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6

Frozen Section Use in the


Diagnosis of Ovarian Pathology
Paul A. Cross

Abstract

This chapter aims to highlight the pros and cons of the use of a frozen
section (FS) in the diagnosis of ovarian pathology at the time of surgery.
Like all approaches, it is not perfect and does rely on a very close working
relationship between the pathologist and surgeon to ensure that when, and
if, it is used the maximum patient benefit is obtained. A FS (like all
diagnostic pathology) will never be fully accurate. However, if one accepts
its potential limitations, it can be a very good tool in the management of
patients with suspected ovarian pathology. This chapter will aim to
highlight major issues with the use of a FS service for ovarian diagnosis
and will outline potential pitfalls. It is not intended to be a textbook of FS
ovarian pathology the remainder of this book describes in far greater
detail the diagnostic criteria for ovarian pathology diagnosis. These still
apply even if based on FS material. A recent survey has shown that FS use
in the UK, when performed, is largely done for ovarian/pelvic masses and
lymph nodes in cervical cancer surgery.

Introduction
This chapter aims to highlight the pros and
cons of the use of a frozen section (FS) in the
diagnosis of ovarian pathology at the time of
surgery. Like all approaches, it is not perfect and
does rely on a very close working relationship
between the pathologist and surgeon to ensure

P.A. Cross, B Med Sci, MBBS, FRCPath


Department of Pathology,
Queen Elizabeth Hospital, Sheriff Hill,
Gateshead, Tyne and Wear NE9 6SX, UK
e-mail: paul.cross@ghnt.nhs.uk

that when, and if, it is used the maximum patient


benefit is obtained. A FS (like all diagnostic
pathology) will never be fully accurate. However,
if one accepts its potential limitations, it can be
a very good tool in the management of patients
with suspected ovarian pathology. This chapter
will aim to highlight major issues with the use of
a FS service for ovarian diagnosis and will outline potential pitfalls. It is not intended to be a
textbook of FS ovarian pathology the remainder of this book describes in far greater detail the
diagnostic criteria for ovarian pathology diagnosis. These still apply even if based on FS material. A recent survey has shown that FS use in

N. Wilkinson (ed.), Pathology of the Ovary, Fallopian Tube and Peritoneum,


Essentials of Diagnostic Gynecological Pathology,
DOI 10.1007/978-1-4471-2942-4_6, Springer-Verlag London 2014

133

P.A. Cross

134

the UK, when performed, is largely done for


ovarian/pelvic masses and lymph nodes in
cervical cancer surgery [1].

Why Do a Frozen Section?


The management of ovarian pathology is impossible without tissue to make a diagnosis. The ovaries can be the site of a vast range of pathologies,
from benign to malignant, with the added problem of borderline lesions, but can also be the presenting site of malignancy elsewhere as a
secondary deposit(s). For this reason, the surgeon/oncologist cannot base any rational treatment option until a definite diagnosis is arrived
at, to both benign and malignant but also to primary site (if possible). Given this, the ideal would
be preoperative diagnosis, but this is not always
possible. If there is a cytology sample (e.g.,
ascitic fluid, FNA), then this may yield a diagnosis (see Chap. 7). However, this can often be
inconclusive or at worst misleading [2], and a
histology sample will always remain the most
likely sample to yield a definitive diagnosis. It is
also important to decide in what circumstances a
FS will be used at operation. Is it for diagnosis of
malignancy (irrespective of stage), or is it only
for cases of potential early-stage disease? One
protocol can only do a FS for potential stage 1 or
2 disease, and hence a staging procedure may be
required, as opposed to a higher-stage disease
where debulking surgery rather than staging is
performed. It can be argued that these later
higher-stage cases are equally in need of diagnosis. However, the surgical approach is very different between the two.
Often much liked by surgeons, a FS can be
viewed with suspicion by pathologists. A FS can
be stressful for all involved and does require
guaranteed availability of laboratory staff and a
pathologist. There is also a large difference
between an occasional one off FS and a routine
FS service as is used in some centers for intraoperative ovarian diagnosis.
In clinical terms a FS offers the possibility of
a one-stage operation, rather than the more usual
biopsy-action flow (e.g., operate, take biopsy,

await report, and then reoperate some time later


to perform definitive surgery). This is more akin
to the see and treat vs. see and biopsy
approach used in colposcopy in which gynecological pathologists and surgeons are familiar
with. The one-stage FS approach can reduce the
need for a second operation and anesthetic, and
their inherent potential risks, but only if the FS
diagnosis is robust enough to ensure that correct
surgery is undertaken with a high probability of
success [2, 3].
A FS can also allow for tissue taken at one
hospital site to be remotely reported at another
hospital site if the correct technology and skills
are available [4]. This of course applies to all histology in principle, but given the need for rapid
diagnosis, the expertise to report a FS (given its
immediate patient management impact) does not
have to be at the same site as the actual surgery.
Given that fresh tissue will be sent to the laboratory for the FS to be taken, a FS service also
allows fresh tissue to be taken for research, given
of course that the correct patient consent and
research/ethics protocols are followed.

Ground Rules for FS Use


Before any FS is undertaken, both sides (surgeon
and pathologist) must understand the use and
issues with a FS. A FS will not always yield a
definite diagnosis, but this should be relatively
rare. Both sides should accept and understand
this. It is imperative that an agreed protocol is
decided upon before an ovarian FS is undertaken,
particularly with respect to cases called borderline on FS. If a FS is not going to affect what procedure the surgeon actually performs at that time,
then a FS is not needed this should go without
saying but does need emphasizing!
In reporting terms a FS diagnosis has one of
three outcomes: benign, malignant, or defer to
paraffin (relatively uncommon). Very few papers
quote a defer rate, but rates of zero [5] to up to
6.3 % [6] are quoted in studies with reasonable
numbers of cases. However, in ovarian pathology
there is also the category of borderline (BL). This
must be accounted for in any agreed protocol

Frozen Section Use in the Diagnosis of Ovarian Pathology

between pathologist and surgeon. This category


is certainly not as robust a diagnosis as one of
benign or malignant and the degree of inaccuracy
does appear to depend largely on the size/weight
and type of lesion [5, 7] and to some extent on the
experience of the reporting pathologist [8]. Our
protocol places a BL lesion into the malignant
category clinically and would evoke a staging
procedure. However not all would agree and feel
this could lead to unnecessary overstaging [9]. It
must be clear how a BL diagnosis will be
responded to in the clinical protocol. A diagnosis
of at least borderline is perfectly acceptable in
difficult BL/malignant cases [10] as it does aid
the surgeon.

FS Booking/Transport
Given that nearly all cases of suspected malignancy will be discussed within the setting of an
MDT preoperatively, cases where a FS may be
of use can be identified. This allows the surgeons
to plan their operating lists and equally allows
them to prewarn the laboratory of the need for a
FS ideally at least 24 hours in advance. This
allows the laboratory to ensure sufficient staffing, including alerting the pathologist. How such
a planned FS is dealt with and rostered within
the laboratory will depend on each individual
laboratorys approach to how it works. It is vital
to ensure a reporting pathologist is identified.
Given that a FS will only involve up to 510 min
of a pathologists time (description/block taking/
reporting), this should not be overly disruptive to
the pathologists routine working pattern. Such
prior booking also ensures that all staff involved
with the specimen transfer (in particular portering staff and lab reception staff) are alerted in
advance.
If the FS is no longer required for any reason,
it should also be self-evident that the surgical
team should inform the laboratory so that they
can be stood down for that FS.
It is obvious that a reliable cryostat is essential
to the performance of a FS. Most laboratories
within the UK will have one, but it is often infrequently used. In the UK, FS use is not common,

135

whereas in other countries, e.g., the USA, it is far


more used. Hence, in a UK laboratory the general
experience of the FS process is far more limited,
both at the technical and pathologist level. From
the technical point of view, it may require practice to ensure consistent, quality sections. This
must cover not only the freezing/section stage but
also hand staining.

How Long Does a FS Take?


Given that the patient is anesthetized, the time of
a FS must not materially impact on patient safety
in the operating room. One must factor in the
total time for the FS process from theater, transport to the laboratory, processing, and reporting.
For FS overall, Novis and Zarbo [11] found that
over 90 % of FS can be processed and reported
back to the surgeon within 20 min of receipt
within the laboratory. This is a target that is
achievable. Mean times of 18.5 min, range
1045 min, are reported [12], with the longer
times usually reflecting FS being taken on more
than one ovary or site.

Communication of Results
Whenever a FS is performed, clear, concise,
unambiguous communication is vital between
the requesting surgeon and reporting pathologist.
It should go without saying that the patient demographics on the request form and specimen pot
must be consistent with each other and easy to
read. The request form must state why the FS is
required and also any relevant clinical findings or
history. This should include operative findings,
but also any abnormal tumor markers. It must
also include any relevant medical history, and in
this context any previous history of malignancy is
essential. It is amazing how often such a history
appears to be forgotten about! Given the potential
for secondary malignancy presenting as an ovarian mass, any history of prior malignancy is vital
for the reporting pathologist. Such information
may allow the pathologist to suggest that any
malignancy may not be of ovarian origin and

P.A. Cross

136

hence point the surgeon in another direction.


However, it must also be remembered that this
may be the first presentation of an occult primary
malignancy elsewhere, and in this context the
separation (if possible) of a secondary malignancy from an ovarian primary can dramatically
affect the surgeons approach.
It is also vital that the form indicates who the
pathologist must contact to give the FS report.
Invariably this will be by telephone. Very few (if
any) operating theaters these days have the FS
taken and processed within the theater suite, and
most specimens are conveyed by portering staff
to the pathology laboratory for processing. It is
all too easy to waste 510 min ringing around to
find the correct operating theater or surgeon in
order to give back a report!
Given that any FS is an urgent request, it must
not be delayed in its transport or reporting. The
use of a high visibility FS form, e.g., yellow/
orange, can help ensure that LEAN visual management principles are applied [13].

Health and Safety Aspects


A FS is a fresh unfixed specimen and as such is
a potential health risk to anyone who may come
into direct contact with it. The specimen must be
transported in compliance with appropriate
guidance and is suitably identified as a fresh
specimen. Any standard operating procedure
(SOP) must cover aspects of potential spillage/
leakage, as well as handling for dissection
a

purposes to minimize any possible unnecessary


exposure. If the patient is of potential high-risk
category (e.g., hepatitis B positive, HIV positive), then consideration should be given as to
whether the FS could be avoided and routine histology performed to minimize any possible
exposure risks.

Gross Description/Block Selection


The gross description of the FS sample is just as
vital as the actual histological reporting. In general the FS will be a salpingo-oophorectomy but
depending on the operative findings may be an
oophorectomy, an ovarian biopsy, or just a pelvic mass. Occasionally a TAH/TLH with BSO
may be received. Whatever specimen is received,
the general principles of macroscopic description
apply [14]. Particular note should be made of any
defect/tear of any ovarian mass and as to whether
it is intact or not and if any obvious tumor is seen
on the ovarian surface or elsewhere. Weighing
the intact ovarian mass is advised for future reference. On section, mention must be made of the
nature of the ovarian lesion, i.e., solid, cystic, or
solid/cystic (Figs. 6.1 and 6.2). Is it obviously
necrotic or congested/hemorrhagic? If cystic, is it
uni- or multilocular? Do any cysts contain seroustype fluid, mucin, blood (fresh or clotted), or a
combination? Any obvious coloration may also
point to a potential lesion (e.g., some sex cordstromal hormone-producing lesions may have a
yellowish tinge). A full description, however, can
b

Fig. 6.1 Gross view of intact simple serous cyst (a) and of smooth, internal lining (b)

Frozen Section Use in the Diagnosis of Ovarian Pathology

137

Fig. 6.2 Gross view of simple mucinous cyst (a) and of multiloculated appearances on section (b)

await until after proper fixation and until routine


blocks are taken.
For a FS any tissue taken must try to be representative of the lesion overall and be reported
upon. Any necrotic areas must be avoided, as
must any obviously calcified foci, as they will not
process for a FS. If the lesion is solid, blocks
from apparently non-necrotic areas are advised.
If cystic, then any firm/raised/locule intersections
are recommended, as these appear more often as
the site of any possible atypia if present. If purely
cystic, then a Swiss roll approach can be used
to maximize the amount of cyst wall tissue taken.
If the whole lesion is apparently necrotic/
infarcted (and invariably congested), then the
least affected areas are advised. However, in the
latter circumstances, one may anticipate that the
FS may not be of diagnostic use.

How Many Blocks?


Any FS is a trade-off between obtaining a report
that represents the ovarian lesion and getting the
answer to the surgeon in a timely manner without
compromising patient safety. In my experience,
two blocks for a FS allows for this balance.
Careful block selection (as outlined above) maximizes the potential diagnostic yield. It also allows
a backup section if for some reason the other is
problematic to process or interpret. The use of
two blocks allows a turnaround time of typically
1520 min from receipt in the laboratory to report
issue. This time is not wasted by the surgeon,

often allowing them to proceed with some of the


operation that they need to perform (e.g., hysterectomy). More blocks can be taken if desired, but
the time taken will be longer. It is likely that if
more FS blocks are taken, the diagnostic accuracy may improve, but there is no apparent evidence in the literature for this despite the intuitive
nature of this statement. Less blocks may be
quicker, but diagnostic accuracy again may be
less with less material to review.

FS Appearance/Artifacts
Because the FS tissue is not processed through
the usual histological process of dehydration/
rehydration, a FS has a different, albeit similar,
microscopic appearance to routinely processed
histological material. While the architecture is
essentially the same, the cellular detail is different, with larger nuclei and often more prominent
nucleoli i.e., less shrinkage artifact. Mitotic figures, whatever the nature of the lesion, are often
more apparent than on routine material.
Overinterpretation of what are routine FS changes
must be avoided, and comparison with any recognizable benign tissue within the section should be
taken to assess variation from the norm.
Avoidance of any necrotic/infarcted areas is
essential, as is overinterpretation of pyknosis/
karyorrhexis. Hopefully careful block selection
as outlined above will minimize this. There is
also often an apparent multilayering of simple
epithelium more so than is seen in routine

P.A. Cross

138

processed sections. This is most likely due to the


FS being thicker than the routinely processed
sections, typically of the order of 67 um rather
than the routine paraffin-processed tissue section
of some 3 um. The ability to see fine histological
detail in a FS is also less, and more reliance on
disorganized/abnormal architecture, malignanttype necrosis, nuclear pleomorphism, atypia, and
abnormal/excessive mitotic activity are key, but
are still easily recognizable. Specific issues with
specific lesions will be dealt with later on.
Pathologists sometimes balk at reporting FS
due to a lack of familiarity with the material and
FS appearance. This is understandable, but experience can easily be obtained. In the initial stages,
samples can be sent fresh to the laboratory and
FS material taken but not reported upon urgently.
Pathologist experience and confidence will soon
develop if this is done. FS material from other
centers can also be used to gain experience.
Correlation of the FS slide with the routinely processed equivalent block is essential to educate the
reporting pathologist to be able to better recognize features for future reporting.

How Good Is a FS?


There is a wealth of literature on the use of FS in
the reporting of ovarian pathology. Many are
small series, dealing with a general service, but
many lack sufficient detail to allow more in-depth
analysis. Several reviews [6, 15, 16] highlight

studies that do allow meaningful data analysis, as


do some of the larger single-site papers [5, 12].
Heatley [15] makes the plea for papers detailing
a FS service to include more detail on tumor
types, but also a more detailed breakdown by
report (benign, malignant, and also borderline)
and also of clinical context/picture. Overall, the
outcomes for a FS do vary by tumor type (including size and weight) and diagnostic category.
Table 6.1 outlines overall values and suggests
that ovarian FS can be an effective, accurate tool.
One may ask what the equivalent values are for
the gold standard of routinely processed histological material, to which the FS is of course
compared. FS reporting compares very favorably
considering the limitations of less blocks and a
more pressurized reporting situation.
How a FS is evaluated compared to the
paraffin-processed gold standard is also a moot
point. While most would quote sensitivity and
specificity, values for positive predictive value
(PPV) and negative predictive value (NPV) are
quoted [15], as are values for pre- and post-test
probability [12] as well as likelihood ratios [15,
16]. These different approaches all show good
operating values for ovarian FS. The poorest
value in any of these approaches is with a
borderline FS diagnosis. How the borderline category is grouped (with benign or malignant) also
alters the overall values. Table 6.2 gives a flavor
of these other approaches.
The paper by Cross et al. [12] summarizes the
overall data from their center as follows in

Table 6.1 Pooled typical literature values for sensitivity and specificity for ovarian FS diagnosis by report category

Medeiros et al.a
Heatleya
Geomni et al.a
Ilvan et al.b
Cross et al.b

Benign vs. BL/carcinoma


Sensitivity Specificity
(%)
(%)
99
88
98.7
89.9
6597
97100
100
94.9
98.6
91.2

Benign vs. BL
Sensitivity Specificity
(%)
(%)
99
66
98.9
70.8

100
86.8
99
72.3

Benign vs. carcinoma


Sensitivity Specificity
(%)
(%)
94
99
99.7
95.8
71100
99.3100
100
97.2
99.6
95.6

BL vs. carcinoma
Sensitivity Specificity
(%)
(%)
91
95
93.6
93.1

100
88.9
98
83.5

Some values derived from values within papers


BL borderline tumor
a
Literature review based on suitable papers (Medeiros et al., 14 papers, 3,659 women; Heatley 18 papers, 4,542
women; Geomoni et al., 18 papers, 4,387 women)
b
Large single-center studies (Cross et al., 1,342 women; Ilvan et al., 617 women)

Frozen Section Use in the Diagnosis of Ovarian Pathology

Table 6.2 Typical literature values for other statistical


approaches at looking at FS diagnoses

PPV
NPV
LR+
LR

Benign vs.
carcinoma
97.9
(97.398.4)
99.5
(98.999.7)
23.99
(18.5231.1)
0.003
(0.010.006)

Benign vs.
BL
94.9
(94.195.7)
92.3
(8994.6)
3.384
(2.943.89)
0.015
(0.010.022)

BL vs.
carcinoma
77.7
(73.587.4)
98.2
(97.398.8)
13.293
(10.9416.15)
0.069
(0.0470.103)

From Table 2 in Heatley [15]


BL borderline, PPV positive predictive value, NPV negative predictive value, LR positive likelihood ratio, LR
negative likelihood ratio

clinical terms: of the 1,342 women who had a


total of 1,439 FS, 1,268 (94.5 %) women had the
correct surgical procedure at the time the FS was
reported; 58 (4.3 %) women were understaged,
and 16 women (1.2 %) were overstaged based on
the FS report. However, the actual effect of
understaging may be clinically minimal [17].
The literature indicates that certain types of
ovarian tumors are less accurately reported at FS
than others. This applies in particular to mucinous lesions [5, 12, 18]. These are invariably
larger, heavier complex lesions than other epithelial lesions. The often focal nature of both borderline and malignant changes in mucinous tumors
is also an issue. Current evidence also suggests
that the majority of mucinous lesions of the ovary
are not of primary ovarian origin, and hence any
mucinous lesion should be considered potentially
of metastatic origin [19], even if apparently of
obvious benign appearance. Given this, any
mucinous tumor should be considered potentially
malignant and may require close surgical examination of the bowel and appendix in particular.
The diagnosis of BL on an ovarian FS is less
reliable than one of benign or malignant. The
issue depends on how a BL lesion is classified
and hence the clinical action resulting from that
diagnosis (staging or not). Accuracy (i.e., a BL
diagnosis remaining as a BL diagnosis) is of the
order of 50 % [12, 16]. The majority of the incorrect diagnoses uplift a BL diagnosis to one of
malignancy; hence, a clinical approach which

139

places a BL diagnosis along with a malignant


diagnosis is tenable and does not have a real clinical impact [17]. This does vary by epithelial subtype and is least accurate with a mucinous lesion
[12, 18, 20, 21]. These papers, and the literature
review ones, show that increasing tumor size
(and weight) renders the BL diagnosis less robust.
In this situation, a variation from 91.7 % accuracy for small (<450 g) lesions to 66.7 % for
larger (>1,360 g) lesions has been found [21].
The false-negative reporting rate (i.e., called BL
but actually carcinoma) can vary 5.4-fold
between serous BL and mucinous BL [12],
reflecting the greater diagnostic problems with a
mucinous lesion.
Errors with FS diagnosis essentially are due to
two causes: sampling errors or interpretational
errors [12]. The former may reflect poor block
selection, but is intrinsic to the FS approach
where only limited material is taken due to time
constraints. Interpretational errors are also inherent to diagnostic pathology. Educational review
of such cases by the reporting pathologist team
can help reduce this, but this should be common
practice in all cellular pathology departments to
help reduce inaccurate diagnoses.
The overall outcome of FS reporting must be
of sufficient quality to allow the surgeon who is
relying upon it to base their surgical action upon
it. This information is also a necessity in ensuring
that the patient herself has accurate information
to make an informed decision for operative consent. This is vital, as effectively the woman does
not know exactly what procedure she will be having before surgery, and hence she also must have
an appreciation of how good (or bad) a FS can be
upon which her exact surgery is going to be
based. Each unit should produce its own data on
this with sufficient numbers and time, but initially typical literature values can be used to help
with these discussions.

Specic Diagnostic Challenges


The criteria for diagnosis in a FS are essentially
no different to those of a paraffin section,
although the appearances are different from that

P.A. Cross

140

of the routinely processed material as outlined


above. It is not intended to describe all the types
of lesions or tumors that may be seen within an
ovary, which are covered in more detail in the rest
of this book. However, certain problematic areas
will be outlined to help with FS diagnosis.

Benign Nonneoplastic Lesions


It must not be forgotten that an ovary (or ovaries)
can appear clinically suspicious or even malignant without actually being so. The literature
does not cover this aspect of ovarian FS well,
being not surprisingly preoccupied with malignant diagnoses. Table 6.3 outlines the typical
nonneoplastic diagnoses quoted at ovarian
FS. Processes such as endometriosis (Fig. 6.3),
salpingo-oophoritis, or physiological cysts can
present as unilateral (or sometimes bilateral)
masses, sometimes associated with torsion. The
FS of viable areas will show typical features of
Table 6.3 Benign nonneoplastic diagnoses at ovarian FS
Nonneoplastic
diagnosis
Endometriosis
Inflammation/abscess
Normal ovarian cysts
Others
Total numbers

Cross et al.
(11.6 % of all
FS diagnoses)
112
37
18
0
167

Ilvan et al.
(18.3 % of all
FS diagnoses)
71
13
27
2
113

these processes, and critical evaluation of the


lack of malignant features ought to allow correct
diagnosis. Many ovarian endometriotic cysts
may appear fibrotic, with evidence of old hemorrhage, and the classic features of both benign
endometriotic stroma and glands may not always
be apparent.
Features of congestion and hemorrhagic
infarction may be seen in any ovarian lesion
these appearances typify torsion and inspection
of viable areas (if any can be found) is essential
to try and allow for diagnosis. The gross appearance is typically that of a markedly congested
and necrotic mass, the nature (solid or cystic) of
which will reflect the underlying lesion. In many
torted ovaries, however, residual viable tissue can
be very problematic to find and may not be identified even after extensive sampling for routine
processing, and so FS material may not yield a
firm diagnosis in this situation.
A hydrosalpinx may be mistaken for an ovarian cyst and submitted for FS as an ovarian/paraovarian or tubo-ovarian cyst. It does not matter
for the purposes of a FS as all are essentially
those of a benign serous cyst, the exact origin of
which can await more extensive sampling on routine processing. Features such as the ovarian cortex or primordial follicles may help identify the
ovary, but are not essential if no malignant features are seen.
Physiological cysts (e.g., follicular or luteal)
(Fig. 6.4) are unilocular, smooth, and invariably

Fig. 6.3 Frozen section appearance of benign endometriosis showing glands and stroma (a F 10), and at higher view
(b F 40), note the bland glands and stroma and intimate association of the two

Frozen Section Use in the Diagnosis of Ovarian Pathology

141

Fig. 6.4 Simple follicular cyst (a FS 10, b FS 40). Note multilayering and variable nuclear size. An occasional
mitosis may also be seen. However, note the simple cyst architecture, and no invasion is present

solitary except under unusual circumstances


(e.g., hyperstimulation, polycystic ovary syndrome) but again show features of benign cysts.
Exact classification is not essential at a FS, but be
aware that physiological cysts can show quite a
high mitotic rate, and some luteal cysts can show
some pleomorphism, but again the overall architecture, and invariably history, will help in
diagnosis.

Specic Problem Areas


in Ovarian FS Diagnosis
Primary Ovarian Epithelial Lesions
The majority of ovarian lesions in adults subjected to a FS will be of epithelial origin. Many
will be simple/benign cysts. These are not usually problematic. For more detailed descriptions
of ovarian pathology in general, the reader is
advised to read the other chapters of this book.
While this section will not cover every possible
ovarian pathology, it will from experience try and
highlight common problems.
Serous cysts are usually unilocular and smooth
lined (Fig. 6.5). Serous cysts may have papillary
areas on the internal aspect, but these can also be
encountered on the capsular surface as exophytic
ovarian lesions (Fig. 6.6). These papillary (or
solid) areas, if present, are the ones best sampled.
Borderline serous lesions may be architecturally

complex with multilayering and show some mild


cytological atypia (Fig. 6.7). Such low-grade
borderline areas and true micropapillary lesions
may require careful scrutiny under the microscope, but the degree of architectural complexity
seen together with the minor cytological changes
is too marked for simple benign serous epithelium. High-grade serous borderline change is not
problematic as marked nuclear atypia with epithelial stratification and a high mitotic rate are
present. These features usually accompany architectural complexity (Fig. 6.8).
Mucinous lesions are usually multiloculated
complex cysts with multiple cyst intersections
and often solid areas (Fig. 6.2). Again, solid/cyst
intersection areas are best sampled for FS. Any
diagnosis of a mucinous lesion (even if apparently benign) (Fig. 6.9) may reflect secondary
spread [19]. If apparently benign this appears to
be at low risk, especially if the lining is endocervical in type. If enteric and BL, then it is more
difficult to be so certain (Fig. 6.10). Given this
problem, an algorithm based on size and uni- or
bilaterality of mucinous lesions [22] has been
proposed to help classify malignant mucinous
lesions as primary or secondary. In essence, this
classifies all bilateral mucinous carcinomas as
metastatic, unilateral mucinous carcinomas
<10 cm as metastatic, and unilateral mucinous
carcinomas 10 cm as primary ovarian mucinous
carcinomas and can correctly classify up to 90 %
of neoplasms. However, while this may be of

P.A. Cross

142

Fig. 6.5 Simple serous cyst (a frozen section 40, b paraffin section 40). Note apparent multilayering on FS but lack
of other atypical features, confirmed on the PS

Fig. 6.6 Gross specimen exhibiting surface papillary


areas, in keeping with serous surface proliferation. It is
not possible to say if this is benign or not on gross
inspection

assistance, it does require information on both


ovaries (or both for FS evaluation) and also has
an error rate. Others [23, 24] have suggested
amendments to this approach with varying
degrees of success.
Secondary mucinous tumors are most commonly of the large bowel (Fig. 6.11) or upper
gastrointestinal tract, especially the stomach.
One will often find the typical features of dirty
necrosis or signet ring forms with these two particular sites, respectively, both of which can help
identify and suggest secondary spread at FS. The
appendix must also be considered as a potential
primary site for mucinous lesions of the ovary. A
FS which consists mostly (if not solely) of mucin

may represent an inspissated mucinous cyst, a


mucinous adenocarcinoma, or a pseudomyxoma.
In these circumstances if only mucin is seen at
FS, then a diagnosis as such cannot be given. In
these cases given the inherent lower accuracy of
a FS in the presence of a mucinous lesion, a diagnosis of borderline may be offered, and further
surgery/staging may depend also on the overall
clinical picture. If any epithelium is seen, this
may point to one lesion or another and help with
better classification.
Endometrioid adenocarcinomas are easily
confused at FS with high-grade serous carcinoma, and this can also occur on routinely processed material. In practical terms it is not a
distinction that will matter, as both will appear
malignant, and exact classification can await
routine slides. Clear cell carcinomas can be
deceptively bland on FS (Fig. 6.12) this may
be due to the clear cytoplasm, but scrutiny of the
nuclear features and overall architecture should
help with diagnosis [25]. The distinction
between primary and secondary clear cell
lesions of the ovary is not possible on a
FS. Carcinosarcomas can occur in the ovary but
are invariably easily diagnosed as malignant
given the typically high-grade malignant features, even if the actual mixed nature of the
tumor is not recognized at FS.
Brenner (benign urothelial) tumors (Fig. 6.13)
may present as tumors in their own right or be
associated with mucinous tumors. Their typically
irregular nests of cells may suggest malignancy

Frozen Section Use in the Diagnosis of Ovarian Pathology

143

Fig. 6.7 Borderline serous lesion (a FS 10, b FS 40). Note architectural complexity and multilayering and nuclear
variability

Fig. 6.8 Necrotic/solid ovarian tumor (a) which could be


many lesions but is a high-grade serous carcinoma of the
ovary. (b) (FS 10) and (c) (FS 40) show marked pleo-

morphism and mitotic activity, as well as some psammoma bodies in (c). PS of final histology from same block
(d, 40)

architecturally, but the typical urothelial


nuclei with some nuclear grooves and lack of
other malignant features should allow correct
diagnosis. If necrosis, pleomorphism, or fre-

quent mitotic figures are present, then a borderline or frankly malignant diagnosis should be
considered, but such malignant urothelial lesions
are relatively rare.

P.A. Cross

144

Fig. 6.9 Simple mucinous cyst. (a) (FS 20) and (b) (FS 40) show bland mostly enteric glands, with no atypical
cellular features although some complexity of the actual cyst lining is not unusual

Fig. 6.10 Borderline mucinous cyst (all FS, a 10, b 10, c 40) showing marked atypia and complexity, but with no
invasion seen

Sex Cord-Stromal Lesions


The majority of sex cord-stromal tumors (SCST)
will be benign, the most common being fibro-

thecomas. These can be cystic with associated


Brenner tumors, but display no malignant features. However, one must look to exclude secondary tumors from the stomach (the classic

Frozen Section Use in the Diagnosis of Ovarian Pathology

145

Fig. 6.11 FS of metastatic colonic adenocarcinoma (a 10, b 40). Note high-grade nuclear features and typical (when
present) dirty-type necrosis

Fig. 6.12 Clear cell carcinoma. (a) Gross specimen with


no obvious differentiating features from other malignant
tumors. (b) (FS 20) and (c) (FS 40) show architectur-

ally complex clear cells with markedly variable nuclei, but


with very few mitoses typically. Focal necrosis is also
present

Krukenberg tumor) or breast (especially lobular


carcinoma) which can look grossly like a typical
fibro-thecoma.

Tumors such as granulosa cell lesions


(Fig. 6.14) or Sertoli-Leydig tumors will display
their typical histological features. Both tumors

P.A. Cross

146

Fig. 6.13 Benign Brenner tumor (a FS 10, b FS 40).


Some complex-appearing glands set in a fibrous stroma
may at first glance appear alarming, but typical urothelial

Fig. 6.14 Gross specimen of adult granulosa cell tumor

may display a wide range of appearances, but


again the overall features make recognition of a
non-benign process usually straightforward. A
granulosa cell tumor may exhibit a yellow
appearance to the naked eye, and while not diagnostic this may suggest a steroid-producing
lesion.
A FS will not always allow exact classification
as to the tumor type, but this is to be expected. The
function of a FS is to assist the surgeon, and as
such recognition of a non-benign process is key.

Germ Cell Lesions


The most common germ cell tumor (GCT) is the
mature cystic teratoma (dermoid cyst). As such

cells and nuclei and lack of other atypical features allow a


correct diagnosis

its gross appearance is diagnostic with a typical


greasy hair ball centrally. Malignant change is
uncommon and can be of epithelial origin (typically a squamous cell carcinoma) but can occur
in any of the germ cell layers present. As such,
sampling of solid/suspicious areas is advocated
for FS, but one must be prepared to consider virtually any diagnosis possible. Monodermal teratomas (e.g., struma ovarii) can be more tricky
(Fig. 6.15), but again are invariably associated
with more typical teratomatous areas, but these
may be lacking in a true monodermal teratoma.
Secondary thyroid tumors to the ovary are rare.
Tumors such as dysgerminoma or embryonal
carcinoma are straightforward on FS given their
typical features.

Pediatric Ovarian FS
The range and type of possible ovarian pathology, both benign and malignant, are very different in the pediatric age range. No tumor has an
absolute age predilection, but one must consider
a potentially different range of tumors in the
young. However, the approach to surgery is typically far more conservative in children, and diagnosis will usually rest on routinely processed
material rather than on a FS diagnosis. As such, a
routine FS approach to pediatric pathology in
general appears more limited, which is supported

Frozen Section Use in the Diagnosis of Ovarian Pathology

147

Fig. 6.15 Monodermal teratoma struma ovarii (FS, a 10 and b 40). Note well-defined follicles with mostly single
cell layers, with plentiful eosinophilic material (colloid)

Fig. 6.16 Metastatic lobular carcinoma to ovary (a FS 40, b PS 40). Note typical lobular Indian file arrangement and
occasional intracytoplasmic lumen in some cells

by a dearth of such literature on this topic [26],


but it does highlight a relatively high error and
defer rate.

Secondary Tumors to the Ovary


One of the questions that should be asked at every
ovarian FS is is the lesion seen primary ovarian
or secondary to the ovary? In the vast majority
of times, it will be the former. However, as has
been highlighted earlier, any mucinous lesion
may be secondary. Tumors with a signet ring
appearance are likely to be metastatic (possibly
from the stomach or appendix), while ones with a
neuroendocrine (carcinoid, well-differentiated

neuroendocrine carcinoma) appearance can be


primary or secondary. Colonic carcinoma has a
typical histological appearance of overtly malignant adenocarcinoma with dirty necrosis which
is not usually seen in other tumors (Fig. 6.11).
Lobular carcinoma will have its typical appearance (Fig. 6.16), but may be difficult to spot (as
may be signet ring cells) if scanty and set within
a fibrous stroma. In many cases, however, identification as a secondary tumor may not be possible
on a FS. Given that colonic carcinoma appears to
be the most common tumor to spread to the ovaries, in many cases this can be identified. In one
study, secondary tumors formed 4.8 % of ovarian
tumors at FS, of which the largest single group
were of gastrointestinal/appendiceal origin (57

148

out of 69) and overall 77 % were reported at FS


as most likely of metastatic origin [12]. Such
information, if it can be diagnosed, is of use
allowing the surgeon to look for a primary site
elsewhere and hence potentially adjust the surgical approach accordingly.

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