Protocol Helps Identify Candidates for CRT

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PHILADELPHIA – A protocol for using serial gated single-photon emission computed tomography with a single injection radiotracer helped in patient selection for cardiac resynchronization therapy and guided left ventricle lead placement, investigators at the University of Pittsburgh reported.

The phased analysis protocol involved leaving the cardiac resynchronization therapy (CRT) device inactive at the time of implantation, injecting a single dose of radiotracer, and acquiring a resting gated single-photon emission computed tomography (SPECT); then activating the CRT and acquiring another gated SPECT, said Dr. Mati Friehling. The study was selected as winner of the ASNC's Young Investigator Award Competition.

“There is great value of phase analysis which suggests a new technique to evaluate LV synchrony,” Dr. Friehling said. “There's a linear relationship between the count changes throughout the cardiac cycle and myocardial wall thickening.”

The count changes are key to determining the precise mechanical contraction for CRT, he said.

“One question is, why do we care about the acute response?” Dr. Friehling said. “When we put a CRT device in, based on conventional criteria, we assume that acute resynchronization occurs, and this will give us a long-term benefit, but not always.

“We decided to use a gated SPECT-based approach because it gives us a congregant evaluation of the patient, including function and scar location and scar extent, which may be helpful for actual LV lead position.”

The single-dose radiotracer was devised to limit radiation exposure, he said.

The study analyzed a total of 44 patients after CRT device implantation, 18 of whom had improvement of dyssynchrony, 11 of whom had no change, and 15 of whom actually had deterioration of dyssynchrony, Dr. Friehling said.

The leads were concordant in 22 patients, only 1 of whom actually worsened. In the remaining 22 with discordant leads, 8 had improvement or were unchanged, and 14 saw their dyssynchrony worsen, according to Dr. Friehling.

“There's a very high specificity and positive predictive value for an improving or unchanged synchrony,” said Dr. Friehling.

“The responses are based on small changes in LV volume injection fraction according to echocardiography, which can be highly variable. We used harder end points such as death, CHF hospitalizations, ICD shocks, and viability of patients secondary to HF failure symptoms,” he noted.

Five deaths were reported among the 29 patients in the study group who had improved or unchanged dyssynchrony, Dr. Friehling said, while among the 15 patients who had deterioration of dyssynchrony, 8 had a cardiac event.

“Serial imaging based on conventional criteria can result in acute worsening of synchrony in some patients,” Dr. Friehling said.

“The acute change in synchrony does appear to be associated with long-term outcome, and we may be able to use a baseline SPECT study to guide LV lead placement and to predict the acute response. Therefore SPECT may be a valuable tool for selecting patients for CRT.”

Dr. Friehling had no disclosures, but two of his coinvestigators disclosed relationships with Emory Cardiac Toolbox.

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PHILADELPHIA – A protocol for using serial gated single-photon emission computed tomography with a single injection radiotracer helped in patient selection for cardiac resynchronization therapy and guided left ventricle lead placement, investigators at the University of Pittsburgh reported.

The phased analysis protocol involved leaving the cardiac resynchronization therapy (CRT) device inactive at the time of implantation, injecting a single dose of radiotracer, and acquiring a resting gated single-photon emission computed tomography (SPECT); then activating the CRT and acquiring another gated SPECT, said Dr. Mati Friehling. The study was selected as winner of the ASNC's Young Investigator Award Competition.

“There is great value of phase analysis which suggests a new technique to evaluate LV synchrony,” Dr. Friehling said. “There's a linear relationship between the count changes throughout the cardiac cycle and myocardial wall thickening.”

The count changes are key to determining the precise mechanical contraction for CRT, he said.

“One question is, why do we care about the acute response?” Dr. Friehling said. “When we put a CRT device in, based on conventional criteria, we assume that acute resynchronization occurs, and this will give us a long-term benefit, but not always.

“We decided to use a gated SPECT-based approach because it gives us a congregant evaluation of the patient, including function and scar location and scar extent, which may be helpful for actual LV lead position.”

The single-dose radiotracer was devised to limit radiation exposure, he said.

The study analyzed a total of 44 patients after CRT device implantation, 18 of whom had improvement of dyssynchrony, 11 of whom had no change, and 15 of whom actually had deterioration of dyssynchrony, Dr. Friehling said.

The leads were concordant in 22 patients, only 1 of whom actually worsened. In the remaining 22 with discordant leads, 8 had improvement or were unchanged, and 14 saw their dyssynchrony worsen, according to Dr. Friehling.

“There's a very high specificity and positive predictive value for an improving or unchanged synchrony,” said Dr. Friehling.

“The responses are based on small changes in LV volume injection fraction according to echocardiography, which can be highly variable. We used harder end points such as death, CHF hospitalizations, ICD shocks, and viability of patients secondary to HF failure symptoms,” he noted.

Five deaths were reported among the 29 patients in the study group who had improved or unchanged dyssynchrony, Dr. Friehling said, while among the 15 patients who had deterioration of dyssynchrony, 8 had a cardiac event.

“Serial imaging based on conventional criteria can result in acute worsening of synchrony in some patients,” Dr. Friehling said.

“The acute change in synchrony does appear to be associated with long-term outcome, and we may be able to use a baseline SPECT study to guide LV lead placement and to predict the acute response. Therefore SPECT may be a valuable tool for selecting patients for CRT.”

Dr. Friehling had no disclosures, but two of his coinvestigators disclosed relationships with Emory Cardiac Toolbox.

PHILADELPHIA – A protocol for using serial gated single-photon emission computed tomography with a single injection radiotracer helped in patient selection for cardiac resynchronization therapy and guided left ventricle lead placement, investigators at the University of Pittsburgh reported.

The phased analysis protocol involved leaving the cardiac resynchronization therapy (CRT) device inactive at the time of implantation, injecting a single dose of radiotracer, and acquiring a resting gated single-photon emission computed tomography (SPECT); then activating the CRT and acquiring another gated SPECT, said Dr. Mati Friehling. The study was selected as winner of the ASNC's Young Investigator Award Competition.

“There is great value of phase analysis which suggests a new technique to evaluate LV synchrony,” Dr. Friehling said. “There's a linear relationship between the count changes throughout the cardiac cycle and myocardial wall thickening.”

The count changes are key to determining the precise mechanical contraction for CRT, he said.

“One question is, why do we care about the acute response?” Dr. Friehling said. “When we put a CRT device in, based on conventional criteria, we assume that acute resynchronization occurs, and this will give us a long-term benefit, but not always.

“We decided to use a gated SPECT-based approach because it gives us a congregant evaluation of the patient, including function and scar location and scar extent, which may be helpful for actual LV lead position.”

The single-dose radiotracer was devised to limit radiation exposure, he said.

The study analyzed a total of 44 patients after CRT device implantation, 18 of whom had improvement of dyssynchrony, 11 of whom had no change, and 15 of whom actually had deterioration of dyssynchrony, Dr. Friehling said.

The leads were concordant in 22 patients, only 1 of whom actually worsened. In the remaining 22 with discordant leads, 8 had improvement or were unchanged, and 14 saw their dyssynchrony worsen, according to Dr. Friehling.

“There's a very high specificity and positive predictive value for an improving or unchanged synchrony,” said Dr. Friehling.

“The responses are based on small changes in LV volume injection fraction according to echocardiography, which can be highly variable. We used harder end points such as death, CHF hospitalizations, ICD shocks, and viability of patients secondary to HF failure symptoms,” he noted.

Five deaths were reported among the 29 patients in the study group who had improved or unchanged dyssynchrony, Dr. Friehling said, while among the 15 patients who had deterioration of dyssynchrony, 8 had a cardiac event.

“Serial imaging based on conventional criteria can result in acute worsening of synchrony in some patients,” Dr. Friehling said.

“The acute change in synchrony does appear to be associated with long-term outcome, and we may be able to use a baseline SPECT study to guide LV lead placement and to predict the acute response. Therefore SPECT may be a valuable tool for selecting patients for CRT.”

Dr. Friehling had no disclosures, but two of his coinvestigators disclosed relationships with Emory Cardiac Toolbox.

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MRI Role in Knee Osteoarthritis Diagnosis Proposed by Expert Panel

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BRUSSELS – The use of magnetic resonance imaging may enable earlier recognition of knee osteoarthritis, and should be incorporated into recommended diagnostic criteria, a panel of 16 osteoarthritis experts concluded.

Using MRI to define knee osteoarthritis (OA) may allow detection of the disease before radiographic changes occur. But despite a growing body of literature on the role of MRI in OA, little uniformity exists for its diagnostic application, perhaps because of the absence of criteria for an MRI-based structural diagnosis of OA, the group said.

    Dr. Tuhina Neogi

The Osteoarthritis Research Society International (OARSI) organized the 16-member panel, the OA Imaging Working Group, to develop an MRI-based definition of structural OA. The working group sought to identify structural changes on MRI that defined a structural diagnosis of knee OA, Dr. David J. Hunter and the other members of the working group wrote in a poster presented at the World Congress on Osteoarthritis, which was organized by OARSI.

The working group began with a literature review through April 2009, a process that yielded 25 studies that met the group’s inclusion criteria and evaluated MRI diagnostic performance. The 16 members also contributed candidate propositions dealing with key aspects of MRI diagnosis of knee OA.

Through a multiphase process of discussion and voting, the group agreed on the following set of nine propositions based on MRI criteria of knee OA:

1. MRI changes of OA may occur in the absence of radiographic findings of OA.

2. MRI may add to the diagnosis of OA and should be incorporated into the ACR diagnostic criteria including x-ray, clinical, and laboratory parameters.

3. MRI may be used for inclusion in clinical studies according to the criteria detailed above, but should not be a primary diagnostic tool in a clinical setting.

4. Certain MRI changes that occur in isolation are not diagnostic of OA. These include cartilage loss, change in cartilage composition, cystic change and development of bone marrow lesions, ligamentous and tendinous damage, meniscal damage, and effusion and synovitis.

5. No single finding is diagnostic of knee OA.

6. MRI findings indicative of knee OA may include abnormalities in all tissues of the joint (bone, cartilage, meniscus, synovium, ligament, and capsule).

7. Given the multiple tissue abnormalities detected by MRI in OA, diagnostic criteria are likely to involve several possible combinations of features.

8. Definite osteophyte production is indicative of OA.

9. Joint space narrowing as assessed by (nonweight bearing) MRI cannot be used as a diagnostic criterion.

Similarly, the working group agreed on the following two definitions for MRI findings that were diagnostic of knee OA:

1. Tibiofemoral OA should have either both features from group A (below), or one feature from group A and at least two features from group B. Examination of the patient must also rule out joint trauma within the last 6 months (by history) as well as inflammatory arthritis (diagnosed by radiographs, history, and laboratory findings).

• Group A features: Definite osteophyte formation; full thickness cartilage loss.

• Group B features: Subchondral bone marrow lesion or cyst not associated with meniscal or ligamentous attachments; meniscal subluxation, maceration, or degenerative (horizontal) tear; partial-thickness cartilage loss (without full thickness loss).

2. Patellofemoral OA requires both of the following features involving the patella or the anterior femur or both:

• Definite osteophyte formation.

• Partial- or full-thickness cartilage loss.

These constitute “statements of preamble and context setting.” The two definitions “offer an opportunity for formal testing against other diagnostic constructs,” said Dr. Hunter, a rheumatologist and professor of medicine at the University of Sydney and his associates in the working group.

The working group noted that the American College of Rheumatology in 1986 first released the current standard criteria for diagnosing OA, which deal only with radiographic imaging (Arthritis Rheum. 1986;29:1039-49). The European League Against Rheumatism published more current recommendations this year, but focused on a clinical diagnosis that did not involve imaging (Ann. Rheum. Dis. 2010;69:483-9).

The working group aimed to “include MRI as a means to define the disease with the intent that one may be able to identify early, pre-radiographic disease, thus enabling recruitment of study populations where structure modification (or structure maintenance) may be realistic in a more preventive manner.”

The group cautioned that prior to using the definitions, “it is important that their validity and diagnostic performance be adequately tested.” They also stressed that “the propositions have been developed for structural OA, not for a clinical diagnosis, not for early OA, and not to facilitate staging of the disease.” The propositions “are not to detract from, nor to discourage the use of traditional means for diagnosing OA.”

 

 

An osteoarthritis specialist who was not involved with the working group cautioned that waiting for MRI structural changes that are specific for OA may still miss a truly early diagnosis, before irreversible pathology occurred.

“It’s too early to know the definition of OA on MRI. We know what features of OA are on MRI, but that doesn’t mean we can make a diagnosis based on MRI,” commented Dr. Tuhina Neogi, a rheumatologist at Boston University. “There are early changes [seen with MRI] that are not picked up on radiographs, but we don’t yet have a standardized, validated definition of an earlier stage” on MRI, Dr. Neogi said in an interview.

Dr. Hunter said that he has received research support from AstraZeneca, DJO Inc. (DonJoy), Eli Lilly & Co., Merck & Co., Pfizer Inc., Stryker Corp., and Wyeth. Eight of the other members of the working group also provided disclosures, whereas the remaining seven members said they had no disclosures. Dr. Neogi had no disclosures.

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BRUSSELS – The use of magnetic resonance imaging may enable earlier recognition of knee osteoarthritis, and should be incorporated into recommended diagnostic criteria, a panel of 16 osteoarthritis experts concluded.

Using MRI to define knee osteoarthritis (OA) may allow detection of the disease before radiographic changes occur. But despite a growing body of literature on the role of MRI in OA, little uniformity exists for its diagnostic application, perhaps because of the absence of criteria for an MRI-based structural diagnosis of OA, the group said.

    Dr. Tuhina Neogi

The Osteoarthritis Research Society International (OARSI) organized the 16-member panel, the OA Imaging Working Group, to develop an MRI-based definition of structural OA. The working group sought to identify structural changes on MRI that defined a structural diagnosis of knee OA, Dr. David J. Hunter and the other members of the working group wrote in a poster presented at the World Congress on Osteoarthritis, which was organized by OARSI.

The working group began with a literature review through April 2009, a process that yielded 25 studies that met the group’s inclusion criteria and evaluated MRI diagnostic performance. The 16 members also contributed candidate propositions dealing with key aspects of MRI diagnosis of knee OA.

Through a multiphase process of discussion and voting, the group agreed on the following set of nine propositions based on MRI criteria of knee OA:

1. MRI changes of OA may occur in the absence of radiographic findings of OA.

2. MRI may add to the diagnosis of OA and should be incorporated into the ACR diagnostic criteria including x-ray, clinical, and laboratory parameters.

3. MRI may be used for inclusion in clinical studies according to the criteria detailed above, but should not be a primary diagnostic tool in a clinical setting.

4. Certain MRI changes that occur in isolation are not diagnostic of OA. These include cartilage loss, change in cartilage composition, cystic change and development of bone marrow lesions, ligamentous and tendinous damage, meniscal damage, and effusion and synovitis.

5. No single finding is diagnostic of knee OA.

6. MRI findings indicative of knee OA may include abnormalities in all tissues of the joint (bone, cartilage, meniscus, synovium, ligament, and capsule).

7. Given the multiple tissue abnormalities detected by MRI in OA, diagnostic criteria are likely to involve several possible combinations of features.

8. Definite osteophyte production is indicative of OA.

9. Joint space narrowing as assessed by (nonweight bearing) MRI cannot be used as a diagnostic criterion.

Similarly, the working group agreed on the following two definitions for MRI findings that were diagnostic of knee OA:

1. Tibiofemoral OA should have either both features from group A (below), or one feature from group A and at least two features from group B. Examination of the patient must also rule out joint trauma within the last 6 months (by history) as well as inflammatory arthritis (diagnosed by radiographs, history, and laboratory findings).

• Group A features: Definite osteophyte formation; full thickness cartilage loss.

• Group B features: Subchondral bone marrow lesion or cyst not associated with meniscal or ligamentous attachments; meniscal subluxation, maceration, or degenerative (horizontal) tear; partial-thickness cartilage loss (without full thickness loss).

2. Patellofemoral OA requires both of the following features involving the patella or the anterior femur or both:

• Definite osteophyte formation.

• Partial- or full-thickness cartilage loss.

These constitute “statements of preamble and context setting.” The two definitions “offer an opportunity for formal testing against other diagnostic constructs,” said Dr. Hunter, a rheumatologist and professor of medicine at the University of Sydney and his associates in the working group.

The working group noted that the American College of Rheumatology in 1986 first released the current standard criteria for diagnosing OA, which deal only with radiographic imaging (Arthritis Rheum. 1986;29:1039-49). The European League Against Rheumatism published more current recommendations this year, but focused on a clinical diagnosis that did not involve imaging (Ann. Rheum. Dis. 2010;69:483-9).

The working group aimed to “include MRI as a means to define the disease with the intent that one may be able to identify early, pre-radiographic disease, thus enabling recruitment of study populations where structure modification (or structure maintenance) may be realistic in a more preventive manner.”

The group cautioned that prior to using the definitions, “it is important that their validity and diagnostic performance be adequately tested.” They also stressed that “the propositions have been developed for structural OA, not for a clinical diagnosis, not for early OA, and not to facilitate staging of the disease.” The propositions “are not to detract from, nor to discourage the use of traditional means for diagnosing OA.”

 

 

An osteoarthritis specialist who was not involved with the working group cautioned that waiting for MRI structural changes that are specific for OA may still miss a truly early diagnosis, before irreversible pathology occurred.

“It’s too early to know the definition of OA on MRI. We know what features of OA are on MRI, but that doesn’t mean we can make a diagnosis based on MRI,” commented Dr. Tuhina Neogi, a rheumatologist at Boston University. “There are early changes [seen with MRI] that are not picked up on radiographs, but we don’t yet have a standardized, validated definition of an earlier stage” on MRI, Dr. Neogi said in an interview.

Dr. Hunter said that he has received research support from AstraZeneca, DJO Inc. (DonJoy), Eli Lilly & Co., Merck & Co., Pfizer Inc., Stryker Corp., and Wyeth. Eight of the other members of the working group also provided disclosures, whereas the remaining seven members said they had no disclosures. Dr. Neogi had no disclosures.

BRUSSELS – The use of magnetic resonance imaging may enable earlier recognition of knee osteoarthritis, and should be incorporated into recommended diagnostic criteria, a panel of 16 osteoarthritis experts concluded.

Using MRI to define knee osteoarthritis (OA) may allow detection of the disease before radiographic changes occur. But despite a growing body of literature on the role of MRI in OA, little uniformity exists for its diagnostic application, perhaps because of the absence of criteria for an MRI-based structural diagnosis of OA, the group said.

    Dr. Tuhina Neogi

The Osteoarthritis Research Society International (OARSI) organized the 16-member panel, the OA Imaging Working Group, to develop an MRI-based definition of structural OA. The working group sought to identify structural changes on MRI that defined a structural diagnosis of knee OA, Dr. David J. Hunter and the other members of the working group wrote in a poster presented at the World Congress on Osteoarthritis, which was organized by OARSI.

The working group began with a literature review through April 2009, a process that yielded 25 studies that met the group’s inclusion criteria and evaluated MRI diagnostic performance. The 16 members also contributed candidate propositions dealing with key aspects of MRI diagnosis of knee OA.

Through a multiphase process of discussion and voting, the group agreed on the following set of nine propositions based on MRI criteria of knee OA:

1. MRI changes of OA may occur in the absence of radiographic findings of OA.

2. MRI may add to the diagnosis of OA and should be incorporated into the ACR diagnostic criteria including x-ray, clinical, and laboratory parameters.

3. MRI may be used for inclusion in clinical studies according to the criteria detailed above, but should not be a primary diagnostic tool in a clinical setting.

4. Certain MRI changes that occur in isolation are not diagnostic of OA. These include cartilage loss, change in cartilage composition, cystic change and development of bone marrow lesions, ligamentous and tendinous damage, meniscal damage, and effusion and synovitis.

5. No single finding is diagnostic of knee OA.

6. MRI findings indicative of knee OA may include abnormalities in all tissues of the joint (bone, cartilage, meniscus, synovium, ligament, and capsule).

7. Given the multiple tissue abnormalities detected by MRI in OA, diagnostic criteria are likely to involve several possible combinations of features.

8. Definite osteophyte production is indicative of OA.

9. Joint space narrowing as assessed by (nonweight bearing) MRI cannot be used as a diagnostic criterion.

Similarly, the working group agreed on the following two definitions for MRI findings that were diagnostic of knee OA:

1. Tibiofemoral OA should have either both features from group A (below), or one feature from group A and at least two features from group B. Examination of the patient must also rule out joint trauma within the last 6 months (by history) as well as inflammatory arthritis (diagnosed by radiographs, history, and laboratory findings).

• Group A features: Definite osteophyte formation; full thickness cartilage loss.

• Group B features: Subchondral bone marrow lesion or cyst not associated with meniscal or ligamentous attachments; meniscal subluxation, maceration, or degenerative (horizontal) tear; partial-thickness cartilage loss (without full thickness loss).

2. Patellofemoral OA requires both of the following features involving the patella or the anterior femur or both:

• Definite osteophyte formation.

• Partial- or full-thickness cartilage loss.

These constitute “statements of preamble and context setting.” The two definitions “offer an opportunity for formal testing against other diagnostic constructs,” said Dr. Hunter, a rheumatologist and professor of medicine at the University of Sydney and his associates in the working group.

The working group noted that the American College of Rheumatology in 1986 first released the current standard criteria for diagnosing OA, which deal only with radiographic imaging (Arthritis Rheum. 1986;29:1039-49). The European League Against Rheumatism published more current recommendations this year, but focused on a clinical diagnosis that did not involve imaging (Ann. Rheum. Dis. 2010;69:483-9).

The working group aimed to “include MRI as a means to define the disease with the intent that one may be able to identify early, pre-radiographic disease, thus enabling recruitment of study populations where structure modification (or structure maintenance) may be realistic in a more preventive manner.”

The group cautioned that prior to using the definitions, “it is important that their validity and diagnostic performance be adequately tested.” They also stressed that “the propositions have been developed for structural OA, not for a clinical diagnosis, not for early OA, and not to facilitate staging of the disease.” The propositions “are not to detract from, nor to discourage the use of traditional means for diagnosing OA.”

 

 

An osteoarthritis specialist who was not involved with the working group cautioned that waiting for MRI structural changes that are specific for OA may still miss a truly early diagnosis, before irreversible pathology occurred.

“It’s too early to know the definition of OA on MRI. We know what features of OA are on MRI, but that doesn’t mean we can make a diagnosis based on MRI,” commented Dr. Tuhina Neogi, a rheumatologist at Boston University. “There are early changes [seen with MRI] that are not picked up on radiographs, but we don’t yet have a standardized, validated definition of an earlier stage” on MRI, Dr. Neogi said in an interview.

Dr. Hunter said that he has received research support from AstraZeneca, DJO Inc. (DonJoy), Eli Lilly & Co., Merck & Co., Pfizer Inc., Stryker Corp., and Wyeth. Eight of the other members of the working group also provided disclosures, whereas the remaining seven members said they had no disclosures. Dr. Neogi had no disclosures.

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Disclosures: Dr. Hunter said that he has received research support from AstraZeneca, DonJoy, Lilly, Merck, Pfizer, Stryker, and Wyeth. Eight other members of the working group also provided disclosures, whereas the remaining seven members said they had no disclosures.

Multidetector CT Angiography Highly Sensitive, Specific for Vascular Extremity Injury

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BOSTON – Physical examination is still the gold standard for patients with vascular injury of the extremities, and can reduce unnecessary imaging in the majority of patients. But when imaging is called for, multidetector CT angiography is a highly sensitive and specific noninvasive option, said Dr. Kenji Inaba.

In a prospective study involving 73 patients with extremity trauma but uncertain signs of vascular injury, multidetector CT angiography (MCTA) flagged 24 injuries, all but 1 of which were confirmed in the operating room, Dr. Inaba said at the annual meeting of the American Association for the Surgery of Trauma.

“There are a lot of potential advantages to using CT angio: It’s widely available everywhere using preexisting hardware and software, it’s fast and becoming faster, and it’s available 24 hours a day without any delay from calling the interventional radiology team in,” said Dr. Inaba from the division of trauma and surgical critical care at the Los Angeles County Hospital/University of Southern California Medical Center.

Because the technique is not performed under a sterile field, it simplifies patient monitoring, and it produces “surgeon-friendly,” three-dimensional multiplanar images.

“Not only does it let us look at the vasculature, it also lets us look at soft tissues and all the bone structures as well. Unlike conventional angio, it doesn’t need a central arterial catheterization – all the contrast is given through peripheral venous access,” Dr. Inaba said.

He and his colleagues took a prospective look at the ability of MCTA to detect arterial injuries in the arms and legs. They studied patients aged 16 and older treated from January 2009 to August 2010 who presented with either penetrating injury, blunt crush, or long bone fracture or dislocation. Arm injuries could be anywhere down to the wrist, and leg injuries were anywhere down to the ankle.

A total of 635 patients were assigned to one of three treatment groups based on findings at physical examination. Those with hard signs of vascular injury (35 patients) were sent into surgery. Hard signs were defined as absent pulses, active hemorrhage, expanding/pulsatile hematoma, bruit or thrill, or shock unresponsive to resuscitation.

Those with no signs (527 patients) were put on observation for a minimum of 24 hours. Patients were considered to have no vascular injury signs if they had asymptomatic limbs and an ankle-brachial index (ABI) or a brachial-brachial index (BBI) of 0.9 or greater.

The remaining 73 patients had “soft” signs, such as venous oozing, nonexpanding or nonpulsatile hematoma, diminished pulses, or an abnormal ankle-brachial/brachial-brachial index. These patients underwent MCTA.

The patients underwent a total of 89 MCTA studies. The mean age was 30.3 years (range, 16-77); 88% were male; and 70% had penetrating injuries. The mean injury severity score was 10 plus or minus 8.1, and 38% of the patients had an abbreviated injury score of 3 or higher. Nearly half of all injuries were to the thigh. Other sites were the upper arm, knee, groin, shoulder/axilla, forearm, elbow, and calf.

Indications for MCTA included nonexpanding or nonpulsatile hematoma or an abnormal ABI or BBI (in 35.6% each), venous oozing in 21.9%, diminished pulses in 19.2%, and proximity of injury to a major vessel in 15.1%; some patients had more than one indication. Imaging for proximity was not one of the study indications, Dr. Inaba noted. The investigators classified the MCTA findings as either nondiagnostic, negative, or positive. Seven of the 89 studies were deemed to be nondiagnostic: 5 because of retained shotgun pellets or bullets causing artifacts that obscured potential injuries, and 2 because of technical problems that occurred with unfamiliar equipment in the new Los Angeles County facility during the early months of the study. These patients underwent conventional angiography, and there were no missed diagnoses, Dr. Inaba said.

Most of the MCTA studies (58) were negative. The patients were followed for a minimum of 24 hours (range, 1-41 days), and none had clinically significant missed injuries.

The remaining 24 studies were positive, and all but 1, a posterior tibular injury, were confirmed in the operating room.

“CT angio was not only able to locate the site of the injury, but it was also able to well characterize the injury itself,” Dr. Inaba said.

Limitations of the study included a lack of confirmatory imaging in the patients with negative studies because of the cost, time, and unjustifiable extra radiation exposure. In addition, 21% of these patients were sent home after 24 hours of observation, and it’s possible that CT angiography missed injuries that were later picked up at another hospital. The investigators also relied on final radiology reports rather than de novo blinded readings.

 

 

“These CT scanners are improving on a daily basis, and there’s true concern that we may be detecting clinically nonsignificant injuries,” he added.

Although Dr. Inaba said that the study showed MCTA sensitivity and specificity for vascular injury to be 100% each, the inconclusive study results indicate that neither could be 100%, said Dr. David Spain of the division of trauma/critical care at Stanford (Calif.) University Hospital. He was the invited discussant.

“The sensitivity and specificity analysis isn’t just for CTA. It’s actually for a structured physical exam followed by a CTA,” Dr. Spain commented.

The study was internally funded. The authors said they had no conflicts of interest.

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BOSTON – Physical examination is still the gold standard for patients with vascular injury of the extremities, and can reduce unnecessary imaging in the majority of patients. But when imaging is called for, multidetector CT angiography is a highly sensitive and specific noninvasive option, said Dr. Kenji Inaba.

In a prospective study involving 73 patients with extremity trauma but uncertain signs of vascular injury, multidetector CT angiography (MCTA) flagged 24 injuries, all but 1 of which were confirmed in the operating room, Dr. Inaba said at the annual meeting of the American Association for the Surgery of Trauma.

“There are a lot of potential advantages to using CT angio: It’s widely available everywhere using preexisting hardware and software, it’s fast and becoming faster, and it’s available 24 hours a day without any delay from calling the interventional radiology team in,” said Dr. Inaba from the division of trauma and surgical critical care at the Los Angeles County Hospital/University of Southern California Medical Center.

Because the technique is not performed under a sterile field, it simplifies patient monitoring, and it produces “surgeon-friendly,” three-dimensional multiplanar images.

“Not only does it let us look at the vasculature, it also lets us look at soft tissues and all the bone structures as well. Unlike conventional angio, it doesn’t need a central arterial catheterization – all the contrast is given through peripheral venous access,” Dr. Inaba said.

He and his colleagues took a prospective look at the ability of MCTA to detect arterial injuries in the arms and legs. They studied patients aged 16 and older treated from January 2009 to August 2010 who presented with either penetrating injury, blunt crush, or long bone fracture or dislocation. Arm injuries could be anywhere down to the wrist, and leg injuries were anywhere down to the ankle.

A total of 635 patients were assigned to one of three treatment groups based on findings at physical examination. Those with hard signs of vascular injury (35 patients) were sent into surgery. Hard signs were defined as absent pulses, active hemorrhage, expanding/pulsatile hematoma, bruit or thrill, or shock unresponsive to resuscitation.

Those with no signs (527 patients) were put on observation for a minimum of 24 hours. Patients were considered to have no vascular injury signs if they had asymptomatic limbs and an ankle-brachial index (ABI) or a brachial-brachial index (BBI) of 0.9 or greater.

The remaining 73 patients had “soft” signs, such as venous oozing, nonexpanding or nonpulsatile hematoma, diminished pulses, or an abnormal ankle-brachial/brachial-brachial index. These patients underwent MCTA.

The patients underwent a total of 89 MCTA studies. The mean age was 30.3 years (range, 16-77); 88% were male; and 70% had penetrating injuries. The mean injury severity score was 10 plus or minus 8.1, and 38% of the patients had an abbreviated injury score of 3 or higher. Nearly half of all injuries were to the thigh. Other sites were the upper arm, knee, groin, shoulder/axilla, forearm, elbow, and calf.

Indications for MCTA included nonexpanding or nonpulsatile hematoma or an abnormal ABI or BBI (in 35.6% each), venous oozing in 21.9%, diminished pulses in 19.2%, and proximity of injury to a major vessel in 15.1%; some patients had more than one indication. Imaging for proximity was not one of the study indications, Dr. Inaba noted. The investigators classified the MCTA findings as either nondiagnostic, negative, or positive. Seven of the 89 studies were deemed to be nondiagnostic: 5 because of retained shotgun pellets or bullets causing artifacts that obscured potential injuries, and 2 because of technical problems that occurred with unfamiliar equipment in the new Los Angeles County facility during the early months of the study. These patients underwent conventional angiography, and there were no missed diagnoses, Dr. Inaba said.

Most of the MCTA studies (58) were negative. The patients were followed for a minimum of 24 hours (range, 1-41 days), and none had clinically significant missed injuries.

The remaining 24 studies were positive, and all but 1, a posterior tibular injury, were confirmed in the operating room.

“CT angio was not only able to locate the site of the injury, but it was also able to well characterize the injury itself,” Dr. Inaba said.

Limitations of the study included a lack of confirmatory imaging in the patients with negative studies because of the cost, time, and unjustifiable extra radiation exposure. In addition, 21% of these patients were sent home after 24 hours of observation, and it’s possible that CT angiography missed injuries that were later picked up at another hospital. The investigators also relied on final radiology reports rather than de novo blinded readings.

 

 

“These CT scanners are improving on a daily basis, and there’s true concern that we may be detecting clinically nonsignificant injuries,” he added.

Although Dr. Inaba said that the study showed MCTA sensitivity and specificity for vascular injury to be 100% each, the inconclusive study results indicate that neither could be 100%, said Dr. David Spain of the division of trauma/critical care at Stanford (Calif.) University Hospital. He was the invited discussant.

“The sensitivity and specificity analysis isn’t just for CTA. It’s actually for a structured physical exam followed by a CTA,” Dr. Spain commented.

The study was internally funded. The authors said they had no conflicts of interest.

BOSTON – Physical examination is still the gold standard for patients with vascular injury of the extremities, and can reduce unnecessary imaging in the majority of patients. But when imaging is called for, multidetector CT angiography is a highly sensitive and specific noninvasive option, said Dr. Kenji Inaba.

In a prospective study involving 73 patients with extremity trauma but uncertain signs of vascular injury, multidetector CT angiography (MCTA) flagged 24 injuries, all but 1 of which were confirmed in the operating room, Dr. Inaba said at the annual meeting of the American Association for the Surgery of Trauma.

“There are a lot of potential advantages to using CT angio: It’s widely available everywhere using preexisting hardware and software, it’s fast and becoming faster, and it’s available 24 hours a day without any delay from calling the interventional radiology team in,” said Dr. Inaba from the division of trauma and surgical critical care at the Los Angeles County Hospital/University of Southern California Medical Center.

Because the technique is not performed under a sterile field, it simplifies patient monitoring, and it produces “surgeon-friendly,” three-dimensional multiplanar images.

“Not only does it let us look at the vasculature, it also lets us look at soft tissues and all the bone structures as well. Unlike conventional angio, it doesn’t need a central arterial catheterization – all the contrast is given through peripheral venous access,” Dr. Inaba said.

He and his colleagues took a prospective look at the ability of MCTA to detect arterial injuries in the arms and legs. They studied patients aged 16 and older treated from January 2009 to August 2010 who presented with either penetrating injury, blunt crush, or long bone fracture or dislocation. Arm injuries could be anywhere down to the wrist, and leg injuries were anywhere down to the ankle.

A total of 635 patients were assigned to one of three treatment groups based on findings at physical examination. Those with hard signs of vascular injury (35 patients) were sent into surgery. Hard signs were defined as absent pulses, active hemorrhage, expanding/pulsatile hematoma, bruit or thrill, or shock unresponsive to resuscitation.

Those with no signs (527 patients) were put on observation for a minimum of 24 hours. Patients were considered to have no vascular injury signs if they had asymptomatic limbs and an ankle-brachial index (ABI) or a brachial-brachial index (BBI) of 0.9 or greater.

The remaining 73 patients had “soft” signs, such as venous oozing, nonexpanding or nonpulsatile hematoma, diminished pulses, or an abnormal ankle-brachial/brachial-brachial index. These patients underwent MCTA.

The patients underwent a total of 89 MCTA studies. The mean age was 30.3 years (range, 16-77); 88% were male; and 70% had penetrating injuries. The mean injury severity score was 10 plus or minus 8.1, and 38% of the patients had an abbreviated injury score of 3 or higher. Nearly half of all injuries were to the thigh. Other sites were the upper arm, knee, groin, shoulder/axilla, forearm, elbow, and calf.

Indications for MCTA included nonexpanding or nonpulsatile hematoma or an abnormal ABI or BBI (in 35.6% each), venous oozing in 21.9%, diminished pulses in 19.2%, and proximity of injury to a major vessel in 15.1%; some patients had more than one indication. Imaging for proximity was not one of the study indications, Dr. Inaba noted. The investigators classified the MCTA findings as either nondiagnostic, negative, or positive. Seven of the 89 studies were deemed to be nondiagnostic: 5 because of retained shotgun pellets or bullets causing artifacts that obscured potential injuries, and 2 because of technical problems that occurred with unfamiliar equipment in the new Los Angeles County facility during the early months of the study. These patients underwent conventional angiography, and there were no missed diagnoses, Dr. Inaba said.

Most of the MCTA studies (58) were negative. The patients were followed for a minimum of 24 hours (range, 1-41 days), and none had clinically significant missed injuries.

The remaining 24 studies were positive, and all but 1, a posterior tibular injury, were confirmed in the operating room.

“CT angio was not only able to locate the site of the injury, but it was also able to well characterize the injury itself,” Dr. Inaba said.

Limitations of the study included a lack of confirmatory imaging in the patients with negative studies because of the cost, time, and unjustifiable extra radiation exposure. In addition, 21% of these patients were sent home after 24 hours of observation, and it’s possible that CT angiography missed injuries that were later picked up at another hospital. The investigators also relied on final radiology reports rather than de novo blinded readings.

 

 

“These CT scanners are improving on a daily basis, and there’s true concern that we may be detecting clinically nonsignificant injuries,” he added.

Although Dr. Inaba said that the study showed MCTA sensitivity and specificity for vascular injury to be 100% each, the inconclusive study results indicate that neither could be 100%, said Dr. David Spain of the division of trauma/critical care at Stanford (Calif.) University Hospital. He was the invited discussant.

“The sensitivity and specificity analysis isn’t just for CTA. It’s actually for a structured physical exam followed by a CTA,” Dr. Spain commented.

The study was internally funded. The authors said they had no conflicts of interest.

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FROM THE ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR THE SURGERY OF TRAUMA

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Panel Evaluates Use of MRI in Breast Cancer

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WASHINGTON – While the use of magnetic resonance imaging as a screening tool for breast cancer has increased significantly over the past decade, there is still little evidence of its clinical benefits and cost-effectiveness, according to a panel of experts who addressed a capacity crowd at the annual clinical congress of the American College of Surgeons.

    Dr. Monica Morrow

Patients at high risk of developing breast cancer (e.g., those with BRCA mutations or a greater than 20% risk of developing breast cancer during their lifetime) could benefit from breast MRI. The panel, however, pointed to a wide range of U.S., Canadian, and European studies showing that there is no evidence that MRI improves breast cancer survival, and it increases the rate of mastectomies. The panel members included Dr. Elisa R. Port and Dr. Monica Morrow, both of Memorial Sloan-Kettering Cancer Center in New York, Dr. Isabelle Bedrosian of MD Anderson Cancer Center in Houston, and Dr. Richard J. Bleicher of Fox Chase Cancer Center in Philadelphia.

The American Cancer Society and the National Comprehensive Cancer Network have developed MRI screening guidelines to distinguish which groups of patients should or should not be screened. However, there are very few data thus far to indicate just when to start or stop screening, or how often to perform screening, said Dr. Bedrosian.

“There are no data on the impact of MRI screening on survival outcomes,” she said, noting that the data to support MRI screening in terms of outcomes are based on disease stage migration, not survival.

She added that there are very few data about the cost-effectiveness of breast MRI screening. Patient age, BRCA gene mutations, breast density, and the cost of MRI must all be factored into the cost-effectiveness of MRI screening. The data show that MRI screening is more cost effective for higher-risk patients, but the panel wondered whether breast MRI screenings could be contributing to the nation’s rising health care costs.

There are currently 70 million women in the United States between the ages of 30 and 70. Of those, 1% are at high risk of developing breast cancer and are eligible for screening, which translates to a potential 1 million MRI screenings per year, said the panel.

“The most troubling finding is that it causes us to think about breast cancer the way we thought about it in the 1970s, the 1980s, and the early 1990s – that the disease burden in the breast is the sole or primary determinant of breast cancer outcome,” said Dr. Morrow. “The modern era tells us that’s really not true.”

In addition, she mentioned two retrospective studies (one in the United States and the other from the Netherlands Cancer Institute) that showed no decrease in unplanned mastectomy for patients who had preoperative MRI.

To answer the question of whether or not obtaining an MRI increases the likelihood of obtaining negative margins, Dr. Morrow summarized the results of four retrospective studies involving more than 2,500 patients. “The studies showed no statistically significant benefit in terms of reducing positive margins with MRI,” she said.

Another prospective randomized trial of 1,600 women showed that the net effect of MRI was a slightly higher rate of mastectomy in patients who had an MRI preoperatively, but no reduction in the need for further surgery.

Dr. Morrow added that in patients who have unifocal cancer, MRI can’t underestimate the extent of disease but instead overestimates the extent of disease in a third of the patients. In the case of multifocal or multicentric disease, MRI is accurate in a third of the patients, it overestimates the disease in another third, and it misses the disease a third of the time.

“There’s no possibility that MRI will improve breast cancer survival,” Dr. Morrow said. It takes a difference in local failure rates of greater than 10% at 5 years post treatment to see a survival difference in 15 years, she added. “Current rates of local recurrence at 10 years are less than 10%, and there should be no expectation that MRI will change survival.”

Medicare data show that the number of MRIs (all types) performed has increased over the past decade. While the total cost of treating breast cancer patients in the United States is increasing at 4% per year, the imaging costs are increasing at 10% a year, said Dr. Bleicher.

Although there are no national data showing what percentage of health care costs is attributable to breast MRIs, “one of the things that’s not in dispute [is that] breast MRI usage in breast cancer patients is increasing,” and its contribution to rising health care costs is “highly suggestive,” he added.

 

 

Furthermore, fear of lawsuits among surgeons and radiologists also influences the decision to order these tests.

“So what can we do?” asked Dr. Bleicher. “Always do what’s best for the patient, [and] you need to document your rationale. MRI is indeed a valuable tool, but we really do need to define its indications both to justify the cost involved and to clarify when not performing it is true breach of duty to the patient.”

The panel concluded that there is a need to establish evidence-based criteria for ordering MRIs in different clinical scenarios. “The potential research applications of MRI should not be confused with routine clinical practice,” said Dr. Morrow.

“MRI is not emerging – it has fully emerged – and in some respects, the train has already left the station,” said Dr. Port. “I think what we need to do at this point is really re-establish definitive guidelines for [MRI] use in women with newly diagnosed breast cancer for whom there are no clear-cut guidelines and for whom practice patterns range widely.”

The panel members reported no relevant conflicts of interest.

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WASHINGTON – While the use of magnetic resonance imaging as a screening tool for breast cancer has increased significantly over the past decade, there is still little evidence of its clinical benefits and cost-effectiveness, according to a panel of experts who addressed a capacity crowd at the annual clinical congress of the American College of Surgeons.

    Dr. Monica Morrow

Patients at high risk of developing breast cancer (e.g., those with BRCA mutations or a greater than 20% risk of developing breast cancer during their lifetime) could benefit from breast MRI. The panel, however, pointed to a wide range of U.S., Canadian, and European studies showing that there is no evidence that MRI improves breast cancer survival, and it increases the rate of mastectomies. The panel members included Dr. Elisa R. Port and Dr. Monica Morrow, both of Memorial Sloan-Kettering Cancer Center in New York, Dr. Isabelle Bedrosian of MD Anderson Cancer Center in Houston, and Dr. Richard J. Bleicher of Fox Chase Cancer Center in Philadelphia.

The American Cancer Society and the National Comprehensive Cancer Network have developed MRI screening guidelines to distinguish which groups of patients should or should not be screened. However, there are very few data thus far to indicate just when to start or stop screening, or how often to perform screening, said Dr. Bedrosian.

“There are no data on the impact of MRI screening on survival outcomes,” she said, noting that the data to support MRI screening in terms of outcomes are based on disease stage migration, not survival.

She added that there are very few data about the cost-effectiveness of breast MRI screening. Patient age, BRCA gene mutations, breast density, and the cost of MRI must all be factored into the cost-effectiveness of MRI screening. The data show that MRI screening is more cost effective for higher-risk patients, but the panel wondered whether breast MRI screenings could be contributing to the nation’s rising health care costs.

There are currently 70 million women in the United States between the ages of 30 and 70. Of those, 1% are at high risk of developing breast cancer and are eligible for screening, which translates to a potential 1 million MRI screenings per year, said the panel.

“The most troubling finding is that it causes us to think about breast cancer the way we thought about it in the 1970s, the 1980s, and the early 1990s – that the disease burden in the breast is the sole or primary determinant of breast cancer outcome,” said Dr. Morrow. “The modern era tells us that’s really not true.”

In addition, she mentioned two retrospective studies (one in the United States and the other from the Netherlands Cancer Institute) that showed no decrease in unplanned mastectomy for patients who had preoperative MRI.

To answer the question of whether or not obtaining an MRI increases the likelihood of obtaining negative margins, Dr. Morrow summarized the results of four retrospective studies involving more than 2,500 patients. “The studies showed no statistically significant benefit in terms of reducing positive margins with MRI,” she said.

Another prospective randomized trial of 1,600 women showed that the net effect of MRI was a slightly higher rate of mastectomy in patients who had an MRI preoperatively, but no reduction in the need for further surgery.

Dr. Morrow added that in patients who have unifocal cancer, MRI can’t underestimate the extent of disease but instead overestimates the extent of disease in a third of the patients. In the case of multifocal or multicentric disease, MRI is accurate in a third of the patients, it overestimates the disease in another third, and it misses the disease a third of the time.

“There’s no possibility that MRI will improve breast cancer survival,” Dr. Morrow said. It takes a difference in local failure rates of greater than 10% at 5 years post treatment to see a survival difference in 15 years, she added. “Current rates of local recurrence at 10 years are less than 10%, and there should be no expectation that MRI will change survival.”

Medicare data show that the number of MRIs (all types) performed has increased over the past decade. While the total cost of treating breast cancer patients in the United States is increasing at 4% per year, the imaging costs are increasing at 10% a year, said Dr. Bleicher.

Although there are no national data showing what percentage of health care costs is attributable to breast MRIs, “one of the things that’s not in dispute [is that] breast MRI usage in breast cancer patients is increasing,” and its contribution to rising health care costs is “highly suggestive,” he added.

 

 

Furthermore, fear of lawsuits among surgeons and radiologists also influences the decision to order these tests.

“So what can we do?” asked Dr. Bleicher. “Always do what’s best for the patient, [and] you need to document your rationale. MRI is indeed a valuable tool, but we really do need to define its indications both to justify the cost involved and to clarify when not performing it is true breach of duty to the patient.”

The panel concluded that there is a need to establish evidence-based criteria for ordering MRIs in different clinical scenarios. “The potential research applications of MRI should not be confused with routine clinical practice,” said Dr. Morrow.

“MRI is not emerging – it has fully emerged – and in some respects, the train has already left the station,” said Dr. Port. “I think what we need to do at this point is really re-establish definitive guidelines for [MRI] use in women with newly diagnosed breast cancer for whom there are no clear-cut guidelines and for whom practice patterns range widely.”

The panel members reported no relevant conflicts of interest.

WASHINGTON – While the use of magnetic resonance imaging as a screening tool for breast cancer has increased significantly over the past decade, there is still little evidence of its clinical benefits and cost-effectiveness, according to a panel of experts who addressed a capacity crowd at the annual clinical congress of the American College of Surgeons.

    Dr. Monica Morrow

Patients at high risk of developing breast cancer (e.g., those with BRCA mutations or a greater than 20% risk of developing breast cancer during their lifetime) could benefit from breast MRI. The panel, however, pointed to a wide range of U.S., Canadian, and European studies showing that there is no evidence that MRI improves breast cancer survival, and it increases the rate of mastectomies. The panel members included Dr. Elisa R. Port and Dr. Monica Morrow, both of Memorial Sloan-Kettering Cancer Center in New York, Dr. Isabelle Bedrosian of MD Anderson Cancer Center in Houston, and Dr. Richard J. Bleicher of Fox Chase Cancer Center in Philadelphia.

The American Cancer Society and the National Comprehensive Cancer Network have developed MRI screening guidelines to distinguish which groups of patients should or should not be screened. However, there are very few data thus far to indicate just when to start or stop screening, or how often to perform screening, said Dr. Bedrosian.

“There are no data on the impact of MRI screening on survival outcomes,” she said, noting that the data to support MRI screening in terms of outcomes are based on disease stage migration, not survival.

She added that there are very few data about the cost-effectiveness of breast MRI screening. Patient age, BRCA gene mutations, breast density, and the cost of MRI must all be factored into the cost-effectiveness of MRI screening. The data show that MRI screening is more cost effective for higher-risk patients, but the panel wondered whether breast MRI screenings could be contributing to the nation’s rising health care costs.

There are currently 70 million women in the United States between the ages of 30 and 70. Of those, 1% are at high risk of developing breast cancer and are eligible for screening, which translates to a potential 1 million MRI screenings per year, said the panel.

“The most troubling finding is that it causes us to think about breast cancer the way we thought about it in the 1970s, the 1980s, and the early 1990s – that the disease burden in the breast is the sole or primary determinant of breast cancer outcome,” said Dr. Morrow. “The modern era tells us that’s really not true.”

In addition, she mentioned two retrospective studies (one in the United States and the other from the Netherlands Cancer Institute) that showed no decrease in unplanned mastectomy for patients who had preoperative MRI.

To answer the question of whether or not obtaining an MRI increases the likelihood of obtaining negative margins, Dr. Morrow summarized the results of four retrospective studies involving more than 2,500 patients. “The studies showed no statistically significant benefit in terms of reducing positive margins with MRI,” she said.

Another prospective randomized trial of 1,600 women showed that the net effect of MRI was a slightly higher rate of mastectomy in patients who had an MRI preoperatively, but no reduction in the need for further surgery.

Dr. Morrow added that in patients who have unifocal cancer, MRI can’t underestimate the extent of disease but instead overestimates the extent of disease in a third of the patients. In the case of multifocal or multicentric disease, MRI is accurate in a third of the patients, it overestimates the disease in another third, and it misses the disease a third of the time.

“There’s no possibility that MRI will improve breast cancer survival,” Dr. Morrow said. It takes a difference in local failure rates of greater than 10% at 5 years post treatment to see a survival difference in 15 years, she added. “Current rates of local recurrence at 10 years are less than 10%, and there should be no expectation that MRI will change survival.”

Medicare data show that the number of MRIs (all types) performed has increased over the past decade. While the total cost of treating breast cancer patients in the United States is increasing at 4% per year, the imaging costs are increasing at 10% a year, said Dr. Bleicher.

Although there are no national data showing what percentage of health care costs is attributable to breast MRIs, “one of the things that’s not in dispute [is that] breast MRI usage in breast cancer patients is increasing,” and its contribution to rising health care costs is “highly suggestive,” he added.

 

 

Furthermore, fear of lawsuits among surgeons and radiologists also influences the decision to order these tests.

“So what can we do?” asked Dr. Bleicher. “Always do what’s best for the patient, [and] you need to document your rationale. MRI is indeed a valuable tool, but we really do need to define its indications both to justify the cost involved and to clarify when not performing it is true breach of duty to the patient.”

The panel concluded that there is a need to establish evidence-based criteria for ordering MRIs in different clinical scenarios. “The potential research applications of MRI should not be confused with routine clinical practice,” said Dr. Morrow.

“MRI is not emerging – it has fully emerged – and in some respects, the train has already left the station,” said Dr. Port. “I think what we need to do at this point is really re-establish definitive guidelines for [MRI] use in women with newly diagnosed breast cancer for whom there are no clear-cut guidelines and for whom practice patterns range widely.”

The panel members reported no relevant conflicts of interest.

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X-Ray Analysis Predicts Knee Osteoarthritis Progression

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X-Ray Analysis Predicts Knee Osteoarthritis Progression

BRUSSELS – Analysis of plain x-ray images of knee joints from 60 patients with osteoarthritis confirmed that a novel method for assessing bone trabecular structure adjacent to knee joints provides a reliable prediction of future disease progression.

Assessment of bone trabecular integrity by fractal signature analysis “provides an osteoarthritis imaging biomarker that is a prognostic marker of knee osteoarthritis progression,” Dr. Virginia Byers Kraus said at the annual World Congress on Osteoarthritis.

Dr. Virginia Byers Kraus    

Baseline bone trabecular integrity predicted roughly 85% of the change in joint space area during 2 years of follow-up in patients with osteoarthritis (OA). The new study, which used x-rays from 60 patients with OA and 67 controls, is the second report to document the prognostic accuracy of fractal signature analysis of bone trabecular integrity in OA patients. The first report, also from Dr. Kraus and her associates, came out last year, and involved 138 OA patients who were followed for 3 years (Arthritis Rheum. 2009;60:3711-22).

“The next step is to compare fractal signature analysis head to head with MRI and look at its ability to predict MRI changes” in OA patients, and “its ability to identify OA in the preradiographic stage,” Dr. Kraus said in an interview.

Fractal signature analysis of bone trabecular integrity using x-ray images “gives you the ability to more fully phenotype patients than we’ve been able to, and it is less costly than MRI,” said Dr. Kraus, a rheumatologist and professor of medicine at Duke University in Durham, N.C. “It’s very promising for identifying patients at high risk for progression in [an intervention] trial, and possibly to screen patients in the clinic.”

Fractal signature analysis evaluates the complexity of detail of a two-dimensional image. Researchers first reported using fractal signature analysis in 1991 to assess bone architecture in radiographs of OA joints. Past studies also successfully used the method to assess osteoporosis and arthritis of the spine, hip, wrists, hands, and knees before and after surgery. Fractal signature analysis has the major advantage of not being very sensitive to image-acquisition quality.

Although fractal signature analysis involves a complex statistical analysis of x-ray image data of bone structure adjacent to a patient’s knee joint, Dr. Kraus and her associates incorporated that analysis into “KneeAnalyzer” software developed by Optasia Medical, a British company. Now that the software exists, “it is easy to use. It’s just a tool to get at bone trabecular integrity. I think it can easily be widely adopted,” she said.

The new study used data collected in a non–therapeutic methods trial sponsored by Pfizer Inc. The data set included 60 women with knee OA, an average age of 58 years, and an average body mass index of 35.6 kg/m2. (All participants in this arm of the study had a BMI of at least 30.) The 67 women controls had an average age of 55 years, all had a BMI of 28 or less, and all had no knee symptoms, no radiographic signs of knee OA, and no history of knee fracture, surgery, or disease.

The researchers assessed bone trabecular integrity using fractal signature analysis on radiographs taken at baseline, and after 12 and 24 months. The results showed that baseline measurements in the vertical dimension of bone trabecular integrity predicted changes in joint space area at 12 and 24 months, and in joint space width at 24 months. Baseline measures in the horizontal dimension were not predictive. The predicted changes based on baseline bone trabecular integrity accounted for 85%-87% of the actual change in joint space area over 24 months, Dr. Kraus reported at the congress, which was organized by the Osteoarthritis Research Society International.

Analysis of baseline and follow-up measures in the control subjects allowed the researchers to attribute progression in patients to an OA-specific process and not as the result of aging.

Dr. Kraus said that she had no relevant disclosures. One coauthor is an employee of Optasia Medical, and Optasia provided the software used for the radiograph analyses. Another coauthor is an employee of Pfizer, and Pfizer supplied the database used in the study.

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BRUSSELS – Analysis of plain x-ray images of knee joints from 60 patients with osteoarthritis confirmed that a novel method for assessing bone trabecular structure adjacent to knee joints provides a reliable prediction of future disease progression.

Assessment of bone trabecular integrity by fractal signature analysis “provides an osteoarthritis imaging biomarker that is a prognostic marker of knee osteoarthritis progression,” Dr. Virginia Byers Kraus said at the annual World Congress on Osteoarthritis.

Dr. Virginia Byers Kraus    

Baseline bone trabecular integrity predicted roughly 85% of the change in joint space area during 2 years of follow-up in patients with osteoarthritis (OA). The new study, which used x-rays from 60 patients with OA and 67 controls, is the second report to document the prognostic accuracy of fractal signature analysis of bone trabecular integrity in OA patients. The first report, also from Dr. Kraus and her associates, came out last year, and involved 138 OA patients who were followed for 3 years (Arthritis Rheum. 2009;60:3711-22).

“The next step is to compare fractal signature analysis head to head with MRI and look at its ability to predict MRI changes” in OA patients, and “its ability to identify OA in the preradiographic stage,” Dr. Kraus said in an interview.

Fractal signature analysis of bone trabecular integrity using x-ray images “gives you the ability to more fully phenotype patients than we’ve been able to, and it is less costly than MRI,” said Dr. Kraus, a rheumatologist and professor of medicine at Duke University in Durham, N.C. “It’s very promising for identifying patients at high risk for progression in [an intervention] trial, and possibly to screen patients in the clinic.”

Fractal signature analysis evaluates the complexity of detail of a two-dimensional image. Researchers first reported using fractal signature analysis in 1991 to assess bone architecture in radiographs of OA joints. Past studies also successfully used the method to assess osteoporosis and arthritis of the spine, hip, wrists, hands, and knees before and after surgery. Fractal signature analysis has the major advantage of not being very sensitive to image-acquisition quality.

Although fractal signature analysis involves a complex statistical analysis of x-ray image data of bone structure adjacent to a patient’s knee joint, Dr. Kraus and her associates incorporated that analysis into “KneeAnalyzer” software developed by Optasia Medical, a British company. Now that the software exists, “it is easy to use. It’s just a tool to get at bone trabecular integrity. I think it can easily be widely adopted,” she said.

The new study used data collected in a non–therapeutic methods trial sponsored by Pfizer Inc. The data set included 60 women with knee OA, an average age of 58 years, and an average body mass index of 35.6 kg/m2. (All participants in this arm of the study had a BMI of at least 30.) The 67 women controls had an average age of 55 years, all had a BMI of 28 or less, and all had no knee symptoms, no radiographic signs of knee OA, and no history of knee fracture, surgery, or disease.

The researchers assessed bone trabecular integrity using fractal signature analysis on radiographs taken at baseline, and after 12 and 24 months. The results showed that baseline measurements in the vertical dimension of bone trabecular integrity predicted changes in joint space area at 12 and 24 months, and in joint space width at 24 months. Baseline measures in the horizontal dimension were not predictive. The predicted changes based on baseline bone trabecular integrity accounted for 85%-87% of the actual change in joint space area over 24 months, Dr. Kraus reported at the congress, which was organized by the Osteoarthritis Research Society International.

Analysis of baseline and follow-up measures in the control subjects allowed the researchers to attribute progression in patients to an OA-specific process and not as the result of aging.

Dr. Kraus said that she had no relevant disclosures. One coauthor is an employee of Optasia Medical, and Optasia provided the software used for the radiograph analyses. Another coauthor is an employee of Pfizer, and Pfizer supplied the database used in the study.

BRUSSELS – Analysis of plain x-ray images of knee joints from 60 patients with osteoarthritis confirmed that a novel method for assessing bone trabecular structure adjacent to knee joints provides a reliable prediction of future disease progression.

Assessment of bone trabecular integrity by fractal signature analysis “provides an osteoarthritis imaging biomarker that is a prognostic marker of knee osteoarthritis progression,” Dr. Virginia Byers Kraus said at the annual World Congress on Osteoarthritis.

Dr. Virginia Byers Kraus    

Baseline bone trabecular integrity predicted roughly 85% of the change in joint space area during 2 years of follow-up in patients with osteoarthritis (OA). The new study, which used x-rays from 60 patients with OA and 67 controls, is the second report to document the prognostic accuracy of fractal signature analysis of bone trabecular integrity in OA patients. The first report, also from Dr. Kraus and her associates, came out last year, and involved 138 OA patients who were followed for 3 years (Arthritis Rheum. 2009;60:3711-22).

“The next step is to compare fractal signature analysis head to head with MRI and look at its ability to predict MRI changes” in OA patients, and “its ability to identify OA in the preradiographic stage,” Dr. Kraus said in an interview.

Fractal signature analysis of bone trabecular integrity using x-ray images “gives you the ability to more fully phenotype patients than we’ve been able to, and it is less costly than MRI,” said Dr. Kraus, a rheumatologist and professor of medicine at Duke University in Durham, N.C. “It’s very promising for identifying patients at high risk for progression in [an intervention] trial, and possibly to screen patients in the clinic.”

Fractal signature analysis evaluates the complexity of detail of a two-dimensional image. Researchers first reported using fractal signature analysis in 1991 to assess bone architecture in radiographs of OA joints. Past studies also successfully used the method to assess osteoporosis and arthritis of the spine, hip, wrists, hands, and knees before and after surgery. Fractal signature analysis has the major advantage of not being very sensitive to image-acquisition quality.

Although fractal signature analysis involves a complex statistical analysis of x-ray image data of bone structure adjacent to a patient’s knee joint, Dr. Kraus and her associates incorporated that analysis into “KneeAnalyzer” software developed by Optasia Medical, a British company. Now that the software exists, “it is easy to use. It’s just a tool to get at bone trabecular integrity. I think it can easily be widely adopted,” she said.

The new study used data collected in a non–therapeutic methods trial sponsored by Pfizer Inc. The data set included 60 women with knee OA, an average age of 58 years, and an average body mass index of 35.6 kg/m2. (All participants in this arm of the study had a BMI of at least 30.) The 67 women controls had an average age of 55 years, all had a BMI of 28 or less, and all had no knee symptoms, no radiographic signs of knee OA, and no history of knee fracture, surgery, or disease.

The researchers assessed bone trabecular integrity using fractal signature analysis on radiographs taken at baseline, and after 12 and 24 months. The results showed that baseline measurements in the vertical dimension of bone trabecular integrity predicted changes in joint space area at 12 and 24 months, and in joint space width at 24 months. Baseline measures in the horizontal dimension were not predictive. The predicted changes based on baseline bone trabecular integrity accounted for 85%-87% of the actual change in joint space area over 24 months, Dr. Kraus reported at the congress, which was organized by the Osteoarthritis Research Society International.

Analysis of baseline and follow-up measures in the control subjects allowed the researchers to attribute progression in patients to an OA-specific process and not as the result of aging.

Dr. Kraus said that she had no relevant disclosures. One coauthor is an employee of Optasia Medical, and Optasia provided the software used for the radiograph analyses. Another coauthor is an employee of Pfizer, and Pfizer supplied the database used in the study.

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Major Finding: Bone trabecular integrity, assessed by fractal signature analysis of plain radiographs, correctly predicted about 85% of the joint space change in patients with knee OA.

Data Source: Review of radiographs taken from 60 patients with OA and 67 controls at baseline and at 12 and 24 months’ follow-up.

Disclosures: Dr. Kraus said that she had no relevant disclosures. One coauthor is an employee of Optasia Medical; Optasia provided the software used for the radiograph analyses. Another coauthor is an employee of Pfizer; Pfizer supplied the database used in the study.

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Early MRI Helpful After Spontaneous Intracerebral Hemorrhage

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SAN FRANCISCO – Early routine MRI helped with the diagnosis of spontaneous intracerebral hemorrhage when added to CT imaging in a prospective, blinded study of 157 patients.

Previous analyses had suggested that adding MRI to brain CT imaging increased correct diagnoses of the cause of spontaneous intracerebral hemorrhage (ICH) by 26% and changed management in 15% of cases, but these percentages were based on the treating physician’s view, not independent neurologists, Dr. Christine A.C. Wijman noted.

The current study, called the Diagnostic Accuracy of MRI in Spontaneous Intracerebral Hemorrhage (DASH) study, supports those results. Two independent neuroradiologists found an absolute additive diagnostic benefit of 35% when MRI was added to CT imaging for diagnosing the etiology of ICH or intraventricular hemorrhage (IVH), Dr. Wijman said at the annual meeting of the Neurocritical Care Society.

Consecutive, prospectively enrolled patients underwent brain CT imaging, laboratory testing, and gadolinium-enhanced MRI or a magnetic resonance angiogram (MRA). If they met prespecified criteria, they underwent catheter angiography.

The cohort had a mean age of 63 years and 45% were female. Seventy-one percent had a history of hypertension, and 69% were on an antihypertensive drug at the time of admission.

Their intracranial hemorrhages had a mean initial volume of 25 cc, and associated IVH was present in 43%. The ICH location was lobar in 45% of cases and deep in 38%. The mean Glasgow Coma Score on admission was 14.

The study excluded patients with a known preexisting cause of ICH, an inability to undergo MRI, or a Glasgow Coma Scale score less than 6 on admission.

Initially, two independent neuroradiologists reviewed the admission CT and assigned a presumed cause of the ICH or IVH to 1 of 12 categories, rating the cause as “possible,” “likely,” or “highly probable.” They were blinded to all clinical data other than the patient’s age and sex. Next, two separate independent, blinded neuroradiologists used the first available MRI plus the CT results to do similar evaluations.

Their diagnoses were compared with determination of the etiology at 3 months by a stroke neurologist after review of the medical record including a 90-day clinic visit and follow-up MRI, if those were available.

The added information from the MRI changed the diagnosis of etiology in 24% of cases and improved diagnostic confidence in 11% of cases in which the identified cause did not change, for a combined “additive yield” of 35%, reported Dr. Wijman, director of critical care neurology at Stanford (Calif.) University.

The final diagnoses determined the cause of ICH or IVH to be longstanding or acute hypertension in 42% of cases, cerebral myeloid angioplasty in 15%, vascular malformation in 10%, infarct with hemorrhagic transformation in 8%, other diagnoses in 16%, and unknown causes in 8%. (Percentages do not equal 100% because of rounding.)

CT alone captured the final diagnosis in only 3% of patients. MRI or MRA alone captured the final diagnosis in 24%. Use of information from both imaging modalities captured the final diagnosis in 43%, and neither modality identified the etiology in 31%, Dr. Wijman said. (Percentages exceed 100% because of rounding.)

The MRI information changed the diagnosis of etiology in 10 (15%) of 66 cases of hypertension-related ICH and in 9 (38%) of 24 cases involving cerebral amyloid angiopathy or a variant of this disorder. The MRI information improved confidence in an unchanged diagnosis in eight of the hypertension-related cases (12%) and in five of the cerebral amyloid angiopathy cases (21%).

The additive yield of MRI was relatively highest for cases involving cerebral amyloid angiopathy, vascular malformations, hypertension, and other specific causes.

MRI or MRA proved helpful even in cases where it might be expected to be least useful. For example, the MRI/MRA results changed the diagnosis in 6 (13%) of 46 patients aged older than 45 years who had longstanding hypertension and a deep ICH, she added. It improved the diagnostic confidence in three of those cases (7%), for an overall diagnostic yield of 20%.

Disclosures: Dr. Wijman said the investigators have no pertinent conflicts of interest.

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SAN FRANCISCO – Early routine MRI helped with the diagnosis of spontaneous intracerebral hemorrhage when added to CT imaging in a prospective, blinded study of 157 patients.

Previous analyses had suggested that adding MRI to brain CT imaging increased correct diagnoses of the cause of spontaneous intracerebral hemorrhage (ICH) by 26% and changed management in 15% of cases, but these percentages were based on the treating physician’s view, not independent neurologists, Dr. Christine A.C. Wijman noted.

The current study, called the Diagnostic Accuracy of MRI in Spontaneous Intracerebral Hemorrhage (DASH) study, supports those results. Two independent neuroradiologists found an absolute additive diagnostic benefit of 35% when MRI was added to CT imaging for diagnosing the etiology of ICH or intraventricular hemorrhage (IVH), Dr. Wijman said at the annual meeting of the Neurocritical Care Society.

Consecutive, prospectively enrolled patients underwent brain CT imaging, laboratory testing, and gadolinium-enhanced MRI or a magnetic resonance angiogram (MRA). If they met prespecified criteria, they underwent catheter angiography.

The cohort had a mean age of 63 years and 45% were female. Seventy-one percent had a history of hypertension, and 69% were on an antihypertensive drug at the time of admission.

Their intracranial hemorrhages had a mean initial volume of 25 cc, and associated IVH was present in 43%. The ICH location was lobar in 45% of cases and deep in 38%. The mean Glasgow Coma Score on admission was 14.

The study excluded patients with a known preexisting cause of ICH, an inability to undergo MRI, or a Glasgow Coma Scale score less than 6 on admission.

Initially, two independent neuroradiologists reviewed the admission CT and assigned a presumed cause of the ICH or IVH to 1 of 12 categories, rating the cause as “possible,” “likely,” or “highly probable.” They were blinded to all clinical data other than the patient’s age and sex. Next, two separate independent, blinded neuroradiologists used the first available MRI plus the CT results to do similar evaluations.

Their diagnoses were compared with determination of the etiology at 3 months by a stroke neurologist after review of the medical record including a 90-day clinic visit and follow-up MRI, if those were available.

The added information from the MRI changed the diagnosis of etiology in 24% of cases and improved diagnostic confidence in 11% of cases in which the identified cause did not change, for a combined “additive yield” of 35%, reported Dr. Wijman, director of critical care neurology at Stanford (Calif.) University.

The final diagnoses determined the cause of ICH or IVH to be longstanding or acute hypertension in 42% of cases, cerebral myeloid angioplasty in 15%, vascular malformation in 10%, infarct with hemorrhagic transformation in 8%, other diagnoses in 16%, and unknown causes in 8%. (Percentages do not equal 100% because of rounding.)

CT alone captured the final diagnosis in only 3% of patients. MRI or MRA alone captured the final diagnosis in 24%. Use of information from both imaging modalities captured the final diagnosis in 43%, and neither modality identified the etiology in 31%, Dr. Wijman said. (Percentages exceed 100% because of rounding.)

The MRI information changed the diagnosis of etiology in 10 (15%) of 66 cases of hypertension-related ICH and in 9 (38%) of 24 cases involving cerebral amyloid angiopathy or a variant of this disorder. The MRI information improved confidence in an unchanged diagnosis in eight of the hypertension-related cases (12%) and in five of the cerebral amyloid angiopathy cases (21%).

The additive yield of MRI was relatively highest for cases involving cerebral amyloid angiopathy, vascular malformations, hypertension, and other specific causes.

MRI or MRA proved helpful even in cases where it might be expected to be least useful. For example, the MRI/MRA results changed the diagnosis in 6 (13%) of 46 patients aged older than 45 years who had longstanding hypertension and a deep ICH, she added. It improved the diagnostic confidence in three of those cases (7%), for an overall diagnostic yield of 20%.

Disclosures: Dr. Wijman said the investigators have no pertinent conflicts of interest.

SAN FRANCISCO – Early routine MRI helped with the diagnosis of spontaneous intracerebral hemorrhage when added to CT imaging in a prospective, blinded study of 157 patients.

Previous analyses had suggested that adding MRI to brain CT imaging increased correct diagnoses of the cause of spontaneous intracerebral hemorrhage (ICH) by 26% and changed management in 15% of cases, but these percentages were based on the treating physician’s view, not independent neurologists, Dr. Christine A.C. Wijman noted.

The current study, called the Diagnostic Accuracy of MRI in Spontaneous Intracerebral Hemorrhage (DASH) study, supports those results. Two independent neuroradiologists found an absolute additive diagnostic benefit of 35% when MRI was added to CT imaging for diagnosing the etiology of ICH or intraventricular hemorrhage (IVH), Dr. Wijman said at the annual meeting of the Neurocritical Care Society.

Consecutive, prospectively enrolled patients underwent brain CT imaging, laboratory testing, and gadolinium-enhanced MRI or a magnetic resonance angiogram (MRA). If they met prespecified criteria, they underwent catheter angiography.

The cohort had a mean age of 63 years and 45% were female. Seventy-one percent had a history of hypertension, and 69% were on an antihypertensive drug at the time of admission.

Their intracranial hemorrhages had a mean initial volume of 25 cc, and associated IVH was present in 43%. The ICH location was lobar in 45% of cases and deep in 38%. The mean Glasgow Coma Score on admission was 14.

The study excluded patients with a known preexisting cause of ICH, an inability to undergo MRI, or a Glasgow Coma Scale score less than 6 on admission.

Initially, two independent neuroradiologists reviewed the admission CT and assigned a presumed cause of the ICH or IVH to 1 of 12 categories, rating the cause as “possible,” “likely,” or “highly probable.” They were blinded to all clinical data other than the patient’s age and sex. Next, two separate independent, blinded neuroradiologists used the first available MRI plus the CT results to do similar evaluations.

Their diagnoses were compared with determination of the etiology at 3 months by a stroke neurologist after review of the medical record including a 90-day clinic visit and follow-up MRI, if those were available.

The added information from the MRI changed the diagnosis of etiology in 24% of cases and improved diagnostic confidence in 11% of cases in which the identified cause did not change, for a combined “additive yield” of 35%, reported Dr. Wijman, director of critical care neurology at Stanford (Calif.) University.

The final diagnoses determined the cause of ICH or IVH to be longstanding or acute hypertension in 42% of cases, cerebral myeloid angioplasty in 15%, vascular malformation in 10%, infarct with hemorrhagic transformation in 8%, other diagnoses in 16%, and unknown causes in 8%. (Percentages do not equal 100% because of rounding.)

CT alone captured the final diagnosis in only 3% of patients. MRI or MRA alone captured the final diagnosis in 24%. Use of information from both imaging modalities captured the final diagnosis in 43%, and neither modality identified the etiology in 31%, Dr. Wijman said. (Percentages exceed 100% because of rounding.)

The MRI information changed the diagnosis of etiology in 10 (15%) of 66 cases of hypertension-related ICH and in 9 (38%) of 24 cases involving cerebral amyloid angiopathy or a variant of this disorder. The MRI information improved confidence in an unchanged diagnosis in eight of the hypertension-related cases (12%) and in five of the cerebral amyloid angiopathy cases (21%).

The additive yield of MRI was relatively highest for cases involving cerebral amyloid angiopathy, vascular malformations, hypertension, and other specific causes.

MRI or MRA proved helpful even in cases where it might be expected to be least useful. For example, the MRI/MRA results changed the diagnosis in 6 (13%) of 46 patients aged older than 45 years who had longstanding hypertension and a deep ICH, she added. It improved the diagnostic confidence in three of those cases (7%), for an overall diagnostic yield of 20%.

Disclosures: Dr. Wijman said the investigators have no pertinent conflicts of interest.

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A young woman with a breast mass: What every internist should know

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A 40-year-old premenopausal woman presents with a palpable lump in her left breast. She first noted it 2 months ago on self-examination, and it has steadily grown in size regardless of the phase of her menstrual cycle.

The patient has never undergone mammography. Her menarche was at age 12. At age 35, she had one child (whom she breastfed) after a normal first full-term pregnancy. She took oral contraceptives for 10 years before her pregnancy. She has no other medical problems. She has no family history of breast or ovarian cancer.

On examination, her breasts are slightly asymmetric, without skin discoloration, tenderness, swelling, nipple retraction, or discharge. A 1.5- to 2-cm, rubbery, mobile lump can be felt in the left breast at about the 2 o’clock position. No axillary lymph nodes can be palpated. The rest of her examination is normal.

BREAST CANCER MUST BE RULED OUT

Benign breast disease is found in approximately 90% of women 20 to 50 years of age who come to a physician with a breast problem.1

Nevertheless, breast cancer is of major concern. It is the most common type of cancer in women in the United States, responsible for an estimated 194,440 new cases and 40,610 deaths in 2009. It is also the leading cause of cancer-related death in women age 45 to 55 years in this country.2,3

Breast cancer is most common in postmenopausal women, its incidence rising sharply after the age of 45 and leveling off at age 75. The median age at diagnosis is 61 years. Still, 1.9% of breast cancers in women are diagnosed at age 20 to 34, 10.6% at age 35 to 44, and 22.4% at age 45 to 54.4

Thus, it is paramount to perform a thorough assessment and workup of women who have breast lumps, regardless of their age. Doing so allows breast cancer to be detected at an early stage. The 5-year survival rate is 98.0% for women with localized disease, 83.6% with regional disease, and 23.4% with distant disease.4

WHAT IS THE APPROPRIATE WORKUP?

1. Which of the following are appropriate in the workup of this patient?

  • Mammography
  • Ultrasonography
  • Percutaneous needle biopsy of the lesion
  • Magnetic resonance imaging (MRI) of the brain
  • Computed tomography (CT) of the chest, abdomen, and pelvis
  • Positron emission tomography (PET)

She should undergo mammography, ultrasonography, and percutaneous needle biopsy.

Physical findings that suggest breast cancer include a hard, isolated, sometimes nonmobile lump, serosanguinous nipple discharge, and unilateral nipple retraction. Peau d’orange skin discoloration can occur. A scaly, vesicular, or ulcerated rash with or without pruritus, burning, irritation, or pain of the nipple or skin (Paget disease of the breast) is found in 1% to 3% of breast cancers and may be initially dismissed as mastitis.5,6 Palpable enlarged axillary lymph nodes can suggest invasive breast cancer.

Mammography is recommended in all cases of suspicious breast lumps. In a patient with a palpable lump, diagnostic mammography has a positive predictive value of 21.8%, a specificity of 85.8%, and a sensitivity of 87.7%, which are higher values than in a patient without signs or symptoms.7

The BIRADS score. Mammographic findings are summarized using a scoring system devised by the American College of Radiology called BIRADS (Breast Imaging Reporting and Data System). This system is based on mass irregularity, density, spiculation, and presence or absence of microcalcifications. It standardizes the results of mammography, gives an estimate of the risk of breast cancer, and recommends the frequency of follow-up examinations.8 Scores range from 0 to 6:

  • 0—Incomplete assessment warranting additional evaluation
  • 1—Completely negative mammogram
  • 2—Benign lesion
  • 3—Requires follow-up mammogram at 6 months
  • 4—Risk of cancer is 2% to 95%; core biopsy needed
  • 5—Risk of cancer is more than 95%; core biopsy needed
  • 6—Cases that have already been proven to be malignant.

Ultrasonography is also done if a suspicious lesion is found on mammography or physical examination. It helps differentiate between solid and cystic masses. If a mass is identified as a cyst, ultrasonography can further characterize it as simple, complicated-simple, or complex. Simple cysts and complicated-simple cysts are unlikely to be malignant.9,10 Complex cysts or cysts associated with solid tissue are evaluated by biopsy.

Percutaneous needle biopsy should be done for a definitive diagnosis of most suspicious breast masses.

MRI can sometimes provide more accurate information about the possibility of multifocal breast cancer by revealing additional lesions missed on mammography or ultrasonography. It is also useful in determining more accurately the size of the breast tumor and looking for any possible contralateral lesions. In addition, it can sometimes detect enlarged axillary lymph nodes. However, it has poor specificity for breast cancer and may lead to additional and sometimes unnecessary diagnostic tests, which can delay treatment.

MRI’s role is therefore not clearly established, but it is commonly used in clinical practice. It is argued that workup of MRI findings may help in planning more accurate surgical procedures and may prevent reoperations. Based on retrospective analyses, results of breast MRI may lead to altered surgical treatment in approximately 13% of patients.11

Interestingly, a recent randomized trial showed no difference in reoperation rates between patients who underwent MRI before surgery vs those who did not. However, diagnostic workup of new MRI findings was not mandated by the study protocol, making the results of this trial difficult to interpret.12

 

 

DIFFERENTIAL DIAGNOSIS

2. Which of the following is in the differential diagnosis of a woman presenting with a breast abnormality?

  • Fibrocystic changes
  • Breast cyst
  • Ductal ectasia
  • Simple fibroadenoma
  • Intraductal papilloma
  • Ductal carcinoma in situ
  • Mastitis
  • Infiltrating ductal carcinoma
  • Phyllodes tumor

All of these choices are part of the differential diagnosis.

Benign breast lesions

Benign breast lesions are divided into those that are proliferative and those that are nonproliferative. Some (but not all) proliferative lesions pose a higher risk of progressing to malignancy than nonproliferative lesions do.13 Benign breast lesions that do not increase the risk of breast cancer are listed in Table 1.

Simple fibroadenoma, one of the most common proliferative lesions, is not associated with a higher risk of developing breast cancer.

Fibrocystic changes are the most common nonproliferative lesions. Occasionally breast pain, nipple discharge, or significant lumpiness that varies during the course of the menstrual cycle can occur. The nipple discharge in women with fibrocystic changes is physiologic and pale green to brown in color. It can also be yellow, whitish, clear, or bloody. Bloody nipple discharge is considered pathologic and suggests a process other than fibrocystic changes, necessitating further workup. However, bloody discharge is not always a sign of malignancy, as it can have a benign cause as well.

Ductal ectasia, another nonproliferative lesion, is a result of dilation of subareolar ducts that contain fluid with a crystalline material. It can penetrate the duct, forming a nodule, which causes pain and occasionally fever.

Precancerous and cancerous lesions

Lesions that can increase the risk of breast cancer are listed in Table 2. The degree of risk depends on the complexity and amount of atypia found on the biopsy specimen. The relative risk of developing breast cancer in patients with simple proliferative lesions without atypia is 1.6 to 1.9, compared with 3.7 to 5.3 for complex lesions with high degrees of atypia.14

Ductal carcinoma in situ is a true neoplasm that has not yet developed the ability to invade through the basement membrane of the ducts. The likelihood of progression to invasive breast cancer depends on the histologic grade, the tumor size, and the patient’s age.

Lobular carcinoma in situ arises from lobules and terminal ducts of breast tissue. Much controversy surrounds this type of tumor, which was thought to be a marker of increased risk of developing ipsilateral and contralateral breast cancer and not to be a malignant lesion itself.15 However, there is emerging evidence to suggest that a pleomorphic variant of lobular carcinoma in situ is associated with development of breast cancer in the same site as the lesion, whereas a nonpleomorphic form is a marker of increased risk of ipsilateral and contralateral breast cancer.16

Invasive ductal and lobular carcinomas are the true invasive breast cancers, with a potential to metastasize.

Phyllodes tumors are uncommon fibroepithelial lesions that account for less than 1% of all breast neoplasms. The median age at presentation is 45 years.17 Despite the historical name “cystosarcoma phyllodes,” these lesions are not true sarcomas and have stromal and epithelial components.

These tumors display very heterogeneous behavior and, based on predefined histologic criteria, are often classified as benign, borderline, or malignant. Benign phyllodes tumors are similar to fibroadenomas in both histology and prognosis, making their diagnosis challenging. The most aggressive phyllodes tumors lose their epithelial component and have high metastatic potential. These tumors often have a biphasic growth pattern, and women may present with a smooth, round, well-defined breast lump that was stable for many years but then started to grow rapidly.17

Surgical resection with wide margins is the primary management of these tumors.18

Mastitis, ie, inflammation of the breast tissue, often presents with symptoms of breast erythema, swelling, tenderness, and nipple discharge. It may be secondary to infection (most often in lactating women) or other causes such as radiation or underlying malignancy. A complication of infectious mastitis is formation of a breast abscess. Underlying malignancy, especially inflammatory breast cancer, is a common cause of noninfectious mastitis and is very important to recognize.19

 

 

RISK FACTORS FOR BREAST CANCER

3. Which of the following are risk factors for breast cancer?

  • Menarche before age 12
  • Female sex
  • Personal history of breast cancer
  • Obesity
  • Never having had children, or having given birth for the first time at an older age
  • Older age
  • History of hormone replacement therapy with estrogen and progesterone
  • Family history of breast cancer

All of these choices are risk factors for breast cancer.

Family history

The overall relative risk of developing breast cancer in a woman with a first-degree relative with the disease is 1.7. However, the relative risk is about 3 if the first-degree relative developed breast cancer before menopause, and 9 if the first-degree relative developed bilateral breast cancer before menopause.5

Familial syndromes are a major factor in 5% to 7% of cases of breast cancer. Most frequently, they involve mutations in the BRCA1 and BRCA2 genes, which encode DNA excision repair proteins. Such mutations are present in about 2.2% of the Ashkenazi Jewish population, and carriers have a lifetime risk of developing breast cancer of 56% to 85%.20,21 Other common familial syndromes associated with breast cancer include the Cowden and Li-Fraumeni syndromes (Table 3).22–25

Estrogen exposure

The duration and amount of estrogen exposure are also risk factors. For example, menarche before age 12 and menopause after age 55 are associated with a higher risk. Women who go through menopause after age 55 have a twofold higher risk of breast cancer compared with women who go through menopause at an early age. Pregnancy before age 30 lowers the risk of breast cancer; late first full-term pregnancy or nulliparity increases it. Lactation, on the other hand, has a protective effect.5

Oral contraceptives have traditionally been thought to increase the risk of breast cancer. In the 1990s, a meta-analysis involving 153,506 women found that those who had used oral contraceptives had a 24% higher risk of developing breast cancer.26 However, this association has come into question since newer oral contraceptive pills containing different progestins and lower amounts of estrogen have become available. In fact, recent studies showed no link between oral contraceptive use and breast cancer.27,28 Nevertheless, women at higher risk of developing breast cancer are advised not to use oral contraceptives.

Hormone replacement therapy with estrogen and progesterone was found to increase the risk of breast cancer by 26% in the Women’s Health Initiative (WHI) study, which involved 16,608 healthy women followed for a median of 5.6 years.29

In a study reported separately, the WHI investigators randomized 10,739 women who had undergone hysterectomy to receive either hormone replacement therapy with unopposed estrogen (which is feasible only in women without a uterus) or placebo. They found no increase in the risk of invasive breast cancer in women on hormone replacement therapy with estrogen alone. In fact, the study showed a trend towards a modest reduction of this risk (odds ratio 0.77; 95% confidence interval 0.59–1.01).30

After the results of the WHI were published, the use of hormone replacement therapy in postmenopausal women declined significantly. And in 2003—1 year later—the incidence of breast cancer had dropped by 6.7%.31

Most experts now recommend that estrogen-progestin combinations be used only selectively to treat the symptoms of menopause, and only for the short term.

Other risk factors

Other factors found to modestly increase the risk of breast cancer include:

  • Alcohol use
  • Obesity
  • Radiation exposure. Patients are at higher risk of breast cancer 15 to 20 years after receiving upper-mantle radiotherapy for Hodgkin lymphoma.5

Case continues: Bad news on mammography, ultrasonography, biopsy

The patient undergoes mammography, which shows a 2.5-cm spiculated lesion with areas of calcifications (BIRADS score of 5). Subsequently, ultrasonography confirms that the suspicious mass is not a cyst. Ultrasound-guided core needle biopsy reveals that the lesion is a high-grade invasive ductal carcinoma. The tumor is positive for both estrogen and progesterone receptors and negative for HER2/neu overexpression.

STAGING EVALUATION

4. Given these findings, what is the next step to take?

  • CT of the chest, abdomen, and pelvis
  • MRI of the brain
  • PET
  • Referral to a surgeon for a possible mastectomy with sentinel lymph node dissection
  • Referral to a surgeon for a possible lumpectomy with sentinel lymph node dissection

At this point, the patient should be referred to a surgeon for possible mastectomy or lumpectomy.

Women who appear clinically to have early breast cancer, such as in this case, should have a complete blood count, comprehensive metabolic panel, and chest x-ray as their initial staging evaluation. No further studies are recommended unless the findings on history, physical examination, or the above testing suggest possible metastases.

 

 

Mastectomy vs lumpectomy

Early-stage breast cancer is managed with definitive surgery. The two options are mastectomy and breast conservation therapy, the latter involving lumpectomy followed by breast radiation therapy.

Multiple randomized studies comparing mastectomy and lumpectomy showed no difference in survival rates, but patients in the lumpectomy groups had higher rates of local recurrence.32 Breast radiation therapy after lumpectomy lowered the rates of local recurrence and breast cancer death.33 Therefore, most patients can opt to undergo either lumpectomy with radiation or mastectomy, depending on personal preference.

However, mastectomy rather than breast conservation therapy is still recommended in cases of prior radiation therapy, inability to achieve negative surgical margins (as in cases of large tumors), multicentric disease (cancer in separate breast quadrants), or multiple areas of calcifications. Mastectomy is also preferred in most pregnant women unless the diagnosis of breast cancer is made in the third trimester and radiation therapy can be given after delivery. Patients who have large lesions in a small breast may also choose mastectomy with breast reconstruction rather than breast conservation therapy. Patients with a history of scleroderma are encouraged to undergo mastectomy because of increased toxicity from radiation treatment.

Sentinel vs axillary lymph node dissection

Knowledge of axillary lymph node involvement is important because it determines the stage in the tumor-node-metastasis (TNM) system, and it influences the choice of further therapy. Therefore, all patients with nonmetastatic invasive breast cancer must have their axillary lymph nodes sampled.

Conventionally, this involves axillary lymph node dissection. Unfortunately, upper extremity lymphedema develops in 6% to 30% of patients within the first 3 years, and in 49% of patients after 20 years following axillary lymph node dissection.34

Sentinel lymph node dissection was developed to minimize this complication. This procedure involves the injection of a blue dye, isosulfan blue (Lymphazurin), around the edge of the tumor or in the dermis overlying the tumor. The most proximal axillary lymph nodes that stain blue are dissected. Alternatively, a radioactive colloid (most commonly technetium sulfur colloid agents) may be injected, allowing sentinel lymph nodes to be identified by lymphoscintigraphy. If no metastases are found in the sentinel lymph nodes, axillary lymph node dissection is not performed.

A prospective study in 536 women found that at 5 years of follow-up, lymphedema developed in only 5% of patients after sentinel lymph node dissection compared with 16% of those who underwent axillary lymph node dissection (P < .001), with comparable outcomes in terms of disease recurrence.35

Case continues: Patient undergoes surgery

The patient elects to undergo lumpectomy with sentinel lymph node dissection. Pathologic review of the resection specimen reveals a 2.5-cm poorly differentiated invasive ductal carcinoma. Sentinel lymph node dissection shows metastases, and therefore axillary lymph node dissection is performed. One of eight lymph nodes removed is positive for metastases. All surgical margins are negative.

POSTOPERATIVE CARE

5. What would be the next step for our patient?

  • Radiation followed by observation
  • Tamoxifen (Nolvadex) for 5 years
  • Observation only
  • Chemotherapy followed by radiation therapy and 5 years of tamoxifen

She should receive chemotherapy, followed by radiation therapy and then tamoxifen for 5 years.

Chemotherapy. Almost all patients who have lymph-node-positive disease are advised to undergo chemotherapy.

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) performed a metaanalysis of 194 randomized trials that compared adjuvant chemotherapy and no treatment in early-stage breast cancer. Chemotherapy led to a 10% absolute improvement in survival at 15 years for women younger than 50 years and 3% in women age 51 to 69.36

Indications for chemotherapy include axillary lymph node involvement, locally advanced disease, and other risk factors for recurrence such as young age at diagnosis, strong positive family history of breast cancer, prior history of breast cancer, or lymph-node-negative, estrogen-receptor-negative tumors that are larger than 1 cm in diameter.

The Oncotype DX assay is a new tool to help oncologists decide whether to use chemotherapy in cases of estrogen-receptor-positive breast cancer, in which the benefit of chemotherapy is uncertain. It is a polymerase chain reaction assay that measures the expression of 16 cancer-specific genes and five reference genes within the breast tumor. Based on the pattern of expression of these genes, breast cancer can be characterized as low-risk, intermediate-risk, or high-risk. Patients in the high-risk group have a high chance of cancer recurrence and benefit from chemotherapy. Patients in the low-risk group are unlikely to have a recurrence or to benefit from chemotherapy.37 It is far less clear if patients in the intermediate-risk group benefit from chemotherapy, but this assay might eventually prove useful in deciding for or against chemotherapy in this group of patients as well.38 The Oncotype DX assay is presently being studied in a clinical trial.

Radiation therapy after mastectomy is recommended in patients who have breast tumors larger than 5 cm or metastases to more than three axillary lymph nodes.39

Antiestrogen therapy. After chemotherapy, patients with estrogen-receptor-positive cancers also receive 5 years of antiestrogen therapy. Available antiestrogen agents for such patients include tamoxifen, which is a selective estrogen receptor modulator, and drugs called aromatase inhibitors that block conversion of androgens to estrogens in peripheral tissues. Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are examples of available aromatase inhibitors. Premenopausal women are treated with tamoxifen, and postmenopausal women are offered aromatase inhibitors.

The EBCTCG meta-analysis found a 12% absolute reduction in mortality rates and a 9% absolute reduction in relapse rates at 15 years of follow-up in patients who took tamoxifen for 5 years.36

Table 4 lists the most common adverse effects of these agents. Aromatase inhibitors are associated with a higher risk of osteoporosis and arthralgia, while tamoxifen increases the risks of thromboembolism, endometrial cancer, and vaginal discharge. Both agents may produce menopausal symptoms such as hot flashes and mood swings.

 

 

Case continues: Seven years later, metastases in the spine

The patient achieves a complete remission. She is seen for a routine visit 7 years after diagnosis. She now reports mid-back pain that has worsened over the last 2 months. A bone scan reveals diffuse metastatic disease in the spine and in both humeral bones. CT of the chest, abdomen, and pelvis is negative for visceral metastases. Bone marrow aspiration and biopsy study show marrow infiltration by adenocarcinoma that stains positive for estrogen receptors and negative for HER2. The patient otherwise feels well and has no other symptoms.

WHAT TREATMENT FOR METASTATIC BREAST CANCER?

6. What should you now do for our patient?

  • Discuss end-of-life care and refer her to a hospice program
  • Educate the patient that no options for treatment exist and recommend enrolling in a phase I clinical trial
  • Refer her to an oncologist for consideration of chemotherapy
  • Refer her to an oncologist for consideration of endocrine treatment

She should be referred to an oncologist for consideration of endocrine treatment.

The most common sites of breast cancer metastases are the bones, followed by the liver and lungs. Metastatic breast cancer almost always is incurable. However, treatment can palliate symptoms.

Although a randomized trial of treatment vs best supportive care has never been done, many believe that treatment may improve survival. 40 The median survival of patients treated with standard therapy is about 3 years if the breast cancer is estrogen-receptor-positive and 2 years if it is estrogen-receptor-negative, but survival rates vary widely from patient to patient.41,42

Standard therapy or enrollment in a clinical phase II or III trial is indicated for this patient before considering enrollment in a phase I clinical trial or supportive care alone.

Endocrine therapy is the first-line therapy in women with estrogen-receptor-positive metastatic breast cancer. Postmenopausal women usually receive an aromatase inhibitor first.43,44 Response to endocrine therapy usually takes weeks to months but may last for several years.

Premenopausal women with estrogen-receptor-positive breast cancer also receive ovarian ablation therapy (oophorectomy or chemical ovarian ablation) with gonadotropin-releasing hormone agonists.

In addition, most patients with bone involvement are treated with high doses of intravenous bisphosphonates, which can reduce skeletal complications.45

Chemotherapy is reserved for patients with estrogen-receptor-negative breast cancer and those with cancer that progresses despite treatment with multiple antiestrogen agents. The time to response when chemotherapy is used is quicker, but the duration of response is usually shorter, lasting on average less than 1 year.37

Trastuzumab (Herceptin), a monoclonal humanized murine antibody to the extracellular domain of the HER2 protein, is indicated in patients with HER2-overexpressing tumors.46,47

STABLE 2 YEARS LATER

The patient was started on letrozole and a bisphosphonate, zolendronic acid (Zometa). Ovarian ablation was initiated with goserelin (Zoladex) given monthly. A bone scan performed 2 months after starting treatment showed improvement in bony metastases. She also noted significant improvement in pain. Her disease remains stable 2 years after starting endocrine therapy.

References
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  9. Hong AS, Rosen EL, Soo MS, Baker JA. BI-RADS for sonography: positive and negative predictive values of sonographic features. AJR Am J Roentgenol 2005; 184:12601265.
  10. Berg WA, Campassi CI, Ioffe OB. Cystic lesions of the breast: sonographic-pathologic correlation. Radiology 2003; 227:183191.
  11. Schell AM, Rosenkranz K, Lewis PJ. Role of breast MRI in the preoperative evaluation of patients with newly diagnosed breast cancer. AJR Am J Roentgenol 2009; 192:14381444.
  12. Turnbull L, Brown S, Harvey I, et al. Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial. Lancet 2010; 375:563571.
  13. Worsham MJ, Abrams J, Raju U, et al. Breast cancer incidence in a cohort of women with benign breast disease from a multiethnic, primary health care population. Breast J 2007; 13:115121.
  14. Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985; 312:146151.
  15. Page DL, Kidd TE, Dupont WD, Simpson JF, Rogers LW. Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease. Hum Pathol 1991; 22:12321239.
  16. Sneige N, Wang J, Baker BA, Krishnamurthy S, Middleton LP. Clinical, histopathologic, and biologic features of pleomorphic lobular (ductallobular) carcinoma in situ of the breast: a report of 24 cases. Mod Pathol 2002; 15:10441050.
  17. Telli ML, Horst KC, Guardino AE, Dirbas FM, Carlson RW. Phyllodes tumors of the breast: natural history, diagnosis, and treatment. J Natl Compr Canc Netw 2007; 5:324330.
  18. Reinfuss M, Mitus J, Duda K, Stelmach A, Rys J, Smolak K. The treatment and prognosis of patients with phyllodes tumor of the breast: an analysis of 170 cases. Cancer 1996; 77:910916.
  19. Kamal RM, Hamed ST, Salem DS. Classification of inflammatory breast disorders and step by step diagnosis. Breast J 2009; 15:367380.
  20. Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA. The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 1999; 64:963970.
  21. Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med 2003; 348:23392347.
  22. Clarke-Pearson DL. Clinical practice. Screening for ovarian cancer. N Engl J Med 2009; 361:170177.
  23. Hisada M, Garber JE, Fung CY, Fraumeni JF, Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 1998; 90:606611.
  24. Bell DW, Varley JM, Szydlo TE, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 1999; 286:25282531.
  25. Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007; 297:23602372.
  26. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:17131727.
  27. Hankinson SE, Colditz GA, Manson JE, et al. A prospective study of oral contraceptive use and risk of breast cancer (Nurses’ Health Study, United States). Cancer Causes Control 1997; 8:6572.
  28. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med 2002; 346:20252032.
  29. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321333.
  30. Anderson GL, Limacher M, Assaf AR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291:17011712.
  31. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 2007; 356:16701674.
  32. Fisher B, Anderson S, Redmond CK, Wolmark N, Wickerham DL, Cronin WM. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995; 333:14561461.
  33. Clarke M, Collins R, Darby S, et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366:20872106.
  34. Petrek JA, Senie RT, Peters M, Rosen PP. Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer 2001; 92:13681377.
  35. McLaughlin SA, Wright MJ, Morris KT, et al. Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements. J Clin Oncol 2008; 26:52135219.
  36. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:16871717.
  37. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351:28172826.
  38. Albain KS, Barlow WE, Shak S, et al; Breast Cancer Intergroup of North America. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol 2010; 11:5565.
  39. Harris JR, Halpin-Murphy P, McNeese M, Mendenhall NP, Morrow M, Robert NJ. Consensus Statement on postmastectomy radiation therapy. Int J Radiat Oncol Biol Phys 1999; 44:989990.
  40. Gennari A, Conte P, Rosso R, Orlandini C, Bruzzi P. Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies. Cancer 2005; 104:17421750.
  41. Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003; 21:21012109.
  42. Gamucci T, D’Ottavio AM, Magnolfi E, et al. Weekly epirubicin plus docetaxel as first-line treatment in metastatic breast cancer. Br J Cancer 2007; 97:10401045.
  43. Bonneterre J, Thürlimann B, Robertson JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 2000; 18:37483757.
  44. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 2000; 18:37583767.
  45. Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 1996; 335:17851791.
  46. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:16731684.
  47. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783792.
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A 40-year-old premenopausal woman presents with a palpable lump in her left breast. She first noted it 2 months ago on self-examination, and it has steadily grown in size regardless of the phase of her menstrual cycle.

The patient has never undergone mammography. Her menarche was at age 12. At age 35, she had one child (whom she breastfed) after a normal first full-term pregnancy. She took oral contraceptives for 10 years before her pregnancy. She has no other medical problems. She has no family history of breast or ovarian cancer.

On examination, her breasts are slightly asymmetric, without skin discoloration, tenderness, swelling, nipple retraction, or discharge. A 1.5- to 2-cm, rubbery, mobile lump can be felt in the left breast at about the 2 o’clock position. No axillary lymph nodes can be palpated. The rest of her examination is normal.

BREAST CANCER MUST BE RULED OUT

Benign breast disease is found in approximately 90% of women 20 to 50 years of age who come to a physician with a breast problem.1

Nevertheless, breast cancer is of major concern. It is the most common type of cancer in women in the United States, responsible for an estimated 194,440 new cases and 40,610 deaths in 2009. It is also the leading cause of cancer-related death in women age 45 to 55 years in this country.2,3

Breast cancer is most common in postmenopausal women, its incidence rising sharply after the age of 45 and leveling off at age 75. The median age at diagnosis is 61 years. Still, 1.9% of breast cancers in women are diagnosed at age 20 to 34, 10.6% at age 35 to 44, and 22.4% at age 45 to 54.4

Thus, it is paramount to perform a thorough assessment and workup of women who have breast lumps, regardless of their age. Doing so allows breast cancer to be detected at an early stage. The 5-year survival rate is 98.0% for women with localized disease, 83.6% with regional disease, and 23.4% with distant disease.4

WHAT IS THE APPROPRIATE WORKUP?

1. Which of the following are appropriate in the workup of this patient?

  • Mammography
  • Ultrasonography
  • Percutaneous needle biopsy of the lesion
  • Magnetic resonance imaging (MRI) of the brain
  • Computed tomography (CT) of the chest, abdomen, and pelvis
  • Positron emission tomography (PET)

She should undergo mammography, ultrasonography, and percutaneous needle biopsy.

Physical findings that suggest breast cancer include a hard, isolated, sometimes nonmobile lump, serosanguinous nipple discharge, and unilateral nipple retraction. Peau d’orange skin discoloration can occur. A scaly, vesicular, or ulcerated rash with or without pruritus, burning, irritation, or pain of the nipple or skin (Paget disease of the breast) is found in 1% to 3% of breast cancers and may be initially dismissed as mastitis.5,6 Palpable enlarged axillary lymph nodes can suggest invasive breast cancer.

Mammography is recommended in all cases of suspicious breast lumps. In a patient with a palpable lump, diagnostic mammography has a positive predictive value of 21.8%, a specificity of 85.8%, and a sensitivity of 87.7%, which are higher values than in a patient without signs or symptoms.7

The BIRADS score. Mammographic findings are summarized using a scoring system devised by the American College of Radiology called BIRADS (Breast Imaging Reporting and Data System). This system is based on mass irregularity, density, spiculation, and presence or absence of microcalcifications. It standardizes the results of mammography, gives an estimate of the risk of breast cancer, and recommends the frequency of follow-up examinations.8 Scores range from 0 to 6:

  • 0—Incomplete assessment warranting additional evaluation
  • 1—Completely negative mammogram
  • 2—Benign lesion
  • 3—Requires follow-up mammogram at 6 months
  • 4—Risk of cancer is 2% to 95%; core biopsy needed
  • 5—Risk of cancer is more than 95%; core biopsy needed
  • 6—Cases that have already been proven to be malignant.

Ultrasonography is also done if a suspicious lesion is found on mammography or physical examination. It helps differentiate between solid and cystic masses. If a mass is identified as a cyst, ultrasonography can further characterize it as simple, complicated-simple, or complex. Simple cysts and complicated-simple cysts are unlikely to be malignant.9,10 Complex cysts or cysts associated with solid tissue are evaluated by biopsy.

Percutaneous needle biopsy should be done for a definitive diagnosis of most suspicious breast masses.

MRI can sometimes provide more accurate information about the possibility of multifocal breast cancer by revealing additional lesions missed on mammography or ultrasonography. It is also useful in determining more accurately the size of the breast tumor and looking for any possible contralateral lesions. In addition, it can sometimes detect enlarged axillary lymph nodes. However, it has poor specificity for breast cancer and may lead to additional and sometimes unnecessary diagnostic tests, which can delay treatment.

MRI’s role is therefore not clearly established, but it is commonly used in clinical practice. It is argued that workup of MRI findings may help in planning more accurate surgical procedures and may prevent reoperations. Based on retrospective analyses, results of breast MRI may lead to altered surgical treatment in approximately 13% of patients.11

Interestingly, a recent randomized trial showed no difference in reoperation rates between patients who underwent MRI before surgery vs those who did not. However, diagnostic workup of new MRI findings was not mandated by the study protocol, making the results of this trial difficult to interpret.12

 

 

DIFFERENTIAL DIAGNOSIS

2. Which of the following is in the differential diagnosis of a woman presenting with a breast abnormality?

  • Fibrocystic changes
  • Breast cyst
  • Ductal ectasia
  • Simple fibroadenoma
  • Intraductal papilloma
  • Ductal carcinoma in situ
  • Mastitis
  • Infiltrating ductal carcinoma
  • Phyllodes tumor

All of these choices are part of the differential diagnosis.

Benign breast lesions

Benign breast lesions are divided into those that are proliferative and those that are nonproliferative. Some (but not all) proliferative lesions pose a higher risk of progressing to malignancy than nonproliferative lesions do.13 Benign breast lesions that do not increase the risk of breast cancer are listed in Table 1.

Simple fibroadenoma, one of the most common proliferative lesions, is not associated with a higher risk of developing breast cancer.

Fibrocystic changes are the most common nonproliferative lesions. Occasionally breast pain, nipple discharge, or significant lumpiness that varies during the course of the menstrual cycle can occur. The nipple discharge in women with fibrocystic changes is physiologic and pale green to brown in color. It can also be yellow, whitish, clear, or bloody. Bloody nipple discharge is considered pathologic and suggests a process other than fibrocystic changes, necessitating further workup. However, bloody discharge is not always a sign of malignancy, as it can have a benign cause as well.

Ductal ectasia, another nonproliferative lesion, is a result of dilation of subareolar ducts that contain fluid with a crystalline material. It can penetrate the duct, forming a nodule, which causes pain and occasionally fever.

Precancerous and cancerous lesions

Lesions that can increase the risk of breast cancer are listed in Table 2. The degree of risk depends on the complexity and amount of atypia found on the biopsy specimen. The relative risk of developing breast cancer in patients with simple proliferative lesions without atypia is 1.6 to 1.9, compared with 3.7 to 5.3 for complex lesions with high degrees of atypia.14

Ductal carcinoma in situ is a true neoplasm that has not yet developed the ability to invade through the basement membrane of the ducts. The likelihood of progression to invasive breast cancer depends on the histologic grade, the tumor size, and the patient’s age.

Lobular carcinoma in situ arises from lobules and terminal ducts of breast tissue. Much controversy surrounds this type of tumor, which was thought to be a marker of increased risk of developing ipsilateral and contralateral breast cancer and not to be a malignant lesion itself.15 However, there is emerging evidence to suggest that a pleomorphic variant of lobular carcinoma in situ is associated with development of breast cancer in the same site as the lesion, whereas a nonpleomorphic form is a marker of increased risk of ipsilateral and contralateral breast cancer.16

Invasive ductal and lobular carcinomas are the true invasive breast cancers, with a potential to metastasize.

Phyllodes tumors are uncommon fibroepithelial lesions that account for less than 1% of all breast neoplasms. The median age at presentation is 45 years.17 Despite the historical name “cystosarcoma phyllodes,” these lesions are not true sarcomas and have stromal and epithelial components.

These tumors display very heterogeneous behavior and, based on predefined histologic criteria, are often classified as benign, borderline, or malignant. Benign phyllodes tumors are similar to fibroadenomas in both histology and prognosis, making their diagnosis challenging. The most aggressive phyllodes tumors lose their epithelial component and have high metastatic potential. These tumors often have a biphasic growth pattern, and women may present with a smooth, round, well-defined breast lump that was stable for many years but then started to grow rapidly.17

Surgical resection with wide margins is the primary management of these tumors.18

Mastitis, ie, inflammation of the breast tissue, often presents with symptoms of breast erythema, swelling, tenderness, and nipple discharge. It may be secondary to infection (most often in lactating women) or other causes such as radiation or underlying malignancy. A complication of infectious mastitis is formation of a breast abscess. Underlying malignancy, especially inflammatory breast cancer, is a common cause of noninfectious mastitis and is very important to recognize.19

 

 

RISK FACTORS FOR BREAST CANCER

3. Which of the following are risk factors for breast cancer?

  • Menarche before age 12
  • Female sex
  • Personal history of breast cancer
  • Obesity
  • Never having had children, or having given birth for the first time at an older age
  • Older age
  • History of hormone replacement therapy with estrogen and progesterone
  • Family history of breast cancer

All of these choices are risk factors for breast cancer.

Family history

The overall relative risk of developing breast cancer in a woman with a first-degree relative with the disease is 1.7. However, the relative risk is about 3 if the first-degree relative developed breast cancer before menopause, and 9 if the first-degree relative developed bilateral breast cancer before menopause.5

Familial syndromes are a major factor in 5% to 7% of cases of breast cancer. Most frequently, they involve mutations in the BRCA1 and BRCA2 genes, which encode DNA excision repair proteins. Such mutations are present in about 2.2% of the Ashkenazi Jewish population, and carriers have a lifetime risk of developing breast cancer of 56% to 85%.20,21 Other common familial syndromes associated with breast cancer include the Cowden and Li-Fraumeni syndromes (Table 3).22–25

Estrogen exposure

The duration and amount of estrogen exposure are also risk factors. For example, menarche before age 12 and menopause after age 55 are associated with a higher risk. Women who go through menopause after age 55 have a twofold higher risk of breast cancer compared with women who go through menopause at an early age. Pregnancy before age 30 lowers the risk of breast cancer; late first full-term pregnancy or nulliparity increases it. Lactation, on the other hand, has a protective effect.5

Oral contraceptives have traditionally been thought to increase the risk of breast cancer. In the 1990s, a meta-analysis involving 153,506 women found that those who had used oral contraceptives had a 24% higher risk of developing breast cancer.26 However, this association has come into question since newer oral contraceptive pills containing different progestins and lower amounts of estrogen have become available. In fact, recent studies showed no link between oral contraceptive use and breast cancer.27,28 Nevertheless, women at higher risk of developing breast cancer are advised not to use oral contraceptives.

Hormone replacement therapy with estrogen and progesterone was found to increase the risk of breast cancer by 26% in the Women’s Health Initiative (WHI) study, which involved 16,608 healthy women followed for a median of 5.6 years.29

In a study reported separately, the WHI investigators randomized 10,739 women who had undergone hysterectomy to receive either hormone replacement therapy with unopposed estrogen (which is feasible only in women without a uterus) or placebo. They found no increase in the risk of invasive breast cancer in women on hormone replacement therapy with estrogen alone. In fact, the study showed a trend towards a modest reduction of this risk (odds ratio 0.77; 95% confidence interval 0.59–1.01).30

After the results of the WHI were published, the use of hormone replacement therapy in postmenopausal women declined significantly. And in 2003—1 year later—the incidence of breast cancer had dropped by 6.7%.31

Most experts now recommend that estrogen-progestin combinations be used only selectively to treat the symptoms of menopause, and only for the short term.

Other risk factors

Other factors found to modestly increase the risk of breast cancer include:

  • Alcohol use
  • Obesity
  • Radiation exposure. Patients are at higher risk of breast cancer 15 to 20 years after receiving upper-mantle radiotherapy for Hodgkin lymphoma.5

Case continues: Bad news on mammography, ultrasonography, biopsy

The patient undergoes mammography, which shows a 2.5-cm spiculated lesion with areas of calcifications (BIRADS score of 5). Subsequently, ultrasonography confirms that the suspicious mass is not a cyst. Ultrasound-guided core needle biopsy reveals that the lesion is a high-grade invasive ductal carcinoma. The tumor is positive for both estrogen and progesterone receptors and negative for HER2/neu overexpression.

STAGING EVALUATION

4. Given these findings, what is the next step to take?

  • CT of the chest, abdomen, and pelvis
  • MRI of the brain
  • PET
  • Referral to a surgeon for a possible mastectomy with sentinel lymph node dissection
  • Referral to a surgeon for a possible lumpectomy with sentinel lymph node dissection

At this point, the patient should be referred to a surgeon for possible mastectomy or lumpectomy.

Women who appear clinically to have early breast cancer, such as in this case, should have a complete blood count, comprehensive metabolic panel, and chest x-ray as their initial staging evaluation. No further studies are recommended unless the findings on history, physical examination, or the above testing suggest possible metastases.

 

 

Mastectomy vs lumpectomy

Early-stage breast cancer is managed with definitive surgery. The two options are mastectomy and breast conservation therapy, the latter involving lumpectomy followed by breast radiation therapy.

Multiple randomized studies comparing mastectomy and lumpectomy showed no difference in survival rates, but patients in the lumpectomy groups had higher rates of local recurrence.32 Breast radiation therapy after lumpectomy lowered the rates of local recurrence and breast cancer death.33 Therefore, most patients can opt to undergo either lumpectomy with radiation or mastectomy, depending on personal preference.

However, mastectomy rather than breast conservation therapy is still recommended in cases of prior radiation therapy, inability to achieve negative surgical margins (as in cases of large tumors), multicentric disease (cancer in separate breast quadrants), or multiple areas of calcifications. Mastectomy is also preferred in most pregnant women unless the diagnosis of breast cancer is made in the third trimester and radiation therapy can be given after delivery. Patients who have large lesions in a small breast may also choose mastectomy with breast reconstruction rather than breast conservation therapy. Patients with a history of scleroderma are encouraged to undergo mastectomy because of increased toxicity from radiation treatment.

Sentinel vs axillary lymph node dissection

Knowledge of axillary lymph node involvement is important because it determines the stage in the tumor-node-metastasis (TNM) system, and it influences the choice of further therapy. Therefore, all patients with nonmetastatic invasive breast cancer must have their axillary lymph nodes sampled.

Conventionally, this involves axillary lymph node dissection. Unfortunately, upper extremity lymphedema develops in 6% to 30% of patients within the first 3 years, and in 49% of patients after 20 years following axillary lymph node dissection.34

Sentinel lymph node dissection was developed to minimize this complication. This procedure involves the injection of a blue dye, isosulfan blue (Lymphazurin), around the edge of the tumor or in the dermis overlying the tumor. The most proximal axillary lymph nodes that stain blue are dissected. Alternatively, a radioactive colloid (most commonly technetium sulfur colloid agents) may be injected, allowing sentinel lymph nodes to be identified by lymphoscintigraphy. If no metastases are found in the sentinel lymph nodes, axillary lymph node dissection is not performed.

A prospective study in 536 women found that at 5 years of follow-up, lymphedema developed in only 5% of patients after sentinel lymph node dissection compared with 16% of those who underwent axillary lymph node dissection (P < .001), with comparable outcomes in terms of disease recurrence.35

Case continues: Patient undergoes surgery

The patient elects to undergo lumpectomy with sentinel lymph node dissection. Pathologic review of the resection specimen reveals a 2.5-cm poorly differentiated invasive ductal carcinoma. Sentinel lymph node dissection shows metastases, and therefore axillary lymph node dissection is performed. One of eight lymph nodes removed is positive for metastases. All surgical margins are negative.

POSTOPERATIVE CARE

5. What would be the next step for our patient?

  • Radiation followed by observation
  • Tamoxifen (Nolvadex) for 5 years
  • Observation only
  • Chemotherapy followed by radiation therapy and 5 years of tamoxifen

She should receive chemotherapy, followed by radiation therapy and then tamoxifen for 5 years.

Chemotherapy. Almost all patients who have lymph-node-positive disease are advised to undergo chemotherapy.

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) performed a metaanalysis of 194 randomized trials that compared adjuvant chemotherapy and no treatment in early-stage breast cancer. Chemotherapy led to a 10% absolute improvement in survival at 15 years for women younger than 50 years and 3% in women age 51 to 69.36

Indications for chemotherapy include axillary lymph node involvement, locally advanced disease, and other risk factors for recurrence such as young age at diagnosis, strong positive family history of breast cancer, prior history of breast cancer, or lymph-node-negative, estrogen-receptor-negative tumors that are larger than 1 cm in diameter.

The Oncotype DX assay is a new tool to help oncologists decide whether to use chemotherapy in cases of estrogen-receptor-positive breast cancer, in which the benefit of chemotherapy is uncertain. It is a polymerase chain reaction assay that measures the expression of 16 cancer-specific genes and five reference genes within the breast tumor. Based on the pattern of expression of these genes, breast cancer can be characterized as low-risk, intermediate-risk, or high-risk. Patients in the high-risk group have a high chance of cancer recurrence and benefit from chemotherapy. Patients in the low-risk group are unlikely to have a recurrence or to benefit from chemotherapy.37 It is far less clear if patients in the intermediate-risk group benefit from chemotherapy, but this assay might eventually prove useful in deciding for or against chemotherapy in this group of patients as well.38 The Oncotype DX assay is presently being studied in a clinical trial.

Radiation therapy after mastectomy is recommended in patients who have breast tumors larger than 5 cm or metastases to more than three axillary lymph nodes.39

Antiestrogen therapy. After chemotherapy, patients with estrogen-receptor-positive cancers also receive 5 years of antiestrogen therapy. Available antiestrogen agents for such patients include tamoxifen, which is a selective estrogen receptor modulator, and drugs called aromatase inhibitors that block conversion of androgens to estrogens in peripheral tissues. Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are examples of available aromatase inhibitors. Premenopausal women are treated with tamoxifen, and postmenopausal women are offered aromatase inhibitors.

The EBCTCG meta-analysis found a 12% absolute reduction in mortality rates and a 9% absolute reduction in relapse rates at 15 years of follow-up in patients who took tamoxifen for 5 years.36

Table 4 lists the most common adverse effects of these agents. Aromatase inhibitors are associated with a higher risk of osteoporosis and arthralgia, while tamoxifen increases the risks of thromboembolism, endometrial cancer, and vaginal discharge. Both agents may produce menopausal symptoms such as hot flashes and mood swings.

 

 

Case continues: Seven years later, metastases in the spine

The patient achieves a complete remission. She is seen for a routine visit 7 years after diagnosis. She now reports mid-back pain that has worsened over the last 2 months. A bone scan reveals diffuse metastatic disease in the spine and in both humeral bones. CT of the chest, abdomen, and pelvis is negative for visceral metastases. Bone marrow aspiration and biopsy study show marrow infiltration by adenocarcinoma that stains positive for estrogen receptors and negative for HER2. The patient otherwise feels well and has no other symptoms.

WHAT TREATMENT FOR METASTATIC BREAST CANCER?

6. What should you now do for our patient?

  • Discuss end-of-life care and refer her to a hospice program
  • Educate the patient that no options for treatment exist and recommend enrolling in a phase I clinical trial
  • Refer her to an oncologist for consideration of chemotherapy
  • Refer her to an oncologist for consideration of endocrine treatment

She should be referred to an oncologist for consideration of endocrine treatment.

The most common sites of breast cancer metastases are the bones, followed by the liver and lungs. Metastatic breast cancer almost always is incurable. However, treatment can palliate symptoms.

Although a randomized trial of treatment vs best supportive care has never been done, many believe that treatment may improve survival. 40 The median survival of patients treated with standard therapy is about 3 years if the breast cancer is estrogen-receptor-positive and 2 years if it is estrogen-receptor-negative, but survival rates vary widely from patient to patient.41,42

Standard therapy or enrollment in a clinical phase II or III trial is indicated for this patient before considering enrollment in a phase I clinical trial or supportive care alone.

Endocrine therapy is the first-line therapy in women with estrogen-receptor-positive metastatic breast cancer. Postmenopausal women usually receive an aromatase inhibitor first.43,44 Response to endocrine therapy usually takes weeks to months but may last for several years.

Premenopausal women with estrogen-receptor-positive breast cancer also receive ovarian ablation therapy (oophorectomy or chemical ovarian ablation) with gonadotropin-releasing hormone agonists.

In addition, most patients with bone involvement are treated with high doses of intravenous bisphosphonates, which can reduce skeletal complications.45

Chemotherapy is reserved for patients with estrogen-receptor-negative breast cancer and those with cancer that progresses despite treatment with multiple antiestrogen agents. The time to response when chemotherapy is used is quicker, but the duration of response is usually shorter, lasting on average less than 1 year.37

Trastuzumab (Herceptin), a monoclonal humanized murine antibody to the extracellular domain of the HER2 protein, is indicated in patients with HER2-overexpressing tumors.46,47

STABLE 2 YEARS LATER

The patient was started on letrozole and a bisphosphonate, zolendronic acid (Zometa). Ovarian ablation was initiated with goserelin (Zoladex) given monthly. A bone scan performed 2 months after starting treatment showed improvement in bony metastases. She also noted significant improvement in pain. Her disease remains stable 2 years after starting endocrine therapy.

A 40-year-old premenopausal woman presents with a palpable lump in her left breast. She first noted it 2 months ago on self-examination, and it has steadily grown in size regardless of the phase of her menstrual cycle.

The patient has never undergone mammography. Her menarche was at age 12. At age 35, she had one child (whom she breastfed) after a normal first full-term pregnancy. She took oral contraceptives for 10 years before her pregnancy. She has no other medical problems. She has no family history of breast or ovarian cancer.

On examination, her breasts are slightly asymmetric, without skin discoloration, tenderness, swelling, nipple retraction, or discharge. A 1.5- to 2-cm, rubbery, mobile lump can be felt in the left breast at about the 2 o’clock position. No axillary lymph nodes can be palpated. The rest of her examination is normal.

BREAST CANCER MUST BE RULED OUT

Benign breast disease is found in approximately 90% of women 20 to 50 years of age who come to a physician with a breast problem.1

Nevertheless, breast cancer is of major concern. It is the most common type of cancer in women in the United States, responsible for an estimated 194,440 new cases and 40,610 deaths in 2009. It is also the leading cause of cancer-related death in women age 45 to 55 years in this country.2,3

Breast cancer is most common in postmenopausal women, its incidence rising sharply after the age of 45 and leveling off at age 75. The median age at diagnosis is 61 years. Still, 1.9% of breast cancers in women are diagnosed at age 20 to 34, 10.6% at age 35 to 44, and 22.4% at age 45 to 54.4

Thus, it is paramount to perform a thorough assessment and workup of women who have breast lumps, regardless of their age. Doing so allows breast cancer to be detected at an early stage. The 5-year survival rate is 98.0% for women with localized disease, 83.6% with regional disease, and 23.4% with distant disease.4

WHAT IS THE APPROPRIATE WORKUP?

1. Which of the following are appropriate in the workup of this patient?

  • Mammography
  • Ultrasonography
  • Percutaneous needle biopsy of the lesion
  • Magnetic resonance imaging (MRI) of the brain
  • Computed tomography (CT) of the chest, abdomen, and pelvis
  • Positron emission tomography (PET)

She should undergo mammography, ultrasonography, and percutaneous needle biopsy.

Physical findings that suggest breast cancer include a hard, isolated, sometimes nonmobile lump, serosanguinous nipple discharge, and unilateral nipple retraction. Peau d’orange skin discoloration can occur. A scaly, vesicular, or ulcerated rash with or without pruritus, burning, irritation, or pain of the nipple or skin (Paget disease of the breast) is found in 1% to 3% of breast cancers and may be initially dismissed as mastitis.5,6 Palpable enlarged axillary lymph nodes can suggest invasive breast cancer.

Mammography is recommended in all cases of suspicious breast lumps. In a patient with a palpable lump, diagnostic mammography has a positive predictive value of 21.8%, a specificity of 85.8%, and a sensitivity of 87.7%, which are higher values than in a patient without signs or symptoms.7

The BIRADS score. Mammographic findings are summarized using a scoring system devised by the American College of Radiology called BIRADS (Breast Imaging Reporting and Data System). This system is based on mass irregularity, density, spiculation, and presence or absence of microcalcifications. It standardizes the results of mammography, gives an estimate of the risk of breast cancer, and recommends the frequency of follow-up examinations.8 Scores range from 0 to 6:

  • 0—Incomplete assessment warranting additional evaluation
  • 1—Completely negative mammogram
  • 2—Benign lesion
  • 3—Requires follow-up mammogram at 6 months
  • 4—Risk of cancer is 2% to 95%; core biopsy needed
  • 5—Risk of cancer is more than 95%; core biopsy needed
  • 6—Cases that have already been proven to be malignant.

Ultrasonography is also done if a suspicious lesion is found on mammography or physical examination. It helps differentiate between solid and cystic masses. If a mass is identified as a cyst, ultrasonography can further characterize it as simple, complicated-simple, or complex. Simple cysts and complicated-simple cysts are unlikely to be malignant.9,10 Complex cysts or cysts associated with solid tissue are evaluated by biopsy.

Percutaneous needle biopsy should be done for a definitive diagnosis of most suspicious breast masses.

MRI can sometimes provide more accurate information about the possibility of multifocal breast cancer by revealing additional lesions missed on mammography or ultrasonography. It is also useful in determining more accurately the size of the breast tumor and looking for any possible contralateral lesions. In addition, it can sometimes detect enlarged axillary lymph nodes. However, it has poor specificity for breast cancer and may lead to additional and sometimes unnecessary diagnostic tests, which can delay treatment.

MRI’s role is therefore not clearly established, but it is commonly used in clinical practice. It is argued that workup of MRI findings may help in planning more accurate surgical procedures and may prevent reoperations. Based on retrospective analyses, results of breast MRI may lead to altered surgical treatment in approximately 13% of patients.11

Interestingly, a recent randomized trial showed no difference in reoperation rates between patients who underwent MRI before surgery vs those who did not. However, diagnostic workup of new MRI findings was not mandated by the study protocol, making the results of this trial difficult to interpret.12

 

 

DIFFERENTIAL DIAGNOSIS

2. Which of the following is in the differential diagnosis of a woman presenting with a breast abnormality?

  • Fibrocystic changes
  • Breast cyst
  • Ductal ectasia
  • Simple fibroadenoma
  • Intraductal papilloma
  • Ductal carcinoma in situ
  • Mastitis
  • Infiltrating ductal carcinoma
  • Phyllodes tumor

All of these choices are part of the differential diagnosis.

Benign breast lesions

Benign breast lesions are divided into those that are proliferative and those that are nonproliferative. Some (but not all) proliferative lesions pose a higher risk of progressing to malignancy than nonproliferative lesions do.13 Benign breast lesions that do not increase the risk of breast cancer are listed in Table 1.

Simple fibroadenoma, one of the most common proliferative lesions, is not associated with a higher risk of developing breast cancer.

Fibrocystic changes are the most common nonproliferative lesions. Occasionally breast pain, nipple discharge, or significant lumpiness that varies during the course of the menstrual cycle can occur. The nipple discharge in women with fibrocystic changes is physiologic and pale green to brown in color. It can also be yellow, whitish, clear, or bloody. Bloody nipple discharge is considered pathologic and suggests a process other than fibrocystic changes, necessitating further workup. However, bloody discharge is not always a sign of malignancy, as it can have a benign cause as well.

Ductal ectasia, another nonproliferative lesion, is a result of dilation of subareolar ducts that contain fluid with a crystalline material. It can penetrate the duct, forming a nodule, which causes pain and occasionally fever.

Precancerous and cancerous lesions

Lesions that can increase the risk of breast cancer are listed in Table 2. The degree of risk depends on the complexity and amount of atypia found on the biopsy specimen. The relative risk of developing breast cancer in patients with simple proliferative lesions without atypia is 1.6 to 1.9, compared with 3.7 to 5.3 for complex lesions with high degrees of atypia.14

Ductal carcinoma in situ is a true neoplasm that has not yet developed the ability to invade through the basement membrane of the ducts. The likelihood of progression to invasive breast cancer depends on the histologic grade, the tumor size, and the patient’s age.

Lobular carcinoma in situ arises from lobules and terminal ducts of breast tissue. Much controversy surrounds this type of tumor, which was thought to be a marker of increased risk of developing ipsilateral and contralateral breast cancer and not to be a malignant lesion itself.15 However, there is emerging evidence to suggest that a pleomorphic variant of lobular carcinoma in situ is associated with development of breast cancer in the same site as the lesion, whereas a nonpleomorphic form is a marker of increased risk of ipsilateral and contralateral breast cancer.16

Invasive ductal and lobular carcinomas are the true invasive breast cancers, with a potential to metastasize.

Phyllodes tumors are uncommon fibroepithelial lesions that account for less than 1% of all breast neoplasms. The median age at presentation is 45 years.17 Despite the historical name “cystosarcoma phyllodes,” these lesions are not true sarcomas and have stromal and epithelial components.

These tumors display very heterogeneous behavior and, based on predefined histologic criteria, are often classified as benign, borderline, or malignant. Benign phyllodes tumors are similar to fibroadenomas in both histology and prognosis, making their diagnosis challenging. The most aggressive phyllodes tumors lose their epithelial component and have high metastatic potential. These tumors often have a biphasic growth pattern, and women may present with a smooth, round, well-defined breast lump that was stable for many years but then started to grow rapidly.17

Surgical resection with wide margins is the primary management of these tumors.18

Mastitis, ie, inflammation of the breast tissue, often presents with symptoms of breast erythema, swelling, tenderness, and nipple discharge. It may be secondary to infection (most often in lactating women) or other causes such as radiation or underlying malignancy. A complication of infectious mastitis is formation of a breast abscess. Underlying malignancy, especially inflammatory breast cancer, is a common cause of noninfectious mastitis and is very important to recognize.19

 

 

RISK FACTORS FOR BREAST CANCER

3. Which of the following are risk factors for breast cancer?

  • Menarche before age 12
  • Female sex
  • Personal history of breast cancer
  • Obesity
  • Never having had children, or having given birth for the first time at an older age
  • Older age
  • History of hormone replacement therapy with estrogen and progesterone
  • Family history of breast cancer

All of these choices are risk factors for breast cancer.

Family history

The overall relative risk of developing breast cancer in a woman with a first-degree relative with the disease is 1.7. However, the relative risk is about 3 if the first-degree relative developed breast cancer before menopause, and 9 if the first-degree relative developed bilateral breast cancer before menopause.5

Familial syndromes are a major factor in 5% to 7% of cases of breast cancer. Most frequently, they involve mutations in the BRCA1 and BRCA2 genes, which encode DNA excision repair proteins. Such mutations are present in about 2.2% of the Ashkenazi Jewish population, and carriers have a lifetime risk of developing breast cancer of 56% to 85%.20,21 Other common familial syndromes associated with breast cancer include the Cowden and Li-Fraumeni syndromes (Table 3).22–25

Estrogen exposure

The duration and amount of estrogen exposure are also risk factors. For example, menarche before age 12 and menopause after age 55 are associated with a higher risk. Women who go through menopause after age 55 have a twofold higher risk of breast cancer compared with women who go through menopause at an early age. Pregnancy before age 30 lowers the risk of breast cancer; late first full-term pregnancy or nulliparity increases it. Lactation, on the other hand, has a protective effect.5

Oral contraceptives have traditionally been thought to increase the risk of breast cancer. In the 1990s, a meta-analysis involving 153,506 women found that those who had used oral contraceptives had a 24% higher risk of developing breast cancer.26 However, this association has come into question since newer oral contraceptive pills containing different progestins and lower amounts of estrogen have become available. In fact, recent studies showed no link between oral contraceptive use and breast cancer.27,28 Nevertheless, women at higher risk of developing breast cancer are advised not to use oral contraceptives.

Hormone replacement therapy with estrogen and progesterone was found to increase the risk of breast cancer by 26% in the Women’s Health Initiative (WHI) study, which involved 16,608 healthy women followed for a median of 5.6 years.29

In a study reported separately, the WHI investigators randomized 10,739 women who had undergone hysterectomy to receive either hormone replacement therapy with unopposed estrogen (which is feasible only in women without a uterus) or placebo. They found no increase in the risk of invasive breast cancer in women on hormone replacement therapy with estrogen alone. In fact, the study showed a trend towards a modest reduction of this risk (odds ratio 0.77; 95% confidence interval 0.59–1.01).30

After the results of the WHI were published, the use of hormone replacement therapy in postmenopausal women declined significantly. And in 2003—1 year later—the incidence of breast cancer had dropped by 6.7%.31

Most experts now recommend that estrogen-progestin combinations be used only selectively to treat the symptoms of menopause, and only for the short term.

Other risk factors

Other factors found to modestly increase the risk of breast cancer include:

  • Alcohol use
  • Obesity
  • Radiation exposure. Patients are at higher risk of breast cancer 15 to 20 years after receiving upper-mantle radiotherapy for Hodgkin lymphoma.5

Case continues: Bad news on mammography, ultrasonography, biopsy

The patient undergoes mammography, which shows a 2.5-cm spiculated lesion with areas of calcifications (BIRADS score of 5). Subsequently, ultrasonography confirms that the suspicious mass is not a cyst. Ultrasound-guided core needle biopsy reveals that the lesion is a high-grade invasive ductal carcinoma. The tumor is positive for both estrogen and progesterone receptors and negative for HER2/neu overexpression.

STAGING EVALUATION

4. Given these findings, what is the next step to take?

  • CT of the chest, abdomen, and pelvis
  • MRI of the brain
  • PET
  • Referral to a surgeon for a possible mastectomy with sentinel lymph node dissection
  • Referral to a surgeon for a possible lumpectomy with sentinel lymph node dissection

At this point, the patient should be referred to a surgeon for possible mastectomy or lumpectomy.

Women who appear clinically to have early breast cancer, such as in this case, should have a complete blood count, comprehensive metabolic panel, and chest x-ray as their initial staging evaluation. No further studies are recommended unless the findings on history, physical examination, or the above testing suggest possible metastases.

 

 

Mastectomy vs lumpectomy

Early-stage breast cancer is managed with definitive surgery. The two options are mastectomy and breast conservation therapy, the latter involving lumpectomy followed by breast radiation therapy.

Multiple randomized studies comparing mastectomy and lumpectomy showed no difference in survival rates, but patients in the lumpectomy groups had higher rates of local recurrence.32 Breast radiation therapy after lumpectomy lowered the rates of local recurrence and breast cancer death.33 Therefore, most patients can opt to undergo either lumpectomy with radiation or mastectomy, depending on personal preference.

However, mastectomy rather than breast conservation therapy is still recommended in cases of prior radiation therapy, inability to achieve negative surgical margins (as in cases of large tumors), multicentric disease (cancer in separate breast quadrants), or multiple areas of calcifications. Mastectomy is also preferred in most pregnant women unless the diagnosis of breast cancer is made in the third trimester and radiation therapy can be given after delivery. Patients who have large lesions in a small breast may also choose mastectomy with breast reconstruction rather than breast conservation therapy. Patients with a history of scleroderma are encouraged to undergo mastectomy because of increased toxicity from radiation treatment.

Sentinel vs axillary lymph node dissection

Knowledge of axillary lymph node involvement is important because it determines the stage in the tumor-node-metastasis (TNM) system, and it influences the choice of further therapy. Therefore, all patients with nonmetastatic invasive breast cancer must have their axillary lymph nodes sampled.

Conventionally, this involves axillary lymph node dissection. Unfortunately, upper extremity lymphedema develops in 6% to 30% of patients within the first 3 years, and in 49% of patients after 20 years following axillary lymph node dissection.34

Sentinel lymph node dissection was developed to minimize this complication. This procedure involves the injection of a blue dye, isosulfan blue (Lymphazurin), around the edge of the tumor or in the dermis overlying the tumor. The most proximal axillary lymph nodes that stain blue are dissected. Alternatively, a radioactive colloid (most commonly technetium sulfur colloid agents) may be injected, allowing sentinel lymph nodes to be identified by lymphoscintigraphy. If no metastases are found in the sentinel lymph nodes, axillary lymph node dissection is not performed.

A prospective study in 536 women found that at 5 years of follow-up, lymphedema developed in only 5% of patients after sentinel lymph node dissection compared with 16% of those who underwent axillary lymph node dissection (P < .001), with comparable outcomes in terms of disease recurrence.35

Case continues: Patient undergoes surgery

The patient elects to undergo lumpectomy with sentinel lymph node dissection. Pathologic review of the resection specimen reveals a 2.5-cm poorly differentiated invasive ductal carcinoma. Sentinel lymph node dissection shows metastases, and therefore axillary lymph node dissection is performed. One of eight lymph nodes removed is positive for metastases. All surgical margins are negative.

POSTOPERATIVE CARE

5. What would be the next step for our patient?

  • Radiation followed by observation
  • Tamoxifen (Nolvadex) for 5 years
  • Observation only
  • Chemotherapy followed by radiation therapy and 5 years of tamoxifen

She should receive chemotherapy, followed by radiation therapy and then tamoxifen for 5 years.

Chemotherapy. Almost all patients who have lymph-node-positive disease are advised to undergo chemotherapy.

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) performed a metaanalysis of 194 randomized trials that compared adjuvant chemotherapy and no treatment in early-stage breast cancer. Chemotherapy led to a 10% absolute improvement in survival at 15 years for women younger than 50 years and 3% in women age 51 to 69.36

Indications for chemotherapy include axillary lymph node involvement, locally advanced disease, and other risk factors for recurrence such as young age at diagnosis, strong positive family history of breast cancer, prior history of breast cancer, or lymph-node-negative, estrogen-receptor-negative tumors that are larger than 1 cm in diameter.

The Oncotype DX assay is a new tool to help oncologists decide whether to use chemotherapy in cases of estrogen-receptor-positive breast cancer, in which the benefit of chemotherapy is uncertain. It is a polymerase chain reaction assay that measures the expression of 16 cancer-specific genes and five reference genes within the breast tumor. Based on the pattern of expression of these genes, breast cancer can be characterized as low-risk, intermediate-risk, or high-risk. Patients in the high-risk group have a high chance of cancer recurrence and benefit from chemotherapy. Patients in the low-risk group are unlikely to have a recurrence or to benefit from chemotherapy.37 It is far less clear if patients in the intermediate-risk group benefit from chemotherapy, but this assay might eventually prove useful in deciding for or against chemotherapy in this group of patients as well.38 The Oncotype DX assay is presently being studied in a clinical trial.

Radiation therapy after mastectomy is recommended in patients who have breast tumors larger than 5 cm or metastases to more than three axillary lymph nodes.39

Antiestrogen therapy. After chemotherapy, patients with estrogen-receptor-positive cancers also receive 5 years of antiestrogen therapy. Available antiestrogen agents for such patients include tamoxifen, which is a selective estrogen receptor modulator, and drugs called aromatase inhibitors that block conversion of androgens to estrogens in peripheral tissues. Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are examples of available aromatase inhibitors. Premenopausal women are treated with tamoxifen, and postmenopausal women are offered aromatase inhibitors.

The EBCTCG meta-analysis found a 12% absolute reduction in mortality rates and a 9% absolute reduction in relapse rates at 15 years of follow-up in patients who took tamoxifen for 5 years.36

Table 4 lists the most common adverse effects of these agents. Aromatase inhibitors are associated with a higher risk of osteoporosis and arthralgia, while tamoxifen increases the risks of thromboembolism, endometrial cancer, and vaginal discharge. Both agents may produce menopausal symptoms such as hot flashes and mood swings.

 

 

Case continues: Seven years later, metastases in the spine

The patient achieves a complete remission. She is seen for a routine visit 7 years after diagnosis. She now reports mid-back pain that has worsened over the last 2 months. A bone scan reveals diffuse metastatic disease in the spine and in both humeral bones. CT of the chest, abdomen, and pelvis is negative for visceral metastases. Bone marrow aspiration and biopsy study show marrow infiltration by adenocarcinoma that stains positive for estrogen receptors and negative for HER2. The patient otherwise feels well and has no other symptoms.

WHAT TREATMENT FOR METASTATIC BREAST CANCER?

6. What should you now do for our patient?

  • Discuss end-of-life care and refer her to a hospice program
  • Educate the patient that no options for treatment exist and recommend enrolling in a phase I clinical trial
  • Refer her to an oncologist for consideration of chemotherapy
  • Refer her to an oncologist for consideration of endocrine treatment

She should be referred to an oncologist for consideration of endocrine treatment.

The most common sites of breast cancer metastases are the bones, followed by the liver and lungs. Metastatic breast cancer almost always is incurable. However, treatment can palliate symptoms.

Although a randomized trial of treatment vs best supportive care has never been done, many believe that treatment may improve survival. 40 The median survival of patients treated with standard therapy is about 3 years if the breast cancer is estrogen-receptor-positive and 2 years if it is estrogen-receptor-negative, but survival rates vary widely from patient to patient.41,42

Standard therapy or enrollment in a clinical phase II or III trial is indicated for this patient before considering enrollment in a phase I clinical trial or supportive care alone.

Endocrine therapy is the first-line therapy in women with estrogen-receptor-positive metastatic breast cancer. Postmenopausal women usually receive an aromatase inhibitor first.43,44 Response to endocrine therapy usually takes weeks to months but may last for several years.

Premenopausal women with estrogen-receptor-positive breast cancer also receive ovarian ablation therapy (oophorectomy or chemical ovarian ablation) with gonadotropin-releasing hormone agonists.

In addition, most patients with bone involvement are treated with high doses of intravenous bisphosphonates, which can reduce skeletal complications.45

Chemotherapy is reserved for patients with estrogen-receptor-negative breast cancer and those with cancer that progresses despite treatment with multiple antiestrogen agents. The time to response when chemotherapy is used is quicker, but the duration of response is usually shorter, lasting on average less than 1 year.37

Trastuzumab (Herceptin), a monoclonal humanized murine antibody to the extracellular domain of the HER2 protein, is indicated in patients with HER2-overexpressing tumors.46,47

STABLE 2 YEARS LATER

The patient was started on letrozole and a bisphosphonate, zolendronic acid (Zometa). Ovarian ablation was initiated with goserelin (Zoladex) given monthly. A bone scan performed 2 months after starting treatment showed improvement in bony metastases. She also noted significant improvement in pain. Her disease remains stable 2 years after starting endocrine therapy.

References
  1. Barton MB, Elmore JG, Fletcher SW. Breast symptoms among women enrolled in a health maintenance organization: frequency, evaluation, and outcome. Ann Intern Med 1999; 130:651657.
  2. Petrelli NJ, Winer EP, Brahmer J, et al. Clinical cancer advances 2009: major research advances in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology. J Clin Oncol 2009; 27:60526069.
  3. Jemal A, Siegel R, Ward E, et al. Cancer statistics 2008. CA Cancer J Clin 2008; 58:7196.
  4. National Cancer Institute. SEER Stat Fact Sheets. www.seer.cancer.gov/statfacts/html/breast.html#ref09. Accessed June 7, 2010.
  5. Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ; the publishers of the journal Oncology. Cancer Management: A multidisciplinary Approach. Medical, Surgical & Radiation Oncology. 11th ed. CMP Medica; 2008.
  6. Kollmorgen DR, Varanasi JS, Edge SB, Carson WE. Paget’s disease of the breast: a 33-year experience. J Am Coll Surg 1998; 187:171177.
  7. Barlow WE, Lehman CD, Zheng Y, et al. Performance of diagnostic mammography for women with signs or symptoms of breast cancer. J Natl Cancer Inst 2002; 94:11511159.
  8. American College of Radiology. Breast Imaging Reporting and Data System: BIRADS Atlas. 4th ed. Reston, VA: American College of Radiology; 2003.
  9. Hong AS, Rosen EL, Soo MS, Baker JA. BI-RADS for sonography: positive and negative predictive values of sonographic features. AJR Am J Roentgenol 2005; 184:12601265.
  10. Berg WA, Campassi CI, Ioffe OB. Cystic lesions of the breast: sonographic-pathologic correlation. Radiology 2003; 227:183191.
  11. Schell AM, Rosenkranz K, Lewis PJ. Role of breast MRI in the preoperative evaluation of patients with newly diagnosed breast cancer. AJR Am J Roentgenol 2009; 192:14381444.
  12. Turnbull L, Brown S, Harvey I, et al. Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial. Lancet 2010; 375:563571.
  13. Worsham MJ, Abrams J, Raju U, et al. Breast cancer incidence in a cohort of women with benign breast disease from a multiethnic, primary health care population. Breast J 2007; 13:115121.
  14. Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985; 312:146151.
  15. Page DL, Kidd TE, Dupont WD, Simpson JF, Rogers LW. Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease. Hum Pathol 1991; 22:12321239.
  16. Sneige N, Wang J, Baker BA, Krishnamurthy S, Middleton LP. Clinical, histopathologic, and biologic features of pleomorphic lobular (ductallobular) carcinoma in situ of the breast: a report of 24 cases. Mod Pathol 2002; 15:10441050.
  17. Telli ML, Horst KC, Guardino AE, Dirbas FM, Carlson RW. Phyllodes tumors of the breast: natural history, diagnosis, and treatment. J Natl Compr Canc Netw 2007; 5:324330.
  18. Reinfuss M, Mitus J, Duda K, Stelmach A, Rys J, Smolak K. The treatment and prognosis of patients with phyllodes tumor of the breast: an analysis of 170 cases. Cancer 1996; 77:910916.
  19. Kamal RM, Hamed ST, Salem DS. Classification of inflammatory breast disorders and step by step diagnosis. Breast J 2009; 15:367380.
  20. Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA. The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 1999; 64:963970.
  21. Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med 2003; 348:23392347.
  22. Clarke-Pearson DL. Clinical practice. Screening for ovarian cancer. N Engl J Med 2009; 361:170177.
  23. Hisada M, Garber JE, Fung CY, Fraumeni JF, Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 1998; 90:606611.
  24. Bell DW, Varley JM, Szydlo TE, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 1999; 286:25282531.
  25. Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007; 297:23602372.
  26. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:17131727.
  27. Hankinson SE, Colditz GA, Manson JE, et al. A prospective study of oral contraceptive use and risk of breast cancer (Nurses’ Health Study, United States). Cancer Causes Control 1997; 8:6572.
  28. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med 2002; 346:20252032.
  29. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321333.
  30. Anderson GL, Limacher M, Assaf AR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291:17011712.
  31. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 2007; 356:16701674.
  32. Fisher B, Anderson S, Redmond CK, Wolmark N, Wickerham DL, Cronin WM. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995; 333:14561461.
  33. Clarke M, Collins R, Darby S, et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366:20872106.
  34. Petrek JA, Senie RT, Peters M, Rosen PP. Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer 2001; 92:13681377.
  35. McLaughlin SA, Wright MJ, Morris KT, et al. Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements. J Clin Oncol 2008; 26:52135219.
  36. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:16871717.
  37. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351:28172826.
  38. Albain KS, Barlow WE, Shak S, et al; Breast Cancer Intergroup of North America. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol 2010; 11:5565.
  39. Harris JR, Halpin-Murphy P, McNeese M, Mendenhall NP, Morrow M, Robert NJ. Consensus Statement on postmastectomy radiation therapy. Int J Radiat Oncol Biol Phys 1999; 44:989990.
  40. Gennari A, Conte P, Rosso R, Orlandini C, Bruzzi P. Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies. Cancer 2005; 104:17421750.
  41. Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003; 21:21012109.
  42. Gamucci T, D’Ottavio AM, Magnolfi E, et al. Weekly epirubicin plus docetaxel as first-line treatment in metastatic breast cancer. Br J Cancer 2007; 97:10401045.
  43. Bonneterre J, Thürlimann B, Robertson JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 2000; 18:37483757.
  44. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 2000; 18:37583767.
  45. Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 1996; 335:17851791.
  46. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:16731684.
  47. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783792.
References
  1. Barton MB, Elmore JG, Fletcher SW. Breast symptoms among women enrolled in a health maintenance organization: frequency, evaluation, and outcome. Ann Intern Med 1999; 130:651657.
  2. Petrelli NJ, Winer EP, Brahmer J, et al. Clinical cancer advances 2009: major research advances in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology. J Clin Oncol 2009; 27:60526069.
  3. Jemal A, Siegel R, Ward E, et al. Cancer statistics 2008. CA Cancer J Clin 2008; 58:7196.
  4. National Cancer Institute. SEER Stat Fact Sheets. www.seer.cancer.gov/statfacts/html/breast.html#ref09. Accessed June 7, 2010.
  5. Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ; the publishers of the journal Oncology. Cancer Management: A multidisciplinary Approach. Medical, Surgical & Radiation Oncology. 11th ed. CMP Medica; 2008.
  6. Kollmorgen DR, Varanasi JS, Edge SB, Carson WE. Paget’s disease of the breast: a 33-year experience. J Am Coll Surg 1998; 187:171177.
  7. Barlow WE, Lehman CD, Zheng Y, et al. Performance of diagnostic mammography for women with signs or symptoms of breast cancer. J Natl Cancer Inst 2002; 94:11511159.
  8. American College of Radiology. Breast Imaging Reporting and Data System: BIRADS Atlas. 4th ed. Reston, VA: American College of Radiology; 2003.
  9. Hong AS, Rosen EL, Soo MS, Baker JA. BI-RADS for sonography: positive and negative predictive values of sonographic features. AJR Am J Roentgenol 2005; 184:12601265.
  10. Berg WA, Campassi CI, Ioffe OB. Cystic lesions of the breast: sonographic-pathologic correlation. Radiology 2003; 227:183191.
  11. Schell AM, Rosenkranz K, Lewis PJ. Role of breast MRI in the preoperative evaluation of patients with newly diagnosed breast cancer. AJR Am J Roentgenol 2009; 192:14381444.
  12. Turnbull L, Brown S, Harvey I, et al. Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial. Lancet 2010; 375:563571.
  13. Worsham MJ, Abrams J, Raju U, et al. Breast cancer incidence in a cohort of women with benign breast disease from a multiethnic, primary health care population. Breast J 2007; 13:115121.
  14. Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985; 312:146151.
  15. Page DL, Kidd TE, Dupont WD, Simpson JF, Rogers LW. Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease. Hum Pathol 1991; 22:12321239.
  16. Sneige N, Wang J, Baker BA, Krishnamurthy S, Middleton LP. Clinical, histopathologic, and biologic features of pleomorphic lobular (ductallobular) carcinoma in situ of the breast: a report of 24 cases. Mod Pathol 2002; 15:10441050.
  17. Telli ML, Horst KC, Guardino AE, Dirbas FM, Carlson RW. Phyllodes tumors of the breast: natural history, diagnosis, and treatment. J Natl Compr Canc Netw 2007; 5:324330.
  18. Reinfuss M, Mitus J, Duda K, Stelmach A, Rys J, Smolak K. The treatment and prognosis of patients with phyllodes tumor of the breast: an analysis of 170 cases. Cancer 1996; 77:910916.
  19. Kamal RM, Hamed ST, Salem DS. Classification of inflammatory breast disorders and step by step diagnosis. Breast J 2009; 15:367380.
  20. Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA. The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 1999; 64:963970.
  21. Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med 2003; 348:23392347.
  22. Clarke-Pearson DL. Clinical practice. Screening for ovarian cancer. N Engl J Med 2009; 361:170177.
  23. Hisada M, Garber JE, Fung CY, Fraumeni JF, Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 1998; 90:606611.
  24. Bell DW, Varley JM, Szydlo TE, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 1999; 286:25282531.
  25. Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007; 297:23602372.
  26. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:17131727.
  27. Hankinson SE, Colditz GA, Manson JE, et al. A prospective study of oral contraceptive use and risk of breast cancer (Nurses’ Health Study, United States). Cancer Causes Control 1997; 8:6572.
  28. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med 2002; 346:20252032.
  29. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321333.
  30. Anderson GL, Limacher M, Assaf AR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291:17011712.
  31. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 2007; 356:16701674.
  32. Fisher B, Anderson S, Redmond CK, Wolmark N, Wickerham DL, Cronin WM. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995; 333:14561461.
  33. Clarke M, Collins R, Darby S, et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366:20872106.
  34. Petrek JA, Senie RT, Peters M, Rosen PP. Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer 2001; 92:13681377.
  35. McLaughlin SA, Wright MJ, Morris KT, et al. Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements. J Clin Oncol 2008; 26:52135219.
  36. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:16871717.
  37. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351:28172826.
  38. Albain KS, Barlow WE, Shak S, et al; Breast Cancer Intergroup of North America. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol 2010; 11:5565.
  39. Harris JR, Halpin-Murphy P, McNeese M, Mendenhall NP, Morrow M, Robert NJ. Consensus Statement on postmastectomy radiation therapy. Int J Radiat Oncol Biol Phys 1999; 44:989990.
  40. Gennari A, Conte P, Rosso R, Orlandini C, Bruzzi P. Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies. Cancer 2005; 104:17421750.
  41. Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003; 21:21012109.
  42. Gamucci T, D’Ottavio AM, Magnolfi E, et al. Weekly epirubicin plus docetaxel as first-line treatment in metastatic breast cancer. Br J Cancer 2007; 97:10401045.
  43. Bonneterre J, Thürlimann B, Robertson JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 2000; 18:37483757.
  44. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 2000; 18:37583767.
  45. Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 1996; 335:17851791.
  46. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:16731684.
  47. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783792.
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Cleveland Clinic Journal of Medicine - 77(8)
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Cleveland Clinic Journal of Medicine - 77(8)
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