Left Mammogram MLO view. Arrow points to palpable area of irregular density and architectural distortion.

Invasive lobular carcinoma (ILC) can elude diagnosis due to its variable appearances.  Knowledge of its pathology explains why this tumor can grow under the radar of mammography and why recognizing the MRI pattern of lobular carcinoma requires special understanding.  This issue of  The WCC Note on invasive lobular carcinoma reviews its gross and microscopic features and summarizes recent literature profiling its genetics, molecular, and biobehavioral footprints.

What is the incidence of invasive lobular carcinoma (ILC)?

1. ILC represents between 5% and 15% of breast cancer, and often has accompanying in situ lesions.  The histology is diverse, ranging from the classical variety, which has a more favorable outcome, to solid, and to pleomorphic.  The majority are hormone receptor-positive.  HER2 gene overexpression is lower than in infiltrating carcinoma (IDC). (1)
2. Of the special types of breast cancer, ILC is the most frequent.  Most are histologically low-grade, express hormone receptors, and lack HER2 overexpression.  A variant of ILC is the pleomorphic variety which displays atypical cells with pleomorphic nuclei and is reported to display an aggressive clinical behavior. (2)
3. ILC was first described by Foot and Stewart in 1941, with subsequent subtypes described in the 1970s and 1980s, including alveolar, solid, pleomorphic, signet ring cell, histiocytoid, and apocrine. (3)
4. ILC carries distinct prognostic and biological implications compared to IDC. (4)
   a.   A review of 12,206 breast cancer patients from 15 international breast cancer study group trials
   performed  between 1978 and 2002 by the International Breast Cancer Study Group, revealed the following percentages: 70.5% IDC, 6.2% ILC, and 23.2% other.
   b.  The ILC patients were noted to be of an older age and have larger lesions, better differentiation, ER-positive  tumor association, and less vessel invasion.
   c.  The ILC cohort demonstrated a significant early advantage in disease-free survival and overall survival, followed by a significant late advantage for the IDC cohort.
   d.  ILC had association with increased incidence of bone events but decreased regional and lung events. (4)
5. According to The Centers for Disease Control and Prevention, the ILC incidence decreased 20% between 1999 and 2004.  The CDC Cancer Surveillance Branch reported that the decreased incidence coexisted with reduced use of combined hormone replacement therapy, though they noted that other factors could also be responsible. (5)

What is the gross anatomic appearance of invasive lobular carcinoma?

1. Roughly one-fourth show diffuse invasion without marked desmoplasia.
2. Most show irregular margins, appearing firm to hard.
3. A discrete mass may not be present; instead diffuse thickening may be the hallmark. (6)
4. Metastases of ILC differ from other breast cancers.  They preferentially involve the peritoneum, retroperitoneum, gastrointestinal tract, ovaries, uterus, and leptomeninges rather than the lungs and pleura. (6)

What is the microscopic appearance of invasive lobular carcinoma?

1. Single cells infiltrate and can do so in single file or in loose clusters or sheets.
2. Cells lack cohesion, not forming tubules or papillae.
3. Tumor cells often align in concentric rings around normal ducts.
4. Variants include those with large groups of cells and marked pleomorphism. (6)
5. A report published in Cancer of 530 patients with pure ILC showed:
   a.  57% classic, 19% alveolar, 11% solid, and 13% pleomorphic, signet ring cell, histiocytoid, or apocrine features.
   b.  Significant prognostic factors were noted to be size, nodal involvement, and hormone status, with “classic” type showing lower nodal involvement and lower grade, and “non-classic” types demonstrating an increased number of breast events, decreased disease-free survival, and overall survival. (3)
6. Nottingham grading of breast carcinoma is a subjective evaluation of three morphologic features: tubule formation, nuclear pleomorphism, and mitosis. (7)

What do we know about the genetics and molecular features of invasive lobular carcinoma?

1. Most ILCs demonstrate a regional loss on chromosome 16.
   a.  This area involves genes for cell adhesion such as e-cadherin and beta-catenin. (6)
2. Well-differentiated and moderately differentiated ILC:
   a.  Are usually doploid, have positive hormone receptors, and have associated lobular carcinoma in situ  (LCIS).
   b.  Rarely overexpress HER2/neu. (6)
3. Poorly-differentiated ILC are:
   a.  Usually aneuploid with negative hormone receptors.
   b.  May overexpress HER2/neu. (6)
4. The genetics basis of lobular and ductal carcinoma is noted to show a shared genetic abnormality and may share a common precursor lesion. (8)
5. The molecular framework of classic ILC and pleomorphic ILC were found to be remarkably similar in a study from the Netherlands Cancer Institute published in 2010.  The authors concluded that both pathologies should be considered as a part of a spectrum of lesions.  This Study also compared subtype matched ILC to IDC tumors, finding different expression of genes for cell adhesion, cell-to-cell signaling, and actin cyskeleton signaling. (2)
6. A common molecular genetic pathway between the pleomorphic and classic variants of ILC had also been reported by researchers from Brisbane, Australia. (9)

What updates have been reported about the biobehavior of ILC?

1. A 2009 study from Yale University reported their experience with early-stage ILC and IDC.  Patients underwent breast conservation treatment and were followed a median of 6.8 years.  A higher percentage of ILC patients presented at >40 years of age compared to IDC and had more mammographically occult tumors.  ILC patients had higher contralateral breast relapses (26% versus 12%).  At 10 years, no difference was noted in breast relapse nor distant relapse, nor cause-specific survival. (10)
2. Invasive lobular carcinoma has been reported as almost always ER-positive, and typically lower-grade than IDC.  It has been reported as showing a general decreased response to neoadjuvant chemotherapy compared to IDC but not to a survival disadvantage.  Authors from the Swiss Group of Clinical Cancer Research in Berne, Switzerland note that studies of adjuvant hormonal therapy do not generally distinguish between ILC and IDC. (11)

What do we know about mixed ILC and IDC?

1. In a study by the University of Nottingham, UK, mixed ductual and lobular breast carcinoma (compared to pure IDC) were reported as showing association with lower grade, ER positivity, and lower frequency of development of distant metastases. (12)
2. ILC and “mixed” carcinoma tends to be diagnosed in a more advanced stage but displays overall superior survival to IDC, according to authors from Washington University School of Medicine, ILC and mixed carcinoma are more likely to be low-grade, ER- positive, PR-positive but have overall    higher survival than those patients with IDC, despite being diagnosed at a more advanced stage. (13)

Conclusion: Classic invasive lobular carcinoma and its subtypes display a range of gross and microscopic diversity.  Cellular infiltration can be loose or single file and lack desmoplasia, potentially evading detection by mammography and physical exam. and influencing the MRI appearance.

Research and reporting by Margaret D. Phillips, M.D.
Reviewer and publisher:  Stephen J. Pomeranz, M.D.

For full sources and credit, please download the PDF copy of the newsletter here

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.