2 - 3 Clemmens 2018 ALCL...Report confirmed cases to ASPS/FDA PROFILE Registry 4. FDA, ASPS, ASAPS...

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1

Mark Clemens, MD

Mark W. Clemens, MD, FACSAssociate Professor

MD Anderson Cancer Center

Kaiser Permanente

2018 Plastic Surgery Symposium

February 10, 2018

Breast Implant Associated Anaplastic Large Cell Lymphoma

What every plastic surgeon should know

Mark Clemens, MD

None

Chair BIA‐ALCL Taskforce for ASPS

ASPS Liaison to FDA

Coauthor Lymphoma NCCN Guidelines

Financial disclosures/conflicts of interest

Mark Clemens, MD

ASPS ASAPS Joint Statement January 10, 2018

1. All government authorities and oncology organizations classify

BIA‐ALCL as a lymphoma

2. To date, only noted to occur with textured implants.

3. Report confirmed cases to ASPS/FDA PROFILE Registry

4. FDA, ASPS, ASAPS support NCCN Guidelines for Diagnosis and

Treatment

5. After PET/CT for oncologic workup, Treatment is surgery with

removal of implant and capsule for most patients

6. For clinical situations where use of a smooth vs. textured device is

equivocal, should consider a smooth device

7. Deaths and advanced cases emphasize need for prompt

identification and proper treatment

Mark Clemens, MD

• Worldwide consensus by pathologists, clinicians and basic scientists1

• BIA‐ALCL provisional classification as a lymphoma1

• ALCL now has three types: ALK+, ALK‐, BIA1

• If confined to capsule, surgery alone1

1. Swerdlow SH, et al. Blood 2016;127:20.

2016 World Health Organizationclassification on lymphoma

1

Mark Clemens, MD

1. FDA. BIA‐ALCL. Available at: https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/BreastImplants/ucm239995.htm. Last accessed March 2017; 2. American Society of Plastic Surgeons. Available at: https://www.plasticsurgery.org/news/press‐releases/joint‐asps‐and‐asaps‐advisory‐to‐members‐on‐fdas‐update‐regarding‐breast‐implant‐associated‐alcl. Last accessed May 2017.

2011, 2016, 2017 FDA safety communication

ASPS ASAPS Response2

• Agrees with World Health Organization BIA‐ALCL is a rare T‐cell lymphoma around breast implants1

• Support NCCN Guidelines for diagnosis and management1

• Support PROFILE Registry reporting1

• 359 adverse event reports, nine deaths1

• Textured surface cases predominate1

Mark Clemens, MD

1. Clemens MW, Horwitz SM. Aesthet Surg J 2017;37:285–89; 2. NCCN guidelines. Breast implant‐associated ALCL Version 2.2017.

NCCN BIA‐ALCL Guidelines 20161

Diagnosis2

Management2

• Standardized guidelines for the diagnosis and management of BIA‐ALCL1

• Based upon best evidence‐based approach1

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Mark Clemens, MD Mark Clemens, MD

Mark Clemens, MD

• Internationally recognised algorithms for the diagnosis and treatment of cancer

• Utilized by the majority of oncologists

• Adopted by international societies

2016 NCCN Guidelines1

1. Clemens MW, Horwitz SM. Aesthet Surg J 2017;37:285–89.

Mark Clemens, MD

Personal communication, Dr Mark Clemens, April 2017. Images courtesy of Dr Mark Clemens.

A story of four BIA‐ALCL cases: A patient‐focused approach

BETH

DAWNCARA

ABBY

Mark Clemens, MD

1. Clemens MW, et al. Gland Surg 2017;6:169–84; 2. Personal communication, Dr Mark Clemens, May 2017. 3. NCCN Guidelines. Breast implant‐associated ALCL Version 2.2017.

Case study: Abby

• 70‐year‐old female1

• 1992: mastectomy and breast reconstruction NIS implants1

• 2016: acute swelling of right breast1

• Ultrasound: fluid, no masses2

• FNA: normal2

3

3

Images from Clemens MW, et al. Gland Surg 2017

Mark Clemens, MD

BIA‐ALCL presentation

1. Miranda R, et al. J Clin Oncol 2014;32:114–20; 2. Personal communication, Dr Mark Clemens, May 2017.3. Clemens MW, et al. J Clin Oncol 2016;34:160–68;

0

5

10

15

20

Frequency2

Age30 40 50 60 70 80 90

Median onset ALCL from implantation:8 years (range, 2–25 years)3

0

5

10

15

20

Frequency2

Years to diagnosis0 5 10 15 20 25 30 35

• Effusion 79.3%• Mass 40% • Capsular contracture 8%• Skin rash 2%• Lymphadenopathy 8%

Do not test normal fluid1

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Mark Clemens, MD

1. McGuire P, et al. Plast Reconstr Surg 2017;139:1–9; 2. Clemens MW, et al. Gland Surg 2017;6:169–84.

CA/CARE Clinical Trials Delayed seroma (>1 year)

• McGuire et al. 2017

• 17,656 patients, 31,985 implants1

• 6 BIA‐ALCL: 1:2943 (95%CI:1350,8000)

• 9‐13% of delayed seromas may be BIA‐ALCL

Mark Clemens, MD

Image courtesy of Dr Olaya Sanchez Crespo

Image from Clemens MW, et al. Gland Surg 2017.

Image from van Dorp M, et al. Plast Reconstr Surg Glob Open 2016

1. Clemens MW, et al. Gland Surg 2017;6:169–84; 2. Personal communication, Dr Mark Clemens, May 2017. 3. NCCN Guidelines. Breast implant‐associated ALCL Version 2.2017; 4. van Dorp M, et al. Plast Reconstr Surg Glob Open 2016; 4:e688; 4.

Case study: Abby





• FNA: normal2

3

3

Mark Clemens, MD

1. Clemens MW, et al. Gland Surg 2017;6:169–84; 2. Personal communication, Dr Mark Clemens, May 2017. 3. NCCN Guidelines. Breast implant‐associated ALCL Version 2.2017; 4. Clemens MW, Miranda RN. Aesthet Surg J 2017. doi: 10.1093/asj/sjx040; 4.

Case study: Abby

Wright Giemsa Stain:Lymphocytes/histiocytes4 CD30 IHC4

Benign seroma Normal4





• FNA: normal2

3

3

Mark Clemens, MD

Criteria for diagnosis of BIA‐ALCL1,2

1 A tumour with adequate pathological specimen for analysis either involving an effusion surrounding a breast implant or in continuity with a breast implant capsule

2 Neoplasm with large lymphoid cells with abundant cytoplasm and pleomorphic nuclei

3 Tumour demonstrates T‐cell markers with uniform expression of CD30 on immunohistochemistry

4 Negative for ALK protein or translocations involving the ALK gene at chromosome 2q23

1. Clemens MW, Miranda RN. Clin Plast Surg 2015;42:605–13; 2. Clemens MW, Miranda RN. Aesthet Surg J 2015;35:545–7.

Diagnosis of BIA‐ALCL

CD30 IHC

Anaplastic cells

T‐cell clone

1. CD30+ IHC: diagnostic screen1,2

2. Cell block cytology: large and anaplastic polymorphic cell shapes2

• Horseshoe‐shaped nuclei, reniform shape1

• Nuclear folding1

3. Flow cytometry: single T‐cell clone2

Images from Clemens MW, Miranda RN. Clin Plast Surg 2015.

Mark Clemens, MD

Wright Giemsa Stain:anaplastic large cells3 CD30 IHC3

1. Personal communication, Dr Mark Clemens, May 2017. 2. NCCN Guidelines. Breast implant‐associated ALCL Version 2.2017; 3. Clemens MW, Miranda RN. Aesthet Surg J 2017. doi: 10.1093/asj/sjx040; 3.

Case study: Beth


• 2004: bilateral cosmetic augmentation1


• FNA: ALCL1

2

2

Images courtesy of Dr Mark Clemens.

Mark Clemens, MD




• FNA: ALCL1

1. Personal communication, Dr Mark Clemens, May 2017. 2. NCCN Guidelines. Breast implant‐associated ALCL Version 2.2017; 2.

Case study: Beth 2

2



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Mark Clemens, MD

1. NCCN Guidelines. Breast implant‐associated ALCL Version 2.2017.

Total capsulectomy implant removal

• Oncologic technique1

• Orientation sutures

• Surgical clips in tumour bed

• Excision of suspicious lymph nodes1

• Complete resection of capsule, including posterior wall

• Tumescence may aid in removal of the back wall

• Mass with negative margins

• Excision biopsy of lymph nodes

• No obvious role for sentinel lymph node biopsy Images courtesy of Dr Mark Clemens

Mark Clemens, MD

BIA‐ALCL smooth implant Immediate reconstruction

• 2016: implant removal, total capsulectomy

• Pathology: ALCL

• No chemo or XRT

• Surveillance: CT Scan every 6 months




• FNA: ALCL1

Images courtesy of Dr Mark Clemens

Preop

One Stage Postop

Mark Clemens, MD

Solid tumorprogression

Lymph node invasion

BIA‐ALCL behaves like a SOLID tumour (like lung or breast cancer) and therefore treated surgically1

1. Effusion only:

• 35% of cases• Lymphoproliferative disorder

2. Cell penetration into capsule: 11%

3. Aggregation into mass: 13%

4. Mass infiltration through capsule: 25%

5. Lymph node mets: 14%

6. Organ mets: 3%

Luminal side of capsule

Breasttissue

Lymphoma cell

Thickened capsule

1

2

3 4 5

6

1

2

3

4

5

6

1. Personal communication, Dr Mark Clemens, May 2017. Images courtesy of Dr Mark Clemens.

Mark Clemens, MD

• TNM classification

• Clinical–pathological staging system

1. Clemens MW, et al. J Clin Oncol 2016;34:160–8.

MDACC BIA‐ALCL staging1

BIA‐ALCL TNM stagingTumour size

T

T1 Confined to effusion

T2Early capsule invasion

T3Mass aggregate, confined to capsule

T4Tumourlocally invasive out of capsule

Lymph nodes

N

N0No lymph node involvement

N1One regional lymph node

N2Multipleregional lymph nodes

Metastasis

MM0No distant spread

M1Other organs/ distant sites

Image from Clemens MW, et al. J Clin Oncol 2016

Mark Clemens, MD

• T1: disease confined to effusion only or non‐invasive layer luminal side

• N0 M0

1. Clemens MW, et al. J Clin Oncol 2016;34:160–8; 2. Personal communication, Dr Mark Clemens, September 2015.

MDACC BIA‐ALCL staging: Stage 1A1


35% Effusion only2


Mark Clemens, MD


MDACC BIA‐ALCL staging: Stage 1B1

Image courtesy of Dr Mark Clemens

11% early infiltration2


• T2: early invasion, mix of lymphocytes with ALCL within capsule

• N0 M0

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Mark Clemens, MD

• T3: aggregate mass confined by the capsule

• N0, M0


MDACC BIA‐ALCL staging: Stage 1C1

13% capsule mass2



Mark Clemens, MD

• T4: invasive mass outside of capsule

• N0 M0


MDACC BIA‐ALCL staging: Stage 2A1

Images courtesy of Dr Mark ClemensImage from Clemens MW, et al. J Clin Oncol 2016

25% mass through capsule2

Mark Clemens, MD

Mass 18‐25% of BIA‐ALCLWorse Prognosis• Important to image prior to surgery• Must resect all of the malignancy

Mark Clemens, MD

Reported Stage Presentations Worldwide

StudyAnn

Arbor MDA Solid Tumor TNM Stage

IE IIE IA IB IC IIA IIB III IV

Brody 2015 (n=173)

USA

89.6 10.4 NR NR

Clemens 2016 (n=87)

USA

86.2 13.8 35.6 11.5 13.8 25.3 4.6 9.2 0

Loch-Wilkinson 2017 (n=55)

Australia

96.4 3.6 76.4 0 10.9 9.1 0.0 1.8 1.8 De Boer 2017

(n=32)

Netherlands

81.3 18.8 45.2 NR

Campanale 2017 (n=22)

Italy

81.8 18.2 68.2 0 4.5 9.0 9.0 0 9.0 InfiltrativeEffusion

Only

Mark Clemens, MD

1. Clemens MW, et al. J Clin Oncol 2016;34:160–8.

Event‐free survival Overall survival2

Surgery essential for cure

Treatment1 year (%)

3 years (%)

5 years (%)

Overall 35 50.8 50.8

Limited surgery

60 89 89

Complete surgery

4 4 4

Radiation 18 28 28

Chemotherapy 24 32 32

Treatment after diagnosis Number %

Limited surgery 43 52.9

Complete surgery 74 85.1

Radiation 39 44.8

Chemotherapy 51 58.6

ASCT 6 6.9

Immunotherapy 2 2.3

Patients can progress or up‐stage if untreated

Mark Clemens, MD

Preoperative Imaging Guides SurgeryComplete Resection Critical

DIEP Flap

BIA‐ALCLMass

Widely metastatic BIA‐ALCL to bone

DIEP flap recon of BIA‐ALCL

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Mark Clemens, MD

1. Carty M, et al. Plast Reconstr Surg 2011;128:3; 2. NCCN Guidelines. Breast implant‐associated ALCL Version 2.2017.

Case study: Cara


• 1979: augmentation mastopexy1

• Multiple exchanges for CC in 19991

• 2007: lymphadenopathy

• Left capsule mass, chest wall invasion

• Left implant removal, partial capsulectomy

• Five cycles CHOP+ left EBRT

• Right chest wall recurrence

• Right implant removal, total capsulectomy

• Five cycles ESHAP+ right EBRT

• Left chest recurrent mass

• Left EBRT boost, salvage ESHAP, SCT

• Chest wall invasion mediastinum, pleural effusion

• 2010: death

Implant removal and partial capsulectomy1

2

Mark Clemens, MD

1. Clemens MW, Mirand RN. Clinics Plast Surg 2015;42:605–13. Images courtesy of Dr Mark Clemens.

Understanding Beth versus Cara:Partial resection higher recurrence

• 2013: acute swelling of left breast1

• Aspirated multiple times1

• Partial capsulectomy, mastopexy, and implant removal1

• Pathology: ALCL1

• 2014: total capsulectomy and mass removal1

• Pathology: ALCL1

• No chemo or XRT1

• Surveillance: US/CT scan every 6 months1

• 1993: cosmetic augmentation

• Silicone textured implants1

• 52‐year‐old woman

• PMHx: BMI 27

• Ann Arbor: Stage I

• MDACC: Stage 2A

1

Mark Clemens, MD

x400

CD30

Images courtesy of Dr Mark Clemens.Posterior wall removed, found to have residual tumour –

following completion capsulectomy, now disease‐free 2 years, no chemo1

1. Clemens MW, et al. Gland Surg 2016. doi: 10.21037/gs.2016.11.03. Images courtesy of Dr Mark Clemens.

Retained disease on chest wall

Mark Clemens, MD

1. Clemens MW, et al. Gland Surg 2016 doi: 10.21037/gs.2016.11.03. 2. NCCN Guidelines. Breast implant‐associated ALCL Version 2.2017. Image courtesy of Dr Mark Clemens.

Case study: Dawn

• 47‐year‐old female

• 2009: augmentation mammaplasty SL implants

• 2015: implant contracture, lymphadenopathy, chest wall mass

• 6/2015: implant exchange

Dx BIA‐ALCL

• 7/2015: partial capsulectomy

• Six rounds of CHOEP

• Two rounds of GDP

• Referred for hospice

Chest wall invasionMets to small bowel

After surgery, positive marginsDisease progression on CHOP

2

Mark Clemens, MD

• T4: invasive disease beyond the capsule

• N1–2: multiple regions of lymph nodes

• M0

1. Clemens MW, et al. J Clin Oncol 2016;34:160–8; 2. Ivaldi C, et al. Ann Chir Plast Esthet 2013;58:688–93; 3. Personal communication, Dr Mark Clemens, May 2017.

MDACC BIA‐ALCL:Stage 31

Image from Ivaldi C, et al. Ann ChirPlast Esthet 2013


14% Lymph node metastasis

BIA‐ALCL3

Small cell lung cancer

Mark Clemens, MD

• 13% of BIA‐ALCL Cases

• 85% Axillary, 10% Supraclav, 5% internal mammary

• Mass, LNI portend Worse Prognosis

Ferrufino‐Schmidt. Clinicopathologic Features and Prognostic Impact of Lymph Node Involvement in Patients With BreastImplant‐associated Anaplastic Large Cell Lymphoma. Am J Surg Pathol. 2017

Patterns of Lymph Node Involvement

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Mark Clemens, MD

1. Clemens MW, et al. J Clin Oncol 2016;34:160–8; 2. Zimmerman A, et al. Cancer Control 2015;22:369–73; 3. Personal communication, Dr Mark Clemens, May 2017.

MDACC BIA‐ALCL: Stage 4

3% distant organ metsImage from Clemens MW, et al. J Clin Oncol 2016.

• T‐any, N‐any

• M1: distant disease spread

Poor prognosis3

• Described locations:• Lung pleural effusion• Base of skull• Spine• Small intestine• Liver with obstructive jaundice

Mark Clemens, MD

1. Miranda R, et al. J Clin Oncol 2014;32:114–20; 2. Vaklavas C, Forero‐Torres A. Ther Adv Hematol 2012;3:209–25; 3. NCCN Guidelines. Breast implant‐associated ALCL Version 2.2017.

CD30‐targeted therapy

• Anti‐CD30‐targeted therapy2

• Brentuximab vedotin for refractory sALCL: objective response rate – 86%

CD30‐targeted therapy2

3

• Adjunct chemotherapy: anthracycline based

• 100% CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone1

• 8% ICE: ifosfamide, carboplatin, etoposide1

• 4% CVAD: cyclophosphamide, vincristine, doxorubicin, dexamethasone1

• BIA‐ALCL: 32% recurrence rate at 3 years

• Salvage radiation therapy for unresectable disease

Mark Clemens, MD

Complete Remission on BV

Case study: Brentuximab

• 47‐year‐old female

• 2009: augmentation mammaplasty, SL implants

• 2015: implant contracture, lymphadenopathy, chest wall mass

• June 2015: implant exchange

• Dx BIA‐ALCL

• July 2015: total capsulectomy

• Six rounds of CHOEP

• Two rounds of GDP

• Four rounds of brentuximab vedotin

• Complete remission BIA‐ALCL Disease progression on CHOP

2

Mark Clemens, MD

1. Personal communication, Dr Mark Clemens, May 2017.

CD30‐targeted therapy

• Anti‐CD30 therapy1

• BIA‐ALCL: nine R/R patients treated achieved complete remission

• Complete remission in relapsed and refractory BIA‐ALCL with BV

• Versus 32% recurrence rate at 3 years with anthracycline‐based regimen

Mark Clemens, MD

1. Clemens MW, et al. J Clin Oncol 2016;34:160–8; 2. Therapeutic Goods Administration Update on BIA‐ALCL, December 20, 2016; 3. Personal communication, Dr Mark Clemens, May 2017.

Deaths rare, Good prognosis if treated

Reference AgeTumour size (cm)

Treatments Cause of death

Unpublished 1 52 7Limited surgery,

chemo, RT

ALCL, mediastinal mass with progressive bronchial compression

Aladily et al.1 47 2.5 Chemo, RT

ALCL, mediastinal mass with progressive bronchial compression, pleural effusion, pneumonia

Carty et al.1 57 ‘large’Limited surgery,

chemo, RTALCL, chest wall invasion, pleural infiltration, respiratory failure

Miranda et al.1 63 1.2Limited surgery,

chemo

DLBCL, follicular lymphoma, disseminated disease. Free of ALCL for 120 months and at death

Ivaldi et al.1 53‘Voluminou

’Limited surgery

ALCL, axillary and internal mammary lymph nodes, tracheal narrowing, pleural effusion, respiratory failure

Lechner et al.1 43 NALimited surgery,

chemo, RT

ALCL, mediastinal mass with progressive bronchial compression, pleural effusions

Unpublished.3 52 NALimited surgery,

chemoALCL, chest wall invasion, respiratory failure

Unpublished.3 42 8Complete surgery,

chemo, SCTSepsis, multiorgan dysfunction during SCT

Unpublished.3 56 6Limited surgery,

chemo

ALCL, axillary lymph nodes, tracheal narrowing, mediastinalmass, respiratory failure

Unpublished –TGA3 X X

Limited surgery, chemo, SCT

Death during SCT


Limited surgery, chemo

Mediastinal invasion


Limited surgery, chemo

Mediastinal invasion

• 16 attributable deaths*1,2

• Delay in treatment or mistreatment

• 45‐month mean follow up1

• Range 3–217 months

• 13 years median overall survival1

• 93% at 3 years

• 89% at 5 years

Mark Clemens, MD

• 2015 37yo female, Subglandular textured augmentation 295ml

• 5/16/2017 Periprosthetic Seroma, breastswelling

• 5/30/2017 Implant removal, seromadrainage

• 6/19/2017 Skin ulcers, antibiotics andcorticosteroids, HBO2

• 7/12/2017 Chest wall invasion, pulmonarycompromise, enlargement periaortic, pre‐carinal and subcarinal lymph nodes. Open breast capsule biopsy BIA‐ALCL, CHOP initiated

• 9/28/2017 Pseudomonal infection, sepsis, respiratory failure, death

Case courtesy of Fernando Araujo, MD

Case Example

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Mark Clemens, MD

1. Srinivasa D, et al. Plast Reconstr Surg 2017;139:1029–39.

Registries Critical To Understanding

• 194 patients reported to ASPS PROFILE Registry2

• 52 patients treated at MDACC3

Mark Clemens, MD

BIA‐ALCL Global Network Roundtable

Consistent messaging on diagnosis and treatment across international societies

Global prospective registry with standardised data

Cross‐country data exchange

Network for disbursement of disease updates

Localised access to medical care

Centralised tissue repositories

26 countries represented

Australia: Anand Deva, MD

Belgium: Moustapha Hamdi, MD

Brazil: Alexandre Passos, MD

Canada: Peter Lennox, MD FRCSC

Finland: Catarina Svarvar, MD

France: Michael Atlan, MD

Japan: Toshiharu Minabe, MD

Ireland: Catriona Lawlor, MD

Israel: Yoav Barnea, MD

Italy: Riccardo Carnino, Antonella Campanale MD

Mexico: Guillermo Ramos Gallardo, MD

Netherlands: Hinne Rakhorst, MD

New Zealand: Julian Lofts, MD

South Africa: Chris Snijman, MD

South Korea: Roe, Tae Suk MD

Spain: Antonio Diaz Gutierrez, MD

Sweden: Per Heden, MD

Taiwan: Nai‐Chen Cheng, MD

United Kingdom: Joe O’Donoghue, MD

Mark Clemens, MD

BIA‐ALCL Global Network Roundtable

517 World Cases, Unique and pathology confirmed

16 Deaths Worldwide

28 countries

Australia: 71 Cases, 3 deaths

Belgium: 5 Cases

Brazil: 3 Cases, 1 death

Canada: 23 Cases

Colombia: 6 Cases

Denmark: 7 Cases

Finland: 1 Case

France: 42 Cases, 2 deaths

Germany: 6 cases

Israel: 5 Cases

Mexico: 4 Cases

Netherlands: 40 Cases, 1 Death

New Zealand: 12 Cases, 1 death

South Africa: 1 Case

South Korea: None

Spain: 24 Cases

Sweden: 6 Cases, 2 death

Taiwan: None

United Kingdom: 33 Cases, 1 death

Thailand: 1 Case

United States: 194 Cases, 5 deaths

Argentina: 1 Case

Chile: 2 Cases

Italy: 28 Cases

Russia: 1 case

Venezuela: 1 case

Mark Clemens, MD

0

100

200

300

400

500

600

1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018 2020 2022

All unique cases from 28 countries. US data from PROFILE Registry, www.thepsf.orf/PROFILE

BIA‐ALCL turns 20 years

Worldwide 513

US 190

Deaths 16

• One Year Increase

• Worldwide 44%

• US 45%

• Deaths 77%

Mark Clemens, MD

1. Clemens MW, et al. Gland Surgery 2016; doi: 10.21037/gs.2016.11.03; 2. Brody GS, et al. Plast Reconstr Surg 2015;135:695–705.

Comparison of ManufacturersMD Anderson Tracking1

Adapted Brody 20152

Manufacturer n %

Unknown 91 47.4

Allergan/Inamed/ McGhan

81 42.2

Mentor 6 3.1

Nagor 3 1.6

Eurosilicone 1 0.5

PIP 5 2.6

Sientra/Silimed 4 2.1

Bioplasty 1 0.5

Manufacturer n %

Unknown 61 35

Allergan/Inamed/ McGhan

97 56

Mentor 3 1.7

Nagor 3 1.7

Eurosilicone 0 0

PIP 5 2.9

Sientra/Silimed

1 0.5

MAUDE FDA Database1

Manufacturer n %

Unknown 22 9.6

Allergan/ Inamed/ McGhan

184 80.3

Mentor 20 8.7

CUI 1 0.4

Sientra 1 0.4

US MAUDE represents a nearly two manufacturer market compared with world data

Mark Clemens, MD

1. Palraj B, et al. J Foot Ankle Surg 2010;49:561–4; 2. Yoon HJ, et al. Int J Surg Pathol 2015;23:656–61; 3. Engberg A, et al. J Clin Oncol 2013;31:e87–e89. 4. Kellogg B et al. Annals Plastic Surgery 2013; 73(4).

Prosthesis‐associated?

Dental implant ALCL2

Chest port ALCL3

Tibial implant ALCL1

• Tibial Implant

• Dental implant ALCL2

• Chest port ALCL3

• Total hip arthroplasties have higher rates of lymphoma4

• Shoulder repair ALCL

• Lap Band ALCL

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Mark Clemens, MD

No Confirmed Pure Smooth Cases To Date

1. Largent J, et al. Eur J Cancer Prev 2012, 21:274–280; Lazzeri D, et al. Clin Breast Cancer 2011;11(5):283–96; 3. Brody GS, et al. Plast Reconstr Surg 2015; 135:695–705.

70 to 80 percent of implants sold in North America are smooth.No cases of ALCL were found in patients with documented smooth devices only.3

58‐year‐old woman who had undergone bilateral cosmetic breast augmentation with a smooth silicone gel breast implants 19 years previously. In 2006, her device had already been replaced for the same complication.2

Age 71: left breast cancer (1980), treated with radiotherapy and reconstructive breast surgery (device unknown). Right breast cancer (1990) treated with mastectomy and reconstructive surgery (device unknown).1

Out of 359 adverse event reports, 28 reports of “smooth implants” cases.Smooth implant reports had either no clinical history or a very superficial unreliable history.

Mark Clemens, MD

• 100 US pathologically confirmed cases up to 20151

• Incidence rate: 2.03 in 1,000,000 person‐years1

• 67.6 times higher than that of breast ALCL (3 per 100 million) p<0.001

• Assuming that BIA‐ALCL occurs only in textured breast implants1

• Based on extrapolated sales data• 6.7% implant removal rate at 10 years

• Lifetime risk 1:30,000 women with textured implants

1. Doren E, et al. Plast Reconstr Surg 2017;139:1042–50.

US incidence1

0

1

2

3

4

5

6

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

Incidence of BI‐ALCL1

Incidence per 1,000,000 person‐years

Lifetime risk:1:30,000 textured implants

Mark Clemens, MD

• US: 1:30,000 (100 cases, 2016)

• Netherlands 1:6920 (32 cases)

• Australia, New Zealand, 83 cases,1,2

17 PU cases

• Risk 1:1000‐1:10,000?1 for textured implants

• Allergan Biocell (1:3705)

• Silimed polyurethane (1:3894)

• Mentor Siltex (1:60631)

1. Therapeutic Goods Administration update, 20 December 2016; 2. Smith TJ. Breast 2012;21:102–4.

Geographic variation?

2

October, 2017 Mark Clemens, MD

• IL‐13 is the signature cytokine of allergic inflammation

• Th2 Lymphocytes and ALCL both express GATA3 (Th2 transcription factor) and both secrete IL‐13

• Creates Feedback loop

Mechanism of Allergic Inflammation

Antigen ‐Multifactorial

Chronic inflammation of capsules with fibrosis, plasma cells, lymphocytes

mast cells produce prostaglandin D2 (PGD2)

Th2 Lymphocytes and ALCL express GATA3 and secrete IL‐13

IL‐13 Ig induces class switch of B cells to produce IgE

8‐10 Years

Plasma cells expressing IgE in capsule and lymph nodes

IgE Release

IL‐13 Release

PGD2 Release

Receptor for PGD2 on ALCL cells

Mark Clemens, MD

1. Crescenzo R, et al. Cancer Cell 2015;27:516–32; 2. Malcolm TIM, et al. Open Biol 2016;6:160232.

Determination of origin cell

2

2

• IL 13 production – allergic reaction

• IL 26 production – Th17 antibacterial cytokine

• BIA‐ALCL Th17 phenotype

• Th17 contribute to pathogen clearance at mucosal surfaces and chronic inflammation

• Detailed evaluation of biomarkers

• CD30+ in all (n=64) cases,

• CD3+ 15 of 62 (24%) cases

• CD4+ 43 of 61 (70%),

• CD8+ 6 of 57 (11%),

• CD43+ 37 of 46 (80%),

• CD45+ 29 of 49 (59%),

• TCR αβ+ 5 of 24 (21%)

• TCR γδ+ 1 of 23 (4%)

• TCR was silent on 18 of 24 (75%)

Mark Clemens, MD

Blombery P, et al. Haematologica2016;10:e387–90; 2. Di Napoli A, et al. Br J Haematol2016.

Gene sequencing BIA‐ALCL

1

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• Blombery 20161

• Mutations on two patients

• STAT3, JAK1, JAK3

• Di Napoli 20162

• Mutations in two patients

• DNMT3A

• STAT3, TP53, SOCS1

These mutations predispose to lymphoma in a chronically stimulated environment with high T‐cell replication

2/7/2018

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Mark Clemens, MD

Image courtesy of Dr Mark Clemens

Finding the super antigen

Implant capsule interface

SEM: 300x

ALCL clusters on implant

SEM: 4,000x

Individual ALCL cells

• Multifactorial related to textured implant

• Silicone particulate

• Mechanical abrasion

• Bacteria/biofilm LPS SEM: 40x

Mark Clemens, MD

1. Hu H, et al. Plast Reconstr Surg 2015;135:319–29.

Gram Negative LPS Antigen1

Glycoproteinmatrix

BIA‐ALCL

Bacteria

Bacteria

BacteriaGlycoproteinmatrix

• Ralstonia pickettii

• Ralstonia spp

• Gram‐Negative Bacteria

Mark Clemens, MD

Univariate

BMI, p=0.04

Age>52, p=0.005

Comorbidity, p=0.02

SNLBx, p=0.04

High Intraop fill, p=0.08

NSM, p=0.06

CA vs. Proph, p=0.08

Duct vs Lob, p=0.004

Bra>700cc, p=0.003

High drain time, p=0.003

Multivariate

Postop XRT, p=0.02 2.3x

SLNBx, p=0.009 2.45x

100cc of fill volume, p=0.0001 5x

Breast ReconstructionInfection Predictors

Selber JC, Wren JH, Garvey PB, Zhang H, Erickson C, Clemens MW, Butler CE. Critical Evaluation of Risk Factors and Early Complications in 564 Consecutive Two‐Stage Implant‐Based Breast Reconstructions Using ADM at a Single Center. Plast ReconstrS 2015

Level III Evidence

Mark Clemens, MD

High BMI

Comorbidity

Diabetes

Hypertension

CAD

Postop XRT

CA vs. Proph

In situ vs. invasive

Duct vs Lob

Bra>700cc

Nipple sparing mastectomy

Axillary Dissection

Cosmetic versus reconstructive

Textured Versus Smooth Implant

Predictors and Protectors of Infection

Betadine irrigation

ADM use

Drain Use and duration

Incision Placement

Plane of Implant

Intraoperative ABX

Changing gloves and instruments

No touch technique

Mastectomy flap necrosis

Mark Clemens, MD

Particulate digestion stimulates immune system

Activated B cells

Activated TH cells

Mark Clemens, MD

• Chronic macrophage engulfment of particulate

• Development of foamy cells

• Cytokine induced lymphocyte chemotaxis

• Synovitis rare sequelae of implant arthroplasties

Macrophage Particulate Digestion

Particulate Foamy macrophage

BIA‐ALCL & particulate

BIA‐ALCL & particulate

2/7/2018

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Mark Clemens, MD

• Recommended as part of informed consent for all breast implants

• Downloadable examples

• ASPS recommendation

1. Clemens MW, et al. Plast Reconstr Surg 2016:137:1117–22.

Best practice: Surgery consentInform, not frighten1

“The FDA has found that women with breast implants have a very low but increased risk of developing anaplastic large cell lymphoma (ALCL), a rare form of lymphoma, a cancer of the immune system. The main symptoms of ALCL in women with breast implants were a delayed fluid collection around a breast implant, often years after implant placement. Notify your health care provider if you develop any unusual signs or symptoms of your breast implants.”1

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Mark Clemens, MD

Report confirmed cases to PROFILE

• Patient Registry and Outcomes For breast Implants and anaplasticlarge cell Lymphoma etiology and Epidemiology (PROFILE)

• Contact: [email protected]

• ASPS/PSF and FDA Cooperative Research and

Development Agreement Submit a case

BIA‐ALCL Subcommittee

• Mark Clemens (Chair)

• Bill Adams, MD

• Anu Antony, MD

• Garry Brody, MD

• Patrick Garvey, MD

• Colleen McCarthy, MD

• Michael Olding, MD

• Devinder Singh, MD

• Raman Mahabir, MD

• John Potochny, MD

Charge

• Increase clinical efforts of PROFILE registry

• Foster and facilitate international research

• Increase physician and patient education

Mark Clemens, MD

• April Plastic Reconstructive Surgery Journal

• Evidence‐based approach to diagnosis and management

• Mark Clemens, Garry Brody, Raman Mahabir, Roberto Miranda

CME: Diagnosis and Management of BIA‐ALCL

Mark Clemens, MD

• All implants carry a reasonable assurance of safety and efficacy

• BIA‐ALCL is a lymphoma based on pathology and clinical course

• Ensure to test any late seroma more than 1 year post‐implantation1

• Follow NCCN guidelines for the diagnosis and management of BIA‐ALCL

1. Clemens MW, et al. Gland Surgery 2016. doi: 10.21037/gs.2016.11.03

Conclusions

Image from Clemens and Miranda 2015.1

Do not test normal fluid1

Mark Clemens, MD

Thank you

[email protected]@clemensmd

Wei Yang, MDBreast Diagnostic Radiology

Roberto Miranda, MDHematopathology

Kelly Hunt, MDBreast Surgical Oncology

Yasuhiro Oki, MDLymphoma Oncology

Mark Clemens, MDPlastic Surgery

Gregg Staerkel, MDCytopathology

2 - 3 Clemmens 2018 ALCL...Report confirmed cases to ASPS/FDA PROFILE Registry 4. FDA, ASPS, ASAPS...

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