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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5528_Библиотеки_им_академика_М_И_Перельмана.pdf
200 J. M. Eschbacher
et al.
Other limitations include the contact nature of the probe and the small
field of view. The small field of view (575 × 237µm) limits the surface
area that can feasibly be imaged at a single point in time during a procedure and potentially impacts wide-margin evaluation. However, the probe
can be rapidly moved across and to various locations for real time imaging. Furthermore, unlike other organ tissues, brain tissue is malleable and
soft, and it compresses easily under pressure from the contact probe. The
naturally delicate properties of the brain can therefore limit visualization
of histologic slices at some imaging sites. Anatomic sites inaccessible to
the rigid probe can also be a limiting factor to incorporating CLE into the
surgical setting for some tumors.
Interpretation of images and use of the instrument requires specific
training by both the pathologist and the neurosurgeon, and the lack of training is an additional potential limiting factor. However, confocal microscopy
is a rapidly growing field, and courses on confocal microscope use and data
interpretation are becoming more readily available. Another limitation is
the production of an abundance of images during the procedure, which can
overburden the surgeon or the pathologist. However, to reduce time, these
can be viewed as a video stream. The number of images can also be limited
by using adjunct programs for computer-aided sorting and diagnosis. These
programs could allow the preselection of diagnostic images and even suggest possible differential diagnoses, potentially significantly expediting the
10
process of imaging interpretation in the future.
Clinical use has shown,
however, that informative or actionable surgical images can be obtained
within seconds of the initiation of scanning.
Future Directions
In vivo confocal imaging of intracranial and spinal neoplasms and diseases has great potential to change how we approach intraoperative diagnosis. Diagnostic error by surgical missampling, a common problem in
current intraoperative diagnosis, may be lessened by the use of CLE. Common diagnostic complicating factors, such as frozen section artifact and
cautery artifact, may also be avoided. Time to diagnosis is shortened with
CLE, as images are viewed in real time, possibly having implications for
Central Nervous System 201
surgical margin evaluation. In vivo tumor imaging ma y also improve the
selection of a cellular neoplasm for molecular testing and tissue banking.
Because all images are captureddigitally, electronic transmittal of images to
pathologists distant from the neurosurgical suite is another potential application. Digital images can also be stored in electronicdatabases or libraries.
Developments of new tumor-targeting probes with high selectivity and
brighter fluorescent signal, such as targeted antibodies,
and switchable aptamers,
16
could further advance the field of CLE. The
15
metabolic probes,
current CONVIVO system has been augmented with a surgeon-pathologist
online cloud-based secure “workplace.” This system allows for an intraoperative real-time inspection of images and discussion of the tissue being
imaged, essentially bringing the pathologist into the operating room. The
pathologist can log in from anywhere to view and discuss the images. Such
a system may play a great role in arriving at timely surgical decisions,
obtaining other opinions of the tissue, or assisting in situations in which a
specialist in neuropathology is not otherwise available.
17,18
The incorporationof this novelmethod of optical imaginginto the neurosurgical operating suite and pathology laboratory workflow could shape
the future of how we approach surgical resection and intraoperative diagnosis of brain tumors.Thus, it has the potential to improvegross-total resection
and more rapid intraoperative tissue diagnosis.
Disclosures
Instrument provided by Carl Zeiss Meditec, AG, Oberkochen, Germany.
Zeiss had no influence on the study design, data acquisition, analysis, paper
preparation, or decision to publish. This study was funded in part by funds
from the Newsome Chair in Neurosurgery Research held by Dr. Preul and
the Barrow Neurological Foundation.
Financial Support
None declared.
202 J. M. Eschbacher
et al.
Acknowledgments
The authors thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.
Abbreviations
CLE, confocal laser endomicroscopy; CNS, central nervous system.
References
1. Martirosyan, N. L., Eschbacher, J. M., Kalani, M. Y., et al. Prospective evaluation
of the utility of intraoperative confocal laser endomicroscopy in patients with brain
neoplasms using fluorescein sodium: Experience with 74 cases. Neurosurgical Focus,
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2. Martirosyan, N. L., Georges, J., Eschbacher, J. M., Cavalcanti, D. D., Elhadi, A. M.,
Abdelwahab, M. G., Scheck, A. C., Nakaji, P., Spetzler, R. F., Preul, M. C. Potential
application of a handheld confocal endomicroscope imaging system using a variety
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3. Abramov, I., Park, M. T., Belykh, E., Dru, A. B., Xu, Y., Gooldy, T. C., Scherschinski,
L., Farber, S. H., Little, A. S., Porter, R. W., Smith, K. A., Lawton, M. T., Eschbacher,
J. M., Preul, M. C.: Intraoperative confocal laser endomicroscopy: prospective in vivo
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(2022).
4. Belykh, E., Zhao, X., Ngo, B., Farhadi, D. S., Kindelin, A., Ahmad, S., Martirosyan,
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Neurosurgery, 116(4): 854–860 (2012).
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the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas. Journal
of Neurosurgery, 115(4): 740–748 (2011).
9. Pavlov, V., Meyronet, D., Meyer-Bisch, V., et al. Intraoperative probe-based
confocal laser endomicroscopy in surgery and stereotactic biopsy of low-grade and
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10. Izadyyazdanabadi, M., Belykh, E., Martirosyan, N., et al. Improving utility of brain
tumor confocal laser endomicroscopy: Objective value assessment and diagnostic
frame detection with convolutional neural networks. Paper presented at: SPIE Medical
Imaging. https://arxiv.org/abs/1801.02101 (2017).
11. Wright, J. R. Jr. The development of the frozen section technique, the evolution of surgical biopsy, and the origins of surgical pathology. Bulletin of the History of Medicine,
59(3): 295–326 (1985).
12. Brainard, J. A., Prayson, R. A., and Barnett, G. H. Frozen section evaluation of stereotactic brain biopsies: Diagnostic yield at the stereotactic target position in 188 cases.
Archives of Pathology & Laboratory Medicine, 121(5): 481–484 (1997).
13. Zoeller, G. K., Benveniste, R. J., Landy, H., Morcos, J. J, Jagid, J. Outcomes and management strategies after nondiagnostic stereotactic biopsies of brain lesions. Stereo-
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14. Meyer, M., Keith-Rokosh, J., Reddy, H., Megyesi, J., and Hammond, R. R. Sources
of error in neuropathology intraoperative diagnosis. Canadian Journal of Neurological
Sciences, 37(5): 620–624 (2010).
15. Martirosyan, N. L., Georges, J., Kalani, M. Y., et al. Handheld confocal laser
endomicroscopic imaging utilizing tumor-specific fluorescent labeling to identify
experimental glioma cells in vivo. Surgical Neurology International, 7(Suppl 40):
S995–S1003 (2016).
16. Georges, J. F., Liu, X., Eschbacher, J., et al. Use of a conformational switching aptamer
for rapid and specific ex vivo identification of central nervous system lymphoma in a
xenograft model. PLoS One, 10(4): e0123607 (2015).
17. Abramov, I., Park, M. T., Gooldy, T. C., Xu, Y., Lawton, M. T., Little, A. S., Porter,
R.W.,Smith,K.A.,Eschbacher,J.M.,andPreul,M.C.Real-timeintraoperative
telesurgical pathology using confocal laser endomicroscopy. Neurosurg Focus, 52(6):
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Lawton, M. T., Eschbacher, J. M., Preul, M. C. Introduction of in vivo confocal laser
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© 2024 World Scientific Publishing Company
https://doi.org/10.1142/9789813206984_0011
Head and Neck Chapter
11
Daniel Kwon∗, Brett A. Miles†, and
Alexandros D. Polydorides
Introduction
‡
The majority of head and neck malignancies arise from the mucosa of
the upper aerodigestive tract. Specifically, squamous cell carcinomas comprise greater than 90% of these cancers and often have relatively poor outcomes.
accepted that carcinomas arise from an accumulation of genetic and molecular alterations that allow cells to progress to a malignant phenotype.
This step-wise model of carcinogenesis is evidenced by the histologic
∗
University of Southern California, Los Angeles, USA.
†
lar Reconstructive Surgery, Oral and Maxillofacial Surgery, Lenox Hill Hospital; Manhattan
Eye Ear and Throat Hospital; Northwell Health System, New York, USA.
‡
at Mount Sinai/The Mount Sinai Hospital, New York, USA.
1
While the field of carcinogenesis is ever expanding, it is generally
2, 3
Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine,
Otolaryngology Head and Neck Surgery , Division Head and Neck Oncology, Microvascu-
Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine
205
206 D. Kwon
et al.
changes of gradually increasing epithelial dysplasia (semiquantitatively
graded in squamous epithelium as mild, moderate, and severe) as aprecursor
to invasive carcinoma. Additionally, the concept of “field cancerization”
(i.e. histopathologic changes of a premalignant phenotype extending wider
than and identified in tissue adjacent to a known tumor) supports the progression model of tissue through the steps of molecular carcinogenesis.
Considering this, multiple optical modalities have been developed to
attempt to improve head and neck cancer outcomes by examining surface
tissue changes. This chapter will review and address the role of optical
technologies in the treatment of head and neck cancer.
Applications
The utilization of in vivo optical imaging in head and neck surgery is centered on the principle that the cellular changes of cancerous or dysplastic
tissue can be detected on the squamous mucosal surface prior to grossly
visible disease. As cellular mutations and tissue alterations accumulate,
certain characteristics have been identified to delineate between normal
and abnormal tissues. These characteristics can range from subtle spectral
changes, or tagged molecular markers imperceptible to standard optical
techniques, to morphological cellular a nd nuclear changes which can be
readily demonstrated with microscopy. The common factor is that none
of these characteristics can be detected with the naked eye and that optical technology is required to evaluate the tissue. Regardless of imaging
modality, the recogniza nce of abnormal tissue is a valuable tool for diagnostics, surgical treatment, and surveillance. The individual characteristics
and accuracy of the optical system dictate its clinical applicability in this
setting.
4
Diagnosis and evaluation
Accurate diagnosis and staging of squamous cell carcinoma are essential
for risk assessment and treatment selection. The stage at presentation is the
most significantprognostic factor, but due to the rich lymphatic drainageand
propensity for symptomless growth in the upper aerodigestivetract, cancers
often present at a late stage (i.e. with lymph node metastases). Due to the
Head and Neck 207
multiple folds and c rypts in the oral cavity and pharynx, the location of the
primary tumor can often prove difficult to identify with up to 10% of cases
having no identifiable primary tumor on routine exam. Additionally, squamous cell carcinomas of the head and neck typically arise from precursor
lesions of dysplasia and carcinoma in situ, providing a particularly attractive target for early detection and treatment. In high-risk patients (previous
cancer, history of tobacco or alcohol abuse, or lichen planus), screening
for lesions before they become invasive is crucial. Therefore, there is great
interest in improvements in localization of primary tumors as well as early
detection of pre-malignant lesions and early-stage cancers.
There have been several commercial and experimentaloptical systems
designed to aid in the detection and diagnosis of mucosal lesions of the
head and neck. Typically paired with a digital endoscope, these technologies include fairly simple surface evaluation, such as narrow-band imaging
and chromoendoscopy. These modalities detect abnormal tissue by focusing on irregular vascularity by filtering reflected wavelengths absorbed by
hemoglobin or by highlighting subtle surface changes using dyes. Lugol
chromoendoscopy has been described and shown to increase the diagnostic yield in detecting early superficial carcinomas, primarily in the esophagus. However, due to the discomfort caused by the topical application
of the staining solution, chromoendoscopy is not commonly used in the
5, 6
head and neck.
In contrast, narrow-band imaging has been well adopted
during the in-office and operative endoscopic evaluation to help in screening and detection of early cancers.
7
Narrow-band imaging is non-invasive
and easy to use. Coupled with a high-definition endoscopic camera, it can
highlight surface microvasculature, detecting characteristic irregular vascular patterns in dysplastic and cancerous tissue. It has been shown in
prospective, randomized controlled trials to be superior to regular white
light endoscopy in detecting early squamous cell cancers with higher sen-
7,8
sitivity and accuracy.
Its usage is especially helpful in guiding biopsies
for cancer screening in patients with history of smoking or alcohol use who
often exhibit field cancerization. Nevertheless, narrow-band imaging does
not offer ideal sensitivity and specificity in order to detect positive margins
in malignant mucosal cancers with a high degree of accuracy. This lack of
specificity is a common disadvantage among imaging systems that examine
tissue morphology rather than molecular, fluorescent, or spectral signals.
208 D. Kwon
et al.
Such optical systems often focus on examining the intrinsic fluorescence of normal and abnormal mucosa in the oral cavity and oropharynx.
A wide array of devices have been developedlooking at epithelial or subepithelial characteristics for purposes of improved detection and diagnosis.
10
Simple office screeninglights such as the Velscope (LED Medical Diagnostics, Vancouver, Canada) have been shown to aid in visualization of oral
mucosal lesions, often uncovering previously undetected lesions. These
devices can detect the loss of normal tissue autofluorescence that has been
described due to metabolic and structural changes occurring at the cellular
level. These devices are commonly used in the dental or general otolaryngology practice setting for cancer screening, but in clinical trials, they also
suffer from reduced accuracy and have not been shown to be able to reliably distinguish high- from low-risk lesions, having poor sensitivity and
11,12
specificity.
Thus, they have not been able to significantly guide treat-
ment or workup decisions.
More advanced optical technologies utilizing fluorescence have also
been explored for use in head and neck cancer detection. By incorporating contrast agents, tumor-specific probes, and confocal microscopy, they
aim to identify precancerous and cancerous tissues. There are several fluorescent nanoprobes that have been studied that are activated by the tumor
tissue via various pathways, including antibodies, pH activation, and tumorspecific enzymes.
13–16
These activated probes can help distinguish tumor
from normal tissue in vivo. Laser-induced fluorescence spectroscopy has
been shown to reliably delineate cancerous tissue from normal by focusing on the spectroscopic properties of specific biomolecules.
17,18
Confocal
microscopy allows for in vivo microscopic examination and was first incorporated in upper and lower gastrointestinal endoscopy. Probes specifically
designed for use in the oral cavity and upper aerodigestive tract have now
19,20
been developed.
Often described with topical or intravenous contrast
agents, laser-scanning confocal endomicroscopy allows for visualization
of surface and subepithelial microscopic tissue characteristics indicative
of cancer, such as microvascular changes and disorganized tissue architecture. Pilot studies have demonstrated the ability of confocal microscopy to
identify dysplasia and early carcinomas in animal and human models.
21,22
These studies suggest that confocal microscopy may be used to direct biopsies and even provide an in vivo “optical biopsy”.
9
Head and Neck 209
Currently, most in vivo optical technologies studied for diagnosis and
detection of head and neck cancer rely on relatively superficial evaluation.
High-resolution ultrasonography and optical tomography survey tissue at
greater depth than confocal microscopy or conventional fluorescent optical
systems. Both optical tomography and high-resolution ultrasonography are
able to evaluate multiple tissue levels and produce computer-assisted threedimensional images. By observing disrupted tissue planes and vasculature,
oral cancers havebeen reliably identified in animal and human models.
23–25
While many of these modalities are experimental, there is a clear role that
optical technologies can play in head and neck cancer care as an adjunct
for identifying and characterizing high-risk lesions.
Surgical treatment
While there have been considerable growth and utilization of nonsurgical treatment of these cancers, such as radiation, chemotherapy, and
immunotherapy, surgical ablation remains a tenet of head and neck cancer
treatment. Complete (i.e. margin-negative) removal of the malignancy is a
crucial prognostic factor for overall survival and disease-free control.
Currently, the standard of care is conventional light field microscopic
evaluation of the surgical margins, utilizing intraoperative pathologic consultation (“frozen section”) with routine permanent processing for followup (Figure 1). However, there are several limitations and pitfalls in this
approach including unpredictable tumor growth patterns, the complex
three-dimensional nature of the upper digestive tract, sampling and processing errors, and false negative interpretations.
28–30
In vivo optics and imaging have been applied to help guide surgical
resections as well as provide real-time margin evaluation. High-resolution
microendoscopy utilizes a fiberoptic imaging probe and offers real-time
images of cellular morphology and architecture in the tissue. These images
can clearly delineate normal from cancerous mucosa similarly to standard cross-sectional light microscopy (Figures 2(a–b)). High-resolution
microendoscopy has been shown, in both ex vivo and in vivo studies, to
have >90% accuracy, sensitivity, and specificity in diagnosing benign versus neoplastic mucosa in a variety of head and neck sites when compared
to hematoxylin-and-eosin-stained sections under light microscopy.
26,27
31,32