Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): diagnosis and management

Introduction

BIA-ALCL is an uncommon and emerging T-cell lymphoma caused by textured surface breast implants placed either for reconstructive or cosmetic indications. Safety communications by the US Food and Drug Administration (FDA) in 2011, and annually since 2016, have cautioned about BIA-ALCL and textured breast implants including clinical presentation, prognosis, and treatment options, and subsequently increased public and physician awareness. This warning was based upon case series dating back to a sentinel case described by Keech and Creech in 1997. Since the FDA safety communication in 2011, a number of major government agencies around the world have developed BIA-ALCL patient and physician recommendations. The National Comprehensive Cancer Network (NCCN) adopted standardized diagnosis and treatment guidelines for BIA-ALCL in 2016, originally developed at MD Anderson Cancer Center and recommended by the American Society of Plastic Surgeons (ASPS) and the American Society of Aesthetic Plastic Surgeons (ASAPS). The World Health Organization (WHO) officially recognized BIA-ALCL as a subset of ALCL and the International Agency for Research on Cancer (IARC) designated BIA-ALCL a priority for further research to determine malignancy etiology and mechanism of pathogenesis. Driven by the risk of BIA-ALCL associated with textured breast implants, 38 countries banned the use of macrotextured Allergan Biocell. In July 2019, the US FDA called for a class I device recall of Allergan Biocell textured implants and expanders, which immediately led to a voluntary recall by Allergan among the remaining countries worldwide. The past two decades have been marked by a transition from limited case reports of a novel periprosthetic T-cell lymphoma to our current understanding and recognition of BIA-ALCL. Several evolving concepts have helped to define current risk of disease development, diagnostic tools, therapeutic strategies, and outcomes of BIA-ALCL and are the focus of this chapter.

Lymphoma background

Lymphoma is a cancer of the immune system developing from lymphocytes and is the most common malignancy of the blood. Lymphoma broadly includes Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), and a variety of lymphoproliferative disorders. In the USA, approximately 65,000 cases of NHL were diagnosed in 2010. Stein and colleagues first described ALCL in 1985 as a novel type of NHL characterized by large anaplastic lymphoid cells that express the cell surface protein CD30. Estimated incidence of T-cell NHL diagnoses in the USA in 2014 was 17,302. This included 1982 cases of ALCL, 758 of which occurred in females.

ALCL was added as a distinct entity to the Kiel classification in 1988 and to the Revised European-American Lymphoma (REAL) classification in 1994. The WHO classification of lymphomas recognized the disease in 2001 and further delineated variants in their updated 2008 classification. NHL prognosis is determined using the International Prognostic Index (IPI) based upon presence of recognized risk factors such as the Ann Arbor staging system, advanced age, elevated serum lactate dehydrogenase (LDH), poor performance status, and increased number of extranodal sites of disease. Clinicopathologic subtypes of ALCL include a spectrum of diseases from the more aggressive systemic ALCL down to the indolent CD30 positive lymphoproliferative disorders of the skin that include a benign lymphomatoid papulosis and sometimes the indolent primary cutaneous ALCL (pcALCL) (5-year OS [overall survival] > 90–95%, lymph node metastases 5%). Multiple sites of disease, frequent lymphadenopathy, and wide dissemination characterize systemic ALCL. Systemic ALCL is further classified by either the expression or absence of the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor gene translocation. ALK is most commonly expressed as a result of the t(2;5) translocation involving the 2p23 and the 5q35 chromosomes that create an oncogenic fusion protein of the ALK gene and the nucleophosmin gene. ALK+ ALCL accounts for approximately 50–80% of all ALCLs, occurs most commonly in males (male/female ratio: 6.5:1) under the age of 30 years, and has a 5-year OS by IPI point value of 0/1: 90%, 2: 68%, 3: 33%, 4/5: 23%. In contrast, ALK− ALCL is an immunophenotypically and cytogenetically heterogeneous group and has a 5-year OS by IPI points value of 0/1: 74%, 2: 62%, 3: 31%, 4/5: 13%. When treated with chemotherapy, ALK+ ALCL has a higher overall 5-year survival rate than systemic ALK− ALCL (58% vs. 34%, respectively).

BIA-ALCL is distinct from primary breast lymphoma (PBL), which is a disease of the breast parenchyma, representing 0.04–0.5% of breast cancers and 1–2% of all lymphomas. PBL is predominantly a B-cell lymphoma (65–90%), while BIA-ALCL is purely a T-cell lymphoma arising either in an effusion and/or scar capsule surrounding a breast implant. All confirmed reported cases of BIA-ALCL are ALK− and express the CD30 cell surface protein ( Box 11.1 , Figs. 11.1A,B & 11.2 ). Most cases are diagnosed during implant revision surgery performed for a late-onset (>1 year) persistent seroma and may be associated with symptoms of pain, breast lumps, swelling, or breast asymmetry. The number of BIA-ALCL cases reported in primary augmentation and reconstruction for breast cancer or prophylaxis are nearly equivalent. BIA-ALCL most commonly follows an indolent course provided there is adequate surgical ablation of the implant and surrounding capsule without systemic therapy; however, the disease may be aggressive in some patients, and disease progression and death do occur without proper treatment.

The few cases of BIA-ALCL in the literature in patients with smooth implants have been associated with a prior history of textured breast device, or absent history. At the second World Consensus Conference on BIA-ALCL ( www.biaalclconference.com ), Dr. Binita Ashar, the US FDA director of the Division of Surgical Devices, clarified, “We have received a report of a smooth implant and ALCL that has no history of a textured implant. We are asked by many if this is a pure smooth case. No, we cannot confirm this is a pure smooth case. We cannot verify at this time”. The FDA cautions that reports from their adverse event database are potentially “incomplete, inaccurate, untimely, unverified, or biased data”. No cases have been reported in case reports, case series, or registries worldwide with a clinical history of only smooth surface devices. As BIA-ALCL arises in patients with saline- or silicone-filled implants, but not in smooth implants, textures shell surface rather than implant contents appears to be the essential driver in pathogenesis.

BIA-ALCL pathogenesis

It is likely that there are multiple factors that contribute to lymphogenesis in BIA-ALCL. The process necessary for triggering transformation is complex with contributions from initiators of chronic inflammation, subsequent dysregulation of multiple pathways in the adaptive and innate immune system and patient genetic susceptibility. What is clear is that this process does take time, an average of 7–8 years following initial placement of the breast implant.

Inflammation is becoming increasingly recognized as a driver for disease, especially through an exaggerated and pathologic immune response. The quadrat of fibrosis, allergy, autoimmune disease and lymphoma are all end products of unchecked chronic and exaggerated activation of immune response. A number of triggers of inflammation have been proposed as potentially pathogenic in BIA-ALCL, including mechanical friction of textured implants, silicone implant particulates, leachables and bacterial biofilm.