The WCC Note

Your Weekly Guide to Harmonizing Clinical Trial Imaging

Volume 4, Number 5 – July 8, 2010 FATTY LIVER: The Epidemic Wolf in Sheep’s Clothing - August 4th, 2010 by worldcare

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in the United States, affecting all age groups.  It encompasses a spectrum of disease, ranging from simple steatosis, steatohepatitis (NASH), fibrosis and cirrhosis, to hepatocellular carcinoma.  (1)  This issue of The WCC Note examines the imaging avenues to diagnosis and quantify hepatic steatosis.

What does recent literature report about ultrasound imaging of hepatic steatosis?
1.   The gray scale findings include the following:                          
a.  The diagnosis of fatty liver can be made if:
i.    The liver is more echogenic than
 the renal cortex and spleen.
ii.   Ultrasound wave attenuation is present.
iii.  The diaphragm loses definition.
iv.  The intrahepatic architecture has poor
delineation.
v.   There should be more than just one or
two of the above present. (2)
b.  A 2008 review reported ultrasound sensitivity
ranged 67-84% and specificity 77-100% for
severe fatty liver (more than 30% fat by weight).
It has been reported as poor at diagnosing
lesser degrees of steatosis. (3)
c.  Subjective visual assessment of fatty liver at
ultrasound has marked observer variability. (4)
d.  A 2009 study reported that a hepatorenal sono-
graphic index of 1.49 (the ratio between the
mean brightness levels in a region of interest in
the liver and spleen) predicted steatosis of >5%
with a sensitivity of 90%, specificity 90%.  Steato-
sis of >60%; specificity 93%). (5)
2.   Elastography
 a. A significant positive correlation was reported between
median acoustic radiation force
impulse elastography (ARFI) and liver fibrosis in patients
with NAFLD. (6)

What are some updates on CT of hepatic steatosis?                        
1.    Hepatic steatosis can be diagnosed on
CT if:
a.  Noncontract
i.   Liver attenuation is at least
10 Hounsfield units (HU) less
than the spleen.
ii. The liver attenuation is<48
HU (7, 8, 9); or <40 HU when
lipid is about 30% . (9, 10)
b. With contrast:
i.    The comparison of the liver
and spleen HU is not as reliable. (2)
ii.   Fatty liver can be diagnosed if liver
attenuation is less than 40 HU. (2)
2.   Then if the liver is <40 HU, is that spe-
cific for liver steatosis?
a.   No. Ischemic or mucinous metasta-
ses, or abscesses can have this
attenustion.  Clinical laboratory, and
other imaging features need consid-
eration. (2)
3.    Lipid quantification can be preformed by
the following methods:
a.  Hepatic attenuation measurement
i.  A value of 40 HU is reported
to represent fetty change of
approximately 30%. (9, 10)
b.  Hepatic attenuation index
i.  A ratio of hepatic HU to splenic
HU less than 0.8 is reported as
highly specific for moderate to
severe (>30%) macrovesicular
steatosis.  (11, 9)
c.  Hepatic attenuation difference at
dual-energy CT
i.  Ma et al note, in review, that
while there is a paucity of literature
to validate its use, an increase in fatty
content associates with desreased HU at low
 energy;  when the energy level increases, the
fat attenuation increases. (9)
4.    Unenhanced CT studies have reported:
a.  Visual grading and liver attentuation index were shown reliable and similarly accurate for
diagnosis of 30% or higher macrovesicular steatosis in living hepatic donor candidates.  (12)
b.  Moderate to severe macrovesicular steatosis (i.e. >30%) can be accurately diagnosed in
the living hepatic donor, avoiding biopsy, but biopsy is still needed if the CT calculates
<30% fat.  Coexistent fatty liver and hemosiderin or occult liver disease would be possible.
(13, 14, 15)
c.  Low dose unenhanced CT detected hepatic steatosis in asymptomatic patients, while
clinical risk factor profiles proved unreliable. (16)

What MRI methods are used to evaluate hepatic steatosis?
1.  Spectroscopy
a.   This technique uses the frquency position along the x-axis to separate and character-
ize chemicals within voxels.  (17)
b.  Localized or single-voxel MRI.  Sequences include:
i.   Point-resolved spectroscopy  (PRESS)
ii.  Stimulated echo acquisition mode  (STEAM)
iii. A reconfigured STEAM sequence has been reported with breath-hold acquisition of
TZ-corrected lipid measurement.  (18)
iv. A disadvantage is that a large, single voxel is studied.  (19)
c.    The summation of individual lipid peaks calculates the total liver triglyceride content.  (9)

2.  Chemical shift imaging:  Fat and water protons precess at different frequencies in a magnetic
field.  Exploiting this allows for detection and quantification of fatty infiltration.  Multiple
sequences have been developed on this basis.  These are:
a.  Two-point Dixion MRI
i.   This techniques offsets the rephasing pulse in a spin echo (SE) sequence to create
out -of-phase images, with the unmodified SE images used as in-phase.  Summation
and subtration of these images yields water-only and fat-only images to quantify fat,
but magnetic field inhomogeneity and longer scan times limit its use  (9)

ii.   A recent study  at 3T reported a 2D decomposition technique to identify distinct
in-phase/opposed and fat/water ratios for in vitro steatosis, iron overload, and
combined disease.  (20)
b.  Three-point Dixon MRI
i.      Developed to overcome the field inhomogeneity, it uses a third image with phase
correction but increases scan time.  (9)
c.  Modified Dixon
i.      When faast gradient echo (GRE) was developed, this methodused shorter TEs and
TRs to decrease scan time and allow breath hold images.
ii.     As reviewed by Ma et al, it can detect mild hepatic fat of 10% or more.  (9)
d.  Triple-echo chemical shift GRE
i.      This breath-hold low flip angle technique with correction for T2* was reported to
accurately quantify hepatic fat.  (21)

e.   Opposed-phase T1
i.    When fat and water proton magnetization are in phase, their signal is additive.
when out-of-phase, signal intensity decreases.
ii.  Dual echo fast GRE sequences decrease scan time, allow breath hold imaging,
and minimize T2* when shorter TEs are used.
iii. Opposed-phase T1-weighted images showed signal intensity loss that could be
used to grade the severity of liver steatosis.  (22)
iv.  A relative signal decrease of less than 20% allowed correst prediction of liver
donation appropriateness in 53 of 57 patients.  (23)
v.    Using MR spectroscopy as the referenceee standard, in-and out-of-phase imaging
rapidly estimated liver fat content.  A cutoff value of 5.1% discriminated between
normal and elevated liver fat.  (24)
vi.   Potential pitfall include:
1.  The presence of liver iron, which can cause signal intensity loss on in-
phase images.  (25)
2.  Fat fractions>50%, which cannot be reliably assessed (26)
3.  Fat is spectrally complex.  (26)

3.  MR elastography
a.  This technique employs three phases.  Mechanical waves are generated in tissue.  The
micron-level displacements are imaged using motion-sensitizing gradients.  Wave images
are processed to generate quantitative maps.  (26)
b.  MR 7T elastography detected early steatohepatitis in rats by showing increased elasticity.
(27, 28)
4.   Low-flip-angle multiecho GRE
a.    This is reported to provide high diagnostic and fat-grading accuracy in NAFLD.  (29)
b.    According to O’Regan et al., it can provide fat measurement without acquiring a separate
T2* map (unlike dual echo) and correlates highly with T2-corrected proton MR spectro-
scopy.  (30)
5.   Fast spin echo (FSE)
a.  T2-weighted fat saturated FSE images are compared to T2-weighted non-fat-saturated
FSE images.  A decrease in signal intensity on the fat-saturated images suggests fatty
infiltration.
b.  This method avoids the T2* effect signal loss of liver iron in the cirrhotic patient, which
can be problematic in GRE sequences.  (31, 9)

What are the patterns of hepatic fat deposition?
1.   Diffuse fatty infiltration is most common.  (2)
2.   Focal depostion or diffuse fatty infiltration with focal sparing shows:
a.   No mass effect,
b.   Geographic shape,
c.   Poorly defined margins,
d.   Positioning adjacent to the porta hepatis, gallbladder fossa, ligamentum venosum, or
falciformm ligament (perhaps because of variant venous circulation), and
e.   Contrast enhancement similar to or less than normal liver.  (2)
3.   Multifocal depostition:
a.    Is an uncommon pattern with multiple fat foci an atypical locations,
b.    May be round or oval,
c.    Is a difficult diagnosis,
d.    Must have microscopic fat,
e.    Chemical shift GRE may be helpful, and
d.    May be seen with regenerative nodules in cirrhosis.  (2)
4.   Perivascular:
a.     Has fat halos around hepatic and/or portal veins;
b.     Has an unknown pathogenesis.  (2)
5.   Subcapsular:
a.     This distribution occurs in insulin-dependent diabetics on peritoneal dialysis who get
insulin added to the peritoneal dialysate.
b.     The etiology is thought to be due to direct exposure of that region to a higher
concentration of insulin.  (2)
6.    Patients with fatty liver and concomitant focal liver lesions may display peritumoral sparing of
the fat, leading to atypical imaging appearances.  (32)

What tumors are pitfalls and can contain microscopic fat?
1.     Hepatic adenomas may contain microscopic fat.
Hepatocellular carcinoooooomas, angiomyolipoma, and nodular hyperplasia may contain
microscopic fat and soft tissue.  (2, 33)

Conclusion:  Noncontrast CT can accurately diagnose moderate to severe hepatic steatosis (>30%)
but is not accurate at lower levels.  MRI techniques to detect and quantify hepatic steatosis currently
emphasize chemical shift imaging, with spectroscopy as the gold standard.  Ultrasound suffers from
subjectivity and inability to diagnose lesser degrees of hepatic fat, though a recent study of hepatorenal index  was encouraging.

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Volume 4, Number 4 – May 6, 2010 FATTY LIVER: The Epidemic Wolf in Sheep’s Clothing, PART 1 - May 6th, 2010 by worldcare

Nonalcoholic fatty liver disease (NAFLD) has escalated to the number one liver disease in the United States.  No longer just “fatty liver, or fatty liver with focal sparing” noted as almost an afterthought on imaging reports, it has now become an epidemic problem with potential for very real morbidity and mortality.  Afflicting children and adults, its pathogenesis is multifactorial, but its increase prevalence strongly concides with the mounting Western obesity rate.  This issue of  The WCC Note commences a two-part series on hepatic steatosis, beginning with reviews of its prevalence, pathology, and clinical consequences.

How is nonalcoholic fatty liver disease defined?

1.  NAFLD is defined as macrovesicular steatosis in more
than 5% of hepatocytes (1) in the absence of significant
ethol consumption or other specific cause of liver disease.
2.  NAFLD encompasses a spectrum of disease, ranging from:
a.  Simple steatosis
b.  Steatohepatitis (NASH)
c.  Fibrosis and cirrhosis, to
d.  Hepatocellular carcinoma. (2)

How many people have fatty liver?

  1. An estimated 31 million Americans, 31% of men and 16% of women have NAFLD.  It is thought to be the most plausible cause for the elevated serum aminotransferases and/or gamma glutamyl transpeptidase levels recorded in 24% of U.S. adults. (3)
  2. The United States National Institutes of Health estimates that nonalcoholic steatopatitis (NASH) affects 2% to 5% of Americans, with an additional 10% to 20% having fatty liver, i.e. hepatic fat without current inflammation or liver damage. (4)
  3. The true prevalence in children is not known but is reported at 2.5% to 10% and from 8%  to 80% in obese children. (5) NAFLD is reported as a common cause of liver disease in children and adolescents. (1, 6)

Who gets fatty liver?

1.  The most common associations are:
a.  Obesity is the number one cause. Eighty percent of patients with NAFLD are obese, and 80% of  obese
individuals have NAFLD
b.  Type 2 diabetes mellitus
c.  Dyslipidemia (2)
 2.  NAFLD affects children, adolescents, (1,6) and adults.  It affects boys more than girls (1) and men and women
equally. (3)
3.   Insulin resistance is reported as almost universal in adults NAFLD and highly prevalent in afflicted children
and adolescents. (1)
4.   Both genetic and environmental factors are thought to be responsible for the major ethnic variations in
prevalence.  (1) Recently, for example, variants in apolipoprotein C3 gene have shown association with
NAFLD. (7)
5.   The current Western diet, high in saturated fats and fructose, is considered highly responsible. (8)

Why does fatty liver disease occur?  What is the pathogenesis?

1. NAFLD is considered to be the liver’s manifestation of a metobolic syndrome called “syndrome X” or “insulin
resistance syndrome.”  The syndrome links NAFLD with obesity, diabetes mellitus type 2, hypertension, and
hyperlipidemia. (1)
2. Evidence points to a two-hit theory.
a.   The first hit:
i.   The  “first hit” involves accumulation of fat in the liver.
ii.  Free fatty acids (FFA) are elevated in the serum, become oversupplied to the liver, and lead to
steatosis. (2)
b.   The second hit:
i    Steatosis makes the liver vulnerable to additional biochemical insults, the “second hit.”  These include
oxidative stree, mitochondrial dysfunction, pro-inflammatory cytokines, adipocytokine imbalance,
dysregulated apoptosis, and stellate cell activation.  The result can lead to inflammation causing NASH
and fibrosis. (5, 9)

What is the pathology of nonalcoholic fatty liver?

1.  Liver steatosis consist of large and small vesicles of fat, predominantly
triglycerides inside hepatocytes. (3)
2.  The histology may differ between children and adult. (10)

Figure at right: Fatty liver in a 44-year -old man.
Axial contrast-enhanced CT scan shows linear high
attenuation along the hepatic surface (arrow), a finding
that represents pseudoenhancement.   The diaphragm has
attenuation of the fatty liver and thus mimics an enhanced
hepatic capsule. (14)

What is the pathology of nonalcoholic steatohepatitis
(NASH) ?1.     Steatosis, multifocal parenchymal inflammation, Mallory hyaline,
hepatocyte death from ballooning degeneration and also apoptosis, and
sinusoidal fibrosis occur. (3)

What effect does fat have on the liver?1.     NAFLD is suspected to be responsible for up to 70% of chronic hepatitis
cases of “unknown” cause.  Studies suggest that cirrhosis may eventually
develop in up to 10% to 30% of those with NAFLD. (3)
2.     NAFLD may contribute to progression of other liver diseases. (3)

What are some recent nutritionally related studies?

1.  Daily frutose ingestion by patients with NAFLD shows association with increase hepatic fibrosis. (11)
2.  In contradistinction, berry consumption has been shown to enhance liver function. (12)

What other diseases are associated with NAFLD?1.  Chronic kidney disease and retinopathy show higher prevalence in type 1 diabetic patients
who have NAFLD. (13)
2.   Hepatic steatosis is an independent marker for increased cardiovascular risk. (10)

Conclusion:  Nonalcoholic fatty liver disease has become the most common chronic liver disease
in Western children, adolescents, and adults.  It can have association with hepatitis, cirrhosis, and
hepatocellular carcinoma.

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

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 - March 4th, 2010 by worldcare

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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2009: Looking Back and Looking Ahead in Imaging – Vol. 3, Number 11 - December 31st, 2009 by worldcare

Last summer while reviewing literature for this newsletter, I spent an afternoon on a porch elevated alongside an Idaho road.  While mountains made a diaphanous blanket of color in the distance, and breezes prickled through tree leaves that flickered and shuffled like molecules in entropy, it occurred to me that our understanding of disease processes, due to our ability to image them, has altered fundamentally since I entered radiology 20 years ago.  Rather like a J.D. Salinger’s Glass family member, I felt a kind of epiphany, as silly as that sounds, sitting in a lawn chair among the plants withering in the mountain heat.  And yet, it is this kind of realization about our profession – that it does not and will not stand still – that makes us so lucky to be a part of it.

As the panorama of molecular, in vivo cellular, and micro environmental imaging spreads before us, along with a continuing stream of new technologies that fire out of laboratories with so many endless possibilities, it is our great fortune to work in a profession that allows us, at its core, to serve as fly wheels of steady utility as diagnosticians and also play a role in medical innovations that are occurring today and that will continue to do so for years to come.

This year’s final issue of The WCC Note veers away from the mainstream of practiced radiology and takes us down less-traveled roads toward some experimental imaging highlights of 2009.  From Dr. Pomeranz and myself, we wish you very happy holidays and a joyous and healthy new year.

- Margaret D. Phillips and Stephen J. Pomeranz

ACCOLADES FOR IMAGING ADVANCES

In 2008, the Nobel Prize in Chemistry Went for the Discovery of Green Fluorescent Protein, Which Revolutionized the Imaging of Small Structures, Allowing In Vivo Cellular Imaging.  What Major Accolades Were Bestowed for Imaging This Year?

  1. Once again, a Nobel Prize went to imaging – this time for techniques that allow digital imaging and electronic communications, such as this newsletter.  These discoveries ultimately revolutionized the practice of radiology.
    a.  In 2009, the Nobel committee awarded the Physics prize for inventing an imaging semiconductor circuit, the charge-coupled device (CCD), and for developments in optical fibers that allowed communications based on transmission of light.
    b.  The prize went to two U.S. researchers, Willard S. Boyle and George E. Smith, from Bell Laboratories in Murray Hill, NJ, as well as Charles K. Kao of the United Kingdom and Hong Kong, China.
    c.  The charge-coupled device came to fruition from a desire to create a memory storage device, and it originated after a 1.5-hour discussion between Drs. Boyle and Smith one afternoon in 1969.  It relied on the photoelectric effect discovered by Einstein, for which Einstein himself won the Nobel Prize in 1921.  Attempting to make advances toward a picture phone, Boyle and Smith imagined arrays of photocells that would emit electrons in proportion to the intensity of incoming light.  The electrons in the photocells would then be read and thereby make an image – changing an optical image to a digital one.
    d.  In an online interview, Drs. Boyle and Smith were asked what set apart Bell Laboratories, which has received seven Nobel Prizes.  Their answers were freedom, intelligent management that allows pursuit of interests, an institution financially well positioned to afford appropriate equipment, and excellent people – allowing fellowship and interchange of ideas.
    e.  Dr. Kao used ultra-pure glass fibers to transmit light in 1966.  Since the frequency of light waves is so much greater than electrical waves, transmission is much faster than with copper cables and radio waves.
  2. The Japan Prize from the Science and Technology Foundation of Japan went to radiologist David Kuhl, M.D. from the University of Michigan.  His work in the 1950s developed radionuclide emission tomography that led to, among other areas, PET scanning.

NEW DIRECTIONS IN IMAGING

What Were Some Experimental or Progressive Techniques Published in 2009 That Reflect New Directions or Hold Promise for the Future?

  1. The in vivo tracking of cells with MRI has undergone clinical study outside the United States using superparamagnetic iron oxide particles.
  2. Imaging atoms within an organic molecule absorbed on a surface was performed with scanning tunneling microscopy.
  3. Breast-specific gamma imaging with a high-resolution gamma camera was reported to show 93 percent sensitivity in 28 biopsy-proved known lobular carcinomas, in a retrospective multicenter study.
  4. Molecular imaging of the breast underwent review with description of, among others, the gene array analysis of tumors, phenotypic imaged tumor differences, MR tumor spectroscopy, and fluorescent probe imaging.
  5. Atherosclerotic plaque was imaged in vivo at the molecular levels by using the MR contrast agent P947 that targets matrix metalloproteinases in plaque.
  6. Using infared imaging guidance, researchers caused subtotal ablation of mice tumors, which resulted in T-cell immune responses and tumor regression.
  7. Minimally invasive autopsy to detect cause of death as an alternative to conventional autopsy was reported to show 93 percent of overall findings and 94 percent of major findings.  The technique used whole-body CT, MR, and ultrasound-guided 12-gauge needle biopsy of the heart, both lungs, liver, both kidneys, and spleen.
  8. Apoptotic (early cell death) processes underwent time-lapse imaging in live cells.  Researchers used a polarity-sensitive biosensor with switchable fluorescence states that allowed only the apoptotic cells to be detected.
  9. Reporter gene imaging of human mesenchymal stem cells implanted in porcine myocardium was performed with PET-CT.
  10. A single atom could be imaged by detecting electrons emerging from its surface using an aberration-corrected electron microscope.

CONCLUSION

The year 2009 saw Nobel Prizes awarded for techniques that ultimately brought about digital imaging and filmless teleradiology, the Japan Prize given for radioisotope tomography leading to PET; and a myriad of experimental imaging science that increasingly refined and exploited visualization of small structures – down to the atomic level.

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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