Review | Breast implant-associated anaplastic large cell lymphoma

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare but emerging novel disease presenting a treatment challenge to clinicians. A multidisciplinary approach to define the diagnostic work-up and determine the appropriate treatment for each patient is required.

Though it remains a rare disease (~ 600 confirmed and unconfirmed cases worldwide), there has been an increasing number of cases of BIA-ALCL, likely associated with the increased usage of breast implants in aesthetic, oncologic, and risk-reducing surgery. The World Health Organization (WHO) identifies BIA-ALCL as a distinct subtype of lymphoma that is typically associated with good outcomes. Most cases are effectively managed with surgical excision of the implant, though a small number of patients experience relapse and widespread dissemination.

Antonio Marra, European Institute of Oncology IRCCS and colleagues recently published a comprehensive review of BIA-ALCL in Cancer Treatment Reviews, which is summarized by the Lymphoma Hub here.¹

What is BIA-ALCL and what causes BIA-ALCL?

BIA-ALCL is a non-Hodgkin lymphoma (NHL) of T-cell origin that is CD30-positive, epithelial membrane antigen positive, and ALK negative. T-cell antigen expression is variable — CD4 is often found but CD3, CD45, and CD2 are less frequently expressed. The pathogenesis has not yet been fully uncovered. Most cases are associated with breast implants with textured surfaces, with high-textured, high-surface area implants (grade 4 surface) associated with the highest risk.

What is the pathogenesis of BIA-ALCL?

• Mechanisms underlying the BIA-ALCL pathogenesis are not well understood
• Potential etiological factors:
  • Chronic inflammation and the immune response: studies of the microenvironment have identified a high level of interleukin (IL)-2 and IL-6 receptors in BIA-ALCL, a strong activation of signal transducer and activator of transcription 3 (STAT3) signaling, and high levels of IL-13 and immunoglobulin (Ig)-E
  • Bacterial biofilm formation: textured implants lead to a higher bacterial load than smooth implants
  • Patient genetics: somatic mutations in genes of the JAK/STAT signaling pathway and in TP53 and DNMT3A have been observed, along with recurrent mutations of epigenetic modifiers in > 70% of cases
• Gene expression profiling has shown BIA-ALCLs
  • upregulate genes involved in cell motility processes (e.g., chemokine receptor 6 [CCR6], MET, hepatocyte growth factor [HGF], and chemokine [C-X-C motif] ligand 14 [CXCL14]) and other genes (peroxisome proliferator-activated receptor gamma [PPARg] and Janus kinase 2 [JAK2])
  • may present with programmed death ligand-1 (PD-L1) expression or copy number alterations, indicating the PD1/PD-L1 axis may have a role in the microenvironment
    • This provides preliminary rationale to test anti-PD-1/PD-L1 immunotherapy in patients with advanced disease

What is the incidence and risk of BIA-ALCL?

• There are limitations to understanding the incidence of BIA-ALCL, such as a necessity to determine how many women have implants and what type they are, the fact that increased awareness of BIA-ALCL may be increasing the number of women reporting with symptoms, and a lack of  clinical management and diagnosis that may mean the number of cases are underestimated
• Overall, the number of cases has increased dramatically over time:
  • Estimation of all women with implants: 1 per 20,000–30,000
  • This is higher in patients with textured breast implants: 1 per 2,832
  • As of July 2019, the United States (US) Food & Drug Administration (FDA) had 573 medical device reports for BIA-ALCL, with 33 deaths
• PROFILE (Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology) collects information on  reported cases to inform future clinical practice
• Current estimated incidence in the US: 33 per 1 million persons with textured breast implants
  • Mean time from implant placement to diagnosis: 10.7 ± 4.6 years

How do patients typically present, clinically?

• Most cases present with localized disease, which is associated with improved prognosis
• Up to 80% of women present with persistent seroma, periprosthetic effusion, or seroma around the implant that may be accompanied by breast swelling, asymmetry, or pain
• In women with delayed seromas (> 1-year post-implantation of a textured breast implant), the risk of BIA-ALCL rises to 10%, however the occurrence of delayed seromas is rare (0.05–0.1%) and ruling out alternative diagnoses (e.g., external trauma and infections) is key
• Development of a tumor mass with possible nodal involvement is rare (10–20% of cases)
• Some cases have reported cutaneous lesions, capsular contractures, and B-type symptoms.
• Cases with liver, small bowel, central nervous system (CNS), and bone involvement have also been reported
• Bilateral breast capsular involvement has rarely been reported: all cases therefore deserve multidisciplinary approaches in a case-by-case manner
• By Ann Arbor Staging System, most patients have early-stage disease:
  • Stage IE: 83%
  • Stage IIE: 10–16%
  • Involvement at sites other than ipsilateral breast and regional lymph nodes is considered stage IV
• Clinical presentation may have prognostic implications, for example outcomes vary between patients without infiltration of the implant capsule and patients with diffuse infiltration of the capsule and adjacent tissues
  • Patients with infiltrative BIA-ALCL have a significantly shorter 2-year overall survival
• Lymph node involvement may also negatively impact the outcomes
• Most disease-related death is due to invasion into the chest wall and mediastinum

How is BIA-ALCL diagnosed?

• Ultrasound breast imaging should be used to detect effusion or mass
• In the presence of a mass, breast magnetic resonance imaging (MRI) may be useful
• Aspiration of fluid or biopsy of the mass is essential
  • For effusion: fine needle aspiration guided by ultrasound
    • A large volume of fluid, ≥ 10 ml, but ideally 50 ml, should be obtained — the fluid is often cloudy
    • Cytology and flow cytometry (with evaluation of CD30 expression) is required
    • The pathologist should be informed of the suspicion of BIA-ALCL
    • On smears/cytological analysis, the neoplastic cells are large and pleomorphic with irregular cell membranes, abundant, vacuolated cytoplasm, and large, eccentric, polymorphic kidney-shaped nucleus with prominent nucleoli
      • This should be combined with immunohistochemistry and flow cytometry for a definitive diagnosis
  • For breast mass: a biopsy is required
    • Flow cytometry and evaluation of T-cell markers, e.g., CD30 
• After histopathologic confirmation, lymphoma work-up is required to stage the disease
  • Positron emission tomography (PET)/computed tomography (CT) is recommended but the timing is debated: pre-surgery it can be used to identify capsular masses, chest wall invasion, and disease outside breast, including suspicious lymph nodes, however other clinicians prefer to use PET/CT post-surgery
  • Bone marrow biopsy is only recommended in cases where there is suspicion of bone marrow involvement or persistent/unexplained cytopenia
  • A multidisciplinary team conference should be held with surgeons, medical oncologists, radiologists and hemato-pathologists (see a Mayo Clinic example at the end of this article)
• Following removal of the mass, examination of the whole capsule adjacent to the implant should be conducted to confirm depth of invasion and negativity of the margins

What is the recommended treatment?

• Since most cases are localized, surgical excision of the mass with negative margins alone is standard of care  
• Lymph node dissection and sentinel lymph node biopsy are not recommended in cases where the cancer has not spread to the lymph nodes
• In cases of local residual disease post-surgery or unresectable tumors, other therapies may be required, though there is no standard in this setting:
  • These cases should be discussed at a multidisciplinary tumor board (see a Mayo Clinic example at the end of this article)
• For locally advanced or disseminated disease, systemic chemotherapy is recommended as with other T-cell lymphomas:
  • Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP with etoposide added (CHOEP)
  • Brentuximab vedotin, an antibody drug conjugate that targets CD30, has some activity in case reports
  • JAK/STAT inhibitors may also have a therapeutic role

Emotional and psychological burden

Many women find breast reconstruction symbolic following cancer treatment and the potential risk of BIA-ALCL may cause anxiety surrounding the development of a secondary cancer. There is a wealth of communication on the internet surrounding BIA-ALCL, leading to widespread worry and confusion and a subsequent risk that women may choose to refuse breast reconstruction based on the potential to develop BIA-ALCL. Additionally, many women will overestimate their risk of developing this rare cancer.

Therefore, information should be provided in a clear way and adapted to the specific patient scenario to increase awareness of facts. Decision aids or interactive health communication systems may be effective tools in this setting, and psycho-cognitive factors should be considered and integrated into clinical decisions.

Context

The FDA has recalled all textured breast implants and expanders produced by a specific company in the US. In France, the sale of macro-textured surface implants has been restricted, and in Canada, licenses for a company that produces macro-textured implants have been suspended.

Key take-home messages

• All women (and men) with breast implants should have a yearly physical examination
• If there is suspicion of seroma or masses, diagnosis should be confirmed with breast ultrasound
• Suspicious cases should be referred to institutions with experience in BIA-ALCL to be discussed at multi-disciplinary tumor board meetings
• Physician awareness of this novel disease should be increased, and all cases should be reported to government agencies
• Risks should be discussed with patients prior to surgery to empower them to make an informed and educated decision
• Further research is required to determine the mechanism for development of BIA-ALCL

Read more

To read more about overview and management of BIA-ALCL based on a series of 18 cases in the United Kingdom, click here. To watch a multidisciplinary team discuss suspected cases of BIA-ALCL, watch the video below.