2 - 3 clemmens 2018 alcl...report confirmed cases to asps/fda profile registry 4. fda, asps, asaps...
TRANSCRIPT
2/7/2018
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
• 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
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
• 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
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
• 48‐year‐old female1
• 2004: bilateral cosmetic augmentation1
• 2016: acute swelling of right breast1
• FNA: ALCL1
2
2
Images courtesy of Dr Mark Clemens.
Mark Clemens, MD
• 48‐year‐old female1
• 2004: bilateral cosmetic augmentation1
• 2016: acute swelling of right breast1
• 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
Images courtesy of Dr Mark Clemens.
Images courtesy of Dr Mark Clemens.
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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
• 48‐year‐old female1
• 2004: bilateral cosmetic augmentation1
• 2016: acute swelling of right breast1
• 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
Images courtesy of Dr Mark Clemens
35% Effusion only2
Image from Clemens MW, et al. J Clin Oncol 2016
Mark Clemens, MD
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 1B1
Image courtesy of Dr Mark Clemens
11% early infiltration2
Image from Clemens MW, et al. J Clin Oncol 2016
• 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
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 1C1
13% capsule mass2
Image from Clemens MW, et al. J Clin Oncol 2016
Images courtesy of Dr Mark Clemens
Mark Clemens, MD
• T4: invasive mass outside of capsule
• 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 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
• 57‐year‐old female1
• 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
Image from Clemens MW, et al. J Clin Oncol 2016
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
Unpublished –TGA3 X X
Limited surgery, chemo
Mediastinal invasion
Unpublished –TGA3 X X
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
1
1
• 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
1
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