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60 B. Sanabria
(c)(
)
et al.
(a)
Figure 2. RCM images at the DEJ. (a) Normal skin with an edged ring pattern of papillae.
(b) A melanoma with numerous bright atypical cells present around the hair follicle in the center
of the image. (c) Lentigo maligna, a form of melanoma in situ. (d) A benign melanocytic nevus at the
DEJ. The green arrows indicate dermal nests. Each square represents a 0.5 × 0.5 mm
(b)
d
2
area.
elastosis, and tumor aggregates.16A meta-analysis of RCM studies for
AK, SCC, SCC in situ, and KA found an overall range of sensitivity and
specificity of 79–100% and 78–100%, respectively.
17
Beyond diagnosis, RCM can be used for pre-surgical and intraoperative margin mapping, evaluating non-surgical treatment response, and
monitoring for cancer recurrence.
18
There are some important limitations of reflectance confocal
microscopy. As previously mentioned, reflectance confocal microscopes
are limited to a depth of 250 mm. This impedes the assessment of hypertrophic and deep nodular lesions, as well as lesions on volar skin where
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Figure 3. RCM image of BCC at the level of the dermis. The yellow arrows indicate the borders of
tumor lobules.
the stratum corneum is thicker. There are also areas of the body that cannot be accessed by the microscope probe. Reading RCM images requires
a trained interpreter. Finally, the microscope itself represents a significant
investment.
increasing body of evidence supporting its use, it is inevitable that
reflectance confocal microscopy will become widespread in clinical practice. It is important for pathologists and clinicians to be familiar with this
technology and the interpretation of RCM images as its adoption increases.
Electrical Impedance Spectroscopy (EIS)
Electrical impedance spectroscopy was developed in the 1990s and
uses measurements of electrical impedance to differentiate normal and
Subsequent to the approval of CPT reimbursement codes and the
62 B. Sanabria
et al.
(a)
(c)
Figure 4. RCM image of (a) normal skin and (b) actinic keratosis at the level of the epidermis. The
white arrows indicate focal keratinocyte dysplasia. (c) Squamous cell carcinoma at the level of the
epidermis. There are large areas of dysplastic keratinocytes.
(b)
cancerous skin. A handheld probe with a disposable electrode is applied
to the skin. The probe contains pins that penetrate the stratum corneum
and measure impedance at frequencies between 1 kHz and 2.5 MHz at
four depths in 10 permutations. Impedance at lower frequencies depends
on the extracellular environment, while at higher frequencies, it depends
on the intracellular environment, the extracellular environment, and the
properties of cell membranes. The 150 mV voltage and 75 µA current are
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Figure 5. EIS in practice. Photo courtesy of SciBase.
64 B. Sanabria
et al.
imperceptible to the patient and the entire study takes a few seconds to
perform. A score from 0 to 10 is calculated and a dichotomous negative or
positive result is displayed on a touch screen.
A multicenter, prospective, blinded study of 1951 patients used EIS
on lesions determined to be suspicious by dermatologists and scheduled
to be excised. The EIS system yielded an observed sensitivity of 100%
for non-melanoma skin cancer (NMSC). The sensitivity and specificity for
melanoma were 96.6% and 34.4%, respectively.
19
EIS has not been well studied for other lesions such as lentigines and
EIS may incorrectly classify seborrheic keratosis as malignant.
20
Further
work is required to determine if EIS is a ble to differentiate between different subtypes of skin cancer. While the specificity of EIS and its ability to
distinguish between different pathologies is not as great as that of OCT or
RCM, its advantage is its speed and simple interpretation.
Future Directions
The three technologies discussed in this chapter, OCT, RCM, and EIS, have
been developed over decades. Their safety and efficacy have been established in international, multicenter, prospective studies. More research is
necessary to create and standardize better diagnostic algorithms. The capabilities of these devices will continue to improve. It will be incumbent on
clinicians and pathologists to learn to use these systems, interpret their
results, and incorporate them into patient care. While histology will remain
the gold standard, it is inevitable that in vivo microscopy will fill the space
between visual inspectionand biopsy and will spread beyondresearch institutions into clinics everywhere.
References
1. Levine, A., Wang, K., and Markowitz, O. Optical coherence tomography in the diagnosis of skin cancer. Clinics in Dermatology, 35(4): 465–488 (2017).
2. Olsen, J., Themstrup, L., De Carvalho, N., Mogensen, M., Pellacani, G., and Jemec,
G. B. Diagnostic accuracy of optical coherence tomography in actinic keratosis and
basal cell carcinoma. Photodiagnosis and Photodynamic Therapy, 16: 44–49 (2016).
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Ulrich, M., Themstrup, L., De Carvalho, N., et al. Dynamic optical coherence tomog-
raphy in dermatology. Dermatology (Basel), 232(3): 298–311 (2016).
3. Gambichler, T., Plura, I., Schmid-wendtner, M., et al. High-definition optical coherence tomography of melanocytic skin lesions. Journal of Biophotonics, 8(8): 681–686
(2015).
4. Gambichler, T., Plura, I., Kampilafkos, P., et al. Histopathological correlates of basal
cell carcinoma in the slice and en face imaging modes of high-definition optical
coherence tomography. British Journal of Dermatology, 170(6): 1358–1361 (2014).
5. Maher, N. G., Blumetti, T. P., Gomes, E. E., et al. Melanoma diagnosis may be a pitfall
for optical coherence tomography assessment of equivocal amelanotic or hypomelanotic skin lesions. British Journal of Dermatology, 177(2): 574–577 (2017).
6. Wang, K. X., Meekings, A., Fluhr, J. W., et al. Optical coherence tomography-based
optimization of Mohs micrographic surgery of Basal cell carcinoma: A pilot study.
Dermatologic Surgery, 39(4): 627–633 (2013).
7. Sattler, E., Kästle, R., and Welzel, J. Optical coherence tomography in dermatology.
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8. Rajadhyaksha, M., Marghoob, A., Rossi, A., Halpern, A. C., and Nehal, K. S.
Reflectance confocal microscopy of skin in vivo: From bench to bedside. Lasers in
Surgery and Medicine, 49(1): 7–19 (2017).
9. Pellacani, G., Guitera, P., Longo, C., Avramidis, M., Seidenari, S., and Menzies, S.
The impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of
melanoma and equivocal melanocytic lesions. Journal of Investigative Dermatology,
127(12): 2759–2765 (2007).
10. Giambrone, D., Alamgir, M., Masud, A., Bronsnick, T., and Rao, B. The diagnostic
accuracy of in vivo confocal microscopy in clinical practice. Journal of the American
Academy of Dermatology, 73(2): 317–319 (2015).
11. Stevenson, A. D., Mickan, S., Mallett, S., and Ayya, M. Systematic review of diagnostic accuracy of reflectance confocal microscopy for melanoma diagnosis in patients
with clinically equivocal skin lesions. Dermatology Practical & Conceptual, 3(4):
19–27 (2013).
12. Pellacani, G., Cesinaro, A. M., and Seidenari, S. Reflectance-mode confocal
microscopy of pigmented skin lesions — Improvement in melanoma diagnostic specificity. Journal of the American Academy of Dermatology, 53(6): 979–985 (2005).
13. Kadouch, D. J., Schram, M. E., Leeflang, M. M., Limpens, J., Spuls, P. I., and Derie,
M. A. In vivo confocal microscopy of basal cell carcinoma: A systematic review of
diagnostic accuracy. Journal European Academy of Dermatology and Venereolo gy,
29(10): 1890–1897 (2015).
14. Haroon, A., Shafi, S., and Rao, B. K. Using reflectance confocal microscopy in skin
cancer diagnosis. Clinics in Dermatology, 35(4): 457–464 (2017).
15. Shahriari, N., Grant-kels, J. M., Rabinovitz, H., Oliviero, M., and Scope, A. In vivo
reflectance confocal microscopy image interpretation for the dermatopathologist.
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16. Nguyen, K. P., Peppelman, M., Hoogedoorn, L., Vanerp, P. E., and Gerritsen, M. P.
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17. Hibler, B. P ., Cordova, M., Wong, R. J., and Rossi, A. M. Intraoperative real-time
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© 2024 World Scientific Publishing Company
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https://doi.org/10.1142/9789813206984_0005
Upper Gastrointestinal Tract Chapter
5
Daniel Schmolze∗and Vani J. A. Konda
†,‡
Introduction
In vivo microscopy of the upper gastrointestinal tract is highly developed,
particularly for the esophagus. FDA-approved devices are available and are
being used clinically, validated diagnostic criteria have been published, and
in vivo microscopy training has become incorporated into some gastroenterology training programs.
The dominant technologies are optical coherence tomography (OCT)
and confocal laser endomicroscopy (CLE). Endomicroscopy has been successfully applied to a broad range of applications in the upper gastrointestinal tract, including Barrett’s esophagus, Gastric neoplasia, and H. Pylori
gastritis.
This chapter will provide a broad overview of the major advances and
current state of the art with a focus on the esophagus and stomach.
∗
Digital Pathology, City of Hope National Medical Center, Duarte, CA, USA.
†
Baylor Scott & White Center for Esophageal Diseases, Dallas, TX, USA.
‡
Texas A&M College of Medicine, Dallas, TX, USA.
67
68 D. Schmolze & V. J. A. Konda
Esophagus
In vivo microscopy has one of the most robust experiences in Barrett’s
esophagus (BE). Barrett’s esophagus, which is the replacement of the normal esophageal squamous lining with specialized intestinal metaplasia, is
a risk factor for the development of esophageal adenocarcinoma. Patients
with multiple risk factors for esophageal cancer are screened for Barrett’s
esophagus with an upper endoscopy. Those patients who have BE undergo
routine endoscopic surveillance every three to five years to monitor for the
development o f dysplasia. High-grade dysplasia (HGD) and intramucosal
carcinoma are amenable to endoscopic therapy, which offers minimally
invasive approaches to either cure or prevent esophageal cancer. Despite
these a dvances in endoscopy therapeutic strategies, a challenge remains in
identifying who may be harboring dysplasia when early neoplastic lesions
are often subtle. While the standard of care approach is to perform biopsies
of visible lesions and then four-quadrant biopsies at every one to two centimeters of Barrett’s segment to assess for occult neoplasia, this approach
is subject to both sampling error as well as poor adherence.
Endomicroscopy enables the endoscopist to map out more of the
esophagus than would be achieved by histological biopsies alone. Thus,
tissue acquisition may potentially be optimized to take “smarter” biopsies
that have a higher yield of pathology and decrease the number of random
negative surveillance biopsies. Endomicroscopy platforms that have been
widely used in the esophagus include confocallaser endomicroscopy (CLE)
and optical coherence tomography (OCT)-based technologies.
Confocal laser endomicroscopy providesreal-time microscopic imaging of the esophageal epithelium down to a resolution between 0.7 and 1.0
microns. CLE requires the use of a contrast agent in the gastrointestinal
tract, and the most commonly used agent is intravenous fluorescein. Imaging characteristics have been classified to enable differentiation between
squamous epithelium, cardia, Barrett’s esophagus, and neoplasia for each
probe-based confocal laser endomicroscopy (pCLE) and endoscope-based
confocal laser endomicroscopy (eCLE).
variable depth of imaging from 0 to 250 microns, whereas the pCLE platform has a fixed depth of imaging of around 65 microns for the probe used
1,2
The eCLE platforms enable
Upper Gastrointestinal Tract 69
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(a) (b) (c)
(d) (e) (f )
Figure 1. Squamous epithelium and Barrett’s esophagus in probe-based confocal laser endomicroscopy. Probe-based confocal laser endomicroscopy images are demonstrated in A, B, and C.
Squamous epithelium are typically flat cells as shown in (a). Villiform architecture is seen with
columnar-lined epithelium in non-dysplastic Barrett’s as shown in (b) and (c). Goblet cells (red arrows)
may be seen with variable density on imaging as demonstrated in (c), which has more prominent
goblet cells. Representative histological images are shown in (d) of squamous epithelium and (e) and
(f) of non-dysplastic Barrett’s esophagus.
most commonly in the esophagus. In squamous epithelium, visualization
of the fine, flat cells may be appreciated as well as occasional interspersed
interpapillary capillary loops. In non-dysplastic Barrett’s esophagus, there
is a regular villiform architecture with the columnar lined epithelium with
mucin-filled goblet cells (see Figure 1). In gastric cardia, typically there
are round glandular structures with occasional vessels, particularly in the
deeper layers. Areas suspicious for high-grade dysplasia or adenocarcinoma demonstrate disorganization or loss of that architecture, black or
darker cells, and more irregular vessels. Additional criteria proposed to
differentiate dysplasia from non-dysplastic Barrett’s esophagus include
two or more of the following: epithelial surface appears saw-tooth, goblet cells are not equidistant, glands are unequal in size and shape, cells are
enlarged, or cells are irregular and not equidistant from one another (see
Figure 2).
3