DOI: 10.1111/tog.

12945 2024;26:183–8
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Urethral caruncles
Naomi Harvey MB BcH BAO BSc (Hons) MRCOG,*a Kathryn Bottrell MBBS BSc,b Esme White MB ChB BC MRCS (Urol),
c

Angela Birnie BSc MBBS FRCS (Urol) MMedEd, FHEA,c Melanie Tipples MBBS MRCOG FRCS(ed)d
a
ST6 Obstetrics & Gynaecology, St Richards Hospital, Chichester PO19 6SE, UK
b
ST1 Obstetrics & Gynaecology, St Richards Hospital, Chichester PO16SE, UK
c
Consultant Urologist, St Richards Hospital, Chichester PO19 6SE, UK
d
Consultant Gynaecologist, St Richards Hospital, Chichester PO19 6SE, UK
*Correspondence: Naomi Harvey. Email: [email protected]

Accepted on 26 July 2024. Published online 20 September 2024.

Key content:  To review the management options of urethral caruncle including

 Urethral caruncle is a common post-menopausal finding. medical and surgical excision.
 This common benign lesion can be mistaken as a malignancy.  To highlight primary care management of urethral caruncle.
 Management should be based on the patient’s symptoms.
Ethical issues:
 Vaginal estrogen should be considered as first-line management
 Owing to poor recognition of urethral caruncle, many patients are
before surgical excision.
put through the emotional distress of referral to cancer pathways.
 Surgery should be considered first line for large urethral caruncle
Learning objectives:
or in symptomatic patients.
 To evaluate the symptomatic presentation of
urethral caruncle. Keywords: post-menopausal / urethral caruncle / urethral masses /
 To establish the differential diagnosis of a mass in the urethra. vaginal estrogen

Please cite this paper as: Harvey N, Bottrell K, White E, Birnie A, Tipples M. Urethral caruncles. The Obstetrician & Gynaecologist 2024;26:183–8. https://doi.org/
10.1111/tog.12945

Introduction Aetiology of urethral caruncles

A urethral caruncle is the most common benign tumour of The female urethra is a tubular structure approximately 4 cm
the female urethra, accounting for 90% of urethral masses in to 5 cm long and 8 mm in diameter. It lies between the
post-menopausal females.1 It is rarely observed in urethral pelvic ligaments, where proximally it is lined by
pre-menopausal women and there is only one case report transitional epithelium and distally by non-keratinised
of urethral caruncle occurring in a male.2,3 The average age stratified squamous epithelium. The outer layers consist of
of presentation is 68 years.4 It is usually an incidental finding a complex network of smooth muscle and vascular structures.
in which a soft pink or red polypoid nodule is noted to Microscopically, urethral caruncle consists of vascular
protrude from the distal urethral meatus (Figure 1).2 They connective tissue loosely surrounded with transitional and
vary in size but are typically under 1 cm in diameter. squamous epithelial cells.7 Histologically, it is composed of a
Presenting symptoms include dysuria, dyspareunia and hyperplastic benign epithelium with inflammatory infiltrate,
bleeding, although approximately one-third of patients in particular polymorphonuclear cells, and tufts of capillaries
are asymptomatic.4 in a stroma. Depending on the state of inflammation,
The eversion of urethral transitional epithelium was first vascularity and fibrosis, there are three subtypes of urethral
described in 1750 by Samuel Sharp.2 Despite being a known caruncle: papillomatous, angiomatous and granulomatous.5
pathology for over two centuries, urethral caruncle remains a Furthermore, reactive patterns, such as fibrocapillary
poorly recognised condition owing to the nature of its proliferation (granulomatous), hypervascularity
appearance, and it can be frequently erroneously referred to (angiomatous), epithelial hyperplasia (papillamatous) or
secondary care as a potential malignancy. However, the intestinal metaplasia (mucinous), can be observed.5
overall incidence of malignancy in a urethral caruncle is low: Immunohistochemistry for immunoglobulin G has been
the reported rate of carcinoma following excision ranges shown in a subset of patients, suggesting a possible
from 1.6% to 12%.4,6 autoimmune factor.8

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Urethral caruncles

Figure 1. Varying appearances of a urethral caruncle.

The precise aetiology and pathogenesis of urethral

Box 1. Presentation of urethral caruncle
caruncles remains mainly theorised. As the main
predisposing risk factor is being of post-menopausal age,  Dysuria
and as it is believed that urethral prolapses are a result of  Dyspareunia
estrogen deficiency, a hypoestrogenic state may contribute  Haematuria
 Vaginal mass
to the development of urethral caruncle by a similar  Vaginal bleeding
mechanism.7 Decreasing estrogen levels lead to urogenital  Pain
atrophy and lack of support of the surrounding smooth  Vaginal discharge
muscle, which causes the urethral epithelium to become  Urinary tract infection
 Urinary retention (rare)
more susceptible to prolapse.9,10 Chronic irritation of the
then exposed urethra can lead to the formation of
caruncles; this theory is further supported by the
histological findings of chronic inflammation.4,11 secondary care, one-third of patients were asymptomatic
Other proposed mechanisms are chronic inflammation or (32%), and it was an incidental finding on vaginal
irritation of the urethra from factors such as ruptured Skene’s examination.4,7 When present, the most common
ducts or urethritis.4,12 Congestion of the urethra, infection symptoms are dysuria (20%), pain (37%) and haematuria
and trauma have also been proposed as possible (27%).4 Typically, it may present with bleeding or spotting
aetiological factors.4,12 noted on underwear or upon wiping, which is mistaken for
vaginal bleeding.
A urethral caruncle usually presents as a pink or red,
Clinical presentation of urethral caruncles
fleshy, exophytic lesion of less than 1 cm in diameter that is
Urethral caruncles may present with multiple symptoms effectively a single quadrant urethral prolapse.13 Typically,
(Box 1). In a clinical and histopathological review of 41 they arise on the posterior margin of the external urethral
patients with confirmed urethral caruncle on presentation to meatus and do not obstruct the orifice. They can be

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Harvey et al.

pedunculated or sessile, are generally highly vascular and are

Table 1. Differentials of urethral caruncles
disposed to thrombosis, so on rare occasions they may look
purple or black.4,14 Category
Urethral caruncles can cause dysuria, but they are an of lesion Lesion Presenting features

unlikely cause of voiding or storage symptoms. In patients

with incontinence, it was found that those with a urethral Non- Urethral caruncle 1 cm, single quadrant
caruncle did not report any difference in lower urinary tract cancerous On posterior urethral meatus
symptoms or have different findings on urodynamics studies lesions Red/pink, purple/black
compared with incontinent women without a urethral (thrombosed)
Friable
caruncle.15 However, large urethral caruncles, which were Soft, smooth fleshy appearance
mistaken for a genital prolapse, have been described in case
reports as a cause of acute urinary retention.13 Cases of Urethral prolapse Smooth, red
‘Donut’ circumferential appearance
urethral caruncle in children have also been reported, with
only 14 case reports in the English-language literature to Urethral polyp Pedunculated lesion, more
date.16 The mechanism is believed to be due to common in children
chronic inflammation.
Para-urethral Smooth, round fluid filled lesion at
A urethral caruncle should be differentiated from other
(Skene’s gland) urethral meatus
urethral lesions. Clinical differential diagnoses include cyst
carcinoma in situ, urethral diverticulum, urethroceles,
urethral polyp, varicosities, condyloma and cysts of Skene’s Urethral Outpouching of the urethra with a
diverticulum narrow communicating neck
glands.10 A variety of other urethral lesions have been
described that mimic urethral caruncles and include urethral Bartholin’s cyst Cystic mass lateral to urethral/
melanoma, tuberculosis, lymphoma, urethral leiomyoma and vaginal introitus
urethral carcinoma.10,11,14 A few case reports describe the rare Fluid filled swelling
occurrence of a squamous cell carcinoma in a urethral Condyloma Warty skin growths around the
caruncle.6 Unusual presentations of interstitial cystitis, urethra due to HPV infection
vaginal wall cysts, vaginal leiomyoma and Gartner’s duct
cyst/abscess and pelvic inflammatory disease should also be Malignant Urethral Irregular, friable mass around
lesions carcinoma urethra
considered.17 Table 1 provides a summary of differentials of May be hard to touch with
urethral caruncles. palpable lymphadenopathy
Traditionally, urethral caruncles were described as
Bladder cancer Papillary tumours may prolapse
extremely painful, with patient descriptions such as
through urethra
‘scalding’, ‘cutting’ and ‘burning’ attributed to them. Reducible
However, recent case reports have suggested they are
usually painless lesions but can cause discomfort if forming Urethral Nodular tumour protruding from
leiomyoma meatus
a polypoid mass or when ulcerated.7
Vulval cancer Ulcerated lesion arising separately
from urethral meatus
Investigations
A urethral caruncle is a clinical diagnosis on physical
examination, and further investigation is unnecessary in the
vast majority of cases.
A thorough examination involves close inspection and
palpation of the lesion, accompanied by a routine speculum cystoscopy, rigid cystourethoscopy, ultrasound/computed
and bimanual examination, especially if vaginal or tomography (CT) or hysteroscopy. For more complex
post-menopausal bleeding is a presenting symptom. If there urethral lesions, ultrasound can help distinguish urethral
is any suspicion of malignancy, the inguinal lymph nodes caruncle from other solid masses. On ultrasound,
should be examined. urethral caruncles are hypoechoic/isoechoic and rich in
Further investigations will depend on individual patient blood flow signal.18 Pelvic sonography to exclude
symptoms. This may include urinalysis and microscopy and endometrial pathology should be considered, if appropriate,
culture to exclude an infectious element. When the source of especially if the presenting complaint is postmenopausal
haematuria is unclear, or malignant pathologies need to be bleeding as an endometrial thickness of 4 mm or less has a
excluded, investigations to consider include flexible greater than 99% negative predictive value for endometrial

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Urethral caruncles

cancer.19 If indicated, magnetic resonance imaging (MRI) treatment with topical estrogens, or where diagnosis is
can aid exclusion of underlying malignancy where they uncertain, for example owing to atypical appearance.22
appear as T2-hyperintense tissue surrounding the external Surgical excision may also be considered for thrombosis,
urethral meatus (Figure 2).20,21 significant or recurrent bleeding or acute urinary retention.24
If there is any suspicion of a malignant pathology, tissue Best practice dictates that excision should be undertaken by a
biopsy of the urethra is advised (Appendix 1). urogynaecologist or a very experienced gynaecologist
or urologist.
The most common method of surgical management is
Management of urethral caruncles
simple excision (Figure 3).2 This is usually performed as a
Conservative management day case procedure, under general anaesthetic, with
Provided there is no concern for malignancy, the majority of placement of a urethral catheter for 48 to 72 hours post-
urethral caruncles can be managed conservatively. operatively. Local practices and surgeon preferences will vary;
Approximately one-third of urethral caruncles are below is an outline of the key principles when undertaking
asymptomatic and these can be managed with no surgical excision of a urethral caruncle.
intervention, depending on patient preference.7 The key surgical steps include:10,23
 Prophylactic antibiotic dose in line with local
Medical management hospital guidelines
The mainstay of treatment is with low-dose topical estrogens  Cystoscopy followed by placement of a Foley catheter to
with pessaries or topical creams.7,22 The management is often reduce risk of clot retention
complemented with sitz baths and topical non-steroidal anti-  Use of stay-sutures in the proximal epithelium to prevent
inflammatories or steroids for additional symptom relief, mucosal retraction and meatal stenosis
though there is limited evidence for their effectiveness.  Excision of the lesion
Patients often notice improvement in symptoms within  Oversewing the edges with 3-0 or 4-0 absorbable sutures
6 weeks of initiating treatment with topical estrogens, though (e.g. Vicryl)
maximum effect of therapy is 3 to 6 months.23  Trial removal of catheter at 48–72 hours post-operatively
A systematic review of the literature on urethral caruncle An alternative surgical management technique is the
management reveals mainly retrospective case series and ligation method completed under local anaesthetic,
small cohort studies, with no randomised controlled trials to whereby a ligature is placed at the base of the caruncle
date.4 The traditional focus is primarily on surgical excision. allowing it to atrophy and fall off.25 Urethral caruncles can
also be removed by cauterisation and laser vaporisation.
Surgical management of urethral caruncles Potential risks of surgical excision include clot retention
Surgical intervention is rarely required and is largely reserved leading to urinary retention, meatal retraction, stenosis,
for urethral caruncles that remain symptomatic, despite infection, wound breakdown and recurrence. One case series

Figure 2. MRI appearance of a urethral caruncle -axial (left) and sagittal (right) T2-weighted MR images demonstrate a high-signal-intensity cuff
(arrows) surrounding the external urethral meatus. (Reproduced with permission from Siegelman et al.21)

186 ª 2024 Royal College of Obstetricians and Gynaecologists.

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Harvey et al.

be referred to secondary care via the 2-week wait suspected

cancer pathway.

Advice for primary care

An incidental finding of a urethral lesion in a
post-menopausal patient should raise the likelihood of a
benign urethral caruncle. However, if there is any concerning
appearance to the lesion, which is not in keeping with a
benign mass, e.g. bleeding to touch, irregular hard
appearance or with palpable pelvic lymphadenopathy, the
patient should be referred on a fast-track urological
malignancy pathway to allow exclusion of carcinoma. If
there is any uncertainty but absence of sinister characteristics,
consider referral to the local 2-week wait or gynaecology
advice and guidance service. Clinical photography, especially
if a referral is being made, should be considered.
Figure 3. Post-surgically treated urethral caruncle. For post-menopausal or peri-menopausal patients,
consider trial of vaginal estrogen for 6 weeks and review. A
suitable regime, for example, would be a pea-sized amount of
of 41 patients reports a recurrence rate of 7%.4 All patients topical vaginal cream or pessaries to be applied/used daily for
should be fully informed of these potential risks, as they may 4 weeks, then alternate days for 2 weeks. If there has been an
prefer to avoid surgery. improvement, continue with maintenance twice weekly
No specific follow-up guidelines exist for patients who application with no indication for cessation. Encourage the
have had surgical removal of a benign urethral caruncle. patient to self-monitor the lesion and practice good vulval
However, best practice would suggest advising long-term use care. There is no indication for long-term review, if the
of low-dose topical vaginal estrogens post-surgery to prevent patient remains asymptomatic with no concerns regarding
recurrence, with no routine follow-up necessary. the appearance of her urethra.
If there has been no clinical change despite trial of vaginal
estrogen, consider secondary care referral as a routine
Malignancy
referral. Encourage the patient to continue vaginal estrogen.
The diagnosis of urethral caruncle can be a challenge owing If there has been the development of ‘red flag’ symptoms or
to the variety of differential diagnoses. The exact incidence of irregularity of appearance, consider urgent referral.
caruncles containing carcinomas is unknown, with one
reported rate as 1.6% while a further study reported that
Conclusion
12% of excised caruncles contained carcinoma.4,6
The malignant differentials include urethral carcinoma, Urethral caruncles are a common finding in the
bladder cancer and vulval cancer.10 post-menopausal urethra that should not cause
Primary urethral carcinoma is rare; more commonly it is consternation. Familiarity with their appearance should
spread directly from the bladder (or the prostate in men). provide reassurance that it is a benign lesion with low
The most common primary urethral malignancy is squamous malignant potential. Trial of vaginal estrogen should be
cell carcinoma, the remainder are transitional cell carcinoma, considered for the majority of patients prior to referral to
adenocarcinomas, sarcomas or melanomas.26 secondary care. However, in patients who are symptomatic or
Bladder cancers are most commonly transitional cell when malignant change is suspected, urgent referral to
carcinomas (TCC). They can prolapse into the urethra and gynaecology or urology should be considered.
therefore may be reducible. Bladder TCC commonly have a
papillary appearance, often described as resembling a coral Disclosure of interests
reef. Their distinct appearance is therefore usually rather There are no conflicts of interest.
different from a urethral caruncle.
Vulval cancers, although close to the urethral meatus, arise Contribution to authorship
separate to it. They usually appear ulcerated and irregular. EW, AB and MT instigated and edited the article. NH, KT
Malignancy should always be considered if a urethral and EW researched and wrote the article. All authors
lesion looks atypical. Where there is any doubt, patients can approved the final version.

ª 2024 Royal College of Obstetricians and Gynaecologists. 187

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Urethral caruncles

identifying endometrial abnormality. Am J Obstet Gynecol 1991;164:47–

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26 Cimentepe E, Bayrak O, Unsal A, Kocß A, Ataog lu O, Balbay MD. Urethral
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2011;1;14–6. adenocarcinoma mimicking urethral caruncle. Int Urogynecol J Pelvic Floor
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10 Clark J, Olson L, Kujawa M. A review of the diagnosis and management of 2. Elevate the lesion by subepidermal infiltration of 1%
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18 Wang X, Lei J, Zhang W, Zhou J, Song L, Ying T. The ultrasonographic
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19 Granberg S, M Wikland, Karlsson B, Anders Norstr€ om, Friberg LG.
Endometrial thickness as measured by endovaginal ultrasonography for

188 ª 2024 Royal College of Obstetricians and Gynaecologists.

 DOI: 10.1111/tog.12948 2024;26:189–96
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Endometriosis as a risk factor for ovarian cancer: an

update on screening, risk reduction, treatment
and prognosis
Rosie Campbell MBBCh BSc (Hons) MRCOG,*a Kirsty Milford MBBS BSc (Hons) MRCOG,b
Benjamin Peyton-Jones MB ChB FRCOG, Michael Hannemann PhD MRCOGd
c

a
Subspeciality Trainee in Gynae-Oncology, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK
b
Speciality Trainee in Obstetrics & Gynaecology, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK
c
Consultant Obstetrician and Gynaecologist and Endometriosis Specialist, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK
d
Consultant Subspecialist in Gynaecological Oncology, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK
*Correspondence: Rosie Campbell. Email: [email protected]

Accepted on 16 August 2024. Published online 18 September 2024.

Key content: Learning objectives:

 Endometriosis affects up to 10% of women. While many regard  To increase knowledge of the association between endometriosis
endometriosis as a benign (non-cancerous) disease, there are and EOC.
well-established links to epithelial ovarian cancer (EOC).  To understand the updated evidence for screening, risk and risk
 Proposed mechanisms for malignant transformation include reduction strategies.
chronic inflammation, hyperestrogenism and oxidative stress.  To be informed of potential novel therapies currently in the
Mutations in the tumour suppressor gene ARID1A have also been clinical trial stage of development.
implicated in the development of endometriosis-associated ovarian
Ethical issues:
cancer (EAOC). 
 Endometriosis is reported to almost double a woman’s background
Increased public awareness and improved clinician knowledge may
lead to more and earlier-stage disease detection.
risk of ovarian cancer.  Women are more informed, necessitating clinicians to deliver
 Risk reduction strategies are effective in reducing the incidence of
evidence-based counselling to meet their informational needs.
EAOC. These include tubal ligation, excision of endometriosis and
combined hormonal contraception. Keywords: endometriosis / epithelial ovarian cancer /
 Novel therapies targeting tumour suppressor gene mutations endometriosis-associated ovarian cancer / gynaecological oncology /
present in EAOC are undergoing phase I & II clinical trials. tumour suppressor genes

Please cite this paper as: Campbell R, Milford K, Peyton-Jones B, Hannemann M. Endometriosis as a risk factor for ovarian cancer: an update on screening, risk
reduction, treatment and prognosis. The Obstetrician & Gynaecologist 2024;26:189–96. https://doi.org/10.1111/tog.12948

specific histological subtypes of EOC, such as endometrioid

Introduction
carcinoma (EC) and clear cell carcinoma (CCC).2-4 These
Endometriosis is a complex and often painful condition two subtypes are often referred to as endometriosis-
associated with cyclical pelvic pain and subfertility. Defined associated ovarian cancer (EAOC).
by the presence of endometrial tissue outside the uterus, it The lifetime risk of developing the most common female
can mimic malignant pathology with metastatic spread, cancers is significant: 14 in 100 for breast cancer, 3 in 100 for
tissue invasion, angiogenesis and proliferation. Although endometrial cancer and 2 in 100 for ovarian cancer.5-9
commonly considered a benign (non-cancerous) condition, However, for women with endometriosis, the risk of ovarian
its association with epithelial ovarian cancer (EOC) is a topic cancer doubles to 4 in 100.2,4 Endometriosis currently affects
of evolving interest. 1 in 10 premenopausal women in the UK.6 The most recent
The relationship between endometriosis and EOC was first version of the European Society of Human Reproduction and
described in 1925, and in recent years, numerous studies have Embryology (ESHRE) guideline on endometriosis indicates
consistently found a correlation between the two that the condition adds an additional 1.2% to an individual’s
conditions.1-4 Specifically, endometriosis is associated with background risk.7 For instance, an individual with a BRCA1

ª 2024 Royal College of Obstetricians and Gynaecologists. 189

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Endometriosis as a risk factor for ovarian cancer

gene mutation would see their risk of ovarian cancer rise These mutations result in the loss of BAF250a protein
from 39–44% to 40.2–45.2% owing to endometriosis.10 expression, a key component utilised by the SWItch/Sucrose
Conversely, a person without other predisposing risk factors, Non-Fermentable (SWI-SNF) complex. The SWI-SNF
except for endometriosis, would experience an increase in complex, functioning as an epigenetic regulator, plays a
their risk from 2% to 3.2%. This highlights the need for vital role in DNA transcription and repair and chromatin
continued research into the complex relationship between the substrate facilitation. Other common mutations found
two conditions and to equip clinicians with the most up- in both endometriosis and EAOC include phosphatase
to-date evidence in order to provide informed counselling to and tensin homolog (PTEN ), phosphatidylinositol-
individuals with endometriosis.5,6 4,5-biphosphate 3-kinase catalytic subunit alpha (PI3KCA),
catenin beta-1 (CTNNB1), Kirstin rat sarcoma virus (KRAS ),
tumour protein 53 (TP53), protein phosphatase 2 scaffold
Pathophysiology of EAOC
subunit Aalpha (PPP2R1A), AT-rich interaction domain 1B
The pathophysiological mechanism leading to EAOC is still (ARID1B) and phosphoinositide-3-kinase regulatory subunit
an ongoing topic of research. Despite the lack of a definitive 1 (PI3K3R1). Figure 2 outlines the reported frequencies of
answer, emerging evidence suggests that the relationship is these tumour suppressor gene mutations found in EAOC
causal, not correlative.11-13 Proposed mechanisms for and endometriosis.13,15
malignant change include chronic inflammation, The PI3K/AKT/mTOR pathway is an extensively studied
hyperestrogenism and oxidative stress.11,14 cellular mechanism in oncology. It is an intracellular signalling
Recent studies have uncovered a significant association pathway that regulates the cell cycle and suppresses apoptosis.
between specific mutations in tumour suppressor genes and In many cancers, this pathway is overstimulated, reducing
the development of EAOC. Notably, the AT-rich interaction apoptosis and the proliferation of neoplastic cells.16 Many
domain 1A (ARID1A) gene, which is present in factors can stimulate the pathway, including the loss of PTEN
approximately 20% of human cancers and is crucial for expression, which is observed in EAOC.12,13
DNA repair and chromatin remodelling, frequently exhibits
mutations in both endometriosis and EAOC (refer to
Risk
Figure 1 for a simplified molecular mechanism).2,11-13,15
It is now accepted that endometriosis is a risk factor for EOC.
Multiple studies have shown an association between the two
conditions.3,4,17-10 Our literature search identified three
BAF250a SWI-SNF meta-analyses quantifying the risk of EAOC.4,17,19 In 2014,
ARID1A Kim et al. found a statistically significant association between
endometriosis and EOC (RR 1.265, 95% CI 1.214–1.318).4
BAF250a/SWI-SNF complex
has roles in:
They also found that those with EAOC were twice as likely to
• epigenetic regulation present with earlier stage disease (stage I-II) when compared
• DNA transcription with non-EAOC (RR 1.959, 95% CI 1.367–2.807). Further
• DNA repair BAF250a
• chromatin substrate subgroup analysis showed that grade 1 disease was more
facilitation
SWI-SNF
common in EAOC (RR 1.319, 95% CI 1.367–2.807);
however, the likelihood of achieving optimal debulking
surgery was no different between EAOC and non-EAOCs
(RR 1.403, 95% CI 0.915–2.152). Wang et al. in 2016 also
found endometriosis to be a significant risk factor for EOC
BAF250a
(OR 1.42, 95% CI 1.28–1.57).17 More recently, in 2021,
SWI-SNF
Kvaskoff et al.19 had similar findings: endometriosis doubled
ARID1A a woman’s risk of EOC (RR 1.93, 95% CI 1.68–2.22); for
CCC, the risk tripled (RR 3.44, 95% CI 2.82–4.42) and it
Mutations in the tumour
suppressor gene ARID1A
doubled for EC (RR 2.33, 95% CI 1.82–2.98). It is
(found in endometriosis noteworthy that none of these meta-analyses considered the
and EAOC) leads to a loss BAF250a severity of endometriosis in their analysis. A large cohort
of expression of BAF250a,
resulting in an impaired study by Saavalainen et al. addressed this gap by assessing the
BAF250a/SWI-SNF SWI-SNF risk of EAOC in various forms of surgically confirmed
complex
endometriosis, including peritoneal, ovarian and deep
endometriosis.20 The findings indicated that only ovarian
Figure 1. Simplified molecular expression of ARID1A gene. endometriosis significantly increased the overall risk of EOC

190 ª 2024 Royal College of Obstetricians and Gynaecologists.

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Campbell et al.

Comparison of reported gene mutation frequencies

Clear Cell Endometroid Ovarian endometriosis
60%

50%

40%

30%

20%

10%

0%
ARID1A PIK3CA CTNNB1 PTEN KRAS TP5 PPP3R1A ARID1B PIK3R1

Figure 2. Comparison of reported gene mutation frequencies in CCC, EC and ovarian endometriosis. CCC = clear cell carcinoma; EC = endometrial
cancer.

Table 1. Overview of risk ration (RR) and odds ratio (OR) associated with endometriosis-associated ovarian cancer.

Risk Reference

EAOC All endometriosis RR 1.265 (95% CI 1.214–1.318) Kim et al.4

OR 1.42 (95% CI 1.28–1.57) Wang et al.17
RR 1.93 (95% CI 1.68-2.22) Kvaskoff et al.19

Peritoneal endometriosis RR 1.32 (95% CI 0.99–1.72) Saavalainen et al.20

Ovarian endometriosis RR 2.46 (95% CI 1.98–3.27) Saavalainen et al.20

Deep endometriosis RR 1.41 (95% CI 0.29–4.10) Saavalainen et al.20

Stage I-II presentation RR 1.959 (95% CI 1.367–2.807) Kim et al.4

Grade I RR 1.319 (95% CI 1.367–2.807) Kim et al.4

Optimal debulking surgery RR 1.403 (95% CI 0.915–2.152) Kim et al.4

RR & confidence interval (CI) given in italics represents an insignificant association.

EAOC = endometriosis-associated ovarian cancer

(RR 2.46, 95% CI 1.98–3.27). There was no significant Kingdom Collaborative Trial of Ovarian Cancer Screening
association with peritoneal (RR 1.32, 95% CI 0.99–1.72) or (UKCTOCS) was a randomised controlled trial that screened
deep endometriosis (RR 1.41, 95% CI 0.29–4.10). When the general population with multimodal screening. They used
considering histological subtypes, both peritoneal and serial CA-125 and transvaginal ultrasound (TV USS) as a
ovarian endometriosis were found to increase the risk of secondary test in conjunction with the risk of ovarian cancer
EC (RR 2.03, 95% CI 1.05–3.54) and CCC (RR 4.72, 95%CI algorithm (ROCA) and showed high sensitivity and
2.75–7.56), respectively. Notably, for CCC, only ovarian specificity. They also found significantly more low-volume
endometriosis emerged as a significant risk factor (RR 10.1; disease compared with unscreened controls. The results of
95%CI 5.50–16.9). Table 1 outlines the associated RR and OR the trial were encouraging; however, they failed to find a
for different variations of endometriosis. mortality benefit, so it has not been implemented as
a screening programme.21-23 A sister trial, the United
Kingdom Familial Ovarian Cancer Screening Trial
Screening and surveillance
(UKFOCS), investigated the effectiveness of screening
Currently, there exists no national screening programme for high-risk individuals. They conducted a prospective
the general female population for ovarian cancer. The United multi-cohort screening study on those with a 10% or

ª 2024 Royal College of Obstetricians and Gynaecologists. 191

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Endometriosis as a risk factor for ovarian cancer

Table 2. Associated risk reduction of epithelial ovarian cancer in those with endometriosis

Risk reduction of EOC in those with endometriosis

Intervention

EC CCC Reference

Tubal ligation RR 0.54 (95% CI 0.43–0.69) RR 0.55 (95% CI 0.39–0.77) Gaitskell et al.27
RR 0.40 (95% CI 0.30–0.53) Cibula et al.28

BSO All EOC*: RR** 0.34 (95%CI, 0.15–0.76) Hermens et al.30

Deep excisional surgery All EOC*: OR 0.37 (95% CI 0.25–0.55) Melin et al.32

Aspirin All EOC*: RR 1.15 (95% CI 0.80–1.65) Hurwitz et al.33

CHC 21% reduction in risk*** 27% reduction in risk*** Ref.34

Dienogest No long-term data available

LNG-IUS RR 0.71 (95% CI 0.23–1.65) RR 0.42 (95% CI 0.01–2.34) Soini et al.39

All EOC*: RR 0.53 (95% CI 0.32–0.88) Jareid et al.38

DMPA All EOC*: OR 0.61 (95% CI 0.44–0.85) Wilailak et al.37

*The study did not include histological subtypes in the analysis

**RR stated the risk of EOC in those with endometriosis following BSO.
***After 5 years of use. RR/OR & CI given in italics represents an insignificant association.
BSO = bilateral salpingo-oophorectomy; CCC = clear cell carcinoma; CHC = combined hormonal contraception; DMPA = depot medroxyprogesterone
acetate; EC = endometriod cancer; EOC = epithelial ovarian cancer; LNG-IUS = levonorgestrel releasing intrauterine device.

greater lifetime risk of OC. Their findings were also 40–45 years old, respectively.25 Lynch syndrome carriers are
encouraging, showing that screening the high-risk offered RRS (hysterectomy + BSO) depending on their
population resulted in a significant shift in the stage of mismatch repair (MMR) status, but this can be at as young as
disease when detected; however, the study was unable to 35 years old.26 Currently, there exists no national guidance
demonstrate long-term morbidity and mortality benefits.24 on offering RRS to those with endometriosis. However,
Until now, there hasn’t been any trial dedicated to screening evidence suggests the EAOC subtypes may benefit most from
women and people with endometriosis for early detection of both surgical and medical methods. Table 2 summarises the
EAOC. Considering that such screening hasn’t demonstrated risk reductions of EOC with various therapies.
improved mortality in other at-risk groups, its potential
benefits for individuals with endometriosis appear unlikely. Tubal ligation
The ESHRE endometriosis guideline highlights the It is well documented that tubal ligation (salpingectomy and
detrimental effects of false-positive screenings, noting not occlusive methods) can reduce the risk of EOC.27-29 In 2016, a
only the psychological impact but also the physical harm prospective study by Gaitskell et al.27 found that risk reduction
caused by unnecessary interventions.7 of EOC via tubal ligation varied significantly according to the
histological subtype. The following relative risk of EOC
following tubal ligation was found according to histological
Risk reduction strategies
subtype: high-grade serous (RR 0.77, 95% CI 0.67–0.89),
Individuals with a genetic predisposition for ovarian cancer low-grade serous/borderline tumours (RR 1.13, 95% CI
are offered risk-reducing surgery (RRS) once their families 0.89–1.42), EC (RR 0.54, 95% CI 0.43–0.69), CCC (RR 0.55,
are complete. This usually takes the form of a bilateral 95% CI 0.39–0.77) and mucinous (RR 0.99, 95% CI
salpingo-oophorectomy (BSO) or can include a 0.84–1.18).27 A meta-analysis performed by Cibula et al. also
hysterectomy. For those with BRCA1, the lifetime risk of found a variation in RR following tubal ligation according to
ovarian cancer is 39–44 in 100 and BRCA2 11–17 in 100, so histological subtype.28 They also found the most significant risk
therefore studies advise BSO from 35–40 years old and reduction in EC (RR 0.40, 95% CI 0.30–0.53); however, they

192 ª 2024 Royal College of Obstetricians and Gynaecologists.