nuclear imaging in breast cancer

8/12/2019 Nuclear Imaging in Breast Cancer

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233RADIOLOGIC TECHNOLOGY January/February 2010, Vol. 81/No. 3

After reading this article, readers should be able to:

Differentiate between anatomical and functional imaging. Understand the various anatomical breast imaging modalities, including their strengthsand weaknesses.

Explain the principles of nuclear imaging of the breast. Discuss the advantages and disadvantages of specific nuclear imaging modalities as they apply to

breast imaging and breast cancer. Summarize current and future trends in nuclear breast imaging.

Nuclear imaging of the breastshows physiological changesthat usually are due tomalignancies. These changesare detectable earlier thanthose visible on other imagingmodalities. Recent advancesin functional breast imaginghave given us promising newtools positron emissionmammography and breast- specific gamma imaging that combine the advantages

of functional imaging with a finer resolution than that of positron emission tomographyand scintimammography. Ifits promises bear out, breast- specific functional imagingwill provide a powerful newtool in the fight againstbreast cancer and willassume a larger role in thecoming years.

This article is a DirectedReading. Your access to

Directed Reading quizzes forcontinuing education creditis determined by your area ofinterest. For access to otherquizzes, go to www.asrt.org /store.

ADI FERRARA, BS, ELS

Nuclear ImagingIn Breast Cancer

Breast cancer is the secondmost common canceramong women in theUnited States, followingskin cancer. A woman in

this country has a 1 in 8 chance ofreceiving a breast cancer diagnosis dur-ing her lifetime. 1 In 2009 more than250 000 women in the United States

were projected to receive a breast cancerdiagnosis, including both invasive andin situ (localized, early stage) disease. 1

About 40 610 women were projected todie of the disease in 2009; it is the sec-ond leading cause of cancer death inU.S. women, behind lung cancer. 1

The past several decades have seengreat strides in screening, diagnosisand treatment of breast cancer. What

was possibly the greatest change in theapproach to this disease has been therecognition of breast cancer as a system-ic disease one that affects the wholebody if it is not caught and stoppedearly. Recognizing breast cancer as asystemic disease brought about changesin treatments, such as a growing use of

neoadjuvant chemotherapy. 2 Because ofall these developments, the death ratefrom breast cancer has been declining. 3 Currently, the average 5-year survivalrate for all stages of breast cancer is75%. This rate ranges from 15% inpatients with stage IV disease to 92% inpatients with stage I. 4

Breast Imaging OverviewBreast imaging is an integral part of

the fight against breast cancer. Imagingis used to screen for breast cancer in thegeneral population, to pay closer atten-tion to high-risk populations throughmore sensitive imaging (such as mag-netic resonance [MR] imaging), toassist in the diagnosis and staging ofbreast cancer and to monitor responseto treatment. Imaging modalities canbe roughly classified as anatomical orfunctional. Anatomical imaging looksfor structural abnormalities in the body.Functional imaging illustrates a physio-logical behavior in the area of the bodythat is under investigation.

Currently, no breast imaging modal-ity, be it functional or anatomical, is


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234 January/February 2010, Vol. 81/No. 3 RADIOLOGIC TECHNOLOGY

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Mammography Mammographys history goes back to the early 20th

century. In 1930, Stafford Warren published the firstpaper on Roentgenologic Study of the Breast, 5 basedon his experience dating back to the 1920s. However,

what we consider modern mammography did notdevelop until the 1960s, when substantially improvedtechnologies became available. 6

Screening mammography is currently the goldstandard in screening the general population forbreast cancer. It is the tool by which many breastcancers are found. Diagnostic mammography is per-formed on women who have symptoms or suspicious

findings on screening mammography that mightreflect cancer. According to Bartella et al, tumorsdetected in diagnostic mammography tend to belarger, and are more likely to involve the lymph nodes,compared with tumors detected in screening mam-mography. 3

There is no denying the immense positive influ-ence that mammography has had on the continuedbattle against breast cancer. For example, a Swedishstudy looked at breast cancer mortality in the coun-trys Uppsala region before and after mammography

was introduced to the area. Mortality rates fromthe disease plunged 39% with the advent of regular

screenings.3

These findings are by no means unique other studies yielded similar results in Italy and theUnited States. 3

Mammography, however, has several serious limita-tions. It misses approximately 10% of breast canceroccurrences (even if a palpable mass exists), and itssensitivity decreases sharply (reportedly reaching aslow as 68%) in dense breasts. 3 In addition, mammog-raphy has a high false-positive rate. Only 25% to 45%of biopsies performed because of mammographicabnormalities yield an actual malignancy. The restare benign.

The use of digital mammography, in which a digital

signal sensor replaces the x-ray film, has alleviated someof the sensitivity problems of mammography, but onlyin certain groups. The Digital Mammographic ImagingScreening Trial, a multicenter study that enrolled 49 528asymptomatic women, found that although

[t]he overall diagnostic accuracy of digital andfilm mammography as a means of screening forbreast cancer is similar digital mammographyis more accurate in women under the age of 50

years, women with radiographically dense breasts,and premenopausal or perimenopausal women. 7

perfect for screening and diagnostic purposes. Everymodality has its Achilles heel that makes it prone tomissing certain malignancies, or misdiagnosing benignlesions as malignant. Researchers still are striving for theright balance between sensitivity and specificity in breastimaging. The strength of breast imaging today lies in theability to look at results from several different modalitiesand collate the information in a way that gives us thebest available clinical picture for that particular patient.

Functional imaging, when it is sensitive enough,offers a potential advantage over anatomical imagingin the area of breast cancer detection. Breast cancertumors metabolism rates are often higher than those

of normal breast tissue. According to Dr Marie Tartar,director of advanced breast imaging at Scripps GreenHospital in La Jolla, California, the metabolic changesoccurring in a malignant breast tumor may be detect-able before cancer changes manifest in anatomicalstudies such as mammography (oral communication,

June 2009). Functional imaging, therefore, potentiallycan offer an earlier indication of an abnormal processcompared with anatomical imaging.

As mentioned above, in addition to screening forbreast cancer, imaging studies also are used for stag-ing breast cancer and monitoring its response to treat-ment. In this last arena, especially, functional imaging

such as positron emission tomography (PET) offersdistinct advantages: 2 Anatomical imaging cannot reliably differentiate

between an active tumor and scar tissue result-ing from treatment they often look the same.Functional imaging, looking at metabolic rates,usually can differentiate between the 2.

Anatomical response to treatment (eg, tumorshrinkage) may take weeks to be noticeable in animaging study. Functional response (eg, lower flu-orodeoxyglucose [FDG] uptake) happens muchfaster and is noticeable earlier.

It also is difficult to tell the difference betweenslow progression of the disease and an actualresponse to treatment in anatomical imaging.Functional imaging can differentiate betweentumors that still are active and those whosemetabolism has slowed down significantly inresponse to therapy.

Anatomical Breast Imaging Anatomical breast imaging includes mammogra-

phy, ultrasound, MR imaging and computed tomog-raphy (CT).


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tested the utility of ultrasound as an additional screen-ing modality, alongside mammography. 8 The results,based on analysis of 2637 high-risk women, found thatthe addition of a screening breast ultrasound examto mammography improved the diagnostic accuracyfrom 78% (for mammography only) to 91% (for mam-mography plus ultrasound). Based on the ACRIN 6666results, the addition of this single ultrasound screeningalso will find between 1.1 and 7.2 additional cases per1000 high-risk women.

The majority of the cases found only on ultrasound were small, node-negative cancers, which have a betterprognosis. Conversely, there was a substantial increase in

the number of false-positive results with the addition ofan ultrasound exam. 7 According to an ACRIN statement, ACRIN 6666 established standardized techniqueand interpretive criteria as well as experiencerequirements for physicians performing theseexaminations. At centers which follow similar prac-tice, US [ultrasound] may improve detection ofearly breast cancer in women at increased risk ofbreast cancer who are not currently recommendedfor MRI. These results do not justify the recom-mendation for screening ultrasound for the gen-eral public or in lieu of or in addition to MRI for

very high-risk women. 9

One of the greatest advantages of ultrasound imag-ing is this modalitys use of sound waves, rather thanionizing radiation, to obtain its images. Another con-siderable advantage is the ability to use ultrasound toguide percutaneous needle biopsy of the lymph nodes.Patients with positive results can be spared the moreinvasive sentinel lymph node biopsy, although they still

would need axillary lymph node dissection as part oftheir workup. Ultrasound imaging often can differen-tiate between cysts and solid tumors, an asset in thediagnostic workup of suspicious findings in the breast.This form of breast imaging, like MR, is not affected bybreast density and it is easily accessible and widely used.

The main disadvantage of ultrasound breast imag-ing, besides its low positive predictive value, is itsdependence on operator experience and technique. Itis also a time-consuming procedure.

Computed Tomography CT is not used for general breast cancer screening

or diagnosis because it is hard to differentiate betweenbenign and malignant lesions on CT images. It is usedmainly for staging, very often with PET, and it espe-cially is valuable because it can suggest malignancies

Magnetic ResonanceMR imaging is an extremely sensitive tool, and it

frequently is used as an adjunct to mammography inhigh-risk patients, such as those carrying the breastcancer genes BRCA1 and BRCA2 . Studies suggest that,compared with mammography, MR diagnoses cancers inhigh-risk women at earlier, more curable stages. 3 Whenstaging breast cancer, MR can detect additional areas ofmalignancy in the breast that other anatomical imagingtechniques miss in up to one-third of patients. 3 Althoughthis is a potentially beneficial feature of MR imaging andcan lead to changes in treatment plans, some cliniciansargue that MR can lead to overtreatment, such as mastec-

tomy instead of breast-conserving surgery. According toBartella et al, the challenge in MR imaging lies in under-standing what is clinically significant on the images and

which lesions can be treated with radiation and do notrequire surgery. As of today, there is no way to tell. 3

In addition to its high sensitivity (finding mostmalignancies), MR imaging yields valuable informationabout the cancer itself. It provides 3-D images of thebreast and the tumor (or tumors) and, with contrastenhancement, information about the tumor vascularity.It also allows for imaging of the chest wall.

Drawbacks of MR imaging include its high cost andthe length of the examination. MR also tends to have

a high false-positive rate (lower specificity). Accordingto Dr Tartar, this often is due to hormonal effects. InDr Tartars experience, the most accurate results of MRimaging are achieved in women who undergo MR stud-ies on days 7 to 10 of their menstrual cycle (oral com-munication, June 2009).

MR is not suitable for all patients. Among patients who cannot undergo an MR examination are women with pacemakers. Women who are claustrophobicmay need medication to help them tolerate the exam.Those who cannot lie prone for the required length ofthe examination also may require medication.

UltrasoundUltrasound is the modality of choice in examining

suspicious breast findings in women younger than30 years, pregnant women and nursing mothers. 3 Italso is used as an adjunct to mammography in sus-pected breast cancer cases. In several studies, ultra-sound findings changed the management of breastcancer in nearly two-thirds of patients and preventeda significant number of unwarranted biopsies. 3

A multicenter, large-scale study (ACRIN 6666) bythe American College of Radiology Imaging Network


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PET uses positron emitters, which are radioac-tive particles emitting a positively charged particle asthey decay. When the positron travels through tissue,it eventually collides with an electron (a negativelycharged particle), and the 2 annihilate each other.This results in the release of 2 photons, each with anenergy of 511 keV for FDG (or 140 keV for sestamibi),moving away from each other at almost 180. Thereleased energy is detected in the PET scanner.

Though several radiopharmaceutical tracers existfor use with PET, most breast imaging today is done

with FDG. Because of their high metabolic rate, manybreast tumor cells take up glucose avidly. FDG, a glu-

cose analog, is transported into the cells via the glucosetransport mechanism. The FDG then undergoes phos-phorylation but cannot be metabolized inside the cells,so its accumulation in these cells gives clinicians a truepicture of a tumors glucose metabolism.

A semiquantitative measurement of FDG uptakeoften is calculated using standard uptake values (SUV),a function of the injected FDG dose, the patients

weight and the radioactivity of the imaged tissue. TheSUV can be used alongside the visual interpretationof PET to better differentiate between benign andmalignant tissue. According to Avril and Adler, SUVcorrection for partial volume effects and normalization

to blood glucose has been shown to yield the highestdiagnostic accuracy for breast imaging. 4 (Partial vol-ume effect is the result of having more than one tissuetype in the same part of the image.)

Sensitivity and Specificity In various studies, the sensitivity and specificity

of PET in detecting breast cancer varied somewhatdepending on the patient population. Avril et al evalu-ated 144 patients (185 confirmed tumors) with conser-

vative and sensitive PET readings. 11 Conservative read-ing considers a PET scan to be positive only if there is adefinite increase in FDG uptake. Sensitive reading alsoconsiders a diffuse uptake or moderately increasedfocal uptake as positive. Using conservative reading,the sensitivity of PET was 64.4%, with a specificityof 94.3%. Using sensitive reading, the sensitivity ofPET increased to 80.3%, but with a significant toll onspecificity, which fell to 75.5%. As expected, sensitivityincreased with increased tumor size.

Regardless of the reading method, however, the posi-tive predictive value of PET was an impressive 96.6%.This study is typical of the sensitivity and specificityranges for other studies of breast cancer using PET

in the lymph nodes.10

(A review of PET-CT technologyappeared in the July/August 2005 issue of RadiologicTechnology .)

Sometimes a breast abnormality is discoveredon CT during scanning for an unrelated condition.

When this happens, the abnormal f indings should beevaluated by the usual means that apply to all suspi-cious breast lesions: mammography, biopsy and othertests as needed.

Nuclear Breast Imaging OverviewNuclear breast imaging refers to functional imaging

of the breast through the use of radiopharmaceuticals

such as18

FDG or99m

Tc-sestamibi. The radiopharmaceu-tical does not change normal physiological processes,but rather allows clinicians to visualize them.

Functional imaging can show changes in cell metab-olism that are due to malignancies, often identifyingdisease earlier than anatomical imaging can. It is, in a

way, a biological assay carried out in the body, withoutthe need for invasive procedures.

Two relative newcomers to the nuclear imagingfield are positron emission mammography (PEM) andbreast-specific gamma imaging (BSGI). Both methodsare similar in their evolution, the advantage they offerover other breast imaging modalities and their imple-

mentation. PEM and BSGI are promising new toolsthat combine the advantages of functional imaging with suff icient resolution for early detection of smallerbreast lesions. If its promises bear out, breast-specificfunctional imaging will provide a powerful new tool indetecting breast cancer.

The modality that currently is used most widely infunctional breast imaging is PET. In this article, thediscussion of PET refers to whole-body PET. PEM workson the same principles as PET, but it is a breast-specificimaging tool, modified to provide the best spatial reso-lution to image even very small breast tumors.

Positron Emission TomographyPET has proven to be an immensely useful tool in

the staging of breast cancer and in monitoring thecancers response to treatment. It is, in fact, superiorto anatomical imaging in differentiating betweenpatients who have responded to treatment and those

who have not shown a response after 1 or 2 cycles ofchemotherapy. However, in the screening and diag-nostic arenas, PET has been lacking. Its spatial reso-lution limits its diagnostic sensitivity to lesions 1 cmand larger.


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els of FDG uptake include the tumors histologic type(ductal tumors take up FDG significantly more thanlobular malignancies) and tumor proliferation (higherFDG uptake is seen in the more proliferative tumors). 4

FDG uptake can increase under certain benign oreven normal conditions such as physical activity, whichincreases muscle uptake of FDG. Uptake is naturallyhigh in certain parts of the body, including the braincortex, the heart muscle and brown fat. Increased FDGuptake also occurs in irradiated areas after radiationtherapy treatments. All of these circumstances mustbe taken into account when interpreting PET imagesto minimize false-positive readings. Brown fat, for

example, is regularly seen on PET as high-uptake spotsin the supraclavicular areas of some patients. 4 This phe-nomenon could lead to a false-positive reading.

Monitoring Treatment Response The importance of monitoring response to treat-

ment in breast cancer goes beyond the prognostic value of a responsive tumor. (Obviously, patients whorespond to treatment live longer and have longerdisease-free periods.) Because chemotherapy for breastcancer is associated with many severe and sometimeslife-threatening side effects, it is important to identifypatients who are not responding to treatment. They

can be spared the adverse effects, and possibly bestarted earlier on a different regimen that might yielda response. 13 (Because breast cancer tumors are usu-ally chemosensitive, even patients who do not show aresponse to one therapy have several second-line treat-ment options available to them.)

Tumor response to treatment has clinical and patho-logical aspects. A clinical response is the shrinkage ordisappearance of the tumor. A pathological response isa reduction in the number of malignant cells, or theircomplete disappearance.

Most studies find no relationship between clinicaland pathological responses to treatment. Current ana-tomical imaging modalities cannot reliably differenti-ate between scarred or fibrotic tissue and an activetumor. Consequently, situations arise in which thereis a complete pathological response but little or noevidence of clinical response. 13 The reverse is also true,because microscopic cells might still be present even ifthe tumor itself disappears.

The World Health Organization has set criteria for aclinical response. However, these criteria are not basedon any studies that proved a relationship between a spe-cific decrease in tumor size and the patients outcome. 13

technology. In addition to size, as discussed below,tumor type (ie, ductal vs lobular) also determines FDGuptake, and therefore affects the sensitivity of PET.

A small study by Goerres et al compared PET andMR in diagnosing a suspected recurrence or a contral-ateral occurrence of breast cancer. 12 The 32 patientsunderwent breast MR imaging and whole-body PET.The sensitivity of PET was 79% in this study, com-pared with 100% sensitivity for MR. However, thespecificity of PET was 94%, whereas MRs specificity

was only 72%. In addition, whole-body PET founddistant metastases in 5 out of 32 patients. MR images,

which were limited to the breast area only, missed

those distant metastases in all 5 patients. The diagnos-tic accuracy of both modalities was similar 88% forMR and 84% for PET.

Imaging Procedure The usual PET procedure for breast imaging

requires the patient to fast for 4 to 6 hours so thatplasma glucose levels are sufficiently low at the time ofFDG injection. (The ideal glucose level is ~140 g/dL.)The tracer is injected into a vein in the contralateralarm. This is done so that any leakage of the injectedtracer wont cause a false-positive image in the axil-lary area of the breast suspected of having a cancerous

tumor. A normal dose is 10 mCi (370 mBq). Becausephysical activity can increase muscle uptake of FDG,the patient should rest in a quiet area for approximately60 minutes following the injection to allow for optimalcellular uptake of FDG.

Avril and Adler recommended attenuation correc-tion of the images to better localize the tumor andassist with SUV calculations. 4 In addition, for whole-body PET scanning, they mentioned the possibility ofinjecting 20 to 40 mg each of furosemide and butylsco-polamine along with the tracer. The former reducesthe accumulation of tracer in the bladder; the latterreduces tracer uptake by the bowel.

FDG-PET Biology Different breast tumors take up FDG at different

rates, for reasons that are not understood completely.Tumor grade, the level of tumor differentiation fromhealthy cells, is one reason for that difference. Lower-grade tumors (ie, ones that are more like normal cellsand therefore less aggressive) take up less FDG thanhigher-grade tumors. PETs ability to detect lower-grade tumors is therefore lower than its ability to detecthigher-grade ones. Other factors that correlate with lev-


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A single whole-body PET scan takes approximately1 hour. When combined with CT, the images that aregenerated outperform other modalities in the qualityand quantity of information they supply and detectsystemic disease earlier than conventional imagingmodalities. Furthermore, a single whole-body PET-CTscan takes the place of multiple imaging studies such asradiographs, ultrasound and MR imaging combined,according to Dr Selin Carkaci, assistant professor,Department of Diagnostic Radiology, University ofTexas M.D. Anderson Cancer Center in Houston, Texas(written communication, June 2008).

In a British Columbia study, a full third of breast

cancer patients who were found to have distant metas-tases were thought to have only locoregional diseasebefore whole-body PET scanning. 14 In another studyof 125 patients in the United States, whole-body PETincreased the diagnosed stage of breast cancer in 43%of the patients, decreased the diagnosed stage in 24%of patients and brought about a change in treatmentplans in 32% of the patients. 15

Looking Ahead New tracers are under study for both PET and

PEM. Among them are 3-deoxy-3- 18F-fluorothymidine( 18F-FLT), a nucleic acid analog that can evaluate

tumor proliferation, and18

F-fluoroestradiol (18

F-FES), which is a marker for the estrogen receptor (ER) ontumors. Because ER status is important in determiningtreatment for breast cancer, the ability to determineER status without a biopsy is an exciting possibility.Furthermore, multiple tumors can be a mix of ER+ andER- tissue. Studies with FES show that it has the abilityto pinpoint multiple areas of ER positivity (S. Carkaci,MD, written communication, June 2008). FES, there-fore, may eventually be more accurate than a biopsyassay in determining the patients suitability for hor-mone therapy. Studies already indicate that high FESuptake, seen on PET prior to the start of treatment,predicts a response to hormone therapy. 2,16

Positron Emission MammographyPositron emission mammography is a modification

of PET that allows for a much finer spatial resolutionby putting the photon detectors near the breast. Thefirst proof-of-concept study of PEM, using a breastphantom, was published by Thompson et al in 1994. 17 By mounting the positron detectors onto a mammog-raphy unit, the investigators also hoped to get thetype of coregistered anatomical and functional images

Several studies established the utility of FDG-PETin predicting tumor response to treatment based onearly metabolic response. In 1993, 11 patients withnewly diagnosed disease about to begin chemotherapytreatments received a baseline FDG-PET scan plus 4additional scans during the first 3 cycles of their treat-ment. After 9 cycles, histopathological determinationof tumor response was carried out and compared

with the results of the PET scans. The authors foundthat FDG uptake in patients responding to treatments(n = 8) started decreasing early in the treatment cycleand continued decreasing. On day 8 of treatment, themean uptake in responders was 78% of baseline, and

on day 63 (the last scan) it was 52%. Patients with noresponse to treatment showed no significant changes inFDG uptake. 13

In 1999, 16 patients were scanned twice within10 days with FDG-PET while receiving no therapy.There were no significant changes in FDG uptakebetween these scans. 13 More studies that followedsupported these findings and refined them. It wasestablished that in patients receiving neoadjuvant che-motherapy, a highly accurate prediction of responsecan be established after the first cycle. A 55% decreasein SUV (from baseline) after the first chemotherapycycle seems to be the threshold for identifying 100%

of responders.13

However, more large-scale studies areneeded to standardize the definition of tumor responsebased on FDG uptake. The prediction of responsebased on declining FDG uptake seems to apply to met-astatic lesions as well, not just primary tumors. 13

The exception to the rule of early decrease in FDGuptake seems to be patients who respond to hormonetherapy, in whom an activity f lare is seen within thefirst 2 weeks after treatment. Here again, studiesshow that this temporary increase in FDG uptake con-trasts with no change in uptake in tumors resistantto hormone therapy. The increased metabolic activ-ity apparently results from the fact that antiestrogentreatments f irst act as estrogen agonists. That is, theycombine with estrogen receptors in the tumor andexert the same physical effect on the tumor as estro-gen does. 13

Staging Although PETs performance in detecting axillary

node involvement is lukewarm at best (sensitivities in various trials range from 20% to 79% 4), according to various studies, it is unequalled in the whole-body stag-ing of breast cancer.


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we see today with PET-CT (see Figure 1). 18

Results of the first clinical trial with PEM were pub-lished in the Journal of Nuclear Medicine in 2000. 19 Of 10patients with malignancies, PEM correctly identified8 lesions as malignant. There were no false-positiveresults and 2 false-negative results. These results trans-lated to 80% sensitivity, 100% specificity and 86% accu-racy for this first-ever PEM trial. The protocol involved2 mCi FDG injected into the contralateral arm andscanning times of 2 to 5 minutes. 19 Todays PEM scansuse 10 mCi FDG (370 mBq) and a scan time of approx-imately 10 minutes per view (M. Tartar, MD, oral com-munication, June 2009). The images obtained withPEM are in the same projections as mammography,

although currently there are no available combinationPEM-mammography units.

Technical Considerations According to Dr Kathy Schilling, medical direc-

tor of breast imaging and intervention at Boca RatonCommunity Hospitals Center for Breast Care in BocaRaton, Florida, PEM can detect lesions as small as1.5 mm, far smaller than lesions detectable by PET(see Figure 2). (K. Schilling, MD, oral communication,

June 2009). The PEM unit requires breast compression

Figure 1. Correlation of the intensity-thresholded PEM-1 imageand a hyperdense region of the mammogram using the coregistra- tion technique developed for this instrument. The field of view ofthe mammogram is bigger than that of the PEM-1 detectors, andin the active PEM region, alternate pixels are assigned to PEMand radiograph images in a manner identical to that commonlyused for PET-CT image display. Reprinted with permission fromThompson CJ. Instrumentation for positron emission mammogra-

phy. PET Clin . 2006;1(1):133-138.

Figure 2. Right breast. A. Whole-body PET found a largelesion. B. PEM clearly depicted 2 additional satellite lesions (multifocal grade II infiltrating ductal carcinoma). PEM provides 1.5to 2.0 mm resolution. Images courtesy of Kathy Schilling, MD,

from Boca Raton Community Hospital in Boca Raton, FL.

B.

A.


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prophylactic mastectomies, Dr Schilling said. As such,its benefits outweigh the small elevated risk from theradiation involved (K. Schilling, MD, oral communica-tion, June 2009).

In addition, investigations are ongoing to see whether it is possible to lower the radiation dose in

PEM while maintaining the same quality of imaging(M. Tartar, MD, oral communication, June 2009). Thehope is to bring the dose down to as little as 3 to 5 mCi(111 to 185 mBq), said Dr Schilling (oral communica-tion, June 2009). Drs Tartar and Schilling both believethat PEM eventually will move outside the cancer arenaand into the screening field for high-risk patients (oralcommunication, June 2009).

Current Research In 2005, Tafra et al published results of a multicenter

pilot study assessing the utility of PEM in patients with arecently diagnosed breast cancer. 20 Following confirma-tion by biopsy, but before surgery, 44 patients underwentPEM scans with a median dose of 13 mCi (481 mBq)FDG (range 8 to 21 mCi [296 to 777 mBq]). The mediandelay before imaging was 99 minutes (range 48 to 148minutes). Each image was acquired over 10 minutes. Theresults were not disclosed to the surgeons or used in any

way to change treatment. PEM readers were blinded tosurgical plans and outcomes.

The study looked at 4 aspects of PEM, including itsability to:

Detect the lesion that prompted the follow-up

to prevent movement of the breast and allow for accu-rate reading, but not thinning of the breast tissue. Asa result, the pressure required for imaging the breast

with PEM is much less than the compression appliedduring mammography (K. Schilling, MD, oral com-munication, June 2009). The higher resolution of PEMcompared with PET is due to the fact that PEM detec-tors are mounted on the breast compression plates (seeFigure 3), thereby minimizing the distance between thesource of radiation (ie, the breast) and the detectors.

Using PEM PEM is a fairly new modality. Although no longer

experimental it is approved by the FDA for use inpatients proven to have cancer the exact role thismodality will play in breast cancer imaging still isevolving. Until very recently, PEM studies have been

very small, and therefore it is unclear where and howPEM fits in the workup of breast cancer patients (M.Tartar, MD, oral communication, June 2009). It is cur-rently indicated for local staging of new breast cancer,restaging and monitoring patients on neoadjuvantchemotherapy (K. Schilling, MD, oral communica-tion, June 2009).

The radiation dose to the breast that a patientreceives from PEM is slightly higher than that of a

regular mammogram. The whole-body radiation dosea patient receives is approximately 3 times that of amammogram, and is highest mainly in the bladder(M. Tartar, MD, oral communication, June 2009). Thishigher whole-body radiation dose is a barrier to imple-menting PEM as a screening modality in the generalpopulation, according to Dr Tartar, along with theexpense of the procedure and the relatively low yield ofcancer diagnoses in the general population. However,

when used in patients with proven cancer, the dose isnot sufficiently high to be an issue (M. Tartar, MD, oralcommunication, June 2009).

Dr Schilling added that PEMs usefulness outsidethe cancer arena would be with high-risk patients,such as women who carry the BRCA1 and BRCA2 genes (oral communication, June 2009). These

women currently receive annual MR exams and, asmentioned previously, MR imaging tends to result in ahigh rate of false-positive studies, necessitating repeatbiopsies. Ultimately, the high rate of repeat biopsiesmay be what drives many BRCA carriers to chooseprophylactic double mastectomies. PEM could sparethese women unnecessary repeat procedures andperhaps reduce the number of women who resort to

Figure 3. Photo of PEM scanner in stand-alone configuration for upright or seated examination. Reprinted with permission from Tafra L, Cheng Z, Uddo J, et al. Pilot Clinical Trial of 18F- fluorodeoxyglucose positron-emission mammography in the surgicalmanagement of breast cancer. Am J Surg . 2005;190:628-632.


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90%, specificity of 86%, positive and negative predic-tive values of 88% and accuracy of 88%. The exclusionof patients with diabetes and those who clearly hadbenign tumors (as evident on mammograms and ultra-sounds) brought PEMs sensitivity to 91%, specificity to93%, positive predictive value to 95%, negative predic-tive value to 88% and accuracy to 92%.

The largest study of PEM to date closed in November2008, and results are currently being analyzed (M.Tartar, MD, oral communication, June 2009). The mul-ticenter prospective study looked at the performanceof PEM by itself and in comparison to MR imaging inpreoperative staging of more than 400 women with newly

diagnosed breast cancer. Participants had undergone afull diagnostic workup, including mammogram, ultra-sound scanning and a physical examination. In addi-tion, each participant had undergone contrast MR andPEM imaging studies. The study looked at what surgicaltreatment changes (if any) resulted from these 2 imag-ing modalities, each by itself and in combination. 22 (Forexample, was there additional information in a PEMstudy that suggested additional biopsies were needed?

Were those biopsies truly positive?) With regard to PEM,the investigators hope to gain more information concern-ing which tumors are detected or missed and how accu-rately PEM can predict tumor size and extent.

Further Considerations PEM and PET share some of the same advantages

and disadvantages. As functional imaging tools, theyenable earlier detection of many breast cancers, andboth can predict treatment response during the earlystages of treatment.

Both modalities have lower sensitivity for low-gradetumors. The same benign conditions that cause highFDG uptake in PET (eg, infection, inflammation andfat necrosis) may cause false-positive results in PEM.Glucose control in patients with diabetes is anothercommon problem in PET and PEM. Patients who can-not bring their glucose levels to the accepted parame-ters for PEM or PET cannot undergo either procedure.

In PEM, visualization of the chest wall is currentlynot possible. On the other hand, PEM now has a biopsyunit that works with the scanner, similar to the ultra-sound biopsy setup (K. Schilling, MD, oral communica-tion, June 2009).

There is only one commercially available, FDA-approved PEM scanner in the United States at themoment, manufactured by Naviscan PET Systems(San Diego, California) (see Figure 4). There are

evaluation (ie, the index lesion); 70% of theselesions were nonpalpable. Detect multifocal disease (the presence of several

tumor spots in the same quadrant of the breast). Detect other confirmed malignancies, anywhere

in the breasts. Predict whether breast-conserving surgery would

be possible (ie, the extent of the tumor or tumorsin the breast ducts and tumor margin status).

PEM identified 89% (39 of 44) of the index lesionscorrectly. One lesion was missed because the unit usedin that center was not free-standing. Rather, it wasmounted on a stereotactic biopsy table, and the lesion

was too posterior for imaging. Three other lesions were intermediate- and low-grade lesions, and the fifthlesion was 1 mm. In 3 cases, PEM found significantductal carcinoma in situ that was missed by all otherimaging studies. PEM detected 4 of 5 (80%) of addi-tional breast malignancies, 3 of which were missed bymammography, MR imaging and ultrasound.

Thirty-one patients were evaluated for multifocaldisease. PEM predicted 64% of multifocal disease cases(9 of 14 patients), and correctly identified the absence ofmultifocal disease in the remaining 17 patients (100%).

Of 19 patients who were evaluated for the accuracyof PEM in determining tumor margins, PEM correctly

predicted 75% (6 of 8 patients) of positive margin status,and 100% (11 of 11 patients) of negative margin status.The studys results were encouraging, despite its

small size. Two significant advantages of PEM stoodout. First, PEM was not affected by breast density.Twenty-three women in the study had dense breastsand all of their lesions were detected and correctlydiagnosed. (According to Dr Schilling, PEM is notaffected by hormonal status either, oral communica-tion, June 2009.) Second, PEM showed good sensitiv-ity for detecting ductal carcinoma in situ (DCIS), adiff icult malignancy to detect. Too often, physiciansmiss DCIS when planning treatment for a patient with

known breast cancer. The presence of DCIS predictspositive margins, and the need to perform a mastec-tomy on a patient who has been initially told she canhave breast-conserving surgery. As screening improves,DCIS also is detected more often, 20 and a reliable wayto detect it before it becomes invasive is essential. PEMmight just be the modality to do so.

A study by Berg et al 21 supported this last point.The study was designed to evaluate PEMs diagnosticutility. PEM identified 10 of 11 (91%) cases of DCIS.Overall, the study found that PEM had a sensitivity of


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U.S. study found the sensitivity and specificity of scinti-mammography to be 92.2% and 89.2%, respectively, ina cohort with a mean tumor size of 2.82 cm. 24

Breast-specific Gamma ImagingBreast-specific gamma imaging (BSGI, sometimes

also known as molecular breast imaging) is theready-for-prime-time version of scintimammography,said Dr Tartar (oral communication, June 2009).Like PEM, it is a functional imaging tool and it usessestamibi, the same agent used in scintimammogra-phy. In BSGI, however, the gamma camera used todetect emission is much smaller and much closer to

the patients breast (the source of radiation). In thatrespect, the relationship between scintimammographyand BSGI is analogous to that of PET and PEM. Infact, Dr Tartar said, BSGI and PEM are more like eachother than other breast imaging modalities (oral com-munication, June 2009).

The current FDA-approved BSGI device is a single-head detector mounted opposite a compression plate,so the breast is compressed between detector and plate(see Figure 5). The device is manufactured by DilonDiagnostics (Newport News, Virginia). Experimentaldual-head units are currently under study. Figures 6and 7 show typical BSGI images compared with a mam-

mogram (Figure 6) and an MR image (Figure 7).In 2008 Hruska and colleagues published resultsof 6 years worth of BSGI studies in the Mayo Clinic,Rochester, Minnesota. 24 The researchers used severalstudy protocols to evaluate the usefulness of single-head and dual-head BSGI cameras as screening anddiagnostic tools. Table 1 summarizes the findings.

The first study involved 100 women with suspiciouslesions who were scheduled for biopsies. The lesions

were 2 cm or smaller and were found on a mammo-gram, an ultrasound exam or both. Patients received20 mCi (740 mBq) sestamibi and were scanned witha single-head device 10 minutes after injection. Fifty-three women were found to have breast cancer, witha total of 67 tumors, 8 of which were detected onlyby BSGI. The overall sensitivity of BSGI in this study

was 85%, with an average tumor size of 1.3 cm. Wheninvestigators looked at tumors smaller than 10 mm,the overall sensitivity of single-head BSGI was 74%.

When tumors smaller than 10 mm were excludedfrom the results, the overall sensitivity of single-headBSGI was 97%. There were 7 patients with false-nega-tive results (a total of 10 tumors). Of these 7 patients,5 had lesions smaller than 5 mm, and all 7 had very

currently 30 units installed across the country, whichrepresents a significant growth over the past few years(M. Tartar, MD, oral communication, June 2009).The Naviscan PEM scanner has a 16.3 x 24 cm field of

view, according to the companys Web site.

Note that PEM cannot take the place of breast can-cer staging performed with whole-body PET becausePEM is limited to breast views only.

ScintimammographyScintimammography was used in the 1990s when

it was shown that breast tumors rapidly take up thesame 99mTc-sestamibi used in cardiac perfusion stud-ies. Sestamibi binds to the mitochondria in the cellscytoplasm, and malignant cells have a higher density ofmitochondria in their cytoplasm than normal cells. 23

As is the case with whole-body PET, however, thedetectors distance from the patient in scintimam-mography made this modality unreliable for detectingtumors smaller than 1 cm. Studies evaluating scin-timammography found its sensitivity to be 75%, onaverage, with an average specificity of 83%. 24 The stud-ies, however, were encouraging enough and includedenough patients so that the basic idea of sestamibibreast imaging was not abandoned. For example,a Canadian study with a cohort comprising mostlypatients with advanced disease (and therefore largertumors) showed the sensitivity and specificity of scinti-mammography to be 91.5% and 94.4%, respectively. A

Figure 4. PEM Scanner. Courtesy of Naviscan Inc, San Diego, CA.


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Insurance Considerations Data from scintimammography studies carried out

in the 1990s on thousands of patients was sufficientlyencouraging to lead to the development of BSGI.These studies, however, only evaluated scintimammog-raphy as a detection modality, not as a diagnostic one.Nevertheless, on the basis of these studies, many insur-ance companies have relaxed their guidelines for cover-age of BSGI, compared with PEM coverage (M. Tartar,

MD, oral communication, June 2009). On the otherhand, Dr Tartar noted, the disappointing performanceof scintimammography and lack of large-scale experi-ence with BSGI has enabled some insurers to refusecoverage for this new modality on the grounds of itbeing experimental (oral communication, June 2009).

Some private insurers might pay for PEM with anindeterminate diagnosis (suspicion of cancer), but manyof them do not cover the procedure unless cancer is afirm diagnosis. For BSGI coverage, a patient can havea less specific diagnosis, such as known or suspectedbreast cancer, suspected recurrence, or known or sus-pected breast abnormality. Insurers are also less likely

to rely on studies of PET for coverage of PEM without acancer diagnosis because whole-body PET imaging hasbeen used almost exclusively in the cancer arena (M.Tartar, MD, oral communication, June 2009).

Comparing BSGI and PEMBoth modalities are still in their infancy as far as clini-

cal experience goes. Dr Tartar noted that she has per-formed around 80 of each procedure. In her experience,it is equally easy to learn to interpret the images acquiredby these modalities (oral communication, June 2009).

large breasts. Poor positioning of the breast alsoappeared to have been a factor in 5 of the 7 patients.The study protocol above was repeated with 150

patients using the dual-head camera, which is current-ly an experimental device only. Eighty-eight patientshad breast cancer in this group, with a total of 128tumors. Of these tumors, 9 were found only on BSGI.The overall sensitivity of the dual-headed device was91%. The sensitivity of dual-headed BSGI for tumorslarger than 10 mm was 97%. There were 11 tumorsthat were missed on BSGI, including 2 due to poorpositioning of the breast and 5 due to small tumorsize (10 mm 97% 97%

Sensitivity for tumors


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FDG is a higher-energy compound compared withsestamibi (511 keV for FDG vs 140 keV for sestamibi),and therefore PEM images are crisper. However, thisadditional clarity has no proven clinical or diagnosticsignificance at this time; both modalities seem equallysuccessful at identifying malignancies (M. Tartar, MD,oral communication, June 2009). Both BSGI and PEM,according to current studies, can achieve sensitivitiesof more than 90%. At the moment, the average sen-sitivity of PEM is somewhat higher in existing studies 93% compared with BSGIs 89%, but BSGI has ahigher negative predictive value, approaching 100%,compared with PEMs 88% negative predictive value. 23

Overall, both modalities seem on par with each otherand equally effective in their current roles. These rolesmay very well expand as more experience is gained andmore clinical studies are published.

In terms of setup, BSGI is easier to implement andmore patient friendly. The use of PEM requires fasting,checking glucose levels before the injection of FDGand an uptake wait time of approximately 60 minutes.

With BSGI, there is no need for special preparationsand scanning can commence within 5 to 10 minutesafter injection of 99mTc-sestamibi. The whole-body radia-tion dose is similar in both modalities, so the amountof absorbed radiation shouldnt be the deciding factor

(M. Tartar, MD, oral communication, June 2009).Ultimately, Dr Tartar believes the nature of the practice will determine which technology physicians will adopt. APET center, already set up to handle the pre-scanning pro-cedures associated with PET studies, will most likely findit easier to adopt the PEM technology. Conversely, a breastcenter might find BSGI easier to implement. She stressedthat at this time, there is no proven clinically significantadvantage to either imaging modality over the other (oralcommunication, June 2009).

ConclusionThese are exciting times in breast imaging,

said Dr Tartar. The latest developments in the fieldallow us to collect physiological information nonin-

vasively with better clarity and accuracy than before.Functional nuclear imaging has come a long way at adizzying pace, and future developments may be evenmore exciting. New tracers for PET and PEM use maysoon be able to image tumor cells responses to specif-ic treatments, leading us to a better understanding ofbreast cancer biology. Furthermore, these new tracerscould spare some patients painful biopsies and allowbetter-targeted treatments tailored to each patients

Figure 6. Mammogram (mediolateral oblique image at left)showing a 20 mm infiltrating ductal carcinoma. The correspond- ing molecular breast imaging study (mediolateral oblique imageat right) showed an additional 10 mm infiltrating ductal carcinoma occult on mammogram. Reprinted with permission fromHruska CB, Boughey JC, Phillips SW, et al. Scientific ImpactRecognition Award: molecular breast imaging: a review of theMayo Clinic experience. Am J Surg . 2008;196:470-476.

Figure 7. An example of a patient with concordant molecularbreast imaging (left) and breast MR (right) findings. Molecularbreast imaging shows linear focal abnormal tracer uptake in the

posterolateral left breast with orientation toward the nipple. Thereare 3 foci of intense tracer uptake, suggesting a combination ofinvasive breast cancer and ductal carcinoma in situ. MR shows anirregular enhancing mass in the outer breast measuring 4.6 x 1.8 x2.2 cm. Reprinted with permission from Hruska CB, Boughey JC,Phillips SW, et al. Scientific Impact Recognition Award: molecular breast imaging: a review of the Mayo Clinic experience. Am JSurg. 2008;196:470-476.


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1st ed. Philadelphia, PA: Mosby Inc; 2008:35.11. Avril N, Rose CA, Schelling M, et al. Breast imaging

with positron emission tomography and fluorine-18fluorodeoxyglucose: use and limitations. J Clin Oncol .2000:18(20):3495-3502.

12. Goerres GW, Michel SC, Fehr MK, et al. Follow-up of women with breast cancer: comparison between MRI andFDG PET. Eur Radiol . 2003;13(7):1635-1644.

13. Sassen S, Fend F, Avril N. Histopathologic and metaboliccriteria for assessment of treatment response in breast can-cer. PET Clin . 2006;1:83-94.

14. Weir L, Worsley D, Bernstein V. The value of FDG positronemmission tomography in the management of patients

with breast cancer. Breast J . 2005;11(3):204-209

15. Brenner RJ, Parisky Y. Alternative breast-imagingapproaches. Radiol Clin North Am . 2007;45(5):907-923.

16. Dehdashti F, Mortimer JE, Trinkaus K, et al. PET-based estradiol challenge as a predictive biomarker ofresponse to endocrine therapy in women with estrogen-receptor-positive breast cancer. Breast Cancer Res Treat .2009;113(3):509-517.

17. Thompson CJ, Murthy K, Weinberg IN, Mako F. Feasibilitystudy for positron emission mammography. Med Phys .1994;21(4):529-538.

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22. Study the role of positron emission mammography in pre-surgical planning for breast cancer. National Institutes ofHealth Web site. http://clinicaltrials.gov/ct2/show /NCT00484614. Accessed June 8, 2009.

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24. Hruska CB, Boughey JC, Phillips SW, et al. ScientificImpact Recognition Award: Molecular breast imag-ing: a review of the Mayo Clinic experience. Am J Surg .2008;196:470-476.

specific needs and administered earlier in the courseof the disease.The ability to noninvasively image the physiological

processes that occur in breast cancer already has givenus many advantages, including earlier detection, betterstaging capabilities and the important ability to predictresponse to treatment early. With improved technologiesand more clinical trials validating the new advances infunctional breast imaging, this field will undoubtedlyassume a much larger role in the fight against breast can-cer in years to come. In addition, nuclear breast imaging

will step out of the cancer arena and become a part ofroutine screening in high-risk, healthy women.

References1. Detailed guide: breast cancer What are the key statistics

for breast cancer? American Cancer Society Web site. www .cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_breast_cancer_5.asp?sitearea.Revised May 13, 2009. Accessed June 1, 2009.

2. Mankoff DA, Dunnwald LK. Changes in glucose metabo-lism and blood f low following chemotherapy for breastcancer. PET Clin . 2006;1:71-81.

3. Bartella L, Smith CS, Dershaw DD, Liberman L. Imagingbreast cancer. Radiol Clin North Am . 2007;45(1):45-67.

4. Avril N, Adler LP. F-18 fluorodeoxyglucose-positronemission tomography imaging for primary breast can-cer and loco-regional staging. Radiol Clin North Am .2007;45(4):645-657, vi.

5. Warren SL. Roentgenologic study of the breast. Am JRoentgenol . 1930;24:113-124.

6. Lill S. History of mammography. In: Andolina V, LillS, Willison KM. Mammographic Imaging: A Practical Guide .2nd ed. Baltimore, MD: Lippincott Williams & Wilkins;2001:4-5.

7. Pisano ED, Gatsonis C, Hendrick E, et al. Diagnostic per-formance of digital versus film mammography for breast-cancer screening. N Engl J Med . 2005;353(17):1773-1783.Correction published in N Engl J Med . 2006;355(17):1840.

8. Berg WA, Blume JD, Cormack JB, et al. Combined screen-

ing with ultrasound and mammography vs mammographyalone in women at elevated risk of breast cancer. JAMA .2008;299(18):2151-2163.

9. ACR, SBI statement on ACRIN breast ultrasound trialresults and role of ultrasound in breast imaging care.

American College of Radiology Web site. www.acr.org/MainMenuCategories/media_room/FeaturedCategories/PressReleases/Archive/ACRSBIStatementon

ACRINTrialResults.aspx. Accessed May 29, 2009.10. Tartar M, Comstock CE, Kipper MS. CT identification of

unknown breast cancer in an asymptomatic patient. BreastCancer Imaging: A Multidisciplinary, Multimodality Approach .


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Adi Ferrara, BS, ELS, is a freelance medical writer andeditor living in Bellevue, Washington. She gratefully acknowl- edges the invaluable help of Dr Marie Tartar, director ofadvanced breast imaging at Scripps Green Hospital in San

Diego, California, and Dr Kathy Schilling, medical director ofbreast imaging and intervention at Boca Raton CommunityHospitals Center for Breast Care in Boca Raton, Florida.Both provided tremendous help and wonderful informationduring the preparation of this Directed Reading article.

Reprint requests may be sent to the American Society ofRadiologic Technologists, Communications Department,15000 Central Ave SE, Albuquerque, NM 87123-3909, ore-mail [email protected].

2010 by the American Society of Radiologic Technologists.

Errata An error occurred in the Directed Reading answersheets for Imaging in Podiatry and Sarcoidosis: APrimer, which appeared in Radiologic Technology 2008;80(1):100-101. The answer sheets incor-rectly stated that the Directed Readings expireon September 30, 2010. The answer sheets shouldhave shown an expiration date of October 31,2010. The error did not affect the post-test.

An error occurred in the On the Job column Worksheet Aids in C-Spine Imaging, whichappeared in Radiologic Technology 2009;81(2):188-193. The Figures in the article incorrectly reversedthe kVp and mAs numbers. Although the measure-ments are correct in the caption, Figure 1B shouldindicate 80 kVp and 40 mAs. Similarly, Figures 2B,3B and 4B should read 80 kVp and 32 mAs.

nuclear imaging in breast cancer

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