Skip to main content

Per- and polyfluoroalkyl substances (PFAS) exposure in melanoma patients: a retrospective study on prognosis and histological features

This article has been updated

Abstract

Per- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals which could be associated with cancer development, such as kidney and testicular cancers, pancreatic and hepatocellular carcinoma and thyroid tumor. Available scientific literature offers no information on the role of PFAS in melanoma development/progression. Since 1965, a massive environmental contamination by PFAS has occurred in northeastern Italy. This study compared histopathology and prognosis between melanoma patients exposed (n = 194) and unexposed (n = 488) to PFAS. All patients were diagnosed and/or treated for melanoma at the Veneto Oncological Institute and the University Hospital of Padua (Italy) in 1998–2014. Patients were categorized in exposed or unexposed groups according to their home address and the geographical classification of municipalities affected by PFAS contamination as provided by Veneto Government in 2018. Presence of mitoses was found in 70.5% of exposed patients and 58.7% of unexposed patients (p = 0.005). Median follow-up was 90 months (IQR 59–136). 5-year overall survival was 83.7% in exposed patients and 88.0% in unexposed patients (p = 0.20); 5-year disease-specific survival was 88.0% in exposed patients and 90.9% in unexposed patients (p = 0.50); 5-year disease-free survival was 83.8% in exposed patients and 87.3% in unexposed patients (p = 0.20). Adjusting for imbalanced characteristics at baseline (presence of mitoses), survival was not statistically different between exposed and unexposed patients (overall survival: HR 1.10, 95% CI 0.77 to 1.58, p = 0.57; disease-specific survival: HR 0.99, 95% CI 0.62 to 1.59, p = 0.99; disease-free survival: HR 1.10, 95% CI 0.74 to 1.64, p = 0.62). Although the magnitude of PFAS exposure was not quantifiable, our findings suggested that exposure to PFAS was associated with higher level of mitosis in melanoma patients, but this did not translate into a survival difference. Further studies are required to investigate this relationship and all effects of PFAS on prognosis.

Peer Review reports

Background

The incidence of melanoma is continuously increasing in both adult and pediatric populations around the world, with a faster pace compared to other malignancy [1, 2]. The development of melanoma is multifactorial and mainly related to ultraviolet light exposure and genetic susceptibility [3]. However, several studies reveal significant correlations between chemical exposure and melanoma incidence [4]. Per-and polyfluoroalkyl substances (PFAS) are a group of man-made organic chemicals that are persistent environmental contaminants because of their resistance to biodegradation, photo-oxidation, direct photolysis, and hydrolysis [5]. PFAS have been manufactured since the 1940s and widely used in a variety of consumer and industrial products (such as carpeting, clothing, upholstery, food paper wrappings, fire-fighting foams) and in processes such as polytetrafluoroethylene (PTFE) polymer production and metal plating. PFAS are persistent and ubiquitously distributed in the environment thus growing into a global contamination problem. Previous studies have associated PFAS with several health conditions such as hepatotoxicity, dyslipidemia, endocrine outcomes, immunotoxicity outcomes, hyperuricemia, pregnancy-induced hypertension and cancer development such as kidney and testicular cancers, pancreatic and hepatocellular carcinoma, and thyroid tumor [68]. Cancer is one of the health effects of interest in relation to PFAS exposure [8]. In 2013, the Italian National Research Center (IRSA-CNR), triggered by the outcomes of the European PERFORCE project, found a high presence of PFAS in water and soil of large areas of North-eastern Italy. The main source of contamination was a chemical plant in the Province of Vicenza (Veneto Region), which had produced PFAS compounds since early 60 s. The contaminated area includes 30 small towns of the province of Vicenza, Verona and Padova for a total of approximately 140,000 people (Fig. 1) directly exposed to the PFAS pollution [9, 10]. The “Veneto Cancer Registry” records melanoma as the most common cancer diagnosis in males, the third most common cancer in females under 50 years of age and the sixth most common cancer overall in the Veneto Region (Italy). Based on its endocrine disrupting action and the relationship with vitamin D and mitotic rate [11], we hypothesized that PFAS exposure might affect the biological aggressiveness of melanoma. Hence, we compared melanoma patients stratified by the potential exposure to PFAS, to investigate differences in terms of tumor histological characteristics and prognosis between patients exposed and those unexposed to PFAS.

Fig. 1
figure 1

Unexposed and exposed area in Veneto Region

Methods

This was a retrospective cohort study on PFAS exposure in patients who were diagnosed and /or treated for primary melanoma at Veneto Institute of Oncology and at the University Hospital of Padua between 1998 and 2014.

Patients

All patients who were diagnosed and/or treated for primary melanoma in 1998–2014 at Veneto Institute of Oncology and at the University Hospital of Padua (Italy) were considered for inclusion in this study. The two participating hospitals are level III referral centers located in the Veneto Region (North-eastern Italy). Most patients are referred for diagnosis and/or first-line treatment, while some patients are referred for disease progression after being treated in local level II centers. Main inclusion criteria were age ≥ 15 years and living in the Veneto Region. In 2018, the regional administration produced a document (no. 691 of 21 May 2018) where regional areas were classified according to PFAS contamination [12]. In our study, patients living in PFAS areas until the initial diagnosis of melanoma were included in the exposed cohort, while patients living outside PFAS areas in the province of Venice were included in the unexposed cohort. Patients did not report a change in home address. In the exposed cohort, the source of water was either municipal systems or private wells. The inclusion period (1998–2014) was chosen to potentially achieve a minimum follow-up period of 5 years at the analysis.

Diagnosis and treatment

All melanoma diagnoses were histologically confirmed according to the fourth edition of the World Health Organization classification of skin tumors and the staging was updated to the 8th edition of the Union for International Cancer Control (UICC) TNM Classification of Malignant Tumours [13, 14]. The pathologist was blind to patient’s residency area Patients were treated according to the National Italian Medical Oncology Association (AIOM) guidelines [15].

Data collection

All data were extracted from a local database. Data collection included demographics (residence at diagnosis, age at diagnosis, sex), tumor characteristics (subtype of melanoma, primary site, Breslow thickness, ulceration, number of mitoses, pTNM stage) and follow-up information. Follow-up data were extracted from scheduled visits. Overall survival (OS) was calculated from date of diagnosis to date of death or last visit. Disease-specific survival (DSS) was calculated from date of diagnosis to date of disease-related death, or date of last visit/disease-unrelated death. Disease-free survival (DFS) was calculated from date of diagnosis to date of recurrence, or date of last visit/death. Recurrence could include local recurrence, regional skin/in-transit metastases, regional lymph node metastases and/or distant metastases.

Statistical analysis

Continuous data were summarized as median and interquartile range (IQR). Comparisons between exposed and unexposed cohorts were performed using the Chi Square test or Fisher’s exact test (categorical data), and Mann–Whitney test (continuous data). A logistic regression model was estimated to assess the relationship between PFAS exposure and presence of mitoses, adjusting for age and sex. Survival estimates were calculated using the Kaplan–Meier method and compared between exposed and unexposed cohorts using log-rank test (unadjusted analysis) and Cox regression models with unbalanced baseline characteristics as additional independent variables (adjusted analysis). Effect sizes were reported as odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI). No adjustment for multiple testing was applied given the exploratory purpose of the study. All tests were two-sided and a p-value of less than 0.05 was considered statistically significant. Statistical analyses were performed using R 4.1 (R Foundation for Statistical Computing, Vienna, Austria) [16].

Ethics considerations

The study was approved by the Ethics Committee of the Veneto Institute of Oncology (CESC-IOV) on 20 January 2020 (Approval n° 2/2020). The study was conducted according to Helsinki Declaration principles, and all patients gave their consent to have their anonymized data used for scientific purposes.

Results

Patients

The analysis included 194 melanoma patients living in the PFAS areas (“exposed cohort) and 488 melanoma patients living outside the PFAS areas (“unexposed cohort). All patients were Caucasian and aged > 15 years. Demographics and tumor characteristics are reported in Table 1. The presence of mitoses was higher in exposed vs. unexposed patients (70.5% vs. 58.7%, p = 0.005; Table1), and the association was confirmed when adjusting for age and sex (OR 1.68, 95% CI 1.17 to 2.43; p = 0.005). No other statistically significant differences were found in the two cohorts (Table 1).

Table 1 Demographics and tumor characteristics according to the geographical area of residency

Survival

At a median follow-up of 90 months (IQR 59–136), overall 135 patients died (84 from the disease and 51 due to other causes) and 542 were alive, while the information was not available in five patients who were lost to follow-up. 5-year OS was 83.7% in exposed patients and 88.0% in unexposed patients (p = 0.20); 5-year DSS was 88.0% in exposed patients and 90.9% in unexposed patients (p = 0.50); 5-year DFS was 83.8% in exposed patients and 87.3% in unexposed patients (p = 0.20) (Fig. 2). Adjusting for imbalanced characteristics at baseline (presence of mitoses), survival was not statistically different between exposed and unexposed patients (OS: HR 1.10, 95% CI 0.77 to 1.58, p = 0.57; DSS: HR 0.99, 95% CI 0.62 to 1.59, p = 0.99; DFS: HR 1.10, 95% CI 0.74 to 1.64, p = 0.62), while higher number of mitoses per mm2 was associated with impaired OS (HR 5.87, 95% CI 3.24 to 10.65; p < 0.0001), DSS (HR 7.85, 95% CI 3.41 to 18.05; p < 0.0001) and DFS (HR 7.05, 95% CI 3.55 to 13.95; p < 0.0001).

Fig. 2
figure 2

Overall survival A, disease-specific survival B, and disease-free survival C: comparison between exposed and unexposed cohorts

Conclusions

In the last decade, the contamination of water by PFAS has gained increasing interest in medical research. Previous studies showed an association between PFAS exposure and testicular Leydig cell adenomas, pancreatic and hepatocellular carcinoma or thyroid tumor in the rats [8, 17, 18], as well as neonatal mortality, neurotoxicity and metabolic alterations [19]. Many recent studies investigated the serum PFAS concentration and reported associations with cardiovascular disease, reproductive disorders, Alzheimer’s or some neoplasms [2025]. Available scientific literature offers limited information on the role of PFAS in melanoma development/progression. A recent scoping review found sparse evidence on the relationship between PFAS and melanoma in epidemiologic studies [8]. On the other hand, a previous laboratory study on developing rats found that exposure to perfluorooctane sulfonate (PFOS) potentially altered pathways associated with different cancers including melanoma [26]. Our findings suggest that exposure to PFAS was associated with higher presence of mitoses in human melanoma, while other tumor characteristics (e.g., site, Breslow thickness, ulceration, stage, and subtype) were comparable between exposed and unexposed cohorts. Previous studies suggested that PFAS exposure may cause alterations in telomere length and vitamin D metabolism [2729], with a potential cascade on cancer pathogenesis. In 2015, a systematic review showed that cutaneous melanoma was associated with telomere lenghtening, although the underlying mechanisms is not fully understood yet [30]. The endocrine disrupting action of perfluoro-octanoic acid (PFOA) is one of the predominant forms in human samples of PFAS. Due to the molecular similarity between vitamin D and steroid hormones, PFOA competes with 1,25-dihydroxyvitamin D on the same binding site in its receptor, which is involved in the genomic actions of vitamin D (cell cycle progression, differentiation and apoptosis, immunomodulation) [29]. The binding with PFAS could be responsible for the deficiency or the inactivation of vitamin D, thus altering those signaling pathways [31]. Literature suggests that vitamin D and its derivates may have anti melanoma development properties, promoting cellular differentiation and inhibiting proliferation [11, 3234]. Previous studies reported an inverse association between vitamin D levels and number of mitoses [3235], which may contribute to explain the higher number of mitoses in PFAS-exposed cohort in our study. In our series, mitotic index was strongly associated with patient survival as reported by many other investigators [3638]. However, our data did not suggest an association between PFAS exposure and patient survival. We acknowledge that such relationship is complex and may be found in subgroups of patients which had small size in our analysis. Therefore, we cannot exclude that PFAS exposure may have some impact on patient survival, or provide indications about the clinically significance of such impact. Moreover, the heterogeneity in terms of source of water within the exposed cohort might have influenced the magnitude of PFAS exposure. Of note, our study has some limitations that should be considered by the reader. First, the retrospective design limited data availability. For example, plasma level of PFAS at diagnosis was not available, and patients were stratified according to area of residency and IRSA-CNR analysis on drinking waters. Second, the majority of patients were diagnosed with a stage I melanoma and a 10-y OS will be more appropriate for this stage. Hence, we cannot exclude that actual PFAS contamination may have a prognostic role in melanoma patients. Third, the generalizability of the findings may be limited to similar settings. Finally, no adjustment for multiple testing was applied (because of the exploratory purpose of the study) hence further studies are required to confirm the findings. In conclusions, our data showed that melanoma patients living in PFAS-contaminated areas (thus potentially exposed to PFAS) had higher presence of mitoses compared to unexposed patients, but this association did not translate into a survival difference. However, the limitations of the study (mainly regarding the unquantifiable magnitude of PFAS exposure in our patients) suggest caution when drawing any conclusions, hence further studies may provide a better understanding of the impact of PFAS exposure on the biological aggressiveness of cutaneous melanoma. 

Availability of data and materials

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://doi.org/10.5281/zenodo.6976964 (accessed on 2 May 2022).

Change history

  • 15 December 2022

    In the author name, the surname of the third to the last author is "Dei Tos" and not "Tos"

Abbreviations

PFAS:

Per- and polyfluoroalkyl substances

PFOA:

Perfluoro-octanoic acid

PTFE:

Polytetrafluoroethylene

IRSA-CNR:

Italian National Research Center

OS:

Overall survival

DSS:

Disease-specific survival

DFS:

Disease-free survival

UICC:

Union for International Cancer Control

AIOM:

Italian Medical Oncology Association

IQR:

Interquartile range

CI:

Confidence interval

CESC-IOV:

Ethics Committee of the Veneto Institute of Oncology

ALM:

Acral Lentiginous Melanoma

LMM:

Lentigo Maligna Melanoma

NM:

Nodular Melanoma

SSM:

Superficial Spreading Melanoma

References

  1. N Howlader, AM Noone, M Krapcho, D Miller, A Brest, M Yu, J Ruhl, Z Tatalovich, A Mariotto, DR Lewis, HS Chen, EJ Feuer, KA Cronin eds. SEER Cancer Statistics Review, 1975–2017. Bethesda, MD: National Cancer Institute (2020). Available at: https://seer.cancer.gov/csr/1975_2017/. based on November 2019 SEER data submission, posted to the SEER web site, April 2020.

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.

    Article  Google Scholar 

  3. Berwick M, Buller DB, Cust A, Gallagher R, Lee TK, Meyskens F, Pandey S, Thomas NE, Veierød MB, Ward S. Melanoma epidemiology and prevention. Cancer Treat Res. 2016;167:17–49. https://doi.org/10.1007/978-3-319-22539-5_2.

    Article  Google Scholar 

  4. Dika E, Fanti PA, Vaccari S, Patrizi A, Maibach HI. Causal relationship between exposure to chemicals and malignant melanoma? a review and study proposal. Rev Environ Health. 2010;25(3):255–9. https://doi.org/10.1515/reveh.2010.25.3.255.

    Article  CAS  Google Scholar 

  5. Buck RC, Franklin J, Berger U, Conder JM, Cousins IT, de Voogt P, et al. Perfluoroalkyl and polyfluoroalkyl substances in the environment: terminology, classification, and origins. Integr Environ Assess Manag. 2011;7(4):513–41.

    Article  CAS  Google Scholar 

  6. Sunderland EM, Hu XC, Dassuncao C, Tokranov AK, Wagner CC, Allen JG. A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects. J Expo Sci Environ Epidemiol. 2019;29(2):131–47.

    Article  CAS  Google Scholar 

  7. Ward-Caviness CK, Moyer J, Weaver A, Devlin R, Diaz-Sanchez D. Associations between PFAS occurrence and multimorbidity as observed in an electronic health record cohort. Environ Epidemiol. 2022;6(4): e217.

    Article  Google Scholar 

  8. Steenland K, Winquist A. PFAS and cancer, a scoping review of the epidemiologic evidence. Environ Res. 2021;194: 110690. https://doi.org/10.1016/j.envres.2020.110690.

    Article  CAS  Google Scholar 

  9. Mazzola M., Saccardo I., Cappellin R. 2013. Stato dell‘inquinamento da sostanze perfluoroalchiliche (PFAS) in provincia di Vicenza, Padova, Verona – Aspetti geologici e idrogeologici, la rete idrografica, il sito potenzialmente inquinato e prima delimitazione dell’inquinamento al 30.09.2013. Rapporto ARPAV

  10. Valsecchi S., Polesello S. 2013. Rischio associato alla presenza di sostanze perfluoro-alchiliche (PFAS) nelle acque potabili e nei corpi idrici recettori di aree industriali nella Provincia di Vicenza e aree limitrofe. IRSA-CNR 25 marzo 2013.

  11. Moreno-Arrones OM, Zegeer J, Gerbo M, Manrique-Silva E, Requena C, Traves V, Nagore E. Decreased vitamin D serum levels at melanoma diagnosis are associated with tumor ulceration and high tumor mitotic rate. Melanoma Res. 2019;29(6):664–7. https://doi.org/10.1097/CMR.0000000000000638.

    Article  CAS  Google Scholar 

  12. Veneto Regional Deliberation no. 691 of 21 May 2018. Available online: https://bur.regione.veneto.it/BurvServices/pubblica/DettaglioDgr.aspx?id=370611 (accessed on 23 June 2022)

  13. Elder DE, Massi D, Scolyer RA, Willemze R, World Health Organization classification of skin tumours. Lyon: International Agency for Research on Cancer; 2018.

  14. Gershenwald JE, Scolyer RA. Melanoma Staging: American Joint Committee on Cancer (AJCC) 8th Edition and Beyond [Published Correction Appears in Ann Surg Oncol. 2018 Dec;25(Suppl 3):993–994]. Ann Surg Oncol. 2018;25(8):2105–10. doi: https://doi.org/10.1245/s10434-018-6513-7

  15. Melanoma AIOM guidelines, update 2021. Available online : https://snlg.iss.it/wp-content/uploads/2021/10/LG-127_Melanoma_agg2021.pdf (accessed on 23 June 2022)

  16. R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing (2021).

  17. Wolf CJ, Takacs ML, Schmid JE, Lau C, Abbott BD. Activation of mouse and human peroxisome proliferator-activated receptor alpha by perfluoroalkyl acids of different functional groups and chain lengths. Toxicol Sci. 2008;106(1):162–71. https://doi.org/10.1093/toxsci/kfn166.

    Article  CAS  Google Scholar 

  18. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 110: Some Chemicals Used as Solvents and in Polymer Manufacture. Lyon, France: International Agency for Research on Cancer (IARC); 2017. p. 37–110. Available online: https://www.ncbi.nlm.nih.gov/books/NBK436263/pdf/Bookshelf_NBK436263.pdf (accessed on 23 June 2022)

  19. Lau C, Anitole K, Hodes C, Lai D, Pfahles-Hutchens A, Seed J. Perfluoroalkyl acids: a review of monitoring and toxicological findings. Toxicol Sci. 2007;99(2):366–94. https://doi.org/10.1093/toxsci/kfm128 (Epub 2007 May 22 PMID: 17519394).

    Article  CAS  Google Scholar 

  20. Xu Y, Jurkovic-Mlakar S, Li Y, Wahlberg K, Scott K, Pineda D, et al. Association between serum concentrations of perfluoroalkyl substances (PFAS) and expression of serum microRNAs in a cohort highly exposed to PFAS from drinking water. Environ Int. 2020;136: 105446.

    Article  CAS  Google Scholar 

  21. Zhu Y, Bartell SM. Per- and polyfluoroalkyl substances in drinking water and hypertensive disorders of pregnancy in the United States during 2013–2015. Environ Epidemiol. 2022;6(3):e209. Published 2022 May 4. doi:https://doi.org/10.1097/EE9.0000000000000209

  22. Messmer MF, Salloway J, Shara N, Locwin B, Harvey MW, Traviss N. Risk of cancer in a community exposed to Per- and Poly-Fluoroalkyl Substances. Environ Health Insights. 2022;16:11786302221076708. https://doi.org/10.1177/11786302221076707.

    Article  Google Scholar 

  23. Li H, Hammarstrand S, Midberg B, et al. Cancer incidence in a Swedish cohort with high exposure to perfluoroalkyl substances in drinking water. Environ Res. 2022;204(Pt C): 112217. https://doi.org/10.1016/j.envres.2021.112217.

    Article  CAS  Google Scholar 

  24. Di Nisio A, De Rocco PM, Giadone A, Rocca MS, Guidolin D, Foresta C. Perfluoroalkyl substances and bone health in young men: a pilot study. Endocrine. 2020;67(3):678–84. https://doi.org/10.1007/s12020-019-02096-4.

    Article  CAS  Google Scholar 

  25. Di Nisio A, Rocca MS, Sabovic I, et al. Perfluorooctanoic acid alters progesterone activity in human endometrial cells and induces reproductive alterations in young women. Chemosphere. 2020;242: 125208. https://doi.org/10.1016/j.chemosphere.2019.125208.

    Article  CAS  Google Scholar 

  26. Wang F, Liu W, Jin Y, Wang F, Ma J. Prenatal and neonatal exposure to perfluorooctane sulfonic acid results in aberrant changes in miRNA expression profile and levels in developing rat livers. Environ Toxicol. 2015;30(6):712–23.

    Article  CAS  Google Scholar 

  27. Rachakonda S, Kong H, Srinivas N, Garcia-Casado Z, Requena C, Fallah M, Heidenreich B, Planelles D, Traves V, Schadendorf D, Nagore E, Kumar R. Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk. Genes Chromosomes Cancer. 2018;57(11):564–72. https://doi.org/10.1002/gcc.22669.

    Article  CAS  Google Scholar 

  28. Clarity C, Trowbridge J, Gerona R, Ona K, McMaster M, Bessonneau V, et al. Associations between polyfluoroalkyl substance and organophosphate flame retardant exposures and telomere length in a cohort of women firefighters and office workers in San Francisco. medRxiv 2020 Nov 10.

  29. Di Nisio A, Rocca MS, De Toni L, Sabovic I, Guidolin D, Dall'Acqua S, et al. Endocrine disruption of vitamin D activity by perfluoro-octanoic acid (PFOA). Sci Rep. 2020;10(1):16789–020–74026–8.

  30. Caini S, Raimondi S, Johansson H, De Giorgi V, Zanna I, Palli D, et al. Telomere length and the risk of cutaneous melanoma and non-melanoma skin cancer: a review of the literature and meta-analysis. J Dermatol Sci. 2015;80(3):168–74.

    Article  CAS  Google Scholar 

  31. Vasilovici AF, Grigore LE, Ungureanu L, Fechete O, Candrea E, Trifa AP, Vișan S, Șenilă S, Cosgarea R. Vitamin D receptor polymorphisms and melanoma. Oncol Lett. 2019;17(5):4162–9. https://doi.org/10.3892/ol.2018.9733.

    Article  CAS  Google Scholar 

  32. Lombardo M, Vigezzi A, Ietto G, Franchi C, Iori V, Masci F, et al. Role of vitamin D serum levels in prevention of primary and recurrent melanoma. Sci Rep. 2021;11(1):5815–021–85294–3.

  33. Lim A, Shayan R, Varigos G. High serum vitamin D level correlates with better prognostic indicators in primary melanoma: a pilot study. Aust J Dermatol. 2018;59(3):182–7.

    Article  Google Scholar 

  34. Brozyna AA, Hoffman RM, Slominski AT. Relevance of Vitamin D in melanoma development. Progression and Therapy Anticancer Res. 2020;40(1):473–89.

    Article  CAS  Google Scholar 

  35. Thompson JF, Soong SJ, Balch CM, Gershenwald JE, Ding S, Coit DG, Flaherty KT, Gimotty PA, Johnson T, Johnson MM, Leong SP, Ross MI, Byrd DR, Cascinelli N, Cochran AJ, Eggermont AM, McMasters KM, Mihm MC Jr, Morton DL, Sondak VK. Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. J Clin Oncol. 2011;29(16):2199–205. Erratum in: J Clin Oncol. 2011;29(21):2949.

  36. Buja A, Bardin A, Damiani G, et al. Prognosis for cutaneous melanoma by clinical and pathological profile: a population-based study. Front Oncol. 2021;11: 737399. https://doi.org/10.3389/fonc.2021.737399.

    Article  Google Scholar 

  37. Evans JL, Vidri RJ, MacGillivray DC, Fitzgerald TL. Tumor mitotic rate is an independent predictor of survival for nonmetastatic melanoma. Surgery. 2018;164(3):589–93. https://doi.org/10.1016/j.surg.2018.04.016.

    Article  Google Scholar 

  38. Kashani-Sabet M, Miller JR 3rd, Lo S, et al. Reappraisal of the prognostic significance of mitotic rate supports its reincorporation into the melanoma staging system. Cancer. 2020;126(21):4717–25. https://doi.org/10.1002/cncr.33088.

    Article  Google Scholar 

Download references

Acknowledgements

The authors wish to thank “Piccoli Punti ONLUS” and “Fondazione LuciaValentini Terrani” for their long-lasting support.

Funding

This research has received "Current Research" funds from the Italian Ministry of Health to cover publication costs.

Author information

Authors and Affiliations

Authors

Contributions

“Conceptualization, P.D.F., F.C.,C.B and A.D.M; methodology, P.D.F,F.C.; validation, A.B. and, A.V.; formal analysis, R.C.and L.N; investigation, B.F.; data curation, A.D.M,G.T,S.V.,J.P.,L.P.; writing—original draft preparation, P.D.F,B.F. and, M.M.; writing—review and editing, F.C.; visualization, C.C; supervision, A.P.D.T.,M.A.,C.M.,F.B.,V.C.S., and S.M. All authors have read and agreed to the published version of the manuscript.” The author(s) read and approved the final manuscript.

Corresponding author

Correspondence to Paolo Del Fiore.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the Ethics Committee of the Veneto Institute of Oncology (CESC-IOV) on 20 January 2020 (Approval n° 2/2020). The study was conducted according to Helsinki Declaration principles, and all patients gave their consent to have their anonymized data used for scientific purposes.

Competing interests

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Del Fiore, P., Cavallin, F., Mazza, M. et al. Per- and polyfluoroalkyl substances (PFAS) exposure in melanoma patients: a retrospective study on prognosis and histological features. Environ Health 21, 126 (2022). https://doi.org/10.1186/s12940-022-00944-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12940-022-00944-x

Keywords

  • PFAS
  • Perfluoroalkyl substances
  • Compounds
  • Melanoma
  • Cutaneous melanoma
  • Skin cancer
  • Endocrine disruptor
  • Vitamin D
  • PFOA
  • PFOS