1. Malignancies with Low Fluorodeoxyglucose Uptake at PET/CT: Pitfalls and Prognostic Importance
Robert R. Flavell, MD, PhD, David M. Naeger, MD, Carina Mari Aparici, MD, Randall A. Hawkins, MD, PhD, Miguel H. Pampaloni, MD, PhD, Spencer C. Behr, MD
Department of Radiology and Biomedical Imaging, University of California, San Francisco.
Corresponding author: Spencer C. Behr, MD, , 505 Parnassus Ave, San Francisco, CA,
Presentation NME124, RSNA 2014, Awarded Certificate of Merit
Dr. Flavell acknowledges an RSNA research fellow grant, a Society of Nuclear Medicine and Molecular Imaging–Educational Research Foundation Mitzi & William Blahd, MD, pilot grant, and NIH 5T32EB for funding.
All authors have disclosed no relevant relationships.

2. Presentation Background
Fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used for staging and restaging of many solid tumors.
However, not all tumors take up high levels of FDG, which may cause challenges in scan interpretation.
In some tumors, the level of metabolic activity has prognostic importance.
In other tumors, uptake of FDG is inversely correlated with uptake of another radiotracer (the flip-flop phenomenon).

3. Presentation Objectives
Review common malignancies with low-level uptake of FDG on PET images.
Understand the prognostic importance of high-level FDG uptake in hepatocellular carcinoma (HCC), lymphoma, and prostate cancer.
Review the flip-flop phenomenon, in which uptake of FDG is inversely correlated with uptake of another radiotracer.

4. Learning Objectives
By the end of this presentation, the reader will be able to:
Identify which malignancies commonly have low-level FDG metabolic activity.
List tumors in which the presence of high-level FDG avidity carries poor prognostic importance.
Discuss the prognostic importance of the flip-flop phenomenon in thyroid and neuroendocrine cancers.

5. Malignancies with Low FDG Uptake
FDG uptake correlates with glycolysis levels and is generally much higher than that of normal tissues in many common malignancies including lung, breast, and colon cancer.
Other tumor subtypes may have low-level uptake, including renal cell cancer, mucinous tumors, and low-grade adenocarcinoma spectrum lesions in the lungs.

6. Malignancies with Low FDG Uptake: Possible Causes of Poor FDG Uptake
Tumor causes:
More indolent tumor type, with lower glycolysis resulting in lower FDG uptake
Tumors with low cellularity (mucinous neoplasms)
Small tumor size with partial volume effect; lesions smaller than 0.5–1.0 cm are not reliably detected
Patient causes:
Hyperglycemia
Diabetes
Postprandial scan

7. Malignancies with Low FDG Uptake: Technical Considerations
Tumors with low FDG avidity could be obscured by poor patient preparation, including postprandial or hyperglycemic scans.
Traditionally, lesions smaller than 1 cm are thought to be below the threshold for detection with PET.
Recent improvements in technique, such as time-of-flight PET and optimized reconstruction technologies, enable detection of subcentimeter lesions.1
Postprandial FDG PET
image.
1Koopman et al. J Nucl Med Tech, 2015

8. Malignancies with Low FDG Uptake: Mucinous Neoplasms
FDG PET is insensitive for detection of mucinous adenocarcinoma (one study found 59% sensitivity1).
Mean standardized uptake value (SUV) is 3.4 for ovarian mucinous neoplasms.2
Magnetic resonance (MR) imaging or contrast material–enhanced computed tomography (CT) is preferred.
CT (left) and PET/CT (right) images in a 46-year-old woman with mucinous adenocarcinoma of the appendix (arrow) (maximum SUV [SUVmax], 3.0).
1 Berger et al. AJR, 2000
2 Tanizaki et al. Int J Gynecol Cancer, 2014

9. Malignancies with Low FDG Uptake: Mucinous Neoplasms
PET/CT images in a 31-year-old woman with widespread peritoneal mucinous adenocarcinoma
(arrow), with low FDG avidity in both lesions (SUVmax of 1.7 for pelvic and perihepatic lesions).

10. Malignancies with Low FDG Uptake: Renal Cell Cancer, Primary Tumor
Detection hampered by clearance of FDG in the renal collecting system.
One study found 60% sensitivity and 100% specificity of FDG uptake for renal cell cancer.1
Mean SUV for primary renal cell carcinoma (RCC) is 2.6.2
CT (left) and PET/CT (right) images in a 51-year-old woman with RCC (arrow) without FDG uptake
above background (SUVmax, 4.9).
1 Kang et al. J Urol, 2004
2 Lee et al. Nucl Med Mol Imag, 2014

11. Malignancies with Low FDG Uptake: Renal Cell Cancer, Primary Tumor
CT (top left) and PET/CT (bottom left, right) images in a 95-year-old man with RCC (arrow) without detectable FDG uptake above background (SUVmax, 2.9).

12. Malignancies with Low FDG Uptake: Renal Cell Cancer Metastases
Although FDG PET is more sensitive for RCC metastasis than for primary tumor, some cases are still missed.
One recent meta-analysis found a pooled 91% sensitivity and 88% specificity for PET/CT for detection of metastatic RCC.1
PET/CT images in a 77-year-old woman with low FDG avidity primary RCC (SUVmax, 3.0) with hypermetabolic right ilium metastasis (SUVmax, 9.8).
1 Wang et al. Cancer Imaging, 2012

13. Malignancies with Low FDG Uptake: Renal Cell Cancer Metastases
PET/CT image (left) in a 77-year-old woman with a history of metastatic RCC demonstrates low background levels of hypermetabolism in the pancreatic tail (SUVmax, 3.6). Subsequent T1-weighted gadolinium-enhanced fat-saturated abdominal MR image (right) demonstrates an enhancing mass in the pancreatic tail (arrow), consistent with metastasis.

14. Malignancies with Low FDG Uptake: Low-Grade Adenocarcinoma of the Lung
Low-grade adenocarcinoma spectrum lesions (formerly called bronchoalveolar carcinoma or BAC) often demonstrate low or no FDG uptake.
Previous studies have documented low sensitivity of FDG PET for detecting these lesions, ranging from 43%–60%.1,2
Average SUV is 1.2.3
Low-grade adenocarcinoma spectrum lesions (arrow) typically present as ground-glass–attenuation nodules, as on this CT image in a 75-year-old man.
1 Higashi et al. J Nucl Med, 1998
2 Heyneman and Patz. Lung Cancer, 2002,
3 Aquino et al. Int J Mol Med, 2007

15. Malignancies with Low FDG Uptake: Low-Grade Adenocarcinoma of the Lung
CT (left) and PET/CT (right) images in a 77-year-old man with a history of melanoma. A left upper-lobe ground-glass–attenuation nodule (arrow) had slowly increased in size over multiple prior scans and is consistent with adenocarcinoma in situ (left). There was no definite FDG uptake above background (SUVmax, 0.8) (right).

16. Malignancies with Low FDG Uptake
Low-grade pulmonary adenocarcinoma spectrum lesions
Low-grade lymphomas, including mucosa-associated lymphoid tissue, chronic lymphocytic leukemia or small lymphocytic lymphoma, marginal zone lymphoma, peripheral T-cell lymphoma
Renal cell cancer
Prostate cancer
Pancreatic cancer
Mucinous neoplasms
HCC
Some soft-tissue sarcomas
Thyroid cancer
Neuroendocrine tumors
Uterine malignancies
Lobular breast cancer
Teratoma
Low-grade glioma

17. Prognostic Importance of FDG Uptake
In many types of cancer, there is strong evidence that higher FDG uptake correlates with poor prognosis.
Therefore, it is important to report the level of FDG uptake in cases of HCC, lymphoma, and prostate cancer.

18. Prognostic Importance of FDG Uptake: HCC
Greater than liver =
Poorly differentiated
(SUVmax, 4.8)
Equal to liver =
Well to moderately
differentiated
(SUVmax, 2.5)
Less than liver =
Well differentiated
(SUVmax, 1.8)
Average liver SUV is 2.0–2.5 and can change on the basis of age, weight, and blood glucose level.1
1Groheux et al. Clin Nuc Med, 2013,

19. Prognostic Importance of FDG Uptake: HCC
FDG PET uptake predicted poor response to radiation1 and transarterial chemoembolization.2
High FDG uptake predicts higher stage as well as presence of metastatic disease.3
High FDG uptake predicts recurrence after liver transplantation.4
1 Huang et al. J Nucl Med, 2013,
2 Song et al. Eur J Nucl Med Mol Imag, 2013,
3 Pant et al. Nucl Med Comm, 2013,
4 Lee et al. Transpl Int, 2013, 50-60

20. Prognostic Importance of FDG Uptake: HCC
83% sensitivity for HCC metastatic disease,1 lesions often missed at CT
CT (top) and PET/CT (bottom) images in a 67-year-old woman with femoral HCC metastasis (arrow) (SUVmax, 4.3).
CT (top) and PET/CT (bottom) images in a 58-year-old man with supraclavicular node HCC metastasis (arrow) (SUVmax, 3.2).
1 Sugiyama et al. J Gastroenterol, 2004;39:

21. Prognostic Importance of FDG Uptake: Lymphoma
Low-grade lymphomas typically demonstrate low FDG uptake.1
This is common in chronic lymphocytic leukemia, marginal zone lymphoma, and mucosa-associated lymphoid tissue.
PET/CT image in a 67-year-old woman with a history of chronic lymphocytic leukemia, with low FDG avidity pelvic and inguinal lymphadenopathy (SUVmax, 1.8).
1Weiler-Sagie et al. J Nucl Med, 2010

22. Prognostic Importance of FDG Uptake: Lymphoma
The presence of high FDG uptake in a patient with known low-grade lymphoma is suspicious for high-grade transformation (Richter transformation).
An SUVmax of 5 is accepted as a cutoff for concern for transformation.1
In general, high FDG uptake in lymphoma correlates with higher grade.2,3
PET/CT image in a 65-year-old woman with a history of chronic lymphocytic leukemia. Marked FDG uptake in the right inguinal lymph nodes (SUVmax, 10.1) is concerning for high-grade transformation. Excisional biopsy results confirmed transformation to diffuse large B-cell lymphoma.
1 Falchi et al. Blood, 2014
2 Noy et al. Ann Oncology, 2009,
3 Rodriguez et al. J Nucl Med, 1995,

23. Prognostic Importance of FDG Uptake: Lymphoma
The Deauville criteria have been proposed as a method of following response to treatment, on the basis of uptake at FDG PET:1 Deauville 1: No uptake Deauville 2: Uptake less than or equal to mediastinum Deauville 3: Uptake greater than mediastinum, less than or equal to liver Deauville 4: Uptake greater than liver Deauville 5: Uptake markedly higher than liver and/or new lesions Other authors have advocated using a quantitative approach of SUV measurement for predicting response, with a greater than 71% reduction in SUV being strongly correlated with treatment response.2
1 Barrington et al. J Clin Oncology, 2014,
2 Rossi et al. J Nucl Med, 2014,

24. Prognostic Importance of FDG Uptake: Prostate Cancer
Most cases of low-grade prostate cancer have little FDG uptake.1
Mean SUV in lymph node metastases is 1.1 and 1.0 for local recurrences.2
High-grade castrate-resistant prostate cancer can demonstrate increased FDG uptake, and higher SUV is associated with decreased survival.3
Neuroendocrine-type prostate cancer has higher FDG avidity (average SUV, 4.5).4
PET/CT images in a 66-year-old man with metastatic small cell prostate cancer with liver and mediastinal metastases (SUVmax, 11.1 and 13.2).
1 Jadvar et al. J Nucl Med, 2013,
2 Fricke et al. Eur J Nucl Med Mol Imag, 2003
3 Jadvar, Eur J Nucl Med Mol Imag, 2013, S5-S10
4 Spratt et al. Prostate, 2014,

25. Prognostic Importance of FDG Uptake: Prostate Cancer
Images in a 69-year-old man with a history of metastatic prostate cancer. FDG PET/CT images (left) demonstrate a sclerotic lesion without detectable hypermetabolism above background (SUVmax, 2.0). Corresponding image from an anterior projection bone scan and single-photon emission computed tomographic (SPECT) image (right) demonstrate an osteoblastic L5 metastasis (arrow).

26. The Flip-Flop Phenomenon
FDG
uptake
Receptor
targeting
tracer
uptake
Poorly differentiated
Aggressive phenotype
Resistant to receptor-targeted therapy
Well differentiated
Indolent phenotype
Express cell surface receptors
Amenable to receptor-targeted therapy
The flip-flop phenomenon is a rough correlation where FDG uptake is inversely correlated with uptake of another tracer, such as iodine 131 (131I) or indium 111 (111In) pentetreotide.1
Differentiated tumors resemble the normal underlying tissue, express cell surface receptors such as sodium-iodine symporter and somatostatin receptors, and take up 131I or 111In pentetreotide, but dedifferentiated tumors lose this feature and become more glucose dependent and hypermetabolic.
1Feine et al. J Nucl Med, 1995, 1468–1472

27. Flip-Flop Phenomenon: Neuroendocrine Tumors
111In pentetreotide uptake results from somatostatin receptor expression and can be inversely correlated with FDG uptake.
Average SUV of well-differentiated lesions is 2.9.1
Tumors that take up pentetreotide are amenable to therapy with octreotide.
1Kayani et al. Cancer, 2008

28. Flip-Flop Phenomenon: Neuroendocrine Tumors
Neuroendocrine tumors (as well as other neoplasms) have considerable intratumoral heterogeneity, which can provide important prognostic information.1
One study found an average of 54 months of progression-free survival in patients with positive pentetreotide uptake versus 3 months for those without.2
The same study found 3 months of progression-free survival in those with FDG uptake versus 72 months in those without.
1 Yang et al. Am J Surg Path, 2011,
2 Bahri et al. J Nucl Med, 2014,

29. Flip-Flop Phenomenon: Neuroendocrine Tumors
FDG PET/CT
111In- Pentetreotide
111In-Pentetreotide
Images in a 56-year-old woman with a history of renal cell cancer with an incidentally discovered carcinoid tumor. The presence of pentetreotide uptake and low FDG uptake (SUVmax, 1.2) is a favorable prognostic indicator.

30. Flip-Flop Phenomenon: Neuroendocrine Tumors
111In-Pentetreotide
18F-FDG
PET image (right) and frontal projection image from 111In pentetreotide scan (left) in a 28-year-old woman with a diffusely metastatic neuroendocrine tumor. Some metastases demonstrate high pentetreotide and low FDG uptake (liver mass, yellow arrow, SUVmax of 2.5), others demonstrate high uptake of both tracers (liver mass, blue arrow, SUVmax of 4.8), while others demonstrate low pentetreotide uptake and high FDG uptake (retroperitoneal lymph node, red arrow, SUVmax of 4.9). The presence of FDG avid, pentetreotide negative metastases is a poor prognostic indicator.

31. Flip-Flop Phenomenon: Thyroid Cancer
FDG uptake may be inversely correlated with sodium-iodide symporter expression, and therefore with iodine uptake, in patients with thyroid cancer.1,2
High FDG and low iodine uptake is associated with dedifferentiated tumor and poor prognosis.3
Patients with high iodine uptake may undergo treatment with 131I, whereas those without will not typically benefit from treatment.
Patients with distant metastases with negative iodine scan findings and positive FDG uptake may be treated with tyrosine kinase inhibitors.4
1Feine et al. J Nucl Med, 1996, 1468–1472
2Feine et al. Nuklearmedizin, 1995,
3Hong et al. Nuklearmedizin, 2013,
4Busaidy and Cabanillas, J Thy Res, 2012

32. Flip-Flop Phenomenon: Thyroid Cancer—When to Use FDG versus Iodine Imaging
123I or 131I scan is preferred for differentiated thyroid cancers and can assist in treatment planning.
PET/CT is useful in patients with papillary thyroid cancer with rising thyroglobulin level and negative iodine scan findings for detection of potentially curable disease.1
FDG PET/CT is also useful in all patients with selected histologic subtypes of thyroid cancer, including Hürthle cell, tall cell, and anaplastic thyroid cancers.2
1 Schluter et al. J Nucl Med, 2001
2 Abraham and Schoder, Semin Nucl Med, 2011

33. Flip-Flop Phenomenon: Thyroid Cancer
Images in a 45-year-old man with a history of metastatic papillary thyroid cancer. FDG PET/CT image (left) demonstrates a hypermetabolic pulmonary metastasis (arrow) (SUVmax, 28.6). No uptake was seen on post–131I treatment scan (right). Note physiologic salivary gland uptake. These findings suggest tumor dedifferentiation and are associated with poor treatment response and poor prognosis.

34. Flip-Flop Phenomenon: Thyroid Cancer
Images in a 66-year-old man with a history of papillary thyroid cancer. FDG PET/CT image (left) demonstrates a mass inferior to the right hepatic lobe with low-level hypermetabolism (SUVmax, 1.5). SPECT/CT image (right) obtained after 131I treatment (150 mCi [5550 MBq]) demonstrates tracer uptake in the mass (arrow). These findings are associated with well-differentiated tumors and good treatment response.

35. Conclusions
Many common neoplasms have low FDG uptake, including renal cell cancer, mucinous neoplasms, and low-grade lung adenocarcinoma spectrum lesions.
In many tumors, FDG uptake is associated with dedifferentiation and poor prognosis, including HCC, prostate cancer, and low-grade lymphoma.
In neuroendocrine tumors and thyroid cancer, FDG uptake is associated with poor prognosis and can be inversely correlated with uptake of 131I and 111In pentetreotide, respectively.

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