Case Study

A 53-year-old presented to the emergency department (ED) with a six-week history of increasing vaginal odour and pelvic pain on the background of a 12-month history of vaginal bleeding. Her periods had become irregular, and she was unsure of her menopausal status.

Her medical history was significant for anxiety, depression, haemochromatosis, and polymyalgia. She had had two vaginal deliveries and a tubal ligation. Her family was complete. She was a current smoker with a 20 pack-year history.

She was under-screened for cervical cancer. A self-collect cervical screening test (CST) two years prior to presentation was HPV-negative (HPV-ve). Previous Papanicolaou screening tests were 12- and 32-years prior to presentation, and both were normal.

Although a self-collect test was not due, one was undertaken seven months prior to her ED presentation and was HPV-ve. Six months later, a clinician-collected liquid-based cytology (LBC) reported a possible high-grade squamous intraepithelial lesion (pHSIL) with no abnormal glandular cells identified. The clinical findings are unknown. A referral was made to the local public gynaecology outpatient service. Given the HPV-ve and pHSIL, her referral was triaged as a category two. Her presentation to ED came prior to her clinic review.

A speculum examination in the emergency department identified a 5cm mass arising from the anterior cervix/vagina. The cervix could not be appreciated separate to the mass. She was admitted under the gynaecology oncology service for additional investigations.

Further clinical examination suggested bilateral parametrial invasion. An LBC, endometrial biopsy (Pipelle), and cervical biopsy were collected. A rectal examination did not identify any rectal invasion.

Investigations included a whole-body positron emission tomography computed topography (PET-CT) and magnetic resonance imaging (MRI) of the pelvis. These identified a malignant lesion in the cervix with extension into the vagina and uterus and bilateral parametrial invasion with complete and partial encasement of the left and right ureters respectively. Lymph node metastases were radiologically identified in bilateral pelvis, mesorectal, and retroperitoneal spaces up to the L3 level in the left para-aortic and aortocaval areas. No definite supradiaphragmatic nodal metastatic disease was identified and there was no metastatic disease identified in the solid abdominal organs, lungs, or bones (Figures 1 and 2).

Fig. 1. Sagittal and coronal PET images demonstrating the avid cervical mass and lymph nodes.

Fig. 2. T2 weighted MR image of pelvis demonstrating cervical mass.

The histopathology from the Pipelle and cervical biopsy demonstrated a squamous cell carcinoma. The cervical screening test did not detect HPV. In-situ hybridisation for HPV mRNA was undertaken which confirmed the tumour was not HPV-related.

The final diagnosis was Stage IIIC1r (FIGO Staging 2018) squamous cell carcinoma of the cervix (non-HPV). The local multidisciplinary team recommended concurrent chemoradiotherapy with an intracervical brachytherapy boost. Concurrent chemotherapy was with weekly cisplatin and three-weekly pembrolizumab during radiation, and then six-weekly for a further 15 cycles.

Discussion

Cervical cancer is a leading cause of morbidity and mortality in females worldwide; it is the fourth most common cancer in women globally.¹ The overwhelming burden of this disease is in low- and middle-income countries, accounting for 94% of all cervical cancer deaths in 2022. In Australia in 2021, 886 women aged 25–74 were diagnosed with cervical cancer.²

There are two key elements in Australia’s aim to eliminate cervical cancer as a public health program by 2035 (that is fewer than four new cases per 100,000 women each year. The incidence in 2021 was 6.2 cases per 100,000 women).² They are the HPV vaccination program and the cervical screening program. HPV has been implicated in 99.7% of SCC of the cervix,³ and the incidence of adenocarcinoma that is HPV-related is 90% in women under 40 but drops to 43% in women above 40.⁴

The change from Papanicolaou testing to primary HPV testing in December 2017 has identified patients at risk of cervical cancer at an earlier stage of HPV-related disease. This more sensitive test allows for earlier interventions and is decreasing the rate of HPV-related cancer.²

In Australia, HPV-associated cervical cancer almost always develops in women who are under-screened or never screened.⁵

This has driven the implementation of self-collected screening. Equally sensitive for the detection of HPV compared to the clinician-collected test, self-collection increases access for those with anxiety, trauma, or barriers to care.⁵

Both clinician- and self-collected tests remain screening tests. Their use in this instance is an example of either improper understanding, patient reluctance, or clinician factors. Part five of the Cancer Council Australia National Cervical Screening Program Guidelines provides clear instructions on this issue, stating, “Before offering screening, the healthcare provider should take a history to determine whether the person has any symptoms suggestive of cervical cancer, including unexplained postcoital bleeding or persistent intermenstrual bleeding; postmenopausal bleeding; or unexplained persistent unusual vaginal discharge. People with these symptoms are not eligible for screening and should instead follow a diagnostic pathway.”⁵

HPV-ve cervical cancer is poorly characterised, is often diagnosed at later stages, and therefore associated with a poorer prognosis.⁶ HPV-ve tumours are probably a more aggressive subtype of cervical cancer, although more research is needed.⁶

This patient’s diagnosis was delayed due to false reassurance from a self-collected test. If she had been examined and had a clinician-collected sample, her diagnosis may have been recognised at least six months earlier. LBC either independently or as part of the co-test can identify abnormal cells from throughout the gynaecological tract, which should lead to ongoing investigation even in the absence of a lesion. An additional benefit of a clinician-collected sample is the opportunity to examine the external and internal genitalia and identify any occult disease processes.

Conclusion

This case is a reminder that although self-collect HPV testing forms an important part of population-level screening and has increased the uptake of screening in previously under-screened populations, it is not a diagnostic test and is not the appropriate choice in the presence of signs or symptoms suggestive of cervical cancer. In the presence of symptoms, physical examination of the cervix and genitalia is an essential part of the assessment. An LBC should be requested as well as HPV testing (co-test), and referral for further evaluation should be undertaken when the initial clinician is unable to reach a diagnosis.