Commentary on: Breast Erythema in a Patient With Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Case Report Discussing Cutaneous Manifestations

Commentary on: Breast Erythema in a Patient With Breast Implant-Associated Anaplastic Large Cell... “One can state, without exaggeration, that the observation of and the search for similarities and differences are the basis of all human knowledge.”1 – Alfred Nobel “We are continually faced with a series of great opportunities brilliantly disguised as insoluble problems.”2 – John W. Gardner This case report outlines a presentation of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) in a 71-year-old Caucasian female who developed significant erythema, fever, leukocytosis, and a raised C reactive protein whilst undergoing neoadjuvant chemotherapy prior to definitive surgical treatment.3 The authors note that her symptoms and white cell count settled after antibiotic treatment. Both skin biopsy and aspiration of complex fluid collection that developed in parallel with the erythema failed to grow any microorganisms and histology showed dermatitis and eosinophilic spongiosis. The authors raise a number of possibilities including a direct effect of the cancer, tumor lysis syndrome, or infection. Observation and publication of clinical features from interesting case reports has been somewhat devalued in the face of the growth of evidence-based research. We should remember that prior to the rise of the all-conquering randomized controlled trial, much of what we have discovered in medicine was on the basis of keen and sometimes serendipitous observation—such as the discovery of penicillin.4 Whilst a structured scientific approach is important, there are growing calls for acknowledgement of the role of observation, experience, understanding, and wisdom in making medical decisions.5 This case looks and feels like an infection. When a patient has an implant in situ and develops erythema, warmth, fever, a rising erythrocyte sedimentation rate, leukocytosis, and a fluid collection, chances are that there is sepsis brewing. Recovery of bacteria once a patient is commenced in antibiotic therapy is, as the authors acknowledge, difficult. Furthermore, we have shown that in the setting of biofilm infection, the recovery of causative organisms using traditional culture techniques will more than likely give a false negative result.6 Clinical response to antibiotics over 2 weeks should support the observation that this presentation is likely to be a manifestation of subclinical infection of the underlying breast implant. The role of infection as a potential driver for BIA-ALCL has been covered previously.7,8 The authors cite our work on the detection and characterization of bacterial biofilm infection in BIA-ALCL9 The recent publication and commentary on the epidemiology of BIA-ALCL in Australia and New Zealand and the observation of a 10-fold higher risk for high surface area textured implants support the role of bacteria as a causative factor.10 The growing recognition of the role of the microbiome (bacterial population on our skin, gut, breast, mucosa) in the genesis of other cancers such as breast, oral, prostate, and colon and other diseases is also being further studied and defined.11 The recent reporting of allergic inflammation around 3 tumor cell lines and BIA-ALCL samples,12 whilst requiring a larger sample size to corroborate the findings, is consistent with an infective biological antigenic driver. There is link between chronic infection (both viral and bacterial) to the genesis of allergies and a double hit of a mucosal response to infection, triggering an abnormal immune response and sensitization to environmental allergens in genetically susceptible individuals.13 A few other potential drivers of inflammation have been put forward. These include silicone particles,14,15 friction,16 and heavy metals.17 In fact, heavy metals and silicone now feed into a growing belief that chemicals/metals and silicone from breast implants cause a range of local and systemic symptoms which are grouped under “breast implant illness”18,19 and autoimmune syndrome induced by adjuvants (ASIA).20 Further study of patients with these conditions is underway and it is important to approach this with an open mind. I suspect that in some patients, there may well be underlying pathology derived from the placement of breast implants that drives disease. Transformative cell biology, however, supports that the antigen driver is more likely to be biologically derived rather than an inorganic compound or metal. T-cell receptor activation and transformation do require the binding of a biologically derived antigen (eg, peptide, polysaccharide, or protein). The pathway from bacterial antigen/receptor activation to lymphoma has been proven for helicobacter pylori and gastric mucosal associated lymphoid tissue lymphoma and gastric cancer.21 More recently, in a process that may be remarkably similar to the role of bacteria and genetics in BIA-ALCL, gluten − a biologically derived peptide − in combination with the intestinal microbiome has been shown to drive T-cell receptor changes in patients with celiac disease toward transformation into lymphoma.22,23 Understanding the interaction between genes, the microbiome, and immunity may well provide new approaches to both the treatment and prevention of cancer. There is plenty of work to be done. Our laboratory, in partnership with others around the world, is on the hunt for the antigenic driver. We are currently looking closely at the role of bacterial antigens in driving T-cell and tumor cell activation and transformation. We hope to report our findings in the coming months. In parallel, the genome of patients with BIA-ALCL is being closely studied to identify potential germline and tumor mutations that trigger malignant transformation in the setting of antigen-derived inflammation. Genetics, bacteria, textured implants, and time form the 4 factors that weave together in the unifying hypothesis put forward to explain the likely genesis of BIA-ALCL.10 As of now, we have two modifiable targets to potentially reduce the risk of this cancer, our choice of implant surface (high surface area, low surface area, smooth) and the use of antibacterial mitigation when these implants are inserted. It is important that both surgeons and patients are kept fully informed of the developments in this area, as they begin to bring much needed change to the use of breast implants for both aesthetic and reconstructive surgery around the world. Disclosures Prof Deva has previously coordinated research and been a consultant to Allergan (Irvine, CA), Mentor (Santa Barbara, CA), and KCI (San Antonio, TX). Funding The author received no financial support for the research, authorship, and publication of this article. REFERENCES 1. Nobelprize.org. Aphorisms by Alfred Nobel . 2017; https://www.nobelprize.org/alfred_nobel/biographical/aphorisms.html. Accessed December 3, 2017. 2. Gardner JW. On leadership . New York: The Free Press; 1990. 3. Elswick SM, Nguyen MT. Breast erythema in a patient with breast implant-associated anaplastic large cell lymphoma: a case report discussing cutaneous manifestations. Aesthet Surg J . 2018;38(3):N47-N52. 4. Ban TA. The role of serendipity in drug discovery. Dialogues Clin Neurosci . 2006; 8( 3): 335- 344. Google Scholar PubMed  5. Miller CG, Miller DW. The real world failure of evidence-based medicine. Int J Pers Cent Med . 2011; 1( 2): 295- 300. 6. Pajkos A, Deva AK, Vickery K, Cope C, Chang L, Cossart YE. Detection of subclinical infection in significant breast implant capsules. Plast Reconstr Surg . 2003; 111( 5): 1605- 1611. Google Scholar CrossRef Search ADS PubMed  7. Deva AK. Commentary on: CD30+ T Cells in Late Seroma May Not Be Diagnostic of Breast Implant-Associated Anaplastic Large Cell Lymphoma. Aesthet Surg J . 2017; 37( 7): 779- 781. Google Scholar CrossRef Search ADS PubMed  8. Deva AK. Response to “Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): why the search for an infectious etiology may be irrelevant”. Aesthet Surg J . 2017; 37( 9): NP122- NP128. Google Scholar CrossRef Search ADS PubMed  9. Hu H, Johani K, Almatroudi Aet al.   Bacterial biofilm infection detected in breast implant-associated anaplastic large-cell lymphoma. Plast Reconstr Surg . 2016; 137( 6): 1659- 1669. Google Scholar CrossRef Search ADS PubMed  10. Loch-Wilkinson A, Beath KJ, Knight RJWet al.   Breast implant-associated anaplastic large cell lymphoma in Australia and New Zealand: high-surface-area textured implants are associated with increased risk. Plast Reconstr Surg . 2017; 140( 4): 645- 654. Google Scholar CrossRef Search ADS PubMed  11. Balter M. Taking stock of the human microbiome and disease. Science . 2012; 336( 6086): 1246- 1247. Google Scholar CrossRef Search ADS PubMed  12. Kadin ME, Epstein AL, Adams WPAJet al.   Evidence that some breast implant associated anaplastic large cell lymphomas arise in the context of allergic inflammation. Presented at the American Society of Hematology Annual Meeting, Atlanta, GA; December 9-12, 2017. 13. Wang JY. The sticky relationship between allergies and infections. Asia Pac Allergy . 2015; 5( 3): 133- 135. Google Scholar CrossRef Search ADS PubMed  14. Fleury EF, Rêgo MM, Ramalho LCet al.   Silicone-induced granuloma of breast implant capsule (SIGBIC): similarities and differences with anaplastic large cell lymphoma (ALCL) and their differential diagnosis. Breast Cancer (Dove Med Press) . 2017; 9: 133- 140. Google Scholar PubMed  15. Wolfram D, Rabensteiner E, Grundtman Cet al.   T regulatory cells and TH17 cells in peri-silicone implant capsular fibrosis. Plast Reconstr Surg . 2012; 129( 2): 327e- 337e. Google Scholar CrossRef Search ADS PubMed  16. Mazzocchi M, Dessy LA, Corrias F, Scuderi N. A clinical study of late seroma in breast implantation surgery. Aesthetic Plast Surg . 2012; 36( 1): 97- 104. Google Scholar CrossRef Search ADS PubMed  17. Ravi-Kumar S, Sanaei O, Vasef M, Rabinowitz I, Fekrazad MH. Anaplastic large cell lymphoma associated with breast implants. World J Plast Surg . 2012; 1( 1): 30- 35. Google Scholar PubMed  18. Brook MA. Platinum in silicone breast implants. Biomaterials . 2006; 27( 17): 3274- 3286. Google Scholar CrossRef Search ADS PubMed  19. Tang SY, Israel JS, Afifi AM. Breast implant illness: symptoms, patient concerns, and the power of social media. Plast Reconstr Surg . 2017; 140( 5): 765e- 766e. Google Scholar CrossRef Search ADS   20. Watad A, Quaresma M, Bragazzi NLet al.   The autoimmune/inflammatory syndrome induced by adjuvants (ASIA)/Shoenfeld’s syndrome: descriptive analysis of 300 patients from the international ASIA syndrome registry. Clin Rheumatol . 2018; 37( 2): 483- 493. Google Scholar CrossRef Search ADS PubMed  21. Peek RMJr, Kuipers EJ. Gained in translation: the importance of biologically relevant models of Helicobacter pylori-induced gastric cancer. Gut . 2012; 61( 1): 2- 3. Google Scholar CrossRef Search ADS PubMed  22. Hardy MY, Tye-Din JA. Coeliac disease: a unique model for investigating broken tolerance in autoimmunity. Clin Transl Immunology . 2016; 5( 11): e112. Google Scholar CrossRef Search ADS PubMed  23. Han A, Newell EW, Glanville Jet al.   Dietary gluten triggers concomitant activation of CD4+ and CD8+ αβ T cells and γδ T cells in celiac disease. Proc Natl Acad Sci U S A . 2013; 110( 32): 13073- 13078. Google Scholar CrossRef Search ADS PubMed  © 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Aesthetic Surgery Journal Oxford University Press

Commentary on: Breast Erythema in a Patient With Breast Implant-Associated Anaplastic Large Cell Lymphoma: A Case Report Discussing Cutaneous Manifestations

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Oxford University Press
Copyright
© 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com
ISSN
1090-820X
eISSN
1527-330X
D.O.I.
10.1093/asj/sjx259
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Abstract

“One can state, without exaggeration, that the observation of and the search for similarities and differences are the basis of all human knowledge.”1 – Alfred Nobel “We are continually faced with a series of great opportunities brilliantly disguised as insoluble problems.”2 – John W. Gardner This case report outlines a presentation of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) in a 71-year-old Caucasian female who developed significant erythema, fever, leukocytosis, and a raised C reactive protein whilst undergoing neoadjuvant chemotherapy prior to definitive surgical treatment.3 The authors note that her symptoms and white cell count settled after antibiotic treatment. Both skin biopsy and aspiration of complex fluid collection that developed in parallel with the erythema failed to grow any microorganisms and histology showed dermatitis and eosinophilic spongiosis. The authors raise a number of possibilities including a direct effect of the cancer, tumor lysis syndrome, or infection. Observation and publication of clinical features from interesting case reports has been somewhat devalued in the face of the growth of evidence-based research. We should remember that prior to the rise of the all-conquering randomized controlled trial, much of what we have discovered in medicine was on the basis of keen and sometimes serendipitous observation—such as the discovery of penicillin.4 Whilst a structured scientific approach is important, there are growing calls for acknowledgement of the role of observation, experience, understanding, and wisdom in making medical decisions.5 This case looks and feels like an infection. When a patient has an implant in situ and develops erythema, warmth, fever, a rising erythrocyte sedimentation rate, leukocytosis, and a fluid collection, chances are that there is sepsis brewing. Recovery of bacteria once a patient is commenced in antibiotic therapy is, as the authors acknowledge, difficult. Furthermore, we have shown that in the setting of biofilm infection, the recovery of causative organisms using traditional culture techniques will more than likely give a false negative result.6 Clinical response to antibiotics over 2 weeks should support the observation that this presentation is likely to be a manifestation of subclinical infection of the underlying breast implant. The role of infection as a potential driver for BIA-ALCL has been covered previously.7,8 The authors cite our work on the detection and characterization of bacterial biofilm infection in BIA-ALCL9 The recent publication and commentary on the epidemiology of BIA-ALCL in Australia and New Zealand and the observation of a 10-fold higher risk for high surface area textured implants support the role of bacteria as a causative factor.10 The growing recognition of the role of the microbiome (bacterial population on our skin, gut, breast, mucosa) in the genesis of other cancers such as breast, oral, prostate, and colon and other diseases is also being further studied and defined.11 The recent reporting of allergic inflammation around 3 tumor cell lines and BIA-ALCL samples,12 whilst requiring a larger sample size to corroborate the findings, is consistent with an infective biological antigenic driver. There is link between chronic infection (both viral and bacterial) to the genesis of allergies and a double hit of a mucosal response to infection, triggering an abnormal immune response and sensitization to environmental allergens in genetically susceptible individuals.13 A few other potential drivers of inflammation have been put forward. These include silicone particles,14,15 friction,16 and heavy metals.17 In fact, heavy metals and silicone now feed into a growing belief that chemicals/metals and silicone from breast implants cause a range of local and systemic symptoms which are grouped under “breast implant illness”18,19 and autoimmune syndrome induced by adjuvants (ASIA).20 Further study of patients with these conditions is underway and it is important to approach this with an open mind. I suspect that in some patients, there may well be underlying pathology derived from the placement of breast implants that drives disease. Transformative cell biology, however, supports that the antigen driver is more likely to be biologically derived rather than an inorganic compound or metal. T-cell receptor activation and transformation do require the binding of a biologically derived antigen (eg, peptide, polysaccharide, or protein). The pathway from bacterial antigen/receptor activation to lymphoma has been proven for helicobacter pylori and gastric mucosal associated lymphoid tissue lymphoma and gastric cancer.21 More recently, in a process that may be remarkably similar to the role of bacteria and genetics in BIA-ALCL, gluten − a biologically derived peptide − in combination with the intestinal microbiome has been shown to drive T-cell receptor changes in patients with celiac disease toward transformation into lymphoma.22,23 Understanding the interaction between genes, the microbiome, and immunity may well provide new approaches to both the treatment and prevention of cancer. There is plenty of work to be done. Our laboratory, in partnership with others around the world, is on the hunt for the antigenic driver. We are currently looking closely at the role of bacterial antigens in driving T-cell and tumor cell activation and transformation. We hope to report our findings in the coming months. In parallel, the genome of patients with BIA-ALCL is being closely studied to identify potential germline and tumor mutations that trigger malignant transformation in the setting of antigen-derived inflammation. Genetics, bacteria, textured implants, and time form the 4 factors that weave together in the unifying hypothesis put forward to explain the likely genesis of BIA-ALCL.10 As of now, we have two modifiable targets to potentially reduce the risk of this cancer, our choice of implant surface (high surface area, low surface area, smooth) and the use of antibacterial mitigation when these implants are inserted. It is important that both surgeons and patients are kept fully informed of the developments in this area, as they begin to bring much needed change to the use of breast implants for both aesthetic and reconstructive surgery around the world. Disclosures Prof Deva has previously coordinated research and been a consultant to Allergan (Irvine, CA), Mentor (Santa Barbara, CA), and KCI (San Antonio, TX). Funding The author received no financial support for the research, authorship, and publication of this article. REFERENCES 1. Nobelprize.org. Aphorisms by Alfred Nobel . 2017; https://www.nobelprize.org/alfred_nobel/biographical/aphorisms.html. Accessed December 3, 2017. 2. Gardner JW. On leadership . New York: The Free Press; 1990. 3. Elswick SM, Nguyen MT. Breast erythema in a patient with breast implant-associated anaplastic large cell lymphoma: a case report discussing cutaneous manifestations. Aesthet Surg J . 2018;38(3):N47-N52. 4. Ban TA. The role of serendipity in drug discovery. Dialogues Clin Neurosci . 2006; 8( 3): 335- 344. Google Scholar PubMed  5. Miller CG, Miller DW. The real world failure of evidence-based medicine. Int J Pers Cent Med . 2011; 1( 2): 295- 300. 6. Pajkos A, Deva AK, Vickery K, Cope C, Chang L, Cossart YE. Detection of subclinical infection in significant breast implant capsules. Plast Reconstr Surg . 2003; 111( 5): 1605- 1611. Google Scholar CrossRef Search ADS PubMed  7. Deva AK. Commentary on: CD30+ T Cells in Late Seroma May Not Be Diagnostic of Breast Implant-Associated Anaplastic Large Cell Lymphoma. Aesthet Surg J . 2017; 37( 7): 779- 781. Google Scholar CrossRef Search ADS PubMed  8. Deva AK. Response to “Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL): why the search for an infectious etiology may be irrelevant”. Aesthet Surg J . 2017; 37( 9): NP122- NP128. Google Scholar CrossRef Search ADS PubMed  9. Hu H, Johani K, Almatroudi Aet al.   Bacterial biofilm infection detected in breast implant-associated anaplastic large-cell lymphoma. Plast Reconstr Surg . 2016; 137( 6): 1659- 1669. Google Scholar CrossRef Search ADS PubMed  10. Loch-Wilkinson A, Beath KJ, Knight RJWet al.   Breast implant-associated anaplastic large cell lymphoma in Australia and New Zealand: high-surface-area textured implants are associated with increased risk. Plast Reconstr Surg . 2017; 140( 4): 645- 654. Google Scholar CrossRef Search ADS PubMed  11. Balter M. Taking stock of the human microbiome and disease. Science . 2012; 336( 6086): 1246- 1247. Google Scholar CrossRef Search ADS PubMed  12. Kadin ME, Epstein AL, Adams WPAJet al.   Evidence that some breast implant associated anaplastic large cell lymphomas arise in the context of allergic inflammation. Presented at the American Society of Hematology Annual Meeting, Atlanta, GA; December 9-12, 2017. 13. Wang JY. The sticky relationship between allergies and infections. Asia Pac Allergy . 2015; 5( 3): 133- 135. Google Scholar CrossRef Search ADS PubMed  14. Fleury EF, Rêgo MM, Ramalho LCet al.   Silicone-induced granuloma of breast implant capsule (SIGBIC): similarities and differences with anaplastic large cell lymphoma (ALCL) and their differential diagnosis. Breast Cancer (Dove Med Press) . 2017; 9: 133- 140. Google Scholar PubMed  15. Wolfram D, Rabensteiner E, Grundtman Cet al.   T regulatory cells and TH17 cells in peri-silicone implant capsular fibrosis. Plast Reconstr Surg . 2012; 129( 2): 327e- 337e. Google Scholar CrossRef Search ADS PubMed  16. Mazzocchi M, Dessy LA, Corrias F, Scuderi N. A clinical study of late seroma in breast implantation surgery. Aesthetic Plast Surg . 2012; 36( 1): 97- 104. Google Scholar CrossRef Search ADS PubMed  17. Ravi-Kumar S, Sanaei O, Vasef M, Rabinowitz I, Fekrazad MH. Anaplastic large cell lymphoma associated with breast implants. World J Plast Surg . 2012; 1( 1): 30- 35. Google Scholar PubMed  18. Brook MA. Platinum in silicone breast implants. Biomaterials . 2006; 27( 17): 3274- 3286. Google Scholar CrossRef Search ADS PubMed  19. Tang SY, Israel JS, Afifi AM. Breast implant illness: symptoms, patient concerns, and the power of social media. Plast Reconstr Surg . 2017; 140( 5): 765e- 766e. Google Scholar CrossRef Search ADS   20. Watad A, Quaresma M, Bragazzi NLet al.   The autoimmune/inflammatory syndrome induced by adjuvants (ASIA)/Shoenfeld’s syndrome: descriptive analysis of 300 patients from the international ASIA syndrome registry. Clin Rheumatol . 2018; 37( 2): 483- 493. Google Scholar CrossRef Search ADS PubMed  21. Peek RMJr, Kuipers EJ. Gained in translation: the importance of biologically relevant models of Helicobacter pylori-induced gastric cancer. Gut . 2012; 61( 1): 2- 3. Google Scholar CrossRef Search ADS PubMed  22. Hardy MY, Tye-Din JA. Coeliac disease: a unique model for investigating broken tolerance in autoimmunity. Clin Transl Immunology . 2016; 5( 11): e112. Google Scholar CrossRef Search ADS PubMed  23. Han A, Newell EW, Glanville Jet al.   Dietary gluten triggers concomitant activation of CD4+ and CD8+ αβ T cells and γδ T cells in celiac disease. Proc Natl Acad Sci U S A . 2013; 110( 32): 13073- 13078. Google Scholar CrossRef Search ADS PubMed  © 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com

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Aesthetic Surgery JournalOxford University Press

Published: Mar 1, 2018

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