UK Guidelines on the Diagnosis and Treatment of Breast ImplantAssociated Anaplastic Large Cell Lymphoma on behalf of the Medicines and Healthcare products Regulatory Agency Plastic, Reconstructive and Aesthetic Surgery Expert Advisory Group

 [bib_ref] Our experiences with the silastic gel breast prosthesis, Cronin [/bib_ref] [bib_ref] Breast implants and the risk of anaplastic large-cell lymphoma in the breast, De Boer [/bib_ref] [bib_ref] Safety of Silicone Breast Implants, Bondurant [/bib_ref] [bib_ref] Anaplastic T-cell lymphoma in proximity to a saline-filled breast implant, Keech [/bib_ref] [bib_ref] Primary breast lymphoma in a patient with silicone breast implants: a case..., Newman [/bib_ref] [bib_ref] Primary Breast Lymphoma in the United States: 1975-2013, Thomas [/bib_ref] [bib_ref] The lifetime risk of developing breast cancer, Feuer [/bib_ref] [bib_ref] Anaplastic large cell lymphoma occurring in women with breast implants: analysis of..., Brody [/bib_ref] [bib_ref] Anaplastic large cell lymphoma occurring in women with breast implants: analysis of..., Brody [/bib_ref] [bib_ref] The 2016 revision of the World Health Organization classification of lymphoid neoplasms, Swerdlow [/bib_ref] [bib_ref] Breast implant associated anaplastic large cell lymphoma: the UK experience. Recommendations on..., Johnson [/bib_ref] [bib_ref] Epidemiology of breast implant-associated anaplastic large cell lymphoma, Doren [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma: a systematic review, Leberfinger [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma in Australia and New Zealand: high-surface-area..., Loch-Wilkinson [/bib_ref] [bib_ref] Breast implants and the risk of anaplastic large-cell lymphoma in the breast, De Boer [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma in Australia and New Zealand: high-surface-area..., Loch-Wilkinson [/bib_ref] [bib_ref] Global adverse event reports of breast implant-associated ALCL: an International Review of..., Srinivasa [/bib_ref] [bib_ref] Risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) in a cohort..., Ghione [/bib_ref] [bib_ref] Risk of breast implant associated anaplastic large cell lymphoma (BIA-ALCL) in a..., Cordeiro [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma in Australia: a longitudinal study of..., Loch-Wilkinson [/bib_ref] [bib_ref] Risk of breast implant associated anaplastic large cell lymphoma in a cohort..., Mercer [/bib_ref] [bib_ref] Epidemiology of breast implant-associated anaplastic large cell lymphoma, Doren [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma: a systematic review, Leberfinger [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma in Australia and New Zealand: high-surface-area..., Loch-Wilkinson [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma in Australia: a longitudinal study of..., Loch-Wilkinson [/bib_ref] [bib_ref] NCCN Consensus Guidelines for the Diagnosis and Management of Breast Implant-Associated Anaplastic..., Clemens [/bib_ref] [bib_ref] NCCN Consensus Guidelines on the Diagnosis and Treatment of Breast Implant-Associated Anaplastic..., Clemens [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): an overview of presentation and..., Jones [/bib_ref] 

## Implant monitoring
In the UK, routine radiological surveillance to assess implant health is not recommended within the NHS or private sector. [bib_ref] Breast imaging for aesthetic surgery: British Society of Breast Radiology (BSBR), Association..., Lowes [/bib_ref] Any additional breast imaging is usually symptom-driven by patient/surgeon concern or following clinical review.
In order to monitor and improve patient safety, a Breast and Cosmetic Implant Registry (BCIR) was introduced in the UK in October 2016, recording the implants that have been used for patients and the organisations and surgeons that have carried out the procedures. The registry aims to provide the data needed to detect any early safety signals in relation to an implant and provide a mechanism for managing patients in the event of an implant recall. All providers of breast implant surgery are expected to participate.Referral for breast assessment Patients with implants who develop breast symptoms may initially present to their general practitioner (GP) or the private surgeon/clinic. In the absence of private medical insurance, the cumulative cost of consultations and investigation in the independent sector can be prohibitive such that anyone with a breast symptom and a breast implant should be referred to the local NHS symptomatic breast clinic irrespective of the initial pathway for implant surgery, as long as they meet the NHS UK residency eligibility criteria. This will improve the quality of assessment, have no self-funding implications and should reduce the risk of missed or late diagnosis.
Patients without breast symptoms but concerned about BIA-ALCL and/or their breast implant health can be reassured by their GP or private breast surgeon/clinic and directed to the MHRA website. 13

## Clinical presentation and investigation
Symptoms and signs BIA-ALCL presents at a median of 8-10 years following reconstructive or cosmetic breast implantation. Early occurrence has been reported and the diagnosis should therefore be considered in any cases where implants have been in situ for longer than 12 months. [bib_ref] Anaplastic large cell lymphoma occurring in women with breast implants: analysis of..., Brody [/bib_ref] [bib_ref] Breast implant associated anaplastic large cell lymphoma: the UK experience. Recommendations on..., Johnson [/bib_ref] [bib_ref] NCCN Consensus Guidelines on the Diagnosis and Treatment of Breast Implant-Associated Anaplastic..., Clemens [/bib_ref] [bib_ref] Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients, Miranda [/bib_ref] [bib_ref] Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma..., Mccarthy [/bib_ref] The lymphoma develops from the luminal aspect of the peri-implant capsule (85%), commonly precipitating the rapid development of a periprosthetic effusion, resulting in distortion to the breast including breast swelling or new-onset breast asymmetry. While commonly only one breast is affected, rare bilateral cases have been reported. [bib_ref] Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma..., Mccarthy [/bib_ref] [bib_ref] Complete surgical excision is essential for the management of patients with breast..., Clemens [/bib_ref] Less commonly (15%) presentation is with a palpable mass, or a combination of effusion and mass. [bib_ref] Breast implant associated anaplastic large cell lymphoma: the UK experience. Recommendations on..., Johnson [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma: a systematic review, Leberfinger [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma in Australia and New Zealand: high-surface-area..., Loch-Wilkinson [/bib_ref] [bib_ref] Global adverse event reports of breast implant-associated ALCL: an International Review of..., Srinivasa [/bib_ref] [bib_ref] Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma..., Mccarthy [/bib_ref] More subtle presentations may occur that are difficult to identify, particularly in the presence of pre-existing breast asymmetry [fig_ref] Fig 1: Examples of clinical presentations of implant-associated breast effusion due to breast implant-associated... [/fig_ref].
Approximately one third of patients report pain and additional signs such as erythaema (14%), or skin lesions/ulceration (8%), [bib_ref] Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients, Miranda [/bib_ref] [bib_ref] Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma..., Mccarthy [/bib_ref] [fig_ref] Fig 1: Examples of clinical presentations of implant-associated breast effusion due to breast implant-associated... [/fig_ref]. In a small proportion of cases, local dissemination presents with ipsilateral axillary, supraclavicular, internal mammary chain or mediastinal lymphadenopathy. In 9% of cases, systemic 'B' symptoms consisting of unexplained weight loss, fevers or night sweats, are observed. [bib_ref] Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma..., Mccarthy [/bib_ref] BIA-ALCL may occasionally be an incidental Guideline finding on routine histology after capsulectomy for capsular contraction or implant rupture. [bib_ref] Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients, Miranda [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma: Sensitivity, specificity, and findings of imaging..., Adrada [/bib_ref] There are important differentials to consider in presentations of both the 'effusion-only' and 'mass-forming' subtypes of BIA-ALCL. Late seroma is a rare and usually benign complication that affects up to 0A1% of all breast implant procedures. [bib_ref] Risk Factor Analysis for Capsular Contracture, Malposition, and Late Seroma in Subjects..., Mcguire [/bib_ref] [bib_ref] Seroma as a late complication after breast augmentation, Pinchuk [/bib_ref] Despite the broad range of causes (silicone bleed, trauma, infection, idiopathic, haematoma, BIA-ALCL and implant rupture), up to 10% of cases may be attributable to BIA-ALCL. In the assessment of patients presenting with a mass-forming lesion or lymphadenopathy, important differentials include reactions to silicone, primary breast cancer, other lymphoma subtypes, sarcoma and metastases from other primary malignancies such as melanoma; all occur at a significantly greater frequency than BIA-ALCL. In contrast to other lymphomas involving the breast, breast cancer or benign lesions of the breast, the parenchyma is usually not involved in BIA-ALCL except in cases where the malignancy extends through the implant capsule into the surrounding tissue. Skin lesions in isolation may represent primary cutaneous ALCL, rather than BIA-ALCL.

## Initial assessment
Investigation for a diagnosis of BIA-ALCL should be conducted in clinical units equipped with the necessary diagnostic expertise and should follow the proposed UK guidelines diagnostic algorithm [fig_ref] Fig 2: The UK Diagnostic algorithm for the assessment of new clinical signs in... [/fig_ref] , based on the principle of triple assessment: clinical examination, imaging and biopsy.
A detailed medical history should be taken that includes the patient's family history of cancer as this may prompt a genetics referral in accordance with the updated National Institute for Health and Care Excellence (NICE) guidelines on familial breast cancer (CG164).Of note, some cases of BIA-ALCL have been linked to Li Fraumeni Syndrome [bib_ref] Increasing evidence for the association of breast implant-associated anaplastic large cell lymphoma..., Adlard [/bib_ref] and BRCA gene mutations, [bib_ref] Breast implants and the risk of anaplastic large-cell lymphoma in the breast, De Boer [/bib_ref] [bib_ref] Increased prevalence of BRCA1/2 mutations in women with macro-textured breast implants and..., Boer [/bib_ref] and whether a genetic predisposition for breast cancer is similarly a risk factor for BIA-ALCL is as yet unanswered and needs further investigation to clarify the risk. At present, patients diagnosed with BIA-ALCL are not eligible for genetic testing under NHS commissioning guidelines unless the standard family history criteria are met.Radiology in BIA-ALCL Imaging for BIA-ALCL can be challenging, due to its unique biology and frequently non-specific appearance. [bib_ref] Breast implant-associated anaplastic large cell lymphoma: Sensitivity, specificity, and findings of imaging..., Adrada [/bib_ref] It is important that those performing breast imaging and clinicians should consider the diagnosis of BIA-ALCL in the appropriate setting.

## Ultrasound (us)
US is the initial investigation of choice to assess pain, swelling or a mass related to a breast implant. [bib_ref] NCCN Consensus Guidelines on the Diagnosis and Treatment of Breast Implant-Associated Anaplastic..., Clemens [/bib_ref] [bib_ref] Managing late periprosthetic fluid collections (Seroma) in patients with breast implants: a..., Bengtson [/bib_ref] It has a sensitivity of over 80% for detecting a peri-implant collection, with a specificity of less than 50% in elucidating the underlying cause. [bib_ref] Breast implant-associated anaplastic large cell lymphoma: Sensitivity, specificity, and findings of imaging..., Adrada [/bib_ref] US should include assessment for axillary lymphadenopathy and evaluation of the contralateral implant, where present.
US evaluation is operator dependent. The image should be optimised to evaluate the implant membrane, capsule and material contents along with the adjacent breast parenchyma. The entire implant should be integrated in the field of view. A high frequency [bib_ref] Primary breast lymphoma in a patient with silicone breast implants: a case..., Newman [/bib_ref] [bib_ref] Primary Breast Lymphoma in the United States: 1975-2013, Thomas [/bib_ref] [bib_ref] The lifetime risk of developing breast cancer, Feuer [/bib_ref] [bib_ref] Anaplastic large cell lymphoma occurring in women with breast implants: analysis of..., Brody [/bib_ref] MHz) linear array probe should be used to delineate the membrane and capsule. [bib_ref] Multimodality imaging-based evaluation of single-lumen silicone breast implants for rupture, Seiler [/bib_ref] Knowledge of implant type greatly assists assessment and will avoid potential misinterpretation. The appearance of dual lumen implants can mimic peri-implant effusions and intracapsular leaks. A small volume of fluid (< 10 ml) around an implant is often seen as a normal incidental finding and in an asymptomatic patient does not warrant further investigation. [bib_ref] NCCN Consensus Guidelines on the Diagnosis and Treatment of Breast Implant-Associated Anaplastic..., Clemens [/bib_ref] [bib_ref] Multimodality imaging-based evaluation of single-lumen silicone breast implants for rupture, Seiler [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma: review and multiparametric imaging paradigms, Sharma [/bib_ref]. Effusions associated with BIA-ALCL are usually homogeneous [fig_ref] Fig 3: Ultrasound [/fig_ref] with inflammatory features in the periprosthetic breast tissue and in some cases a thickened irregular capsule. Masses can also be observed and may be solid or mixed cystic/solid and are usually ovoid [fig_ref] Fig 3: Ultrasound [/fig_ref].

## Mammography
If the patient is over 40 years of age, mammography should also be undertaken. Mammography has a low sensitivity and specificity for BIA-ALCL, but it may be used to assess for any potential mimics/masses and other diagnoses including in situ and invasive primary breast malignancy. In cases of BIA-ALCL, the capsule may be thickened and the membrane contour may be disrupted. [bib_ref] Breast implant-associated anaplastic large cell lymphoma: Sensitivity, specificity, and findings of imaging..., Adrada [/bib_ref] 

## Magnetic resonance (mr) imaging
In cases of diagnostic uncertainty or inconclusive US, MR imaging should be undertaken to assess the implant, effusion, capsule and for any potential mass and local lymphadenopathy. When the diagnosis has been established from the initial US fine-needle aspiration (FNA) or core biopsy, MR imaging should be performed to assess disease extent and aid surgical planning. Non-contrast sequences (T2-weighted and siliconeselective) may show implant membrane disruption (rupture), pericapsular effusions and signs of gel bleed [fig_ref] Fig 3: Ultrasound [/fig_ref]. In addition, dynamic contrast-enhanced (DCE) sequences should be utilised to assess for capsular enhancement [fig_ref] Fig 3: Ultrasound [/fig_ref] and masses which may not have been detected on US. [bib_ref] Breast implantassociated Anaplastic large cell lymphoma (BIA-ALCL): Imaging findings, Fernandez [/bib_ref] 

## Fdg pet/ct
2-[Fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG PET/CT) plays an important role in the oncological staging of the majority of subtypes of lymphoma, although BIA-ALCL was recognised subsequent to the most recent Lugano Classification Guidelines and so the utility of FDG PET/CT in this context has yet to be formally validated. [bib_ref] Role of imaging in the staging and response assessment of lymphoma: consensus..., Barrington [/bib_ref] be undertaken for pre-operative staging of local extent and distant disease .Carrying out PET/CT prior to the surgical intervention is necessary because post-surgical inflammation in the chest wall, surrounding breast and regional nodes, may at times persist for a few months and hinder the identification of the uncommon patients that have extracapsular or nodal involvement. PET/CT is also required for response assessment (pre or post-surgery), where systemic therapy has been administered . [bib_ref] NCCN Consensus Guidelines on the Diagnosis and Treatment of Breast Implant-Associated Anaplastic..., Clemens [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma: Sensitivity, specificity, and findings of imaging..., Adrada [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma: review and multiparametric imaging paradigms, Sharma [/bib_ref] Evaluation of peri-implant effusion and/or mass lesions
Where an effusion is present, the key to diagnosis of BIA-ALCL is FNA of the entire volume of peri-implant fluid for initial cytology and then secondary assessment where indicated (please see the subsequent section on preparation for pathology), and/or 14-gauge core biopsy of any associated capsular mass or pathological node as per the diagnostic algorithm presented in [fig_ref] Fig 2: The UK Diagnostic algorithm for the assessment of new clinical signs in... [/fig_ref] If capsular nodular lesions detected on imaging are not amenable to core biopsy, open surgical excision or repeat interval imaging should be considered.
The chance of an accurate diagnosis is greatest on the initial peri-implant aspirate, and small-volume aspiration or subsequent repeat aspiration(s) are associated with greater false-negative cytology, due to a dilution effect. [bib_ref] Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): an overview of presentation and..., Jones [/bib_ref] The main sample is sent as three separate specimens with these suggested volumes: Haematological Malignancy Diagnostic Service (HMDS), 10 cc in two purple-top EDTA tubes; microbiology, 5-10 cc in a white-capped sterile universal container; cytology should receive the entire remaining volume (at least 50 cc but can be over 500 cc), sent in multiple standard universal containers.
Local pathways must be established to ensure the correct handling and timely assessment of specimens and the request forms must clearly state concerns for a diagnosis of BIA-ALCL. It is prudent to alert the lab to prevent a delay in analysis. The cytology department should be advised that the entire effusion sample is to be analysed.
[formula] (A) (B) (C) (D) (E) [/formula]

## Primary histopathological assessment
We recommend that the evaluation of peri-implant associated effusions and tissue masses is conducted as a two-stage process where the primary assessment is morphological. Tumour cells may be found in both the fluid and the capsule mass (where both are present) but may be seen in only one or the other. 14,24 Cells within fluid samples are collected by centrifugation to produce cytospins which are stained according to local preferences [fig_ref] Fig 5: Cytology [/fig_ref]. The cells in the remaining fluid should also be collected by centrifugation to improve the diagnostic yield. The cells should be fixed with liquid preservative, subject to centrifugation and processed to create cytoblocks for immunohistochemistry. The characteristic morphological abnormalities seen on standard cytology are regarded as a gold standard pre-requisite for a diagnosis of BIA-ALCL [fig_ref] Fig 5: Cytology [/fig_ref]. [bib_ref] Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): an overview of presentation and..., Jones [/bib_ref] [bib_ref] Cytological diagnostic features of late breast implant seromas: from reactive to anaplastic..., Napoli [/bib_ref] This primary assessment should be conducted first; acellular samples and those composed entirely of bland inflammatory cells can be reported as negative and do not require further analysis. [bib_ref] Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): an overview of presentation and..., Jones [/bib_ref] While the vast majority of peri-implant effusions are not related to ALCL, patients should be made aware of the limitations of diagnostic testing and the possibility of false negative results, given cytologic assessment to detect BIA-ALCL has a sensitivity of about 78%. [bib_ref] Breast implant-associated anaplastic large cell lymphoma: Sensitivity, specificity, and findings of imaging..., Adrada [/bib_ref] If clinical or radiological suspicions remain after negative cytology, multidisciplinary team (MDT) discussion and referral to a tertiary centre are recommended. Secondary assessment of cytospins/cytoblocks may also be conducted as described below. In the absence of suspicion, patients should be followed up at three months to ensure that the swelling does not recur. Patients should be advised to report any symptoms that return.
[formula] (B) (A) (D) (E) (C) (F) [/formula]

## Pre-treatment post-treatment

## Secondary assessment
All diagnoses of BIA-ALCL should be reviewed by a haematopathologist within a specialist integrated HMDS, as per NICE guidelines.Where BIA-ALCL is suspected morphologically, further analysis is performed by immunohistochemistry using markers to confirm the haematopoietic origin of the cells: CD45; T-cell markers: for example, CD2, CD3, CD4, CD5, CD7 and CD8; cytotoxic markers: for example, TIA1 and Granzyme B; other markers: anaplastic lymphoma kinase (Alk-1) which by definition should be negative, CD30 which should be positive; and a B-cell panel: for example, CD20, CD79a, PAX5 and EBER to exclude the rare cases of fibrin-associated diffuse large B-cell lymphoma (DLBCL) as these can display aberrant expression of CD30 and other T-cell markers. [bib_ref] Breast implant-associated EBV-positive large B-cell lymphomas: report of three cases, Rodriguez-Pinilla [/bib_ref] Other markers such as CD68, CD138, BCL-2, IRF4, Ki67 and pan-keratin may also be useful. It can be difficult to define an aberrant/neoplastic T-cell phenotype as the tumour cells often lack expression of T-cell antigens, and CD30 expression alone is not a defining feature as it is also present on normal activated T-, B-and natural killer cells. [bib_ref] Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): an overview of presentation and..., Jones [/bib_ref] [bib_ref] Cytological diagnostic features of late breast implant seromas: from reactive to anaplastic..., Napoli [/bib_ref] [bib_ref] Regulation of CD30 antigen expression and its potential significance for human disease, Kadin [/bib_ref] For this reason, screening of effusion fluid for CD30-positive cells by flow cytometry in the absence of morphological abnormalities on cytology may lead to difficulties in interpretation and a false-positive diagnosis. [bib_ref] Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): an overview of presentation and..., Jones [/bib_ref] The clonality of T cells should be confirmed by polymerase chain reaction (PCR) for T-cell receptor (TR) gene rearrangements. 51,52 FISH can be used to assess the absence of the ALK translocation and to exclude other translocations seen in a proportion of systemic ALCL but not BIA-ALCL such as those involving IRF4/DUSP22 and TP63. While not part of the diagnostic algorithm, numerous recurrent mutations have been detected in BIA-ALCL. The most frequently reported are mutations that involve the JAK-STAT pathway genes such as JAK1 and STAT3 mutations and epigenetic modifiers, for example DNMT3A. [bib_ref] Frequent activating STAT3 mutations and novel recurrent genomic abnormalities detected in breast..., Blombery [/bib_ref] [bib_ref] Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast..., Laurent [/bib_ref] [bib_ref] Genetic subtyping of breast implant-associated anaplastic large cell lymphoma, Oishi [/bib_ref] [bib_ref] Dual JAK1 and STAT3 mutations in a breast implant-associated anaplastic large cell..., Letourneau [/bib_ref] [bib_ref] Targeted next generation sequencing of breast implant-associated anaplastic large cell lymphoma reveals..., Napoli [/bib_ref] Processing samples for research purposes
Hypotheses proposed regarding the pathogenesis of BIA-ALCL include chronic inflammation driven by a bacterial biofilm, microparticles shed from the implant shell, repetitive trauma/friction between the implant shell and the capsule, carcinogenic toxins leaching from the implant or genetic predisposition. [bib_ref] Increasing evidence for the association of breast implant-associated anaplastic large cell lymphoma..., Adlard [/bib_ref] [bib_ref] Increased prevalence of BRCA1/2 mutations in women with macro-textured breast implants and..., Boer [/bib_ref] [bib_ref] Frequent activating STAT3 mutations and novel recurrent genomic abnormalities detected in breast..., Blombery [/bib_ref] [bib_ref] Cell of Origin and Immunologic events in the pathogenesis of breast implant-associated..., Turner [/bib_ref] [bib_ref] The Cellular Origins of Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL): implications..., Turner [/bib_ref] [bib_ref] Whole exome sequencing reveals activating JAK1 and STAT3 mutations in breast implant-associated..., Blombery [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma in a Li-FRAUMENI patient: a case..., Pastorello [/bib_ref] [bib_ref] Challenging perspectives on the cellular origins of lymphoma, Malcolm [/bib_ref] [bib_ref] IL-13 is produced by tumor cells in breast implant-associated anaplastic large cell..., Kadin [/bib_ref] [bib_ref] Commentary on: a case report of a breast implant-associated plasmacytoma and literature..., Kadin [/bib_ref] Details of ongoing active UK research studies can be found here: https://www.cancerresearchuk.org/ about-cancer/find-a-clinical-trial/a-study-find-more-about-ca uses-breast-implant-associated-anaplastic-large-cell-lym phoma-bia-alcl, and clinicians are encouraged to contact the investigators for further details. It is hoped that in the future, a centralised biobank of samples for research purposes can be developed.

## Management of an indeterminate breast assessment: reactive effusions
Approximately 90% of chronic delayed seromas are clear or haemo-serous, have no atypical cells and are not associated with malignancy. However, as a paucity of neoplastic cells can make diagnosis difficult (hence, the requirement to assess the whole seroma by cytologysee above), clinicians must always exercise caution when faced with a reactive seroma report in case of a false-negative result. If reasonable suspicion persists, consider the following options: referral to a tertiary centre with expertise in the diagnosis and management of BIA-ALCL, MDT discussion, repeat assessment with US and further aspiration for cytology, additional imaging with magnetic resonance imaging (MRI), diagnostic total en-bloc capsulectomy and explantation, or close monitoring. The pros and cons of each approach need careful case-by-case consideration, with shared decision-making, taking into account the degree of concern, differential diagnosis and the morbidity from interventions such as total en-bloc capsulectomy. This includes pneumothorax in up to 4% of cases, a possibility of chronic pain and significant cosmetic sequelae.

## Management of confirmed cases
The optimal approach to patient treatment is based on the revised National Comprehensive Cancer Network (NCCN) guidelines and evolving experience from treated cases. [bib_ref] NCCN Consensus Guidelines on the Diagnosis and Treatment of Breast Implant-Associated Anaplastic..., Clemens [/bib_ref] [bib_ref] Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients, Miranda [/bib_ref] All confirmed BIA-ALCL patients must be referred to a tertiary centre for their further management. A proposed treatment algorithm is shown in Cases must always be recorded in the BCIR (https://clinica laudit.hscic.gov.uk) and reported to the MHRA using the yellow-card scheme for a medical device adverse incident (https://yellowcard.mhra.gov.uk/). After central registration of the case, clinicians will be contacted for further information. They must respond promptly and maintain up-to-date contact information for this process. The implant manufacturer has a regulatory duty to report device failures or adverse incidents to the regulatory authority. They should be contacted to collect and analyse the implant after removal and provide any findings in their Vigilance report.

## Pre-operative investigations
Discussion of cases of BIA-ALCL must occur in the MDT meeting prior to any intervention. We advocate this due to the crucial requirement for shared management of these patients between haemato-oncology and breast surgery, therefore early collaboration is likely to improve patient outcomes. All imaging results including PET/CT and breast MRI should be reviewed. Routine pre-operative blood tests include: full blood count (FBC), urea and electrolytes (U&E), Liver function tests (LFTs), lactate dehydrogenase (LDH) and virology. Bone marrow aspiration and trephine to assess for the presence of marrow disease is recommended prior to surgery in all cases of BIA-ALCL where the disease is aggressive, defined as local-regional or distant lymph node involvement or unexplained cytopenia. [bib_ref] NCCN Consensus Guidelines on the Diagnosis and Treatment of Breast Implant-Associated Anaplastic..., Clemens [/bib_ref] [bib_ref] Complete surgical excision is essential for the management of patients with breast..., Clemens [/bib_ref] Explantation with total en-bloc capsulectomy Surgery is the recommended primary treatment for all patients with BIA-ALCL, except the minority who present with locally advanced or distant metastatic disease who may benefit from initial systemic therapy. Surgery should be performed by an experienced member of the oncoplastic breast or plastic surgery team, familiar with performing implant-Guideline based surgery and with additional expertise in capsulectomy and tumour extirpation.
Early BIA-ALCL is confined to the peri-implant effusion or contained within the capsule [fig_ref] Fig 1: Examples of clinical presentations of implant-associated breast effusion due to breast implant-associated... [/fig_ref]. Total enbloc surgical excision plays a pivotal role in reducing stage progression, future recurrence and to improve overall survival (OS). [bib_ref] Complete surgical excision is essential for the management of patients with breast..., Clemens [/bib_ref] With a total en-bloc capsulectomy the specimen is removed as one complete piece comprising the entire unbreached capsule and any associated mass; the implant and associated effusion are fully retained within the explanted specimen . This technique is distinctly different to the piecemeal or partial capsulectomy approach sometimes used when dealing with capsular contraction. Where inadvertent dissection into a thin capsule results in effusion fluid contaminating the operative field, the cavity should be thoroughly irrigated before wound closure. One case of local recurrence in the UK series was thought to be related to the seeding of effusion fluid from the drain exit site. [bib_ref] Breast implant associated anaplastic large cell lymphoma: the UK experience. Recommendations on..., Johnson [/bib_ref] If there is an axillary mass/enlarged axillary nodes, attempts should always be made to characterise these pre-operatively. However, it should not be assumed that enlarged axillary lymph nodes seen on the staging PET scan are definitive evidence of lymphomatous involvement as these can be reactive or enlarged due to silicone lymphadenopathy. [bib_ref] Silicone lymphadenopathy after breast augmentation: case reports, review of the literature, and..., Zambacos [/bib_ref] [bib_ref] Extensive silicone lymphadenopathy after breast implant insertion mimicking malignant lymphadenopathy, Lee [/bib_ref] While there is no role for sentinel node biopsy, histological confirmation with excision of enlarged nodes at the time of surgery should be sought. [bib_ref] Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients, Miranda [/bib_ref] [bib_ref] Pathology of lymph nodes from patients with breast implants: a histologic and..., Katzin [/bib_ref] The capsule of sub-pectoral implants may be densely adherent or inseparable from the rib surface/intercostal muscles such that pneumothorax is a recognised risk. The operation note must record if the procedure was completed enbloc, or if any areas of capsule could not be removed for technical reasons. A simultaneous contralateral explantation and total capsulectomy should be strongly considered, as incidental BIA-ALCL may be found in 2-4A6% of cases. [bib_ref] Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma..., Mccarthy [/bib_ref] [bib_ref] Complete surgical excision is essential for the management of patients with breast..., Clemens [/bib_ref] Data on immediate reconstruction are very limited and where this is requested, it is preferable to consider it in the delayed setting after a period of observation. [bib_ref] Breast Reconstruction Following Breast Implant-Associated Anaplastic Large Cell Lymphoma, Lamaris [/bib_ref] A repeat PET/ CT or MRI at least six months after surgery should be considered before any decision is made. Options that might be explored include autologous flaps, fat grafting and even reconstruction with implants although in this latter case, smooth implants should be the predominant option.

## Processing the specimen post-explant
The contained peri-implant effusion, which commonly comprises turbid fluid, should be drained from the specimen by making a 2-mm cut into the capsule on the inferior pole and the fluid sent for cytology be opened as a full inferior capsulotomy that extends from the 9 o'clock to 6 o'clock to 3 o'clock position (clam shell capsulotomy) .
All removed implants, intact or ruptured, must be treated as a biohazard, appropriately labelled and stored as such, until collected by the manufacturer to fulfil their Vigilance obligations. If there has been a catastrophic rupture and the filler material is not recoverable, the silicone shell of the implant should still be retained. Patients should be warned that this is a regulatory requirement and that it is not appropriate, therefore, for the patient to take them home. We recommend that photographs are taken of the implant after explantation, at the end of the procedure, whether intact or ruptured. This should include a close-up of the posterior 'patch' to show the manufacturer's name, implant style and lot number, which must be recorded in the operation note. These images will act as both a clinical and medico-legal record and will facilitate identification of the implant.
The capsule should be inspected to identify areas of concern to highlight to the pathologist. The capsule must be formally orientated by placing external sutures, for example, short silk to superior, long silk to lateral, medium silk to medial and double loop silk to anterior . If a double capsule is present, the inner layer should be peeled off the implant and sent separately as BIA-ALCL may be present separately in this layer . Primary analysis of the capsule is morphological and is usually carried out by the breast pathology team, working closely with haematopathology for secondary molecular assessment as described above [fig_ref] Fig 5: Cytology [/fig_ref]. As many capsules look macroscopically normal, or are affected by areas of silicone impregnation, it is essential that multiple representative sections are taken to increase the detection of small areas of tumour cells within the capsule or on the luminal surface, as these are challenging to detect. [bib_ref] Breast implant-associated anaplastic large-cell lymphoma can be a diagnostic challenge for pathologists, Talagas [/bib_ref] [bib_ref] A proposal for pathologic processing of breast implant capsules in patients with..., Lyapichev [/bib_ref] Miranda et al. reported that no mass could be identified on macroscopic examination of the capsule in 42 of 56 (75%) cases in their report of 60 patients with BIA-ALCL. [bib_ref] Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients, Miranda [/bib_ref] In cases that despite exhaustive microscopic assessment fail to reveal any abnormal cells, the disease is categorised as effusion-limited (stage 1A). [bib_ref] Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): an overview of presentation and..., Jones [/bib_ref] 

## Management of bia-alcl found incidentally on capsulectomy specimens
Capsulectomy is commonly performed at the same time as implant exchange or explantation for grade 3-4 capsular contracture, and it is recommended that capsules are removed in one piece wherever possible and submitted for routine histological analysis. Specimens should be orientated to maximise the value of histopathology. In the rare scenario where BIA-ALCL is found incidentally in this manner [bib_ref] Anaplastic large cell lymphoma occurring in women with breast implants: analysis of..., Brody [/bib_ref] [bib_ref] Breast implant associated anaplastic large cell lymphoma: the UK experience. Recommendations on..., Johnson [/bib_ref] subsequent patient management should follow the diagnostic and treatment algorithms provided in this document.

## Staging
The American Joint Committee on the cancer tumour-nodemetastasis (TNM) staging system for solid tumours should be used in preference to the Lugano modification of the Ann-Arbor classification traditionally used for lymphoid neoplasms, as proposed by Clemens et al. [bib_ref] Complete surgical excision is essential for the management of patients with breast..., Clemens [/bib_ref] [fig_ref] Table I: Proposed TNM staging system for BIA-ALCL, adapted from Clemens et al [/fig_ref]. This not only better reflects the in situ or local infiltrative patterns associated with the disease but also allows better prognostic classification. Patients with disease limited to the effusion or confined to the capsule have a good/excellent prognosis with up to 93% reported to achieve complete remission at a median follow-up of two years. [bib_ref] Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients, Miranda [/bib_ref] Presentation with a tumour mass that extends beyond the capsule, with lymph node or more distant involvement reflects aggressive disease and is associated with lower disease-free (DFS) or overall survival (OS). [bib_ref] Breast implant associated anaplastic large cell lymphoma: the UK experience. Recommendations on..., Johnson [/bib_ref] One local/regional node involved 2B T1-3N1M0 N2
More than one local/regional node involved [bib_ref] Complete surgical excision is essential for the management of patients with breast..., Clemens [/bib_ref] Due to the rarity of advanced BIA-ALCL, optimal chemotherapeutic choice is extrapolated from studies investigating systemic ALK-negative ALCL. National guidelines for the treatment of systemic disease are published by the British Committee for Standards in Haematology (BCSH). [bib_ref] Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous..., Dearden [/bib_ref] At present, CHOP (cyclophosphamide, hydroxydaunorubicin (doxorubicin), (onco)vincristine and prednisolone) chemotherapy is most frequently used for the upfront treatment of ALCL based on experience with this regimen from high-grade B-cell lymphoma, despite poorer outcomes in the T-cell lymphoma setting. [bib_ref] A systematic review and meta-analysis of front-line anthracycline-based chemotherapy regimens for peripheral..., Abouyabis [/bib_ref] There is conflicting evidence as to whether the addition of etoposide leads to improved outcomes. [bib_ref] Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of..., Schmitz [/bib_ref] [bib_ref] Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01, D&apos;amore [/bib_ref] [bib_ref] Peripheral T-cell lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, D&apos;amore [/bib_ref] [bib_ref] Redefining the role of etoposide in first-line treatment of peripheral T-cell lymphoma, Kim [/bib_ref] [bib_ref] Comparison of CHOP vs CHOPE for treatment of peripheral T-cell lymphoma: a..., Deng [/bib_ref] Recently, ECHELON-2, a large phase III double-blinded randomised trial, demonstrated an improved median progression-free survival (PFS) with BV-CHP [brentuximab vedotin (BV), an anti-CD30 antibody drug conjugate, given in place of vincristine] compared to standard CHOP, with PFS improving to 48A2 from 20A8 months (HR 0A71, 95% CI 0A54-0A93, P = 0A0110) with no significant differences in toxicity. [bib_ref] Brentuximab vedotin with chemotherapy for CD30-positive peripheral Tcell lymphoma (ECHELON-2): a global,..., Horwitz [/bib_ref] An OS benefit was also seen in favour of BV-CHP (HR 0A66, 95% CI 0A46-0A95). This improvement was most significant in the ALCL subgroup. Following FDA approval of this combination for use in patients with untreated CD30positive T-cell lymphomas and European Medicines Agency (EMA) approval for untreated systemic ALCL, NICE approved its use in the NHS as per EMA indication in July 2020.
Single-agent BV is currently licensed and funded in the UK for relapsed/refractory ALCL based on data from a phase 2 study showing a favourable response rate of 86% with a complete response of 57%. [bib_ref] Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell..., Pro [/bib_ref] It is likely to be used less frequently in the refractory setting as its use as part of the upfront combination increases. There is some evidence that retreatment can lead to clinical responses, particularly if a long remission is achieved initially. [bib_ref] Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies, Bartlett [/bib_ref] Currently, in the UK, patients not refractory to BV-CHP are eligible for retreatment with BV at relapse. There are two case reports of patients achieving long-term remission following adjunct treatment with BV as a single agent following surgery for BIA-ALCL due to associated lymphadenopathy, although neither case had histological confirmation of nodal spread of disease. [bib_ref] Brentuximab vedotin as monotherapy for unresectable breast implant-associated anaplastic large cell lymphoma, Stack [/bib_ref] [bib_ref] Frontline brentuximab vedotin in breast implant-associated anaplastic large-cell lymphoma, Alderuccio [/bib_ref] A further report details a patient with BIA-ALCL who progressed whilst having CHOP chemotherapy but responded to single-agent BV, allowing subsequent bilateral total capsulectomy and implant removal. [bib_ref] Breast implant associated anaplastic large cell lymphoma: the UK experience. Recommendations on..., Johnson [/bib_ref] The prognosis for relapsed or refractory ALK-negative ALCL, is poor and where possible, treatment within a clinical trial should be considered. If a patient has already had BV or is intolerant, standard platinum-based salvage regimens such as GDP (gemcitabine, dexamethasone, prednisolone) are alternatives in the relapse setting. [bib_ref] Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous..., Dearden [/bib_ref] The role of autologous stem cell transplantation as consolidation in first remission of advanced stage (stage 3 or 4) ALCL is controversial with poor quality and conflicting evidence. [bib_ref] Efficacy of High-Dose Therapy and Autologous Hematopoietic Cell Transplantation in Peripheral T..., El-Asmar [/bib_ref] [bib_ref] Role of up-front autologous stem-cell transplantation in peripheral T-cell lymphoma for patients..., Fossard [/bib_ref] [bib_ref] The role of autologous stem cell transplantation in patients with nodal peripheral..., Park [/bib_ref] Given the poor outcomes generally seen following relapse of T-cell lymphoma, allogeneic or autologous stem cell transplantation of appropriate patients as consolidation following salvage treatment should be considered on a caseby-case basis for BIA-ALCL.

## Indications for radiation therapy
Adjuvant chest wall radiotherapy is not routinely recommended after total capsulectomy for histologically confirmed completely excised T1 and T2 tumours. It should be considered when complete excision has not been possible, if surgical margins are positive despite total capsulectomy or where there is chest wall invasion. It is unknown what the optimal radiotherapy dose should be, but doses similar to that given to patients with other high-grade lymphomas [bib_ref] Breast implant-associated anaplastic large cell lymphoma in Australia: a longitudinal study of..., Loch-Wilkinson [/bib_ref] [bib_ref] Risk of breast implant associated anaplastic large cell lymphoma in a cohort..., Mercer [/bib_ref] [bib_ref] NCCN Consensus Guidelines for the Diagnosis and Management of Breast Implant-Associated Anaplastic..., Clemens [/bib_ref] [bib_ref] NCCN Consensus Guidelines on the Diagnosis and Treatment of Breast Implant-Associated Anaplastic..., Clemens [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): an overview of presentation and..., Jones [/bib_ref] [bib_ref] Breast imaging for aesthetic surgery: British Society of Breast Radiology (BSBR), Association..., Lowes [/bib_ref] [bib_ref] Breast implant-associated anaplastic large-cell lymphoma: long-term follow-up of 60 patients, Miranda [/bib_ref] [bib_ref] Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma..., Mccarthy [/bib_ref] [bib_ref] Complete surgical excision is essential for the management of patients with breast..., Clemens [/bib_ref] [bib_ref] Breast implant-associated anaplastic large cell lymphoma: Sensitivity, specificity, and findings of imaging..., Adrada [/bib_ref] [bib_ref] Risk Factor Analysis for Capsular Contracture, Malposition, and Late Seroma in Subjects..., Mcguire [/bib_ref] have been proposed by the NCCN guidelines. [bib_ref] NCCN Consensus Guidelines on the Diagnosis and Treatment of Breast Implant-Associated Anaplastic..., Clemens [/bib_ref] 

## Ongoing surveillance
We advocate joint patient follow-up between the surgical and haemato-oncology teams every 3-6 months, for a minimum of two years and then as indicated. While clinical assessment is required, there is a lack of evidence to support routine imaging surveillance of BIA-ALCL whether limited or advanced stage. [bib_ref] Role of surveillance imaging in patients with peripheral T-cell lymphoma, Tang [/bib_ref] This is analogous to the clinical principles that guide surveillance in other NHL subtypes, that routine imaging does not improve patient outcomes. [bib_ref] Who benefits from surveillance imaging?, Armitage [/bib_ref] [bib_ref] Hodgkin lymphoma patients in first remission: routine positron emission tomography/computerized tomography imaging..., Dann [/bib_ref] [bib_ref] Utility of routine post-therapy surveillance imaging in diffuse large B-cell lymphoma, Thompson [/bib_ref] Our recommendation takes into consideration evidence from a range of lymphoma subtypes, the American Society of Hematology Choosing Wisely Campaign 91 and surveillance guidance provided by the NICE guidelines on NHLs.Patients who become symptomatic should be re-referred to the tertiary centre if there is a concern for disease recurrence, to enable prompt investigation.

# Conclusions
It is essential that we continue to promote widespread education of BIA-ALCL amongst healthcare workers in the UK. Patients who receive implants whether for cosmetic or reconstructive purposes must always be advised of the risk of developing BIA-ALCL and how this relates to implant surface type. They should always report symptoms such as delayed onset breast swelling or a mass to their GP and/or surgeon. There are no recommended changes to the routine medical care in asymptomatic patients with implants. Clinicians faced with anyone who has breast symptoms and a breast implant must consider the possibility of BIA-ALCL and should follow these diagnostic guidelines. The management of BIA-ALCL should be performed in a tertiary centre with multidisciplinary input.
Ongoing international surveillance and research will inform future recommendations for diagnosis and treatment. BIA-ALCL is associated with excellent outcomes for the majority of patients; with early recognition and increased detection there is greater opportunity for successful surgery with curative intent and an improved long-term prognosis.
[fig] Fig 1: Examples of clinical presentations of implant-associated breast effusion due to breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). (A) Effusion in a reconstructed left breast. (B) Effusion in an augmented left breast. (C) Subtle effusion in an augmented left breast, masked due to underlying physiological asymmetry, with a bigger and more redundant right breast. (D) Rash of the lower inner quadrant of the right breast preceded the appearance of a BIA-ALCL mass at the same site. [/fig]
[fig] Fig 2: The UK Diagnostic algorithm for the assessment of new clinical signs in the context of previous breast implantation. Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN) for T-Cell Lymphomas V.1.2020. 2020 National Comprehensive Cancer Network, Inc. All rights reserved. 28 PET CT, positron emission tomography/computed tomography; MRI, magnetic resonance imaging; HMDS, Haematological Malignancy Diagnostic Service; MDT; multidisciplinary team; IHC, immunohistochemistry; BIA-ALCL, breast implant-associated anaplastic large cell lymphoma. [/fig]
[fig] Fig 3: Ultrasound (US) and magnetic resonance (MR) imaging in breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). (A) Transverse US showing a peri-implant effusion (arrows) and implant membrane (open arrow). (B) Transverse US showing a pericapsular ovoid solid mass (arrows). (C) MR imaging: axial T2-weighted image showing an effusion around an intact left breast silicone implant. (D) MR imaging: axial silicone-selective image showing a silicone signal between the intact implant shell and the capsule in keeping with silicone shedding/gel bleed (arrows). (E) MR imaging: axial T1-weighted gadolinium-enhanced fat saturation image showing LEFT effusion and capsular enhancement (arrows), with no effusion or capsular enhancement on the unaffected RIGHT side. [/fig]
[fig] Fig 4. 2 -: [Fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG PET/CT) imaging in breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). FDG PET/CT pre-treatment (A-C), and post-treatment images (D-F) from the same patient six weeks after the last cycle of chemotherapy. Total en-bloc capsulectomy with excision of the BIA-ALCL mass was followed by CHOP chemotherapy. The patient went on to have an autologous stem cell transplant and remains disease-free one year later. (A) Coronal maximum intensity projection (MIP) PET image; there is an intensely avid mass around the left implant (arrow) and avid left axillary nodes (open arrow). (B) Axial fused PET/CT image showing an intensely avid mass in the left breast. (C) Axial fused PET/CT image demonstrating avid left axillary nodes which were confirmed to be involved on biopsy. (D) Post-treatment coronal MIP PET image. There is no uptake of a malignant configuration; the minimal uptake in the surgical bed is in keeping with minor residual inflammation (arrow). (E) Post-treatment axial fused PET/CT showing minimal seroma in the surgical bed (arrow). (F) Post-treatment axial fused PET/CT demonstrating that the axillary nodes have resolved (arrow). [/fig]
[fig] Fig 5: Cytology: morphology of atypical lymphoid cells representative of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). (A) Haematoxylin and eosin (H&E). (B) Pap stains. Arrows indicate atypical cells that would trigger follow-up investigations. (C) Histology demonstrating atypical lymphoid cells suspicious of ALCL on the luminal side of the breast implant capsule detected by H&E and (D) CD30 stains. [/fig]
[fig] Fig 6 Fig 7: Data on reconstrucon is very limited. Consider in the delayed seng if desired and low risk of oncological recurrence has been confirmed BIA-ALCL Treatment Algorithm The UK Treatment algorithm. Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN) for T-Cell Lymphomas V.1.2020. 2020 National Comprehensive Cancer Network, Inc. All rights reserved. 28 US, ultrasound; MRI, magnetic resonance imaging; FNAC, fine-needle aspiration cytology; MDT, multidisciplinary team; BIA-ALCL, breast implant-associated anaplastic large cell lymphoma; PET-CT, positron emission tomography/computed tomography; TNM, tumour-node-metastasis; MHRA, Medicines and Healthcare products Regulatory Agency; BCIR, Breast and Cosmetic Implant Registry. Appearance of a total en-bloc capsulectomy specimen. (A) Specimen with associated anaplastic large cell lymphoma (ALCL) mass and an overlying ellipse of skin. (B) Contralateral (unaffected) implant also removed en-bloc. (C) After en-bloc capsulectomy the capsules have been orientated with a 2-0 silk suture (short superior, long lateral, medium medial and double loop anterior) after removing the implant via an inferior clam shell capsulotomy. The peri-implant effusion fluid has been collected for cytology and HMDS. (D) Florid appearance of ALCL throughout the capsule. (E) Localised nodules of ALCL in the capsule. (F) Inner capsule which was also positive for breast implant-associated (BIA)-ALCL. (G, H) Peri-implant effusion fluid. (I) Appearance after opening the specimen via inferior capsulotomy demonstrating a yellow raised capsular mass on the luminal aspect (arrow). [/fig]
[table] Table I: Proposed TNM staging system for BIA-ALCL, adapted from Clemens et al.34 which should be confirmed after the disease stage has been defined and the case discussed at the haematology and breast MDT meetings. for chemotherapy, monoclonal antibody and/ or autologous stem cell transplant Mass-forming disease, lymph node involvement or distant disease may require systemic treatment, and this is advocated for stage 2-4 disease. An individualised approach to systemic treatment is recommended for more advanced cases. In the series published by Clemens et al. one third of patients that received systemic chemotherapy experienced disease progression due to either a lack of appropriate local surgical control, or disease resistance to the regimen used. [/table]