Table 15GYNAECOLOGICAL CANCER: signs and symptoms, including risk factors

AuthorSettingDescriptionNo.InclusionExclusionResultsGold StdQuality
Bell at al 1998Systematic review of screening for ovarian cancerHigh quality evidence review (HTA)
Flam et al 1998SwedenThe symptamology of ovarian cancer was retrospectively reviewed in patients who had been referred to a single specialist centre. Patients gave an account of their initial symptoms and those that led to medical consultation. The disease was classified at early (stages IA-IIA) or advanced (stages IIB-IV) at diagnosis362Women with diagnosed ovarian cancer referred to Radiumhemmet for treatement between 1975–1976-The most common initial symptoms were abdominal swelling and/or palpable tumour, pain and gastro-intestinal symptoms. The initial symptoms, however, were not necessarily those that prompted patients to seek medical advice. The most common reason was pain in the early group, but abdominal swelling in the advanced group (27.9%).
Gynaecological disease was suspected by 55.2% of the early group and 37.9% of the advanced group.
The results for initial symptoms in early and advanced ovarian carcinoma
The study did not include people presenting in primary care.
Ghurani and Penalver 2001Narrative review on latest literature on vulvar cancerNarrative, authoritative review
Goff et al 2000CanadaThis study observed symptoms and other factors that may contribute to the delayed diagnosis of ovarian carcinoma using a questionnaire survey.1725Patients with Ovarian carcinoma-In terms of whether women had symptoms before the diagnosis of ovarian carcinoma, 77% reported abdominal symptoms, 70% gastrointestinal, 58% pain, 50% constitutional, 34% urinary and 26% pelvic.

Only 11% of women with Stage I/II and 3% with Stage III/IV reported they were completely asymptomatic before their diagnosis.

13% of participants reported being told by their provider that nothing was wrong, 6% were diagnosed with depression, 12% stress, 6% constipation, 15% irritable bowel syndrome, 9% gastritis and 47% were given other diagnoses. Only 20% of patients were told initially they might have ovarian carcinoma.

Women who had the most symptoms were significantly younger. Women with advanced disease were significantly more likely to have symptoms than those with early stage disease. The types of symptoms between both groups were similar however. Those who ignored their symptoms were significantly more likely to have more total symptoms and advanced stage disease compared with those who did not (85% vs. 74%; P=0.002).
Although there was a high response rate and geographic diversity. Bias may have occurred in the survey selection because the women who participated in this study were those who chose to subscribe to a newsletter or those active in support groups.
Jones et al 1997New ZealandThe study aimed to determine trends in the clinicopathology of vulval squamous cell carcinoma over the past two decades, with particular reference to the possible effects of the increasing evidence of vulval intraepithelial neoplasia (VIN) during this time. A retrospective review of the clinical records of two cohorts of women presenting with squamous cell carcinoma to a gynaecological oncology unit. One cohort involved cases between 1965–1974, and the other between 1990–1994113-Any cases in which tissue was unavailable for review.The mean age at presentation was 68.4 (44–92) years (median 72 years) in the 1965–1974 cohort, and 69.2 (22–93) years (median 71 years) in the 1990–1994 cohort. In the 1965–1974 cohort, only one patient was younger than 50 years of age, whereas in the 1990–1994 cohort, 12 women (21%) were younger than 50 years (P = 0.001). There were no statistical differences in FIGO stage between the two cohorts.

When stratified according to age, 11 of 13 women younger than 50 years, compared with 10 of 100 women older than 50 years of age, smoked cigarettes (P < 0.001). Ten of the 13 women younger than 50 years of age, compared with 13 of 100 women 50 years of age or older, had warty and/or basaloid VIN III associated with their invasive carcinoma (P < 0.001). Multiple lower genital tract neoplasia was also more common in women younger than 50 years of age (P < 0.001).
Warty and basaloid VIN was associated with 16 of 19 (84%) warty or basaloid carcinomas and with seven of 94 (7.4%) typical squamous cell carcinomas (P < 0.001). In contrast, non-neoplastic epithelial disorders were associated with 55 of 94 (58.5%) typical squamous cell carcinomas and with none of the 19 basaloid or warty carcinomas.
Messing and Gallup 1995USAThe aim was to determine if young women have a different risk factor history and outcome compared with older women. A retrospective review of the hospital medical records of women treated for squamous cell carcinoma of the vulva over a period of 15 years was conducted. A comparison was made between women younger than 45 years with those 45 years and over for historic risk factors, treatment modality, and outcome.Cases of 78 women.Patients presented with complaints of a lesion, lump, or pain in 70% of cases. There was no significant difference in the duration of symptoms for younger versus older women.

Women under 45 were found to have a stronger history of condyloma (P < 0.001, 95% confidence interval 3.69–87.96). There was no significant difference by age in smoking history, alcohol consumption, or tumour size. Older women were more likely to have advanced stage disease (P = 0.03, 95% CI 0.43–0.91) but no metastatic disease. The median tumour size at presentation was 4 cm (range 0–27). Lesion size over 2cm was significantly associated with the presence of metastatic disease (P < 0.001). The following were associated with decreased survival: FIGO stage IV (P <0.001, 95% CI 1.6–5.1), presence of metastases (P < 0.001, 95% CI 1.5–3.6), and tumour size greater than 2cm (P = 0.002, CI 0.09–0.34). There was no detected difference in survival for women in either group.
Olsen et al 2001USAA retrospective case control study examined the presence and duration of various symptoms of ovarian cancer and the use of medications in comparison with healthy women.168–recently diagnosed patients.

251–Healthy women.
Women were included if they were; over 18 years of age, diagnosed with ovarian cancer, resident in the US and English or Spanish speaking. Inclusion was also dependent upon whether they were considered by their physicians to be well enough to take part.-The symptoms were selected based on reviews of earlier reports in the literature and in consultation with clinicians.
The most common symptoms among cases were: unusual bloating, fullness and pressure in the abdomen (71%); unusual abdominal pain or lower back pain (52%); and lack of energy (43%). The proportions of controls reporting these symptoms were 9%, 15% and 16% respectively, resulting in ORs and 95% CIs of 25.3 (15.6, 40.9), 6.2 (4.0, 9.6), and 3.9 (2.5, 6.1), respectively, for these symptoms
Patients who experienced bloating, fullness and pressure were more likely than controls to report that the symptoms were constant. Most of the symptoms were experienced for a longer period of time by women with early rather than late stage disease.
The study was reported to be limited by relatively small numbers of cases, especially women with early disease, and 35% of affected patients mentioned other symptoms that were not listed on the questionnaire. The most common additional symptom was pain in the side or ribs, mentioned by seven.
The patient samples were based on healthy community controls and those attending hospital, and did not include those attending general practice.
Paley 2001Guidelines for screening women for cancerSome review of the evidence
Parikh et al 2003A meta-analysis was conducted after pooling the data from previously reported case-control studies (n = 57) of cervical cancer or dysplasia, which contained individual-level information on socio-economic characteristics, to investigate the relationship between cervical cancer, social class, stage of disease, geographical region, age and histological increased relative risk of dysplasia and cervical cancer with decreasing social class was observed. Women in the middle social class group were at approximately a 26% increased risk of cervical disease (95% CI 17–36%, whereas women in the lower social class tertile were at approximately 80% increased risk when compared to women in the upper tertile (95% CI 69–92%). These elevated risks persisted after analysis was restricted to those studies which included only women aged <50 years (97% increase in risk of invasive cancer for the low socio-economic group; 95% CI 80–115%, and 58% increase in risk of dysplasia for the low socio-economic group; 95% CI 41–78%). When stratified by geographical region, the increased risk identified in studies that originated from Western Europe appeared to be only moderate, with a 45% increased risk of cervical disease in the low social class group as opposed to the high social class group (95% CI 29–62%). When the analysis was restricted to studies that only included cases of cervical cancer, the increase in risk between social class and invasive cervical cancer was reduced to 28% (95% CI 10–49%) for Western European studies.
There was significant unexplained heterogeneity in most of the pooled odds ratios, which might have been possible because of the inability to control for variables such as background HPV prevalence.
Rosen et al 1997SwedenA retrospective review of the hospital records of patients with histologically confirmed primary invasive vulval cancer (Sweden). The aim was to evaluate the survival after treatment of vulval cancer in relation to various prognostic factors (FIGO staging, tumour grading, age at diagnosis, heredity for any cancer, childbirth, and prior history of any cancer).328 patient records.Patienrs with vulvar cancer.--The most common presenting symptoms were pruritus (24%), smarting pain (15%), and a vulval lesion (15%). Squamous cell carcinoma was the most common histological form of vulval cancer, constituting 91.4% of the cases (n= 300). Melanoma constituted 3% (n = 10), Paget’s disease 2.4% (n = 8), cancer of the Bartholin’s glands 1.8% (n = 6), adenocarcinoma 0.6% (n = 2), and basal cell carcinoma 0.6% (n = 2) of the vulval cancers.
Survival analyses were limited to the 300 patients with squamous cell vulval cancer. The majority of patients with squamous cell vulval cancer were Stages I (35%) or II (37%) at diagnosis. 36% had a well-differentiated tumour, 43% had a moderately differentiated tumour, and 15% had a poorly differentiated tumour. There were significant differences in survival when comparing patients older than mean age at presentation (69 years) with the patients who were younger than mean age (P < 0.01). There were significant (P < 0.00001) differences in corrected survival times between different FIGO stages: 5 year survival rate was 93% for Stage I, 60% for Stage II, 40% for Stage III, and 13% for Stage IV. Histologic grade was also shown to be a significant prognostic marker for survival (P = 0.02): well-differentiated tumours had a 5 year survival rate of approximately 70% while moderately or poorly differentiated tumours had a 5 year survival rate of approximately 55%. Both parity and previous history of cancer did not influence survival times significantly.
SIGN 2002Guidelines on investigation of post-menopausal bleedingEvidence based, but only referred to DoH 2000 referral guidelines
Smith et al 1985USAA case series evaluating the characteristics of ovarian cancer symptoms, their perceived cause and delay in seeking a diagnosis associated with stage, grade and histologic features of disease at diagnosis among patients with cancer of the ovary83Women diagnosed with cancer were identified from the population based Iowa (National Cancer Institute Surveillance, Epidemiology, and End Results) NCI-SEER cancer registry.Those participants who could not be interviewed due to severe illness, refusal or physician refusal to allow contact. Those individuals that did not have their diease staged at the beginning of the study were also excluded.68% of patients had experienced symptoms that prompted a consultation.
The most common number of symptoms occurring together was two (72.2%), with abdominal swelling most likely to be identified with other conditions: fatigue (23.5%), urination problems (17.6%), and pain (17.6%). Swelling, pain and fatigue were commonly seen together (29.4%). Only abdominal pain and swelling were significantly associated (P<0.05) with later stage disease.
Pain was likely to convince women to seek a diagnosis.
Those aged 40–49 years were more likely to report symptoms than patients in other age groups (P<0.05).
No relationship between age and type or number of symptoms was found, nor associations with other sociodemographic factors.
Less frequently noticed symptoms were irregular vaginal bleeding, metrorrhagia, indigestion and urination problems (frequency or difficulty). Symptoms were viewed less seriously if they were believed to be related to indigestion or menopausal conditions. Irregular menstrual cycles often convinced patients with early-stage cancers to seek a diagnosis.
The cohort did not include older patients for whom the results may be less applicable
Stratton et al 1998UKA systematic review of case control and cohort studies with the aim to estimate the relative and lifetime risks of ovarian cancer in women with various categories of family history (1- an unaffected first degree relative, 2- an affected mother, 3- an affected sister, and 4- women with more than one affected relative)15 studiesPublished studies from 1066–1998-studies in which family history had been recorded.--Although there was heterogeneity in the studies used to estimate risk in first-degree relatives, this did not alter the estimate of the pooled relative risk Two studies reported the relative risks to first-degree relatives according to age at diagnosis or death of the index case. The pooled estimate of RR was 1.7 (95% CI 1.2–2.5) where the index case was diagnosed or dies from ovarian cancer before the age of 40, compared with 3.8 (95% CI 2.6–5.5) if the index case was diagnosed or died at an older age. Four studies reported RRs according to the ages of first-degree relatives. For women younger than 50 with an affected first degree relative the RR was 2.9 (95% CI 1.9–4.3), while for women older than 50 with an affected first degree relative the risk was 2 (95% CI 1.5–2.5). The risk to daughters of an affected mother was given in three case-control studies which provided a pooled estimated RR of 6 (95% CI 3.0–11.9). The risk to mothers with an affected daughter was given by two cohort studies and one case-control study. The estimated RR was 1.1 (95% CI 0.8–1.6). Four studies reported risks associated with having an affected sister. The pooled estimate from these studies gave an RR of 3.8 (95% CI 2.9–5.1). Only two case-control studies and no cohort study examined the risks associated with having a second degree relative with ovarian cancer. The pooled relative risk estimated from these studies was 2.5 (95% CI 1.5–4.3). Two studies examined the risks involved in having more than one affected relative (either first or second degree) with ovarian cancer. The pooled risk estimate was 11.7 (95% CI 5.3–25.9).Potential limitations included recall bias since women with ovarian cancer were more likely to recount a family history of ovarian cancer than control subjects
Sturgeon et al 1992USAAn investigation to examine recent trends in the incidence of vulval cancer. The authors identified cases of in situ and invasive cell carcinoma of the vulva diagnosed between 1973 and 1987 from population- based cancer registries.Cases of in situ or invasive squamous cell carcinoma of the vulva diagnosed between 1973 and 1987.-Non-squamous cell malignancies were excluded from the analysisThe annual incidence of in situ vulval carcinoma for all races combined nearly doubled from 1.1 to 2.1 during the period from 1973 to 1976 and 1985 to 1987. The largest proportional increase occurred among white women <35 years old, for whom the rate nearly tripled. Increases were more modest among black women than among white women, with the rate not quite doubling among black women <35 years old. In situ rates among blacks of all ages were higher than those among whites before 1977, but the black-white differential has diminished in more recent years. The peak in situ rate has shifted over time from women > 54 years to women aged 35 to 54.
The invasive squamous cell carcinoma incidence for all races combined was relatively stable over 1973 to 1976 and 1985 to 1987. Rates in each age group were also relatively steady, although among white women they tended to decline among those aged >55. Little racial difference was evident under age 35; rates were higher at ages 35 to 54 among blacks and at ages >54 among whites. In contrast to in situ cancers, invasive rates increased steadily with age.
Vikki et al 1998FinlandAn investigation into the predictive value of bleeding for detecting subsequent gynaecological or urinary cancers among women that were screened negative for cervical cancer.

Data from the Finnish Mass Screening Registry and National Cancer Registry were used to investigate the long term significance of bleeding symptoms. The mean length of follow-up was 7 years.
37,596women in the national population-based mass screening programme for cervical cancer classified as having reported bleeding symptoms when screened--The prevalence of postmenopausal bleeding among the 37,596 women (all ages) was 0.2%, bloody discharge was 1.1%, coital bleeding 0.7%, and irregular bleeding 3.9%. During follow up 753 cancers were observed among women with bleeding symptoms; 197 (26%) of these were gynaecological. The relative risk of cancer of corpus uteri was 3.6 in women with postmenopausal bleeding. The RR of cervical cancer 1.1, (95% CI 0.8–1.4) was not significantly increased during follow up for a maximum period of ten years. Women with bloody discharge had an elevated risk of gynaecological cancers. The excess was attributable to cancer of corpus uteri (SIR 2.2, CI 1.3–3.4). Coital bleeding was rare and not associated with gynaecological cancer (SIR 1.0). Irregular bleeding was associated with an increased risk of cancer of corpus uteri (SIR 1.8, 1.3–2.5). Risk of cancer of the corpus uteri increased with any bleeding symptom (SIR 2.1, 95% CI 1.6–2.6) but postmenopausal bleeding RR was 3.6 (95% CI 2.0–6.0).The symptoms were those reported at the time of screening and not before diagnosis. It is not clear whether these findings can be related to people consulting with these symptoms.
Vine et al 2001USAAn investigation into the types and duration of symptoms among women with invasive versus borderline ovarian tumours. Information about symptoms was obtained using a standardised questionnaire administered by interview conducted in the homes of study participants.767Women aged 20–69 year, and diagnosed histologically as having primary epithelial invasive of borderline ovarian cancer between 1994 and 1998. there was also area of residence criteria.Participants were excluded if English was not spoken or if patients were not mentally competent. cases were also excluded if diagnosis was greater than 6 months, the patient was critically ill or dead, untraceable, the physician did not consent to contact and refusal to participate.The percentage of women with symptoms was significantly higher in invasive versus borderline disease. Women with borderline disease had symptoms for longer periods of time than those with invasive disease or pelvic discomfort, bowel irregularity and urinary frequency/urgency. Pre-diagnostic symptom duration was longer among borderline than in invasive cases. Although women with invasive cancers were significantly older, no differences were found between women with invasive versus borderline tumours with respect to sociodemographic variables. Borderline tumours were more likely than invasive tumours to be mucinous (40 vs 8%) and less likely to be endometroid (2 vs 22%). Borderline and invasive cases reported similar types of symptoms. However, borderline cases were twice as likely as invasive cases to report not having had symptoms (16 vs 8%, P=0.005). Twice as likely as invasive cases to be diagnosed through routine examination (28 vs 16%, P=0.001). Invasive cases were more likely to be diagnosed because of symptoms (62 vs 48%, P=0.002).
Weber et al 1999USA case control study which aimed to identify independent risk factors for endometrial neoplasia in women with abnormal perimenopausal or postmenopausal bleeding in order to develop and test a predictive model.57 cases of endometrial hyperplasia or cancer.

137 controls.
Patients with cancer (defined as any invasive malignancy of the endometrium), adenocarcinoma in situ, and complex endometrial hyperplasia with and without atypia.

Controls were defined by benign histologies on endometrial samplings (including simple hyperplasia)
Patients being investigated for fertility problems with endometrial samplings for menstrual cycle dating and pregnant women were excluded, as were those with cancer or hyperplasia.Parity was related inversely (odds ratio [OR] 0.70; 95% CI 0.56, 0.88; P=0.02) and weight directly (OR 1.02 per kg; 95% CI 1.01, 1.04; P=0.018) to the risk of endometrial neoplasia. Age (OR 1.04 per year; 95% CI 1.00, 1.08; P=0.06) and diabetes (OR 3.50; 95% CI 0.99, 12.33; P=0.052) were significant marginally. Multivariate analysis suggested that increased age and weight, diabetes and lower parity were independently associated with endometrial neoplasia. The clinical model, did not have sufficient predictive ability to determine if women with abnormal perimenopausal or postmenopausal bleeding should have diagnostic testing
Wickborn et al 1993SwedenCase series investigating symptoms in patients with different types of ovarian cancer, by reviewing clinical records to identify information from first consultation to operation and diagnosis.160 patientsPatients diagnosed in a specialist centre between 1981 and 1986 with epithelial ovarian cancer that could be staged.-No specific group of symptoms could be linked with type or stage of ovarian cancer.
Only 21% complained of gynaecological symptoms. The majority of women did not experience symptoms in the genital organs. Women with class IC cancer had significantly more advanced disease than those with 2C–5C cancer as 77% had a stage III–IV tumour compared with 40% of class 2C–5C patients. The mean age was 62.6 years (range 25–87 years).
Several women had more than one type of symptom, pain and abdominal swelling being the most common combinations. Irrespective of stage, 37% had symptoms related to the bladder; approximately 65% had pain and 60% had abdominal swelling. Gastrointestinal and general symptoms were less common in stage 1 than in higher stages. This was not the case with tumour classes 2C–5C disease.

From: Appendix A, Evidence Tables

Cover of Referral Guidelines for Suspected Cancer in Adults and Children
Referral Guidelines for Suspected Cancer in Adults and Children [Internet].
NICE Clinical Guidelines, No. 27.
Clinical Governance Research and Development Unit (CGRDU), Department of Health Sciences, University of Leicester.
Copyright © 2005, National Collaborating Centre for Primary Care.

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