516537

research-article2013

JDMXXX10.1177/8756479313516537Journal of Diagnostic Medical SonographyMapes-Gonnella

Literature Review

The Emerging Role of Elastography in

Cancer: Diagnostic Value in Detecting
and Assessing Therapeutic Response to
Treatment

Journal of Diagnostic Medical Sonography

2014, Vol. 30(1) 1117
The Author(s) 2013
Reprints and permissions:
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DOI: 10.1177/8756479313516537
jdms.sagepub.com

Tia Mapes-Gonnella, BS, RDMS1

Abstract
Real-time elastography is an emerging sonographic imaging technique that provides a noninvasive method of evaluating
biomechanical properties of a lesion: specifically, the elasticity, or stiffness, of the cellular composition relative to
surrounding tissue. Clinical studies have demonstrated the diagnostic capability of elastography to detect specific
cancers with accuracy that may substantially affect patient care and improve outcome. This literature review examines
the basics of elastography, the advantages and limitations of this technique, and the results of research centered on its
role in cancer detection and evaluation of tissue response to cancer therapies.
Keywords
elastography, tumor response, sonographic elastography, cancer detection, ultrasound
Cancer detection maintains a central role in diagnostic
imaging; continued research is performed and technological improvements are made to increase the sensitivity
and specificity of virtually all imaging modalities. The
objective in such trials is to improve patient outcome
through early and accurate characterization of malignancies as well as prevent costly and unnecessary follow-up
studies and/or surgical biopsies. Similarly, imaging methods used to evaluate tumor response to treatment, such as
adjuvant chemotherapy and ablative interventions, have
been the focus of many clinical trials. Researchers are
making increasing efforts to determine the efficacy of
imaging techniques at characterizing these changes earlier in the plan of care, so treatment can be tailored to
each individual in an attempt to decrease mortality rates
and improve patient outcomes.
Real-time elastography (RTE) is an FDA-approved
method of assessing soft tissue structures via a transdermal approach as well as intraoperatively.1 This diagnostic
imaging method assesses the biomechanical properties of
tissue for elasticity, or the ability to resume its original
shape following compression.2 RTE methods consist of
several compression-generating techniques including
quasistatic, shear wave, and acoustic radiation force
impulse (ARFI) imaging. Shear-wave elasticity imaging
generates shear waves through acoustic radiation force.
The velocity of these waves is measured to determine the
stiffness of the tissue.3,4 ARFI uses a focused ultrasound

beam aimed at the targeted tissue for a short period of

time (~0.1 milliseconds) to create and measure resulting
tissue displacements. Quasistatic elastography can be
implemented on many existing ultrasound systems with
the addition of software. This method uses operatorinduced mechanical compression to measure the degree
of deformity, or tissue strain. This is calculated by the
displacement of adjacent tissues producing an elastogram
that maps the relative stiffness of the targeted lesion.5
Fibrotic, inflammatory, and malignant tissues are characteristically less elastic than other tissues, demonstrate a
higher degree of stiffness, and will compress less than
healthy tissue.2,5,6 Tumors with initial elastographic interrogation can be monitored at intervals following treatment to assess for tissue changes such as a decrease in
stiffness, or an increase in elasticity, resulting from tumor
necrosis relating to a positive response to therapy.7
Assessment of tissue elasticity for malignant characterization has been performed in multiple organs including
the pancreas, liver, prostate, and breast.
1

Adventist University of Health Sciences and St. Elizabeth Health

Care, Cincinnati, OH, USA
Corresponding Author:
Tia Mapes-Gonnella, BS, RDMS, Adventist University of Health
Sciences and St. Elizabeth Health Care, 1 Medical Village Drive,
Edgewood, KY 41017, USA.
Email: tiamapesgonnella@gmail.com

12

Journal of Diagnostic Medical Sonography 30(1)

Discussion

Literature Review

Advantages

Variance

Ultrasound is a noninvasive, widely available, cost-effective method of diagnostic imaging with no risk of radiation exposure, adverse reaction to contrast, or other
contraindications such as previous surgeries or impaired
renal function common to other methods such as magnetic resonance imaging (MRI) and computed tomography (CT). In cancer detection, RTE has been reported to
differentiate benign from malignant breast lesions with
sensitivities of 78% to 100% and specificities of 21% to
98%.6 In conjunction with other imaging techniques,
RTE can potentially improve the radiologists ability to
accurately characterize malignant lesions and distinguish
fibrotic tissue from cancerous growths. This capability
has the potential to reduce unnecessary biopsies of characteristically benign masses, lowering costs and improving throughput and overall patient management.5,6

Variance in RTE results largely from a lack of protocol

and standards for the application, measurement, scoring,
and interpretation in this developing technique. The
resulting disagreement between operators, observers, and
interpreters can be misconstrued as evidence against the
reliability of elastography, and this continues to be a challenging limitation of RTE. A clinical trial conducted to
measure the variance in elasticity images was conducted
to determine what factors have the greatest influence on
quality. The results reported that image quality was inadequate in 21 cases (6.7%), low in 134 cases (42.9%), and
high in 157 cases (50.3%).14 According to this study,
higher image quality was reported in conjunction with
smaller lesion size, shallower lesion depth, decreased
breast thickness at the location of the tumor, and benign
pathologic findings. The greatest impact on quality was
inversely proportional to the thickness of the breast at the
location of the target lesion where increasing thickness
resulted in decreased quality. Other variables measured
included age, BMI, mammographic density, and distance
from the nipple; none of these factors had any appreciable
impact on image quality. The reported sensitivity in differentiating benign from malignant masses between
higher quality and lower quality images was 87.0% and
56.8%, respectively.
A study that reviewed previous cases in which RTE
was used to measure liver tissue stiffness as it relates to
fibrosis found a rate of measurement failures, or nondiagnostic quality, of 3.1%, and an additional 15.8% of
reported results were determined to be unreliable.15 The
authors highlighted the strong correlation of failure/
unreliability with variables such as increasing age (>52
years), increased BMI (>30 kg/m2), coexisting type 2
diabetes, and operator inexperience. A similar study
reflected comparable measurements of failure and unreliability at 5.3% and 16%, respectively, as did studies in
France and China, reporting failure rates of approximately 5%. The implication of these studies points to
obesity as a primary factor in unreliable or failed results
in RTE. Despite the limitations noted in such studies,
the variance depicted threatens reliability of RTE in
clinical applications. Contrary to these findings, a study
by Sftoiu et al16 of interobserver variability in the efficacy of elastography in differentiating focal masses in
patients with chronic pancreatitis reported correlations
between 0.86 and 0.94, with good reliability in reproduction of images between observers. The sensitivity
was 93.4%, specificity 66.0%, positive predictive value
92.5%, negative predictive value 68.9%, and overall
accuracy 85.4%.16

Limitations
A particular limitation of RTE in cancer assessment is specific to the histologic cell type of the cancer being evaluated. RTE measures the stiffness of tumors based on the
assumption that malignancies will possess a greater cell
density; however, atypical cancers such as ductal cancers,
medullary cancers, mucinous cancers, and papillary cancers do not follow the principles of this assumption and
may therefore be underreported by RTE assessment
alone.2 Similarly, adjacent inflammatory tissues can
reduce the sensitivity of RTE in cancer detection, as is
seen in the presence of pancreatitis.8,9 Other factors that
increase interobserver variance, and thus reduce reported
accuracy, include the type of cancer and the size of the
lesion. These two factors affect the elasticity of the lesion
and can influence interpretation.2,10 These limitations have
the potential to increase false-negative results.
Ultrasound is an inherently operator-dependent modality, and variance in interobserver agreement can result
from inconsistent technique, level of experience, the available technology, and subjective interpretation of disease.2,11,12 RTE is still in the development stages, and there
is little consistency in the scoring system relative to tissue
characteristics indicative of malignancy. Independent scoring systems have been used in many trials assessing RTE
accuracy, but this lack of standardization reduces the reliability of published results. A great deal of literature centering on body mass index (BMI) as a substantial limitation
suggests that increased body habitus perpetuates variance
in RTE ultrasound. However, technological advancement
in probe development is anticipated to significantly help
overcome this persistent issue in RTE application.13

13

Mapes-Gonnella

Figure 1. Elastography image side by side with conventional

B-mode image of a pancreatic carcinoma, demonstrating the
increased stiffness (blue) of the tumor.

Pancreas
Chronic pancreatitis and pancreatic cancer are often
coexistent, and the detection of focal abnormalities in the
presence of inflammation is challenging. The diagnosis
and plan of care for both pancreatic inflammation and
malignancy, however, are largely dictated by imaging
results.8 RTE is a safe and effective technique that has
been reported to be instrumental in accurately diagnosing
chronic pancreatitis and pancreatic cancer8,17 (Figure 1).
When compared with results of other imaging modalities,
results of RTE assessment and biopsy of pancreatic
masses have achieved a sensitivity of 85% to 90% and a
specificity of virtually 100% in the absence of chronic or
pseudo-tumoral pancreatitis. Considering that 20% to
35% of patients with pancreatic lesions have coexistent
pancreatitis and that in this condition RTE typically has a
lower sensitivity (approximately 75%), caution must be
used when using this technique for diagnosis. A trial to
determine the accuracy of RTE in differentiating between
normal pancreas, chronic pancreatitis, and pancreatic
cancer reported a sensitivity of 91.4%, specificity 88.9%,
and accuracy of 90.6%.8,9 A subgroup analysis within this
study differentiating pancreatic cancer from pseudotumoral pancreatitis reflected good sensitivity at 93.8%
and overall accuracy of 86%, but with low specificity of
only 63.6%.
Another trial measuring RTE sensitivity and specificity in differentiating benign from malignant pancreatic
lesions compared with conventional sonography showed
a sensitivity and specificity for elastography of 92.3%
and 80.0%, respectively, compared with 92.3% and
68.9%, respectively, for conventional B-mode images.18
A trial conducted by Larino-Noia et al19 evaluating RTE
accuracy in characterizing solid pancreatic masses
included RTE assessment of the mass compared with

Figure 2. Elastography image side by side with conventional

B-mode image of a liver with diffuse fibrotic changes, showing
the diffuse nature of the areas of increased stiffness (blue).

adjacent tissue as reference areas. The results were confirmed by histopathologic examination of the gross
specimen. Endoscopic ultrasound (EUS) elastography
had a sensitivity and specificity of strain ratio for detecting pancreatic malignancies of 100% and 92.9%,
respectively.19

Liver
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide, with
the majority (80%) developing in patients with advanced
liver cirrhosis or fibrosis, making it the greatest risk factor for HCC development.20 Fibrotic changes in the liver
have a strong correlation with later development of HCC,
which may be treated by ablative therapies20 (Figure 2).
Elastography has been used to localize hepatic masses to
improve the accuracy of biopsies and to determine the
response of malignancies to therapy21 (Figure 3). Tissue
response to ablation therapy has been researched to determine whether RTE can detect changes in the biomechanical properties of the tumor compared with surrounding
tissues. In one such study, elastography demonstrated the
ablated region as a well-circumscribed area of increased
stiffness compared with nonablated surrounding tissue.
These findings correlated well with contrast-enhanced
CT images as well as with the gross specimen following
resection.22

Prostate
Results of RTE evaluation of the prostate gland for cancer
have been equivocal regarding its diagnostic value
(Figure 4). Despite a clinical trial reporting 76% diagnostic accuracy of endorectal elastography for prostate cancer detection,23 other studies found significantly lower

14

Figure 3. Real-time elastography image side by side

with conventional B-mode image in a patient with
cholangiocarcinoma acquired during an endoscopic,
ultrasound-guided, fine-needle aspiration. The increased
stiffness of the tumor (blue) can be seen clearly in the
elastography image.

Journal of Diagnostic Medical Sonography 30(1)

Figure 5. Elastography image side by side with conventional

B-mode image of a fibroadenoma of the breast. The difference
in stiffness between the lesion and the surrounding breast
tissue is clearly contrasted in the elastography image.

application of real-time elastography in prostate cancer

detection.

Breast

Figure 4. Real-time elastography image side by side with

conventional B-mode image showing a small lesion with
increased stiffness (blue) on the right side of a prostate. The
lesion was later confirmed to be prostate cancer.

reliability of this modality in prostate cancer evaluation.

In a study by Magnoni et al24 examining the sensitivity of
RTE in characterizing malignant prostate masses when
compared with histological samples obtained via transrectal biopsies, only 1 of 102 patients was determined to
be true positive for prostate cancer, and 6 cases demonstrated false negatives. A clinical trial to evaluate malignant prostate tissue response to high-intensity focused
ultrasound by elastographic imaging demonstrated a
marked underestimation of residual tumor volume when
compared with MRI.25 The trial did note that technical
limitations such as bandwidth and frame rate affected
the diagnostic quality of elastographic ultrasound
images. Both studies concluded that the limited accuracy, sensitivity, and specificity do not justify the routine

Breast cancer tissue is less elastic than normal breast tissue; this increased hardness, or stiffness, is the property
that allows some breast cancers to be palpated as well as
characterized by comparative elasticity through RTE
assessment26 (Figure 5). The principle of elastography is
that tissue compression produces strain (displacement)
within the tissue and that the strain is smaller in harder
tissue than in softer tissue. Therefore, by measuring the
tissue strain induced by compression, we can estimate tissue hardness, which may be useful in diagnosing breast
cancer. A study conducted by Ueno et al26 evaluated the
diagnostic value of RTE by examining 111 nodules and
applied varying scoring system standards for characterization in determining its diagnostic accuracy. Elastography
achieved a sensitivity, specificity, and accuracy of 86.5%,
89.8%, and 88.3%, respectively. Applying a different set
of threshold values yielded a sensitivity, specificity, and
accuracy of 71.2%, 96.6%, and 84.7%, respectively. A
separate study using the same scoring system as Ueno et al
demonstrated RTE sensitivity and specificity of 79% and
89%, respectively.2,10 A study using a scoring system different from the preceding studies that included 874 breast
lesions found a high specificity in benign lesions with a
negative predictive value of 98% related to the entire
group of lesions and 100% in lesions less than 5 mm.27 An
imaging comparison trial conducted by Ou et al28 centered
on differentiating benign from malignant breast lesions in
dense breasts. Imaging modalities included B-mode ultrasound, RTE, and mammography, and the study concluded

Mapes-Gonnella

Figure 6. Elastography image side by side with conventional

B-mode image of an invasive ductal carcinoma of the breast.
Note the difference in stiffness of this lesion (blue) compared
with the fibroadenoma of Figure 5.

that RTE demonstrated the highest specificity (95.7%)

and the lowest false-positive rate (4.3%). When compared
with B-mode ultrasound, RTE diagnostic accuracy was
higher at 88.2% vs 72.6%. Positive predictive values
(PPVs) also exceeded B-mode at 87.1% vs 52.5%, respectively. Despite these results, sensitivity, negative predictive value, and false-negative rate were comparable to the
other two methods. Increased false-negative rates in RTE
were seen with invasive ductal carcinomas and those
malignancies with a large area of central necrosis28
(Figure 6). A combination of RTE and B-mode ultrasound
had an improved sensitivity (89.7%), accuracy (93.9%),
false-negative rate (9.2%), specificity (95.7%), and positive predictive value (89.7%).
Destounis et al11 published results of a multicenter
study evaluating the sensitivity and specificity of RTE in
characterizing and differentiating breast lesions.
Sensitivity and specificity obtained by the various centers
participating in the study ranged between 96.7% and
100% and between 66.7% and 95.4%, respectively. The
marked variance in specificity was attributed by the
authors to differences in the examination technique. This
concern about interoperator variance was also raised by
Moon et al12 as a potential limitation that undermines the
reliability of published data and overall utility.

Tumor Response
Ensuring accurate characterization, staging, and monitoring of tumors and their response to therapy is a challenging but critical role of diagnostic imaging modalities
(Figure 7).
Second to malignancies of the skin, breast cancer is
the most frequent type of cancer diagnosed in women;
more than 200,000 new cases of invasive breast cancer

15
were diagnosed in the United States during 2012.7
Approximately 5% to 20% of these patients will present
with locally advanced breast cancer (LABC), which is
defined as stage III or inoperable disease, characterized
by tumors that are larger than 5 cm and/or involving the
skin or chest wall, with or without lymphatic involvement. When compared with early stage breast cancer,
LABC has a much poorer prognosis and higher rate of
recurrence (10%-20%). Only 55% of LABC patients survive to 5 years because of the high risk for metastatic
spread. Approximately 75% of LABCs show marked
response to initial chemotherapy, improving surgical outcome. In more than 50% of cases there is only microscopic tumor, or no residual tumor at all, following
surgical intervention.27
Imaging to assess for early functional changes that
indicate the extent of therapy response is critical in determining the plan of care for cancer patients. The earlier a
response can be detected, the more tailored a patients
treatment can be to improve outcome. In LABC, administration of neoadjuvant therapy is a standard protocol
prior to surgical resection to ensure disease-free margins
and lower the chance of in situ reoccurrence. Such neoadjuvant therapy has been linked to increased survival rates
up to 70%.7,27 A recent study by Falou et al7 centered on
elastographic assessment of tumor response to neoadjuvant therapy. Nine patients demonstrated positive
response to neoadjuvant therapy by elastography evaluation that was confirmed surgically, and five patients demonstrated poor response to therapy by RTE. One patient
demonstrated a false-positive response to therapy due to
the invasive, mucinous nature of her specific LABC, a
pattern that presents with biomechanical properties of
decreased stiffness, atypical of LABC cancers.
Studies have measured tumor response to therapy in
order to determine criteria for treatment efficacy. One
such treatment that has been under development for the
past two decades is percutaneous ethanol injection (PEI),
studied for its effect on small HCCs. Ethanol has a pattern
of diffusion in tissue that creates a cytotoxic environment
resulting from protein denaturation, cellular dehydration,
and microvessel thrombosis contributing to coagulation
necrosis in local HCC cells. Studies have shown that up
to 70% of treated HCC tumors smaller than 3 cm result in
complete coagulation necrosis, and the 5-year survival
rate is between 40% and 65% for PEI-treated patients
who have concomitant hepatic cirrhosis.29 To evaluate the
potential of RTE to measure tumor response to treatment,
Bai et al29 conducted RTE following PEI, using the area
of a lesion created in vivo to depict temporal formation of
the ethanol-induced response. The results demonstrated
the formation of a focal area of lower strain with welldefined borders within 2 minutes of PEI, the maximum
area being reached at 2 minutes. The authors concluded

16

Journal of Diagnostic Medical Sonography 30(1)

Figure 7. Representative elastography and B-mode images in patients with locally advanced breast cancer from a nonresponder
(A) and a responder (B) taken at baseline prior to treatment, at week 1, at week 4, at week 8, and preoperatively.7 (The color
bar on the right indicates relative stiffness; the scale bar equals 1 cm.)

that RTE is a valuable tool for monitoring tumor response

to PEI. Their study also indicated some value in using
RTE for real-time assessment of PEI response by necrotic
formation. This will allow physicians to adjust the dose
of PEI based on RTE findings, thus improving patient
outcome and treatment efficacy and reducing recurrence
rate of inadequately treated tumors.

Conclusion
RTE is an emerging imaging modality that provides data
related to the biomechanical properties of tissue for characterization of malignant and benign masses. Limitations of
RTE include operator dependence, increased BMI, tissue
thickness anterior to breast masses, histologic composition of atypical cancers, and lack of standard scoring
methods and protocols, which hamper reliability. However,
RTE remains a cost-effective, noninvasive, and widely
available technique that poses less risk to patients compared
with other imaging modalities, making it ideal for screening
and monitoring disease processes.2 RTE has established a
developing role in distinguishing benign and malignant
masses in the pancreas, and the high degree of sensitivity in
breast imaging suggests that this modality may reduce
unnecessary biopsies. In addition to screening, published

reports have reflected a strong correlation between RTE and

pathologic response of breast tumors following neoadjuvant chemotherapy.7 This correlation has been documented
in RTE determination of tumor response to ablative therapy
as well.22,29 These findings facilitate the establishment of
protocols for techniques that monitor the response of cancer
to specific therapies. RTE can be instrumental in tailoring
treatment to patients exhibiting a negative tumor response.
This ability of response monitoring has the potential to
improve patient outcome, efficacy, and cost of care, reducing recurrence rates and overall mortality in some cancers.
Overall, while RTE is a relatively new technique, research
has supported the value of this modality in multiple cancerrelated applications that promise to aid in the screening,
detection, and monitoring of malignancies and enhancement of cancer therapies through measured response.
Declaration of Conflicting Interests
The author declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.

Funding
The author received no financial support for the research,
authorship, and/or publication of this article.

Mapes-Gonnella
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8. Wallace M, Gill K: EUS elastography for pancreatic mass
lesions: between image and FNA? Gastrointest Endosc
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9. Vilmann P, Gorunescu F, Suaftoiu A, et al: Neural network analysis of dynamic sequences of EUS elastography
used for the differential diagnosis of chronic pancreatitis
and pancreatic cancer. Gastrointest Endosc 2008;68:1086
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lesions: preliminary report. Radiol Med 2005;110:6976.
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12. Moon WK, Choi JW, Cho N, Jang M, Kim KG, Chung
SY: Differentiation of benign from malignant nonpalpable
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519584
research-article2013

JDMXXX10.1177/8756479313519584Journal of Diagnostic Medical SonographyJDMS CME ArticleSDMS CME Credit

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Article: The Emerging Role of Elastography in Cancer:

Diagnostic Value in Detecting and Assessing Therapeutic
Response to Treatment
Author: Tia Mapes-Gonnella, BS, RDMS
Category: General/Abdominal Sonography
Credit: 1.0 SDMS CME Credit
Objectives: After studying the article entitled The
Emerging Role of Elastography in Cancer: Diagnostic
Value in Detecting and Assessing Therapeutic Response
to Treatment, you will be able to:
1.Describe the different types of elastography imaging
2.Determine appropriate applications for elastography
imaging
3.Describe the limitations of elastography imaging
1. Quasistatic elastography is an imaging technique
that applies stress to tissue and then measures the
resulting tissue
a.Pressure
b.Strain

c.Force
d.Velocity
2. Shear wave elastography determines tissue stiffness by creating shear waves and measuring
their
a.Pressure
b.Strain
c.Displacement
d.Velocity
3. Acoustic radiation force impulse elastography
uses a short burst of focused ultrasound to cause
and then measure tissue
a.Pressure
b.Force
c.Displacement
d.Velocity
4. Typically, the most elastic tissue of those shown
below is
a. Normal tissue
b. Malignant tissue

JDMS CME ArticleSDMS CME Credit

c. Fibrotic tissue
d. Inflammatory tissue
5. The type of cancer that would be most reliably
detected by elastography is
a. Papillary cancer
b.Ductal
c. Medullary cancer
d. Pancreatic cancer
6. In general, the cancer type for which elastography
has been reported to show the lowest sensitivity
has been
a. Pancreatic cancer
b. Liver cancer
c. Prostate cancer
d. Breast cancer
7. When comparing elastography results, the sensitivity of low-quality images compared with highquality images is lower by approximately
a.10%
b.20%
c.30%
d.40%

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8. Failure or inaccuracy of elastography to differentiate benign from malignant lesions in the abdomen is considered primarily to be a result of
a. Patient age
b.Obesity
c.Ethnicity
d. Lesion size
9. Much of the variability in the reported accuracy
of elastography to characterize lesions is considered to be caused by
a.Lack of standardized technique, scoring, and
interpretation
b.Equipment
c. Tumor stage
d. Tumor size
10. For lesions in dense breasts, the positive predictive value of real-time elastography compared
with B-mode ultrasonography has been reported
to be higher by approximately
a.35%
b.25%
c.15%
d.5%