G. Patrick Maxwell1, Joan Largent2, Michael G. Oefelein2

1Maxwell Aesthetics, Nashville, TN; 2Allergan Inc., Irvine, CA

Disclosures G. Patrick Maxwell is a Consultant for Allergan, Inc.

Joan Largent and Michael G. Oefelein are Employees of Allergan, Inc.

ABSTRACTPurpose:. We aimed to review the available evidence on Anaplastic Large Cell Lymphoma (ALCL) and breast implants (BI) including case reports and epidemiologic studies, and provide a critical evaluation.

Methods: Search methods: i) Database=PubMed; ii) Search terms=”breast implant” and “lymphoma”, or “primary breast lymphoma” or “primary T-cell breast lymphoma” or “breast implant and ALCL”; iii) Inclusion criteria: language=English; human studies; iv) Expand search based on review of references.

Results: ALCL is a rare, aggressive T-cell lymphoma characterized by the uniform expression of the CD30 antigen, with the majority of cases also positive for aplastic lymphoma kinase (ALK). ALCL can be either cutaneous or systemic. A review of the literature for reports of ALCL in breast implant recipients revealed a total of 15 published reports describing a total of 25 patients with ALCL in patients with silicone gel-filled or saline-filled breast implants (1 July 2010). Additional findings were: 1) Breast-ALCL has been reported in women with and without BI [5,6] and, 2) with and without a prior cancer history [18]. The only case-control study examining an association between ALCL and BI to date [6] included 6/11 ALK-negative ALCL cases with no history of BI . Nine of 25 (36%) ALCL cases reported among patients with BI had a personal history of breast cancer (N=8) or lymphoma (N=1) [18]. 3) Authors concluded ALCL in the anecdotal case reports behaves indolently, and spontaneous resolutions have been reported; however, most patients with ALCL received chemotherapy and/or radiotherapy [24]. 4) Device type in case reports is often unknown [18]; reports have included saline- and silicone-filled devices [18]. 5) Interval between implantation and ALCL diagnosis varies widely in the reports, between 1-23 years [6]. 6) Primary breast lymphomas may be difficult to definitively diagnose and distinguish from secondary involvement of disease originating elsewhere [8]. Five of 11 ALCL cases in the case-control study had disseminated disease with involvement of other sites providing uncertainty about the breast as the primary site [6]. 7) BI patients have been reported to have demographic and lifestyle characteristics which may influence their risk of certain cancers [3]; the relevance of these characteristics to ALCL risk is unknown. 8) While no prospective epidemiologic studies have examined ALCL risk among BI patients to date, several have reported no significantly increased NHL risk [19].

Conclusions: Overall, the evidence regarding a BI- ALCL association is inconclusive.

OBJECTIVEWe aimed to review the available evidence on Anaplastic Large Cell Lymphoma (ALCL) and breast implants (BI) including case reports and epidemiologic studies, and provide a critical evaluation.

METHODSTo identify cases of breast-associated ALCL, a PubMed search limited to English language, human studies was conducted using search terms ”breast implant” and “lymphoma”, “primary breast lymphoma” or “primary T-cell breast lymphoma” or “breast implant and ALCL”. Additional references of relevance were identified from the reference lists of retrieved publications.

RESULTS

Reference Implant type Age/years Breast Presentation Stage Other Sites CD30/ALK STATUS

Seroma and ALCL

Farkash et al, 2009 Silicone 54 Breast enlargement, chronic inflammatory infiltrate with fibrosis surrounding pseudocystic space

IA No systemic disease NA/ALK-

Olack et al, 2007 Saline 64 Enlarged, tender breast I No metastasis NA/ALK-

Li et al, 2010 Silicone-covered, saline-filled

58 Swelling with painless mass, large atypical mononuclear

I No systemic disease CD30+/ALK-

Miranda et al, 2009 Saline 63 Mass with fluid, neoplastic cells T1a Skin lesions in hip, wrist, vagina

CD30+/ALK-

NA 40 Pain, swelling, neoplastic cell IIE NA CD30+/ALK-

Silicone 65 Swelling, fluid, neoplastic cells NA NA CD30+/ALK-

Newman et al, 2008

Silicone 52 Swelling, palpable fluid collection around implant, atypical cells, anaplastic large cell lymphoma

I No systemic disease NA

Roden et al, 2008 Saline, textured 45 NA IE No systemic disease CD30+/ALK-

Silicone 59 NA IE No systemic disease CD30+/ALK-

Saline 34 Breast enlargement IE No systemic disease CD30+/ALK-

Silicone 44 NA NA NA CD30+/ALK-

Sahoo et al, 2003 Silicone 37 Breast tenderness, swelling, atypical mononuclear cell infiltrate

I No systemic disease CD30+/ALK-

Table 1: Summary of cases in the literature of anaplastic large T-cell lymphoma in patients with breast implants

ALK, anaplastic lymphoma kinase; LN, lymph node; NA, not available

Reference Implant type Age/years Breast Presentation Stage Other Sites CD30/ALK STATUS

ALCL only

Alobeid et al, 2009 Silicone 68 Axillary lymphadenopathy, large cell neoplasm infiltrating and expanding sinuses

II Bilateral axillary lymphadenopathy

CD30+/ALK-

Bishara et al, 2009 Saline 66 Pain, deviation toward axilla, tenderness, erythema, capsular contraction, capsulectomy revealed irregular mass with some necrosis

I No systemic disease CD30+/ALK-

de Jong et al, 2008 PIP Hydrogel 53 Large, polymorphic infiltrate of lymphoid tumor cells with small lymphocytes, macrophages and eosinophils

I NA CD30+/ALK-

Textured silicone, saline filled

49 II NA CD30+/ALK-

43 IV Right infraclavicular LN, right skull base

CD30+/ALK-

29 II Right axillary LN CD30+/ALK-

NA 38 I NA CD30+/ALK-

Fritzsche et al, 2006 Silicone 72 Skin ulcer I None CD30+/ALK-

Gaudet et al, 2002 Silicone covered, saline-filled

87 Mass with intense cellular infiltrate, edema, pain, warmth

I No systemic disease CD30+/ALK-

Silicone 50 Sub-cutaneous nodules overlying implant, infiltrate of atypical cells

I Left lower lode infiltrate and mediastinal lymphadenopathy one year later

CD30+/ALK-

Keech and Creech, 1997

Saline-filled 41 Mobile, nontender mass II Enlarged right axillary LN CD30+/NA

Mora et al, 2009 Silicone 56 Fast growing mass, neoplastic cells I No systemic disease CD30+/ALK- Wong et al, 2008 Silicone 40 Bilateral capsular contractures I No systemic disease CD30+/ALK-

Table 1 (Continued)

ALK, anaplastic lymphoma kinase; LN, lymph node; NA, not available

RESULTSCharacteristic Outcome

Total cases of ALCL n=25

Mean age of ALCL patients, years, (SEM) 52.5 (2.8)

Seroma reported n=11

Mean time to ALCL diagnosis, years, (SEM) 8.9 (1.3)

ALCL stageT1N0M0 (Stage 1)T1N1M0 (Stage 2)T+N+M Unknown/NA

n=17n=5n=1n=2

ProcedureAugmentationReconstructionRevision-augmentationRevision-reconstructionUnknown/NA

n=9n=11n=3n=0n=2

Fill typeSiliconeSalineHydrogelUnknown

n=10n=12n=1n=2

SurfaceTexturedUnknown/NA

n=4n=21

Table 2: Summary of literature cases of anaplastic large T-cell lymphoma in patients with breast implants

ALCL, anaplastic large T-cell lymphoma; NA, not available

CONCLUSIONSThe evidence to date regarding a causal association between breast implants and ALCL is inconclusive and deserves further rigorous scientific study to elucidate: 1) potential cause and effect; 2) proper disease classification; 3) Heterogeneous clinical course, 4) relevance of prior cancer and/or cancer treatment; 5) relevance of late seroma 6) extremely rare occurrence.

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