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180 D. Schmolze
which produces an acoustic wave.26Like optical mammography, the use
of a near-infrared light source allows good tissue penetration at safe energy
levels. Contrast is generated by differential absorption and expansion of
tissue constituents, with hemoglobin and its derivatives being major contributors. Unlike optical mammography, the generated acoustic wave does
not suffer from significant scattering and can be detected with conventional
ultrasound devices already in widespread clinical use.
PAI is at a relatively less developedstage compared to general optical
mammography, but the groundwork has been laid for large-scale clinical
trials. Following initial studies demonstrating feasibility in small patient
cohorts,
27–30
a recent study31imaged 29 patients with suspected breast cancer. The PAI results were compared with conventionalX-ray and ultrasound
findings, and a subset was compared with MRI and with tumor vascular
distribution via histopathologic examination.
The investigators identified three general PAI patterns: “ mass-like”,
“non-mass-like”, and “ring-like” (Figure 4). These patterns corresponded
well withthe MRI findings and werealso correlated with thehistopathologic
distribution of vasculature within the tumor. The latter correlation was not
perfect, suggesting the influence of constituents other than hemoglobin
derivatives.
Photoacoustic imaging has not been extensively studied for monitoring response to neoadjuvant chemotherapy or for screening in high-risk
patients, but there is reason to believe it would perform similarly to optical
mammography with the added ability to use standard ultrasound detectors.
Pairing with existing ultrasound equipment might enable the simultaneous
acquisition of PAI and ultrasound images, yielding data comparable to MRI
at a significantly lower cost and with less patient discomfort.
As for optical mammography, larger-scale clinical trials are needed to
robustly assess the performance of PAI and to determine what role it might
play in the diagnosis and management of breast cancer.
Raman Spectroscopy
When a photon interacts with a molecule, the energy of the photon can
be shifted, followed by alteration of the photon’s path (i.e. scattering).
Breast 181
Figure 4. Photoacoustic imaging of breast cancer. Photoacoustic images of invasive breast cancer
are compared to conventional X-ray and ultrasound findings. Three distinct patterns are described:
“mass-like” (top row), “ring-like” (middle row), and “non-mass-like” (bottom row). Adapted from
Ref. [31].
This energy shift is called the Raman shift or Raman effect, and the magnitude and direction of the shift depend on the specific functional groups
and chemical bonds within the molecule.
32
When the Raman shift of a
tissue is measured across a range of wavelengths, a spectrum is generated
that reflects the chemical composition of that tissue. This spectrum is generally not readily interpretable by humans, so various machine learning
approaches must be applied for analysis.
Raman spectroscopy uses a safe visible to infrared light source, can
be incorporated into small probes, and generates detailed information on
182 D. Schmolze
chemical composition in near real-time, making it an attractive modality
for in vivo diagnosis. In the breast, it has mainly been studied in the context
of intraoperative margin assessment.
In the first in vivo Raman study, Haka and colleaguescollected spectra
from 9 patients undergoing breast-conserving surgery.
33
During surgery,
spectra were collected from the resection cavity margins and analyzed in
real time. The analyzed margins were then excised as separate specimens
and subjected to standard histopathologic assessment.
In all, 31 spectra were collected, and perfect sensitivity and specificity
were achieved for the determination of benign versus malignant. Overall
accuracy was 93% since two cases were categorized as “fibrocysticdisease”
which were ultimatelydeemed to be normal. Significantly, a positive margin
involved by ductal carcinoma in situ was detected by the Raman system,
a finding which would have spared the patient additional surgery had the
system been used for intraoperative decision-making.
A more recent study combined tissue auto-fluorescence and Raman
34
spectroscopy to assess surgical margins of excised breast specimens.
The
study analyzed 121 samples from 107 patients and demonstrated a sensitivity and specificity of 95% and 82% for the detection of carcinoma
(Figure 5). Notably, in situ carcinoma (both lobular and ductal subtypes)
could be discriminated from invasive carcinoma.
Severalother studies have examined Raman spectroscopy for intraoperative margin assessment, and all have demonstrated high accuracy. The
method has been modified to achieve a higher depth of penetration,
35,36
and contrast agents have been incorporated to facilitate more efficient signal collection and faster acquisition times.
37
In addition to real-time margin assessment, Raman spectroscopy has
been investigated for the detection of sentinel lymph node metastases
and circulating tumor cells.
40,41
The technique has even been used to mon-
itor in vivo response to chemotherapeutic and anti-Her2 agents.
38,39
42,43
Future Directions
The optical imaging methods described in this chapter are all relatively
mature; feasibility studies have proven successful, and clinical efficacy has
Breast 183
(a)(
)(
)
b
Figure 5. Raman spectra of normal, benign, and malignant breast tissues. (a) The mean and
standard deviation of all spectra are shown for a number of tissue types (IC = invasive carcinoma,
OT = other tumor, BG = benign growths, IN = inflammation, P = parenchyma, S = healthy stroma,
F+S = fat and stroma, F = fat). The shaded regions represent discriminative peak areas, while the
magenta lines represent discriminative peak intensity differences. (b) The classes are simplified into
three clinically relevant categories, and (c) malignant subtypes are defined (MP= malignant phyllodes
tumor, LCIS = lobular carcinoma in situ, DCIS = ductal carcinoma in situ,IC= invasive carcinoma).
c
been demonstrated, albeit in relatively small patient cohorts. The obvious
next step is larger, prospective clinical trials. Device standardization will
be important for this next phase.
True in vivo imaging devices are now small enough for applications
in solid organs. Technologies such as needle-based confocal laser endomicroscopy (nCLE) will help target biopsies and may eventually lead to realtime in vivo diagnosis in the breast. Completely novel imaging approaches
are now technologically feasible, such as imaging via the breast ductal
system. In vivo microscopy of the breast stands poised for many exciting breakthroughs in the near future, which will ultimately lead to better
outcomes for patients.
184 D. Schmolze
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https://doi.org/10.1142/9789813206984_0010
Central Nervous System Chapter
10
Jennifer M. Eschbacher∗, Evgenii Belykh†,
Mark C. Preul
†
Introduction
, Peter Nakaji
†
Confocal laser endomicroscopy (CLE) is a novel method of imaging used
to histologically examine surface and subsurface tissue properties, with
subcellular resolution. It is increasingly being incorporated into the neurosurgical clinical setting to evaluate histopathologic features of patient
brain tumor tissue in vivo, thus allowing for diagnoses to be made in real
time without excising tissue. With the use of a probe with an integrated
miniature laser scanner and a fluorescent contrast agent, architectural and
cellular tissue features can be visualized at various tissue depths to provide rapid intraoperative feedback to clinicians. Images obtained with CLE
∗
Department of Neuropathology, Barrow Neurological Institute, St. Joseph’s Hospital and
Medical Center, Phoenix, AZ, USA.
†
The Loyal and Edith Davis Neurosurgical Research Laboratory, Department of Neurosurgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix,
AZ, USA.
189