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Originally published as JCO Early Release 10.1200/JCO.2008.17.1496 on August 11 2008

Journal of Clinical Oncology, Vol 26, No 29 (October 10), 2008: pp. 4746-4751
© 2008 American Society of Clinical Oncology.

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Preoperative Staging of Large Primary Breast Cancer With [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Compared With Conventional Imaging Procedures

David Fuster, Joan Duch, Pilar Paredes, Martín Velasco, Montserrat Muñoz, Gorane Santamaría, Montserrat Fontanillas, Francesca Pons

From the Nuclear Medicine Department, Hospital Clínic de Barcelona, Barcelona, Spain

Corresponding author: David Fuster, MD, Nuclear Medicine Department, Hospital Clínic de Barcelona, Villarroel, 170, 08036 Barcelona, Spain; e-mail: dfuster{at}clinic.ub.es


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Purpose To evaluate the utility of positron emission tomography (PET) and [18F]fluorodeoxyglucose in the initial staging of large primary breast tumors.

Patients and Methods This prospective study was approved by the ethics committee, and all patients gave their informed consent before enrollment. Sixty consecutive patients with large (> 3 cm) primary breast cancer diagnosed by clinical examination and breast magnetic resonance imaging (MRI) were entered onto the study. The mean age was 57 ± 13 years. Chest computed tomography (CT), liver ultrasonography, bone scan, and PET/CT were performed in all patients. All findings were histologically confirmed, and/or at least 1 year of follow-up was required. Correlation between parameters was calculated using Pearson's correlation coefficient. P < .05 was considered statistically significant.

Results Primary tumor was identified by both PET/CT and MRI in all patients. Multifocal and/or multicentric tumors were found in 19 patients by MRI. Axillary lymph node metastases were found in 20 of 52 patients. Extra-axillary metastatic lymph nodes were also found in three patients. One patient showed an infiltrated lymph node in the contralateral axilla. The sensitivity and specificity for PET/CT to detect axillary lymph nodes metastases were 70% and 100%, respectively. PET/CT diagnosed all extra-axillary lymph nodes. The overall sensitivity and specificity of PET/CT in detecting distant metastases were 100% and 98%, respectively; whereas the sensitivity and specificity of conventional imaging were 60% and 83%, respectively. PET led to a change in the initial staging in 42% of patients.

Conclusion PET/CT underestimates locoregional lymph node staging in large primary breast cancer patients. PET/CT is a valuable tool to discard unsuspected extra-axillary lymph nodes and distant metastases.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Locally advanced breast cancer is defined as a large tumor (T3 or greater) or advanced axillary disease (N2) without evidence of distant metastases.1 Such patients are commonly treated with neoadjuvant chemotherapy followed by definitive surgery, postoperative chemotherapy, and radiation therapy. Neoadjuvant chemotherapy is used to reduce the tumor volume, is suitable in cases of unfavorable anatomic location, and allows for breast-conserving surgery.2 An accurate prognosis is difficult because of the clinical and biologic heterogenicity of breast cancer. The 5-year local recurrence rate after lumpectomy can be up to 10%, and the risk of disease spread at the time of diagnosis is relatively high.3

Mammography has been shown to be accurate for breast cancer screening except in some specific situations, such as in patients with dense breast, significant architectural distortions, or presence of extensive scarring from prior biopsies.4-7 Contrast magnetic resonance imaging (MRI) can provide detailed information about the size and extent of primary breast cancer and has an additional value for evaluating multifocal and/or multicentric tumors.8 However, conventional imaging cannot precisely detect axillary lymph node involvement and/or the presence of distant metastases, which significantly change therapeutic management of these patients. Whole-body positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) has proven to be an effective imaging modality for staging of malignant tumors. The addition of PET in the standard work-up of breast cancer may lead to the detection of unexpected metastases in the initial staging9 as well as the detection of recurrences.10 However, the studies that have been published are retrospective and/or heterogeneous,11,12 and the role of PET in women with breast cancer remains to be defined. The aim of this study was to evaluate the utility of PET/computed tomography (CT), compared with standard imaging procedures, in the staging of potentially operable patients with large primary breast cancer.


    PATIENTS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Patients
This prospective study was approved by the ethics committee of our institution, and all patients gave their informed consent before enrollment. Sixty consecutive patients with newly diagnosed, noninflammatory, large primary (> 3 cm) breast cancer who were diagnosed by clinical examination and breast MRI were included in the study. The mean age was 57 ± 13 years. Contrast-enhanced chest CT, liver ultrasonography, and whole-body technetium-99m (99mTC)–hydroxylmethylene diaphosphonate bone scan investigations were performed in all patients. The mean tumor size was 4.9 ± 1.8 cm. Diagnosis of invasive breast adenocarcinoma was performed by core needle biopsy in all patients, and the stage of cancer was determined by physical examination of the axillary region and breast MRI. Patients without evidence of metastatic disease underwent lumpectomy and axillary lymphadenectomy. Exclusion criteria were as follows: pregnancy; prior breast surgery, chemotherapy, or radiation therapy; known diabetes; and age younger than 18 years.

PET/CT Imaging
PET/CT scans were performed with a hybrid PET/CT (Biograph; Siemens, Erlangen, Germany) with an Ecat Exact HR+ BGO PET and a helicoidal CT scanner (Somatom Emotion, Siemens). Patients had fasted 4 hours before PET acquisition, and blood glucose had to be less than 7 mmol/L before injection of 740 MBq of FDG. Intravenous injection in the opposite arm to the breast performed using a venous line (to prevent extravasation) was followed by a period of approximately 60 minutes, during which patients remained in a quiet room. CT images were acquired immediately after PET performance (4.86 mm, 100 kV, 50 mA). No muscle relaxants were administered. Patients were allowed to breathe normally (shallow tidal breathing) during PET and CT acquisitions. No oral or intravenous contrast was used. During acquisitions, patients were in supine position with their arms raised above their head.

Whole-body PET data were acquired in two-dimensional mode and for 5 minutes per bed position. PET images were reconstructed using CT data, for attenuation correction, using the ordered-subsets expectation maximization algorithm and without CT-based attenuation correction. Interpretation of PET data was performed independently by two nuclear physicians blinded to clinical, radiologic, and pathologic findings and axillary lymph node status. Breast tumor uptake was visually categorized in three levels (low, moderate, or high). A region of interest (ROI) of 5 to 10 mm was placed manually over the area of maximal activity on slices with the clearest definition of the tumor mass and in the adjacent slices. The standardized uptake value (SUV) was calculated based on the measured activity, decay-corrected injected dose, and patient body weight.

Formula
A maximal SUV of more than 2.5 was considered as a malignant neoplastic process.13

MRI
The patients in the study were examined using a 1-T MRI system (Magnetom Impact; Siemens). Patients were told to remain still during the examination to avoid motion artifacts and obtain acceptable quality images. Images were acquired in the prone position using a dedicated double breast surface coil. Imaging was performed before a rapid bolus injection of gadopentetate dimeglumine 0.16 mmol/kg (Magnevist; Schering, Berlin, Germany) and 20-mL saline flush, which were delivered through an intravenous cannula inserted in an antecubital vein, and five times after injection of contrast. Automated subtraction of the appropriate precontrast and postcontrast images and multiplanar reconstruction of data sets were performed. Two experienced radiologists evaluated the results of MRI by consensus. The lesion size and multifocality or multicentricity were noted. The longest axis of the tumor on the subtracted and reconstructed images was referred to as the lesion size.

Follow-Up
All patients included in the study had histologic confirmation of noninflammatory breast cancer. Axillary staging was performed after surgical lymphadenectomy and posterior analysis of pathologic nodes. Biopsy of suspected pathologic extra-axillary lymph nodes by imaging procedures was performed in all patients. Distant metastases were confirmed histologically in at least one site to establish the patient's operability. Multiple metastatic disease was determined by at least 1 year of follow-up by conventional imaging procedures.

Statistical Methods
Correlations between FDG uptake and tumor size and FDG uptake and prediction of staging were calculated using Pearson's correlation coefficient. Sensitivity, specificity, positive predictive value, and negative predictive value were evaluated by standard methods. P < .05 was considered statistically significant.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Primary tumor was identified by both PET/CT and MRI in all patients (Fig 1). Multicentric (n = 12) and multifocal (n = 7) tumors were found by MRI in 19 patients; 14 of 19 of these tumors were detected by PET/CT. Histologic analysis showed either invasive ductal carcinoma (52 of 60 patients) or invasive lobular carcinoma (eight of 60 patients). In nine of 60 patients, the maximal SUV in the tumor was less than 2.5 and visually graded as low uptake. Axillary lymph node metastases were found in 20 of 52 patients with axillary lymphadenectomy. The overall number of axillary lymph nodes surgically resected was 315 (15.7 lymph nodes per patient), and histologic confirmation of axillary lymph node involvement as a result of breast cancer was found in 84 of the nodes (Table 1). Three cases of extra-axillary metastatic lymph node involvement in the infraclavicular region (n = 2) and the supraclavicular region (n = 1) were also found. One patient without proven disease in the contralateral breast and/or prior breast cancer showed an infiltrated lymph node in the contralateral axilla. Distant metastases were found in eight of 60 patients (Table 2). These were located in the bone (n = 6), lung (n = 2), and liver (n = 2). There was complete agreement between the two readers when evaluating PET/CT findings. No correlation between tumor size or multifocality, both measured by MRI, and the degree of FDG uptake (SUV) was found. No significant correlation between SUV and prediction of staging and/or extent of disease was found. Clinical examination of the axillary region only detected infiltrated lymph nodes in two of 20 patients with axillary involvement.


Figure 1
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Fig 1. Left breast tumor visualized by both positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI). (A) PET and fusion PET/CT images in the transaxial axis show an intense uptake in the left breast lesion. (B) Axial MRI image of contrast series shows regional enhancement in left breast, predominantly in inner quadrants.

 

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Table 1. Results of Positron Emission Tomography/Computed Tomography Obtained in the Group of Patients Affected by Axillary Lymph Node Involvement of the Disease

 

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Table 2. Staging of Patients

 
The sensitivity and specificity for PET/CT to detect axillary lymph nodes metastases on a patient-by-patient basis were 70% and 100%, respectively. On a lymph node count, PET/CT detected 24 of 84 infiltrated lymph nodes. PET/CT diagnosed all extra-axillary lymph nodes. However, an inflammatory laterocervical lymph node showing FDG uptake was considered as a false-positive result for PET/CT. A second lymph node that was positive by PET/CT in the supraclavicular region was later diagnosed as metastasis of a malignant sarcoma.

The overall sensitivity and specificity in detecting distant metastases for PET/CT were 100% and 98%, respectively; whereas the sensitivity and specificity for conventional imaging were 60% and 83%, respectively. Analyzing site-by-site distant metastases showed that PET/CT had detected all the lesions found (Fig 2). One patient showed a focal uptake of FDG in the lung as a result of a benign inflammatory process and was then considered as a false positive. Liver ultrasound was coincident to PET/CT in one of two patients with liver metastases but also showed suspicious lesions in five patients (three angiomas and two cysts). Bone scintigraphy localized only two of six bone metastases. The false-negative lesions (four of six lesions) were lytic in nature, as can be seen in CT images from PET/CT. However, bone scan showed seven false-positive results, which proved to be degenerative joint diseases (n = 3), rib fractures (n = 2), a fibrous dysplasia, and an enchondroma of the femur. Chest CT detected the two patients with lung metastases but, in four patients, found suspicious lung lesions (three nodules and one benign inflammatory process) that were considered as false-positive results of this technique.


Figure 2
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Fig 2. A case of metastatic spread in the liver and in the bone. A whole-body positron emission tomography/computed tomography scan in the (A) coronal and (B) transaxial axes shows multiple focal intense spots in both localizations. (C) Bone scan and (D) liver ultrasound were unremarkable.

 
Additional PET findings downstaged seven of 60 patients with suspected metastatic disease suggested by conventional imaging procedures. However, PET was able to detect unsuspected metastatic lesions as a result of axillary infiltrated nodes (10 of 60 patients), extra-axillary nodes (three of 60 patients), and distant metastases (five of 60 patients), all of which meant an upstaging of the disease (Table 3). PET led to a change in the initial staging in 42% of patients included in this study.


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Table 3. Change in Management by PET/Computed Tomography Findings Compared With Conventional Procedures

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
PET/CT has been recognized as a powerful technique in the detection of malignant tumors. Minn and Soini13 reported a sensitivity and specificity of 100% when diagnosing breast malignancies in 10 patients with confirmed primary breast cancer. In our series, all lesions showed significant FDG uptake. However, the degree of tumor uptake was widely variable, reaching a maximal SUV of less than 2.5 or showing a low uptake in 15% of patients, similar to other series. This indicates that PET may not be a reliable technique for differential diagnosis of breast lesions, as occurs for other malignancies.14 Multifocal and/or multicentric disease was visualized by PET/CT in 14 of 19 of the tumors detected by MRI images. In five of these cases where PET/CT showed only one focus, the tumor uptake was high (maximal SUV > 6), suggesting that the reduced sensitivity was a result of partial volume effects.15

The sensitivity of PET/CT to detect axillary involvement on a patient-by-patient basis is quite high, reaching 70% of the 20 patients with histologically demonstrated infiltrated nodes. As reported in the literature, PET/CT has difficulties diagnosing involved lymph nodes as a result of micrometastases, and it does not seem to be able to replace lymphoscintigraphy with invasive sentinel lymph node biopsy to discard axillary involvement in locally advanced breast cancer patients.16 However, the specificity of PET/CT was 98%, and this may be of value in such patients because it indicates the need for axillary lymphadenectomy.

The infraclavicular lymph nodes lie medial to the medial margin of the pectoralis minor muscle and are associated with extremely poor prognosis.17 PET/CT detected unexpected infraclavicular node involvement in two patients who were then reclassified as having N3a stage disease, as is recommended by the American Joint Committee on Cancer staging system.18 PET/CT also diagnosed one patient with unexpected extra-axillary pathologic nodes located in the supraclavicular region (N3c), and a second patient without proven disease in the contralateral breast showed a metastatic lymph node in the contralateral axilla. However, one inflamed laterocervical lymph node showing FDG uptake was considered as a false-positive result for PET/CT. A second lymph node that was positive by PET/CT in the supraclavicular region was diagnosed as metastasis of a malignant sarcoma. The utility of PET to detect pathologic extra-axillary lymph nodes is suggested in retrospective studies of preoperative breast cancer patients.19 Danforth et al20 found that PET might play a major role for multiple local/regional tumoral sites. Recent guidelines already suggest the utility of PET in the staging and management of different tumors including breast cancer, especially to detect unexpected extra-axillary lymph nodes and distant metastases.21

Results demonstrating the superiority of PET over anatomic imaging modalities in the detection of distant metastases are relatively well documented.22 Dose et al23 found the overall sensitivity and specificity of PET in detecting distant metastases to be 86% and 90%, respectively. This was more accurate than anatomic imaging, which had a sensitivity of only 36% and a specificity of 95%. Our results were similar, with an overall sensitivity and specificity of 100% and 98%, respectively, for PET/CT versus 60% and 83%, respectively, for conventional imaging.

Evaluation of PET/CT compared with 99mTc-labeled methylene diphosphonate bone scintigraphy in the detection of bone metastases relies on their osteoblastic or osteolytic nature.24 We found a lower sensitivity when using bone scintigraphy to detect bone metastases (two of six lesions), especially for lesions localized in the spine (one of three lesions). The reason for high avidity for FDG and negative bone scans in such cases was that lesions were predominantly lytic in nature, which has important prognostic implications. The low degree of specificity of bone scintigraphy is clearly documented,25 and thus, the probability of false-positive findings is high. Our study showed that as many as seven of 60 lesions in bone scintigraphy images were finally confirmed as benign processes. PET/CT diagnosed both patients with liver metastases, whereas liver ultrasound only detected one of two of the patients affected by liver spread. However, some authors recommend the use of contrast-enhanced sonography or CT as being more accurate than liver ultrasound to assess metastatic liver disease.26 Chest CT is the most adequate noninvasive imaging procedure to stage cancer at this level; however, because of its high resolution, it can visualize micronodules that, on occasion, may not be pathologic. Moreover, benign inflammatory processes can also be misinterpreted as malignant lesions by lung CT, as occurred in one patient in this study. PET can also show intense uptake in some cases, especially in chronic granulomatous diseases,27 reading as a false positive in the aforementioned patient.

Byrne et al28 suggest that PET may have a role in the staging of locally advanced breast cancer before surgical or chemotherapeutic intervention, but correlation with anatomic modalities would be required because of the poor resolution of PET. PET/CT can be assessed anatomically by integrated CT images, significantly improving the overall resolution of PET findings. In our series, PET/CT led to a change in the initial staging in 42% of patients included in this study, showing higher values of sensitivity and specificity in detecting distant metastases compared with conventional imaging, which makes this technique recommendable in the staging of patients with large primary breast cancer. The results obtained in our series suggest that PET/CT underestimates locoregional lymph node staging in large primary breast cancer patients. PET/CT is a valuable tool to discard unsuspected extra-axillary lymph nodes and distant metastases.


    AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
The author(s) indicated no potential conflicts of interest.


    AUTHOR CONTRIBUTIONS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Conception and design: David Fuster, Montserrat Muñoz

Administrative support: Gorane Santamaría

Provision of study materials or patients: Montserrat Fontanillas

Collection and assembly of data: Pilar Paredes

Data analysis and interpretation: Joan Duch, Martin Velasco

Manuscript writing: David Fuster, Martin Velasco

Final approval of manuscript: Francesca Pons


    NOTES
 
published online ahead of print at www.jco.org on August 11, 2008

Supported by Insituto de Salud Carlos III Fondo de Investigacion Sanitaria Grant No. 04/0840 and Red Temática de Investigación Cooperativa de Centros de Cáncer.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
1. Beahrs OH: Staging of cancer. CA Cancer J Clin 41:121-125, 1991[CrossRef][Medline]

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9. van der Hoeven JJ, Krak NC, Hoekstra OS, et al: 18F-2-fluoro-2-deoxy-d-glucose positron emission tomography in staging of locally advanced breast cancer. J Clin Oncol 22:1253-1259, 2004[Abstract/Free Full Text]

10. Grahek D, Montravers F, Kerrou K, et al: [18F]FDG in recurrent breast cancer: Diagnostic performances, clinical impact and relevance of induced changes in management. Eur J Nucl Med Mol Imaging 31:179-188, 2004[CrossRef][Medline]

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12. Landheer ML, Steffens MG, Klinkenbijl JH, et al: Value of fluorodeoxyglucose positron emission tomography in women with breast cancer. Br J Surg 92:1363-1367, 2005[CrossRef][Medline]

13. Minn H, Soini I: 18F]fluorodeoxyglucose scintigraphy in diagnosis and follow up of treatment in advanced breast cancer. Eur J Nucl Med 15:61-66, 1989[CrossRef][Medline]

14. Patz EF Jr, Lowe VJ, Hoffman JM, et al: Focal pulmonary abnormalities: Evaluation with F-18 fluorodeoxyglucose PET scanning. Radiology 188:487-490, 1993[Abstract/Free Full Text]

15. Gopalan D, Bomanji JB, Costa DC, et al: Nuclear medicine in primary breast cancer imaging. Clin Radiol 57:565-574, 2002[CrossRef][Medline]

16. Veronesi U, De Cicco C, Galimberti VE, et al: A comparative study on the value of FDG-PET and sentinel node biopsy to identify occult axillary metastases. Ann Oncol 18:473-478, 2007[Abstract/Free Full Text]

17. Newman LA, Kuerer HM, Fornage B, et al: Adverse prognostic significance of infraclavicular lymph nodes detected by ultrasonography in patients with locally advanced breast cancer. Am J Surg 181:313-318, 2001[CrossRef][Medline]

18. Singletary SE, Allred C, Ashley P, et al: Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20:3628-3636, 2002[Abstract/Free Full Text]

19. Bellon JR, Livingston RB, Eubank WB, et al: Evaluation of the internal mammary lymph nodes by FDG-PET in locally advanced breast cancer (LABC). Am J Clin Oncol 27:407-410, 2004[CrossRef][Medline]

20. Danforth DN Jr, Aloj L, Carrasquillo JA, et al: The role of 18F-FDG-PET in the local/regional evaluation of women with breast cancer. Breast Cancer Res Treat 75:135-146, 2002[CrossRef][Medline]

21. Podoloff DA, Advani RH, Allred C: NCCN task force report: Positron emission tomography (PET)/computed tomography (CT) scanning in cancer. J Natl Compr Canc Netw 5:S1-S22, 2007 (suppl 1)

22. Wu D, Gambhir SS: Positron emission tomography in diagnosis and management of invasive breast cancer: Current status and future perspectives. Clin Breast Cancer 4:S55-S63, 2003 (suppl 1)[CrossRef][Medline]

23. Dose J, Bleckmann C, Bachmann S, et al: Comparison of fluorodeoxyglucose positron emission tomography and "conventional diagnostic procedures" for the detection of distant metastases in breast cancer patients. Nucl Med Commun 23:857-864, 2002[CrossRef][Medline]

24. Cook GJ, Houston S, Rubens R, et al: Detection of bone metastases in breast cancer by 18FDG PET: Differing metabolic activity in osteoblastic and osteolytic lesions. J Clin Oncol 16:3375-3379, 1998[Abstract]

25. Ohta M, Tokuda Y, Suzuki Y, et al: Whole body PET for the evaluation of bony metastases in patients with breast cancer: Comparison with 99Tcm-MDP bone scintigraphy. Nucl Med Commun 22:875-879, 2001[CrossRef][Medline]

26. Dietrich CF, Kratzer W, Strobe D, et al: Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI. World J Gastroenterol 12:1699-1705, 2006[Medline]

27. Christensen JA, Nathan MA, Mullan BP, et al: Characterization of the solitary pulmonary nodule: 18F-FDG PET versus nodule-enhancement CT. AJR Am J Roentgenol 187:1361-1367, 2006[Abstract/Free Full Text]

28. Byrne AM, Hill AD, Skehan SJ, et al: Positron emission tomography in the staging and management of breast cancer. Br J Surg 91:1398-1409, 2004[CrossRef][Medline]

Submitted March 11, 2008; accepted June 6, 2008.


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