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Archive for the ‘Cancer’ Category

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.

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 | No Comments »

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 | 5 Comments »

fMRI: Brain, Imaging Angiogenesis, and Nano-Particles/Cancer – Vol. 2, Number 28

Thursday, December 11th, 2008

fMRI: BRAIN

MRI Helps Translate Thought Into Sound for Man with “Locked-In Syndrome”
When Jean-Dominique Bauby wrote his stunning and transcendent memoir, The Diving Bell and the Butterfly, he communicated it letter by letter by blinking his left eye.  Bauby suffered from “locked-in syndrome,” a rare neurological disorder that paralyzes all voluntary muscles except those controlling eye movements.

For such patients, no means of communication exist except nonvocal ones.  However, a recent article describes an advance which could someday allow these individuals to communicate through sound instead of gestures.  Naturenews reports a study that used an implanted brain electrode to permit a man with locked-in syndrome to create vowel sounds, after using functional brain MRI to assess his speech.

Scientists from Boston University placed the electrode in the speech area of the man’s brain and a computer decoded the brain signals.  The electrode activated a speech synthesizer that accurately replicated three vowel sounds.  As reported at the Society for Neuroscience’s annual meeting in November 2008, the team will subsequently work on computer decoding of consonants to allow the creation of complete words.  Naturenews notes that functional MRI or electrodes placed on the skull could also be used to decode brain speech.

Conclusion:  A man with locked-in syndrome was able to create audible vowel sounds using an implanted brain electrode and speech synthesizer, after having his thoughts analyzed by functional MRI.

IMAGING ANGIOGENESIS

Exploiting Novel Molecules That Create and Comprise Cancer Vessels
The new blood vessels that grow and sustain cancer originate when stimulated to occur by molecules released from cancer cells.  These molecular activators of angiogenesis include a host of proteins and small molecules.  The study of these factors may bring to fruition new and robust imaging for tumor detection and surveillance, as well as innovative therapeutic modalities for tumor cure.  The two molecules thought to be the most important sustainers of tumor growth are vascular endothelial factor (VEGF) and basic fibroblast growth factor (bFGF).  Other activators of angiogenesis include prostaglandins E1 and E2, nicotinamide, and interleukin 8, among others.  The resultant new tumor vessels display their own molecules, providing more investigative avenues to target.  The following article highlights one recent attempt to exploit these molecular features of cancer.

NANO-PARTICLES/CANCER

Imaged Nanoparticles Target Cancer Vessels and Decrease Tumor Size
Integrin ανβ3 comprises one factor found on some tumor vascularity.  Researchers at University of California, San Diego created a nanoparticle targeted at integrin that was linked with the chemotherapeutic agent doxorubicin.  The authors made it fluorescent and injected it into a live mouse pancreatic cancer model.  As reported in Proceedings of the National Academy of Science, the authors noted modest decreased primary tumor growth, but significant reduction in the draining lymph-node metastases.  Featured in Naturenews, the study also reported that the treatment reduced metastases in a mouse kidney cancer model.

Conclusion:  Fluorescent nanoparticles, linked with a chemotherapeutic agent, that were targeted at molecules found exclusively on new vessels have been reported to decrease metastases in mice pancreatic and kidney cancers.

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MRI: Lymphoma, Cardiac & Lead Exposure – Vol. 2, Number 20

Friday, August 1st, 2008

MRI: LYMPHOMA

Imaging of pH Change in Cancer Accomplished in Mice
A change in the acid/base milieu accompanies a variety of pathologic conditions, including cancer, ischemia, and inflammation.  Cancer commonly has an acidic pH and will turn bicarbonate into carbon dioxide.  By harnessing this reaction, lead researchers at Cambridge Research Institute and University of Cambridge accomplished in vivo imaging of the pH alteration in lymphoma.  In a study published in the June 12 issue of Nature, the authors report that they were able to create nontoxic, labeled bicarbonate by utilizing dynamic nuclear polarization (DNP).  The ratio of signal intensities in hyperpolarized bicarbonate into mice with subcutaneous lymphoma revealed that the average interstitial pH in the lymphoma was significantly lower than in the surrounding tissue.  The authors present MRI images of this signal difference.

Conclusion:  In vivo imaging of pH alteration in lymphoma has been achieved in a mouse model using labeled bicarbonate.

MRI: CARDIAC

Late MRI Gadolinium Enhancement Portends Higher Risk of Cardiac Event in Patients with Nonischemic Cardiomyophathy
Patients with nonischemic cardiomyophathy (NICM) underwent gadolinium-enhanced cardiovascular MRI to assess whether the presence and extent of late enhancement correlated with adverse outcomes.  As published in the Journal of the American College of Cardiology, authors from John Hopkins prospectively assessed 65 NICM patients with left ventricular ejection fractions of less than 35%.  The cohort had the MRI examinations prior to receiving implantable cardioverter-defibrillators (ICD).  The results showed that 42% of the group had late gadolinium enhancement.  Of these, 44% had either hospitalization for heart failure, appropriate ICD firing, or cardiac death, compared to 8% of those patients who did not have late enhancement.

Conclusion:  Late gadolinium enhancement correlates with increased risk of cardiac events in patients with nonischemic cardiomyopathy.

MRI: LEAD EXPOSURE

Childhood Lead Exposure Associated with Decreased Brain Volume in Adults
The Centers for Disease Control (CDC) report that approximately 310,000 U.S. children between the ages of one and five have current elevated blood levels greater than the level at which action is recommended – 10 micrograms of lead per deciliter of blood.  Lead causes a variety of toxicities, central nervous system injury being dominant among them.

A recent study led by researchers at Cincinnati Children’s Hospital examined young adults who had experienced elevated childhood lead levels and enrolled in a long-term follow-up study.  The cohort had detailed pre- and postnatal low to moderate lead exposure, with behavioral outcomes monitored over 25 years.  The group underwent whole-brain, high-resolution MRI imaging with assessment of global and regional brain changes using voxel-based morphometry.

The results showed significant reductions in gray-matter volume for several cortical regions in individuals with higher mean childhood lead levels.  As published online at PLoS Medicine, the greatest areas affected included the frontal gray matter, specifically the anterior cingulate cortex.  The lead-associated brain volume loss proved much larger in men than women.  Fine-motor scores correlated positively with the gray-matter volume.

Conclusion:  Childhood lead toxicity is associated with region-specific diminished adult brain volume in areas responsible for mood and decision making, and adversely affects males more than females.

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CCTA and MRI: Fibromyalgia & Pancreatic Cancer
Vol. 2, Number 18

Tuesday, July 8th, 2008

MRI: FIBROMYALGIA

Fibromyalgia Patients Demonstrate Different Brain Metabolite Levels on Proton MR Spectroscopy
A study from the University of Michigan investigated brain metabolite differences between people with fibromyalgia (FM) and healthy controls (HC).  The authors sought to test the hypothesis that the broad pain sensitivity experienced by fibromyalgia patients related to a central nervous system processing problem, which would therefore display metabolic alteration in those brain areas involved in processing pain.  Published in the American Journal of Neuroradiology in May 2008, the study examined 21 patients with FM and 27 controls.

Conventional MR was supplemented with 2D-chemical shift imaging (CSI) MR-spectroscopy.  The spectroscopy centered at the basal ganglia and supraventricular white matter.  Within these regions, the study interrogated the spectrographic features of smaller areas implicated in pain processing.  The authors calculated the N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, and NAA/Cho ratios for each voxel.  They also performed clinical and experimental pain assessments on all the subjects.  The Cho/Cr variability in the right dorsolateral prefrontal cortex proved significantly different in patients with fibromyalgia as compared to controls.  NAA/Cho ratios in the left insula and left basal ganglia showed significant correlations with evoked pain threshold.

Conclusion:  Patients with fibromyalgia demonstrate baseline brain metabolite variability differences compared to health controls.  Those with fibromyalgia also show significant correlation between metabolite ratios and pain parameters.

MRI: PANCREATIC CANCER

Targeted Nanoparticles Image Small Pancreatic Cancers and Cancer Precursor Lesions in Mice
Pancreatic cancer typically eludes detection until the tumor ha reached an incurable state.  In an effort to discover small cancers and precursor lesions that may be curable, researchers at the Massachusetts General Hospital and Dana Farber Cancer Institute developed a novel imaging approach.  The technique exploits the cancer cells’ mutations, which cause different cell-surface proteins to be present than in normal cells.  After detecting several peptides bound to the outside of pancreatic cancer cells but absent on normal cells, an imaging probe was created to make use of this difference.

As reported online in April 2008 by the Public Library of Science, the researchers next found a virus phage clone that bound to these mouse tumor cell peptides.  To accomplish imaging the lesions, the investigators then linked the phages to nanoparticles that had both magnetic and fluorescent properties.  Using mouse models, the nanoparticles allowed detection of small pancreatic ductal carcinomas and precursor lesions.

Conclusion:  The imaging of small and precursor pancreatic adenocarcinomas in mice was accomplished by using nanoparticles linked to viral phages which, in turn, bind to pancreatic carcinoma sell surface peptides.  If the approach can be successfully translated for use in humans, some tumors heretofore typically diagnosed when already incurable could be discovered earlier.

CCTA

Dual-Source Coronary Artery CT Angiography Promising for Atrial Fibrillation Patients
Currently, coronary artery computed tomographic angiography (CCTA) technique relies on imaging the vasculature in the setting of a slow heart rate with regular rhythm.  When tachycardia or irregular beats occur during imaging, image blurring may preclude a diagnostic evaluation of the coronary arteries.  Patients with atrial fibrillation are therefore contraindicated, because faster scanner times than those available with 64-slice, multi-detector scanners would be required.

Authors from Cedars-Sinai Medical Center and University of California-Los Angeles examined dual-source CT (DSCT) for coronary evaluation in 24 patietns with atrial fibrillation (AF) and compared it to 119 control patients in sinus rhythm.  The patients underwent B-blockade to achieve heart rates of 65 beats per minute or less and were also given nitroglycerin.  Bolus tracking was employed with retrospective ECG-gating.  The control group underwent tube current modulation; this was not used in the AF patients to maximize the visualization of all phases of the cardiac cycle.  Patients in both groups had similar coronary calcium scores and prevalence of coronary artery disease.  In the atrial fibrillation group, 2 (8%) of studies proved nondiagnostic, compared to 12 (10%) of the nondiagnostic control group exams.

Conclusion:  Atrial fibrillation patients may be able to undergo diagnostic CCTA in dual-source CT scanners.

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