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INFILTRATING LOBULAR CARCINOMA, PART 2: MRI Morphology and Kinetics – Vol. 4, Number 3 – March 31, 2010

Wednesday, March 31st, 2010

A sinister and stealthy marauder, infiltrating lobular carcinoma (ILC) can potentially elude detection due to its pathologic appearance.  As reviewed in the last issue of THE WCC Note, the shape of ILC at pathology varies.  It ranges from tumors with irregular margins; to those displaying diffuse invasion with cells infiltrating single file or loosely associated; to variants with large groups of cells.  The particular pattern influences the MRI appearance of ILC; infiltrating lobular carcinoma may look mass like and possibly explosive, but can look crawling and very subtle.  Understanding this spectrum can help keep ILC from avoiding discovery.

What are the MRI appearances of infiltrating lobular carcinoma?

In our experience, ILC has presented on breast MRI as:

1. An irregular mass or masses with early intense enhancement, often followed by plateau kinetic

2. An irregular mass or masses with lower grade early enhancement followed by progressive/persistent enhancement over time

3. Nonmass type lesion(s) with lower grade early enhancement followed by progressive/persistent enhancement over time

4. Very rarely as an irregular mass with a nearly avascular appearance

The following image sets portray representative examples of ILC, shown with their mammogram and ultrasound, if performed.

Case 1

What MRI enhancement kinetics can occur with infiltrating lobular carcinoma?

To review, in our experience ILC has demonstrated a gamut of kinetics. While the enhancement may appear intense on the early post contrast data sets, some ILC tumors show low grade early enhancement that peaks later and therefore becomes more conspicuous on the later p0st contrast images. The delayed orthogonal plane images may be of particular help in that setting. We have seen the kinetics to be:

1. Early intense, often with plateau over time

2. Early low grade intensity with persistent/progressive increase over time

3. Hypovascular (very rare)

Lopez and Basset summarize the kinetics as tending to show delayed maximal enhancement with washout in only a minority. (1, 2)

What do other authors report as MRI patterns of ILC?

1. Authors report ILC presents on MRI as (1, 2, 3, 4, 5):

a. A solitary irregular or angular mass with spiculated or ill-defined margins, most frequently,

b. A dominant lesion with surrounding multiple enhancing foci,

c. Multiple small enhancing foci with interconnecting enhancing strands or non contiguous clusters,

d. Regional enhancement and architectural distortion,

e. Regional, focal, or multifocal heterogeneous enhancement,

f. Enhancing depta without dominant tumor focus,

g. And with normal findings.

2. Levrini et al from Emilia, Italy (6) reported 21 patients with ILC. They reported the MRI appearances as:

a. Solitary mass with irregular margins (n=8);

b. Mass with smooth margins (n=5);

c. Multiple small enhancing foci with interconnecting enhancing strands (n=4);

d. Dominant lesion surrounded by small foci (n=3)

e. One MR examination was negative.

What are the mammogram appearances of ILC?

1. According to a 2009 review of ILC in Radiographics, Lopez and Bassett report:

a. ILC typically presents as a mass with an opacity that equals or is less than normal fibroglandular tissue. (1)

b. It is commonly not seen on either the craniocaudal view (CC) or mediolateral oblique (MLO), though it is seen more often on the CC than the MLO.

c. The authors summarize the literature regarding the mammographic sensitivity of ILC detection, noting it to be from 57% to 81%, with higher false-negative rates than other invasive cancers due to the difficulty of its mammographic detection.

d. ILC is often a mass with spiculated or ill-defined margines. Rarely, it can present as a round and circumscribed mass.

e. Microcalcifications associated with ILC much less frequently than with invasive ductal carcinoma.

2. A retrospective review of 59 ILC and 59 infiltrating ductal carcinoma (IDC) mammograms in the United Kingdom found:

a. ILC appeared significantly different on the MLO compared to the CC view, while IDC did not.

b. ILC and IDC appeared as spiculated masses more often on the CC than the MLO view.

c. On the MLO view, 41% of ILC appeared as architectural distortions or asymmetric densitites.

d. ILC was often associated with the main glandular density (97%) rather than being isolated (3%)

e. The CC view was optimal for visualizing ILC as a spiculated mass.

f.  Since ILC is often with the main glandular density, optimizing its visualization is critical. (7)

3. A study of 94 ILC lesions on mammography found:

a. 60% masses, of which 71% were irregular and spiculated, 21% were asymmetric densities or calcifications (8)

4. In a 1992 report of 455 pure ILC cases, they showed the following features:

a. Spiculated 28%

b. Architectural distortion 18%

c. Round 1%

d. Microcalcification 24%

e. Skin retraction 25%

f. Nipple retraction 26%

g. Malignancy not diagnosed 57% (9)

What is the sensitivity of imaging to detect ILC?

1. A retrospective study of ILC in 26 women wiht 28 biopsy proven invasive lobular carcinomas yielded the following sensitivities: mammography 79%, sonography 68%, MRI 83%, (12 patients had an MRI exam), and breast-specific gamma imaging (BSGI) 93% (10)

2. The sensitivity of BSGI was 79% for ILC according to the Department of Nuclear Medicine at the Mayo Clinic. (11)

3. MRI was reported as more accurate for ILC tumor size than mammography (12) and can decrease the surgical re-excision rate without increasing the rate of mastectomies, according to authors from The Netherlands. (13)

Conclusion: ILC often appears on MRI as an irregular/spiculated mass or masses, often with plateau kinetic but enhancement can be low grade persistent or, very rarely, negligible. Other patterns include multiple enhancing foci that may have interconnecting strands; nonmass type enhancement; and, reportedly, masses with smoother margins. Careful correlation of the MRI with the mammogram, ultrasound, and any physical exam area of suspicion helps avoid overlooking lesions with subtle to negligible increased vascularity.

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INVASIVE LOBULAR BREAST CARCINOMA: Pathology and genetics reflected by MRI – Vol. 4, Number 2 – March 4, 2010

Thursday, March 4th, 2010

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

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

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Posted in Cancer, Oncology, Women's Health | 2 Comments »

fMRI: Speech, Imaging Angiogenesis, and MRI: Leukemia – Vol. 2, Number 27

Wednesday, December 3rd, 2008

fMRI: SPEECH

Speech Content and Speaker Identification Reflected in Functional Brain MR Images
Attempts to create machines capabile of recognizing human speech commenced in the 1950s, yet the human brain’s ability to understand speech and identify its speaker has proved a profoundly complex and nuanced higher-order function, difficult to mechanically replicate.  Untangling the threads of this intricate process has progressed recently, as researchers examined listeners’ brain auditory cortexes and used neural “fingerprints” to decipher what, and to whom, the subjects were listening.  Researchers from the University of Maastricht, Netherlands, used imaging combined with multivariate statistical pattern recognition of speech sounds to examine the brains’ receptive speech pathways.  Initially, seven participants listened to the speech sounds of three Dutch vowels from three Dutch speakers.  The distinct brain activation patterns underwent scrutiny with high-resolution functional MR imaging (fMRI), the sounds evoking responses in the superior temporal cortexes of the subjects.  As reported in Science, the researchers subsequently expanded on their work by using functional MRI brain images and their response patterns to decode sounds and their speakers.

Conclusion:  Early work by Dutch researchers has deciphered speech content and speaker identification using functional MRI imaging.

IMAGING ANGIOGENESIS

Imaging the Many Faces of Tumor Angiogenesis
The National Cancer Institute describes tumor angiogenesis as a proliferating blood vessel network that penetrates malignant tumors to provide oxygen and nutrients and remove wastes.  Creation of this neovascularity requires molecules released from the tumor cells, and without these molecular signals and their resultant new vessel formation, the cancers cannot progress.

These molecular investigators cause a cascade of events, initially activating host tissue genes that subsequently incite proteins to be produced, which then initiate the new vessels to grow.  The presence of this increased blood flow produces a local environmental change that can be perceived by dynamic contrast-enhanced imaging.

Conclusion:  In this and upcoming issues of The WCC Note, studies will be profiled to illustrate examples in which current and developing imaging techniques capture and exploit angiogenesis, a fundamental biological feature of cancer.

MRI: LEUKEMIA

MRI of Angiogenesis in Leukemia Portends Decreased Chemotherapy Response
A cancer of the blood cells, leukemia strikes blood-forming tissue such as bone marrow, sending an abnormal number of cells into the blood stream.  In the United States, an estimated 44,270 new cases will be diagnosed in 2008.

A recent study in the journal Blood examined dynamic contrast MRI in patients with acute myeloid leukemia (AML) and correlated it with their outcomes.  The authors, from National Taiwan University Hospital in Taipei, prospectively imaged 78 patients with AML at diagnosis and after induction chemotherapy.  Bone-marrow angiogenesis assessment consisted of three factors: peak enhancement ratio (reflecting tissue perfusion), amplitude (denoting vascularity), and volume transfer constant (indicative of vascular permeability).

The results showed peak and amplitude findings decreased significantly with remission.  Those individuals presenting with higher peak or amplitude values exhibited shorter disease-free and overall survival.  Along with old age and unfavorable karyotype, higher peak value at diagnosis independently predicted overall survival.

Conclusion:  Authors reporting a study in Blood showed that heightened bone-marrow angiogenesis on MRI in leukemia patients predicted adverse outcomes.  They suggest the information may help profile which individuals could benefit from anti-angiogenic therapy.

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Real-Time Imaging, MRI & CT Photography, and MRI: Accurate Temperature – Vol. 2, Number 26

Tuesday, November 11th, 2008

REAL-TIME IMAGING

Dynamic Imaging of Cells Accompanying Cancer Achieved in Mice
Neoplasms contain a microenvironment of multiple other cell types that exist alongside the carcinoma cells.  Termed stromal cells, they include such cells as fibroblasts, lymphocytes, dendritic cells, and macrophages.  These elements combine with extracellular factors, such as growth factor collagen, and oxygen, to form a milieu that evolves along with the carcinoma cells and influences tumor growth.  A recent study sought to image and assess these parallel elements, with the authors developing and using multicolor imaging techniques within a live mouse.  As published in Disease Models & Mechanisms and reported in Science, the authors described designing a spinning disk confocal microscope that achieved image acquisition times of 17 and 33 milliseconds for 512 x 512 and 1024 x 1024 pixel images, respectively.  Led by researchers from the University of California, San Francisco, the study typically collected 32,400 images in a 12-hour period, then documented the location and movement of stromal cells and oxygen’s effect upon them.

Conclusion:  A novel in vivo imaging technique affords high-resolution, four-color, prolonged, real-time imaging of cells that accompany cancer.

MRI & CT PHOTOGRAPHY

Radiologist Wins Lennart Nilsson Award for Scientific PhotographyChimp-3d-photo
The journal Nature recently reported that radiologist Anders Persson of Sweden has won the Lennart Nilsson Award for scientific photography, citing his stunning computer-enhanced 3D images made using new techniques in MRI and CT.  Der. Persson was quoted as saying that technical research should benefit the patient, and that he wanted to show precise and colorful details to achieve that end.  He discussed the utility of imaging in forensic medicine, including the performance of virtual autopsies.  Such post-mortem exams can allow discovery of facts not appreciable in conventional autopsies, such as gas in wounds or small metal particles under the skin.  Persson is currently working on several new facets of medical imaging, including multi-energy CT to visualize the body’s chemical constitution.

Conclusion:  The Lennart Nilsson Award for scientific photography has been awarded to Swedish radiologist Anders Persson.

MRI: ACCURATE TEMPERATURE

MRI Pulsing Sequences Yield Accurate Temperature Imaging
Temperature plays an integral role in medicine.  Its change can reflect metabolism, immune function, and cancer.  For example, digital infared thermal imaging for breast cancer detection was recently reported to show high sensitivity and negative predictive value, depending on the method used.  The current and developing arsenal of various disease therapies includes hyperthermic treatments and thermally sensitive agents that can selectively release drugs based on heat range.  Noting that temperature is a fundamental quality of matter that proves extremely difficult to measure noninvasively below an object’s surface, researchers sought to image it in a broad range of environments with magnetic resonance.  As reported recently in Science, researchers at Princeton and Duke Universities have reported accurate temperature imaging with MRI, using a new pulsing method, and obtained in vivo mouse images.

Conclusion:  Newly developed MRI pulsing sequences can achieve rapid and accurate internal temperature images.

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MRI: Brain & Contrast and Cardiac CT – Vol. 2, Number 22

Thursday, September 4th, 2008

MRI: BRAIN

Imaging Reveals Astrocytes Can Respond to Visual Stimuli
Neurons are known as the principal functioning cells in the brain, receiving, storing, and transmitting information.  Higher-order functions such as sight, therefore, rely on neurons.  The brain’s star-shaped astrocyte cells are thought to perform functions for neurons, metabolically buffering, detoxifying, supplying nutrients, and electrically insulating them.  Astrocytes also contribute to brain barriers and play a principal role in brain repair and brain scar formation.  Until now, the ability to see had not been a role ascribed (in part) to astrocytes.  Yet researchers at the Massachusetts Institute of Technology recently documented that astrocytes do indeed respond to visual stimuli.  The authors used two-photon imaging of calcium signals in vivo, employing a ferret visual cortex model.  As reported in Science, astrocytes displayed distinct spatial receptive fields, as well as orientation and spatial associations.  The finding suggests the role of both neurons and astrocytes in vision.  This holds implications for non-invasive imaging techniques that study brain activity, such as functional MRI.

Conclusion:  Imaging shows that astrocytes join neurons as cells known to respond to visual stimuli.

MRI: CONTRAST

Alternative MRI Contrast Agent Can Deliver Therapeutic Drugs
Gadolinium has dominated the MRI contrast market since it was approved for human use 20 years ago.  More than 85 million doese had been administered by 2007, about 5 million annually.  A recent study in the Journal of the American Chemical Society reports the creation of a novel MRI contrast agent that is not gadolinium-based, but rather manganese-labeled, toroidal (doughnut-shaped) nanoparticles.  This new molecular agent can target fibrin, a constituent of a clot.  The authors, from Washington University School of Medicine, Philips HealthCare, and St. Thomas Hospital (London), state that the agent can also incorporate chemotherapeutic compounds, raising the possibility of its exhibiting both diagnostic and therapeutic utilities.

Conclusion:  A novel MRI contrast agent can not only target the fibrin in thrombus, but also deliver therapeutic compounds.

CARDIAC CT

Pericardial Fat Is Related to Calcified Coronary Artery Plaque
The U.S. Centers for Disease Control (CDC) report that an estimated 66 percent of U.S. adults and 17 percent of children and adolscents are overweight.  Inflammatory cytokines exist at higher levels in pericardial fat than in subcutaneous fat.  To assess whether pericardial fat is associated with calcified coronary artery plaque, researchers for the Multiethnic Study of Atherosclerosis examined the volume of pericardial fat on cardiac CT in 159 patients in Forsythe County, NC, and evaluated for calcified coronary artery plaque.  As reported in the research journal Obesity, pericardial fat proved significantly associated with calcified coronary artery plaque, even when adjusting for other cardiovascular risk factors, and was independent of gender and ethnicity.

Conclusion:  Pericardial fat is associated with calcified coronary artery plaque, independent of gender and ethnicity.

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