A Review of Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) and Updated Treatment Guidelines

Abstract

Each year, hundreds of thousands of women undergo aesthetic or reconstructive breast implant surgery and will continue to do so. An increase in surgeries means emphasizing both clinician and patient awareness of benefits and risks of breast implantation. Recently, the risks were publicized due to a recall of certain textured breast implants suggested by the United States Food and Drug Administration (FDA) due to a link between these implants and a rare form of lymphoma, now referred to as Breast Implant-Associated Anaplastic Lymphoma (BIA-ALCL). This malignancy has an indolent course and an excellent prognosis when detected and treated early. The following article reviews the disease process of BIA-ALCL, addresses current public safety advisories, and emphasizes protocol that all clinicians should follow when encountering a patient with textured breast implants.

Introduction

Breast implant surgery is the most commonly performed plastic surgical procedure in the United States and the number of these surgeries continues to increase annually.^1,2 In addition, the majority of women who undergo mastectomy opt for implant-based reconstruction.³ Implant-based breast reconstruction typically occurs in two stages: insertion of tissue expander and exchange of tissue expander for permanent implant. Current implants on the market are categorized by shape (round or anatomic), filling material (silicone or saline), and texture of implant shell surface (smooth or textured). Anatomic, shaped implants have a tear drop shape, meaning more volume is in the inferior portion of the breast and tapers off superiorly, which mimics the natural ptosis of the breast. These implants have a specific apical and basilar orientation, therefore they must remain fixed within the implant pocket or risk an unnatural appearance.⁴ Fixation is achieved by the surface texture promoting fibrous tissue ingrowth and attachment to the implant, thus preventing malrotation. The textured outer shell may also decrease scar tissue formation around the implant, a process defined as capsular contracture, however this concept is debated and requires additional research.¹ In contrast, round implants are symmetric, and thus do not require fixation to avoid rotation.

Anatomic, textured implants were commonly used in women desiring breast augmentation as well as those with breast cancer treated with mastectomy, because these implants created a more natural breast shape. The potential for these anatomic, textured implants to decrease the risk of capsular contracture- a common cause of discomfort, implant malposition, and the need for revision surgery- also contributed to wide adoption and use of these types of implants.¹ However, enthusiasm for the use of textured devices has decreased significantly in recent years given an increase in awareness of a rare form of anaplastic large cell lymphoma (ALCL) around these devices. This disease process has since been termed Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL).

The first case of BIA-ALCL was reported in 1997 in a patient with textured breast implants.⁵ However, a link between ALCL and textured breast implants was not made until many years later, likely secondary to a low incidence rate and lack of reporting measures. As more case reports of ALCL in patients with textured implants were published, the medical community suspected a possible association between this disease and the surface composition of the implant, regardless of the fill (silicone or saline). The United States Food and Drug Administration (FDA) released their first advisory about a potential link between breast implants and ALCL in 2011. In 2016, the World Health Organization (WHO) defined this lymphoma specifically as Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) and recognized that the total case number worldwide proved indeterminant.^6,7 On July 24, 2019, the FDA recommended that Allergan, one of the largest implant manufacturers, recall their textured BIOCELL breast implants and tissue expanders.⁸ Textured devices produced by other manufacturers were not recalled as studies suggested that their implants were less likely to be associated with BIA-ALCL.^4,9 Nevertheless, numerous media outlets were quick to report on this recall which understandably sparked fear amongst women with any textured implant. In fact, google search terms “textured breast implants” and “Allergan breast implant” increased 456% and 659% respectively during this time.¹⁰ Because media can influence public health trends, the treatment of BIA-ALCL is becoming an increasing concern of both women with breast implants and those considering future surgery.

Patients with textured implants commonly ask about the risk of BIA-ALCL and surgical options that can potentially decrease the risk of developing this disease. The most recent data published by the FDA identifies 573 cases of BIA-ALCL and 33 deaths worldwide.⁸ In the United States, 307 cases are suspected or confirmed.¹¹ BIA-ALCL is considered a rare cancer with an excellent prognosis when detected early, reinforcing the need for awareness of the disease in its early stages.^6,11 The FDA does not recommend prophylactic removal of textured implants, therefore careful consideration must be taken when counseling patients with textured implants.⁷ As the medical community continues to learn about this “hot topic” the public will undoubtedly seek guidance. In order to sift through the tangled web of anecdotal data, clinicians must remain informed to practice evidence-based medicine not only for their patients but for themselves.

Pathophysiology

The WHO classifies BIA-ALCL as an anaplastic, kinase-negative, Non-Hodgkin’s T-cell lymphoma.⁶ There is still much that remains unknown about the pathogenesis of this disease but there are several proposed mechanisms. Currently, the hypothesized risk factors related to development of BIA-ALCL are history of a textured device, biofilm formation, and host genomics. The strong association between textured implants and developing ALCL suggests that the implant surface is potentially the most important risk factor.⁸ The implant texturing ranges in size from micro to macro- based on the size of the particle on the implant surface used to create the texturing. BIOCELL (manufactured by Allergan) is a form of macro-texturing, and has demonstrated a stronger association than micro-texturing with BIA-ALCL.^4,8 The surface is more abrasive than other textured implants and is thought to promote T-cell infiltration and a heightened chronic immune response. Chronic inflammation is a risk factor in development of other types of lymphoma, as evidenced by an association between chronic Helicobacter pylori (H.pylori) infection and Mucoid-Associated Lymphoid Tissue lymphoma (MALT).^4,12 Some researchers also feel that the shedding of silicone particulate matter found in macro-textured implants contributes to a chronic inflammatory state associated with BIA-ALCL pathogenesis.¹³ Another proposed mechanism for developing BIA-ALCL is the presence of bacteria on implant insertion and/or development of biofilm over time. Macro-textured implants have a significantly higher bacterial load of biofilm compared to smooth.^4,14 One study showed that gram-negative species were found more often on BIA-ALCL confirmed capsules, but follow-up data remains conflicting.^1,15 Finally, there may also be a genetic component to developing BIA-ALCL. For example, genomes of 11 confirmed ALCL cases were analyzed and variants leading to JAK/STAT activation were detected in 10 out of 11 patients.¹⁶ While experts continue their search for the exact etiology of BIA-ALCL, they generally agree that chronic inflammation at the breast-implant interface is associated with disease development.

Incidence

The medical community has learned much more about the prevalence of BIA-ALCL since the first discussion over 20 years ago. As of July 2019, the FDA confirmed 573 cases of BIA-ALCL. Out of these cases, 481 had a history of BIOCELL textured implants.⁹ In the same safety communication, they estimated that the risk of BIA-ALCL was 6 times higher for BIOCELL implants than other textured implant manufacturers, but also emphasized that macro-textured implants make up less than 5% of the breast implants sold in the US.⁸ The lifetime risk of developing BIA-ALCL is estimated to range between 1/2832¹ and 1/30,000.¹⁷ However, a recent study published on 3546 women who underwent placement of textured breast implants and followed for as long as 15 years suggested that the risk of developing BIA-ALCL is higher than previous estimates. In this study, the risk of developing BIA-ALCL was 1 in 355 women, the highest incidence published to date.¹⁸ It is also important to note that the prevalence does not vary between those with textured implants for augmentation vs. reconstruction^12,19 and that there have been no case reports in women with a history of only smooth surface devices.¹¹ As researchers continue to publish current risk assessments, public health officials will likely revise safety guidelines.

Clinical Presentation

It is estimated that upwards of 80% of patients with BIA-ALCL first present with a fluid collection, or seroma, near the implant.^4,20 The patient may complain of pain, abrupt swelling, or breast asymmetry. Other less common presentations include breast mass, capsular contracture, or lymphadenopathy.⁴ The timing of symptom onset is a critical factor in recognizing BIA-ALCL. The median time from implant placement to diagnosis is estimated to be 11 years.²⁰ Additionally, the risk of BIA-ALCL is approximately 10% for patients who present with seroma at least one year after implant placement.¹²

Diagnosis and Staging

A systematic approach to diagnosis of suspected BIA-ALCL cases was published in 2019 by the National Comprehensive Cancer Network (NCCN).²¹ History includes confirmation that the patient has or had a textured implant in the past. Physical exam is performed to identify late onset fluid collection. If effusion or mass is suspected, ultrasound is typically the imaging of choice to confirm. Breast MRI should be considered in patients with a mass.¹² Fine needle aspiration (FNA) of seroma fluid can be performed and sent for cytology and flow cytometry. If it is not possible to aspirate seroma fluid; for example, there is too little fluid to safely allow non-invasive aspiration, then implant capsule tissue can be sampled using ultrasound-guided biopsy and sent for immunohistochemistry.²¹ Cytologic examination will reveal atypical, large, pleiomorphic cells. Flow cytometry and immunohistochemistry of BIA-ALCL specimens typically show the presence of a single T-cell clone and cell surface expression of the CD30 biomarker, as well as absence of the anaplastic lymphoma kinase (ALK) gene translocation. Other forms of systemic and/or cutaneous ALCL may also be ALK-negative or CD30-positive, therefore comprehensive clinicopathologic examination is required to exclude other malignancies.^12,21 It is important to note the physical findings and degree of suspicion for BIA-ALCL in the pathology requisition form so that the appropriate histological tests are performed. If the results are indeterminate or if the pathologist is unfamiliar with testing protocol, specimens may be sent for analysis at a tertiary center.²¹ Ideally the entire process of diagnosis starting from disease recognition to pathological examination is a collaborative, interdisciplinary effort. Finally, it is important to emphasize that the finding of an isolated peri-implant effusion is not solely diagnostic of BIA-ALCL. The most common cause of this finding is in fact, a leaking silicone implant. Small amounts of fluid on routine imaging around an implant that are asymptomatic may be physiologic. However, a sudden accumulation of a large volume of seroma fluid should cause suspicion.

BIA-ALCL is staged by the location of the disease using the Tumor, Lymph Nodes, Metastasis (TNM) solid tumor staging system.²¹ Stage IA is diagnosed when malignant cells are present only in the peri-implant fluid and in Stage IB, cells are confined to the internal capsule. In Stage IC, the mass may infiltrate the capsule. If a mass is found beyond the capsule it is classified as Stage II. Stage III and IV include lymph node involvement and distant spread respectively. Stage is determined by PET/CT scan which must be performed pre-operatively in any confirmed case of BIA-ALCL.²¹

Treatment

The NCCN continuously updates their treatment guidelines for this disease as more literature is published. Given that most cases of BIA-ALCL are Stage I (confined to capsule) when diagnosed, definitive treatment is an “en bloc” capsulectomy, or removal of the implant and its surrounding capsule. If the mass extends beyond the capsule, the additional disease is also excised.²¹ Approximately 2–4% of ALCL cases also involve the contralateral implant, therefore the removal of bilateral implants should be considered.²¹ Depending on the disease stage, patients may opt for breast reconstruction with either autologous tissue or smooth implants, as most patients do not need further treatment following surgical excision. Most patients (93%) are disease free at 3 years follow-up.¹¹ There are no standardized treatment guidelines for advanced cases of BIA-ALCL due to the low incidence, however patients may undergo a combination of adjuvant chemotherapy and radiation under a team of medical and surgical oncologists. Similar to systemic ALCL, recommended chemotherapeutic regimens may be combination anthracycline-based, such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), although data is limited.²¹ To prevent recurrence, patients should adhere to a strict follow-up routine, including exams every 3–6 months, and imaging such as PET or CT scans every 6 months the first two years after surgery.^4,21 If the patient remains disease free after two years, they can return to routine follow-up, but should seek the opinion of their plastic surgeon or medical oncologist if they notice any changes to the breast such as swelling, pain, or an unexplained rash.

One of the most notable advancements in BIA-ALCL research was the development of a national patient registry entitled “Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology” (PROFILE) in collaboration with the FDA. Clinicians are encouraged to submit their case reports to http://www.thepsf.org/PROFILE in order to study characteristics such as patient demographics, symptoms, and recurrence rates. By tracking long-term follow-up in a structured manner, experts hope to better understand the both the similarities and differences of all BIA-ALCL cases.²⁰

Patient Counseling

Routine monitoring after breast implantation is necessary in facilitating early detection and diagnosis of BIA-ALCL. Women with textured devices should be made aware of the current FDA guidelines, including that asymptomatic patients are not advised to remove their textured implants.⁷ It is also recommended that these patients follow up with their surgeon annually for physical exam and imaging if any should be warranted.²¹ Because of the excellent prognosis of the disease when detected early, it is imperative that primary care clinicians and oncologists are informed about presenting symptoms so they can make a timely referral to a plastic surgeon or specialist. They should also emphasize the importance of self-exam and routine follow-up, which may perhaps give patients a sense of control and ease anxiety. An open discussion about BIA-ALCL with an updated risk assessment should be a part of the informed consent process before any breast implant surgery.⁴ Women who electively remove textured implants without a confirmed diagnosis should be aware that capsulectomy and implant replacement does not come without risk. Participating in a dialogue with patients about newly published safety regulations will both spread awareness and play an integral role in keeping BIA-ALCL classified as rare.

Summary of Current FDA and NCCN Guidelines ^7,8,21

• BIA-ALCL most commonly occurs in the fluid around the breast implant as well as in the capsule.

• Common presenting symptoms are swelling, new mass, or tenderness near the breast implant usually occurring years after implants are placed.

• The diagnosis of BIA-ALCL should be considered in patients with late onset (>1 year) significant implant effusions.

• The risk of BIA-ALCL is estimated to be 6 times higher for BIOCELL, macro-textured, implants than other textured implant manufacturers.

• Medical providers should immediately stop implanting recalled textured devices listed in the July 24, 2019 FDA safety communication.

• Diagnosis is made by sending seroma fluid and/or tissue to pathology to rule out BIA-ALCL. This includes cytological evaluation, flow cytometry, and CD30 and ALK immunohistochemistry. Expression of CD30 without ALK is pathognomonic for BIA-ALCL when other malignancies are excluded.

• Currently, the FDA does not recommend removing any recalled textured devices in asymptomatic patients.

• The overall risk of death from BIA-ALCL is low and most patients are cured with surgical resection of the disease; however, delayed diagnosis can lead to metastatic disease and even death. In these more advanced cases, chemotherapy and/or radiation may be recommended.

• Any patients who have breast implants or are considering surgery should be made aware of the risk of BIA-ALCL through discussion and informed consent.

• Routine follow-up is critical for any woman with breast implants.

• BIA-ALCL is best managed in a collaborative, multidisciplinary approach.

Figure 1.

⁷ Reprinted from “Questions and Answers about Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL)”

https://www.fda.gov/medical-devices/breast-implants/questions-and-answers-about-breast-implant-associated-anaplastic-large-cell-lymphoma-bia-alcl

Table 1.

²¹ Tumor Nodes Metastasis (TNM) Staging of BIA-ALCL

TNM Stage	TNM Classification	Definition	Percent of Patients at Presentation
IA	T1 N0 M0	Presence of effusion without lymph node involvement or distant spread	35–70%
IB	T2 N0 M0	Early capsule involvement without lymph node involvement or distant spread	3–11%
IC	T3 N0 M0	Cell infiltration into the capsule without lymph node involvement or distant spread	8–13%
IIA	T4 N0 M0	Lymphoma extends beyond capsule without lymph node involvement or distant spread	8–25%
IIB	T1–3 N1 M0	Stage IA, IB, or IC disease plus involvement of one regional lymph node, without distant spread	3–5%
III	T4 N1–2 M0	Lymphoma extends beyond the capsule with one or more lymph nodes involved, without distant spread	3–9%
IV	Tany Nany M1	Any disease presence or lymph node involvement plus distant spread	1–2%

(copyright letter attached separately-- although table adapted from source- not copied)