabra, Parc de Salut Mar, Barcelona, Spain c Molecular Imaging Centre, Barcelona Biomedical Research Park, Barcelona, Spain d Pathology Department, University Hospital del Mar-IMIM, Universitat Pompeu Fabra, Parc de Salut Mar, Barcelona, Spain e Nuclear Medicine Department, University Hospital del Mar, Parc de Salut Mar, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 12 June 2014 Accepted 21 July 2014 Available online xxx Keywords: Adenocarcinoma Colorectal cancer Benign colorectal lesion FDG Focal activity PET/CT CT Synchronous neoplasm Second neoplasm
a b s t r a c t Purpose: Unexpected focal colonic or rectal radiotracer activity is an usual finding in patients subjected to a PET study. The aim of this work has been to evaluate the clinical significance of this finding in the prediction of an existing colorectal malignancy. Material and methods: During the last three years, all patients studied with 18 F-FDG PET/CT and PET for oncologic work-up purposes were prospectively surveyed for focal colorectal radiotracer activity. Colonoscopy was performed in all patients with this incidental finding in order to exclude colonic malignancy. CEA level, maximum standardized uptake value (SUVmax), CT findings, colonoscopy findings and histopathological results were prospectively analyzed in all patients. Results: A total of 2290 patients were evaluated, 158 of whom were studied with PET and the remainder with a hybrid PET/CT. Focal FDG colorectal activity was incidentally detected in 27 patients with no previous history of colorectal cancer. Colorectal adenocarcinoma was diagnosed in seven (25.9%) patients. A pre-cancerous lesion was found in eleven patients (40.7%). Eight patients (29.6%) had no macroscopic lesions. One patient was diagnosed with a benign lesion. Any focal activity found in the colon by 18 F-FDG PET/CT examination predicts a probability greater than 50% of an underlying malignant or premalignant lesion in the histopathological analysis (logistic regression, p = 0.01), independently of the calculated SUVmax. Conclusion: According to the results of the present study, we recommend the performance of a colonoscopy and biopsy of any suspicious lesions, in all patients with unexpected focal FDG activity found in colon or rectum during a 18 F-FDG PET/CT examination. © 2014 Elsevier España, S.L.U. and SEMNIM. All rights reserved.
Captación focal incidental de 18 F-FDG en colon en los estudios PET y PET/TAC: Hallazgos histopatológicos y significado clínico r e s u m e n Palabras clave: Adenocarcinoma Cáncer colorectal Lesión colorectal benigna FDG Actividad focal PET/TAC TAC Neoplasia sincrónica Segunda neoplasia
Objetivo: La actividad focal incidental de FDG en colon o recto es un hallazgo usual en pacientes sometidos a una PET. El objetivo de este trabajo es evaluar el significado clínico que tiene este hallazgo en la predicción de la existencia de una lesión colorectal maligna. ˜ todos los pacientes estudiados mediante PET/CT con Material y métodos: Durante los últimos tres anos 18 F con fines oncológicos fueron valorados de forma prospectiva en busca de actividad focal colónica o rectal. Se realizó colonoscopia a todos los pacientes con este hallazgo, para excluir enfermedad maligna. Tanto los hallazgos de la colonoscopia, como los niveles de CEA, SUVmáx, hallazgos TAC y los resultados histopatológicos fueron prospectivamente analizados en todos ellos.
夽 This work was performed in Molecular Imaging Centre, belonging to Barcelona Biomedical Research Park and University Hospital del Mar, Barcelona, Spain. ∗ Corresponding author at: Nuclear Medicine Department, Hospital Universitari Sant Joan, Reus, Av, Josep Laporte 1, 43204 Reus, Spain. Tel.: +34 977337310; fax: +34 977337366. E-mail addresses: [email protected] (J. Fuertes), [email protected] (C. Montagut), [email protected] (S. Bullich), [email protected] ˜ (M.I. Coma), [email protected] (A. Mestre-Fusco), [email protected] (M. Suárez-Pinera), [email protected] (C. Trampal), [email protected] (J. Bellmunt). http://dx.doi.org/10.1016/j.remn.2014.07.008 2253-654X/© 2014 Elsevier España, S.L.U. and SEMNIM. All rights reserved.
Please cite this article in press as: Fuertes J, et al. Incidental focal uptake in colorectal location on oncologic FDG PET and PET/CT studies: Histopathological findings and clinical significances. Rev Esp Med Nucl Imagen Mol. 2014. http://dx.doi.org/10.1016/j.remn.2014.07.008
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Resultados: Un total de 2290 pacientes fueron evaluados, 158 de ellos fueron estudiados con PET y el resto con un equipo híbrido PET/TAC. En 27 de ellos se halló actividad focal de FDG sospechosa en colon o recto. En siete (25,9%) pacientes se diagnóstico adenocarcinoma colorectal. En 11 pacientes (40,7%) se halló una lesión precancerosa. Ocho pacientes (29,6%) no presentaron ninguna lesión macroscópicamente apreciable en la colonoscopia. Un paciente fue diagnosticado de una lesión benigna. Cualquier actividad focal de FDG predice una probabilidad mayor del 50% de corresponder a una lesión premaligna o maligna en el análisis histopatológico (regresión logística, p=0,01), independientemente del SUVmáx. Conclusión: De acuerdo con los resultados del presente estudio recomendamos la realización de una colonoscopia y biopsia de cualquier lesión sospechosa en todos los pacientes en los que se observe actividad focal de FDG en colon o recto en los estudios PET/TAC. © 2014 Elsevier España, S.L.U. y SEMNIM. Todos los derechos reservados.
Introduction
PET: imaging and evaluation
Colorectal cancer is the third most frequent cancer in both sexes, and represents 4–5% of cancer in overall population over 70 years. It is the third leading cause of cancer death in both men and women in the United States. The American Cancer Society estimated 142,820 new cases of colorectal cancer in the US in 2013. It is expected to cause about 50,830 deaths during this year.1 This cancer can be prevented by early detection and excision of a pre-malignant polyp. Five-year survival is in general 40% but this cancer can be cured if detected at an early stage, before metastases occur (90% five-year survival).2 Imaging with computed tomography (CT) is used to assess the anatomic extent of the disease and to determine appropriate treatment. Positron emission tomography (PET) uses the radiopharmaceutical 18 F-2-deoxy-d-glucose (FDG), a d-glucose analog labeled with fluorine-18. The main indications for FDG PET in colorectal carcinoma are the diagnosis of recurrent disease, exclusion of other metastasis before liver/lung resection and the evaluation of a rising carcinogenic embryonic antigen (CEA) serum level with no lesions in conventional imaging. Its use in screening or staging of colorectal cancer is not indicated.3–6 However, incidental colorectal FDG uptake is frequently observed when FDG PET is used for the evaluation of non-colorectal cancer patients.7–11 Physiologic colonic FDG activity is common on PET scans. While diffuse activity can be seen as a normal variant or due to a benign etiology such as inflammation; focal colonic uptake may indicate a potentially relevant lesion that merits further evaluation. The aim of the study was to assess the relevance of focal colorectal FDG activity incidentally found during PET/CT evaluation on predicting an underlying colorectal lesion.
Patients fasted for at least 6 h before FDG injection. PET scans were obtained after intravenous administration of 2.4–2.7 MBq/kg (0.06–0.07 mCi/kg) of FDG and a rest of 60 min. Images were acquired using a hybrid PET/CT scanner (General Electric Discovery ST, Waukesha, Wisconsin, USA) in 23 patients and a dedicated PET scanner (Siemens Exact HR+, Knoxville, TN, USA) in four patients. In PET/CT scanner a low-dose non-contrast enhanced CT (parameters: 120 Kv, 80 mA, 2.5 mm slices) was performed before PET acquisition. Thus, the CT images were used in order to obtain an attenuation map and also guide anatomical localization of lesions appreciated in PET. Two nuclear medicine physicians reviewed all PET scans, recording all patients with suspicious focal activity in large intestine. This image pattern was defined as a well-circumscribed hot spot of FDG activity in colon or rectum, not explained by physiologic colonic excretion of radiotracer and without continuation of activity along the proximal and distal intestinal tube. Opinion of a third nuclear medicine physician was requested in case of disagreement between the two main nuclear medicine physicians. The most common semiquantitative method of evaluating malignancies using PET is FDG maximum standardized uptake value (SUVmax). SUVmax is calculated as a ratio of tissue radiotracer concentration (kBq/mL) and injected dose (MBq) at the time of injection divided by body weight (in kilograms). It was calculated inside a spherical region of interest (ROI), encompassing the whole focal activity. None value of SUVmax was considered as a cut-off for possibility of malignancy.
Material and methods Patients We prospectively examined 2290 consecutive patients who underwent a whole-body PET/CT or PET scan in our institution in the last three years. We looked specifically for focal colon or rectal FDG activity. Patients with a known diagnosis of colorectal cancer and those with any known previous clinical disorder of large intestine, especially inflammatory bowel disease, were excluded. All patients with incidental FDG colorectal activity underwent a complete colonoscopy with biopsy of the lesion if found and CEA blood levels analysis. Colonoscopy and CEA were performed as part of the clinical routine protocol and therefore written informed consent was not necessary.
Colonoscopy All patients who presented focal colonic uptake in PET underwent a colonoscopy 37 days (mean) apart. All lesions found in colonoscopies (45) were biopsied or removed when possible, and its localization recorded. Colon was anatomically divided in eight sections from proximal to distal (cecum, ascending colon, hepatic angle, transverse colon, splenic angle, descending colon, sigmoid and rectum). Final diagnosis of incidental FDG PET/CT findings was made on the basis of histopathological report of specimens that were found on the colonoscopy.
Histopathology Histology of lesions found on colonoscopy was classified into two major categories: cancerous or precancerous lesion (1) and benign lesion or no macroscopic lesion (nml) (0).
Please cite this article in press as: Fuertes J, et al. Incidental focal uptake in colorectal location on oncologic FDG PET and PET/CT studies: Histopathological findings and clinical significances. Rev Esp Med Nucl Imagen Mol. 2014. http://dx.doi.org/10.1016/j.remn.2014.07.008
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PET-CT reports of 2290 patients
Focal FDG colorectal activity (27 patients, 1.17%) 22 more lesions in 15 patients (different location as that observed in PET)
c o l o n o s c o p y 23 lesions found in the same location as focal FDG observed in PET (18 patients)
Adenocarcinoma (8 lesions in 7 patients)
Melanosis coli (1 patient)
No macroscopic lesion in the same location as focal FDG observed in PET (8 patients)
Precancerous lesion (15 lesions in 11 patients)
Fig. 1. Flow chart of patients.
Subjects who presented cancerous or precancerous lesions (1) were divided in two categories: precancerous lesion (A) and cancerous lesion (B). The pathologic classification, tumor staging and grading were based on the 2010 World Health Organization (WHO) classification of tumors.15 Statistical analysis A logistic regression analysis (backward stepwise) was performed to study whether SUVmax had a predictive value for malignancy and premalignancy diagnosis. Subjects with malignant or premalignant lesions (1) and subject with benignant lesions or NML (0) versus the SUVmax values were fitted using logistic regression as follows: (SUVmax) =
eˇ0 +ˇ1 ·SUVmax eˇ0 +ˇ1 ·SUVmax + 1
where (SUVmax) is the probability of malignant or premalignant lesion for a given SUVmax value. The full logistic function was used to fit the data. When any of the parameters of the fitting was not significant, the function was fitted without the non-significant parameters until all the parameters of the fitting were statistically significant. Subjects with malignant lesions (1) and premalignant lesions (0) versus the SUVmax values were also fitted using a logistic regression to determine the probability of malignant versus nonmalignant lesion for a given SUVmax value. Statistical analysis was performed using R software package (v. 2.15.0. The R Foundation for Statistical Computing, Vienna, Austria). Correlation between variables PET and CT results were also analyzed independently, in relation to sensibility of each technique in lesion detection, SUVmax and tumor location, SUVmax and histological characteristics, SUVmax and size lesion and CEA analysis. Comparison of SUVmax and CEA between groups (benign, NML, pre-malignant and malignant) was performed using ANOVA test.
of a preneoplastic or even a malignant lesion underlying the focal colonic FDG uptake was stated and a colonoscopy was recommended. A complete colonoscopy was performed in all 27 patients with incidental colorectal FDG uptake, and biopsy of the lesions found in was performed in all of them, with no immediate complications (Fig. 1). In eighteen patients (66.6%) 23 lesions were found in the same location as FDG focal activity observed in the PET. In seven were diagnosed 8 adenocarcinomas and in 13 patients were diagnosed 15 precancerous lesions. One patient was diagnosed of a benign lesion (melanosis coli). Eight patients (29.6%) had no significant macroscopic lesions. Regardless of PET findings, colonoscopy demonstrated twenty-two more lesions in fifteen patients. The patient characterisitics are summarized in Table 1. Histological findings in patients with proven lesion in colonoscopy Benign lesions One patient had melanosis coli. Precancerous lesions Lesions visualized in PET scan: tubulovillous adenoma with low-grade dysplasia (8 patients, 2 patients with two lesions), tubulovillous adenoma with high-grade dysplasia (1 patient), tubular adenoma with low-grade dysplasia (2 patients), serrated adenoma with low-grade displasia (1 patient), hyperplastic polyp (1 patient). Lesions not visualized in PET scan: tubular adenoma with low-grade displasia (9 patients, 1 patient with two lesions), tubulovillous adenoma with low-grade dysplasia (6 patients, Fig. 2), serrated adenoma with low-grade displasia (2 patients), hyperplastic polyp (2 patients) and sessile micropolyp (2 patients). Cancerous lesions Lesions visualized in PET scan: high-grade adenocarcinoma (1 patient, 2 tumors), low-grade adenocarcinoma (6 patients, Fig. 2). Lesions not visualized in PET scan: All malignant lesions were visualized on PET scan.
Results Discordant findings Twenty-seven (age 72 ± 8 years, mean ± SD, 19 males, 8 females) out of the 2290 evaluated patients displayed incidental focal colonic uptake (32 FDG suspicious foci in colon). This represented an incidence of 1.17% for this finding. Primary malignancies in these patients were: lung cancer (n = 18), non-Hodgkin lymphoma (n = 4), carcinoma of unknown primary (n = 3), gastric cancer (n = 1) and urinary bladder cancer (n = 1). In each PET report the possibility
Two types of mismatch between PET findings and colonoscopy were found (Table 2): - Suspicious focal colorectal uptake in PET with no lesion in colonoscopy, which was considered as a PET false positive result. The rate was 29.6% (8 patients out of 27).
Please cite this article in press as: Fuertes J, et al. Incidental focal uptake in colorectal location on oncologic FDG PET and PET/CT studies: Histopathological findings and clinical significances. Rev Esp Med Nucl Imagen Mol. 2014. http://dx.doi.org/10.1016/j.remn.2014.07.008
CEA
SUVmax
L1
L2
1
71
F
NHL
NA
11.00
10.00
2
82
M
Lung
9.9
3 4 5
79 63 76
M F M
CUP NHL Lung
6 7
84 72
M M
8
55
9
CT findings
Colonoscopy findings
Histopathology
L1
L2
NU L1
NU L2
L1
L2
NU L1
N
TC
DC
S
0
Adenocarcinoma (HGA)
19.62
WT
R
0
DC
0
Adenocarcinoma (HGA) Adenocarcinoma (LGA)
Adenoma (TALGD) Adenoma (TALGD)
3.4 1 12.3
9.70 15.15 29.16
N WT WT
nml nml S
0 0 0
0 0 AC
0 0 0
CUP Lung
9.8 NA
7.77 20.82
Nod N
nml SA
0 DC
0 AC
0 0
F
Lung
NA
7.00
N
S
0
0
0
74
M
Lung
NA
17.13
WT
SA
0
S
0
10
72
M
Lung
14.6
13.61
N
SA
0
HA
AC
11 12 13
83 83 53
M M F
Stomach NHL Lung
4.7 NA NA
16.98 NA NA
N WT a
nml nml C
0 0 0
0 0 b
0 0 0
14
51
F
CUP
6.7
8.20
N
nml
0
C
0
nml
15 16 17
65 74 68
M F M
Lung Lung Lung
2.2 5.7 3.1
5.36 5.99 8.65
a a N
nml nml SA
0 0 0
0 0 DC
0 0 AC
18
70
M
Lung
4.7
13.75
WT
DC
DC
S
0
19
77
F
NHL
3.4
20.00
a
SA
0
S
TC
20
73
M
Lung
NA
20.63
N
S
0
0
0
21
72
M
Lung
1.1
18.73
N
R
0
R
R
22
70
M
Lung
1.8
8.06
N
R
0
0
0
23
68
M
Lung
5.3
3.51
N
nml
0
AC
0
nml nml Adenocarcinoma (LGAc) Adenocarcinoma (LGA) Adenoma (TVALGD) Adenocarcinoma (LGA) Adenoma (TVAHGD) Adenoma (TVALGD) nml
24
76
M
Lung
1.75
12.79
N
S
0
DC
0
25
79
M
Lung
7.4
6.72
N
S
0
S
0
26
69
F
Lung
2.2
1.80
WT
R
0
0
0
27
73
M
Urinary bladder
3
28.00
WT
R
0
0
0
19.19
15.76
nml Melanosis coli Adenoma (TVALGD) nml HP Adenoma (TALGD) Adenoma (TVALGD) Adenoma (TVALGD, 2 lesions) nml nml Adenoma (SALGD)
Adenoma (TVALGD) Adenoma (TVALGD) Adenoma (TALGD) Adenocarcinoma (LGA)
Size
NU L2
Adenoma (TALGD) Adenocarcinoma (LGA)
L1
L2
NU L1
6×2×2
9×3×3
3×3×3
15 × 3 × 3
6×6×3
NP NP 19 × 18 × 15
5×4×3
NP 2×2×2
Adenoma (TALGD)
TNM
NU L2 pT3 pN0 M0 (CT, PET) T3 N0 M0 (transrectalUS, CT, PET) NP NP NP NP pT1 pN0 M0 (CT, PET) NP
8×2×2
5×4×3
16 × 3 × 5
12 × 10 × 7
NP
25 × 20 × 15 17 × 9 × 5
NP
21 × 17 × 7 Adenoma (TVALGD)
Adenoma (TVALGD) Adenoma (TVALGD)
20 × 12 × 5 Adenoma (SALGD)
NP NP 5×3×3
Adenoma (SALGD, TALGD, TVALGD), HP Adenoma (TALGD)
Adenoma (TVALGD)
Adenoma (TALGD) Adenoma (TVALGD) Adenoma (TVALGD)
14 × 14 × 8, 9×7×6
7 × 6 × 4, 3 × 1 × 1, 22 × 20 × 13, 4×4×2 3×2×2
NP
Adenoma (TALGD)
NP NP 5×5×5 55 × 47 × 9
Adenoma (TALGD)
18 × 9 × 6
NP NP NP
21 × 20 × 12 8 × 3 × 3
NP NP pT1 pN0 M0 (CT, PET) pT3 pN0 M1 (CT, PET) NP
15 × 11 × 5
pTis N0 M0 (CT, PET) NP
6×5×4 12 × 11 × 9
NP
2×2×2
21 × 13 × 10
15 × 10 Adenoma (TALGD)
Adenoma (TVALGD)
12 × 10 × 10 10 × 10
Sessile micropolyp Sessile micropolyp HP
NP
NP micropolyp
18 15 × 9 × 6
9×7×3
NP NP
5×5×3
NP
25 × 25 × 20
NP
34
pT3 pN0 M0 (CT, PET)
Abbreviations: P, patient number; NHL, non-Hodgkin lymphoma; CUP, carcinoma of unknown primary; CEA-ng/ml; NA, not available; SUVmax-g/ml; N, normal; WT, wall thickening; Nod, nodule; a, no PET-CT; L1, lesion 1; L2, lesion 2; NU L1, non-FDG uptake lesion 1; NU L2, non-FDG uptake lesion 2; TC, transverse colon; R, rectum; nml, no macroscopic lesions; S, sigma; SA, splenic angle; C, cecum; DC, descending colon; AC, ascending colon; HA, hepatic angle; b, 4 polypoid lesions (adenomatous appearance); HGA, high-grade adenocarcinoma; LGA, low-grade adenocarcinoma; TVALGD, tubulovillous adenoma with low-grade dysplasia; HP, hyperplastic polyp; TALGD, tubular adenoma with low-grade dysplasia; LGAc, LGA in context of TVALGD, TVAHGD, tubulovillous adenoma with high-grade dysplasia; SALGD, serrated adenoma with low-grade dysplasia; size-millimeters (in the threes axis, when available); NP, no proceeds.
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Table 1 Patient characteristics.
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Fig. 2. (A) CT, (B) PET, (C) PET-CT fusion, (D) lesion histopatholgy (hematoxylin and eosin staining). (E) Maximum intensity projection. Patient 18 (see Table 1): focal FDG uptake located in descending colon (two different foci), associated with colonic wall thickening on CT. Large lesion (arrowhead) corresponded to a 55-mm low-grade adenocarcinoma (LGA). The other (arrow) corresponded to a 12-mm tubulovillous adenoma with low-grade dysplasia (TVALGD). Note FDG nodal uptake (little arrowhead) in hepatic dome, visible in the maximum intensity projection (E), concordant with metastatic disease.
- Clinically significant finding on colonoscopy without focal uptake in PET scan. This situation was considered as a PET false negative, and the rate was 55.5% (15 patients out of 27). All lesions not visualized in PET scan were benign. SUV analysis: Logistic regression analysis. A significant logistic regression model without intercept was fitted to the data (ˇ0 = N.S., ˇ1 = 0.066, p = 0.02). The probability of a cancerous/precancerous lesion increased with the SUVmax, as shown by logistic regression (Fig. 3, left panel). Cancerous or precancerous lesion was found at colonoscopy in nine out of the twelve patients (75%) with SUVmax higher than 15. In our sample the probability of a cancerous or precancerous lesion was higher than 50% for any value of SUVmax. Independently of SUVmax a high probability for cancerous or precancerous lesion was expected. No statistical significant logistic regression model was able to be fitted to malignant (1)/premalignant (0) versus SUVmax data (p > 0.5). On the other hand, SUVmax showed poor predictive value in discriminating between precancerous and cancerous lesions (Fig. 3, right panel). Comparison of CT, PET and histopathology of lesions From 27 patients in 23 CT data of PET/CT were available. In ten out of 23 patients (43.5%) the incidental colonic uptake focus detected by PET did not show morphologic alteration on CT. From these patients, four had cancerous lesions and 6 a precancerous lesion (Table 3). SUVmax and tumor location In lesions with FDG uptake no statistical significant differences were found between SUVmax and tumor location.
Precancerous lesions. SUVmax for precancerous lesions with lowgrade dysplasia was 14.47 ± 7.21 (n = 9) and 18.73 ± NA for highgrade dysplasia (n = 1). Cancerous lesions. SUVmax for low-grade adenocarcinoma was 20.14 ± 5.88 (n = 4) and 10.5 ± 0.71 for high-grade adenocarcinoma (n = 2). ANOVA test did not show statistically significant differences between groups (F = 4.7526, df = 1, p = 0.09474). CEA analysis Correlation of pathological findings with CEA levels was as follows: benign lesions tend to have a lower serum CEA level than the precancerous or cancerous lesions (2.85 ± 2.62 (n = 2) (benign), 6.76 ± 5.67 (n = 6) (precancerous) and 5.90 ± 3.56 (n = 3) (cancerous), but showing no statistically significant differences (F = 0.47, df = 2, p-value = 0.6382, ANOVA test). Malignancy and size lesion No statistically significant differences were observed in lesion size between precancerous and cancerous lesions. Discussion PET scan has increased the detection of unsuspected secondary malignancies. Recent publications highlight the relevance of incidental findings of a second malignancy in PET studies, mainly in lung cancer and lymphoma patients.16,17 Furthermore, multiple primary malignant neoplasms have been reported, either as synchronous (about one-third of cases) or metachronous lesions.18,19 Other studies have explored the possibility of finding a colorectal malignancy according to grade and pattern of FDG uptake in the colon in patients with unknown previous diagnosis of colorectal cancer. Zhuang et al. concluded that a large portion of focal
SUVmax and histological characteristics Table 3 Comparison of CT, PET and histopathology of lesions. Table 2 Discordant findings between PET and colonoscopy.
CT (non-diagnostic) findings N
Total
WT
Nod
4 0 6 4
1 1 3 3
1 0 0 0
6 1 9 7
14
8
1
23
Colonoscopy findings
PET-CT scan Positive (FDG uptake) Negative (no FDG uptake)
Lesion
nml
Total
19 15
8 NP
27
Patients nml Benign Precancerous Cancerous Total
Total Abbreviations: nml, no macroscopic lesion; NP, no proceeds.
27
Abbreviations: nml, no macroscopic lesion; N, normal; WT, wall thickening; Nod, nodule.
Please cite this article in press as: Fuertes J, et al. Incidental focal uptake in colorectal location on oncologic FDG PET and PET/CT studies: Histopathological findings and clinical significances. Rev Esp Med Nucl Imagen Mol. 2014. http://dx.doi.org/10.1016/j.remn.2014.07.008
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1.0
1.0 Cancerous / precancerous lesions
Cancerous lesion
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
Precancerous lesion
Benign lesion / NML 0.0
0.0 5
10
15
20
25
30
5
10
SUVmax
15
20
25
30
SUVmax
Fig. 3. SUV analysis. Logistic regression analysis.
colonic FDG accumulation incidentally found in PET scans represented cancer.20 The malignancy patterns in colon are clearly defined in standard anatomic imaging (pericolonic infiltration and parietal thickening in CT). Nevertheless, in PET scan, the reference in functional imaging, malignancy patterns are not clearly defined.28 At the beginning, uptake patterns were investigated (focal, multifocal, segmental, or diffuse hypermetabolism) with PET. Results showed that segmental or diffuse uptake is frequently associated with benign pathologies. Based on these findings, colonoscopy is indicated as a next step for nodular FDG uptake.9 Bowel focal accumulation of FDG is usually identified in the colonic mucosa and rarely in the bowel wall. In PET-CT scans bowel wall activity can be distinguished from tumor by lack of a CT soft tissue correlation or by demonstration of a typical pattern of bowel uptake. Diffuse, intermediate level activity of FDG is commonly identified in colon and in small bowel, as a result of physiologic excretion of radiotracer from liver to intestines. Also there is higher uptake of radiotracer within the cecum and right colon due to the higher concentration of lymphocytes in this region.21 In this study we focused on patients with a pattern of focal uptake in colon, since this is the group most likely to harbor an underlying neoplasia.9,11,13,14,22 Although several methods for decreasing physiologic FDG accumulation in bowel have been attempted, no technique has demonstrated consistently to decrease the bowel uptake of radiotracer. In our population the incidence of focal colonic uptake incidentally observed was 1.17%, slightly lower than that reported in other studies (1.32–3.9%)9–12 and similar with more recent studies.13 The reason for this lower incidence compared with previous studies may be due to the retrospective nature of our study and because only patients who met strict criteria for focal colonic uptake were included in our study. In the studies above referred, a focal colonic uptake was considered to be a premalignant or malignant lesions in a range from 59 to 68%.9–13 Similar findings are observed in our study, where we demonstrated a premalignant or malignant tumor in 66.6% of patients. The main limitation of our study is that no two-phase study was acquired with late abdominal image to rule whether the focal uptake observed corresponded to intestinal transit. We believe this measure would have decreased the false positive rate of the study. Despite its high affinity to malignant tissue, FDG is also strongly taken up by other malignancies (different than primary colon cancer) as well as nonmalignant processes that may be present in patients (diverticulitis, focal colitis or following polypectomy). It is not unusual to find different synchronous neoplasms in PET studies or in other imaging diagnostic tools. To the best of our
knowledge some individual patient cases have been reported,23–25 but only two structured papers have been published about it. Lardinois et al. assessed secondary FDG PET/CT findings in 350 patients initially examined for non-small cell lung cancer.26 The authors found second primary malignancies that were confirmed by biopsy and histopathologic analysis in 6 patients (2%). Lee et al. found focal colorectal FDG uptake in 62 (2.9%) of 2071 patients. Thirtyseven out of sixty-two patients were further studied and clinically unsuspected neoplasms were found in 68% of those investigated.27 It is widely known that SUVmax value orients about grade of malignancy of tumor. Unlike results of most of the reviewed literature,9,12,13 we have found that measurement of SUVmax would be a good marker for discrimination between benign and precancerous/cancerous lesions. Other more recent studies have shown that a SUVmax cut off is related with a high probability of advanced colorectal neoplasm.14 Nonmalignant uptake, which decreases the specificity and sensitivity, is a limitation of FDG PET. Focal hot spots such as focal smooth muscle uptake, non-uniform lymphocyte concentration in cecum and right colon, overlapping intestinal loops, undistended bowel, or diverticulitis may mimic the focal malignant lesion. Diffuse segmental FDG accumulations (inflammation/infection or drugs – metformine) may also occult in premalignant or even malignant focal lesions. In conclusion, a well-circumscribed hot spot of FDG activity in colon or rectum, not attributable to physiologic colonic excretion of radiotracer and without continuation of activity along the proximal and distal intestinal tube, is potentially predictive of subsequent pathologic findings, which may include malignancy. Colonoscopy is a mandatory next step for further diagnostic evaluation in these patients. Funding No funding received to do this work. Conflicts of interest The authors have no conflicts of interest to declare. References 1. American Cancer Society. What are the key statistics about colorectal cancer? http://www.cancer.org/Cancer/ColonandRectumCancer/DetailedGuide/ colorectal-cancer-key-statistics [accessed November 2013].
Please cite this article in press as: Fuertes J, et al. Incidental focal uptake in colorectal location on oncologic FDG PET and PET/CT studies: Histopathological findings and clinical significances. Rev Esp Med Nucl Imagen Mol. 2014. http://dx.doi.org/10.1016/j.remn.2014.07.008
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2. Brown G, Husband JE, Cook G. Colorectal cancer. In: Husband JE, Reznek RH, editors. Imaging in oncology. 2nd ed. London: Taylor and Francis; 2004. p. 217–44. 3. Van Cutsem E, Oliveira J. Primary colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up. Ann Oncol. 2009;20 Suppl. 4:49–50. 4. Boellaard R, O’Doherty MJ, Weber WA, Mottaghy FM, Lonsdale MN, Stroobants SG, et al. FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. Eur J Nucl Med. 2010;37:181–200. 5. Fletcher JW, Djulbegovic B, Soares HP, Siegel BA, Lowe VJ, Lyman GH, et al. Recommendations on the use of 18 F-FDG PET in oncology. J Nucl Med. 2008;49:480–508. 6. O’Connell MJ, Workman RB, Coleman RE. PET in colorectal carcinoma. In: Workman RB, Coleman RE, editors. PET/CT essentials for clinical practice. New York: Springer Science + Business Media; 2006. p. 130–42. 7. Rehani B, Chasen RM, Dowdy Y, Bharija A, Satter M, Strohmeyer P, et al. Advanced adenoma diagnosis with FDG PET in a visibly normal mucosa: a case report. J Med Case Rep. 2007;1:99. 8. Agrawal A, Nair N, Agrawal R, Baghel NS. Unsuspected second malignancy detection by FDG PET scan. Clin Nucl Med. 2008;33:868–9. 9. Gutman F, Alberini JL, Wartski M, Vilain D, Le Stanc E, Sarandi F, et al. Incidental colonic focal lesions detected by FGD PET/CT. Am J Roentgenol. 2005;185:495–500. 10. Tatlidil R, Jadvar H, Bading JR, Conti PS. Incidental colonic fluorodeoxyglucose uptake: correlation with colonoscopic and histopathologic findings. Radiology. 2002;224:783–7. 11. Israel O, Yefremov N, Bar-Shalom R, Kagana O, Frenkel A, Keidar Z, et al. PET/CT detection of unexpected gastrointestinal foci of 18F-FDG uptake: incidence, localization patterns, and clinical significance. J Nucl Med. 2005;46: 758–62. 12. Salazar Andía G, Prieto Soriano A, Ortega Candil A, Cabrera Martín MN, González Roiz C, Ortiz Zapata JJ, et al. Significación de captaciones incidentales en colon en estudios 18F-FDG PET-TAC en pacientes sin tumor colorrectal conocido Valoración del impacto en el manejo del paciente. Rev Esp Med Nucl. 2012;31: 15–21. 13. Treglia G, Calcagni ML, Rufini V, Leccisotti L, Meduri GM, Spitilli MG, et al. Clinical significance of incidental focal colorectal 18 F-fluorodeoxyglucose uptake: our experience and a review of the literature. Colorectal Dis. 2012;14: 174–80. 14. Cho SH, Kim SW, Kim WC, Park JM, Yoo IR, Kim SH. Incidental focal colorectal 18 F-fluorodeoxyglucose uptake on positron emission tomography/computed tomography. World J Gastroenterol. 2013;19:3453–8.
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15. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. American Joint Committee on Cancer staging handbook. From the AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. p. 143–64. 16. Agress Jr H, Cooper BZ. Detection of clinically unexpected malignant and premalignant tumors with whole-body FDG PET: histopathologic comparison. Radiology. 2004;230:417–22. 17. Banzo J, Ubieto MA, Giraldo P, Yus C, Santapau A, Parra A. Accidental finding of a tubulovellous adenoma of rectum by 18 F-FDG PET in a male patient diagnosed of lymphocytic lymphoma. Rev Esp Med Nucl. 2011;30:256–7. 18. Aydiner A, Karadeniz A, Uygun K. Multiple primary neoplasms at a single institution: differences between synchronous and metachronous neoplasms. Am J Clin Oncol. 2000;23:364–70. 19. Demandante CG, Troyer DA, Miles TP. Multiple primary malignant neo-plasms: case report and a comprehensive review of the literature. Am J Clin Oncol. 2003;26:79–83. 20. Zhuang H, Hickeson M, Chacko TK, Duarte PS, Nakhoda KZ, Feng Q, et al. Incidental detection of colon cancer by FDG positron emission tomography in patients examined for pulmonary nodules. Clin Nucl Med. 2002;27:628–32. 21. Abouzied MM, Crawford ES, Nabi HA. 18 F-FDG imaging: pitfalls and artifacts. J Nucl Med Technol. 2005;33:145–55. 22. Kamel EM, Thumshirn M, Truninger K, Schiesser M, Fried M, Padberg B, et al. Significance of incidental 18 F-FDG accumulations in the gastrointestinal tract in PET/CT: correlation with endoscopic and histopathologic results. J Nucl Med. 2004;45:1804–10. 23. Figueroa MA, Rodríguez VS, Briz MJ, Gallego CI, Serrano FA, Borbones MA. Casual finding of adenocarcinoma of the colon on performing PET-CT with 18 F-FDG. Rev Esp Med Nucl. 2009;28:301–2. 24. Adriaensen M, Schijf L, de Haas M, Huijbregts J, Baarslag HJ, Staaks G, et al. Six synchronous primary neoplasms detected by FDG-PET/CT. Eur J Nucl Med. 2008;35:1931. 25. Kaida H, Ishibashi M, Nakamura M, Baba K, Tahara N, Uozumi J, et al. Early gastric cancer and early colon cancer detected simultaneously by PET cancer screening incidentally. Ann Nucl Med. 2006;20:317–20. 26. Lardinois D, Weder W, Roudas M, von Schulthess GK, Tutic M, Moch H, et al. Etiology of solitary extrapulmonary positron emission tomography and computed tomography findings in patients with lung cancer. J Clin Oncol. 2005;23:6846–53. 27. Lee JC, Hartnett GF, Hughes BG, Ravi Kumar AS. The segmental distribution and clinical significance of colorectal fluorodeoxyglucose uptake incidentally detected on PET-CT. Nucl Med Comm. 2009;30:333–7. 28. Prahakkar HB, Sahani DV, Fischman AJ, Mueller PR, Blake MA. Bowel hot spots at PET-CT. RadioGraphics. 2007;27:145–59.
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Original article
Incidental focal uptake in colorectal location on oncologic FDG PET and PET/CT studies: Histopathological findings and clinical significances夽 Jordi Fuertes a,∗ , Clara Montagut b , Santi Bullich c , Mar Iglesias Coma d , Antoni Mestre-Fusco e , e ˜ Marina Suárez-Pinera , Carlos Trampal c , Joaquim Bellmunt b a
Nuclear Medicine Department, Hospital Universitari Sant Joan, Reus, Tarragona, Spain Medical Oncology Department, University Hospital del Mar-IMIM, Universitat Pompeu Fabra, Parc de Salut Mar, Barcelona, Spain c Molecular Imaging Centre, Barcelona Biomedical Research Park, Barcelona, Spain d Pathology Department, University Hospital del Mar-IMIM, Universitat Pompeu Fabra, Parc de Salut Mar, Barcelona, Spain e Nuclear Medicine Department, University Hospital del Mar, Parc de Salut Mar, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 12 June 2014 Accepted 21 July 2014 Available online xxx Keywords: Adenocarcinoma Colorectal cancer Benign colorectal lesion FDG Focal activity PET/CT CT Synchronous neoplasm Second neoplasm
a b s t r a c t Purpose: Unexpected focal colonic or rectal radiotracer activity is an usual finding in patients subjected to a PET study. The aim of this work has been to evaluate the clinical significance of this finding in the prediction of an existing colorectal malignancy. Material and methods: During the last three years, all patients studied with 18 F-FDG PET/CT and PET for oncologic work-up purposes were prospectively surveyed for focal colorectal radiotracer activity. Colonoscopy was performed in all patients with this incidental finding in order to exclude colonic malignancy. CEA level, maximum standardized uptake value (SUVmax), CT findings, colonoscopy findings and histopathological results were prospectively analyzed in all patients. Results: A total of 2290 patients were evaluated, 158 of whom were studied with PET and the remainder with a hybrid PET/CT. Focal FDG colorectal activity was incidentally detected in 27 patients with no previous history of colorectal cancer. Colorectal adenocarcinoma was diagnosed in seven (25.9%) patients. A pre-cancerous lesion was found in eleven patients (40.7%). Eight patients (29.6%) had no macroscopic lesions. One patient was diagnosed with a benign lesion. Any focal activity found in the colon by 18 F-FDG PET/CT examination predicts a probability greater than 50% of an underlying malignant or premalignant lesion in the histopathological analysis (logistic regression, p = 0.01), independently of the calculated SUVmax. Conclusion: According to the results of the present study, we recommend the performance of a colonoscopy and biopsy of any suspicious lesions, in all patients with unexpected focal FDG activity found in colon or rectum during a 18 F-FDG PET/CT examination. © 2014 Elsevier España, S.L.U. and SEMNIM. All rights reserved.
Captación focal incidental de 18 F-FDG en colon en los estudios PET y PET/TAC: Hallazgos histopatológicos y significado clínico r e s u m e n Palabras clave: Adenocarcinoma Cáncer colorectal Lesión colorectal benigna FDG Actividad focal PET/TAC TAC Neoplasia sincrónica Segunda neoplasia
Objetivo: La actividad focal incidental de FDG en colon o recto es un hallazgo usual en pacientes sometidos a una PET. El objetivo de este trabajo es evaluar el significado clínico que tiene este hallazgo en la predicción de la existencia de una lesión colorectal maligna. ˜ todos los pacientes estudiados mediante PET/CT con Material y métodos: Durante los últimos tres anos 18 F con fines oncológicos fueron valorados de forma prospectiva en busca de actividad focal colónica o rectal. Se realizó colonoscopia a todos los pacientes con este hallazgo, para excluir enfermedad maligna. Tanto los hallazgos de la colonoscopia, como los niveles de CEA, SUVmáx, hallazgos TAC y los resultados histopatológicos fueron prospectivamente analizados en todos ellos.
夽 This work was performed in Molecular Imaging Centre, belonging to Barcelona Biomedical Research Park and University Hospital del Mar, Barcelona, Spain. ∗ Corresponding author at: Nuclear Medicine Department, Hospital Universitari Sant Joan, Reus, Av, Josep Laporte 1, 43204 Reus, Spain. Tel.: +34 977337310; fax: +34 977337366. E-mail addresses: [email protected] (J. Fuertes), [email protected] (C. Montagut), [email protected] (S. Bullich), [email protected] ˜ (M.I. Coma), [email protected] (A. Mestre-Fusco), [email protected] (M. Suárez-Pinera), [email protected] (C. Trampal), [email protected] (J. Bellmunt). http://dx.doi.org/10.1016/j.remn.2014.07.008 2253-654X/© 2014 Elsevier España, S.L.U. and SEMNIM. All rights reserved.
Please cite this article in press as: Fuertes J, et al. Incidental focal uptake in colorectal location on oncologic FDG PET and PET/CT studies: Histopathological findings and clinical significances. Rev Esp Med Nucl Imagen Mol. 2014. http://dx.doi.org/10.1016/j.remn.2014.07.008
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Resultados: Un total de 2290 pacientes fueron evaluados, 158 de ellos fueron estudiados con PET y el resto con un equipo híbrido PET/TAC. En 27 de ellos se halló actividad focal de FDG sospechosa en colon o recto. En siete (25,9%) pacientes se diagnóstico adenocarcinoma colorectal. En 11 pacientes (40,7%) se halló una lesión precancerosa. Ocho pacientes (29,6%) no presentaron ninguna lesión macroscópicamente apreciable en la colonoscopia. Un paciente fue diagnosticado de una lesión benigna. Cualquier actividad focal de FDG predice una probabilidad mayor del 50% de corresponder a una lesión premaligna o maligna en el análisis histopatológico (regresión logística, p=0,01), independientemente del SUVmáx. Conclusión: De acuerdo con los resultados del presente estudio recomendamos la realización de una colonoscopia y biopsia de cualquier lesión sospechosa en todos los pacientes en los que se observe actividad focal de FDG en colon o recto en los estudios PET/TAC. © 2014 Elsevier España, S.L.U. y SEMNIM. Todos los derechos reservados.
Introduction
PET: imaging and evaluation
Colorectal cancer is the third most frequent cancer in both sexes, and represents 4–5% of cancer in overall population over 70 years. It is the third leading cause of cancer death in both men and women in the United States. The American Cancer Society estimated 142,820 new cases of colorectal cancer in the US in 2013. It is expected to cause about 50,830 deaths during this year.1 This cancer can be prevented by early detection and excision of a pre-malignant polyp. Five-year survival is in general 40% but this cancer can be cured if detected at an early stage, before metastases occur (90% five-year survival).2 Imaging with computed tomography (CT) is used to assess the anatomic extent of the disease and to determine appropriate treatment. Positron emission tomography (PET) uses the radiopharmaceutical 18 F-2-deoxy-d-glucose (FDG), a d-glucose analog labeled with fluorine-18. The main indications for FDG PET in colorectal carcinoma are the diagnosis of recurrent disease, exclusion of other metastasis before liver/lung resection and the evaluation of a rising carcinogenic embryonic antigen (CEA) serum level with no lesions in conventional imaging. Its use in screening or staging of colorectal cancer is not indicated.3–6 However, incidental colorectal FDG uptake is frequently observed when FDG PET is used for the evaluation of non-colorectal cancer patients.7–11 Physiologic colonic FDG activity is common on PET scans. While diffuse activity can be seen as a normal variant or due to a benign etiology such as inflammation; focal colonic uptake may indicate a potentially relevant lesion that merits further evaluation. The aim of the study was to assess the relevance of focal colorectal FDG activity incidentally found during PET/CT evaluation on predicting an underlying colorectal lesion.
Patients fasted for at least 6 h before FDG injection. PET scans were obtained after intravenous administration of 2.4–2.7 MBq/kg (0.06–0.07 mCi/kg) of FDG and a rest of 60 min. Images were acquired using a hybrid PET/CT scanner (General Electric Discovery ST, Waukesha, Wisconsin, USA) in 23 patients and a dedicated PET scanner (Siemens Exact HR+, Knoxville, TN, USA) in four patients. In PET/CT scanner a low-dose non-contrast enhanced CT (parameters: 120 Kv, 80 mA, 2.5 mm slices) was performed before PET acquisition. Thus, the CT images were used in order to obtain an attenuation map and also guide anatomical localization of lesions appreciated in PET. Two nuclear medicine physicians reviewed all PET scans, recording all patients with suspicious focal activity in large intestine. This image pattern was defined as a well-circumscribed hot spot of FDG activity in colon or rectum, not explained by physiologic colonic excretion of radiotracer and without continuation of activity along the proximal and distal intestinal tube. Opinion of a third nuclear medicine physician was requested in case of disagreement between the two main nuclear medicine physicians. The most common semiquantitative method of evaluating malignancies using PET is FDG maximum standardized uptake value (SUVmax). SUVmax is calculated as a ratio of tissue radiotracer concentration (kBq/mL) and injected dose (MBq) at the time of injection divided by body weight (in kilograms). It was calculated inside a spherical region of interest (ROI), encompassing the whole focal activity. None value of SUVmax was considered as a cut-off for possibility of malignancy.
Material and methods Patients We prospectively examined 2290 consecutive patients who underwent a whole-body PET/CT or PET scan in our institution in the last three years. We looked specifically for focal colon or rectal FDG activity. Patients with a known diagnosis of colorectal cancer and those with any known previous clinical disorder of large intestine, especially inflammatory bowel disease, were excluded. All patients with incidental FDG colorectal activity underwent a complete colonoscopy with biopsy of the lesion if found and CEA blood levels analysis. Colonoscopy and CEA were performed as part of the clinical routine protocol and therefore written informed consent was not necessary.
Colonoscopy All patients who presented focal colonic uptake in PET underwent a colonoscopy 37 days (mean) apart. All lesions found in colonoscopies (45) were biopsied or removed when possible, and its localization recorded. Colon was anatomically divided in eight sections from proximal to distal (cecum, ascending colon, hepatic angle, transverse colon, splenic angle, descending colon, sigmoid and rectum). Final diagnosis of incidental FDG PET/CT findings was made on the basis of histopathological report of specimens that were found on the colonoscopy.
Histopathology Histology of lesions found on colonoscopy was classified into two major categories: cancerous or precancerous lesion (1) and benign lesion or no macroscopic lesion (nml) (0).
Please cite this article in press as: Fuertes J, et al. Incidental focal uptake in colorectal location on oncologic FDG PET and PET/CT studies: Histopathological findings and clinical significances. Rev Esp Med Nucl Imagen Mol. 2014. http://dx.doi.org/10.1016/j.remn.2014.07.008
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PET-CT reports of 2290 patients
Focal FDG colorectal activity (27 patients, 1.17%) 22 more lesions in 15 patients (different location as that observed in PET)
c o l o n o s c o p y 23 lesions found in the same location as focal FDG observed in PET (18 patients)
Adenocarcinoma (8 lesions in 7 patients)
Melanosis coli (1 patient)
No macroscopic lesion in the same location as focal FDG observed in PET (8 patients)
Precancerous lesion (15 lesions in 11 patients)
Fig. 1. Flow chart of patients.
Subjects who presented cancerous or precancerous lesions (1) were divided in two categories: precancerous lesion (A) and cancerous lesion (B). The pathologic classification, tumor staging and grading were based on the 2010 World Health Organization (WHO) classification of tumors.15 Statistical analysis A logistic regression analysis (backward stepwise) was performed to study whether SUVmax had a predictive value for malignancy and premalignancy diagnosis. Subjects with malignant or premalignant lesions (1) and subject with benignant lesions or NML (0) versus the SUVmax values were fitted using logistic regression as follows: (SUVmax) =
eˇ0 +ˇ1 ·SUVmax eˇ0 +ˇ1 ·SUVmax + 1
where (SUVmax) is the probability of malignant or premalignant lesion for a given SUVmax value. The full logistic function was used to fit the data. When any of the parameters of the fitting was not significant, the function was fitted without the non-significant parameters until all the parameters of the fitting were statistically significant. Subjects with malignant lesions (1) and premalignant lesions (0) versus the SUVmax values were also fitted using a logistic regression to determine the probability of malignant versus nonmalignant lesion for a given SUVmax value. Statistical analysis was performed using R software package (v. 2.15.0. The R Foundation for Statistical Computing, Vienna, Austria). Correlation between variables PET and CT results were also analyzed independently, in relation to sensibility of each technique in lesion detection, SUVmax and tumor location, SUVmax and histological characteristics, SUVmax and size lesion and CEA analysis. Comparison of SUVmax and CEA between groups (benign, NML, pre-malignant and malignant) was performed using ANOVA test.
of a preneoplastic or even a malignant lesion underlying the focal colonic FDG uptake was stated and a colonoscopy was recommended. A complete colonoscopy was performed in all 27 patients with incidental colorectal FDG uptake, and biopsy of the lesions found in was performed in all of them, with no immediate complications (Fig. 1). In eighteen patients (66.6%) 23 lesions were found in the same location as FDG focal activity observed in the PET. In seven were diagnosed 8 adenocarcinomas and in 13 patients were diagnosed 15 precancerous lesions. One patient was diagnosed of a benign lesion (melanosis coli). Eight patients (29.6%) had no significant macroscopic lesions. Regardless of PET findings, colonoscopy demonstrated twenty-two more lesions in fifteen patients. The patient characterisitics are summarized in Table 1. Histological findings in patients with proven lesion in colonoscopy Benign lesions One patient had melanosis coli. Precancerous lesions Lesions visualized in PET scan: tubulovillous adenoma with low-grade dysplasia (8 patients, 2 patients with two lesions), tubulovillous adenoma with high-grade dysplasia (1 patient), tubular adenoma with low-grade dysplasia (2 patients), serrated adenoma with low-grade displasia (1 patient), hyperplastic polyp (1 patient). Lesions not visualized in PET scan: tubular adenoma with low-grade displasia (9 patients, 1 patient with two lesions), tubulovillous adenoma with low-grade dysplasia (6 patients, Fig. 2), serrated adenoma with low-grade displasia (2 patients), hyperplastic polyp (2 patients) and sessile micropolyp (2 patients). Cancerous lesions Lesions visualized in PET scan: high-grade adenocarcinoma (1 patient, 2 tumors), low-grade adenocarcinoma (6 patients, Fig. 2). Lesions not visualized in PET scan: All malignant lesions were visualized on PET scan.
Results Discordant findings Twenty-seven (age 72 ± 8 years, mean ± SD, 19 males, 8 females) out of the 2290 evaluated patients displayed incidental focal colonic uptake (32 FDG suspicious foci in colon). This represented an incidence of 1.17% for this finding. Primary malignancies in these patients were: lung cancer (n = 18), non-Hodgkin lymphoma (n = 4), carcinoma of unknown primary (n = 3), gastric cancer (n = 1) and urinary bladder cancer (n = 1). In each PET report the possibility
Two types of mismatch between PET findings and colonoscopy were found (Table 2): - Suspicious focal colorectal uptake in PET with no lesion in colonoscopy, which was considered as a PET false positive result. The rate was 29.6% (8 patients out of 27).
Please cite this article in press as: Fuertes J, et al. Incidental focal uptake in colorectal location on oncologic FDG PET and PET/CT studies: Histopathological findings and clinical significances. Rev Esp Med Nucl Imagen Mol. 2014. http://dx.doi.org/10.1016/j.remn.2014.07.008
CEA
SUVmax
L1
L2
1
71
F
NHL
NA
11.00
10.00
2
82
M
Lung
9.9
3 4 5
79 63 76
M F M
CUP NHL Lung
6 7
84 72
M M
8
55
9
CT findings
Colonoscopy findings
Histopathology
L1
L2
NU L1
NU L2
L1
L2
NU L1
N
TC
DC
S
0
Adenocarcinoma (HGA)
19.62
WT
R
0
DC
0
Adenocarcinoma (HGA) Adenocarcinoma (LGA)
Adenoma (TALGD) Adenoma (TALGD)
3.4 1 12.3
9.70 15.15 29.16
N WT WT
nml nml S
0 0 0
0 0 AC
0 0 0
CUP Lung
9.8 NA
7.77 20.82
Nod N
nml SA
0 DC
0 AC
0 0
F
Lung
NA
7.00
N
S
0
0
0
74
M
Lung
NA
17.13
WT
SA
0
S
0
10
72
M
Lung
14.6
13.61
N
SA
0
HA
AC
11 12 13
83 83 53
M M F
Stomach NHL Lung
4.7 NA NA
16.98 NA NA
N WT a
nml nml C
0 0 0
0 0 b
0 0 0
14
51
F
CUP
6.7
8.20
N
nml
0
C
0
nml
15 16 17
65 74 68
M F M
Lung Lung Lung
2.2 5.7 3.1
5.36 5.99 8.65
a a N
nml nml SA
0 0 0
0 0 DC
0 0 AC
18
70
M
Lung
4.7
13.75
WT
DC
DC
S
0
19
77
F
NHL
3.4
20.00
a
SA
0
S
TC
20
73
M
Lung
NA
20.63
N
S
0
0
0
21
72
M
Lung
1.1
18.73
N
R
0
R
R
22
70
M
Lung
1.8
8.06
N
R
0
0
0
23
68
M
Lung
5.3
3.51
N
nml
0
AC
0
nml nml Adenocarcinoma (LGAc) Adenocarcinoma (LGA) Adenoma (TVALGD) Adenocarcinoma (LGA) Adenoma (TVAHGD) Adenoma (TVALGD) nml
24
76
M
Lung
1.75
12.79
N
S
0
DC
0
25
79
M
Lung
7.4
6.72
N
S
0
S
0
26
69
F
Lung
2.2
1.80
WT
R
0
0
0
27
73
M
Urinary bladder
3
28.00
WT
R
0
0
0
19.19
15.76
nml Melanosis coli Adenoma (TVALGD) nml HP Adenoma (TALGD) Adenoma (TVALGD) Adenoma (TVALGD, 2 lesions) nml nml Adenoma (SALGD)
Adenoma (TVALGD) Adenoma (TVALGD) Adenoma (TALGD) Adenocarcinoma (LGA)
Size
NU L2
Adenoma (TALGD) Adenocarcinoma (LGA)
L1
L2
NU L1
6×2×2
9×3×3
3×3×3
15 × 3 × 3
6×6×3
NP NP 19 × 18 × 15
5×4×3
NP 2×2×2
Adenoma (TALGD)
TNM
NU L2 pT3 pN0 M0 (CT, PET) T3 N0 M0 (transrectalUS, CT, PET) NP NP NP NP pT1 pN0 M0 (CT, PET) NP
8×2×2
5×4×3
16 × 3 × 5
12 × 10 × 7
NP
25 × 20 × 15 17 × 9 × 5
NP
21 × 17 × 7 Adenoma (TVALGD)
Adenoma (TVALGD) Adenoma (TVALGD)
20 × 12 × 5 Adenoma (SALGD)
NP NP 5×3×3
Adenoma (SALGD, TALGD, TVALGD), HP Adenoma (TALGD)
Adenoma (TVALGD)
Adenoma (TALGD) Adenoma (TVALGD) Adenoma (TVALGD)
14 × 14 × 8, 9×7×6
7 × 6 × 4, 3 × 1 × 1, 22 × 20 × 13, 4×4×2 3×2×2
NP
Adenoma (TALGD)
NP NP 5×5×5 55 × 47 × 9
Adenoma (TALGD)
18 × 9 × 6
NP NP NP
21 × 20 × 12 8 × 3 × 3
NP NP pT1 pN0 M0 (CT, PET) pT3 pN0 M1 (CT, PET) NP
15 × 11 × 5
pTis N0 M0 (CT, PET) NP
6×5×4 12 × 11 × 9
NP
2×2×2
21 × 13 × 10
15 × 10 Adenoma (TALGD)
Adenoma (TVALGD)
12 × 10 × 10 10 × 10
Sessile micropolyp Sessile micropolyp HP
NP
NP micropolyp
18 15 × 9 × 6
9×7×3
NP NP
5×5×3
NP
25 × 25 × 20
NP
34
pT3 pN0 M0 (CT, PET)
Abbreviations: P, patient number; NHL, non-Hodgkin lymphoma; CUP, carcinoma of unknown primary; CEA-ng/ml; NA, not available; SUVmax-g/ml; N, normal; WT, wall thickening; Nod, nodule; a, no PET-CT; L1, lesion 1; L2, lesion 2; NU L1, non-FDG uptake lesion 1; NU L2, non-FDG uptake lesion 2; TC, transverse colon; R, rectum; nml, no macroscopic lesions; S, sigma; SA, splenic angle; C, cecum; DC, descending colon; AC, ascending colon; HA, hepatic angle; b, 4 polypoid lesions (adenomatous appearance); HGA, high-grade adenocarcinoma; LGA, low-grade adenocarcinoma; TVALGD, tubulovillous adenoma with low-grade dysplasia; HP, hyperplastic polyp; TALGD, tubular adenoma with low-grade dysplasia; LGAc, LGA in context of TVALGD, TVAHGD, tubulovillous adenoma with high-grade dysplasia; SALGD, serrated adenoma with low-grade dysplasia; size-millimeters (in the threes axis, when available); NP, no proceeds.
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Table 1 Patient characteristics.
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Fig. 2. (A) CT, (B) PET, (C) PET-CT fusion, (D) lesion histopatholgy (hematoxylin and eosin staining). (E) Maximum intensity projection. Patient 18 (see Table 1): focal FDG uptake located in descending colon (two different foci), associated with colonic wall thickening on CT. Large lesion (arrowhead) corresponded to a 55-mm low-grade adenocarcinoma (LGA). The other (arrow) corresponded to a 12-mm tubulovillous adenoma with low-grade dysplasia (TVALGD). Note FDG nodal uptake (little arrowhead) in hepatic dome, visible in the maximum intensity projection (E), concordant with metastatic disease.
- Clinically significant finding on colonoscopy without focal uptake in PET scan. This situation was considered as a PET false negative, and the rate was 55.5% (15 patients out of 27). All lesions not visualized in PET scan were benign. SUV analysis: Logistic regression analysis. A significant logistic regression model without intercept was fitted to the data (ˇ0 = N.S., ˇ1 = 0.066, p = 0.02). The probability of a cancerous/precancerous lesion increased with the SUVmax, as shown by logistic regression (Fig. 3, left panel). Cancerous or precancerous lesion was found at colonoscopy in nine out of the twelve patients (75%) with SUVmax higher than 15. In our sample the probability of a cancerous or precancerous lesion was higher than 50% for any value of SUVmax. Independently of SUVmax a high probability for cancerous or precancerous lesion was expected. No statistical significant logistic regression model was able to be fitted to malignant (1)/premalignant (0) versus SUVmax data (p > 0.5). On the other hand, SUVmax showed poor predictive value in discriminating between precancerous and cancerous lesions (Fig. 3, right panel). Comparison of CT, PET and histopathology of lesions From 27 patients in 23 CT data of PET/CT were available. In ten out of 23 patients (43.5%) the incidental colonic uptake focus detected by PET did not show morphologic alteration on CT. From these patients, four had cancerous lesions and 6 a precancerous lesion (Table 3). SUVmax and tumor location In lesions with FDG uptake no statistical significant differences were found between SUVmax and tumor location.
Precancerous lesions. SUVmax for precancerous lesions with lowgrade dysplasia was 14.47 ± 7.21 (n = 9) and 18.73 ± NA for highgrade dysplasia (n = 1). Cancerous lesions. SUVmax for low-grade adenocarcinoma was 20.14 ± 5.88 (n = 4) and 10.5 ± 0.71 for high-grade adenocarcinoma (n = 2). ANOVA test did not show statistically significant differences between groups (F = 4.7526, df = 1, p = 0.09474). CEA analysis Correlation of pathological findings with CEA levels was as follows: benign lesions tend to have a lower serum CEA level than the precancerous or cancerous lesions (2.85 ± 2.62 (n = 2) (benign), 6.76 ± 5.67 (n = 6) (precancerous) and 5.90 ± 3.56 (n = 3) (cancerous), but showing no statistically significant differences (F = 0.47, df = 2, p-value = 0.6382, ANOVA test). Malignancy and size lesion No statistically significant differences were observed in lesion size between precancerous and cancerous lesions. Discussion PET scan has increased the detection of unsuspected secondary malignancies. Recent publications highlight the relevance of incidental findings of a second malignancy in PET studies, mainly in lung cancer and lymphoma patients.16,17 Furthermore, multiple primary malignant neoplasms have been reported, either as synchronous (about one-third of cases) or metachronous lesions.18,19 Other studies have explored the possibility of finding a colorectal malignancy according to grade and pattern of FDG uptake in the colon in patients with unknown previous diagnosis of colorectal cancer. Zhuang et al. concluded that a large portion of focal
SUVmax and histological characteristics Table 3 Comparison of CT, PET and histopathology of lesions. Table 2 Discordant findings between PET and colonoscopy.
CT (non-diagnostic) findings N
Total
WT
Nod
4 0 6 4
1 1 3 3
1 0 0 0
6 1 9 7
14
8
1
23
Colonoscopy findings
PET-CT scan Positive (FDG uptake) Negative (no FDG uptake)
Lesion
nml
Total
19 15
8 NP
27
Patients nml Benign Precancerous Cancerous Total
Total Abbreviations: nml, no macroscopic lesion; NP, no proceeds.
27
Abbreviations: nml, no macroscopic lesion; N, normal; WT, wall thickening; Nod, nodule.
Please cite this article in press as: Fuertes J, et al. Incidental focal uptake in colorectal location on oncologic FDG PET and PET/CT studies: Histopathological findings and clinical significances. Rev Esp Med Nucl Imagen Mol. 2014. http://dx.doi.org/10.1016/j.remn.2014.07.008
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1.0
1.0 Cancerous / precancerous lesions
Cancerous lesion
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
Precancerous lesion
Benign lesion / NML 0.0
0.0 5
10
15
20
25
30
5
10
SUVmax
15
20
25
30
SUVmax
Fig. 3. SUV analysis. Logistic regression analysis.
colonic FDG accumulation incidentally found in PET scans represented cancer.20 The malignancy patterns in colon are clearly defined in standard anatomic imaging (pericolonic infiltration and parietal thickening in CT). Nevertheless, in PET scan, the reference in functional imaging, malignancy patterns are not clearly defined.28 At the beginning, uptake patterns were investigated (focal, multifocal, segmental, or diffuse hypermetabolism) with PET. Results showed that segmental or diffuse uptake is frequently associated with benign pathologies. Based on these findings, colonoscopy is indicated as a next step for nodular FDG uptake.9 Bowel focal accumulation of FDG is usually identified in the colonic mucosa and rarely in the bowel wall. In PET-CT scans bowel wall activity can be distinguished from tumor by lack of a CT soft tissue correlation or by demonstration of a typical pattern of bowel uptake. Diffuse, intermediate level activity of FDG is commonly identified in colon and in small bowel, as a result of physiologic excretion of radiotracer from liver to intestines. Also there is higher uptake of radiotracer within the cecum and right colon due to the higher concentration of lymphocytes in this region.21 In this study we focused on patients with a pattern of focal uptake in colon, since this is the group most likely to harbor an underlying neoplasia.9,11,13,14,22 Although several methods for decreasing physiologic FDG accumulation in bowel have been attempted, no technique has demonstrated consistently to decrease the bowel uptake of radiotracer. In our population the incidence of focal colonic uptake incidentally observed was 1.17%, slightly lower than that reported in other studies (1.32–3.9%)9–12 and similar with more recent studies.13 The reason for this lower incidence compared with previous studies may be due to the retrospective nature of our study and because only patients who met strict criteria for focal colonic uptake were included in our study. In the studies above referred, a focal colonic uptake was considered to be a premalignant or malignant lesions in a range from 59 to 68%.9–13 Similar findings are observed in our study, where we demonstrated a premalignant or malignant tumor in 66.6% of patients. The main limitation of our study is that no two-phase study was acquired with late abdominal image to rule whether the focal uptake observed corresponded to intestinal transit. We believe this measure would have decreased the false positive rate of the study. Despite its high affinity to malignant tissue, FDG is also strongly taken up by other malignancies (different than primary colon cancer) as well as nonmalignant processes that may be present in patients (diverticulitis, focal colitis or following polypectomy). It is not unusual to find different synchronous neoplasms in PET studies or in other imaging diagnostic tools. To the best of our
knowledge some individual patient cases have been reported,23–25 but only two structured papers have been published about it. Lardinois et al. assessed secondary FDG PET/CT findings in 350 patients initially examined for non-small cell lung cancer.26 The authors found second primary malignancies that were confirmed by biopsy and histopathologic analysis in 6 patients (2%). Lee et al. found focal colorectal FDG uptake in 62 (2.9%) of 2071 patients. Thirtyseven out of sixty-two patients were further studied and clinically unsuspected neoplasms were found in 68% of those investigated.27 It is widely known that SUVmax value orients about grade of malignancy of tumor. Unlike results of most of the reviewed literature,9,12,13 we have found that measurement of SUVmax would be a good marker for discrimination between benign and precancerous/cancerous lesions. Other more recent studies have shown that a SUVmax cut off is related with a high probability of advanced colorectal neoplasm.14 Nonmalignant uptake, which decreases the specificity and sensitivity, is a limitation of FDG PET. Focal hot spots such as focal smooth muscle uptake, non-uniform lymphocyte concentration in cecum and right colon, overlapping intestinal loops, undistended bowel, or diverticulitis may mimic the focal malignant lesion. Diffuse segmental FDG accumulations (inflammation/infection or drugs – metformine) may also occult in premalignant or even malignant focal lesions. In conclusion, a well-circumscribed hot spot of FDG activity in colon or rectum, not attributable to physiologic colonic excretion of radiotracer and without continuation of activity along the proximal and distal intestinal tube, is potentially predictive of subsequent pathologic findings, which may include malignancy. Colonoscopy is a mandatory next step for further diagnostic evaluation in these patients. Funding No funding received to do this work. Conflicts of interest The authors have no conflicts of interest to declare. References 1. American Cancer Society. What are the key statistics about colorectal cancer? http://www.cancer.org/Cancer/ColonandRectumCancer/DetailedGuide/ colorectal-cancer-key-statistics [accessed November 2013].
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