Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), a rare form of peripheral T-cell lymphoma, develops around implants used for breast augmentation or reconstruction [1] .
The underlying etiology of the disease is not fully understood, but is possibly related to the chronic inflammation caused by textured devices, leading to malignant transformation of T cells [2-9]. Those malignant cells are characteristically kinase-negative and CD30-positive anaplastic lymphoma [1,10,11].
BIA-ALCL is a major public health concern, as the use of breast implants has increased globally over the past 2 decades [12-15]. The American Society of Plastic Surgeons estimates that more than 400,000 implant-based cosmetic and reconstructive procedures were performed in the US in 2017 [15]. Although the sale of textured breast implants has decreased since 2000, more than 3 million of these devices have been used on patients in the US, putting a significant number of women at risk for the development of BIA-ALCL [7].
The risk of developing a BIA-ALCL appears to be associated with prolonged exposure to textured implants, with most case series reporting the onset of BIA-ALCL at a median exposure time of 7.5 to 11 years. [1,7,8,16-18], although shorter times (0.4–2 years) have also been reported [16,18,19].
The reported incidence of BIA-ALCL varies widely in the literature, ranging from values as high as 1 in 355 patients to as low as 1 in 30,000 patients [7,8,20-22]. Incidence rates also vary, from as much as 1 in 3215 person-years, to as low as 1 in 500,000 person-years [7,8,22,23].
This variability is probably multifactorial and is related to the relative rarity of the disease, passive data reporting systems, lack of accurate rates of implant utilization, and long time of exposure to implants before disease onset [24].
Many studies have been based on different data sources, such as population-based data registry, case report forms, medical literature, and manufacturers’ sales statistics [7,8,21,23,25]. For example, although 186 unique reports of BIA-ALCL in the US have been documented in the Patient Registry and Outcome for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology , that information alone, without precise knowledge of the total number of implants used in the USA, makes it impossible to estimate with certainty the incidence of the disease [16]. Therefore, a study where the type of implant used, exposure time, and disease development are documented with certainty may provide a more accurate assessment of the incidence and prevalence of BIA-ALCL.
A recent experience of a single surgeon at the institution where the authors of this work operate suggests that the risk of developing BIA-ALCL among women who underwent reconstruction with textured breast implants may be higher than previously estimated. In that study, Cordeiro et al. [22], described a cohort of 3,546 women who underwent breast reconstruction with textured implants, between 1991 and 2017, and who were followed prospectively in the long term.
Of those women, 10 developed BIA-ALCL [22]. That calculated risk of 1/135 women is significantly higher than previous estimates. The limitations inherent in the experience of a single surgeon, however, suggest that a more in-depth analysis, at the institutional level, with an examination of all patients treated during the time period, is warranted.
The primary objective of this study was to determine both the incidence and incidence rate of BIA-ALCL per year of implant exposure, within a single institution that performs a high volume of prosthetic implant placement for breast reconstruction. Due to the presentation and local nature of the development of BIA-ALCL (i.e., in the periprosthetic capsule), the incidence of this disease was calculated per implant and per patient.
The secondary objective was to analyze trends over time with the use of implants (i.e., textured versus smooth devices) at the institution, to understand the impact of these devices on the development of BIA-ALCL among breast cancer survivors. and determine the burden of risk in that population.
| Methods |
After institutional review board approval, all patients who underwent implant-based breast reconstruction between July 1, 1991 and June 30, 2017, at Memorial Sloan Kettering Cancer Center were retrospectively identified ( MSK). Surgical details, including laterality of the procedure, type of implant used (smooth vs. textured; manufacturer), and subsequent procedures for breast reconstruction, were taken from the patients’ medical records.
Subsequent procedures were classified as: explant only, implant removal and replacement, or explant with conversion to autologous reconstruction, for each breast of each patient. Additional variables of interest, including medical history and demographics (age, race/ethnicity, body mass index), were collected. All patients in whom the type of implant used was undetermined were excluded from the analysis.
The diagnosis of BIA-ALCL was confirmed by a board-certified hematopathologist, based on cytology, immunohistochemistry, and microscopic examination. All confirmed cases contained CD-30 positive, anaplastic lymphoma with negative T cells in the periprosthetic fluid, implant capsule, and/or lymph node biopsies.
The time of exposure to the implants was estimated using 2 methods: “follow-up,” which defines exposure as the difference in time from the initial placement of the permanent implant to the most recent institutional follow-up; and “vital status”, which defines exposure time as the time difference between the initial placement of the permanent implant and the date of data collection (03/01/19) or death. The sensitivity analysis to determine robustness was carried out by comparing the results of both methods.
Given the association between BIA-ALCL and textured devices, the exposure time in implant years was estimated for each type of implant (smooth or textured). For both methods, the date of implant change to another with different coverage, explant, or explant with conversion to autologous reconstruction, was factored into the calculation.
The change to an implant of the same type was considered a continuation of exposure for that calculation. This generated a longitudinal exposure time for each implant and allowed each implant to be studied separately in patients who underwent bilateral reconstruction.
Using this approach, the total exposure time to textured or smooth implants was calculated independently for breast laterality, taking into account patients who had bilateral metachronous implant placement, and patients who underwent unilateral removal, conversion to autologous reconstruction, or exchange for smooth implants. The total exposure time to the textured implants was used to calculate the incidence rate per implant-year and person-year.
A time-to-event analysis was performed using Kaplan-Meier estimation with 95% confidence interval (CI) to determine the cumulative incidence of BIA-ALCL. The occurrence of BIA-ALCL was compared to the time of exposure to textured implants for any time period, to provide the most accurate representation of disease incidence. Four curves were generated to show the estimated cumulative incidence of BIA-ALCL per patient and per implant, for both exposure time estimation methods.
Exposure time per patient was defined as the cumulative exposure to textured implants for each individual breast. In that analysis, reasons for censoring (removal from denominator population) included explant without subsequent reconstruction, explant with conversion to autologous reconstruction, switch to smooth implants, loss to follow-up, death, or failure to reach an event of interest within a given exposure time.
A 20-year life table was constructed to report incidence in 2-year intervals. Trends in implant use over the study period were examined for both smooth and textured devices.
All data were analyzed with the R Statistical Software program [26]. The Microsoft Excel program was used to calculate the specific exposure time for the implant and generate the figures.
| Results |
Over the 26-year study period, 9,373 patients underwent implant-based breast reconstruction and had complete electronic medical records for inclusion in the final analysis. The mean age at the first reconstruction was 49.5 ± 10.1 years, and the patients were predominantly white (n = 7848; 83.7%).
Of the 9373 patients, 5771 (61.6%) underwent bilateral reconstruction and 3602 (38.4%) underwent unilateral reconstruction. A total of 16,065 implants were placed during the study period, contributing to a total of 94,667 implant-years, with an average exposure time per implant of 5.63 years (range: 0–27.92 years) for the method. for “follow-up”, and 8.11 years (range: 0–28.02 years) for the “vital status” method, as already described.
When implant surface type was examined, 6149 patients underwent placement of 9589 textured implants, and 3918 patients underwent placement of 6476 smooth implants, including all replacement/secondary procedures.
Assuming the exposure time to the implant by the “follow-up” method, patients with textured implants had a total exposure time of 67,323 implant-years, with a median exposure time of 6.53 years per implant (range: 0–27.9 years). Patients with smooth implants had a total exposure time of 27,344 implant-years, with a median of 3.69 years per implant (range: 0–18.17 years).
Assuming the exposure time to the implant by the “vital status” method, patients with textured implants had a total exposure time of 91,915 implant-years, with a median of 9.37 years per implant (range: 0–27. 90 years). Patients with smooth implants had a total exposure time of 36,625 implant-years, with a median of 5.31 years per implant (range: 0–21.16 years).
11 cases of BIA-ALCL were diagnosed, all in patients treated with textured implants. The mean time to diagnosis was 10.26 years (range: 6.43–15.52 years). Ten of the 11 patients had undergone bilateral reconstruction; all cases of BIA-ALCL were diagnosed unilaterally.
Although one patient had smooth implants at the time of diagnosis, with an exposure time to the smooth implant of 1 year, that patient was initially exposed to a textured implant for 10.26 years, prior to switching to a smooth implant, due to the development of a spontaneous seroma. All BIA-ALCL cases were exposed to Allergan/Inamed/McGhan Biocell textured breast implants.
The overall incidence of BIA-ALCL among patients who underwent placement of textured implants was 1.79 per 1000 patients (1 in 559), and 1.15 per 1000 implants (1 in 871). When the exposure time was estimated with the follow-up method, the estimated incidence rate of BIA-ALCL was 1 per 4020 patient-years and 1 per 6120 implant-years of exposure to the textured implant. When exposure time was estimated using the vital status method, those estimates decreased to 1 per 5514 patient-years and 1 per 8356 implant-years of exposure to the textured implant.
The first events of BIA-ALCL occurred within 6 to 8 years of exposure. Most BIA-ALCL diagnoses occurred 10-12 years after implantation, which includes the median time to diagnosis. In that time period, assuming the exposure time by the follow-up method, the cumulative incidence was 4.35 (95% CI: 1.18–7.50) per 1000 patients, and 3.00 (95% CI: 0.80–5.19) per 1000 implants. However, when exposure time was assumed by the vital status method, the estimated cumulative incidences were notably lower: 2.65 (95% CI: 0.77–4.35) per 1000 patients, and 1.77 (95% CI: 0.51–3.03) per 1000 implants.
After 14 to 16 years of exposure to the textured implant, the cumulative incidence leveled off by the follow-up method to 9.40 (95% CI: 2.70–16.06) per 1000 patients and 6.66 (95% CI : 1.85–11.46 per 1000 implants. By the vital status method, these estimates were 4.82 (95% CI: 1.70–7.93) and 3.31 (95% CI: 1, 14–5.48), respectively.
The number of implants used for breast reconstruction at the authors’ institution has increased steadily over time. Textured devices outnumbered smooth implants between 1991 and 2009. Beginning in 2009, however, there was a decrease in the use of textured implants with a concomitant increase in the use of smooth implants. Subsequently, the use of smooth implants surpassed textured devices after 2011. This trend continues at the institution and the authors rarely use textured devices today.
| Discussion |
This is the largest institutional series evaluating the incidence of BIA-ALCL using time-to-event analysis. Using 26 years of experience with alloplastic reconstruction at a single facility, this long-term follow-up has created a scenario to allow appropriate determination of both the numerator and denominator for the development of BIA-ALCL.
The estimated incidences of 1.79 per 1000 patients and 1.15 per 1000 implants are higher than previous estimates [7,8,21,23,27]. The estimated incidence rates of 1 per 6120 implant-years and 1 per 4020 person-years of textured implant exposure are also higher than previously reported estimates [7,8,23]. Likewise, the estimated cumulative incidence from 14 to 20 years was 9.40 per 1000 patients and 6.66 per 1000 implants. Although the 95% CI of these estimates is wide, these relatively high cumulative risk estimates are important when counseling women who have had textured implants for long periods of time.
Since loss to follow-up was the largest potential bias that could lead to underestimation of exposure time, a second calculation of exposure time was performed, as the time difference from the initial placement of the permanent implant to the date of data collection. data or death, an interval that was defined as vital status of the exposure time.
This estimate assumes that all patients were event-free after their last control and until death and allows a sensitivity analysis to be performed on the estimated incidence rate. This analysis also assumes that all patients who were not followed up were not diagnosed with BIA-ALCL at another institution.
The estimated incidence rates using the vital status analysis method for exposure time were lower than the estimated exposure times, at 1 in 5514 patient-years and 1 in 8356 implant-years. Similarly, the cumulative incidence up to 14 to 20 years of age and beyond was much lower using the vital status analysis method for exposure time, with 4.82 per 1000 patients and 3.3 per 1000 implants. However, these incidence rate estimates were higher than suggested in previous studies, although additional work is needed given the wide CIs [7,8,23].
The findings of this work contrast with those of several recent studies that reported lower incidence and incidence rates of BIA-ALCL [7,8,20,21,23,27]. Although these studies attempted to quantify the incidence and incidence rate of BIA-ALCL on an epidemiological scale, their results are subject to bias and have probably underestimated the incidence, due to a combination of the rarity of the condition, the long exposure time for disease development, and passive data reporting systems.
For example, Jong et al. [23], reported a national incidence of 11 cases in 100,000 to 300,000 women, and an incidence rate among women with breast prostheses of 0.1 to 0.3 per 100,000 women, per year (1 per 1,000,000 to 1 per 333,000 person-years) in the Netherlands. However, there appears to be no indication whether these rates are specifically related to exposure to textured implants.
Doren et al. [7], reported an incidence of 1 per 30,000 women and an incidence rate of 2.03 per 1 million person-years (1 per 490,000 person-years), comparing the number of new diagnoses per year with the number of implants textured in the same year. However, their estimate is biased due to their data sources: one database was used to identify BIA-ALCL diagnoses, while another separate database was used to identify the at-risk population.
For the specific incidence rate per implant, the study by Loch-Wilkenson et al., showed an incidence rate of 1 per 25,640 implant-years among patients with textured Biocell products, and 1 per 357,000 implant-years among patients with textured Siltex products [8]. However, the study also determined years of exposure using sales data, likely leading to an overestimation of years of exposure.
Incidence rate estimates that do not take exposure time into account are probably unreliable. Because BIA-ALCL takes time to develop, the incidence of a given disease cannot be reasonably estimated by comparing annual diagnoses for a given year with annual implants for that same year; Doing so perpetually inflates the “person-years” in the denominator.
Previous estimates using time-to-event analyzes (i.e., Kaplan-Meier) did not adjust for censoring, major registry limitation, or manufacturer records. Censoring occurs when there is incomplete follow-up and should be considered in any time-to-event analysis when examining a dynamic cohort.
With these data sources, patients are not rigorously followed in terms of their implant exposure times or revision procedures, leading to incorrect estimates. In the context of BIA-ALCL, which is associated with implant exposure time, current estimates have not taken these considerations into account.
This study is the largest examining the BIA-ALCL on a time-to-event basis. During almost 7 years of follow-up, the incidence of BIA-ALCL was almost 0%. After that time, however, there was an almost exponential rise in incidence. The cumulative incidence was relatively small at each year or event point, culminating at 6.66 per 1000 implants beyond 14 to 16 years. This time interval is limited by the follow-up of 537 implants, as a result of censoring due to loss to follow-up.
The causes for this loss could have been transfer to another care center, or voluntary abandonment of follow-up. Given concerns about possible overestimation of risk due to censoring, cumulative incidence was also examined using the vital status method, which assumes event-free exposure for all patients, with censoring only for death. This gave a cumulative incidence of 3.31 per 1000 implants at ages 14 to 16 years and thereafter. This study directly addressed loss to follow-up using standard censoring in the Kaplan-Meier time-to-event analysis.
Patients lost to follow-up, or who did not reach a time point in the analysis, were removed from the denominator for risk calculation. This provides the most accurate knowledge of the incidence rate and is consistent with standard practice for reporting patients lost to follow-up in a time-to-event analysis [28,29].
In the present study, the incidence rate was analyzed using implant-year exposure and person-year exposure, in line with previous studies. Considering that textured devices may be associated with an increased risk of BIA-ALCL, patients undergoing bilateral breast reconstruction with textured devices, as opposed to unilateral reconstruction, could conceivably be at increased risk for the development of BIA-ALCL.
Put another way, each breast/implant is likely to be an independent event with its own inherent risk of BIA-ALCL development. This study anecdotally supports this hypothesis, as 10 of the 11 patients in the cohort who developed BIA-ALCL had bilateral reconstructions, while only 61.6% of the total cohort had bilateral reconstruction. Clearly, more research is needed to test this hypothesis.
Of note, data from the sale of textured implants suggests that a high volume of procedures were performed from 1990 to 2005 [7]. Although rates of implant-based reconstruction have continued to increase since 2000 [11,15], the sale of textured implants has decreased over the same time period [7]. However, the annual sale of textured implants was approximately 75,000 in 2015 [7].
The authors’ trend analysis of implant-based procedures showed that many of their patients were approaching 10 years of exposure to textured implants, requiring education and follow-up. The number of patients with BIA-ALCL will likely increase simply because more patients will have an exposure time similar to the median time to diagnosis found in that cohort (10.26 years) and in other reports [16,19,30,31].
Management options for patients with textured devices include continuous implant monitoring, switching to smooth devices, or conversion to autologous tissue reconstruction. It is unknown how removal of the textured device impacts the future development of BIA-ALCL, although it is reasonable to hypothesize that removal of the implant substantially decreases the risk. In this series, 1 patient had textured devices for 10 years, which were changed to smooth implants 1 year before diagnosis.
It is possible that BIA-ALCL was present, but undiagnosed, at the time of the switch. Risk reduction has yet to be clearly quantified in such change procedures and may prove to be even more difficult than assessing the risk of developing BIA-ALCL itself. Additionally, estimates of the incidence and incidence rate of BIA-ALCL appear to vary depending on the textured surface of the device, suggesting that not all textured devices carry the same risk [8,21].
At MSK, all patients with breast implants (both textured and smooth) have been contacted regarding the risk of BIA-ALCL in textured implants, and were encouraged to continue monitoring with their plastic surgeon, particularly if any changes were observed in the reconstructed breast.
Patients seen in the clinic are carefully counseled regarding their risk estimate and options for management. The authors’ reconstructive practice has shifted to primarily using smooth surface implants. The institutional stance toward prophylactic mastectomy and contralateral reconstruction has not changed significantly.
This study has several limitations . It is the experience of a single institution with breast reconstruction, which may limit the generalizability of the results. The incidence of BIA-ALCL in that patient population may differ for patients who received textured implants for cosmetic reasons only. This study is retrospective and limited by review bias, completeness of medical records, and selection bias, which manifests itself in different ways.
1. First, due to patients who continued to be seen at other institutions, this study may underestimate the true incidence of BIA-ALCL, since patients who developed BIA-ALCL may have been captured elsewhere.
2. Second, the mean follow-up time for smooth compared to textured devices was significantly shorter in this study. That makes direct comparisons and conclusions difficult.
3. Third, this study showed a significant loss to follow-up before the median time to diagnosis of BIA-ALCL, which may have led to an underestimation of risk if patients developed BIA-ALCL and sought care elsewhere. , or to an overestimation if the patients who were not followed up were healthy, without adverse events. These opposing consequences of attrition bias exemplify the challenges associated with the analysis of this disease and underscore the importance of long-term follow-up.
Additionally, this is a more in-depth analysis than the one presented by Cordeiro et al. [22], which encompassed a majority of the cohort in this study.
The current findings should be viewed alongside the initial report; However, the data collected, as well as the analyses, were completely independent to reduce the risk of additional bias. Despite these limitations, this study attempts a better understanding of the risk associated with textured implants and the development of BIA-ALCL.
| Conclusions |
BIA-ALCL after placement of a textured implant may have a higher incidence rate than initially estimated. Given the number of patients with textured devices, the prevalence of BIA-ALCL will likely increase in the coming years. In addition to understanding the relationship between textured devices and the development of BIA-ALCL, understanding the reduction in incidence generated by implant exchange, or autologous tissue conversion, remains elusive and warrants further examination. .
