World Journal of Nuclear Medicine

REVIEW ARTICLE
Year
: 2020  |  Volume : 19  |  Issue : 3  |  Page : 187--196

Role of18F-fluorodeoxyglucose positron emission tomography/computed tomography in the evaluation of breast carcinoma: Indications and pitfalls with illustrative case examples


Moheieldin M Abouzied1, Ahmed Fathala1, Ahmad AlMuhaideb1, Mohammed H Al Qahtani2,  
1 Department of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
2 Department of Cyclotron and Radiopharmaceuticals, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Correspondence Address:
Dr. Moheieldin M Abouzied
Department of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh
Saudi Arabia

Abstract

Whole-body18F-fluorodeoxyglucose positron emission tomography (PET) has been used extensively in the last decade for the primary staging and restaging and to assess response to therapy in these patients. We aim to discuss the diagnostic performance of PET/computed tomography in the initial staging of breast carcinoma including the locally advanced disease and to illustrate its role in restaging the disease and in the assessment of response to therapy, particularly after the neoadjuvant chemotherapy. Causes of common pitfalls during image interpretations will be also discussed.



How to cite this article:
Abouzied MM, Fathala A, AlMuhaideb A, Al Qahtani MH. Role of18F-fluorodeoxyglucose positron emission tomography/computed tomography in the evaluation of breast carcinoma: Indications and pitfalls with illustrative case examples.World J Nucl Med 2020;19:187-196


How to cite this URL:
Abouzied MM, Fathala A, AlMuhaideb A, Al Qahtani MH. Role of18F-fluorodeoxyglucose positron emission tomography/computed tomography in the evaluation of breast carcinoma: Indications and pitfalls with illustrative case examples. World J Nucl Med [serial online] 2020 [cited 2020 Sep 19 ];19:187-196
Available from: http://www.wjnm.org/text.asp?2020/19/3/187/290368


Full Text

 Introduction



Locoregional staging with18 F-fluorodeoxyglucose positron emission tomography

Breast cancer is the most common malignancy in women worldwide and is second only to lung cancer as a cause of cancer death. The incidence of breast cancer has increased steadily over the past few decades, but breast cancer mortality seems to be declining, suggesting a benefit from early detection and more effective treatment.[1]

18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is not used for primary breast cancer detection because of false-negative findings, particularly in patients with tumor <1 cm and low tumor grade.[2]

Dedicated breast positron emission mammography (PEM) units have been developed to overcome such limitations of whole-body PET. Owing to its improved count sensitivity, higher spatial resolution, shorter acquisition time, and reduced attenuation, this system can detect smaller lesions <10 mm.[3]

Pritchard et al.[4] conducted a prospective, four-center study of 325 patients in Ontario with Stages I and II breast cancer and clinically negative axilla, who underwent18 F-FDG PET and PET/computed tomography (CT) for axillary nodal staging. Not surprisingly, they had 100% specificity with only 24% sensitivity.

As far as the detection, in 13 patients who were suspected of having distant metastases by18 F-FDG PET, 10 had false-positive findings and only three were confirmed to have Stage IV disease by biopsy or clinical follow-up.

The study clearly confirms the limited sensitivity of18 F-FDG PET for axillary nodal metastases and limited yield for distant disease in early-stage breast cancer. Several others have also stated that18 F-FDG PET/CT has a low diagnostic yield for breast cancer patients with Stage I and early Stage II.[5] Many of the findings are falsely positive,[6] while on the other hand, in patients with large, Stage III tumors or inflammatory breast cancer;18 F-FDG PET detects occult metastases in a substantial proportion of patients (10%–21%) not found by CT and bone scan [Figure 1].[7],[8],[9] The current National Comprehensive Cancer Network (NCCN) consensus guidelines stated that systemic staging, including18 F-FDG PET/CT, is not indicated for early-stage breast cancer in the absence of signs or symptoms suggesting metastasis.[10]{Figure 1}

There is currently no clinical role for routine18 F-FDG PET axillary staging in women with newly diagnosed early-stage breast cancer. A large prospective multicenter study evaluated 360 patients with newly diagnosed breast carcinoma aiming to evaluate its ability to stage the axilla with18 F-FDG PET before surgery. PET results were compared with those of pathologic analysis of axillary nodes. Overall,18 F-FDG G PET was 61% sensitive and 80% specific for axillary metastases, with a positive predictive value of 62% and a negative predictive value of 79%. Receiver operating characteristic curve analysis demonstrated that18 F-FDG PET had high specificity for nodal disease when a threshold standardized uptake value (SUV) of 1.8 was used; however, this increased specificity reduced sensitivity for nodal disease to 32%. On the basis of the results of their analysis, the authors concluded that “18 F-FDG PET is not routinely recommended for axillary staging” in women with breast cancer.[11]

However, in a subset of patients with locally advanced breast carcinoma (Stages III and IV disease) or inflammatory breast carcinoma, there is a high likelihood of axillary nodal metastases Therefore, once confirmed with preoperative18 F-FDG PET, then ultrasound (US)-guided tissue biopsy of any abnormal-appearing nodes can establish the presence of axillary metastases. Patients might proceed directly to axillary dissection rather than sentinel lymph node biopsy. This approach has been supported by several authors [Figure 2].[12],[13]{Figure 2}

Similarly, internal mammary nodal chain can be detected with18 F-FDG PET. Even though its clinical significance is uncertain, yet its detection might justify its inclusion within the radiation therapy port. In some authors' experience, its detection particularly in locally advanced disease carries a worse prognosis [Figure 3].[14]{Figure 3}

 Systemic Restaging of Recurrent Disease With18 F-Fluorodeoxyglucose Positron Emission Tomography



18 F-FDG PET and18 F-FDG PET/CT can improve staging and alter therapeutic options in patients suspected to have breast cancer recurrence and distant metastatic disease, primarily by demonstrating local or distant metastases not detected by other imaging studies.[15],[16]

In a retrospective analysis of 233 scans carried out in 122 patients by a group from Royal Marsden hospital,[17] PET/CT was used effectively for the clarification of indeterminate lesions on CT in 18 patients, on magnetic resonance imaging (MRI) in 15 patients, and on bone scan in 13 patients.

In patients with suspicious of recurrence,18 F-FDG PET can affect treatment decision in up to 44%.[18] For example, local recurrence alone can be treated differently when compared to patients with local recurrence plus metastatic disease [Figure 4].{Figure 4}

Accurate staging is particularly important in these patients because their treatment options may include surgery, radiation, chemotherapy, and hormonal therapy, depending on the distribution and burden of their disease.

One of the more encountered problems in breast cancer patients is rising tumor markers in a symptomatic patient. In this clinical scenario,18 F-FDG PET allows more accurate diagnosis of metastatic disease compared with conventional imaging (CI).

Radan et al.[18] showed in their study that18 F-FDG PET/CT was 90% sensitive for diagnosing recurrent tumor in patients with elevated levels of tumor markers and affected clinical management in 51% of the patients.[20] In this study,18 F-FDG PET/CT demonstrated improved sensitivity, specificity, accuracy, and predictive value compared with CT alone.

Bone metastases is one of the most common sites for breast cancer metastases, accounting for 90% of all the metastatic sites that can appear as osteolytic, osteoblastic, mixed, or even intramedullary without obvious bone changes.[19],[20]

18 F-FDG PET is superior to bone scintigraphy in detecting lytic and intramedullary metastases [Figure 5].{Figure 5}

In many centers, bone scintigraphy and CT remains the standard imaging combination for staging breast cancer, and18 F-FDG PET/CT remained as a second resort to clarify difficult or equivocal cases.

Historically,18 F-FDG PET frequently failed to demonstrate plastic lesions, which are readily detected with bone scintigraphy. However, CT component of18 F-FDG PET/CT can now easily recognize the osteoplastic non-18 F-FDG-avid lesions.[21],[22],[23]

The use of18 F-FDG PET/CT as a single-staging examination is the subject of ongoing studies and has yet to be determined. We evaluated 77 consecutive PET-CT scans in 39 breast cancer patients with suspected local recurrence or distant metastases. All patients had an initial evaluation with enhanced CT of the chest, abdomen, and pelvis along with bone scan Conventional Modalities (CM) within maximum 2 weeks of low-dose nonenhanced PET/CT. Histology (n = 11) or follow-up clinically and radiologically (n = 28) for at least 6 months was employed as the standard of reference for imaging findings.

PET-CT was true negative in ten patients in excluding local recurrence and distant metastases without false-negative reading, with a sensitivity and negative predictive value of 100%. CM was also true negative in ten patients with two false-negative reading, with a sensitivity of 92% and a negative predictive value of 83%.

PET-CT was true positive in 26 and false positive in three patients, in whom the histopathological examination revealed granulomatous disease, with a specificity and a positive predictive value of 76.9% and 89%, respectively. CM was true positive in 24 and false positive in three patients, with a specificity and a positive predictive value of 76.9% and 88%, respectively. The overall accuracy for PET/CT and CM was 92% and 87%, respectively.

We concluded that hybrid18 F-FDG PET/CT outperformed CM in restaging breast cancer patients.[22]

Therefore,18 F-FDG PET/CT has been recommended in the NCCN guidelines as an optional staging study for patients with locally advanced, inflammatory, and recurrent/metastatic breast cancer (MBC), especially when there are questions arising from standard staging studies.[10]

 Monitoring Response to Therapy With18 F-Fluorodeoxyglucose Positron Emission Tomography/computed Tomography



Neoadjuvant therapy response

Neoadjuvant (preoperative) systemic therapy has become the standard treatment for patients with locally advanced breast cancer.

It has an impact on improving surgical options by shrinking the size of the tumor and allowing less radical surgery, but has not been shown to improve survival.[24]

Size-based approach to assess the tumor response by structural radiological modalities such as CT, MRI, and US cannot distinguish between pathological complete response from other types of responses.[24] Changes in18 F-FDG metabolism often precede morphologic changes in tumor, and therefore functional imaging with18 F-FDG PET plays a major role in showing response sooner than CI techniques [Figure 6].{Figure 6}

Most studies evaluating18 F-FDG PET to assess response to neoadjuvant therapy have measured change in18 F-FDG uptake at mid-therapy, compared with baseline, as a measure of response.

Early on, Wahl et al.[25] followed by several other authors have shown significant quantitative differences in the18 F-FDG uptake measured before and after 2 months of therapy for responders versus nonresponders.

Several studies have suggested that18 F-FDG PET may serve as an early predictor of chemotherapy response and, most importantly, as an accurate predictor of lack of response.[26],[27],[28],[29]

Rousseau et al.[30] found that, using a 60% decrease in baseline SUV as the threshold for response,18 F-FDG PET was 61% sensitive and 96% specific after a single cycle, which increased to 89% sensitive and 95% specific after two cycles of therapy.

18 F-FDG PET may miss small-volume residual disease after therapy, however, the presence or absence of18 F-FDG uptake may carry prognostic significance that may be important in directing the intensity of additional therapy and postsurgery surveillance.[31]

Recurrent or metastatic disease response

Assessing the response to therapy in the clinical setting of metastatic disease is a challenging task for the conventional modalities. Even though complete cure is rare, often, these patients show response to therapy.

Cachin et al.[32] evaluated the therapeutic response of MBC patients to high-dose chemotherapy and autologous stem cell transplantation. In their study, 47 patients with MBC were treated with a maximum of three cycles of HDC. The therapeutic response was assessed with CI and by18 F-FDG PET study performed after the last cycle of HDC.

Complete responses were observed in 16 patients (37%) with CI and 34 patients (72%) with18 F-FDG PET. The18 F-FDG PET result was the most powerful and independent predictor of survival; patients with a negative posttreatment18 F-FDG-PET had a longer median survival than patients with a positive18 F-FDG PET (24 months vs. 10 months; P < 0.001).

Dose Schwarz et al.[33] have evaluated the use of sequential18 F-FDG PET to predict response after the first and second cycles of standardized chemotherapy for MBC and have shown that response might be visible as early as after a single cycle of chemotherapy.

One particular problem in assessing response to therapy is bone metastases as none of the current modalities, bone scan, MRI, and CT, can accurately assess response to therapy in bone sites.

Bone scan with its known flare phenomenon can even be more confusing. Even though the majority of untreated bone metastases are positive on PET scans and have a lytic pattern on CT, after treatment, incongruent CT-positive/PET-negative lesions are significantly more prevalent and are generally osteoblastic, which presumably reflects a direct effect of treatment [Figure 7].[34]{Figure 7}

Recent studies have suggested that serial18 F-FDG PET can be helpful in measuring bone metastasis response and that changes in18 F-FDG uptake correlate with clinical response and changes in breast cancer tumor markers.[35]

 Commonly Encountered Pitfalls



False-positive uptake

18 F-FDG is not a tumor-specific probe. In addition to its physiologic accumulation in different organs, it can accumulate in benign nonneoplastic pathologic conditions; including infection, whether acute or chronic infection such as abscess formation; tuberculosis; granulomatous diseases such as sarcoidosis; and autoimmune disease such as Grave's disease.[36]

In addition, the18 F-FDG uptake can be enhanced by inflammatory-induced changes, which include postoperative healing scars and postradiation therapy. The degree of uptake is usually less than the uptake within the neoplastic tissues.[36] However, there is clearly an overlap between the two conditions and in some cases, the uptake could even exceed the neoplastic uptake. Furthermore, the image interpreter should be aware of the accumulation of18 F-FDG to some extent in some benign tumors, such as fibro-adenoma, fibrocystic changes of the breast, atypical ductal dysplasia, duct ectasia, and phyllodes tumor [Figure 8], [Figure 9], [Figure 10].[37]{Figure 8}{Figure 9}{Figure 10}

False-negative uptake

There are many factors that can affect18 F-FDG avidity to breast cancer: small tumor size <1 cm and some less aggressive malignancies such as carcinoma in situ, lobular carcinoma, and tubular subtype of breast carcinoma;[2] such lesions can be easily overlooked by18 F-FDG PET.

Detection of an unexpected primary cancer

The detection of unexpected malignancy could have a major clinical significance not only in breast cancer patients but also in any kind of malignant process staging.

In one study, the prevalence of pathology-proved additional primary malignancies at PET/CT performed for known or suspected malignancies was 1.2%.[38] Further diagnostic work-up would be needed in this clinical scenario as the patient's management is anticipated with the new diagnosis of second primary.

On the other hand, detection of unexpected focal hypermetabolic lesion in the breast parenchyma in patients who are undergoing PET/CT for reasons other than breast cancer staging may represent malignancy [Figure 11], [Figure 12], [Figure 13].{Figure 11}{Figure 12}{Figure 13}

 Conclusions



There has been growing evidence in literatures that18 F-FDG PET/CT is now playing a major role in the early staging of locally advanced and inflammatory breast carcinoma, restaging patients with clinical suspicious of recurrence and in the evaluation of response to therapy post either neoadjuvant chemotherapy or chemotherapy for metastatic breast carcinoma.

One must be familiar with PET/CT limitations such as its limited spatial resolution; an encountered problem in early stages of breast cancer that has been resolved by the new introduction of PEM.

More studies are needed to explore the potential benefits of new tracers other than18 F-FDG; for example,18 F-fluorestradiol to image estrogen receptor expression,18 F-Z (Her-2)(:342)-Affibody to image epidermal growth factor expression (Her-2 neu), and18 F-Fluoride to specifically assess the bony skeletal structures.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.
2Kumar R, Chauhan A, Zhuang H, Chandra P, Schnall M, Alavi A. Clinicopathologic factors associated with false negative FDG-PET in primary breast cancer. Breast Cancer Res Treat 2006;98:267-74.
3Rosen EL, Turkington TG, Soo MS, Baker JA, Coleman RE. Detection of primary breast carcinoma with a dedicated, large-field-of-view FDG PET mammography device: Initial experience. Radiology 2005;234:527-34.
4Pritchard KI, Julian JA, Holloway CM, McCready D, Gulenchyn KY, George R, et al. Prospective study of 2-[18F] fluorodeoxyglucose positron emission tomography in the assessment of regional nodal spread of disease in patients with breast cancer: An Ontario clinical oncology group study. J Clin Oncol 2012;30:1274-9.
5Lovrics PJ, Chen V, Coates G, Cornacchi SD, Goldsmith CH, Law C, et al. A prospective evaluation of positron emission tomography scanning, sentinel lymph node biopsy, and standard axillary dissection for axillary staging in patients with early stage breast cancer. Ann Surg Oncol 2004;11:846-53.
6Norum J, Andreassen T. Screening for metastatic disease in newly diagnosed breast cancer patients. What is cost-effective? Anticancer Res 2000;20:2193-6.
7van der Hoeven JJ, Krak NC, Hoekstra OS, Comans EF, Boom RP, van Geldere D, et al. 18F-2-fluoro-2-deoxy-d-glucose positron emission tomography in staging of locally advanced breast cancer. J Clin Oncol 2004;22:1253-9.
8Carkaci S, Macapinlac HA, Cristofanilli M, Mawlawi O, Rohren E, Gonzalez Angulo AM, et al. Retrospective study of 18F-FDG PET/CT in the diagnosis of inflammatory breast cancer: Preliminary data. J Nucl Med 2009;50:231-8.
9Niikura N, Liu J, Costelloe CM, Palla SL, Madewell JE, Hayashi N, et al. Initial staging impact of fluorodeoxyglucose positron emission tomography/computed tomography in locally advanced breast cancer. Oncologist 2011;16:772-82.
10Carlson RW, Allred DC, Anderson BO, Burstein HJ, Carter WB, Edge SB, et al. Invasive breast cancer. J Natl Compr Canc Netw 2011;9:136-222.
11Wahl RL, Siegel BA, Coleman RE, Gatsonis CG, PET Study Group. Prospective multicenter study of axillary nodal staging by positron emission tomography in breast cancer: A report of the staging breast cancer with PET Study Group. J Clin Oncol 2004;22:277-85.
12Gil-Rendo A, Zornoza G, García-Velloso MJ, Regueira FM, Beorlegui C, Cervera M. Fluorodeoxyglucose positron emission tomography with sentinel lymph node biopsy for evaluation of axillary involvement in breast cancer. Br J Surg 2006;93:707-12.
13Zornoza G, Garcia-Velloso MJ, Sola J, Regueira FM, Pina L, Beorlegui C. 18F-FDG PET complemented with sentinel lymph node biopsy in the detection of axillary involvement in breast cancer. Eur J Surg Oncol 2004;30:15-9.
14Bellon JR, Livingston RB, Eubank WB, Gralow JR, Ellis GK, Dunnwald LK, et al. Evaluation of the internal mammary lymph nodes by FDG-PET in locally advanced breast cancer (LABC). Am J Clin Oncol 2004;27:407-10.
15Rosen EL, Eubank WB, Mankoff DA. FDG PET, PET/CT, and breast cancer imaging. Radiographics 2007;27 Suppl 1:S215-29.
16Constantinidou A, Martin A, Sharma B, Johnston SR. Positron emission tomography/computed tomography in the management of recurrent/metastatic breast cancer: A large retrospective study from the Royal Marsden Hospital. Ann Oncol 2011;22:307-14.
17Eubank WB, Mankoff D, Bhattacharya M, Gralow J, Linden H, Ellis G, et al. Impact of FDG PET on defining the extent of disease and on the treatment of patients with recurrent or metastatic breast cancer. AJR Am J Roentgenol 2004;183:479-86.
18Radan L, Ben-Haim S, Bar-Shalom R, Guralnik L, Israel O. The role of FDG-PET/CT in suspected recurrence of breast cancer. Cancer 2006;107:2545-51.
19Abouzied M, Tuli M, Alsugair A, Alblushi N, Rifai A. Does bone scan add any incremental value to 18FDG PET/CT in restaging patients with breast carcinoma? Radiology; (Supp. 1), 302, November 2007.
20Cook GJ, Houston S, Rubens R, Maisey MN, Fogelman I. Detection of bone metastases in breast cancer by18 FDG PET: Differing metabolic activity in osteoblastic and osteolytic lesions. J Clin Oncol 1998;16:3375-9.
21Nakai T, Okuyama C, Kubota T, Yamada K, Ushijima Y, Taniike K, et al. Pitfalls of FDG-PET for the diagnosis of osteoblastic bone metastases in patients with breast cancer. Eur J Nucl Med Mol Imaging 2005;32:1253-8.
22Algafri A, Al-Tweigeri T, Al-Sugair A, Al-Seabee M, Al-Alawi E, Fathala A, et al. The Diagnostic Accuracy of FDG PET Low Dose None Enhanced CT in the Detection of Local Recurrence and Distant Metastases during Follow-up of Breast Cancer Patients: A Comparison to Enhanced CT and Bone Scan. Vienna, Austria: The European Congress of Radiology; 2012.
23Gralow JR, Zujewski JA, Winer E. Preoperative therapy in invasive breast cancer: Reviewing the state of the science and exploring new research directions. J Clin Oncol 2008;26:696-7.
24Feldman LD, Hortobagyi GN, Buzdar AU, Ames FC, Blumenschein GR. Pathological assessment of response to induction chemotherapy in breast cancer. Cancer Res 1986;46:2578-81.
25Wahl RL, Zasadny K, Helvie M, Hutchins GD, Weber B, Cody R. Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: Initial evaluation. J Clin Oncol 1993;11:2101-11.
26Mankoff DA, Dunnwald LK. Changes in glucose metabolism and blood flow following chemotherapy for breast cancer. PET Clin 2006;1:71-81.
27Schelling M, Avril N, Nährig J, Kuhn W, Römer W, Sattler D, et al. Positron emission tomography using [(18)F] Fluorodeoxyglucose for monitoring primary chemotherapy in breast cancer. J Clin Oncol 2000;18:1689-95.
28Smith I, Welch AE, Hutcheon AW, Miller ID, Payne S, Chilcott F, et al. Positron emission tomography using [18F]-fluorodeoxy-d-glucose to predict the pathologic response of breast cancer to primary chemotherapy. J Clin Oncol 2000;18:1676-88.
29Berriolo-Riedinger A, Touzery C, Riedinger JM, Toubeau M, Coudert B, Arnould L, et al. [18F]FDG-PET predicts complete pathological response of breast cancer to neoadjuvant chemotherapy. Eur J Nucl Med Mol Imaging 2007;34:1915-24.
30Rousseau C, Devillers A, Sagan C, Ferrer L, Bridji B, Campion L, et al. Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by [18F]fluorodeoxyglucose positron emission tomography. J Clin Oncol 2006;24:5366-72.
31Kim SJ, Kim SK, Lee ES, Ro J, Kang S. Predictive value of [18F] FDG PET for pathological response of breast cancer to neo-adjuvant chemotherapy. Ann Oncol 2004;15:1352-7.
32Cachin F, Prince HM, Hogg A, Ware RE, Hicks RJ. Powerful prognostic stratification by [18F]fluorodeoxyglucose positron emission tomography in patients with metastatic breast cancer treated with high-dose chemotherapy. J Clin Oncol 2006;24:3026-31.
33Dose Schwarz J, Bader M, Jenicke L, Hemminger G, Jänicke F, Avril N. Early prediction of response to chemotherapy in metastatic breast cancer using sequential 18F-FDG PET. J Nucl Med 2005;46:1144-50.
34Fogelman I, Cook G, Israel O, Van der Wall H. Positron emission tomography and bone metastases. Semin Nucl Med 2005;35:135-42.
35Stafford SE, Gralow JR, Schubert EK, Rinn KJ, Dunnwald LK, Livingston RB, et al. Use of serial FDG PET to measure the response of bone-dominant breast cancer to therapy. Acad Radiol 2002;9:913-21.
36Abouzied MM, Crawford ES, Nabi HA. 18F-FDG imaging: Pitfalls and artifacts. J Nucl Med Technol 2005;33:145-55.
37Adejolu M, Huo L, Rohren E, Santiago L, Yang WT. False-positive lesions mimicking breast cancer on FDG PET and PET/CT. AJR Am J Roentgenol 2012;198:W304-14.
38Ishimori T, Patel PV, Wahl RL. Detection of unexpected additional primary malignancies with PET/CT. J Nucl Med 2005;46:752-7.