Imaging Analysis

Histopathologic correlates of degree of F-18 fluorodeoxyglucose uptake on PET in breast cancers

A 68-year-old, postmenopausal, gravida 2, para 2, woman with no family history of breast cancer initially noticed a left breast lump for around 1 month duration. Her previous mammogram 5 years ago showed benign nodular breast tissue with scattered punctate calcifications. Her repeat mammogram and ultrasound of bilateral breasts showed a new heterogeneous solid nodule measuring 7 mm in the sub-areolar region of the left breast at the site of palpable nodule. There were scattered calcifications in both breasts, but the breast parenchyma was heterogeneously dense, limiting mammographic evaluation. The ultrasound-guided fine needle aspiration of the left breast lesion showed malignant cells consistent with intermediate to high-grade ductal adenocarcinoma with mucinous features.

To further evaluate the extent of her disease, she had a breast MRI. The left breast showed an 8 mm enhancing mass in the sub-areolar region with an additional 1.9 cm enhancing mass with irregular margins along its posterior margin. There was a 3 cm segment of linear enhancement in the medial left breast in a ductal distribution.

In the right breast, there was a 3 cm focal area of asymmetric enhancement in a band-like distribution in the central right breast with a dominant 1.2 cm mass-like area of enhancement located centrally within this regional enhancement. These findings were suspicious for bilateral breast cancer, including a 2 cm circumscribed high T2 signal right axillary mass, suspicious for metastatic disease. The core biopsy of her left breast lesion showed fibrocystic changes with no evidence of malignant disease. However, biopsy of the right breast mass showed moderately differentiated invasive ductal carcinoma that was positive for estrogen and progesterone receptors and negative for HER-2/neu protein. The ultrasound-guided aspiration biopsy of the right axillary lymph node also showed metastatic ductal carcinoma.

The patient underwent FDG-PET/CT imaging as a part of her staging work up. This showed a mild diffuse metabolic activity in the bilateral breast tissue with SUV values of 1.7 on right and 2.1 on the left. There was an enhancing 1.5 cm nodule in the right breast with SUV of 1.7. The left breast demonstrated an irregular band of soft tissue in the retroareolar region showing mild FDG uptake with SUV 2.1. The right axillary lymph node was hypermetabolic with SUV 6.5. Ultimately, she underwent bilateral mastectomy with axillary lymph node dissection.

Figure 1.
Figure 1. Axial contrast-enhanced CT, PET, fused PET-CT and maximal intensity projection (MIP) images demonstrate low-grade metabolic activity corresponding to the biopsy-proven primary ductal carcinoma (arrow). Lower degree of activity was felt to be at least in part due to mucin production with resultant volume averaging phenomenon.

Photo courtesy M. Ghesani

Figure 2.
Figure 2. Metastatic right axillary lymph node demonstrates considerably higher degree of metabolic activity. There was no mucin production in this lymph node.

Photo courtesy M. Ghesani

Discussion

The role of PET has been increasing in various malignancies. It is now used in initial staging and prognosis to assess the response to chemotherapy, as well as in surveillance. PET scanning has been shown to identify breast cancer lesions with high sensitivity and also helps in differentiating some of the benign and malignant breast masses. The most commonly used radioisotope is the 2-fluoro-2-deoxy-D-glucose (FDG), which gets phosphorylated by the intracellular kinases to FDG-6 phosphate, but cannot be metabolized further. Thus, we can identify the metabolic activity of the cancer cells and with the integration of PET with CT it is now possible to accurately define the anatomic location of the hypermetabolic lesions.

There have been a number of studies in breast cancer to identify the correlates of FDG uptake in the cancer cells. Bos and colleagues identified various biological factors related to increased FDG uptake in breast cancer patients. These included the glucose transporter (Glut-1), hexokinase (HK-1), and hypoxia inducible factor (HIF-1), which are found to be up regulated in breast cancer cells. FDG uptake has also been studied with regard to various prognostic factors in breast cancer; for example, tumor size, grade, histology, hormone receptor status, cell proliferation index, axillary lymph node status, etc. There have been mixed results, but generally high FDG uptake has been shown to be associated with poor prognosis as shown by Ueda.

Invasive ductal carcinomas have been shown to have significantly high FDG uptake when compared with invasive lobular carcinomas. Crippa showed a median SUV of 5.6 for invasive ductal carcinoma, which was significantly higher than that of invasive lobular carcinoma (SUV 3.8, P=.004). This has been confirmed in several subsequent studies; however, we have not been able to identify any biological factor for this increase glucose uptake in the invasive ductal carcinomas. The invasive lobular carcinomas in general are difficult to identify radiographically and they have been shown to have a higher false negative rate with PET imaging as well. Avril showed a 65% false negative rate with invasive lobular carcinomas compared with 24% with invasive ductal carcinomas. The degree of FDG uptake has also been correlated with prognosis in predicting relapse rate in breast cancers.

For example, Oshida showed that with a differential absorption rate (DAR) of less than 3, only one of 49 patients relapsed compared with 8 of 21 patients in the group with a DAR of more than 3. This was also shown to be an independent prognostic factor in a multivariate analysis. For the patient presented here, the intensity of uptake in the primary breast carcinoma was lower than that in the metastatic lymph node. In general, ductal carcinoma lesions express higher degrees of FDG hypermetabolism. This is likely explained on the basis of mucin production in the primary malignancy, with resultant decreased overall uptake, a phenomenon known as volume averaging in radiologic physics.

In conclusion, the role of PET scan in breast cancer has been increasing, not only in the initial staging, but also in predicting prognosis. With its non-invasive nature, it provides an important tool for preoperative assessment of breast cancer lesions and could be used as an independent factor guiding adjuvant therapy.

Sumit Talwar, MD, is an oncology fellow at St. Luke’s-Roosevelt Medical Center.

Munir Ghesani, MD, is associate clinical professor of radiology at Columbia University College of Physicians and Surgeons and Attending Radiologist at St. Luke’s-Roosevelt Medical Center.

For more information:

  • Avril. Clin Positron Imaging. 1999;2(5): 261-271.
  • Bos et al. J Clin Oncol 2002;20(2):379-387
  • Crippa et al. Eur J Nucl Med (1998) 25:1429-1434
  • Oshida et al. Cancer 1998;82:2227-2234
  • Ueda et al. Jpn J Clin Oncol 2008;38(4) 250-258

A 68-year-old, postmenopausal, gravida 2, para 2, woman with no family history of breast cancer initially noticed a left breast lump for around 1 month duration. Her previous mammogram 5 years ago showed benign nodular breast tissue with scattered punctate calcifications. Her repeat mammogram and ultrasound of bilateral breasts showed a new heterogeneous solid nodule measuring 7 mm in the sub-areolar region of the left breast at the site of palpable nodule. There were scattered calcifications in both breasts, but the breast parenchyma was heterogeneously dense, limiting mammographic evaluation. The ultrasound-guided fine needle aspiration of the left breast lesion showed malignant cells consistent with intermediate to high-grade ductal adenocarcinoma with mucinous features.

To further evaluate the extent of her disease, she had a breast MRI. The left breast showed an 8 mm enhancing mass in the sub-areolar region with an additional 1.9 cm enhancing mass with irregular margins along its posterior margin. There was a 3 cm segment of linear enhancement in the medial left breast in a ductal distribution.

In the right breast, there was a 3 cm focal area of asymmetric enhancement in a band-like distribution in the central right breast with a dominant 1.2 cm mass-like area of enhancement located centrally within this regional enhancement. These findings were suspicious for bilateral breast cancer, including a 2 cm circumscribed high T2 signal right axillary mass, suspicious for metastatic disease. The core biopsy of her left breast lesion showed fibrocystic changes with no evidence of malignant disease. However, biopsy of the right breast mass showed moderately differentiated invasive ductal carcinoma that was positive for estrogen and progesterone receptors and negative for HER-2/neu protein. The ultrasound-guided aspiration biopsy of the right axillary lymph node also showed metastatic ductal carcinoma.

The patient underwent FDG-PET/CT imaging as a part of her staging work up. This showed a mild diffuse metabolic activity in the bilateral breast tissue with SUV values of 1.7 on right and 2.1 on the left. There was an enhancing 1.5 cm nodule in the right breast with SUV of 1.7. The left breast demonstrated an irregular band of soft tissue in the retroareolar region showing mild FDG uptake with SUV 2.1. The right axillary lymph node was hypermetabolic with SUV 6.5. Ultimately, she underwent bilateral mastectomy with axillary lymph node dissection.

Figure 1.
Figure 1. Axial contrast-enhanced CT, PET, fused PET-CT and maximal intensity projection (MIP) images demonstrate low-grade metabolic activity corresponding to the biopsy-proven primary ductal carcinoma (arrow). Lower degree of activity was felt to be at least in part due to mucin production with resultant volume averaging phenomenon.

Photo courtesy M. Ghesani

Figure 2.
Figure 2. Metastatic right axillary lymph node demonstrates considerably higher degree of metabolic activity. There was no mucin production in this lymph node.

Photo courtesy M. Ghesani

Discussion

The role of PET has been increasing in various malignancies. It is now used in initial staging and prognosis to assess the response to chemotherapy, as well as in surveillance. PET scanning has been shown to identify breast cancer lesions with high sensitivity and also helps in differentiating some of the benign and malignant breast masses. The most commonly used radioisotope is the 2-fluoro-2-deoxy-D-glucose (FDG), which gets phosphorylated by the intracellular kinases to FDG-6 phosphate, but cannot be metabolized further. Thus, we can identify the metabolic activity of the cancer cells and with the integration of PET with CT it is now possible to accurately define the anatomic location of the hypermetabolic lesions.

There have been a number of studies in breast cancer to identify the correlates of FDG uptake in the cancer cells. Bos and colleagues identified various biological factors related to increased FDG uptake in breast cancer patients. These included the glucose transporter (Glut-1), hexokinase (HK-1), and hypoxia inducible factor (HIF-1), which are found to be up regulated in breast cancer cells. FDG uptake has also been studied with regard to various prognostic factors in breast cancer; for example, tumor size, grade, histology, hormone receptor status, cell proliferation index, axillary lymph node status, etc. There have been mixed results, but generally high FDG uptake has been shown to be associated with poor prognosis as shown by Ueda.

Invasive ductal carcinomas have been shown to have significantly high FDG uptake when compared with invasive lobular carcinomas. Crippa showed a median SUV of 5.6 for invasive ductal carcinoma, which was significantly higher than that of invasive lobular carcinoma (SUV 3.8, P=.004). This has been confirmed in several subsequent studies; however, we have not been able to identify any biological factor for this increase glucose uptake in the invasive ductal carcinomas. The invasive lobular carcinomas in general are difficult to identify radiographically and they have been shown to have a higher false negative rate with PET imaging as well. Avril showed a 65% false negative rate with invasive lobular carcinomas compared with 24% with invasive ductal carcinomas. The degree of FDG uptake has also been correlated with prognosis in predicting relapse rate in breast cancers.

For example, Oshida showed that with a differential absorption rate (DAR) of less than 3, only one of 49 patients relapsed compared with 8 of 21 patients in the group with a DAR of more than 3. This was also shown to be an independent prognostic factor in a multivariate analysis. For the patient presented here, the intensity of uptake in the primary breast carcinoma was lower than that in the metastatic lymph node. In general, ductal carcinoma lesions express higher degrees of FDG hypermetabolism. This is likely explained on the basis of mucin production in the primary malignancy, with resultant decreased overall uptake, a phenomenon known as volume averaging in radiologic physics.

In conclusion, the role of PET scan in breast cancer has been increasing, not only in the initial staging, but also in predicting prognosis. With its non-invasive nature, it provides an important tool for preoperative assessment of breast cancer lesions and could be used as an independent factor guiding adjuvant therapy.

Sumit Talwar, MD, is an oncology fellow at St. Luke’s-Roosevelt Medical Center.

Munir Ghesani, MD, is associate clinical professor of radiology at Columbia University College of Physicians and Surgeons and Attending Radiologist at St. Luke’s-Roosevelt Medical Center.

For more information:

  • Avril. Clin Positron Imaging. 1999;2(5): 261-271.
  • Bos et al. J Clin Oncol 2002;20(2):379-387
  • Crippa et al. Eur J Nucl Med (1998) 25:1429-1434
  • Oshida et al. Cancer 1998;82:2227-2234
  • Ueda et al. Jpn J Clin Oncol 2008;38(4) 250-258