Metastases to the ovary arising from endometrial, cervical and fallopian tube cancer recent advances

REVIEW
Metastases to the ovary arising from endometrial, cervical
and fallopian tube cancer: recent advances
Laura Casey1
& Naveena Singh1,2
1
Department of Cellular Pathology, Barts Health NHS Trust, and 2
Blizard Institute of Core Pathology, Queen Mary
University of London, London, UK
Casey L & Singh N
(2020) Histopathology 76, 37–51. https://doi.org/10.1111/his.13985
Metastases to the ovary arising from endometrial, cervical and fallopian tube cancer: recent
advances
The introduction of genomic studies has enabled
assessment of the clonality of synchronous tumours
involving the ovary and other sites in the female
genital tract in a definitive way. This has led to the
abandonment of conventional approaches to primary
site assignment, and the recognition that most such
synchronous neoplasms are clonally related single
tumours with metastatic spread, rather than inde-
pendent primary tumours. These discoveries have
implications for diagnostic practice, analogous to the
gradual change over the last few decades in our
approach to mucinous neoplasms of the ovary meta-
static from the gastrointestinal tract. In this review,
we first examine the routes of metastasis to the
ovary, and then discuss the diagnostic and clinical
implications of concurrent ovarian carcinomas aris-
ing in combination with endometrial, endocervical
and tubal carcinomas. It is proposed that cases of
primary low-grade endometrioid endometrial carci-
noma with a secondary unilateral ovarian tumour,
both with indolent characteristics, may be classified
as ‘FIGO stage IIIA-simulating independent primary
tumours’, with a comment that conservative
management would be appropriate. It should be
recognised that human papillomavirus-associated
endocervical adenocarcinomas may result in syn-
chronous or metachronous ovarian metastases that
appear to be unrelated to the primary tumour, and
that these may be managed conservatively in the
absence of other sites of disease. In cases of tubo-
ovarian high-grade serous carcinoma, tubal
intraepithelial or contralateral adnexal involvement
should count as a pelvic disease site for staging
purposes.
Keywords: endocervical adenocarcinoma, endometrioid carcinoma, high-grade serous carcinoma, indolent,
metastasis, synchronous, transtubal
Introduction
Although it has long been established that the ovary
is a preferential site of metastatic spread from
tumours originating in diverse and often distant parts
of the body, it is an odd quirk of gynaecological
pathology that, when two tumours are identified con-
currently in the female reproductive tract (one within
the ovary and the other elsewhere), this fact is often
overlooked in favour of models of synchronous/multi-
site primary disease. The aims of this article are: to
reset our understanding of tumour progression within
the gynaecological tract [specifically, of low-grade
endometrial carcinoma, human papillomavirus
(HPV)-associated (HPVA) endocervical adenocarci-
noma (EAC), and tubal high-grade serous carcinoma
(HGSC)]; to introduce the notion that not all ovarian
metastases are equally pernicious; and to explore the
profound implications of these conceptual shifts for
diagnosis and management.
Address for correspondence: N Singh, Department of Cellular
Pathology, Barts Health NHS Trust, 2nd Floor, 80 Newark Street,
London E1 2ES, UK. e-mail: singh.naveena@nhs.net
© 2019 John Wiley & Sons Ltd.
Histopathology 2020, 76, 37–51. DOI: 10.1111/his.13985

Determinants of distant metastasis
Primary tumours are known to shed a large number
of cells into the systemic circulation, but it is esti-
mated that <0.02% of disseminated tumour cells suc-
cessfully seed metastases.1–3
As a result, although
tumour cell dissemination can occur early on in can-
cer progression, there is often a long latency period
between the formation of a primary tumour and the
manifestation of metastatic disease.4–10
The tumour
cells that are successful in establishing themselves in
secondary sites constitute a unique subpopulation of
a heterogeneous whole—metastasis-initiating cells
(MICs). MICs pass through the metastatic cascade,11
acquiring, through a continual process of genetic
mutation, phenotypes advantageous for their contin-
ued survival. The stepwise process of metastatic
spread is one of cell migration, local invasion, entry
into the circulation, arrest at secondary sites, extrava-
sation, and colonisation.9,12,13
Central to the ability
of MICs to proceed through these steps is their
remarkable cellular plasticity. MICs are capable of
retaining the abilities of their primary tumour coun-
terparts (the tumour-initiating cells) while undergo-
ing bidirectional transitions between epithelial and
mesenchymal states, resisting anoikis and apoptosis,
cycling through periods of dormancy, evading the
host immune system, reprogramming metabolic activ-
ities to adapt to different nutrient and oxidative stres-
ses, and either establishing or harnessing an existing
supportive stromal niche.10,12
A full exploration of
these processes is beyond the remit of this article, but
it is useful to expand upon certain of them in order
to further our understanding of what is (and, indeed,
what is not) required of a tumour in order to achieve
secondary spread when in the process of tumorigene-
sis these necessary adaptations/alterations occur, and
specifically how they are relevant to metastasis to the
ovary from within the female genital tract.
Epithelial–mesenchymal transition
Epithelial–mesenchymal transition (EMT) describes
the ability of a transformed or differentiated epithelial
cell to acquire stem cell-like properties by hijacking
developmental programmes that are usually active in
embryonic development and wound healing.10,12,14,15
During EMT, epithelial cells lose their polarity and
cell–cell adhesions and gain mesenchymal traits, such
as increased cell motility and migratory potential. It
is the process of EMT that enables the detachment
and escape of cells from the primary tumour, whereas
its reverse—mesenchymal–epithelial transition—is
required for the subsequent outgrowth of tumour
cells in secondary locations.14,16–18
Angiogenesis and intravasation
Transport of nutrients to and removal of waste from
a tumour by a process of diffusion alone is only possi-
ble when the tumour does not exceed 2 mm in diam-
eter.19
Beyond this point, if a tumour is to continue
to grow, it must establish its own vascular network
within the host tissue by initiating angiogenesis.
Angiogenesis is the sprouting of new vessels from
existing ones, and is governed by the interplay of
proangiogenic and antiangiogenic factors.20,21
After
embryonic morphogenesis, the normal vasculature
becomes relatively quiescent, with only temporary
activation of the ‘angiogenic switch’ during wound
healing and female reproductive cycling. Tumour
cells, however, are capable not only of endogenously
synthesising and secreting proangiogenic factors, but
also of provoking stromal cells within the tumour
microenvironment to do the same.12,13
In this man-
ner, the tumour achieves sustained activation of the
angiogenic switch and a continuous (albeit shoddy)
process of neovascularisation—the vessels produced
by tumours are frequently distorted and enlarged,
marked by convoluted and excessive branching, and
subject to erratic blood flow and leakiness.22,23
Inter-
estingly, and contrary to historical perception, it has
been demonstrated that angiogenesis is induced early
on in the development of invasive cancers and that,
even in premalignant/non-invasive lesions (dysplasias
and in-situ carcinomas), there may be activation of
the angiogenic switch.24,25
In addition to ensuring the adequate delivery of
nutrients and removal of metabolic waste, tumour
vessels provide an entry point into the host circula-
tory system for malignant cells, facilitating wide-
spread dissemination. Tumour cell entry into the
vasculature can be either an active or a passive pro-
cess.26
In active intravasation, tumour cells migrate
towards vessels along nutrient or chemokine gradi-
ents,27
erode and pass through the basement mem-
brane, adhere to mural proteins, and pass through
endothelial cell junctions. It is a complex process
involving the interplay of tumour cells, the tumour
microenvironment, proteases, and signalling mole-
cules. Passive intravasation, however, appears to be a
consequence of high levels of tumour cell shedding,28
immature and poorly structured tumour vessels that
are not well fortified with pericytes and basement
© 2019 John Wiley & Sons Ltd, Histopathology, 76, 37–51.
38 L Casey & N Singh

membrane,29,30
and physical forces relating to cellu-
lar crowding.26
Resistance to programmed cell death
(apoptosis and anoikis)
If a cell survives circulatory shear stress, evades host
immune attack, and extravasates at a secondary site,
it will find itself subject to a barrage of apoptotic
death signals that must be resisted if colonisation is
to be successful. Apoptosis—or programmed cell
death—serves as a natural barrier to cancer develop-
ment,31–33
and is triggered in response to various
physiological stresses encountered during tumorigene-
sis, examples of which include signalling imbalances
related to enhanced levels of oncogene signalling, and
DNA damage associated with hyperproliferation.12
Anoikis describes a specific form of programmed cell
death that occurs when an anchorage-dependent cell
detaches from the surrounding extracellular matrix
(ECM). Suppression of anoikis is fundamental to
tumour cell dissemination. Tumour cells evolve a
variety of strategies to limit or circumvent apoptosis
(high-grade tumours and those resistant to therapy
show reduced levels of apoptosis31,32
), and it is likely
that MICs acquire antiapoptotic mechanisms at the
primary tumour site.34
Tumour spread within the gynaecological
tract
The traditional routes of distant tumour metastasis
are haematogenous, lymphatic, and transcoelomic.
Tumour spread within the gynaecological tract, how-
ever, may also occur locally, whether by destructive
invasion through contiguous tissues, by intraepithe-
lial progression, or by exfoliation. The significance of
these mechanisms of localised extension, and in par-
ticular the latter two, is that they may enable a
tumour cell to achieve spread to a secondary site
without first acquiring the full complement of cancer
hallmarks.12
In this way, a low-grade tumour with a
favourable prognosis may seed a secondary low-grade
tumour with a favourable prognosis, a phenomenon
that is not captured in the current staging systems.
Transtubal metastasis
John Sampson first published his treatise on retro-
grade menstruation in 1927, positing that pelvic
endometriosis resulted from the reflux of menstrual
effluent (blood and viable endometrial cells) along
the fallopian tube and onto the surfaces of the ovar-
ies and peritoneum. These endometrial cells, he
believed, would then adhere, implant, and prolifer-
ate, giving rise to ectopic deposits of endometrial tis-
sue.35
In terms of its ability to account for all
instances of endometriosis, Sampson’s theory is per-
haps imperfect, but what have consistently been
shown to be true are the existence of retrograde
menstruation36–38
and the presence of viable
endometrial cells within the peritoneal cavity.39–46
Extrapolating from this, it is not difficult to imagine
that exfoliated endometrial tumour cells might travel
—either passively or in response to external stimuli
—along the fallopian tube and into the peritoneal
cavity. Over the years, numerous studies have given
credence to the transtubal/implantation model. Intra-
luminal tumour cells have been identified in cytology
samples collected from the fallopian tubes in cases of
endometrial cancer47
and in histological sections of
the tubes in cases of uterine serous carcinoma, in
which both lymphovascular permeation and myome-
trial invasion were absent48
; intraluminal tumour
cells have been shown to be associated with adverse
prognostic features and reduced survival in patients
with early-stage endometrial cancer,49,50
and tubal
ligation has been related to lower-stage disease and
reduced mortality in women with aggressive
endometrial carcinomas.51
Tumour cell exfoliation
Tumours in at least two of the three scenarios consid-
ered in this review are capable of achieving meta-
static spread through a process of tumour cell
exfoliation. In endometrioid carcinoma, malignant
cells detach from the primary tumour mass, enabling
transtubal dissemination, whereas, in tubal HGSC,
exfoliation permits direct seeding from the fimbrial
end of the fallopian tube onto the surface of the
ovary. This is a rare behaviour, differing markedly
from the classic pattern of lymphovascular perme-
ation found in most other epithelial malignancies,
and it suggests that metastatic dissemination in these
lesions is easier to achieve. Rather than requiring cel-
lular transition through the metastatic cascade,
spread may be accomplished simply by cellular adhe-
sion being overcome and anoikis being resisted.
Critical to tumour cell exfoliation is the process of
EMT with loss of E-cadherin expression. The E-cad-
herin molecule facilitates the adhesion of neighbour-
ing epithelial cells,52,53
and its loss therefore results
Ovarian metastases from gynaecological cancers 39

in the disruption of epithelial cell anchorage, and cor-
relates with EMT and the acquisition of an invasive
phenotype.54
The loosening of intercellular attach-
ments allows transformed cells to be shed either sin-
gly or—specifically in the case of HGSC—as
spheroids,55
but the detachment of cells from their
neighbours or from the ECM frequently triggers anoi-
kis.56
In order for detached cells to survive, they must
overcome this process of programmed cell death,
although the mechanisms by which this is achieved
are complex, myriad, and yet to be fully elucidated.
Intraepithelial spread
The route by which EACs metastasise to the ovary is
less distinctly characterised, but certainly involves
intraepithelial spread (i.e. extension of cervical glan-
dular in-situ neoplasia), in either an interrupted or a
continuous fashion, along the endocervical canal,
through the uterine corpus, and into the fallopian
tube.57,58
Whether, upon arriving at the fimbrial end
of the fallopian tube, the lesion spreads to the ovarian
surface by direct extension or tumour cell exfoliation
remains unclear.
Why the ovary?—the ovary as a soil for
metastasis
Writing in 1889, English surgeon Stephen Paget
posed the question, ‘what is it that decides what
organs shall suffer in a case of disseminated cancer?’
Reviewing the autopsy reports of 735 women who
had died from breast cancer, Paget observed a pattern
of preferential metastasis to the liver, ovary and speci-
fic bones59
that could not be explained by Virchow’s
prevailing model of tumour propagation—that of the
entrapment of embolic tumour material within the
narrow vascular lumina of solid organs. Paget con-
cluded that ‘the remote organs cannot be altogether
passive or indifferent regarding embolism’ and offered
an alternative theory, that of ‘seed and soil’. Elaborat-
ing, he explained that ‘when a plant goes to seed, its
seeds are carried in all directions, but they can only
live and grow if they fall on congenial soil’.59
In the
late 1920s, James Ewing challenged the ‘seed and
soil’ theory, attributing organ specificity to mechani-
cal forces and circulatory patterns between primary
and secondary sites.60
The reality is probably a com-
bination of the two models. So, if we ask why
tumours preferentially metastasise to the ovary (and,
indeed, why the bulk of the disease may be located
within the ovary), we must consider not only the
physical relationships between primary and sec-
ondary sites, but also the ‘congenial soil’ of the ovary
itself.
In the 1970s, it was observed that women who
experienced a greater number of ovulatory cycles
were at increased risk of developing epithelial ovarian
cancer. It was theorised that ‘incessant ovulation’
resulted in repeated damage to (and subsequent
repair of) the ovarian surface epithelium, leading to
increased risks of genetic mutation and malignant
transformation.61,62
Although this model was
inspired by rates of ovarian adenocarcinoma in
domestic fowl (frequent egg producers), subsequent
human studies lent support. Women with a history of
multiple pregnancies,63–65
longer periods of breast-
feeding66
and oral contraceptive use63,67
all have a
reduced risk of developing ovarian cancer. The issue
with much of the published material on ovarian car-
cinogenesis—and, specifically, on HGSC—however, is
that it has traditionally focused on the ovarian sur-
face epithelium as the origin of disease. Today, it is
widely accepted that the vast majority of HGSCs
derive from a precursor lesion at the fimbrial end of
the fallopian tube [serous tubal intraepithelial carci-
noma (STIC)], and therefore the aim must be to rec-
oncile the apparent protective effects of ovulatory
suppression with extraovarian origin.
With each ovulatory cycle, a single egg is released
from the ovary. This process of follicle rupture and
repair is associated with the formation of an inflam-
matory microenvironment that abounds with inflam-
matory cells, chemokines, and growth factors.68
The
inflammatory milieu of the ovulatory wound site not
only promotes migration and adhesion of premalig-
nant and malignant cells to the ovary, but also pro-
vides tumorigenic factors that both support
malignant transformation and maintain malignant
cell survival.52
It has also been suggested that the
direct apposition of the tubal fimbria to the ovarian
surface might render it subject to the same inflamma-
tory mediators and oxidative stressors originally
thought to exert a genotoxic effect on the ovarian
surface epithelium following ovulation.69,70
Examples
of these mediators are granulosa cell-secreted stromal
cell-derived factor 1,53,54,71
its receptor (CXCR4),55,56
tumour necrosis factor-a,52,72,73
and interleukin-8.73–
76
It has also been suggested that the ovarian stroma
itself provides a scaffold for the adhesion of extraovar-
ian malignant cells. Stromal cells offer physical struc-
ture, cellular organisation and intercellular
connectivity within the ovary, and stromal cell-se-
creted ECM is capable of regulating cell adhesion,
migration, proliferation, and differentiation.74,77
In-

vitro and ex-vivo studies have indicated that malig-
nant cells adhere more successfully to the ovarian
stroma than to the surface epithelium, owing to the
increased expression of collagen IV and tenascin C,
and that the adhesion of ovarian tumour-initiating
cells is actively enhanced following follicular rupture,
i.e. when they are exposed to the ECM.52
Therefore,
ovulatory suppression may protect against the devel-
opment of tubal HGSC by preventing the release of
follicular fluid and by impeding the formation of an
ovarian inflammatory milieu.
Specific forms of ovarian metastasis
From the above discussion, we can surmise that
metastases to the ovary from sites within the female
genital tract can arise via multiple routes (Figure 1),
and that the ovary can harbour two contrasting bio-
logical forms of these: one in which a characteristi-
cally indolent tumour spreads transtubally to a
congenial ovarian environment, either by exfoliation
or through intraepithelial spread and direct contact
with the ovarian surface, and the other signifying
aggressive disease disseminating via conventional
routes, in which the ovary may be one of multiple
disease sites. The characteristics of these two models
are summarised in Table 1. We now turn to consider
individually the three examples of ovarian metastasis
selected for this review.
Endometrioid carcinomas simultaneously
involving the endometrium and ovary (so-
called ‘synchronous independent’ primary
tumours)
Endometrioid carcinomas account for ~10% of ovar-
ian epithelial malignancies.78
With current manage-
ment algorithms, when these are low-grade (grade 1
or 2) and organ-confined, they are adequately treated
with surgery alone, with uncertain benefit of adju-
vant therapy.79
Similarly, the management of
endometrial cancer is governed by clinicopathological
risk assessment algorithms, which are used to deter-
mine the need for adjuvant treatment.80
Low-grade
endometrioid carcinomas that are confined to the
endometrium or inner half of the myometrium and
show no lymphovascular space invasion are consid-
ered to be low-risk and require no adjuvant
Lymphovascular invasion
Interaepithelial spread
Transcoelomic spread
Tumour cell exfoliation & transtubal spread
Tumour cell exfoliation
1
2
3
4
5
Figure 1. Routes of metastatic spread to the ovary from origins within the female genital tract. 1, Via lymphatic/vascular channels. 2,
Intraepithelial spread via fallopian tube epithelium. 3, Transcoelomic spread between peritoneal surfaces. 4, Tumour cell exfoliation and
transtubal spread. 5, Tumour cell exfoliation and direct implantation onto the ovarian surface. Routes 2–5 may be enhanced by ovulatory
injury. (Courtesy of Lucas Catalan-Galan.)

treatment. The presence of ovarian metastasis, how-
ever, upstages an endometrial carcinoma to FIGO
stage IIIA and assigns it to a high-risk category, man-
dating both external beam radiotherapy and
chemotherapy.81
Given these profound differences in management,
the apparent concurrence of low-grade and low-stage
endometrioid endometrial and ovarian carcinomas
has long been regarded as a difficult diagnostic prob-
lem (Figure 2).82,83
This is reported to occur in 5% of
endometrial carcinomas; however, it is difficult to
provide an accurate estimate of the frequency of this
phenomenon, owing to differences in diagnostic
thresholds. Criteria defined decades ago by Scully
et al. have withstood the test of time,84
and cases
diagnosed as independent primary tumours following
strict adherence to these criteria have been shown to
have excellent clinical outcomes, justifying their con-
servative management.85,86
Many cases, however,
show overlapping features, and this may result in
their being inconsistently staged and managed, with
potential for undertreatment and overtreatment. It is
important to emphasise that this issue exists only for
low-grade endometrioid carcinomas. All endometrial
carcinomas that are morphologically high-risk (grade
3 endometrioid or non-endometrioid histotypes) and
present with a lesion of similar morphology in the
ovary should be uniformly regarded as metastatic
and managed in accordance with traditional proto-
cols.87
Many studies have investigated the relationship
between synchronous endometrial and ovarian carci-
nomas through molecular means, using a variety of
techniques to determine the presence or absence of a
clonal relationship. These have been previously
reviewed,82,83
and have broadly supported the idea of
synchronous independent primary tumours regardless
of the method used, but several important confound-
ing issues need to be appreciated before conclusions
can be drawn. Foremost among these is that, in
almost all instances, the studies have identified both
shared and unique abnormalities in the tumours at
both sites, and have applied arbitrary criteria to sup-
port independent origins. Second, ovarian endometri-
oid carcinomas may harbour the same genomic
alterations as endometrial endometrioid carcinomas
irrespective of clonality—there are mutations that are
common to all such tumours. Third, tumour progres-
sion inevitably engenders heterogeneity, such that
analysis of different regions of a single lesion or of
primary and secondary lesions may result in the
detection of different abnormalities despite a common
clonal origin. It has also been demonstrated that dri-
ver mutations seen in endometriosis-associated carci-
nomas—including endometrioid carcinoma—may be
seen in endometriosis,88
and that endometriosis at
Table 1. Two models of ovarian metastasis from tumours within the female genital tract
Model 1: Aggressive metastasis Model 2: Indolent metastasis
Route of spread Direct invasion; lymphovascular; transcoelomic;
transtubal
Transtubal, including exfoliation and intraepithelial
spread
Cancer cell properties Complex genomic abnormalities related to all
aspects of metastasis formation
Relatively simpler genomic abnormalities, as many
steps are bypassed
Timing of metastasis Early/late but signifies tumour progression Typically early with independent growth within the
ovary; may be late, presenting as temporally
remote isolated metastases
Rate of growth Rapid; often exceeds tumour size at the primary
site
Slow; often exceeds tumour size at the primary site
Pattern of ovarian metastasis Multinodular; surface involvement; hilar location;
presence of lymphovascular space invasion
Unifocal; intraparenchymal
Other sites of disease Usually present Typically absent
Behaviour Aggressive; signifies conventional high-risk disease;
adjuvant treatment required
Indolent; rare; conservative management should be
considered
Typical examples Tubal high-grade serous carcinoma; high-grade
endometrial carcinoma; non-HPV-associated
endocervical adenocarcinoma
Low-grade endometrioid endometrial carcinoma;
some forms of HPV-associated endocervical
adenocarcinoma
HPV, Human papillomavirus.

different sites in the pelvis is itself clonal.89
These dis-
coveries add a further dimension to the enigma, with
the possibility of tumours sharing genomic alterations
arising independently from a common clonal precan-
cerous lesion, a phenomenon that has been described
in a different but analogous context as ‘precursor
escape’.90
Given such confounders, previous studies
have lacked the resolution to address the question of
clonality, and, as these cases are rare, all studies are
hampered by low case numbers.
Two independent studies carried out using high-
resolution next-generation sequencing technologies
have recently cast light on these complex issues.91,92
The first study performed whole exome massively par-
allel sequencing on 5 cases and high-depth targeted
massively parallel sequencing on 18 additional cases
(341 and 410 cancer genes in 4 and 14 cases,
respectively). The results showed 22 cases to be clon-
ally related. Although there were mutations that
were restricted to either the endometrial or the ovar-
ian carcinoma, there were also striking similarities in
somatic mutations and copy number abnormalities in
tumours from the two sites in a given case, and there
was consistency in the mutational processes that
shaped their genomes. A single case of Lynch syn-
drome showed the concurrent endometrial and ovar-
ian carcinomas to be clonally independent.91
In the
second study, 18 cases (including 11 classified patho-
logically as independent primary tumours) were sub-
jected to targeted and exome sequencing of 35 genes
known to be commonly altered in endometrial and
ovarian carcinomas. Seventeen of 18 cases—includ-
ing 10 of 11 considered to be independent primary
tumours on pathological assessment—showed evi-
dence of clonality, and there was no statistical differ-
ence in the number of identical shared mutations in
the group considered to constitute synchronous inde-
pendent primary tumours and in the group consid-
ered to constitute metastatic/indeterminate
tumours.92
It is clear from these results that low-grade
endometrioid carcinomas presenting as ostensibly
independent synchronous low-stage endometrial and
ovarian primary carcinomas are, in fact, clonally
related and represent metastases from one site to the
other. Although the direction of metastasis has not
been determined, it is most likely to be from the endo-
metrium to the ovary, as it has been shown that the
latter is a preferential site of metastasis from tumours
of many body sites, whereas isolated metastasis to the
former from any location is exceedingly rare. In addi-
tion, whereas synchronous ovarian neoplasms are
reported to occur in 5% of endometrial carcinomas,
up to half of ovarian endometrioid carcinomas are
associated with synchronous endometrial carcinoma
or atypical hyperplasia,93,94
further supporting the
likelihood that these represent endometrial primary
tumours with secondary involvement of the ovary.
These findings have important clinical implications.
From historical studies, it is abundantly clear that
A
B I
II
Figure 2. Simultaneous involvement of the ovary in a case of low-
risk endometrial carcinoma. A, Endometrial grade 1 endometrioid
carcinoma with minimal myometrial invasion. B(I), Concurrent
ovarian grade 1 endometrioid carcinoma, low power (B(II), high
power).

cases of low-grade endometrioid endometrial carci-
noma with ovarian involvement may be divided into
two discrete subgroups: (i) those that behave in an
indolent manner, as though they are two separate
low-stage primary carcinomas; and (ii) those that
have outcomes similar to those of other high-risk
endometrial carcinomas. The ovarian lesions in the
first group are probably the product of transtubal
metastasis occurring early on in tumorigenesis,
whereas those in the second group reflect tumour
extension via traditional routes that demand the
acquisition of a greater number of prometastatic
capabilities. Both recent studies identified multiple
independent genomic changes at the two sites that
would support this model. However, because these
two subgroups are not clonally distinct, current
molecular techniques used to divide entities on the
basis of clonality cannot separate them. Determining
the molecular characteristics that define those
tumours that behave in an indolent fashion and
those that are more aggressive should be the subject
of future multicentre, collaborative, well-designed and
adequately powered studies.
In the meantime, we need to incorporate this new
evidence into diagnostic histopathology practice and
to modify our staging systems accordingly.95
The
original criteria for assigning cases as independent
primary tumours are shown in Table 2.84
These are
too inclusive, and a rational way forwards would be
to pare these down, incorporating only those factors
that are included in current risk assessment algo-
rithms. ‘Softer’, purely morphological, characteristics
and confounders of no prognostic value should be
excluded. It is suggested that, until staging systems
are amended to include this scenario, these cases in
which there is a primary endometrial tumour and a
secondary unilateral ovarian tumour, both with indo-
lent characteristics, should be classified as FIGO stage
IIIA simulating independent primary tumours, with a
comment that conservative management would be
appropriate. Cases thus classified should fulfil all of
the following criteria:
• low-grade (grade 1 or 2) endometrioid carcino-
mas involving the endometrium and one ovary;
• uterine involvement confined to the endometrium
or the inner half of the myometrium;
• no involvement of any other site, i.e. absence of
spread to the outer myometrium, the cervical stroma,
the surface (or rupture) of diseased ovary, the con-
tralateral ovary, the lymph nodes, or any other
extrauterine/extra-adnexal site;
• absence of significant96
lymphovascular space
invasion at any location.
These criteria should evolve with any future
amendments to risk categories incorporating molecu-
lar markers. These recommendations are summarised
in Table 3.
Table 2. Comments on traditional criteria for classifying
endometrioid carcinomas of the endometrium and ovary as
independent primary tumours84
Criterion84
Comment
Histological dissimilarity of
the tumours
Tumour progression and
heterogeneity within the primary
and the metastatic tumour can
result in morphological
dissimilarity
No or only superficial
myometrial invasion of
endometrial tumour
Depth of myometrial invasion is an
established risk factor
No vascular space invasion
of endometrial tumour
Lymphovascular space invasion is
an established risk factor
Atypical endometrial
hyperplasia additionally
present
Signifies endometrial precancerous
changes if present, but may be
obscured by tumour growth
Absence of other evidence of
spread of endometrial
tumour
Extrauterine spread is an
Ovarian tumour unilateral
(80–90% of cases)
Bilateral ovarian involvement
supports metastatic spread
Ovarian tumour located in
the parenchyma
Early spread and incorporation of
tumour within the parenchyma
following ovulation injury and
sampling both affect the
identification of surface
involvement
No vascular space invasion,
surface implants, or
predominant hilar location
in the ovary
All of these features support
metastatic spread
Absence of other evidence of
spread of ovarian tumour
Involvement of other sites is an
Ovarian endometriosis
present
Endometriosis is too frequent to
affect assessment; its presence
does not exclude the possibility
of metastatic spread
Different ploidy or DNA
indices, if aneuploid, of the
tumours*
Molecular studies are affected by
tumour heterogeneity versus
sampling; tumours established to
be clonally related show both
shared and differing genomic
abnormalities, regardless of the
techniques utilised
Dissimilar molecular genetic
or karyotypic abnormalities
in the tumours
*The possibility of tumour heterogeneity must be taken into
account in the evaluation of the ploidy findings.

Cervical adenocarcinomas with ovarian
metastases simulating unrelated primary
neoplasms
A second example of indolent metastases from a
female genital tract site to the ovary is that of HPV-as-
sociated endocervical adenocarcinoma (HPVA EAC).
Before examining this issue it is important to acknowl-
edge two recent significant changes proposed to the
classification of EACs,97
which are the subject of a
review within this issue.98
These have been the focus
of an international collaboration formed to define a
clinically meaningful categorization of EAC to super-
sede the previous morphology-based WHO categories.
This principally subdivides EAC into prognostically rel-
evant and reproducible HPV-associated (HPVA) and
non-HPV associated (non-HPVA) histological types.99–
101
The second proposal, also of prognostic impor-
tance, is to replace the conventional, poorly defined
grading systems that have low reproducibility with a
pattern-based classification.102–104
This only applies to
HPVA EAC, as all non-HPVA EAC fall into the poorest
prognosis pattern C category. The incorporation of
these two approaches into clinical management algo-
rithms requires development and prospective evalua-
tion through international collaborative projects.
Cervical adenocarcinomas are reported to metasta-
sise to the ovaries more frequently than squamous
cell carcinomas, with the rate ranging from 4% in
cases treated with radical hysterectomy to 29% in
autopsy series,105,106
the latter signifying the fre-
quency of involvement in advanced cases. For com-
parison, the rates of metastatic cervical squamous cell
carcinoma in the same two series were reported to be
0.2% and 17%, respectively.105,106
The rare occur-
rence of isolated ovarian mucinous neoplasms in
association with apparent low-stage EAC is also well
documented in the literature, and, in most cases,
these were traditionally thought to represent indepen-
dent unrelated neoplasms, owing to their clinical,
gross and microscopic features.107,108
However, it
has now been proven that these tumours represent
primary and secondary tumours, as they harbour
identical HPV infections and show diffuse and strong
positive p16 expression.57,109
When there is isolated
ovarian involvement (i.e. when the ovary is not one
of multiple sites of disease), the clinical outcome is
favourable.57,105
The temporal relationship between the primary cer-
vical and secondary ovarian tumours is of interest. In
the largest single series of such cases (n = 29), clini-
cally detectable ovarian disease was seen to precede,
coincide with or (in the most clinically confounding
of them) occur some years after the index cervical
cancer, indicating their inherent latency.57,58,110
In
17 of 29 cases with documented follow-up (ranging
from 4 to 83 months), the diagnosis was of HPVA
EAC. Twelve of 17 cases had an isolated ovarian sec-
ondary, and 5 of 17 had extraovarian disease. All 12
patients with a single-site ovarian metastasis were
alive at the end of follow-up, including 1 who suf-
fered recurrences at 13 and 16 months but who was
well after 47 months. Of the 5 patients with extrao-
varian disease, 1 was dead and 4 were alive and con-
firmed to be disease-free. In contrast, 3 of 29 patients
were diagnosed with non-HPVA EAC, and, of these 3,
1 died from disease, 1 was alive with disease, and 1
was alive and disease-free. Interestingly, the only one
of the three to show no nodal or extraovarian
involvement was the patient who died from disease at
25 months.57
A striking feature of these cases of HPVA EAC
involving the ovary as an isolated secondary site is
the appearance of the tumour at both locations,
demonstrating either conspicuous lack of, or only lim-
ited, invasion. A useful feature for diagnosing HPVA
EAC and its metastases, identified in the original
reports109
and emphasised in the recent International
Endocervical Adenocarcinoma Criteria and Classification,99
Table 3. Criteria for classification of concurrent low-grade
endometrioid endometrial and ovarian carcinomas as FIGO
stage IIIA endometrial carcinoma simulating independent
primary tumours*
All of these must be fulfilled All of these must be absent
Low-grade (grade 1 or 2)
endometrioid carcinomas
involving the endometrium
and one ovary
High-grade (grade 3) endometrioid
carcinoma; any high-risk
endometrial carcinoma histotype
Uterine involvement
confined to the
endometrium or the inner
half of the myometrium
Outer myometrial invasion;
involvement of any of the
following: cervical stromal, tubal,
lymph nodal or any other
extrauterine/extra-adnexal tissues
Unilateral ovarian
involvement, without
surface involvement or
rupture
Surface involvement/rupture of
diseased ovary; bilateral ovarian
involvement
No lymphovascular space
invasion at any location
Definite lymphovascular space
invasion (exclude artefacts)
*These criteria will evolve as molecular criteria are incorporated
into the clinical risk assessment of endometrial carcinoma, and
molecular markers to distinguish between clonally related and inde-
pendent concurrent endometrial and ovarian endometrioid carcino-
mas are indentified.

is the presence of apoptotic bodies and apical mitotic
figures, visible at scanning or low magnification.
As described above, the route by which in-situ or
minimally invasive HPVA ECA metastasises to the
ovary has not been absolutely characterised, but the
identification of intraepithelial endometrial and tubal
involvement suggests that this is the likely mode of
spread.58
This phenomenon has several important
clinical implications, as cases of EAC with ovarian
involvement (as for low-grade endometrial carci-
noma) may be divided into two separate categories:
those that are high-stage and should be managed
accordingly, and those that are indolent and can be
managed conservatively, i.e. with only surgical
removal. As with the high-risk histotypes of endome-
trial carcinomas above, the possibility of indolent
metastasis should not be considered in non-HPVA
EAC. It is important, therefore, for pathologists and
clinicians to be aware of these distinctions and to
employ p16 immunohistochemistry and/or HPV
detection in order to ensure that the correct diagno-
sis is reached. Another important consideration is the
Silva grading system.111
An issue identified in previ-
ous studies on cases of EAC showing ovarian spread
has been the difficulty in separating definite invasion
from background adenocarcinoma in situ and in
measuring the depth of invasion in cases of very
well-differentiated EAC. Such cases would be cate-
gorised as Silva pattern A or B, and managed
accordingly, with pattern A cases showing isolated
ovarian involvement being suitable for consideration
of conservative management. In line with this, the
updated FIGO staging system for cervical carcinoma
continues to exclude the stage assignment of ovarian
disease, but most oncologists would at least regard
this as a manifestation of pelvic spread, unlike patho-
logical involvement of the uterine corpus, which has
no staging or therapeutic implications. Nevertheless,
women with cervical cancer are increasingly being
offered ovary-conserving surgery. Although most sur-
geons would now carry out opportunistic salpingec-
tomy, for the reasons discussed in the following
section on HGSC, it is imperative for the fallopian
tubes to be removed as part of the ovary-sparing sur-
gical procedure in EAC, for two reasons: (i) examina-
tion of the tube for intraepithelial spread can indicate
the potential for ovarian involvement; and (ii) leav-
ing the tubes behind would retain this route of meta-
static spread unnecessarily. In cases of EAC in which
ovary-conserving surgery has been performed,
detailed examination of the endometrium and fallop-
ian tubes is required in order for the presence of
intraepithelial spread to be detected and documented.
Finally, the option of ovary-conserving surgery for
EAC should include consideration, by the surgical
team and the patient, of the low risk of late and iso-
lated ovarian recurrences that can be managed con-
servatively.
Table 4. Criteria for assignment of yhe primary site in tubo-ovarian high-grade serous carcinoma (HGSC)
Criteria Primary site Comment
STIC present Fallopian tube Regardless of the presence and size of ovarian and
peritoneal disease
Invasive mucosal carcinoma in the tube, with or
without STIC
Fallopian tube Regardless of the presence and size of ovarian and
peritoneal disease
Fallopian tube partially or entirely incorporated into the
tubo-ovarian mass
Fallopian tube Regardless of the presence and size of ovarian and
peritoneal disease
No STIC or invasive mucosal carcinoma in either tube
in the presence of an ovarian mass or microscopic
ovarian involvement
Ovary Both tubes should be clearly visible and fully examined by
use of a standardised SEE-FIM protocol
Regardless of the presence and size of peritoneal disease
Both tubes and both ovaries grossly and
microscopically normal (when examined entirely) or
involved by a benign process in the presence of
peritoneal HGSC
Primary peritoneal
HGSC
As recommended in the WHO blue book 201417
This diagnosis should only be made in specimens removed
at primary surgery prior to any chemotherapy; see below
for samples obtained following chemotherapy
HGSC diagnosed on a small sample, peritoneal/
omental biopsy, or cytology, or HGSC examined
after chemotherapy
Tubo-ovarian Note: this should be supported by clinicopathological
findings, including immunohistochemistry to exclude
mimics, principally uterine serous carcinoma
SEE-FIM, Sectioning and extensively examining the fimbriated end; STIC, Serous tubal intraepithelial carcinoma; WHO, World Health Orga-
nization.

Intraepithelial and invasive tubal HGSC
with ovarian metastasis
Quite distinct in its mechanism and implications is
the third example of spread to the ovary from within
the gynaecological tract, that of STIC112
or invasive
tubal HGSC. Extrauterine HGSC has always been con-
sidered to be the prototype ‘ovarian cancer’, sup-
ported by a simplistic ‘dominant mass’ approach to
assigning primary site. However, evidence that
extrauterine HGSC arises in the fallopian tube contin-
ues to grow,113
alongside continuing disagreement
regarding primary site assignment.113
The evidence
supporting the tubal origin of extrauterine HGSC has
been extensively reviewed previously,114–116
and only
the clinical implications are presented below.
The site of origin in extrauterine HGSC has no treat-
ment implications for an individual patient, as all
cases are similarly managed, and a diagnosis of inva-
sive HGSC of any stage mandates treatment with a
combination of cytoreductive surgery and platinum-
based chemotherapy. The variation in acceptance of
the evidence supporting a tubal origin of extrauterine
HGSC, however, has importance for cancer registra-
tion/epidemiological studies, and results in differences
in the categorisation of low-stage disease.117
Continu-
ing doubt on origin perpetuates belief in the possibility
of a true biological entity of ‘primary peritoneal carci-
noma’, currently defined as a disease of exclusion,
with no gross or microscopic evidence of disease in
either of the tubes or ovaries. Most significantly, con-
tinuing scepticism is an obstacle to studying the
impact of ovary-conserving preventive strategies that
have the potential to reduce HGSC incidence and mor-
tality, both in women with an inherited risk of HGSC
and in the general population. For these reasons, a
proposal for primary site assignment of extrauterine
HGSC has been put forward for reproducible categori-
sation (Table 4), with its basis in scientific evidence
rather than traditional beliefs.118,119
This model has
been recommended for use in international ovarian
cancer pathology reporting guidelines.120
In addition,
it forms the basis for guidance on uniform staging of
low-stage HGSC in areas that have been left to the
pathologist’s discretion in the current FIGO sys-
tem,121,122
resulting in the potential for identical cases
to be staged differently.117
On the basis of evidence of clonality with regard to
low-stage tubal/ovarian HGSC,123
the following have
been recommended in recent guidelines on ovarian
cancer management79
:
• STIC should count as a disease site for staging
purposes. For example, a case with STIC and HGSC
confined to the ovary should be staged as IIA fallop-
ian tube HGSC.
• A multifocal origin of extrauterine HGSC is
exceptionally rare, so bilateral ovarian/tubal HGSCs
currently staged as IB should be considered to be
stage IIA.
Conclusion
Over the last few decades, dramatic changes have been
made to the classification of ovarian epithelial neo-
plasms, and it is important that, as new evidence pre-
sents itself, dramatic changes continue to be made.
Invariably, new concepts are regarded with a degree of
scepticism—recall the resistance, despite a gradually
expanding body of evidence, to the notion that a large
proportion of ovarian mucinous neoplasms were not
primary lesions at all, and, in fact, represented metas-
tases from the gastrointestinal tract. Recent studies
have positively demonstrated the clonal relationship
between synchronous tumours of the ovary and else-
where in the female genital tract, and this new evidence
mandates that we abandon conventional approaches to
primary site assignment and develop algorithms that
enable uniform and reproducible diagnosis. Although
this is seemingly controversial, acceptance of this evi-
dence and recognition of its implications is essential for
appropriate clinical management.
Conflict of interest
The authors have no conflicts of interest to declare.
Author contributions
L. Casey and N. Singh contributed equally to this
manuscript.
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