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To treat or not to treat: PD-L1 inhibitor-induced keratoacanthoma and squamous cell carcinoma

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Abstract

Keratoacanthoma (KA) and squamous cell carcinoma (SCC) are rare side effects of programmed cell death ligand-1 (PD-L1) inhibitors that can disrupt therapy. There is no consensus on optimal treatment. We investigated the management strategy and factors influencing pathophysiology. An institutional cancer registry and literature search were used for this retrospective study. Only PD-L1-induced KA and SCC cases were included. Pathology specimens were stained with immune markers and management strategies were analyzed. Four cases were identified at our institution. Immunohistochemistry of atypical keratinocytes revealed PD-1/PD-L1 positivity, high p53, and low bcl-2 for all cases with differential expression of CD44 and beta-catenin for KA versus SCC. Nivolumab was continued or temporarily held with complete resolution. In addition, a literature search identified 30 additional cases of KA/SCC after PDL-1 inhibitor use. The most common treatment was excision/destruction followed by topical and/or intralesional corticosteroids. Therapy was definitely withheld in 22% of KA patients and in 9% of SCC cases. The expression of PD-L1 by atypical keratinocytes helps to explain the effects of nivolumab on the development of cutaneous neoplasms. The expression of immune markers provides mechanistic insights into pathophysiology. Management may be achieved with conservative therapy and without treatment interruption.

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References

  1. Freites-Martinez A, Kwong BY, Rieger KE, Coit DG, Colevas AD, Lacouture ME (2017) Eruptive keratoacanthomas associated with pembrolizumab therapy. JAMA Dermatol 153(7):694–697

    Article  PubMed  PubMed Central  Google Scholar 

  2. Apalla Z, Nikolaou V, Fattore D, Fabbrocini G, Freites-Martinez A, Sollena P, Lacouture M, Kraehenbuehl L, Stratigos A, Peris K, Lazaridou E, Richert B, Vigarios E, Riganti J, Baroudjian B, Filoni A, Dodiuk-Gad R, Lebbé C, Sibaud V (2022) European recommendations for management of immune checkpoint inhibitors-derived dermatologic adverse events. The EADV task force “Dermatology for cancer patients” position statement. J Eur Acad Dermatol Venereol 36(3):332–350

    Article  CAS  PubMed  Google Scholar 

  3. Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, Atkins MB, Brassil KJ, Caterino JM, Chau I, Davies MJ, Ernstoff MS, Fecher L, Ghosh M, Jaiyesimi I, Mammen JS, Naing A, Nastoupil LJ, Phillips T, Porter LD, Reichner CA, Seigel C, Song JM, Spira A, Suarez-Almazor M, Swami U, Thompson JA, Vikas P, Wang Y, Weber JS, Funchain P, Bollin K (2021) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 39(36):4073–4126

    Article  CAS  PubMed  Google Scholar 

  4. Antonov NK, Nair KG, Halasz CL (2019) Transient eruptive keratoacanthomas associated with nivolumab. JAAD Case Rep 5(4):342–345

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bandino JP, Perry DM, Clarke CE, Marchell RM, Elston DM (2017) Two cases of anti-programmed cell death 1-associated bullous pemphigoid-like disease and eruptive keratoacanthomas featuring combined histopathology. J Eur Acad Dermatol Venereol 31(8):e378–e380

    Article  CAS  PubMed  Google Scholar 

  6. Bednarek R, Marks K, Lin G (2018) Eruptive keratoacanthomas secondary to nivolumab immunotherapy. Int J Dermatol 57(3):e28–e29

    Article  PubMed  Google Scholar 

  7. Chaudhari S, Leon A, Levin E, Neuhaus I, Liao W (2017) Case report of multiple keratoacanthomas and squamous cell carcinomas in a patient receiving pembrolizumab. J Drugs Dermatol 16(5):513–515

    PubMed  Google Scholar 

  8. Crow LD, Perkins I, Twigg AR, Fassett MS, LeBoit PE, Berger TG, Khodosh R (2020) Treatment of PD-1/PD-L1 inhibitor-induced dermatitis resolves concomitant eruptive keratoacanthomas. JAMA Dermatol 156(5):598–600

    Article  PubMed  Google Scholar 

  9. Feldstein SI, Patel F, Larsen L, Kim E, Hwang S, Fung MA (2018) Eruptive keratoacanthomas arising in the setting of lichenoid toxicity after programmed cell death 1 inhibition with nivolumab. J Eur Acad Dermatol Venereol 32(2):e58–e59

    Article  CAS  PubMed  Google Scholar 

  10. Fradet M, Sibaud V, Tournier E, Lamant L, Boulinguez S, Brun A, Pages C, Meyer N (2019) Multiple keratoacanthoma-like lesions in a patient treated with pembrolizumab. Acta Derm Venereol 99(13):1301–1302

    Article  PubMed  Google Scholar 

  11. Fujimura T, Lyu C, Tsukada A, Sato Y, Kambayashi Y, Aiba S (2019) Eruptive keratoacanthoma with spontaneous regression arising from a cervical squamous cell carcinoma patient treated with nivolumab. J Dermatol 46(5):e177–e178

    Article  PubMed  Google Scholar 

  12. Haraszti S, Polly S, Ezaldein HH, Rothbaum R, Delost GR, Beveridge M (2019) Eruptive squamous cell carcinomas in metastatic melanoma: an unintended consequence of immunotherapy. JAAD Case Rep 5(6):514–517

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hwang SJ, Carlos G, Wakade D, Byth K, Kong BY, Chou S, Carlino MS, Kefford R, Fernandez-Penas P (2016) Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort. J Am Acad Dermatol 74(3):455–461

    Article  PubMed  Google Scholar 

  14. Kanekura T, Arimura A, Kirishima M, Tanimoto A (2019) Eruptive squamous cell carcinoma in a patient treated with concomitant pembrolizumab and imiquimod. J Dermatol 46(12):1202–1204

    Article  CAS  PubMed  Google Scholar 

  15. Lee J, Guffey DJ, Noland MB, Russell MA (2019) Eruptive squamous cell carcinomas associated with programmed cell death protein-1 inhibitor therapy. Indian J Dermatol Venereol Leprol 85(1):97–100

    Article  PubMed  Google Scholar 

  16. Marsh RL, Kolodney JA, Iyengar S, Yousaf A, Louden BA, Al-Bouri A, Kolodney MS (2020) Formation of eruptive cutaneous squamous cell carcinomas after programmed cell death protein-1 blockade. JAAD Case Rep 6(5):390–393

    Article  PubMed  PubMed Central  Google Scholar 

  17. Park JH, Yoon D, Lee J, Oh SJ, Kim HJ, Lee JH, Lee DY (2021) Clinical profile of cutaneous adverse events of immune checkpoint inhibitors in a single tertiary center. J Dermatol 48(7):979–988

    Article  CAS  PubMed  Google Scholar 

  18. Preti BTB, Pencz A, Cowger JJM, Vincent MD, Breadner D (2021) Skin deep: a fascinating case report of immunotherapy-triggered, treatment-refractory autoimmune lichen planus and keratoacanthoma. Case Rep Oncol 14(2):1189–1193

    Article  PubMed  PubMed Central  Google Scholar 

  19. Badell A, Marcoval J, Gallego I, Moreno A, Peyrí J (2000) Keratoacanthoma arising in hypertrophic lichen planus. Br J Dermatol 142(2):380–382

    Article  CAS  PubMed  Google Scholar 

  20. Giesecke LM, Reid CM, James CL, Huilgol SC (2003) Giant keratoacanthoma arising in hypertrophic lichen planus. Australas J Dermatol 44(4):267–269

    Article  PubMed  Google Scholar 

  21. Knackstedt TJ, Collins LK, Li Z, Yan S, Samie FH (2015) Squamous cell carcinoma arising in hypertrophic lichen planus: a review and analysis of 38 cases. Dermatol Surg 41(12):1411–1418

    Article  CAS  PubMed  Google Scholar 

  22. Haenen CCP, Buurma AAJ, Genders RE, Quint KD (2018) Squamous cell carcinoma arising in hypertrophic lichen planus. BMJ Case Rep. https://doi.org/10.1136/bcr-2017-224044

    Article  PubMed  PubMed Central  Google Scholar 

  23. Joseph RW, Cappel M, Goedjen B, Gordon M, Kirsch B, Gilstrap C, Bagaria S, Jambusaria-Pahlajani A (2015) Lichenoid dermatitis in three patients with metastatic melanoma treated with anti-PD-1 therapy. Cancer Immunol Res 3(1):18–22

    Article  PubMed  Google Scholar 

  24. Shi VJ, Rodic N, Gettinger S, Leventhal JS, Neckman JP, Girardi M, Bosenberg M, Choi JN (2016) Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell death 1 and anti-programmed cell death ligand 1 immunotherapy. JAMA Dermatol 152(10):1128–1136

    Article  PubMed  PubMed Central  Google Scholar 

  25. Tataroglu C, Karabacak T, Apa DD (2007) Beta-catenin and CD44 expression in keratoacanthoma and squamous cell carcinoma of the skin. Tumori 93(3):284–289

    Article  PubMed  Google Scholar 

  26. Karjalainen JM, Tammi RH, Tammi MI, Eskelinen MJ, Agren UM, Parkkinen JJ, Alhava EM, Kosma VM (2000) Reduced level of CD44 and hyaluronan associated with unfavorable prognosis in clinical stage I cutaneous melanoma. Am J Pathol 157(3):957–965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Thomas L, Byers HR, Vink J, Stamenkovic I (1992) CD44H regulates tumor cell migration on hyaluronate-coated substrate. J Cell Biol 118(4):971–977

    Article  CAS  PubMed  Google Scholar 

  28. Fukumaru K, Yoshii N, Kanzaki T, Kanekura T (2007) Immunohistochemical comparison of beta-catenin expression by human normal epidermis and epidermal tumors. J Dermatol 34(11):746–753

    Article  CAS  PubMed  Google Scholar 

  29. Campos MA, Macedo S, Fernandes MS, Pestana A, Pardal J, Batista R, Vinagre J, Sanches A, Baptista A, Lopes JM, Soares P (2020) Prognostic significance of RAS mutations and P53 expression in cutaneous squamous cell carcinomas. Genes (Basel) 11(7):751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bedir R, Güçer H, Şehitoğlu İ, Yurdakul C, Bağcı P, Üstüner P (2016) The role of p16, p21, p27, p53 and Ki-67 expression in the differential diagnosis of cutaneous squamous cell carcinomas and keratoacanthomas: an immunohistochemical study. Balkan Med J 33(2):121–127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Batinac T, Zamolo G, Coklo M, Hadzisejdic I, Stemberger C, Zauhar G (2006) Expression of cell cycle and apoptosis regulatory proteins in keratoacanthoma and squamous cell carcinoma. Pathol Res Pract 202(8):599–607

    Article  CAS  PubMed  Google Scholar 

  32. Barzilai A, Lyakhovitsky A, Trau H, Fogel M, Huszar M (2007) Expression of p53 in the evolution of squamous cell carcinoma: correlation with the histology of the lesion. J Am Acad Dermatol 57(4):669–676

    Article  PubMed  Google Scholar 

  33. Batinac T, Zamolo G, Jonjić N, Gruber F, Petrovecki M (2004) p53 protein expression and cell proliferation in non-neoplastic and neoplastic proliferative skin diseases. Tumori 90(1):120–127

    Article  PubMed  Google Scholar 

  34. Abu Juba B, Şovrea A, Crişan D, Melincovici C, Coneac A, Badea M, Crişan M (2013) Apoptotic markers in photoinduced cutaneous carcinoma. Rom J Morphol Embryol 54(3 Suppl):741–747

    CAS  PubMed  Google Scholar 

  35. Turan G, Altun E, Aslan F, Kulahci O (2019) The role of p53, Ki-67 and laminin expression in the differential diagnosis of keratoacanthoma and well-differentiated SCC. Indian J Pathol Microbiol 62(4):561–565

    Article  PubMed  Google Scholar 

  36. Min Lee CK, Li S, Tran DC, Zhu GA, Kim J, Kwong BY, Chang ALS (2018) Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study. J Am Acad Dermatol 79(6):1047–1052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Burton KA, Ashack KA, Khachemoune A (2016) Cutaneous squamous cell carcinoma: a review of high-risk and metastatic disease. Am J Clin Dermatol 17(5):491–508

    Article  PubMed  Google Scholar 

  38. Kwiek B, Schwartz RA (2016) Keratoacanthoma: update and review. J Am Acad Dermatol 74:1220–1233

    Article  PubMed  Google Scholar 

  39. Schwartz RA, Blaszczyk M, Jablonska S (2002) Generalized eruptive keratoacanthoma of Grzybowski: follow-up of the original description and 50-year retrospect. Dermatology (Basel) 205:348–352

    Article  Google Scholar 

  40. Mulvaney PM, Massey PR, Yu KK, Drinan JE, Schmults CD (2021) Differential molecular expression patterns associated with metastasis in cutaneous squamous cell carcinoma: a systematic review and meta-analysis. J Invest Dermatol 141(9):2161–2169

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Dermatology, Saint Louis University School of Medicine, St. Louis, MO, USA

    Mackenzie Poole & Albert Alhatem

  2. Departments of Dermatology and Pathology, Rutgers University New Jersey Medical School, Newark, NJ, USA

    Robert A. Schwartz & W. Clark Lambert

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  1. Mackenzie Poole
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M.P., R.A.S., W.C.L. and A.A. designed the project. M.P. and A.A. wrote the main manuscript text and prepared tables 1-3 and figures 1-3. All authors reviewed the manuscript.

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Correspondence to Albert Alhatem.

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Poole, M., Schwartz, R.A., Lambert, W.C. et al. To treat or not to treat: PD-L1 inhibitor-induced keratoacanthoma and squamous cell carcinoma. Arch Dermatol Res 315, 903–915 (2023). https://doi.org/10.1007/s00403-022-02468-3

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  • DOI: https://doi.org/10.1007/s00403-022-02468-3

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