Breast Implant Associated Anaplastic Large Cell Lymphoma: overview and management recommendations based on a series of 18 UK cases

This month, in the European Journal of Surgical Oncology, L. Johnson from St. Bartholomew’s Hospital, London, UK, and colleagues published a report on the multi-disciplinary management of a UK series of Breast Implant Associated Anaplastic Large-Cell Lymphoma (BIA-ALCL) and how the stage of disease can be used to guide treatment strategy.¹

BIA-ALCL overview:

BIA-ALCL is a rare Non-Hodgkin Lymphoma of T-cell origin that occurs in the capsule of breast implants and has been given its own designation by the World Health Organization (WHO).² It presents as a recurrent effusion in 80% of cases or a solid capsule-related mass in the remaining 20% of cases; diagnosis is achieved by identification of abnormal cells in an aspirate/biopsy that are CD30⁺ and ALK^–.^1,3 A new BIA-ALCL specific staging system states that stage I disease remains confined to the effusion or a layer on the luminal side of the capsule and can be treated adequately with implant removal and total capsulectomy (surgical removal of scar tissue or capsule that has become thickened and hardened around a breast implant). Treatment of stage II (locally advanced) and stage III/IV disease (regional and distant spread) may involve adjuvant therapies.^1,4 It has been reported that the median time from time of implant to ALCL presentation is approximately 10 years, and silicone- as well as saline-filled implants have been implicated.⁵

The first ever case was reported in 1997, and the U.S. Food and Drug Administration (FDA) identified the possible association between implants and the development of ALCL in 2011. The rate of diagnosis is rising, possibly due to increased implant use or growing awareness of this rare complication. The exact number of cases and incidence is difficult to ascertain due to limitations in world-wide reporting and a deficit in global implant sales data;^1,6 Daphne de Jong et al. estimate incidence in The Netherlands to be 1–3 cases per 1 million breast implants per year.⁷ More robust epidemiological studies are needed and thus far the etiology of the disease is unknown. So far, the majority of data appears to indicate that BIA-ALCL is more common after the insertion of implants with textured surfaces compared to those with smooth surfaces.⁶

In the UK, it is obligatory to report all confirmed cases to the Medicines and Healthcare Products Regulatory Agency (MHRA). In the US, The Plastic Surgery Foundation (PSF), in partnership with the American Society of Plastic Surgeons (ASPS) and the FDA, are building a BIA-ALCL-specific database (PROFILE registry) for the collection and follow-up of worldwide cases; it is strongly recommended that confirmed cases are submitted to the registry, only upon patient consent.¹

UK patient series:

So far, in the UK there have been 23 reported cases of BIA-ALCL. In the retrospective publication by Johnson et al., they report a series of 18 BIA-ALCL cases that were diagnosed between 2012 and 2016 at 15 different UK centers.¹

Key Highlights:

• Median age at diagnosis = 52 years (range, 29–73)
• Mean lead-time from implant placement to diagnosis = 10 years (range, 3–16)
• Seven pts were diagnosed with BIA-ALCL 1–3 years after initial symptomatic presentation with effusion; of these, 6 had capsule-confined (stage I) disease at eventual diagnosis
• Ten pts were diagnosed pre-operatively: Fine Needle Aspiration (FNA) of effusion fluid (n=5), Needle Core Biopsy (NCB) of the presenting mass (n=3), capsule biopsy alone (n=1), and combination of capsule biopsy and FNA (n=1)
• Three pts were diagnosed following surgery

Stage I disease:

• Fifteen pts; presented with recurrent, large volume effusion
• Treated successfully with implant removal and total capsulectomy
• Mean follow-up = 21 months (to February 2017)
• Two pts had previously been administered breast cancer related adjuvant chemotherapy, chest wall radiotherapy, and endocrine therapy with tamoxifen
• Seven patients still had their initial implants in situ at the time of diagnosis of BIA-ALCL

Stage II disease:

• Three pts presented with stage IIA disease:
  • First patient - presented with a mass 2 months after surgery, BIA-ALCL confirmed on biopsy. Was entered into the ECHELON 2 trial (CHOP vs brentuximab vedotin plus CHOP; NCT01777152), her treatment remains blinded, but achieved complete clinical and radiological (PET-CT) response. Treated with further adjuvant radiotherapy to chest wall
  • Second patient - developed a mass at drain site, BIA-ALCL confirmed on biopsy; underwent wide local excision of mass with adjuvant CHOP and radiotherapy. Currently “remains well with no evidence of recurrence at 4-years post-treatment”
  • Third patient - presented with isolated mass adjacent to implant on anterior chest wall, BIA-ALCL confirmed on biopsy. Underwent 3 cycles of CHOP and progressed rapidly developing life-threatening chest wall/thoracic cavity involvement. A trial of neoadjuvant brentuximab vedotin was started, patient achieved complete clinical and radiological response after 6 cycles and bilateral total capsulectomy and implant removal was carried out, confirming pathological complete response
• To date, all pts have been followed-up with PET-CT and remain disease free

The authors elaborated that cases did not seem to cluster around a specific unit or geographical location, and so hypothesized that local factors may not affect BIA-ALCL development. The group also speculate that the delays in diagnosis of 7 patients in their series are probably due to lack of awareness. They state that their report makes up “part of a wider strategy to raise awareness through education and better information.”

Traditionally, Ann Arbour classification is used to stage ALCL, which the authors point out could potentially result in over-staging and treatment of more localized BIA-ALCL cases; the new BIA-ALCL specific staging system⁴ differentiates very low risk patients (localized intra-luminal disease) from higher risk patients (extra-luminal disease or masses) who appear to benefit from more aggressive systemic treatment. The group state that their findings support this new staging system.

The group recommend that confirmed cases should be managed in specialist tertiary centers, which have the appropriate knowledge and experience in managing BIA-ALCL. The group go on to express that “this will permit consolidation of clinical and research resources and will lead to a better understanding of lymphomagenesis in this context”.

The authors state that more prospective, national, observational studies are required in order to accumulate more complete data. They emphasize the relevance and importance of registries and consenting patients for inclusion. These databases will aid our understanding on the use of implants as well as the subsequent monitoring and collation of long-term after-effects that takes place.

Lastly, the group concludes that, although there is a very low risk of developing BIA-ALCL, “it is nevertheless our duty to inform any patient receiving a breast implant that there is a risk.”

Abstract:

BACKGROUND: Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare, Non-Hodgkin lymphoma arising in the capsule of breast implants. BIA-ALCL presents as a recurrent effusion and/or mass. Tumours exhibit CD30 expression and are negative for Anaplastic Lymphoma Kinase (ALK). We report the multi-disciplinary management of the UK series and how the stage of disease may be used to stratify treatment.

METHODS: Between 2012 and 2016, 23 cases of BIA-ALCL were diagnosed in 15 regional centres throughout the UK. Data on breast implant surgeries, clinical features, treatment and follow-up were available for 18 patients.

RESULTS: The mean lead-time from initial implant insertion to diagnosis was 10 years (range: 3-16). All cases were observed in patients with textured breast implants or expanders. Fifteen patients with breast implants presented with stage I disease (capsule confined), and were treated with implant removal and capsulectomy. One patient received adjuvant chest-wall radiotherapy. Three patients presented with extra-capsular masses (stage IIA). In addition to explantation, capsulectomy and excision of the mass, all patients received neo-/adjuvant chemotherapy with CHOP as first line. One patient progressed on CHOP but achieved pathological complete response (pCR) with Brentuximab Vedotin. After a mean follow-up of 23 months (range: 1-56) all patients reported here remain disease-free.

DISCUSSION: BIA-ALCL is a rare neoplasm with a good prognosis. Our data support the recommendation that stage I disease be managed with surgery alone. Adjuvant chemotherapy may be required for more invasive disease and our experience has shown the efficacy of Brentuximab as a second line treatment.