Cutaneous Squamous Cell Carcinoma (cSCC) Database Development: Focusing on High Risk cSCCs, with a Focus on thePresence of Perineural Invasion (PNInv).
Dr. Scott Fosko
Email
sfosko@dermatology.med.ufl.edu
Phone
(314) 757-0996
Faculty Department/Division
Dermatology
This project is primarily:
Literature Review
Research Project Description:
Cutaneous Squamous Cell Carcinoma (cSCC) Database Development: Focusing on High Risk cSCCs, with a Focus on thePresence of Perineural Invasion (PNInv).
Background
Cutaneous squamous cell carcinoma (cSCC) is a growing public health concern with an estimated 1,000,000 cases to occurannually in the United States. (Rogers et al., 2015) Fortunately, the majority of cSCC present early, have indolent behavior andare effectively managed most commonly with surgery, radiation or other destructive therapies. Most (80-90%) occur on the headand neck area. Long-term survival for all cSCC patients is high with 5 year survival rates greater than 90%. There are a minority(3-5%) of cSCC that display aggressive clinical behavior as either locally advanced cSCC (lacSCC) or metastatic cSCC (mcSCC).(Stratigos et al.,2020; Dessinioti et al., 2022; Schmults et al., 2013) These high risk cSCC have increased risk of local recurrence,regional lymph node disease and distant metastases. Most mcSCC occur on the head and neck with the involvement of theparotid gland and/or cervical lymph nodes. (Venables et al., 2019). Metastatic cSCC have a much worse prognosis with long termsurvival rates significantly decreased with 10 year survival less than 30% reported in one cohort of head and neck cSCCs.(Goepfert et al., 1984) There is some evidence that deaths from cSCC may outpace those from melanoma, due to the muchgreater growing incidence of cSCC. (Karia et al., 2013).
Advanced cSCC disease is a much more challenging cohort and is reported to have higher rates of local recurrence andmetastases. (Dessinioti 2022) Identifying high risk cSCC tumors early in their initial presentation can be challenging. Risk factorspredicting adverse prognosis have been well identified. (Veness, 2007; Schmults et al., 2013, Thompson et al., 2015)Theseinclude tumor clinical features, primarily tumor size and depth of tissue invasion, tumor histopathologic features, primarily degreeof differentiation and the presence of perineural invasion, and host factors, primarily immune status. While high risk features areknown, they are not always identified, especially at the patient’s initial presentation.
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One particular risk factor is the presence of perineural invasion (PNInv). PNInv contributes to a tumor having a higher rate of localrecurrence, regional disease and metastatic potential. (Goepfert et al., 1984; Lobl et al., 2022; Feinstein et al., 2019). Whendetected PNInv prompts a more aggressive management approach. This most commonly involves Mohs surgery, where surgicalmargins are more thoroughly evaluated versus conventional wide local excision (WLE). Further surgical resection maybe requiredfor example with tumors of the head and neck, where a superficial parotidectomy and neck lymph node dissection may berecommended. Additionally, the role of adjuvant radiation therapy is often discussed. (Mendenhall et al., 2012; Holtzman et al.,2020; Han et al., 2007).
Identifying PNInv preoperatively can prompt imaging studies such as computed tomography (CT) scans or magnetic resonanceimaging (MRI). These imaging modalities may detect subclinical disease and support a more aggressive treatment plan. Theidentification of PNInv with cSCC can be difficult to detect histopathologically. There is limited literature providing guidance onwhen to suspect the presence of PNInv when reviewing cSCC histopathologic tissue samples, such as the presence of perineuralinflammation (PNInf) or poorly or moderately differentiated cSCC. (Green et al., 2012; Beal et al., 2018).
Objectives and Hypotheses
The main objective of this research project is to focus on high risk features for cSCC with the focus on PNInv. The question to beaddressed is, “when during a patient’s clinical course is PNInv identified and detected?” Is it found at 1. initial presentation on skinbiopsy? 2. At the time of initial management with surgical resection with Mohs surgery or WLE? or 3. At the time of clinicalrecurrence and its management? The hypothesis is that cSCC with PNInv is more commonly identified at the time of clinicalrecurrence. It is also hypothesized that Mohs surgery provides the opportunity to detect cSCC with PNInv compared toconventional WLE and associated histopathologic evaluation.
Methods
The research project will be a chart review with data collection of cases of cSCC managed at the University of Florida College ofMedicine clinical practices, both in Gainesville and Jacksonville. Potential data sources will include 1. Mohs surgical logs,Jacksonville and Gainesville, including Veterans Administration Hospital 2. Department of Oral and Maxillofacial Surgery,Jacksonville case logs 3. Department of Otolaryngology, Gainesville, , 4. Radiation Oncology case logs, 5. Dermatopathology labinformation system, 6. Surgical pathology lab information system, 7. Cancer Center Tumor Registry. Each of these data sourcesprovide unique opportunities with regard to patient presentations, with primary tumors commonly managed in the Department ofDermatology/Mohs Surgery and recurrent tumors more commonly seen in the Departments of Radiation Oncology and Head andNeck Surgery.
Role of Medical Student
The medical student’s role will be to work with respective Departments’ data sources and extract key data variables and enterthem in the database. Once a sufficient number of cases are entered, data analysis will begin. This will be coordinated with ourbiostatisticians. Students will have the opportunity to participate in various outputs of the research, which include: 1. Oral andPoster presentations at Department Research Symposiums, 2. Abstract submissions, 3. Manuscript development and publication,and 4. Possible presentation of research work at regional and national meetings as funding is available and 5. Grant applications.
The scope of the research project touches many Departments in the College of Medicine. This research project will providemedical students with a broad exposure across many areas of medicine, surgery and pathology. It will support their interestdevelopment with regard to future residency programs. They include Dermatology, Head and Neck Surgery, Radiation Oncology,Medical Oncology, Family Medicine, Internal Medicine, Dermatopathology and Surgical Pathology.
Potential Patient Benefit to the Research
If it is found that PNInv is more commonly detected at tumor recurrence, a time where it is known the patient is now at a significantdisadvantage to having a good outcome, this identifies a clinical practice gap. The gap will focus on identifying why perineural
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invasion is more often identified in a delayed fashion, rather than at the time of the patient’s initial presentation. With thisinformation, data could contribute to practice guidelines that can improve the detection of PNInv at an earlier time in the patient’spresentation. In doing so, this could provide the patient a better initial evaluation and treatment approach and drive better patientoutcomes. It is possible that early detection of perineural invasion can prompt a more thorough evaluation and treatment approachthat will provide patients with survival rates closer to the reported overall high survival rates of all patients with cSCC. This workcan potentially minimize the risk of a patient with cSCC progressing to a more locally advanced cSCC with possible metastases.
An overarching goal from this research, through presentations and publications, will be to document the many benefits ofcoordinated multidisciplinary care for our patients with high risk cSCC at the University of Florida. This can contribute to theUniversity of Florida continue to develop and grow its expertise in the field of cutaneous oncology and strengthen its leadership inpatient care, locally, regionally and nationally.
Funding
Funding will be based on:
- Medical Student Summer Research Program Scholarships
- Department of Dermatology Medical Student Trust Fund
- Cancer Center Funding
Publications
Beal BT, Dhanda MM, Chu, MB, Varra V, Armbrecht ES, Slutsky JB, Fosko, SW. Tumor Characteristics Predicting PerineuralInvasion in Cutaneous Squamous Cell Carcinoma Identified by Stepwise Logistic Regression Analysis.. SKIN The Journal ofCutaneous Medicine, [S.l.], nov. 2018. ISSN 2574-1624. Available at: https://jofskin.org/index.php/skin/article/view/356.
Dessinioti C, Pitoulias M, Stratigos AJ. Epidemiology of advanced cutaneous squamous cell carcinoma. J Eur Acad DermatolVenereol. 2022;36(1):39-50. doi:10.1111/jdv.17709
Feinstein S, Higgins S, Ahadiat O, Wysong A. A Retrospective Cohort Study of Cutaneous Squamous Cell Carcinoma WithLymph Node Metastasis: Risk Factors and Clinical Course. Dermatol Surg. 2019;45(6):772-781.doi:10.1097/DSS.0000000000001828
Goepfert H, Dichtel WJ, Medina JE, Lindberg RD, Luna MD. Perineural invasion in squamous cell skin carcinoma of the head andneck. Am J Surg. 1984;148(4):542-547. doi:10.1016/0002-9610(84)90385-4
Green JS, Tournas JA, Allen EJ, Youker SR, Fosko SW. Mohs frozen tissue sections in comparison to similar paraffin-embeddedtissue sections in identifying perineural tumor invasion in cutaneous squamous cell carcinoma. J Am Acad Dermatol.2012;67(1):113-121. doi:10.1016/j.jaad.2011.03.015
Han A, Ratner D. What is the role of adjuvant radiotherapy in the treatment of cutaneous squamous cell carcinoma with perineuralinvasion?. Cancer. 2007;109(6):1053-1059. doi:10.1002/cncr.22509
Holtzman AL, Mendenhall WM. High-dose conformal proton therapy for clinical perineural invasion in cutaneous head and neckcancer. Oral Oncol. 2020;100:104486. doi:10.1016/j.oraloncology.2019.104486
Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, anddeaths from disease in the United States, 2012. J Am Acad Dermatol. 2013;68(6):957-966. doi:10.1016/j.jaad.2012.11.037
Lobl M, Feinstein S, Lauer S, Sutton A, Wysong A. Recurrence Status, Perineural Invasion, and Hypothyroidism Are AssociatedWith Lymph Node Metastasis in Cutaneous Squamous Cell Carcinoma: A Case-Control Study [published online ahead of print,2022 Feb 1]. Dermatol Surg. 2022;10.1097/DSS.0000000000003396. doi:10.1097/DSS.0000000000003396
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Mendenhall WM, Ferlito A, Takes RP, et al. Cutaneous head and neck basal and squamous cell carcinomas with perineuralinvasion. Oral Oncol. 2012;48(10):918-922. doi:10.1016/j.oraloncology.2012.02.015
Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence Estimate of Nonmelanoma Skin Cancer (KeratinocyteCarcinomas) in the U.S. Population, 2012. JAMA Dermatol. 2015;151(10):1081-1086. doi:10.1001/jamadermatol.2015.1187
Stratigos AJ, Garbe C, Dessinioti C, et al. European interdisciplinary guideline on invasive squamous cell carcinoma of the skin:Part 1. epidemiology, diagnostics and prevention. Eur J Cancer. 2020;128:60-82. doi:10.1016/j.ejca.2020.01.007
Schmults CD, Karia PS, Carter JB, Han J, Qureshi AA. Factors predictive of recurrence and death from cutaneous squamous cellcarcinoma: a 10-year, single-institution cohort study. JAMA Dermatol. 2013;149(5):541-547. doi:10.1001/jamadermatol.2013.2139
Thompson AK, Kelley BF, Prokop LJ, Murad MH, Baum CL. Risk Factors for Cutaneous Squamous Cell Carcinoma Recurrence,Metastasis, and Disease-Specific Death: A Systematic Review and Meta-analysis. JAMA Dermatol. 2016;152(4):419-428.doi:10.1001/jamadermatol.2015.4994
Venables ZC, Autier P, Nijsten T, et al. Nationwide Incidence of Metastatic Cutaneous Squamous Cell Carcinoma in England.JAMA Dermatol. 2019;155(3):298-306. doi:10.1001/jamadermatol.2018.4219
Veness MJ. High-risk cutaneous squamous cell carcinoma of the head and neck. J Biomed Biotechnol. 2007;2007(3):80572.doi:10.1155/2007/80572
Does this project have an international component or travel?
No