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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5528_Библиотеки_им_академика_М_И_Перельмана.pdf
260 J. Mirkovic & E. Yang
the excision of tumors with narrow surgicalmargins as well as ex vivo imaging to confirm complete excision. The authors note that RCM complements
dermatoscopic findings by providing real-time microscopic confirmation
of atypical macroscopic features; brown dots seen on dermatoscopy corresponded to tumor islands on RCM and grayish pigmentation corresponded
to melanophages.
Extramammary Paget disease (EMPD)
EMPD of the vulva is a rare neoplasm that is notoriously difficult to treat
due to high recurrence rates and microscopically positive margins despite
aggressivesurgery.
80
The prospect of real-time margin assessment by IVM
is exciting; however, data are limited to date. Escobar et al. report examining three cases of EMPD by OCT, with features of disease involvement
including epithelial irregularity and loss of a clearly defined basement
membrane.
81
Vagina
Histopathologic overview
The vaginal wall consists of mucosa, muscle, and adventitia, of which the
mucosal layer (epithelium and submucosal stroma) is the primary target
of IVM analysis. The vaginal mucosa is characterized by an undulating
rugal pattern unlike the flat cervical mucosa. This may introduce unique
challenges when evaluating the vagina by IVM. Otherwise, the vaginal
mucosa is anatomically in continuation with the cervical mucosa and the
non-keratinizing squamous epithelium is microscopically indistinguishable. Epithelial thickness varies during the menstrual cycle but is generally about 0.5 mm thick, allowing full thickness evaluation by most
OCT devices. The submucosa is scantly cellular and consists of scattered
fibroblasts embedded within stromal connective tissue that include varying
proportions of collagen and elastin fibers, as well as non-fibrillar ground
substance. As in the vulva, squamous cell carcinoma is the most common
epithelial neoplasm, with the majority attributable to HPV. These lesions
Gynecologic Tract 261
are indistinguishable from the other HPV-driven squamous lesions of the
lower anogenitaltract.
73
Adenocarcinomais rare and occurs predominantly
as clear cell carcinoma or endometrioid adenocarcinoma; metastatic adenocarcinoma must also be considered. Other tumors include small-cell neuroendocrine carcinoma, melanoma, and stromal malignancies (embryonal
rhabdomyosarcoma and leiomyosarcoma). Pelvic organ prolapse and vulvovaginal atrophy are non-neoplastic disorders involving the vagina that
negatively impact the quality of life in postmenopausal women.
IVM features of normal vagina
By OCT at resolutions ranging from 15μmto20μm, predominantly archi-
tectural features of vaginal epithelium are appreciated, including a welldefined squamous epithelium clearly demarcated from the underlying stromal tissue.
mated evaluation of vaginal imaging by OCT has been attempted using a
segmentation algorithm that quantitatively differentiates epithelium from
underlying stroma.
implementation of IVM-aided cancer screening that benefits from largevolume imaging.
82
Cytomorphology is not well defined at this resolution. Auto-
83
Such algorithms will likely become integral for the
IVM features of vaginal pathology
Squamous dysplasia and carcinoma
There is limited IVM literature dedicated to the evaluation of vaginal squamous neoplasia. Available reports significantly overlap with the cervix,
and the reader is referred to the prior section for a comprehensive review
of cervicovaginal squamous lesions.
Vaginal atrophy
Vulvovaginal atrophy (VVA) is a common disorder associated with vaginal dryness, irritation, and dyspareunia that negatively impact the quality
of life in postmenopausal women. Treatments include vaginal moisturizers, topical estrogen, and microablative fractional CO
laser treatment.
2
262 J. Mirkovic & E. Yang
Non-invasive monitoring of treatment efficacy may be beneficial, and to
this end, Vincent et al., using OCT, report success in measuring changes in
the thickness of sheep vaginal epithelium treated with nonoxynol-9 (N-9),
a spermicidal agent that causes epithelial thinning.
83
The composition of
the submucosal stromal tissue may contribute to the symptoms of VVA as
well as pelvic organ prolapse. Although evaluated in ex vivo specimens,
Sikora et al. reported the ability to quantify collagen and elastin content in
the vaginal wall using label-free, multiphoton microscopy.
84
In vivo evaluation of submucosal stromal content could be useful in the comprehensive
evaluation of pelvic floor dysfunction.
Uterine Corpus
Major components of the uterine corpus include the endometrium,
myometrium, and serosa. The endometrium is most commonly sampled for
histologic evaluation in the settingof abnormal uterine bleedingand infertility. The usual suspects include endometrial polyp, submucosal leiomyoma,
endometritis, hormonal alteration, and neoplasia. Submucosal leiomyoma
is generally detected on ultrasound. Endometritis requires a careful search
for stromal plasma cells and is best evaluated on histologic sections in
conjunction with immunohistochemical stains for the most subtle cases.
When endometrial polyps, hormonally altered endometrium, and neoplastic lesions are being evaluated, meticulous assessment of cytomorphologic and architectural features is necessary to distinguish benign changes
from hyperplasia, neoplasia, and carcinoma. Such distinctions are sufficiently challenging on histologic sections with significant interobserver
variability. Furthermore, tissue is needed not only for diagnosis but also for
prognostic ancillary testing for placement into clinically relevant molecular subgroups (POLE mutated, mismatch repair deficient, p53-mutated/
copy-number high, and p53-wild type/copy-number low).
studies demonstrating the possibility of distinguishing benign from malig-
86
nant endometrium by confocal microscopy;
however, in my opinion,
IVM in the current form is not suitable for the evaluation of neoplastic endometrium. Similar arguments may be made for the evaluation of
85
There are pilot
Gynecologic Tract 263
myometrial lesions. With the exception of the most obviously malignant
cases, the distinction of benign vs. malignant smooth muscle neoplasms
can be extremely challenging, with significant subjectivity in the interpretation of malignant features (cytologic atypia, mitotic activity, and tumor
cell necrosis) that is best left for histologic evaluation. A potential exception is the use of IVM to detect myometrial infiltration by an endometrial
stromal neoplasm. Cytologic features cannot distinguish endometrial stromal nodules (benign) from low-grade endometrial stromal sarcoma; the
diagnosis of sarcoma is made by myometrial infiltration or lymphovascular
invasion. Therefore, we may speculate that a biopsy specimen showing an
endometrial stromal proliferation in conjunction with IVM imaging showing myometrial infiltration may facilitate the rendering of a sarcoma diagnosis that would otherwise only be made on hysterectomy. IVM literature
evaluating the uterine corpus is scant and is limited to small pilot studies or
in vivo/ex vivo microscopy of animal models exploring uterine vasculature
and myometrial contractility.
Ovary
Histopathologic overview
The ovarian surface consists of a modified peritoneal epithelium that varies
from cuboidal to ciliated tubal-type columnar cells. These epithelial cells
are separated from the underlying ovarian stroma by a basement membrane.
Ovarianstroma consists of fibroblastic-type spindle cells arranged in a storiform pattern, within which are follicles at varying densities and at various
stages of maturation, depending on the patient’s age. Non-neoplastic ovarian pathology includes benign cysts and endometriosis, as well as changes
related to the hormonal milieu and inflammation. Ovarian tumors are predominantly composed of epithelial-stromal tumors (including borderline
tumors and carcinomas) of various histologic types (endometrioid, serous,
clear cell, transitional, etc.). Mullerian-type sarcomas, includingendometrioid stromalsarcoma, adenosarcoma, and leiomyosarcomamay also be seen.
Sex cord-stromal tumors (fibroma, thecoma, adult granulosa cell tumor,
264 J. Mirkovic & E. Yang
Sertoli-Leydig cell tumor, etc.) as well as germ cell tumors (teratoma,
dysgerminoma, yolk sac tumor, embryonal carcinoma, choriocarcinoma,
etc.) are in the differential of ovarian tumors depending on patient age.
IVM features of normal ovary
OCT is able to evaluate normal microanatomical structures of the ovary,
including the surface epithelium, cortical stroma, inclusion cysts, and corpora albicans, as well as non-neoplastic abnormalities, such as endometriosis. The surface epithelial layer is generally not well visualized; however,
the boundary between the epithelial layer and underlying stroma is visualized as a bright signal.
hyperintense signal with a distinct wavy texture that likely represents the
collagen architecture of the ovarian stroma. Corpora a lbicans are seen as
variably sized, ill-defined hypointense regions. Epithelial inclusion cysts
and blood vessels appear as variably sized, well-defined hypointense ovoid
structures;blood vessels are distinguished from cysts by the shadowing they
cause in the underlying tissue due to light attenuation by blood contents.
Endometriosis may have a variety of appearances. It can be seen as loose
tissue and contour irregularities at the ovarian surface or as hypointense, illdefined cystic structures with mild shadowing underneath due to the bloody
contents.
En face confocal images of the normal ovary demonstrate a regularly spaced, closely packed population of uniformly sized surface
epithelial cells.
with elongated cellular morphology.
87
The c ortical stroma demonstrates a homogeneous
88
The underlying stromal cells are more loosely arranged
88
IVM features of pathologic ovary
Use of IVM for the detection of ovarian pathology has significant clinical potential. Currently, there is no effective program that screens and
detects ovarian cancer at an early stage. Therefore, women with high risk
(e.g. known BRCA mutation) may undergo risk-reducing bilateral salpingooophorectomy (BSO). IVM technology has the potential to detect ovarian
pathology at the time of laparoscopic imaging procedures with significantly
enhanced sensitivity and may become a viable alternative to risk-reducing
Gynecologic Tract 265
Figure 6. Examples of confocal microlaparoscope images of ovaries. The top images were obtained
from normal ovarian epithelial tissue and the bottom images are of ovarian cancer. This figure also
compares ex vivo and in vivo images. The bright punctate structures in these images correspond to
AO-stained nuclei. These images show that normal tissue is distinguished by a regular and uniformly
distributed cellular epithelium. Often, partially denuded epithelial and stromal layers are visible.
Typically, a heterogeneous distribution of size and spacing of nuclei is indicative of ovarian cancer.
The results demonstrated that the confocal microlaparoscope is capable of achieving comparable
image quality in vivo and ex vivo. The results also showed that normal ovary and ovarian cancer have
the same distinguishable features in both in vivo and ex vivo situations.
Source: Reprinted with permission from Risi et al.
89
BSO. Furthermore, accurate classification of lesional tissue as benign vs.
malignant with IVM at the time of surgery can reduce operative times by
avoiding frozen section consultations, which can be time-consuming.
A recent study by Risi et al. supports these notions.
89
Using a confocal microlaparoscope, images of ovarian surface epithelium were obtained
in vivo and ex vivo (Figure 6) that demonstrate monomorphic, evenly distributed nuclei in normal epithelium and significant nuclear size variation
and a rchitectural disarray in malignant epithelium. Diagnostic accuracy
was highest with high-grade lesions (high-grade serous carcinoma) when
compared to other lower-grade lesions (low-grade serous carcinoma and
266 J. Mirkovic & E. Yang
(a) (b) (c) (d)
(e) (f) (g) (h)
Figure 7. Ex vivo images of ovarian tissue stained with acridine orange. Subcaptions indicate
pathology diagnosis. (Circular field of view is 450 μm.)
Source: Reprinted with permission from Tanbakuchi et al.
90
mucinous carcinoma). Accurate tumor histotyping is best deferred to traditional histologic sections. They report that there were no significant discrepancies in diagnostic accuracy between pathologists and non-pathologists.
90
The findings reported by Tanbakuchi et al.
and Brewer et al.88are in
keeping with the above, with normal epithelium characterized by uniform,
evenly spaced cells and carcinoma characterized by increased nuclear size
and variation, as well as disordered architecture (Figure 7).
Hariri et al. utilized a laparoscopic OCT device to visualize ovaries
in patients undergoing laparoscopic oophorectomy.
87
Adenocarcinoma is
characterized by areas of poorly defined, heterogeneously hypointense
structures. The surrounding stroma exhibits increased heterogeneity compared to normal ovarian stroma and demonstrates increased vascularity
present as hypointense linear bands (longitudinal view) or ovoid structures
(cross-sectional view) with underlying tissue shadowing. If the carcinoma
is arising within a pre-existing cyst, there is contrast between the welldefined uniformly signal-poor simple cyst and the ill-defined, heterogeneously hypointense tumor characterized by architectural complexity and
necrosis (Figure 8). In keeping with the above, Brewer et al. found that
Gynecologic Tract 267
Figure 8. Serous cystadenoma and endometrioid adenocarcinoma: (a) OCT image of papillary
serous cystadenoma (4×1.4 mm) and (b) corresponding histopathology. (c) OCT image of endometrioid adenocarcinoma (4 × 1.4 mm) and (d) corresponding histopathology. OCT and histopathology
images are to scale. Scale bar, 500μm.
Notes: C: Cyst, Arrows: Blood vessels,S: Stroma, Circled region: Malignant glands, Asterisk: Imaging
system artifact.
Source: Reprinted with permission from Hariri et al.
87
tumor tissue is characterized by irregular hypointense regions of necrosis
and blood vessels of variable sizes that produce shadowing in the tissue
underneath.
88
An advantage of OCT is the depth of imaging that allows
visualization of tumor masses at the ovarian surface as well as those arising
in deeper seated cortical cysts.
268 J. Mirkovic & E. Yang
Combined modality imaging that integrates OCT, ultrasound, and
photoacoustic imaging promises enhanced tissue characterization by simultaneously providing high-resolution surface morphology, deeper tissue
architecture, and tissue vascularity.
91
Furthermore, by combining the principles of positron emission tomography (PET) and OCT, Yang et al.
mapped
distinguish normal ovaries from malignancies.
18
F-FDG uptake to areas of tissue abnormality to effectively
92,93
OCT in combination with second-harmonic generation microscopy allows high-resolution
microanatomical imaging with emphasized characterization of collagen
architecture,
94,95
which may uncover stromal characteristics associated
with epithelial malignancies.
In addition to morphological assessment, the innately digital nature
of OCT signal readily allows quantitation that could distinguish normal
and malignant ovarian tissue features (e.g. collagen content) that may not
96,97
be otherwise detectable.
Srivastava et al. have also demonstrated the
possibility of computer-aided automatic tumor detection by texture analysis
of confocal microendocope images.
98
Fallopian Tube
Histopathologic overview
The fallopian tube originates from the uterine cornua, extends laterally as
the ampulla and infundibulum, and terminates as the fimbriae, which are
finger-like structures that function to guide ova released from the ovaries
into the tubal lumen. The exterior surface of the fallopian tube (mesosalpinx) is lined by mesothelium. The muscular wall of the fallopian tube
(myosalpinx) is composed of an outer longitudinal s mooth muscle layer
and an inner circular layer. The mucosa of the fallopian tube (endosalpinx)
has a simple architecture toward the ampulla and develops progressively
complex branching folds (plicae) that terminate as the fimbriae. The epithelial lining of the fallopian tube consists of ciliated cells, secretory cells, and
intercalated cells that are thought to be modified secretory cells. The lamina
propria is composed of fibrovascular tissue and is in direct contact with the
myosalpinx.
Gynecologic Tract 269
Non-neoplasticabnormalities of the fallopian tube commonlyencountered in surgical pathology include salpingitis, ectopic pregnancy, and
endometriosis. Serous carcinoma is the most common primary tubal malignancy. It had been thought that ovarian surface epithelial cells are the origin of the majority of adnexal/ovarian tumors; however, recent evidence
suggests that majority of high-grade serous carcinoma arise from the fallopian tube fimbria.
99–102
The preinvasive counterpart of serous carcinoma
is the serous tubal intraepithelial carcinoma (STIC), which is characterized by severe nuclear atypia, loss of epithelial polarity, and evidence of
p53 mutation by immunohistochemistry. Majority of STICs are present
in the fimbriae and distal fallopian tube and may be detected in 5–10%
of salpingectomies of BRCA+ women and in 0.2–0.6% of the routine
103
specimen.
Early detection of these lesions is of paramount importance,
and today, this is largely attempted by prophylactic and opportunistic salpingectomies. Alternative modes of fallopiantube screening, such as through
brush cytology of the fallopian tube, have been suggested;
104,105
however,
further investigation is needed to establish the efficacy of these screening
modalities. IVM applications for non-invasive fallopian tube /ovarian cancer screening is an emerging field of investigation that demonstrates great
promise.
IVM features of normal fallopian tube
By in vivo confocal laser endomicroscopy (CLE), cellular resolution is
achieved and the normal fallopian tube demonstrates cells with uniform,
target-like structures and non-dilated regular vessels in the stroma.
Kirillin et al.
107
have utilized OCT to evaluate pelvic inflammatory
disease in the fallopian tube. A normal fallopian tube imaged from the
peritoneal surface appears unstructured. The single-layeredmesothelial cell
surface is not within the resolution of the system, and the ill-defined layers
of the myosalpinx likely produce the homogeneous appearance. In pelvic
inflammatory disease (PID) with subacute inflammation and edema, large
bands of hypointense areas corresponding to the edematous splaying of
the smooth muscle fibers are seen. In PID with chronic inflammation and
fibrosis, the image appears more heterogenous with areas of higher signal
(likely corresponding to the collagen content in fibrosis) compared to a
106