However, ultrasound is not a good test for screening the breasts – that is, if a healthy woman without any symptoms gets an ultrasound scan, it can be extremely difficult to find a small cancer.  In addition, ultrasound is a poor test in patients with very large or dense breasts, because the sound waves cannot pass through the excess fatty tissue.  Breast ultrasound is useful in evaluating masses that have already been seen on a mammogram or felt by a patient.

Evaluating a Known Mass
If a woman feels a lump in her breast but it can’t be seen on a mammogram, or if a mass is seen on a mammogram but it is uncertain whether it is benign or malignant (which is very common), an ultrasound can be done to evaluate it further.  In these situations, the ultrasound operator already knows the location of the mass and can do a dedicated ultrasound examination of that area to characterize it better.  This is useful because an ultrasound can show that a mass is definitely a benign growth, which would prevent the woman form having to get a biopsy.

The most common benign mass that can be confirmed on an ultrasound is a simple cyst – a small collection of fluid (see Figure 1).  Ultrasound is extremely accurate in identifying simple cysts, because it depends on the transmission of sound waves and simple fluid transmits sound waves very well.  As a result, a simple cyst will appear completely black on ultrasound; this black appearance is “anechoic,” meaning that the fluid produces no echoes, or does not make any of the sound waves bounce back, because the sound waves are transmitted through it so easily.

BIOPSIES: ULTRASOUND, STEREOTACTIC, AND MRI

A biopsy is a procedure where a small piece of a mass that is suspected to be cancer is removed from a patient using a needle, so that it can be examined under a microscope to see what it is.  Ultrasound is also very useful in helping physicians find the right place to insert the needle during a biopsy.  Because it is a “real-time” imaging exam, the images seen on the screen show exactly what is happening at the time the transducer is on the patient see Figure 2).  Thus, a physician can watch in real time as the needle goes through the patient’s skin and into a mass, to make sure it is going to the correct place.

Another method used for breast biopsy is stereotactic biopsy, which uses x-ray (or mammogram) guidance instead of ultrasound guidance.  Because x-rays cannot be done as real-time exams, in a stereotactic biopsy the physician (with the help of a computer program) figures out exactly where to place the needle based on x-rays taken prior to the biopsy.  After careful planning, a machine helps the physician place the needle in the center of the mass.  X-rays are taken again aftre the needle is placed, to confirm that it is in the correct position.

As we discussed in the last edition, a newer technique for breast biopsy is MRI-guided biopsy, which is used only for masses that cannot be seen on either a mammogram or ultrasound.

Given these facts, why doesn’t every woman get breast MRI for screening?  There are several reasons:

• Breast MRI is much more expensive and takes much longer than conventional x-ray mammography. While a mammogram can be completed in less than 15 minutes, a breast MRI usually takes about an hour.
• Because breast MRI is so sensitive, it often detects masses than are not cancerous, as does conventional mammography. This can lead to unnecessary biopsy – a procedure in which a needle is used to collect a piece of a mass to determine if it is cancerous.  One study showed that about 8% of women who get mammograms get biopsies.  Because of our readers’ experience, however, we have been able to decrease the biospy rate by 20% by using breast MRI.

How It’s Done
First, a set of MRI pictures of the breasts is taken.  Then a contrast agent is injected into the patient’s vein, and another set of pictures of the breasts is taken.  The first set of images is subtracted from the contrast-enhanced images, creating a set of pictures (“subtraction images”) that accentuate the areas that take up more of the contrast solution.

This helps the radiologist distinguish tumors from normal breast tissue, because contrast is carried to the tissue by blood vessels.  This means that the amount of contrast that appears in a tissue or tumor is dependent on its vascularity.  In a malignant tumor, the blood vessels are more numerous, more tortuous, and are dysplastic with leaky membranes.  For this reason, flow and perfusion to a cancer is higher than normal tissue, and the leakage of contrast into the cancer is faster.  This allows a radiologist to analyze the perfusion curve of a mass, to determine whether it is malignant.

INDICATIONS FOR BREAST MRI

• Screening women at high risk for breast cancer (because of family history or genetic abnormality)
• Screening women with a previous history of breast cancer
• Looking for other sites of cancer in the same breast and other breast in women with known breast cancer
• Monitoring cancer’s response to treatment
• Clarifying indeterminate results of mammogram or ultrasound

RESEARCH USES OF BREAST MRI

• Measurement of tumor angiogenesis (new vessel production)
• Monitoring chemotherapy response
• Tumor volume and multiplicity
• Oxygen consumption of tumor
• Diffusion characteristics of tumor
• Tumor permeability for chemotherapy delivery
• Tumor elasticity
• Tumor chemistry (choline content)

How the Images are Made
The x-rays used to create mammograms are essentially the same as the ones to make an x-ray of the chest or hand; dense structures (like fat) appear as black.  Low-energy x-rays are used to create mammograms, so that soft tissues (such as masses) are whiter and thus easier to see.  Calcifications are a bright white, soft tissues (breast glands and masses) are a softer white, and breast fat is black.

When we search for a tumor on a mammogram, we are looking for a soft-tissue mass, which will appear white.  This can be difficult to distinguish from normal glandular tissue, which also appears white – particularly in patients with “dense” breasts that contain a lot of glands (especially Asian, younger, or smaller-breasted women).

Mammographers use the characteristics of a mass to determine whether it looks benign or malignant, and they give it a rating on the BI-RADS (Breast Imaging Reporting and Data System) scale (see below).  An indirect sign of a malignant breast mass is a focal area of tiny calcifications, or microcalcifications, which the mammographer can see using magnifying glasses.

MAMMOGRAPHY’S MOST COMMON USES

Screening Mammograms.  A mammogram is the standard screening test for breast cancer today.  A “screening” exam is a test used for routine check-ups, to make sure that presumably healthy people do not have a specific disease.  Other examples of screening tests are colonoscopies to evaluate for colon cancer, or yearly blood tests to evaluate men for prostate cancer.  These tests are performed on all people within a certain age group to evaluate for common diseases, so that they can be recognized and treated early.

Since breast cancer is relatively common, potentially deadly, and treatable, screening for this disease is very important.  A screening mammogram consists of two standard views: craniocaudal (CC), in which the breast is compressed from top to bottom, and mediolateral oblique (MLO), in which the breast is compressed from side to side.  Although mammograms often detect masses that are not cancerous and often miss small cancers, they are currently the best test that we have for screening women at low to average risk for cancer.

Diagnostic Mammograms. Once a mass is found on a screening mammogram, the patient will often return to have a diagnostic mammogram, which consists of specialized, close-up views of the mass with extra compression.  This will help the mammographer better characterize the mass as either benign or malignant.

Ultrasonography has many medical applications in which a machine is used to create these high-frequency sound waves.  The machine has a hand-held wand (or transducer), which is placed directly on the patient’s skin.  The sound waves emanate from the face of the transducer, which is a few inches long, relatively thin, and shaped like an electric shaver.

The sound waves are transmitted through the patient’s body, so the area that is imaged consists of the skin under the transducer and everything below it.  In other words, when you place the transducer on the patient, the image shown on the screen will be a “slice” of the body below the spot where you place it.

How the Images Are Made
Depending on the ability of the tissue to transmit sound, the sound wave will either penetrate through the tissue or bounce back and hit the transducer.  A substance such as water is a very good transmitter of sound; as a result, when ultrasound waves are aimed at water, very little bounces back.  Substances such as fat, air and bone do not transmit sound well, however, so the waves bounce back to the transducer.

The ultrasound machine then records the sound waves that return to the transducer.  It can calculate from where the waves are coming, based on the frequency of the sound.  The machine then creates a grayscale “map” of the information it receives.  Areas from which a lot of sound bounces back appear white (such as fat, bone, or air); areas with not sound return (such as water) appear black.  A liquefied gel is always placed between the transducer and the patient’s skin to eliminate any air between them.

SOME PROS AND CONS OF ULTRASOUND

Advantages

• Cheap
• Fast
• “Real-time” imaging allows examiner to see motion of tissues*
• No radiation (as a result, used often in children)**
• Can distinguish simple cysts from masses reliably
• “Real-time” imaging useful to guide biopsies****
• Can evaluate blood flow

Disadvantages

• Quality of images depends on expertise of operator
• Anatomic detail is poor because of low resolution
• Cannot evaluate bone, lungs, or bowel***
• Images are poor in obese patients***
• Images are poor when air or gas is present
• Small field of view

* Ultrasound images are extremely easy and fast to create; as a result, ultrasound is a “real-time” exam.  In other words, when the transducer is placed on the skin, the image of the tissues below it appears almost immediately on the ultrasound screen.  This allows the examiner to move the wand back and forth to see the actual movement of tissues in the body as it happens.
** There is absolutely no ionizing radiation associated with ultrasound.  The only documented potential adverse effect is that, when used for long periods of time at high intensities, it can cause slight heating of the tissues.
*** Ultrasound cannot be used to evaluate hard structures, such as bone and metal, or structures with a lot of air, such as the lungs or bowel.  Sound waves cannot transmit through these tissues, so they will bounce right off the surface.  On the ultrasound image, this appears as a rim of white (the surface off which the ultrasound bounced) and then pure blackness behind it (an area that the sound waves cannot reach), an effect termed “shadowing.”  In addition, because fat is a poor transmitter of sound, patients with a lot of subcutaneous fat tissue are difficult to image with ultrasound.
****”Doppler ultrasound” can be used to evaluate flow in blood vessels, as well as blood flow in solid organs or masses.

ULTRASOUND’S MOST COMMON USES

Head and Neck:

• The brain, in newborn infants (the fontanelle is used as an opening to see through)
• The thyroid gland

Chest:

• The motion of the heart (echocardiography) – this can be done through the skin (conventional) or through the esophagus (transesophageal)
• Masses in the breast previously seen on mammography or felt by patient or doctor

Abdomen/Pelvis:

• The uterus and ovaries – the transducer can be placed on the skin (transabdominal) or in the vagina (transvaginal)
• Fetuses – good because there is no radiation and the imager can see motion
• The solid abdominal organs (liver, spleen, pancreas), for masses or biliary dilation
  (Note: the pancreas is often difficult to see because of overlying bowel gas)
• The gall bladder, for stones and inflammation
• The kidneys, for mass or hydronephrosis
• The appendix, for inflammation (usually in children)
• The prostate gland (transrectal ultrasound, with the transducer placed in the rectum)

Other Uses:

• The testicles
• Lymph nodes
• Masses anywhere in the body, to determine if they are simple cysts
• Arteries and veins (to look for thrombosis, atherosclerosis, or aneurysm)
• To guide biopsies in any of the above places

More Advanced Uses

• Intravenous ultrasound – to evaluate the inside of blood vessels
• Ultrasound therapy – powerful ultrasound produces heating, which is often used in physical therapy
• Focused ultrasound surgery – for treatment of some tumors, such as uterine fibroids

HOW IS RADIATION MEASURED?

Many units are used to measure radiation dosage.  The unite used in the measurements below is called the “sievert,” a measure of the amount of radiation absorbed by the human body.

Effective Radiation Dosage (in MilliSieverts):
Average background dose in the U.S. . . . . . . . . . 3.6 mSv/year
Three-hour commercial airline flight. . . . . . . . . . 0.015 mSv
Chest X-ray (two views). . . . . . . . . . . . . . . . . . . . . 0.05 mSv
Head CT scan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-2 mSv
Chest CT scan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-7 mSv
Abdomen and pelvis CT scan. . . . . . . . . . . . . . . . . 6-8 mSv
Selective diagnostic coronary angiography. . . . 3-6 mSv
Coronary CT angiography. . . . . . . . . . . . . . . . . . . 8-13 mSv

SOME RADIATION RISK FACTORS

Although exact risk levels from radiation in diagnostic imaging are difficult to quantify, we now know that the impact of radiation on a live subject or patient depends on many factors, including:

• Patient age
  - The younger the subject, the greater the risk to an exposed cell
• The organ affected
  - The ovaries and eyes, for example, are very radiation-sensitive, while the heart and brain are very radiation-resistant
• The body region imaged
  - A CT scan of the pelvis causes more damaging radiation than a CT scan of the head, because the pelvis contains many radiation-sensitive organs
• Cumulative dose
  - A certain amount of radiation delivered all at once (an acute dose) is more damaging than spreading that radiation out over a longer time
  - Even if small doses of radiation are delivered at different times (such as two abdominal x-rays done a week apart), the dose accumulates to cause an increased risk of adverse effects
  - Less radiation is ALWAYS better
• A patient’s genetically inherent resistance to radiation

WorldCare Clinical (WCC) is launching this new electronic publication with one key goal in mind: to educate, inform, and support our colleagues in the clinical research and pharmaceutical/medical device fields about advanced medical imaging.  The WCC Note is intended for anyone interested in medical research, research procurement, or clinical trial management.  Each week, we’ll bring you relevant, useful information distilled down to its basic concepts.  In doing so, we hope to:

• Help raise the bar for patient care and clinical research;
• Offer advice on how to harmonize your approach to using imaging technology;
• Present new ways to navigate the drug or device development pathway more efficiently; and
• Educate non-medical professionals about diagnostic imaging equipment, capabilities, and new developments.

For the next several issues, we’ll present a series on the basics of each modality used in clinical trial imaging, including conventional x-ray radiography, computed tomography (CT), ultrasound, magnetic resonance imaging (MRI), and nuclear medicine.  We’ll also examine the scientific basis for each modality, as well as its clinical applications, strengths, and weaknesses.  We hope you enjoy this first post and we look forward to your comments, questions, and suggestions.
- Stephen J. Pomeranz, M.D., and Resham R. Mendi, M.D.

RADIOLOGY: THE BASIC MODALITIES

Part One: X-Ray Radiography
How it works. X-rays are high-energy photons, which are created by an electric current within a cathode ray tube.  The x-ray is aimed at a patient’s body of interest, with a film plate positioned behind the body part (see diagram at left).  Body parts that are dense, like bone, do not allow the photos to pass through.  Less dense tissues, such as muscle fat, and air, allows the x-rays to pass through and hit the radiographic plate.

The x-rays then produce a chemical reaction in the film, causing it to be exposed.  When the film is developed, the exposed areas turn black (fat) and the non-exposed areas turn white (bone).  The entire image then becomes a reflection of tissue density: high-density tissues are white, intermediate tissue densities are gray, and low-density tissues show up as black.

Common Clinical Indications for X-rays

• Evaluation of bones for fracture, dislocation, arthritis, etc.
• Evaluation for foreign bodies
• Gross evaluation of lungs for pneumonia, large mass, pneumothorax, or pulmonary edema
• Evaluation of heart size
• Evaluation of bowel gas pattern for free air, ileus, or bowel obstruction

SOME PROS AND CONS OF X-RAYS

Advantages

• Fast
• Cheap
• Quick
• Easy to Perform
• Sensitive to detecting calcium, cortical bone, air, gas, and metal
• Produces few artifacts: flaws in the image that may lead to misinterpretation

Disadvantages

• Exposes subjects to radiation, which can cause cumulative damage
• Insensitive to soft-tissue abnormalities involving muscles, masses, blood, water, solid tumors, etc.
• Changes in patient positioning by the technologist can lead to moderate image-quality variability
• Analog technology makes digital image transfer more challenging