Vaginal Bleeding: What’s the Diagnosis?

Dr Stacey Bryan and Dr Adeola Olaitan Explore the Investigation and Management of Vaginal Bleeding in Oncology Through Three Case Studies

There are multiple causes for vaginal bleeding. As oncologists, when a patient presents with vaginal bleeding, we must keep in mind that this is not necessarily an early sign of recurrence, nor of a new cancer that has arisen as a result of previous cancer treatments. In most cases, there is a benign cause—namely, vaginal atrophy, which may or may not be secondary to oncological treatment.¹ However, it remains important to consider oncological causes. This article discusses persistent vaginal bleeding from that perspective, and presents three cases to aid clinicians in the differential diagnoses of this symptom. These cases take into account patient age, history, and the latest clinical guidance.

Case 1

We present the case of a 60-year-old woman with vaginal bleeding and a history of early breast cancer, for which she underwent a mastectomy with axillary lymph node dissection. She did not require endocrine therapy for the breast cancer. During year one of follow up she developed recurrent postmenopausal bleeding (PMB).

Diagnosis

A pelvic ultrasound was requested, as per the NHS clinical pathway for the management of PMB¹ and NICE guidance.² Ultrasound revealed a normal pelvis, normal endometrial thickness, and postmenopausal atrophic ovaries. However, as the patient continued to have persistent bleeding, she underwent a hysteroscopy and biopsy. No abnormality was detected at hysteroscopy and the histology reported a normal endometrium. A few weeks later, she had a significant vaginal bleed and was therefore counselled regarding total laparoscopic hysterectomy, with bilateral salpingo-oophorectomy (BSO), for unidentified cause of recurrent bleeding in a postmenopausal woman.

The final histology identified a small fallopian tube cancer (FTC), cell type serous. As per the NICE³ and British Gynaecological Cancer Society (BGCS)⁴ guidelines on ovarian cancer, she had a computerised tomography scan of her chest, abdomen, and pelvis, as well as subsequent laparoscopic omentectomy with pelvic and para-aortic lymph node dissection for staging—all of which were negative. The staging procedure was performed to identify the necessity and type of adjuvant treatment required.

Clinical Considerations

A key factor to consider is the patient’s history of breast cancer. Performing breast cancer (BRCA) genetic testing is beneficial as it affects outcomes, with non-BRCA-carriers having a poorer prognosis.⁵ In addition, knowledge of BRCA status helps with subsequent management and decisions on whether to offer targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.⁶

Primary FTC is rare and accounts for <1% of all gynaecological cancers.⁵ Abdominal pain and vaginal bleeding or watery discharge are recognised common symptoms of FTC, with Latzko’s triad⁵—colicky lower abdominal pain, pelvic mass, and watery vaginal discharge that relieves the abdominal pain—being described as pathognomonic of FTC.⁷ However, as vaginal bleeding/discharge is a symptom associated with endometrial abnormalities, FTC is often underdiagnosed, with the majority diagnosed on postoperative histology.⁷ A detailed gynaecological history and a high index of suspicion when presented with recurrent bleeding and abdominal pain alongside apparently normal scans and endometrial histology should help in making this diagnosis. If patients are diagnosed at an early stage (that is, stage 1) 5-year survival is 95%.⁵

Persistent abnormal vaginal bleeding in a postmenopausal woman should always prompt further investigation. If these investigations are normal but symptoms persist, and a common cause such as atrophic vagina has been ruled out following topical oestrogen treatment (Box 1),⁸ a diagnosis of FTC should be considered. Close correspondence and early referral to a gynaecologist is warranted.

Management

NICE³ and BGCS⁴ guidelines on ovarian cancer indicate that treatment for primary FTC is aligned with ovarian cancer treatment. For women who have stage 1 disease that is high risk, adjuvant chemotherapy, such as carboplatin, is recommended in addition to surgical pathways.^3,4 This particular patient underwent adjuvant treatment with single agent carboplatin, as per guidelines; the fallopian tubes are open to the peritoneum and therefore microscopic spreading cannot be excluded.

Patients diagnosed with advanced high-grade ovarian or fallopian tube carcinoma, or primary peritoneal cancer, are tested for homologous recombination deficiency (HRD). A positive HRD test result indicates that the cancer cells are unable to efficiently repair themselves; therefore, these patients may be eligible for PARP inhibitor targeted treatment.⁹

Case 2

A 24-year-old patient presented with recurrent intermenstrual and postcoital bleeding. She was referred for an ultrasound scan and placed on a pooled list at a local hospital for hysteroscopy and potential insertion of the Mirena intrauterine system for management of irregular bleeding. This meant that she did not have a named clinician responsible for her care.

Diagnosis

The patient was examined under anaesthetic and found to have an abnormal cervix, from which a biopsy was taken. Her case was discussed at the cancer multidisciplinary team meeting, and a review of the pathology revealed an adenoma malignum (AM) of the cervix.¹⁰ She underwent a magnetic resonance imaging (MRI) scan of the pelvis, which revealed a large cervical mass extending into the parametrium, FIGO stage 2B.¹¹

Also known as minimal deviation adenocarcinoma, AM is a rare (comprising 1–3% of all cervical cancers) disease of the cervix that is difficult to recognise, as it often appears benign.^10,12 Radiologically, it appears as mucin-rich, cyst-like lesions resembling Nabothian follicles.¹⁰ Pathologically, it is a subtype of mucinous adenocarcinoma of the cervix.¹⁰

Very few cases have been reported in the literature, but typical presentation includes profuse mucoid discharge¹² and irregular bleeding,¹² often with normal external genitalia, vagina, and cervix.¹⁰ An ultrasound scan with Doppler examination may be more accurate than a standard scan at assessing multilocular lesions of the cervix,¹³ as AM lesions tend to be hypervascular.^10,13 MRI will reveal high signal intensity within the cystic cervix on diffusion-weighted imaging.¹⁰ The lesion exhibits an endophytic growth pattern on the cervix, making it difficult to detect on cervical screening cytology.¹⁰ AM lesions are also thought to be human papillomavirus (HPV) independent,¹² and would therefore not be picked up by current HPV screening tests. It is seen in 10% of cases with Peutz–Jeghers Syndrome.¹²

Diagnosis of AM is made by deep incision biopsy or conisation.¹⁴ Pathology is characterised by deeply invasive branching glands lined with mucin-distended cells.¹⁰ Differential diagnoses include normal endocervix, microglandular hyperplasia, adenocarcinoma in situ, and well-differentiated (WD) endocervical adenocarcinoma.¹⁰ This can be further delineated using immunohistochemistry (IHC) studies, often with the presence of carcinoembryonic antigen differentiating AM from WD adenocarcinoma.¹⁰

Clinical Considerations

Intermenstrual and postcoital bleeding are not uncommon symptoms in young women, and are typically caused by benign conditions.¹⁵ This patient does not yet meet the current criteria for cervical screening, as she is less than 25 years old and the threshold for cervical screening in England is at 24 years and 6 months of age.¹⁶ Nevertheless, the NHS has developed a guideline specifically for the assessment of women aged less than 25 years who have abnormal vaginal bleeding, which is relevant in this circumstance.¹⁶ The important central feature of the guideline and associated pathway is that, depending on whether the bleeding is postcoital or intermenstrual, speculum and pelvic examination should be performed to help identify cervical, vaginal, or other source of bleeding.¹⁶ Contraceptive side effects and infections are the leading cause of irregular bleeding in this age group; however, more serious causes—such as cervical cancer—must be identified or ruled out through examination.¹⁶

Management

Standard diagnosis and treatment protocols have not been developed for AM because it is so rare; however, any abnormal bleeding in a young patient should warrant examination of the cervix in the first instance, and onward referral to the gynaecology team.¹⁶

Treatment for AM is similar to that of endocervical cancer, for which surgery is the standard method.^10,17 Varying degrees of surgery are reported in the literature, from simple hysterectomy to radical hysterectomy with pelvic lymph node dissection,¹⁰ and survival ranges between 6 months and 7 years.¹⁰ Radicality of treatment and adjuvant radiotherapy does not affect survival for these patients.¹⁰ It is thought to carry a poorer prognosis because it is generally diagnosed at a late stage.¹⁰

Due to her young age, this patient had ovarian transposition to preserve ovarian function, prior to undertaking chemoradiotherapy as primary treatment.¹⁸ She tolerated the treatment well and her prognosis is expected to be good. She maintained ovarian function; however, as the uterus was heavily irradiated, she will require a surrogate to carry a pregnancy.

Case 3

We present an 84-year-old woman on warfarin for previous venous thromboembolism. During an episode of poor international normalised ratio (INR) control, she developed vaginal bleeding. She was initially reassured, but the bleeding persisted after the INR returned to within normal range.

Diagnosis

The patient underwent a pelvic ultrasound that showed a thickened endometrium to 9 mm. Subsequent hysteroscopy and biopsy revealed clear cell cancer of the endometrium. As per the BGCS guidelines on uterine cancer,¹⁹ she had an MRI scan which showed no myometrial invasion, indicating early-stage cancer.

On ultrasound scan, an endometrial thickness ≥5 mm warrants investigation of the endometrium with a biopsy,²⁰ as approximately 7.3% of postmenopausal women who present with this will have atypical hyperplasia or endometrial cancer.²¹

Clinical Considerations

Ninety percent of women who present with PMB will not have endometrial cancer; however, PMB is a symptom present in more than 90% of women with endometrial cancer.²² NICE guidance on suspected gynaecological cancer details the management of women aged greater than 55 years with PMB.² These women should be referred on the 2-week wait suspected cancer pathway for transvaginal ultrasound scan (TVUS) to assess endometrial thickness, followed by hysteroscopy and biopsy if there are any concerns.²

The NHS clinical pathway guidance on the management of PMB helpfully identifies those patients who should be referred for TVUS on the 2-week wait pathway for further investigation.¹ These include:¹

• those on tamoxifen
  • tamoxifen is a selective oestrogen receptor modulator that can cause proliferation of the endometrium, therefore increasing risk of endometrial hyperplasia and cancer²³
• those with prolonged, heavy, or progressive bleeding.

The most common cause of PMB is vaginal atrophy,⁸ which can be treated with vaginal oestrogens for approximately 4–6 weeks.²⁴ In this case, the patient was on warfarin, so stopping anticoagulation for a few days would usually settle the bleeding. However, should there be no improvement despite correction of presumed cause in either scenario, referral for a hysteroscopy and biopsy must be undertaken¹—this can be in the outpatient setting if appropriate.

Management

All patients diagnosed with endometrial cancer are now tested for mismatch repair (MMR) deficiency—gene expression loss of MLH1, MSH2, MSH6, and PMS2.^19,25 MMR deficiency has an association with Lynch syndrome, with approximately 3% of all patients with endometrial cancer having Lynch syndrome.²⁶ MMR deficiency detected on IHC following sampling of the endometrium, or testing of the final histopathology specimen, prompts hypermethylation testing. If Lynch syndrome is proven the patient is referred to a geneticist.^19,25 

Following the diagnosis of early-stage endometrial cancer, this patient underwent a total robotic hysterectomy with BSO and sentinel nodes, which confirmed stage 1A, high-grade disease, MMR intact.¹⁹ The use of sentinel lymph node biopsy for staging rather than full lymphadenectomy of non-bulky nodes reduces morbidity for patients without compromising—and may even improve—diagnostic accuracy.¹⁹ She made a good postoperative recovery, and subsequently underwent adjuvant chemotherapy and radiotherapy. She will be carefully followed up over the next 5 years.

Advanced age has been associated with worse prognosis for endometrial carcinoma patients;²⁷ however, in our clinical experience, age on its own is not the main factor in the decision to offer surgery—fitness for surgery is a more important determinant. It shouldn’t be assumed that bleeding is just due to the use of anticoagulants, particularly when bleeding continues after anticoagulants have been stopped.

Conclusion 

Vaginal bleeding is a nonspecific symptom that is largely caused by benign disorders. However, with good history taking and a knowledge of past medical history, there may be some clues to a more sinister pathology. Abnormal bleeding that persists despite treatment always warrants investigation by examination in the first instance, followed by TVUS as the preferred imaging modality, proceeding to hysteroscopy should there be any concern. This article raises awareness of the more sinister causes of vaginal bleeding, and when further investigation is required.