Patient and Implant Characteristics
Table 1 summarizes the patients’ demographic and clinical characteristics for the BIA-ALCL cases for whom the physician reporter completed a CRF. Median patient age at the time of diagnosis was 52.5 years (range = 31–84 years). Race was reported as White for 82 patients (92%), Black/African American for 1 patient (1%), and was not reported in 6 cases (7%). Fourteen patients (16%) had a history of a nonbreast malignancy, including 1 patient with a history of non-Hodgkin’s lymphoma.
Forty-two patients (47%) had a history of cosmetic breast augmentation alone; 47 (53%) had a history of postmastectomy implant reconstruction. Four patients who underwent postmastectomy reconstruction had a history of prior cosmetic augmentation. All 47 patients in the reconstructive cohort had a diagnosis of breast carcinoma. No patient had a history of bilateral prophylactic mastectomies. Most of the 47 reconstructive patients underwent a postmastectomy reconstruction. There were 30 patients with 2-stage tissue expander/implant reconstruction and 16 patients with single-stage reconstruction. Fifteen women completed chemotherapy; 5 women received chest wall irradiation (see Table 2).
In the 89 patients with complete data, median time from implantation of their current implant to diagnosis of disease was 9.0 years (range = 0.08–27 years). Notably, there was 1 patient who was diagnosed with BIA-ALCL only at 0.08 years. The earliest time to development of BIA-ALCL in an implant-naive patient was 2.2 years. Median time from implantation of any device to diagnosis was 11.0 years (range = 2–44 years). All 89 patients had a breast implant (not tissue expander) at the time of diagnosis.
In total, 38 women (43%) had a history of multiple device exposure. Of this subset, 7 patients had prior permanent implants, whereas the remaining 31 patients had a history of prior temporary tissue expanders (see Table 3).
Implant details are presented in Table 4. Implant filler was reported as saline in 39 women (44%) and silicone in 46 (52%). One patient had a combined saline/silicone implant. In 3 patients, fill type was not reported. At the time of diagnosis, 70 patients (79%) had an implant with a textured shell; in 4 cases (5%) the implant type was smooth. In 15 (16%) cases the texture of the device was not reported.
In the 4 cases in which the diagnosis of BIA-ALCL was made in a patient with a smooth shelled device(s), all 4 patients had a history of prior implantation. In all 4 of these cases, patients had a history of a prior textured permanent implant. In 1 case, a patient had a history of a prior textured tissue expander.
The use of ADM was reported in 7 patients (8% of cases) ultimately diagnosed with BIA-ALCL. Twenty patients (22%) had a documented complication before a diagnosis (see Table 5). The most common complication was implant rupture, which occurred in 12 patients (13.5%). Infection was documented in 2 patients; no patient had a documented history of a hematoma.
Table 6 summarizes the clinical findings of BIA-ALCL. At the time of presentation, 85 (96%) patients had local symptoms and 8 (9%) had concurrent systemic symptoms. The most common local symptom was a periprosthetic fluid collection or seroma in 85.9% of patients (n = 73). When capsular contracture was present, it was most commonly grade III or IV. Palpable breast masses were only found in 15.7% (n = 13) cases. Pain, breast skin lesions, and redness were all uncommon but present in a subset of patients. When systemic symptoms were present, they included fevers, night sweats, weight loss, and nonbreast skin lesions.
In 2 cases (2%), patients were asymptomatic at the time of diagnosis. In the first of these cases, the patient had a history or prior cosmetic breast augmentation. She was subsequently diagnosed with unilateral breast carcinoma and elected to undergo explantation of bilateral breast implants concurrent with her bilateral mastectomies. Pathological examination of her periprosthetic capsules bilaterally revealed unilateral BIA-ALCL. In the second case, the patient had a history of cosmetic breast augmentation and was similarly diagnosed with a unilateral breast carcinoma. She proceeded with a unilateral lumpectomy alone. Routine screening of her silicone implant with magnetic resonance imaging subsequently revealed a ruptured device. She returned to the operating room for removal and replacement at which time periprosthetic fluid was encountered. Based on cytological evaluation of the fluid, BIA-ALCL was diagnosed.
Table 7 provides details regarding BIA-ALCL diagnosis. The majority of patients, 87 (98%), was diagnosed with unilateral BIA-ALCL. By contrast, 2 patients (2%) were diagnosed with bilateral BIA-ALCL. Notably, one of these patients had a history of B-cell non-Hodgkin lymphoma. Both patients had a history of bilateral breast augmentation, developed a unilateral seroma, and proceeded to surgery for bilateral explantation and capsulectomies. Pathologic examination of excised capsules revealed bilateral BIA-ALCL in both cases.
All known cases were anaplastic lymphoma kinase negative and CD30 positive. Most commonly (39.3%, n = 35), patients were diagnosed with stage IE disease (Lugano Modification Ann Arbor Staging). Tumor-node-metastasis solid tumor staging was not available at time of publication.
Treatment and Outcomes
Eighty-one patients (91%) with BIA-ALCL were reported to have undergone surgical resection (see Table 8). In only 66 of these 81 cases, details surrounding the nature of their surgical procedure were submitted. In all these 66 cases, patients reportedly underwent explantation and capsulectomy. In 9 of these 66 cases, patients underwent explantation with the concurrent replacement of a breast implant(s). Whether the replacement implants had smooth or textured shells was not specified. Details regarding the type of capsulectomy performed were only available in 5 of the 66 cases. In only 1 of these 5 cases, a total capsulectomy was performed; in the remaining 4 cases, a partial capsulectomy was documented.
Two patients (2%) with BIA-ALCL were not treated surgically for their disease. In one of these cases, it is documented that the patient refused surgical treatment. In the other case, it is only noted that the patient received chemotherapy. In 5 cases (6%), treatment was not reported.
Adjuvant chemotherapy (28.1%, n = 25) and external beam radiation therapy to the chest wall (13.5%, n = 12) supplemented BIA-ALCL treatment in a minority of cases.
At the time of initial case report submission, 3 deaths were reported. One patient (1%) died of disseminated BIA-ALCL, 9 years after cosmetic breast augmentation. Eight years after augmentation, she developed a palpable mass adjacent to her device and was diagnosed with BIA-ALCL confined to the breast. She reportedly refused any surgical therapy, although she did undergo both chemotherapy and radiation. Ultimately, she developed widely metastatic disease and succumbed to the disease within 1 year. The second patient died of metastatic breast carcinoma, and a third patient reportedly died of natural causes.
PROFILE, a collaboration between the ASPS, the PSF, and the FDA, has been shown to be an essential tool in unifying the collection of data and building a comprehensive knowledge base pertaining to BIA-ALCL. Because of the recent nature of this disease, granular details of cases are critical to understanding characteristics of the patients, implants used, diagnosis, treatment, and outcomes. This article represents the initial report of the first BIA-ALCL patient registry that was established worldwide.
These registry data add several first reports to the literature on BIA-ALCL. In the 89 patients with complete data, there was a clinical history of ADM use in 7 cases (7.9%). Extent of ADM use such as a small patch, inferolateral sling, or full wrap was not reported, and the role of ADM as a potential biological block in each of these situations would require further investigation. A history of fat grafting in 7 patients (7.9%) has also not been previously reported. This is the first US report of a confirmed case in a woman of African American race. This is also the first report of BIA-ALCL detected incidentally during the resection of a second primary of breast cancer. Without denominator data and with just a single tissue expander case, it is not possible to calculate a risk estimate for textured tissue expanders and this type of case remains exceedingly rare. This is the first report of BIA-ALCL detected incidentally during the resection of a second primary of breast cancer. Bilateral BIA-ALCL case reports have been previously reported,6 though this represents the first series of cases from a registry. Bilateral cases require pathology evaluation to determine if these cases represent metastasis or the occurrence of 2 separate primary clones in the same individual. Bilateral cases support the National Comprehensive Cancer Network treatment recommendations for bilateral capsulectomy in confirmed cases.7,8
Although presentation with periprosthetic effusions and/or mass has been widely reported,9–11 the disease characteristics in the current analysis further elucidate disease presentation. Ninety-four percent (83 patients) of registry patients presented with a seroma and/or a mass. Thirty-three percent (29 patients) were found to have a capsular contracture at time of presentation. In all but 1 case, capsular contracture accompanied another symptom. Registry patients had rates of associated skin lesions (n = 7, 8.2%), overlying skin redness (n = 12, 14.1%), and systemic symptoms (n = 8, 9%), all of which were accompanied by at least 1 additional symptom. These symptoms, when present, may further raise suspicion of BIA-ALCL and may warrant investigation.
Since 2011, the FDA has regularly updated the information available on its public website regarding known BIA-ALCL cases, including deaths and known risks.12 The strengths of the PROFILE Registry include the systematic collection of a comprehensive set of critical data elements specifically relating to BIA-ALCL. The registry’s ability to rule out duplicate entries minimizes the risk of overreporting of cases. And finally, PROFILE accepts submissions from physician reporters only, theoretically optimizing the accuracy of the reporting pertaining to specific clinical variables. This knowledge base will ultimately be used to support discussions surrounding the safety, effectiveness, and the benefit/risk profile of breast implants and will be instrumental in determining which factors have a role in the etiology of BIA-ALCL. The more we can learn about this disease, the better positioned we will be to ensure patients are more fully informed of the benefits and risks of breasts implants.
There are several limitations that need to be considered. PROFILE depends on voluntary reports from participating physicians. Some institutions, though not all, require the physician to obtain informed consent from their patients for their data to be entered into the registry. As such, we note that over half of the confirmed cases provided had incomplete information, and therefore, the registry data may not be representative of all BIA-ALCL cases in the United States. Despite 186 unique confirmed cases of BIA-ALCL being reported to PROFILE, physician reporters only provided detail data reporting on 89 (48%) of those cases. The PROFILE Steering Committee has worked to improve the completion of data by contacting reporting physicians. However, the discrepancy between case notification and full reporting persists, despite numerous telephone calls and email follow-up to participating physicians. All cases in this analysis were reviewed, and secondary attempts to complete data for each case were made before this analysis. Barriers for completion of data sets include in some cases incomplete medical records. The large number of data fields in the registry and required time commitment were cited as barriers for completion. Individual physicians may be unable to secure institutional review board approval to submit patient protected information or have institutional barriers preventing their participation in the registry.
And finally, although PROFILE can report the absolute number of unique and distinct cases of BIA-ALCL, without a denominator (the total number of breast implants placed in the United States), the incidence rate remains difficult to determine.
The present study is an initial report of the PROFILE registry. Data to date have broadened our understanding of patient characteristics and disease presentations not previously described. The FDA recommends all confirmed BIA-ALCL cases be reported to the PROFILE registry as this information provides important details that may not be obtained from data received though FDA MedWatch reporting system.12 This study emphasizes the critical importance of disease awareness, physician reporting, and the detailed tracking of BIA-ALCL cases.
This registry is the first of its kind in the United States. PROFILE offers a systematic way to collect complete and consistent data on patients diagnosed with the BIA-ALCL. At a time when the safety of breast implants remains under scrutiny, the ongoing collection of data from this registry will continue to be critical in the evaluation of ALCL and breast implants. The FDA will continue to use the input it receives from all stakeholders, including patient groups, to inform its collaboration with the ASPS/PSF in the management of the PROFILE Registry and in the proposed enhanced surveillance activities and research to characterize BIA-ALCL in patients with breast implants.
The authors would like to thank all reporters of cases to the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology (PROFILE) without whose cooperation and participation the findings of this study would not be possible. They would also like to acknowledge Keith Hume, MA, Hongying (Helen) Jiang, PhD, RAC, Dongyi (Tony) Du, MD, PhD, Sung Yoon, MD, and Benjamin Eloff, PhD, for their contributions.
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