Abstract
Objective
Although the majority of women with ovarian carcinoma report symptoms prior to diagnosis, little is known about comparative symptom presentation by histological type, stage, grade, or ethnicity.
Methods
We conducted a population-based study including 622 women with invasive ovarian carcinoma diagnosed from 1993 to 2008. Epidemiological and symptom data were collected using an interviewer-administered questionnaire. Symptoms established as significant predictors of ovarian carcinoma were examined in relation to patient and tumor characteristics, using unconditional multivariate logistic regression and general linear models.
Results
Symptom presentation and duration differed significantly among women with ovarian carcinoma by stage, tumor histology, and grade, but not ethnicity. Significant differences were observed by histology in reporting a distended abdomen, abnormal vaginal bleeding, and bowel symptoms. Compared to women diagnosed with serous carcinoma, women with mucinous tumors were 2.6 times more likely to report a distended abdomen; women with endometrioid carcinoma were three times more likely to report abnormal bleeding. Women with serous tumors were significantly more likely to report bowel symptoms than were women diagnosed with other histological types. The majority of women with serous tumors were diagnosed with advanced cancer and had shorter duration of symptoms than women with early stage disease. In contrast, women with mucinous tumors were generally diagnosed at an early stage and had longer duration of symptoms (p=0.009) if diagnosed at an advanced stage.
Conclusion
The study provides evidence that the early diagnosis of ovarian cancer is largely determined by tumor histological type.
Keywords: Ovarian carcinoma, symptom presentation, case analysis
Introduction
In the United States, ovarian cancer is the fifth leading cause of cancer death among women [1]. A major reason for the high fatality rate is the inability to identify women with early-stage disease resulting from inadequate screening tools and lack of specific clinical symptoms [2]. Although pelvic ultrasonography and serum CA 125 marker can be valuable in detection of ovarian cancer among asymptomatic women, neither of these methods has an acceptable level of sensitivity or specificity for population screening [3, 4]. Therefore, the diagnosis of ovarian cancer for the majority of women relies on symptom presentation [3]. Recent studies (reviewed in [5]) have demonstrated that a high proportion of women with ovarian cancer report symptoms prior to diagnosis. However, studies of ovarian cancer symptoms have been largely limited to white women, and comparative symptom presentation by histological type and stage was addressed only in a few studies [6-8]. It has long been recognized that ovarian cancer histological subtypes are associated with different natural histories [9]. These subtypes differ dramatically across subgroups of stage; the majority of early stage carcinomas are of nonserous histology whereas advanced stage carcinomas are predominantly of serous subtype [10-12].
In a previous analysis of data from a large population-based case-control study conducted in Hawaii among women with different racial/ethnic backgrounds, we reported that women with ovarian cancer were more likely than controls to complain of abdominal or pelvic pain or discomfort, distended and hard abdomen, urinary symptoms, abnormal vaginal bleeding, and palpable abdominal mass. In addition to these symptoms, women with advanced disease were more likely than controls to experience bowel irregularity, bloating, or flatulence; and fatigue or/and loss of appetite [13]. Using a larger sample of women with invasive ovarian carcinoma, we further evaluated the association of symptoms with stage at diagnosis, ethnicity, and tumor histological type and grade. We also explored whether symptom presentation was mediated by age, education, family and personal history of cancer, parity, use of contraceptive and menopausal hormones, tubal ligation, menopausal status, and body mass index (BMI).
Methods
This population-based case only study was conducted in Hawaii and Los Angeles, California, and included 622 women 19-88 years of age, who were diagnosed with histologically confirmed primary invasive epithelial ovarian carcinoma between 1993 and 2008. Eligible cases were identified through the rapid-reporting systems of the Hawaii Tumor Registry (n=390) and the Cancer Surveillance Program at the University of Southern California (n=232). Both registries are part of the Surveillance, Epidemiology, and End-Results (SEER) Program of the National Cancer Institute [14] with case ascertainment estimated to be greater than 98%. The participation rate was 73%. We attempted to interview all women as close to their diagnoses as possible. The median time from diagnosis to interview was 8.9 months.
Interviews were conducted by uniformly trained personnel and supervised to standardize interviewing and coding techniques. A structured pre-tested questionnaire was used for data collection including socio-demographic and health-related information, menstrual, reproductive and gynecological histories, and exogenous hormone use. All women self-reported the race/ethnicity of their grandparents, and we assigned summary categories for race/ethnicity according to the following rules. A woman was classified into a particular ethnic group if all four of her grandparents were of this ethnic group. In agreement with a common rule applied in the State of Hawaii, women with any Hawaiian background were classified as Native Hawaiian. Small numbers of Chinese, Korean, and other Asian women were combined into ‘Other Asian’ category, and women of all other or mixed ethnicities were classified as ‘Other’.
All women were asked whether they had experienced any of the following 10 symptoms within 12 months prior to their diagnosis: 1) persistent abdominal or pelvic pain or discomfort (further referred to as ‘abdominal pain’); 2) unusual bowel irregularity such as diarrhea or constipation, flatulence, or bloating (‘bowel symptoms’); 3) urinary frequency, difficulty emptying urinary bladder, or dysuria (‘urinary symptoms’); 4) persistent distended and hard abdomen (‘distended abdomen’); 5) persistent fatigue (‘fatigue’); 6) persistent flank or back pain with or without exertion (‘flank/back pain’); 7) vaginal bleeding not associated with periods (‘abnormal vaginal bleeding’); 8) a palpable abdominal mass that the woman herself had noticed (‘abdominal mass’); 9) weight gain and swelling of the lower extremities (weight gain/leg swelling); and 10) nausea, vomiting, or heartburn (‘nausea/heartburn’). In addition, all other symptoms reported by women were recorded. We also collected information about whether diagnosis of ovarian cancer was established because a woman sought medical attention due to described symptoms or incidentally during a routine doctor visit. The duration (in months) for each symptom experienced from onset to the date of diagnosis was recorded. In the current analysis, only symptoms that we found significantly predictive of ovarian carcinoma in our case-control analysis [13] were assessed.
The study was approved by the Institutional Review Boards of the University of Hawaii and the University of Southern California. All study participants signed detailed consent forms.
Statistical analysis
Statistical analysis was performed using the SAS software package (SAS release 9.2, SAS Institute Inc., Cary, NC). Differences in categorical variables by subgroups were tested by the chi-square test of association. Unconditional multiple logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for differences in symptom presentation by ethnicity, stage, histology, and grade. Time from the onset of the first symptom to diagnosis (duration of symptoms) was assessed using general linear models. Means for symptom duration within subgroups were derived from these models and uniformly adjusted for covariates (age, ethnicity, and study). P-values for interaction between histology and stage/grade effects on symptom duration were estimated using the global F-test for the histology-stage/grade cross-product terms. We also tested the following factors as potential confounders or effect modifiers: age, years of education, body mass index (BMI; calculated as the ratio of weight in kilograms divided by the square of the height in meters), family history and personal history of breast and/or ovarian and any other cancer, parity, menopausal status, history of tubal ligation, hysterectomy, and use of contraceptive and menopausal hormones (never; estrogen only, combination of estrogen and progestin). All p-values were derived from two-tailed statistical tests. Statistical significance was considered at a p value less than 0.05.
Results
Participant characteristics
The median age at diagnosis for study participants was 56.9 (standard error: 0.5 years). Of the 622 women included in this analysis, 53% were diagnosed at an early stage (FIGO stages I-II) (Table 1). Overall, serous was the most common histological type of tumor (53%), followed by endometrioid (18%), clear cell (13%), mucinous (11%), and undifferentiated or mixed histology (categorized as ‘other’) (6%). Serous carcinoma was the most common histological type among all ethnic groups (41-65%), although Caucasian women were significantly more likely to be diagnosed with serous tumors and less likely to be diagnosed with mucinous or clear cell carcinomas compared to women of other ethnic backgrounds.
Table 1.
Subject characteristics by ethnicity and tumor histological type
|
Ethnic groups |
||||||||
|---|---|---|---|---|---|---|---|---|
| Characteristics | All cases n=622 |
Caucasian n=224 |
Japanese n=125 |
Hawaiian n=78 |
Filipino n=66 |
Other Asian n=78 |
Other n=51 |
P* |
| Number of cases (%) | ||||||||
| Age (years) | ||||||||
| < 60 | 364 (59) | 126 (56) | 58 (46) | 52 (67) | 43 (65) | 50 (64) | 35 (69) | |
| ≥ 60 | 258 (41) | 98 (44) | 67 (54) | 26 (33) | 23 (35) | 28 (36) | 16 (31) | 0.01 |
| BMI (kg/m2) | ||||||||
| Lean (BMI < 25) | 369 (59) | 146 (65) | 83 (66) | 23 (29) | 36 (55) | 59 (76) | 22 (43) | |
| Overweight (BMI ≥ 25) | 253 (41) | 78 (35) | 42 (34) | 55 (71) | 30 (45) | 19 (24) | 29 (57) | 0.0001 |
| Stage | ||||||||
| Early (FIGO I-II) | 329 (53) | 93 (42) | 74 (59) | 46 (59) | 37 (56) | 48 (62) | 31 (61) | |
| Advanced (FIGO III-IV) | 293 (47) | 131 (58) | 51 (41) | 32 (41) | 29 (44) | 30 (38) | 20 (39) | 0.002 |
| Tumor histological type | ||||||||
| Serous | 328 (53) | 147 (65) | 54 (43) | 40 (51) | 27 (41) | 38 (49) | 22 (43) | |
| Mucinous | 68 (11) | 13 (6) | 18 (14) | 11 (14) | 8 (12) | 11 (14) | 7 (14) | |
| Endometrioid | 110 (18) | 37 (17) | 24 (19) | 14 (18) | 13 (20) | 12 (15) | 10 (20) | |
| Clear cell | 79 (13) | 11 (5) | 24 (19) | 10 (13) | 14 (21) | 15 (19) | 5 (10) | |
| Other | 37 (6) | 16 (7) | 5 (4) | 3 (4) | 4 (6) | 2 (3) | 7 (14) | 0.0001 |
| Tumor grade† | ||||||||
| Low (grade 1-2) | 210 (38) | 79 (38) | 38 (34) | 29 (43) | 23 (43) | 23 (37) | 18 (40) | |
| High (grade 3-4) | 340 (62) | 129 (62) | 73 (66) | 38 (57) | 33 (59) | 40 (63) | 27 (60) | 0.87 |
|
Tumor histological type |
|||||||
|---|---|---|---|---|---|---|---|
| All cases n=622 |
Serous n=328 |
Mucinous n=68 |
Endometrioid n=110 |
Clear cell n=79 |
Other n=37 |
P* | |
| Number of cases (%) |
|||||||
| Age (years) | |||||||
| < 60 | 364 (59) | 166 (51) | 45 (66) | 71 (65) | 56 (71) | 26 (70) | |
| ≥ 60 | 258 (41) | 162 (49) | 23 (34) | 39 (35) | 23 (29) | 11 (30) | 0.0009 |
| BMI (kg/m2) | |||||||
| Lean | 369 (59) | 204 (62) | 39 (57) | 55 (50) | 49 (62) | 22 (59) | |
| Overweight | 253 (41) | 124 (38) | 29 (43) | 55 (50) | 30 (38) | 15 (41) | 0.25 |
| Stage | |||||||
| Early | 329 (53) | 101 (31) | 60 (88) | 82 (75) | 63 (80) | 23 (62) | |
| Advanced | 293 (47) | 227 (69) | 8 (12) | 28 (25) | 16 (20) | 14 (38) | <0.0001 |
| Tumor grade | |||||||
| Low | 210 (38) | 76 (25) | 48 (87) | 66 (62) | 15 (28) | 5 (17) | |
| High | 340 (62) | 231 (75) | 7 (13) | 40 (38) | 38 (72) | 24 (83) | <0.0001 |
Note: Statistically significant values are shown in bold font.
P values from the chi-square tests.
Grade information was missing for 72 women.
The majority of women with serous carcinoma were diagnosed at an advanced stage (69%) compared to 12% of women with mucinous tumors and 20-38% of women with all other histological types. The proportion of high-grade tumors was greater among women with serous (75%), clear cell (72%) and other histology (83%) compared to women diagnosed with mucinous (13%) or endometrioid tumors (38%). High-grade tumors were more likely to be diagnosed at an advanced stage (61%) compared to low-grade tumors (27%), although the majority of nonserous high-grade tumors (76% clear cell, 57% mucinous, and 60% endometrioid) were diagnosed at an early stage (shown in Table 3). In contrast, 74% of high-grade serous tumors were advanced stage carcinomas.
Table 3.
Duration of symptoms from onset to the diagnosis date by stage, grade, and histology.
| Categories of cases by stage and grade | All |
Serous |
Mucinous |
Endometrioid |
Clear cell |
||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| N (%) | Mean* (months) (SE) | N (%) | Mean* (months) (SE) | N (%) | Mean* (months) (SE) | N (%) | Mean* (months) (SE) | N (%) | Mean* (months) (SE) | P§ | |
|
Symptom duration by stage in all cases combined and by grade strata
|
|||||||||||
| All cases | |||||||||||
| Stages I-II | 329 (53) | 13.7 (1.5) | 101 (38) | 16.2 (2.6) | 60 (88) | 6.1 (2.2) | 82 (75) | 19.5 (4.2) | 63 (80) | 7.8 (3.5) | |
| Stages III-IV | 293 (47) | 7.2 (1.7) | 227 (62) | 7.3 (2.1) | 8 (12) | 20.6 (3.0) | 28 (25) | 15.0 (6.5) | 16 (20) | 12.3 (7.4) | 0.02 |
| P† | 0.003 | 0.004 | 0.009 | 0.55 | 0.52 | ||||||
| Low grade | |||||||||||
| Stages I-II | 153 (73) | 9.7 (2.0) | 31 (41) | 14.7 (4.4) | 46 (99.5) | 8.2 (1.5) | 56 (75) | 11.2 (4.7) | 15 (100) | 7.8 (5.7) | |
| Stages III-IV | 57 (27) | 7.0 (3.2) | 45 (59) | 6.4 (3.7) | 2 (0.5) | 25.6 (6.7) | 10 (15) | 8.5 (3.0) | 0 (0) | n/a | 0.008 |
| P‡ | 0.45 | 0.14 | 0.01 | 0.81 | |||||||
| High grade | |||||||||||
| Stages I-II | 131 (39) | 17.8 (2.1) | 61 (26) | 17.5 (3.1) | 4 (57) | 5.7 (4.9) | 24 (60) | 28.3 (7.1) | 29 (76) | 7.9 (3.9) | |
| Stages III-IV | 209 (61) | 9.5 (1.7) | 170 (74) | 8.4 (1.9) | 3 (43) | 16.2 (5.5) | 16 (40) | 21.8 (8.5) | 9 (24) | 12.3 (6.2) | 0.26 |
| P‡ | 0.002 | 0.01 | 0.18 | 0.56 | 0.52 | ||||||
| | |||||||||||
|
Symptom duration by grade in all cases combined and by tumor stage strata
|
|||||||||||
| All cases | |||||||||||
| Low grade | 210 (38) | 7.6 (1.8) | 76 (25) | 10.6 (2.9) | 48 (87) | 15.6 (3.0) | 66 (62) | 9.3 (5.0) | 15 (28) | 10.1 (7.2) | |
| High grade | 340 (62) | 13.4 (1.4) | 231 (75) | 12.9 (1.8) | 7 (13) | 11.1 (3.5) | 40 (38) | 25.2 (5.5) | 38 (72) | 10.1 (3.9) | 0.11 |
| P† | 0.009 | 0.47 | 0.31 | 0.02 | 0.99 | ||||||
| Stages I-II | |||||||||||
| Low grade | 153 (54) | 9.7 (2.0) | 31 (33) | 14.7 (4.4) | 46 (99.2) | 8.2 (1.5) | 56 (70) | 11.2 (4.7) | 15 (34) | 7.8 (5.7) | |
| High grade | 131 (46) | 17.8 (2.1) | 61 (66) | 17.5 (3.1) | 4 (0.8) | 5.7 (4.9) | 24 (30) | 28.3 (7.1) | 29 (66) | 7.9 (3.9) | 0.60 |
| P‡ | 0.005 | 0.60 | 0.64 | 0.04 | 0.99 | ||||||
| Stages III-IV | |||||||||||
| Low grade | 57 (21) | 7.0 (3.2) | 45 (21) | 6.4 (3.7) | 2 (40) | 25.6 (6.7) | 10 (38) | 8.5 (3.0) | 0 (0) | n/a | |
| High grade | 209 (79) | 9.5 (1.7) | 170 (79) | 8.4 (1.9) | 3 (60) | 16.2 (5.5) | 16 (62) | 21.8 (8.5) | 9 (100) | 12.3 (6.2) | 0.52 |
| P‡ | 0.45 | 0.45 | 0.26 | 0.31 | n/a | ||||||
LS means of duration of symptoms from general linear models (GLM), adjusted for age, ethnicity, and study.
P from GLM comparing duration of symptoms by stage (grade) overall and within each histology stratum.
P from GLM comparing duration of symptoms in subgroups by stage and grade overall and within each histology stratum.
P for interaction between histology and stage/grade effects on symptom duration, estimated using F-test of the histology-stage/grade interaction terms.
Symptoms presentation
Fatigue was significantly less likely to be reported by Japanese women (25%) compared to Caucasian women (42%) (p = 0.03) (Table 2). No other significant differences in reporting symptoms were observed by ethnicity after adjustment for stage, histology, grade, and other patient characteristics. Complaints of abdominal pain (58% vs. 47%), abdominal distention (46% vs. 36%), bowel symptoms (47% vs. 31%), and fatigue (42% vs. 33%) were significantly more common among cases with advanced ovarian cancer than among women with localized disease. Reporting other symptoms did not differ significantly by stage of disease.
Table 2.
Ovarian carcinoma symptoms by ethnicity, stage, tumor histology and grade, age, and BMI.
| Characteristics | n | Abdominal pain |
Distended abdomen |
Urinary symptoms |
Abdominal mass |
Abnormal bleeding |
Bowel symptoms |
Fatigue |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n (%) | OR (CI)* | n | OR (CI)* | n | OR (CI)* | n | OR (CI)* | n | OR (CI)* | n | OR (CI)* | n | OR (CI)* | ||
| All | 622 | 326 (52) | 253 (41) | 191 (31) | 74 (12) | 62 (10) | 240 (39) | 229 (37) | |||||||
| | |||||||||||||||
| Ethnicity | |||||||||||||||
| Caucasian | 224 | 124 (55) | 1.0 | 91 (41) | 1.0 | 68 (30) | 1.0 | 21 (9) | 1.0 | 20 (9) | 1.0 | 91 (41) | 1.0 | 94 (42) | 1.0 |
| Japanese | 125 | 61 (49) | 0.9 (0.6-1.5) | 43 (34) | 0.8 (0.5-1.4) | 41 (33) | 1.3 (0.7-2.1) | 16 (13) | 0.9 (0.5-2.0) | 13 (10) | 0.8 (0.3-1.7) | 45 (36) | 0.9 (0.6-1.6) | 31 (25) | 0.5 (0.3-0.8) |
| Hawaiian | 78 | 43 (55) | 0.9 (0.6-1.7) | 32 (41) | 1.0 (0.6-1.8) | 23 (29) | 0.9 (0.5-1.7) | 12 (15) | 1.1 (0.5-2.3) | 8 (10) | 0.7 (0.3-1.8) | 28 (36) | 0.7 (0.4-1.3) | 29 (37) | 0.8 (0.4-1.4) |
| Filipino | 66 | 35 (53) | 0.9 (0.5-1.7) | 31 (47) | 1.4 (0.8-2.5) | 22 (33) | 1.2 (0.6-2.2) | 12 (18) | 1.4 (0.6-3.2) | 9 (14) | 0.9 (0.4-2.4) | 31 (47) | 1.4 (0.8-2.6) | 26 (39) | 0.8 (0.5-1.5) |
| Other Asian | 78 | 38 (49) | 0.8 (0.5-1.4) | 33 (42) | 1.1 (0.6-1.9) | 25 (32) | 1.1 (0.6-1.9) | 7 (9) | 0.9 (0.4-2.3) | 4 (5) | 0.9 (0.3-2.5) | 26 (33) | 0.9 (0.5-1.6) | 28 (36) | 0.8 (0.5-1.5) |
| Other | 51 | 25 (49) | 0.7 | 23 (45) | 1.2 (0.6-2.3) | 12 (24) | 0.7 (0.3-1.5) | 6 (12) | 0.9 (0.3-2.5) | 8 (16) | 1.4 (0.5-3.5) | 19 (37) | 0.9 (0.5-1.8) | 21 (41) | 0.9 (0.5-1.7) |
| P † | 0.95 | 0.75 | 0.73 | 0.95 | 0.86 | 0.60 | 0.16 | ||||||||
| | |||||||||||||||
| Stage | |||||||||||||||
| I-II | 329 | 155 (47) | 1.0 | 117 (36) | 1.0 | 98 (30) | 1.0 | 45 (14) | 1.0 | 39 (12) | 1.0 | 102 (31) | 1.0 | 107 (33) | 1.0 |
| III-IV | 293 | 171 (58) | 1.6 (1.1-2.5) | 136 (46) | 1.7 (1.1-2.6) | 93 (32) | 0.9 (0.6-1.4) | 29 (10) | 0.8 (0.4-1.5) | 23 (8) | 1.2 (0.6-2.5) | 138 (47) | 1.7 (1.1-2.6) | 122 (42) | 1.5 (1.1-2.3) |
| P † | 0.02 | 0.01 | 0.76 | 0.56 | 0.54 | 0.01 | 0.04 | ||||||||
| | |||||||||||||||
| Histology | |||||||||||||||
| Serous | 328 | 177 (54) | 1.0 | 141 (43) | 1.0 | 105 (32) | 1.0 | 39 (12) | 1.0 | 22 (7) | 1.0 | 153 (47) | 1.0 | 125 (38) | 1.0 |
| Mucinous | 68 | 38 (56) | 1.4 (0.7-2.5) | 41 (60) | 2.6 (1.4-4.9) | 20 (29) | 0.7 (0.4-1.4) | 9 (13) | 0.9 (0.4-2.5) | 4 (6) | 0.9 (0.3-3.1) | 22 (32) | 0.6 (0.3-1.1) | 19 (28) | 0.8 (0.4-1.6) |
| Endometrioid | 110 | 60 (55) | 1.2 (0.7-1.9) | 29 (26) | 0.6 (0.3-0.9) | 33 (30) | 0.8 (0.5-1.4) | 11 (10) | 0.6 (0.3-1.4) | 21 (19) | 3.3 (1.5-6.3) | 35 (32) | 0.6 (0.3-0.9) | 37 (34) | 0.9 (0.6-1.5) |
| Clear cell | 79 | 30 (38) | 0.6 (0.4-1.1) | 26 (33) | 0.8 (0.4-1.4) | 23 (29) | 0.8 (0.4-1.4) | 10 (13) | 0.8 (0.4-2.0) | 8 (10) | 1.8 (0.7-4.6) | 15 (19) | 0.3 (0.1-0.5) | 26 (33) | 1.1 (0.6-1.9) |
| Other | 37 | 21 (57) | 1.2 (0.6-2.5) | 16 (43) | 1.1 (0.5-2.2) | 10 (27) | 0.8 (0.3-1.7) | 5 (14) | 0.8 (0.3-2.3) | 7 (19) | 2.3 (0.9-6.2) | 15 (41) | 0.7 (0.3-1.4) | 22 (59) | 2.4 (1.2-5.0) |
| P † | 0.21 | 0.0003 | 0.83 | 0.82 | 0.02 | 0.003 | 0.13 | ||||||||
| | |||||||||||||||
| Grade | |||||||||||||||
| Low (1-2) | 210 | 106 (50) | 1.0 | 79 (38) | 1.0 | 64 (30) | 1.0 | 24 (11) | 1.0 | 25 (12) | 1.0 | 73 (35) | 1.0 | 66 (31) | 1.0 |
| High (3-4) | 340 | 190 (56) | 1.6 (1.1-2.4) | 144 (42) | 1.5 (1.1-2.4) | 110 (32) | 1.1 (0.7-1.7) | 42 (12) | 0.9 (0.5-1.9) | 29 (9) | 0.7 (0.4-1.4) | 150 (44) | 1.4 (0.9-2.2) | 143 (42) | 1.6 (1.1-2.5) |
| P † | 0.02 | 0.03 | 0.57 | 0.98 | 0.31 | 0.09 | 0.02 | ||||||||
| | |||||||||||||||
| Age (years) | |||||||||||||||
| < 60 | 364 | 210 (58) | 1.0 | 162 (45) | 1.0 | 125 (34) | 1.0 | 46 (13) | 1.0 | 37 (10) | 1.0 | 144 (40) | 1.0 | 150 (41) | 1.0 |
| 60+ | 258 | 116 (45) | 0.6 (0.4-0.9) | 91 (35) | 0.6 (0.4-0.9) | 66 (26) | 0.6 (0.3-0.9) | 28 (11) | 0.8 (0.4-1.6) | 25 (10) | 1.2 (0.6-2.5) | 96 (37) | 0.8 (0.5-1.2) | 79 (31) | 0.6 (0.3-0.9) |
| P † | 0.02 | 0.02 | 0.01 | 0.52 | 0.65 | 0.26 | 0.01 | ||||||||
| | |||||||||||||||
| BMI (kg/m2) | |||||||||||||||
| <25 | 369 | 188 (51) | 1.0 | 143 (39) | 1.0 | 122 (33) | 1.0 | 48 (13) | 1.0 | 30 (8) | 1.0 | 137 (37) | 1.0 | 123 (33) | 1.0 |
| 25+ | 253 | 138 (55) | 1.1 (0.8-1.6) | 110 (43) | 1.3 (0.9-2.0) | 69 (27) | 0.7 (0.5-1.1) | 26 (10) | 0.5 (0.3-0.9) | 32 (13) | 1.1 (0.6-2.5) | 103 (41) | 1.3 (0.9-1.8) | 106 (42) | 1.3 (0.9-2.0) |
| P † | 0.56 | 0.14 | 0.13 | 0.02 | 0.84 | 0.25 | 0.16 | ||||||||
Note: significant associations are shown in bold font.
Odds ratio (OR) and 95% confidence interval (CI) from the logistic regression models that included age, ethnicity, study, tumor histology, and disease stage at diagnosis.
P global from multiple logistic regression models adjusted for ethnicity, study, tumor histology, and disease stage at diagnosis.
Reporting distended abdomen, abnormal vaginal bleeding, and bowel symptoms was found to differ significantly by tumor histological type. Women diagnosed with mucinous tumors were significantly more likely (60%), and women diagnosed with endometriod tumors (26%) were significantly less likely, to report a distended abdomen than women diagnosed with serous tumors (43%). Abnormal vaginal bleeding was more likely to be reported by women diagnosed with endometrioid carcinoma (19%) compared to women with serous tumors (7%). Women diagnosed with serous tumors were more likely to report bowel symptoms (47%) than were women diagnosed with nonserous cancers (19-32%), and the difference was significant for endometrioid and clear cell histological types. All differences in symptom presentation by histology remained statistically significant after multivariate adjustment for stage, grade, age, ethnicity, education, menopausal status, use of contraceptive or menopausal hormones, parity, tubal ligation, family or personal history of cancer, and BMI. The same differences by histology were observed in analyses further stratified by stage (data not shown).
Women diagnosed with high-grade tumors were significantly more likely to report abdominal pain (56% vs. 50%), distended abdomen (42% vs. 38%), and fatigue (42% vs. 31%) than were women diagnosed with low-grade tumors.
Independently of stage, grade, histology, or ethnicity, older women (≥ 60 years old) were significantly less likely to report abdominal pain (45% vs. 58%), distended abdomen (35% vs. 45%), urinary symptoms (26% vs. 34%), and fatigue (31% vs. 41%), and overweight women were less likely to have detected an abdominal mass (10% vs. 13%). All other investigated factors did not significantly affect symptom presentation.
Duration of symptoms
Only two factors significantly affected duration of symptoms, stage at diagnosis (p=0.003) and tumor grade (p=0.009) (Table 3). In all women combined, duration of symptoms were significantly shorter in women diagnosed at an advanced stage (7.2 months) when compared to women with early stage disease (13.7 months). However, the association of symptom duration with stage was significantly affected by histological type (p for interaction for serous versus nonserous tumors=0.02). In the analysis by histology strata, symptom duration was significantly shorter in an advanced stage only among women with serous carcinoma (7.3 versus 16.2 months; p=0.004). In contrast, women with mucinous carcinoma diagnosed at an advanced stage had significantly longer duration of symptoms (20.6 versus 6.1 months; p=0.009). No significant differences in duration of symptoms by stage were observed among women with endometrioid and clear cell carcinomas. In the analysis stratified by tumor grade, the same pattern by histology and stage was observed.
Overall, women with high-grade tumors had longer duration of symptoms (13.4 vs. 7.6 months; p=0.009). After further stratification by histology, this association remained statistically significant for women diagnosed with endometrioid tumors only (25.2 versus 9.3 months; p=0.02). However, no interaction of stage and histology on symptom duration was observed (p=0.11). No statistically significant associations between tumor grade and duration of symptoms were observed after further stratification by stage, so an independent effect of grade on symptom duration could not be confirmed for other than endometrioid histological subtypes.
Asymptomatic versus symptomatic women
Only 16% (n=99) of ovarian cancer cases were asymptomatic and were diagnosed at a routine doctor visit (Table 4). The proportion of asymptomatic versus symptomatic women differed significantly by stage (p=0.01), grade (p=0.04), and histology (p=0.04) (Table 4), but not ethnicity (p=0.52) or other factors under investigation (data not shown). Overall, the majority of asymptomatic women were more likely to be diagnosed at early stages of a disease as compared to symptomatic women (65% versus 51%; p=0.01). Although, the majority of asymptomatic women with serous carcinoma were more likely to be diagnosed at an advanced stage (55%) compared to women with mucinous (10%), endometrioid (19%), or clear cell tumors (14%) (p=0.001). Among symptomatic women, similar differences were observed (p=0.0001). Although overall asymptomatic women had a lower proportion of high-grade tumors compared to symptomatic women (52 versus 64%; p=0.04), the majority of asymptomatic (60%) and symptomatic (78%) women with serous carcinoma had high-grade tumors.
Table 4.
Distribution of stage and grade among asymptomatic and symptomatic women.
| All histological types |
Subgroups by histological type |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Categories by stage, and grade | Asymptomatic women |
Symptomatic women |
|||||||||||
| Asymptomatic women n (%) | Symptomatic women n (%) | Serous n (%) | Mucinous n (%) | Endometrioid n (%) | Clear cell n (%) | Other n (%) | Serous n (%) | Mucinous n (%) | Endometrioid n (%) | Clear cell n (%) | Other n (%) | P* | |
| All | 99 (16) | 523 (84) | 47 (14) | 10 (15) | 16 (15) | 22 (28) | 4 (11) | 281 (86) | 58 (85) | 94 (85) | 57 (72) | 33 (89) | 0.04 |
| | |||||||||||||
| Stages I-II | 64 (65) | 265 (51) | 21 (45) | 9 (90) | 13 (81) | 19 (86) | 2 (50) | 80 (28) | 51 (88) | 69 (73) | 44 (77) | 21 (64) | 0.10 |
| Stages III-IV | 35 (35) | 258 (49) | 26 (55) | 1 (10) | 3 (19) | 3 (14) | 2 (50) | 201 (72) | 7 (12) | 25 (27) | 13 (23) | 12 (36) | 0.93 |
| P† | 0.01 | 0.001 | <0.0001 | ||||||||||
| | |||||||||||||
| Low grade | 39 (48) | 171 (36) | 17 (40) | 6 (100) | 9 (60) | 7 (44) | 0 (0) | 59 (22) | 42 (86) | 57 (63) | 8 (22) | 5 (18) | 0.02 |
| High grade | 42 (52) | 298 (64) | 26 (60) | 0 (0) | 6 (40) | 9 (56) | 1 (100) | 205 (78) | 7 (14) | 34 (37) | 29 (78) | 22 (82) | 0.11 |
| P‡ | 0.04 | 0.04 | <0.0001 | ||||||||||
Chi-square P for differences in distribution of histological type between asymptomatic and symptomatic women overall and by stage and grade strata.
Chi-square P for differences in stage distribution between symptomatic and asymptomatic women overall and by histology strata.
Chi-square P for differences in grade distribution between symptomatic and asymptomatic women overall and by histology strata.
Discussion
A central finding of this analysis was the observation that ovarian cancer symptoms differed significantly by tumor histological type. Compared to women diagnosed with serous carcinoma, women with mucinous tumors were 2.6 times more likely to report a distended abdomen; and women with endometrioid carcinoma were three times more likely to report abnormal bleeding and 60% less likely to report a distended abdomen. Women with serous tumors were more likely to report bowel symptoms than were women diagnosed with other histological types of epithelial ovarian cancer; however, this symptom was only a significant predictor of an advanced stage of a disease in our case-control study [13].
We also found that duration of symptoms, calculated as the period of time from onset to diagnosis, was significantly influenced by tumor histological type. Moreover, significant interaction of stage (early versus advanced) and histology (serous versus nonserous) effects on symptom duration was observed. Among women with serous carcinoma, advanced cases had a shorter duration of symptoms relative to early stage disease. In contrast, women with advanced mucinous carcinoma experienced symptoms for a significantly longer period of time than did women with early stage mucinous cancer. Duration of symptoms was affected by grade only among women with endometrioid tumors; those who were diagnosed with high grade had significantly longer delay in diagnosis.
In the analysis of asymptomatic women, who were diagnosed incidentally at a routine doctor visit, we observed that a majority of women with serous tumors (55%) had an advanced stage of ovarian cancer in contrast to women with mucinous (10%), endometrioid (19%) or clear cell (14%) carcinomas. This finding provides indirect evidence that serous carcinoma is a more ‘silent’ disease that other types of ovarian carcinoma. Moreover, the shorter duration of symptoms among women with advanced serous cancer compared to women with early-stage serous tumors suggests that serous carcinoma is predominantly diagnosed at an advanced stage because of its rapid progression rather than a delay in diagnosis. In contrast, considering the significantly longer duration of symptoms among women with advanced mucinous tumors (20.6 months versus 6.1 months among women with early stage disease), diagnosis of the mucinous ovarian carcinoma at an advanced stage might be more likely due to a delay in diagnosis. These findings are in agreement with the accumulating ovarian cancer clinicopathological data [15]. Serous tumors, especially high grade tumors, are rarely confined to the ovary at diagnosis, presumably because they evolve rapidly and spread to extraovarian sites early in their development [15]. On the contrary, most nonserous tumors are slow growing, generally large and are often confined to the ovary at diagnosis.
Only a few other investigators have examined symptom presentation and duration among women with ovarian cancer by histological type and stage. In accord with our findings, mucinous tumors were more likely to be associated with abdominal swelling (distended abdomen, in our study) (Cox's proportional hazard ratio=1.50; CI:1.16-1.96) than the other tumor types in a study by Webb et al [6]. In a small study based on the data from clinical records, Wikborn et al. [7] found differences between women with serous and nonserous carcinomas in relation to gastrointestinal (55 versus 37%) and gynecological symptoms (10% versus 38%). In a study by Olson et al. [16] the majority of the symptoms were experienced for a nonsignificantly shorter period of time by women with advanced disease. This finding was consistent with our results; however, the association was not examined by histologic type. Women with stage I serous carcinoma had shorter duration of symptoms than women with more advanced stages in a study by Wikborn et al. [8]; although, no statistical test of significance was included. No differences in the duration of symptoms by stage were observed in other studies [17,18], although the histological type of tumor was not considered in these analyses. The duration of symptoms was not associated with histologic type of tumor by in a study by Vine et al. [19], but this study did not include stage at diagnosis.
Previous studies showed that the majority of women present with symptoms even at an early stage of disease [5, 13]. In our study, we observed that 80% of women with early stage serous carcinoma presented with symptoms. However, these women constituted a minority (31%) of serous carcinoma cases. The majority of women with invasive serous tumors who were diagnosed at an advanced stage did not appear to delay seeking medical care as they had shorter duration of reported symptoms. Although other studies did not focus on differences in symptom presentation by histology and stage, several investigators suggest that women with early stage ovarian cancer are not beneficiaries of an earlier diagnosis; rather they might have biologically different tumors [20,21] that are larger, better differentiated, and often nonserous histology [20].
In the present analysis, symptoms that we found significantly predictive of invasive ovarian carcinoma in a population-based case-control study in Hawaii [13] were explored in greater detail. We were particularly interested in determining whether symptom presentation differed by ethnicity. SEER data shows that white women are relatively more likely to be diagnosed with serous carcinoma. In contrast, clear cell and endometrioid carcinoma are relatively more common among Asian/Pacific Islander women [10, 22]. These U.S. population data are consistent with the histologic distribution of invasive epithelial ovarian cancer by ethnicity in our study: Caucasian women were significantly more likely to be diagnosed with serous carcinoma and advanced stage disease than were other women. However, we did not find that Caucasian women were more likely to be asymptomatic at diagnosis; nor were there significant differences in symptom presentation by ethnicity with the exception of reduced reports of fatigue among Japanese women when stage, histology, grade, age, and other patient characteristics were accounted for in the analysis. The ethnic difference in reporting fatigue was not likely to be explained by tumor characteristics, but rather by differences in perception of fatigue by Japanese women, as fatigue was also less likely to be reported by Japanese controls included in our case-control study [13].
A major strength of this study is that it takes into account that ovarian carcinomas are a heterogeneous group of neoplasms. Thoroughly collected clinicopathological data was available for a large group of women with different ethnic backgrounds who participated in this study. Another important strength of this study was its population-based approach to subject selection and accurate case ascertainment through Hawaii Tumor Registry and the Cancer Surveillance Program at the University of Southern California. Information regarding symptoms and other individual characteristics was collected by trained personnel using detailed interviewer-administered questionnaires. The possibility of recall bias in interpreting the results of this investigation cannot be excluded, as women with ovarian cancer might over-report symptoms. However, this source of bias should be minimal in this case only analysis.
The present clinical management of ovarian carcinoma patients is not significantly influenced by the histological subtype of the tumor, although accumulating clinicopathological and molecular data suggest that the major subtypes likely represent distinct disease entities [15] that not only behave differently but also develop differently [23]. This investigation highlights the substantial influence of ovarian cancer histology on the presentation and duration of symptoms. The approach to early detection of ovarian carcinoma which focuses on symptom presentation alone might benefit women with slow growing, usually large size nonserous tumors, but would likely miss more aggressive serous carcinomas. The shorter duration of reported symptoms among women with advanced serous carcinoma suggests that this set of common symptoms may prove to have limited benefits to the early diagnosis of this histologic subtype.
Acknowledgments
This study was supported by US Public Health Service grant R01-CA-58598 and contracts N01-CN-55424, N01-PC-67001, and N01-PC-35137 from the National Cancer Institute, NIH, Department of Health and Human Services. The authors thank the physicians, administrators, and cancer registrars at the following institutions for their support of this study: Castle Memorial Hospital, Kaiser Foundation Hospital, Kapiolani Medical Center for Women and Children, Kuakini Medical Center, Queen's Medical Center, Straub Clinic and Hospital, St. Francis Hospital, Tripler Army Hospital, and Wahiawa General Hospital. We would also like to express our appreciation to Dr. Anna H. Wu and her staff for data collection in Los Angeles County.
Footnotes
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Conflict of Interest Statement
The authors declare that there are no conflicts of interest.
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