Abstract
Objective:
To examine the association between keloids, hypertrophic scars, and uterine fibroid incidence and growth. Both keloids and fibroids are fibroproliferative conditions that have been reported to be more prevalent among Blacks than Whites and they share similar fibrotic tissue structure, including extracellular matrix composition, gene expression, and protein profiles. We hypothesized that women with a history of keloids would have greater uterine fibroid development.
Design:
A prospective community cohort study (enrollment 2010–2012) with four study visits over five years to conduct standardized ultrasounds to detect and measure fibroids ≥0.5 cm in diameter, assess history of keloid and hypertrophic scars, and update covariates.
Setting:
Detroit, Michigan area.
Participants:
1,610 self-identified Black/African American women aged 23–35 years at enrollment without previous clinical diagnosis of fibroids.
Exposure(s):
Keloids (raised scars that grow beyond the margins of original injury) and hypertrophic scars (raised scars that stay within the bounds of original injury). Due to difficulty distinguishing keloids and hypertrophic scars, we separately examined history of keloids and history of either keloids or hypertrophic scars (any abnormal scarring) and their associations with fibroid incidence and growth.
Main Outcome Measure(s):
Fibroid incidence (new fibroid after a fibroid-free ultrasound at enrollment) was assessed with Cox proportional-hazards regression. Fibroid growth was assessed with linear mixed models. The estimates for change in log volume per 18 months were converted to estimated percent difference in volume for scarring vs. no-scarring. Both incidence and growth models were adjusted for time-varying demographic, reproductive, and anthropometric factors.
Result(s):
Of 1,230 fibroid-free participants, 199 (16%) reported ever having keloids, and 578 (47%) reported keloids or hypertrophic scars; 293 (24%) developed incident fibroids. Neither keloids (adjusted hazard ratio [aHR] = 1.04; 95% confidence interval [CI]: 0.77, 1.40) nor any abnormal scarring (aHR = 1.10; 95% CI: 0.88, 1.38) were associated with fibroid incidence. Fibroid growth differed little by scarring status.
Conclusion(s):
Despite molecular similarities, self-reported keloid and hypertrophic scars did not show an association with fibroid development. Future research may benefit from examination of dermatologist-confirmed keloids or hypertrophic scars, but our data suggest little shared susceptibility for these two types of fibrotic conditions.
Keywords: Fibroproliferative condition, hypertrophic scar, keloid, uterine fibroid
INTRODUCTION
Uterine fibroids are benign tumors of the uterine muscle that develop in over 70% of women of reproductive age (1). Symptomatic fibroids can result in substantial morbidity (2) and they are the leading indication for hysterectomy in the United States (3). African American women experience fibroid onset an estimated 10 years earlier than U.S. White women (4) and have a disproportionate health burden from fibroids (5). Despite the identification of genetic changes that likely drive fibroid development (6) and consensus on some established risk factors (7, 8), the pathogenesis of uterine fibroids has not been fully elucidated (9, 10).
Keloids, raised scars that grow beyond the margins of an injury (11), arise due to abnormal wound healing which is characterized by pathologic accumulation of extracellular matrix proteins that result in growth of the affected skin tissue (12, 13). This fibroproliferative skin disorder can be triggered by any cutaneous injury including trauma, burns, and infection (14) and results in excess deposition of altered collagen that leads to excess scar tissue (11). Hypertrophic scars, another result of abnormal wound healing, are raised scars that stay within the bounds of the original injury (11). Hypertrophic scars can be difficult to distinguish from keloids on clinical examination (15, 16), and the scar types share some histologic similarities (17, 18); therefore, misclassification of keloids is likely in studies without detailed pathology examination. Both types of scars can be itchy, painful, and aesthetically undesirable, but hypertrophic scars tend to regress within two years of onset, while keloids almost never regress and have a high rate of recurrence after excision (16, 19). Despite these distinctions, there is some evidence to suggest that keloids and hypertrophic scars are different stages of the same fibroproliferative skin disorder with pro-inflammatory factors driving the development of the lesion into one form or the other (20, 21).
Uterine fibroids and keloids share several biological properties including similar fibrotic tissue structure as evidenced by disordered collagen fibers (22, 23), proteoglycan patterns that differ from normal tissues (12), decreased expression of the protein dermatopontin (22, 23), and similar gene expression in the tissue (24). Also, limited histological evidence suggests that scars from uterine surgery may develop into keloid-like scars; although rare, this finding supports a hypothesis that fibroids may originate from abnormal uterine healing (25). In addition to biologic similarities, both fibroids and keloids have been reported to be more common in Black than White individuals (4, 26). However, review papers of keloid scarring often reference the same few studies conducted decades ago where prevalence of keloids was reported among small numbers of surgical or burn patients that were not representative of the general population (14). Thus, prevalence and incidence of keloids and hypertrophic scarring, both overall and by ethnic group, are not well studied (11, 16, 27). Nonetheless, two studies with larger and more diverse study populations that examined postsurgical development of keloids among head and neck surgery patients (28) and Caesarean section (C-section) patients (29) found that African Americans were more likely to develop postsurgical keloids compared to Whites, although the number of patients developing keloids in both studies was small (n = 20 and n = 10, respectively). Additionally, both fibroids and keloids can exhibit an intergenerational familial tendency (30–32). Lastly, there is some evidence supporting similarities in the pathogenesis of post-surgical intra-abdominal adhesions and benign fibroproliferative disorders including keloids and uterine fibroids (33).
If there is a shared susceptibility for uterine fibroids and abnormal scarring, this could result in clinical recommendations for fibroid screening in women with keloids or hypertrophic scars. Careful observation for rapid fibroid growth of those with keloids could lead to earlier and more targeted treatment of this highly burdensome condition (34). Prior epidemiological studies examining the association of keloids, hypertrophic scars, and uterine fibroids are scarce, limited by cross-sectional design, and none examined fibroid growth (35–38), which may be especially important given the tissue similarity.
Given the possible links between abnormal scarring and uterine fibroid development, we hypothesized that participants in our study who reported a history of keloids and/or hypertrophic scars would have increased fibroid incidence and/or fibroid growth compared to those without a history of these abnormal scarring conditions.
MATERIAL AND METHODS
Study Design
The Study of Environment, Lifestyle & Fibroids (SELF) is a prospective study of uterine fibroid incidence and growth among a cohort of young Black/African American women and has been described in detail previously (39). Briefly, SELF recruited participants from 2010 to 2012 in collaboration with the Henry Ford Health System in the Detroit, Michigan area. Given the higher burden of uterine fibroids and earlier age of onset for Black women compared to White women (4), enrollment was restricted to females who self-identified as “Black or African American” among a list of racial and ethnic categories from which they were asked to select all that applied. To be eligible for the study, participants had to be 23 to 35 years of age, premenopausal, and have no prior clinical diagnosis of uterine fibroids. SELF enrolled 1,693 participants who attended an orientation and completed all enrollment activities including a baseline ultrasound examination. Participants were prospectively followed for fibroid development with standardized ultrasound examinations at approximately 20-month intervals over five years for a total of four visits. Participants who missed a follow-up visit were invited to attend the next follow-up visit. Over 90% of participants attended the final study visit, 95% attended at least two study visits, and 79% attended all four study visits. SELF was approved by the institutional review boards of the National Institute of Environmental Health Sciences and Henry Ford Health Systems. All participants provided informed consent as part of the enrollment process.
Assessment of Scarring
Scarring history was reported by participants during systematic interviews. Trained interviewers introduced and asked questions on skin healing in response to injury. Interviewers first described how “sometimes healing results in scar tissue that forms a raised scar, like a bump or lump above the skin,” and how “sometimes the scar tissue grows and spreads up and out beyond the boundary of the original injury.” At enrollment, participants were asked if they had ever had a raised scar and were separately asked if they ever had a scar that grew up and out beyond the original injury. Participants were asked both questions and the response options were “yes,” “no,” and “don’t know.” These questions were not asked at the first follow-up visit, but at the second and third follow-up visits, participants were presented with the same scarring descriptions and questions by the interviewer, and participants were asked if they had developed either type of scar since enrollment or since the date of their last interview, respectively. We defined raised scars as hypertrophic scars and scars that grew beyond the original injury as keloids. For analysis, if participants reported a keloid at any study visit, they were categorized as ‘keloid scar’ and if participants reported either keloids or hypertrophic scars at any study visit, they were categorized as having ‘any abnormal scarring.’ This second scarring category was created to address the difficulty of distinguishing between keloid and hypertrophic scar types (11, 18). The ‘keloid scar’ group was compared to participants who did not report keloids at any visit and the ‘any abnormal scarring’ group was compared to those who did not report keloid or hypertrophic scars at any visit, which we categorized as ‘no abnormal scarring.’
Assessment of Fibroids
The methods for assessing fibroid incidence and growth in the SELF study have been described in detail previously (39, 40). Briefly, transvaginal ultrasounds were conducted by experienced, trained sonographers using 2-D equipment at each clinic visit. Sonographers followed a standardized protocol to detect, measure, and document fibroids ≥0.5 cm in diameter. The largest six fibroids per participant were measured in three perpendicular planes at three separate passes through the uterus during the examination. The measures from the three perpendicular planes were used to calculate a fibroid volume based on the ellipsoid formula, and a mean of the three separate volume calculations was used in analysis. Video and still images were archived, and an 8% sample from each sonographer per month, oversampled for fibroid cases, was reviewed by the lead sonographer for quality control.
Assessment of Covariates
Covariate data were collected at all visits except for age of menarche which was only collected at enrollment by asking participants how old they were when they had their first menstrual period. Time-varying factors, including participant age, hormonal contraception history, pregnancy history, cigarette use, and household income, were asked at enrollment and each follow-up visit. Body mass index (BMI) was calculated using height measured at enrollment and weight measured at each clinic visit. Years since last use of injectable depot medroxyprogesterone acetate (DMPA) was derived from the timing of DMPA use reported at each visit (41). Likewise, number of births (parity) and time since last birth were derived for each follow-up interval for each participant (8).
Analytical Cohort
Of the 1,693 participants enrolled in the SELF cohort, 1,610 returned for one or more follow-up visit. Among this group, 364 participants (23%) had fibroids detected at enrollment, five were excluded due to a nonfibroid-related hysterectomy prior to their first follow-up ultrasound, and nine were excluded due to factors that impeded ultrasound visualization, resulting in 1,232 participants available for incidence analyses. After excluding participants missing scarring data (n = 2), our final analytical dataset for incidence comprised 1,230 participants. Our growth analytical dataset included 429 participants of whom 298 had fibroids detected at enrollment and 131 who had fibroids detected during follow-up; only participants with fibroids that could be matched across successive visits were included in the growth dataset.
Statistical Analyses
Participant characteristics at enrollment were examined according to self-report of keloids and any abnormal scarring (keloids or hypertrophic scarring) compared to no abnormal scarring. Cox proportional hazards regression with age as the time scale was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between scarring and fibroid incidence (PHREG procedure in SAS 9.4 (42)). Incident fibroid cases were defined as participants who were fibroid-free at the enrollment ultrasound but had fibroids detected at a subsequent ultrasound. Participants contributed follow-up time until they had an incident fibroid, nonfibroid-related hysterectomy, loss to follow-up, or their final study ultrasound. Since SELF participants were free of clinically diagnosed fibroids at enrollment, detected fibroids tended to be small.
Our two primary exposures of interest, keloid scars and any abnormal scarring, were modeled as binary variables and were analyzed in separate regression models. Literature on indications for keloid scarring (43–47), risk factors for fibroids (8, 48, 49), and studies examining the association between the two (35–37) were examined to identify relevant covariates for adjustment. We used two models, one that adjusted for age and one that additionally adjusted for reproductive, demographic, and anthropometric factors. While we considered a wide range of potential covariates for adjustment (e.g., maternal history of fibroids, financial difficulty to pay for a major surgery, melanin index), our final models only included those covariates that were previously associated with fibroids in the cohort or where adjustment substantively changed the estimates for the scarring exposures. Thus, the reproductive factors included in the models were age at menarche (≤10, 11, 12, 13, or ≥14 years), parity (0, 1–2, or ≥3 births), years since last birth (<3, or ≥3 years or no births), and years since last DMPA use (<2 years, or ≥2 years including never). Demographic and anthropometric factors included household income (<$20,000, or ≥$20,000 per year), current smoker (no or yes), and BMI (<30.0, 30.0-<35.0, 35.0-<40.0, or ≥40.0 kg/m2). Except for age at menarche, all variables were updated at each visit and were treated as time-varying covariates in the models. There were no missing covariate data; therefore, we conducted complete-case analyses. The proportional hazards assumption, that the relative hazard remains constant over time, was not violated.
For fibroid growth, we conducted a by-fibroid analysis of fibroids detected at enrollment or during follow-up that could be matched across two consecutive visits based on archived images and fibroid locations. Fibroid growth was calculated as the change in the natural logarithm of each fibroid volume and scaled to a growth-rate over 18-months (median interval length between visits: 19 months, 25th-75th percentiles: 18–20). Associations between scarring and fibroid growth were analyzed using linear mixed models (GLIMMIX procedure in SAS 9.4) (40, 50). The random effects portion of the mixed models accounted for correlation among fibroids from the same participant, correlation over time for the same fibroid, and greater variability among volume measures for small compared to large fibroids (40). For increased interpretability, the logarithmic growth rate scale was back transformed to estimate percent difference in volume change per 18 months between participants with and without scarring. The minimally adjusted model included adjustment for age (continuous) and fibroid/uterine factors at the beginning of the interval that had previously been shown to influence fibroid growth (40): fibroid volume (<0.5 cm3, 0.5-<4.2 cm3, 4.2-<14.1 cm3, or ≥14.1 cm3) and number of fibroids in the uterus (ordinal; 1, 2, 3, or ≥4). The fully adjusted growth model also included the same covariates as the fully adjusted incidence model.
Sensitivity analyses were conducted to evaluate possible biases. First, hypertrophic and keloid scars require a skin injury and subsequent wound healing, so it would be valuable to examine the association among participants known to have had significant wounds. Surgery is one of the leading causes of wounds that develop abnormal scarring (44), but we did not have complete surgical history for our participants. However, we did have information on C-section deliveries, a type of surgery where the surgical incision can develop into a hypertrophic or keloid scar (51). Thus, we restricted the incidence and growth analyses to participants who had a history of C-section so that we could examine risk among participants who had the surgical incision, creating an opportunity for all participants in the subset to develop an abnormal scar. Second, we limited the growth analysis to fibroids ≥2 cm in diameter. These fibroids are likely to have developed an extracellular component (52) that may not be seen in very small fibroids, tumors that are often lost (40). Thus, we would be examining growth in the fibroids that would have the greatest tissue similarity to keloid scars (22). Last, since fibroid growth results might be influenced by outliers, we excluded fibroids that had residuals for growth >3 standard deviations from the mean as done in prior analyses (40, 53).
All statistical analyses were conducted with SAS version 9.4 (SAS Institute Inc., Cary, NC).
RESULTS
Participant characteristics at enrollment by report of scarring for both the incidence and growth analytical samples are shown in Table 1. Among 1,230 participants in the incidence sample, 199 (16%) reported keloids and 578 (47%) reported any abnormal scarring (keloid or hypertrophic). Among 429 participants in the growth sample, 63 (15%) reported keloids and 208 (48%) reported any abnormal scarring. Among participants in the incidence sample, those with no abnormal scarring (50%) were more likely to report annual household incomes below $20,000 in comparison with those with keloids (41%) or any abnormal scarring (43%). In both the incidence and growth samples, participants who reported keloids or any abnormal scarring were more likely to have a BMI greater than or equal to 40 kg/m2 (class III obesity) and were less likely to have experienced menarche at or after age 14 in comparison with those with no abnormal scarring.
Table 1.
Participant characteristics at enrollment by scarring status, Study of Environment, Lifestyle & Fibroids (SELF), Detroit, Michigan, 2010–2012.
| Incidence Analytical Sample (n = 1,230)a | Growth Analytical Sample (n = 429)b | |||||
|---|---|---|---|---|---|---|
| Characteristicc | No abnormal scarringd | Keloid scare | Any abnormal scarringf | No abnormal scarringd | Keloid scare | Any abnormal scarringf |
| Totals | 652 (53) | 199 (16) | 578 (47) | 221 (52) | 63 (15) | 208 (48) |
| Age at ultrasound (years) | ||||||
| Mean ± SD | 28.7 ± 3.4 | 29.3 ± 3.4 | 29.1 ± 3.5 | 30.4 ± 3.1 | 29.0 ± 3.4 | 29.9 ± 3.4 |
| 23–25 | 167 (26) | 44 (22) | 145 (25) | 22 (10) | 14 (22) | 31 (15) |
| 26–28 | 181 (28) | 45 (23) | 139 (24) | 48 (22) | 15 (24) | 53 (25) |
| 29–31 | 171 (26) | 62 (31) | 153 (26) | 77 (35) | 20 (32) | 57 (27) |
| 32–35 | 133 (20) | 48 (24) | 141 (24) | 74 (33) | 14 (22) | 67 (32) |
| Highest educational attainment | ||||||
| High school/GED | 176 (27) | 42 (21) | 107 (19) | 50 (23) | 10 (16) | 26 (13) |
| Some college/associates/technical | 325 (50) | 104 (52) | 309 (53) | 105 (48) | 30 (48) | 97 (47) |
| Bachelors/masters/doctorate | 151 (23) | 53 (27) | 162 (28) | 66 (30) | 23 (37) | 85 (41) |
| Yearly household income | ||||||
| <$20,000 | 324 (50) | 82 (41) | 246 (43) | 98 (44) | 29 (46) | 72 (35) |
| $20,000-$50,000 | 243 (37) | 77 (39) | 230 (40) | 74 (33) | 23 (37) | 88 (42) |
| >$50,000 | 85 (13) | 40 (20) | 102 (18) | 49 (22) | 11 (17) | 48 (23) |
| Health insurance coverageg | ||||||
| No | 83 (13) | 29 (15) | 85 (15) | 37 (17) | 16 (25) | 41 (20) |
| Yes | 556 (87) | 166 (85) | 480 (85) | 175 (83) | 47 (75) | 165 (80) |
| Missing | 13 | 4 | 13 | 9 | 0 | 2 |
| Financial difficulty to have major surgery | ||||||
| No | 240 (37) | 58 (29) | 186 (32) | 80 (37) | 16 (25) | 57 (28) |
| Yes | 409 (63) | 141 (71) | 388 (68) | 139 (63) | 47 (75) | 149 (72) |
| Missing | 3 | 0 | 4 | 2 | 0 | 2 |
| Body mass index (kg/m2) | ||||||
| <25.0 | 138 (21) | 32 (16) | 108 (19) | 36 (16) | 10 (16) | 45 (22) |
| 25.0-<30.0 | 150 (23) | 45 (23) | 110 (19) | 54 (24) | 9 (14) | 34 (17) |
| 30.0-<35.0 | 118 (18) | 41 (21) | 113 (20) | 53 (24) | 16 (25) | 39 (19) |
| 35.0-<40.0 | 104 (16) | 32 (16) | 101 (17) | 40 (18) | 11 (17) | 34 (16) |
| ≥40.0 | 142 (22) | 49 (25) | 146 (25) | 38 (17) | 17 (27) | 56 (27) |
| Melanin indexh | ||||||
| Mean ± SD | 65.3 ± 10.9 | 64.5 ± 11.1 | 65.5 ± 11.3 | 65.2 ± 10.8 | 65.9 ± 11.3 | 65.5 ± 11.6 |
| Smoking status | ||||||
| Never/former | 518 (79) | 157 (79) | 473 (82) | 178 (81) | 47 (75) | 172 (83) |
| Current | 134 (21) | 42 (21) | 105 (18) | 43 (19) | 16 (25) | 36 (17) |
| Alcohol usei | ||||||
| None | 215 (33) | 53 (27) | 154 (27) | 65 (29) | 12 (19) | 56 (27) |
| Moderate | 307 (47) | 104 (52) | 314 (54) | 116 (52) | 36 (57) | 112 (54) |
| Heavy | 130 (20) | 42 (21) | 110 (19) | 40 (18) | 15 (24) | 40 (19) |
| Age at menarche (years) | ||||||
| ≤10 | 107 (16) | 41 (21) | 106 (18) | 51 (23) | 15 (24) | 44 (21) |
| 11 | 146 (22) | 36 (18) | 105 (18) | 47 (21) | 16 (25) | 42 (20) |
| 12 | 172 (26) | 61 (31) | 169 (29) | 47 (21) | 13 (21) | 56 (27) |
| 13 | 93 (14) | 35 (18) | 108 (19) | 38 (17) | 12 (19) | 35 (17) |
| ≥14 | 134 (21) | 26 (13) | 90 (16) | 38 (17) | 7 (11) | 31 (15) |
| Parity | ||||||
| 0 births | 223 (34) | 70 (35) | 220 (38) | 100 (45) | 38 (60) | 111 (53) |
| 1–2 births | 296 (45) | 89 (45) | 260 (45) | 92 (42) | 18 (29) | 80 (38) |
| ≥3 births | 133 (20) | 40 (20) | 98 (17) | 29 (13) | 7 (11) | 17 (8) |
| Years since last birth | ||||||
| <3 years | 123 (19) | 58 (29) | 119 (21) | 40 (18) | 11 (17) | 22 (11) |
| ≥3 years or no births | 529 (81) | 141 (71) | 459 (79) | 181 (82) | 52 (83) | 186 (89) |
| Years since last use of DMPA | ||||||
| Never used | 348 (53) | 97 (49) | 316 (55) | 144 (65) | 42 (67) | 151 (73) |
| <2 years | 87 (13) | 23 (12) | 67 (12) | 15 (7) | 5 (8) | 9 (4) |
| ≥2 years | 217 (33) | 79 (40) | 195 (34) | 62 (28) | 16 (25) | 48 (23) |
| Cesarean deliveries | ||||||
| 0 | 492 (75) | 152 (76) | 416 (72) | 169 (76) | 46 (73) | 160 (77) |
| 1–2 | 135 (21) | 40 (20) | 136 (24) | 48 (22) | 17 (27) | 47 (23) |
| ≥3 | 25 (4) | 7 (4) | 26 (4) | 4 (2) | 0 (0) | 1 (0) |
Abbreviations: DMPA, depot medroxyprogesterone acetate, injection progestin-only contraceptive; GED, high school equivalency diploma; SD, standard deviation.
The incidence sample is comprised of 1,230 participants who were fibroid-free at enrollment.
The growth sample is comprised of 429 participants whose fibroids could be matched across successive visits. 298 participants had fibroids detected at their enrollment visit and 131 were participants from the incidence analysis who developed fibroids during the study.
Data are n (%) unless otherwise specified.
Participants who did not report keloid or hypertrophic scars at any visit.
Participants who reported a keloid at any visit.
Participants who reported keloids or hypertrophic scars at any visit.
Health insurance coverage: participant indicated paying for doctor visits by insurance purchased directly from insurer, workplace insurance, or through a government program.
Measured at enrollment on the right inner arm using a digital skin reflectance instrument.
Moderate: 1–5 drinks on days when having alcohol or ≥4 drinks on an occasion no more than once/month; heavy: ≥6 drinks on days when having alcohol or ≥4 drinks on an occasion at least 2x/month.
During 5,312 person-years of follow-up, 293 (24%) of the 1,230 fibroid-free participants at enrollment developed incident fibroids (Table 2). In unadjusted models with age as the time scale, neither keloids (HR = 1.03; 95% CI: 0.77, 1.39) nor any abnormal scarring (HR = 1.08; 95% CI: 0.86, 1.35) showed a significant association with fibroid incidence. After adjustment for reproductive, demographic, and anthropometric factors (fully adjusted models), the hazard ratios for both keloids and any abnormal scarring were essentially unaffected.
Table 2.
Associations between keloids, hypertrophic scars, and fibroid incidence among 1,230 participants in the Study of Environment, Lifestyle & Fibroids (SELF), Detroit, Michigan, 2010–2018.
| Hazard ratio (95% confidence interval) | |||||
|---|---|---|---|---|---|
| Exposure category | No. exposed (n = 1,230) | Incident cases (n = 293) | Person-years (n = 5,312) | Minimally adjusteda | Fully adjustedb |
| Keloid scar | |||||
| No | 1031 | 242 | 4432 | Referent | Referent |
| Yes | 199 | 51 | 880 | 1.03 (0.77, 1.39) | 1.04 (0.77, 1.40) |
| Any abnormal scarringc | |||||
| No | 652 | 147 | 2807 | Referent | Referent |
| Yes | 578 | 146 | 2505 | 1.08 (0.86, 1.35) | 1.10 (0.88, 1.38) |
Cox model with age as the time scale with no further covariate adjustment.
Cox model with age as the time scale further adjusted for age at menarche (≤10, 11, 12, 13, or ≥14 years), and time-varying parity (0, 1–2, or ≥3 births), years since last birth (<3 or ≥3 years ago including no births), years since last use of injection contraceptive (<2 or ≥2 years including never), household income (<$20,000 or ≥$20,000 per year), current smoker (no or yes), and body mass index (<30.0, 30.0-<35.0, 35.0-<40.0, or ≥40.0 kg/m2).
Report of either keloid or hypertrophic scar.
Overall fibroid growth was estimated to average 69% volume increase per 18 months. Fibroid growth rates did not differ by report of scarring (Table 3). The estimated difference in growth rate comparing those with keloids to those without keloids was minimal (−0.3%; 95% CI: −11.5%, 12.4%). A similar growth rate difference was estimated for those with any abnormal scarring compared to those without any abnormal scarring (−0.1%; 95% CI: −8.2%, 8.8%).
Table 3.
Associations between keloids, hypertrophic scars, and fibroid growth among 429 participants in the Study of Environment, Lifestyle & Fibroids (SELF), Detroit, Michigan, 2010–2018.
| Estimated % difference in growth (95% confidence interval) | |||
|---|---|---|---|
| Exposure category | No. growth intervals (n = 1,348) | Minimally adjusteda | Fully adjustedb |
| Keloid scar | |||
| No | 1142 | Referent | Referent |
| Yes | 206 | −1.1 (−13.2, 12.7) | −0.3 (−11.5, 12.4) |
| Any abnormal scarringc | |||
| No | 692 | Referent | Referent |
| Yes | 656 | 3.1 (−6.1, 13.1) | −0.1 (−8.2, 8.8) |
Minimally adjusted models include volume of fibroid (<0.5 cm3, 0.5-<4.2 cm3, 4.2-<14.1 cm3, or ≥14.1 cm3), number of fibroids (ordinal; 1, 2, 3, or ≥4), and age (continuous).
Fully adjusted models further adjust for age at menarche (≤10, 11, 12, 13, or ≥14 years), and time-varying parity (0, 1–2, or ≥3 births), years since last birth (<3 or ≥3 years ago including no births), years since last use of injection contraceptive (<2 or ≥2 years including never), household income (<$20,000 or ≥$20,000 per year), current smoker (no or yes), and body mass index (<30.0, 30.0-<35.0, 35.0-<40.0, or ≥40.0 kg/m2).
Report of either keloid or hypertrophic scar.
In sensitivity analyses where the study population was restricted to participants with a history of C-section, estimates for risk of incident fibroids were similar to the main analyses (Supplemental Table 1). The same was true of the estimates for fibroid growth among C-section participants who reported keloid scarring, however, the estimated difference in growth rates for C-section participants who reported any abnormal scarring (13.5%; 95% CI: −6.2%, 37.5%) was increased compared to the percent differences observed in the main analyses (−0.1%; 95% CI: −8.2%, 8.8%), though the estimates for C-section participants were imprecise (Supplemental Table 2). Estimates for fibroid growth among participants with fibroids ≥2 cm in diameter were also similar to the main analyses (Supplemental Table 3). Lastly, in outlier analysis we identified 17 fibroids with residuals for growth >3 standard deviations from the mean; after exclusion of these outliers, estimated growth difference by scarring remained of small magnitude (Supplemental Table 4).
DISCUSSION
Despite molecular similarities between keloids and fibroids, participants with keloids showed no evidence of increased fibroid incidence or fibroid growth in this community sample of young Black/African American women. The associations for any abnormal scarring (either keloid or hypertrophic scarring) were also null. Secondary analyses in the subset of participants who had a prior C-section (a documented injury providing opportunity for abnormal scarring) showed null associations for fibroid incidence, but a suggestive increase in fibroid growth among those who reported any abnormal scarring. However, the somewhat elevated growth estimate could have arisen by chance given the small sample (n = 100) and broad confidence interval. When we limited our analyses to participants with larger fibroids, those likely to have proportionately more extracellular matrix than the smaller fibroids, we also saw no strong associations between scarring and fibroid growth.
Very few prior studies have examined the association of abnormal scarring and uterine fibroids (35–38). One was a cross-sectional analysis conducted in the SELF cohort at enrollment that found null associations for both scarring groups with baseline fibroid prevalence (35), consistent with the prospective fibroid incidence and growth findings reported here. A 2005 study by Bayat et al. (36) utilized 211 clinical records from a plastic and reconstructive surgery department in a Jamaican hospital to examine the association of various demographic and medical factors associated with single versus multiple anatomical keloid sites. No associations were found between uterine fibroids or other fibrotic diseases and keloid development (36). In contrast, a 2014 study by Sun et al. (37) reported that the odds of having uterine fibroids were higher in patients with keloids compared to those without keloids based on data from the Taiwanese National Health Insurance Research Database (age range 0–89) of health visits during a 1-year period. However, the reported association is likely to be an artifact of the apparent lack of adjustment for age and sex in their multivariate logistic regression analysis. Among the 12 fibrotic-related diseases examined fibroids were the most frequently reported, and those with fibroids have an expected age-range similar to the predominant age-range reported for keloids, linking the two conditions artifactually. Furthermore, the use of a national database for identifying women with fibroids can be problematic; by including only prevalent, clinically diagnosed fibroids in a single year, the NHIRD misses all the women with fibroids who had undiagnosed fibroids. Another study based on health record data (UK Biobank) (38) observed a suggestive association between abnormal scarring (keloid or hypertrophic) and uterine fibroids. However, the same issues of under ascertainment and misclassification for cases and noncases of both conditions makes interpretation and comparisons challenging. The current study, based on a prospective series of ultrasound screenings over five years, allows for observation of all fibroids reaching ≥0.5 cm in diameter, thus providing the detailed fibroid data prior studies have lacked.
Our study has additional strengths, but also some limitations. SELF has a rich database of well-measured covariates. For example, the null association we observed was adjusted for BMI which may be a risk factor for keloids and hypertrophic scars because of the chronic inflammation that can accompany high BMI (47). Our extensive data also allowed us to conduct a subset analysis limited to participants known to have had a similar injury. Yet, our study was limited by potential misclassification of the scarring data. Scarring was self-reported based on a description of the scar types, but identifying keloids is challenging even for clinicians and pathologists (11, 18). Differences between the two scar types include growth patterns, progression over time, and typical bodily location (11). In a histopathological study comparing the two scar types (18), keloidal collagen, a hallmark feature of keloids, was only found in 55% of keloid specimens, whereas α-smooth muscle actin, a differentiating marker of hypertrophic scars, was expressed in both hypertrophic scars (70%) and keloids (45%). While we sought to minimize misclassification by having trained interviewers provide distinct definitions for the two scar types, we did not require scars to be clinically diagnosed or have medical record verification. Our classification of either keloid or hypertrophic scarring into an ‘any abnormal scarring’ group was a way to compensate for the potential misclassification. Additionally, it is possible that participants who are predisposed but who have had only minimal cutaneous injuries will not have developed a keloid scar by the end of the study period, and those participants would be misclassified into the ‘no abnormal scarring’ group. However, our sensitivity analysis among participants with a prior C-section addressed this issue by including only participants with a known opportunity for abnormal scarring; still, this subsample was small.
In summary, we found no strong associations between fibroid incidence or growth with keloids and hypertrophic scars, indicating little evidence for shared susceptibility pathways. Future epidemiological studies may benefit from scarring data that goes beyond self-report to include evaluations by dermatologists and pathologists with expertise in identifying keloids and hypertrophic scars and a more nuanced examination among individuals with an opportunity for abnormal scarring, but a strong shared susceptibility seems unlikely. However, the intriguing similarities of the tissues remain of interest as further research elucidates the pathogenesis of each of these fibrotic conditions.
Supplementary Material
F & S Science Clinical Quick Take:
Uterine fibroids share similar fibrotic tissue structure with keloids, including extracellular matrix composition, gene expression, and protein profiles.
A shared susceptibility for uterine fibroids and abnormal scarring may warrant fibroid screening in women with keloids or hypertrophic scars, yet research examining the association between these fibroproliferative conditions is limited.
Despite molecular similarities, neither keloids nor hypertrophic scars showed an association with fibroid incidence or growth.
Acknowledgments:
The authors thank Drs. Kathryn Dalton and Kemi Ogunsina for their helpful review of a prior draft of this manuscript.
Funding:
Supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences and funds from the American Recovery and Reinvestment Act funds designated for National Institutes of Health research.
Footnotes
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