Introduction: Surgery represents the primary treatment option for cutaneous squamous cell carcinoma (cSCC) aiming for complete tumor resection (R0). Recurrence and metastasis significantly affect survival and outcomes, and poorly differentiated (G3) cSCC is associated with a higher risk of recurrence. However, the specific clinical and histopathological features that predict recurrence and progression in G3-cSCC remain unclear. Methods: A retrospective analysis was conducted on a series of patients with primary G3-cSCC diagnosed at the Turin University Hospital between January 2016 and January 2021. After independent histological revision, logistic regression models were used to identify clinico-pathological predictors of cutaneous recurrence, lymphnode/metastatic progression, and both types of progression. Results: Among the 161 G3-cSCC patients, 80.1% (129/161) showed no signs of local recurrence or metastatic progression, while 19.9% (32 patients) had progressed. In the univariate logistic regression, tumor clinical diameter, depth of infiltration (DOI), and lymphovascular invasion (LVI) were identified as significant predictors across the various types of progression (p < 0.05). In the context of multivariate logistic regression, distinct models proved to be significant. For skin recurrence, a 3-variable model incorporating DOI (OR 1.16, 95% CI, 1.01–1.35, p = 0.050), LVI (OR 3.61, 95% CI, 1.11–11.8, p = 0.034), and desmoplasia (OR 3.45, 95% CI, 1.25–9.5, p = 0.017) was selected. Regarding lymphnode/metastatic progression, a 3-variable model combining pT2 (OR 6.10, 95% CI, 1.15–32.35, p = 0.034), pT3 (OR 14.33, 95% CI, 2.79–73.63, p = 0.001), and LVI (OR 3.86, 95% CI, 1.10–13.62, p = 0.036) was identified. Lastly, a 2-variable model for both types of progression consisted of vertical tumor thickness (OR 5.45, 95% CI, 1.11–27.32, p = 0.039) and LVI (OR 1.15, 95% CI, 1.04–1.26, p = 0.006). Conclusion: Tumor size, DOI, and LVI were significant predictors of recurrence and metastatic progression. Notably, the size of histologically defined tumor-free margins did not affect the risk of recurrence, whilst LVI emerged as a key predictor of all forms of progression. These findings provide insights into risk stratification and suggest that close monitoring and potential adjuvant therapies, such as radiation therapy, may be necessary especially for patients with lymphovascular involvement.

Nagarajan P, Asgari MM, Green AC, Guhan SM, Arron ST, Proby CM, et al. Keratinocyte carcinomas: current concepts and future research priorities. Clin Cancer Res. 2019;25(8):2379–91.
Que SKT, Zwald FO, Schmults CD. Cutaneous squamous cell carcinoma: incidence, risk factors, diagnosis, and staging. J Am Acad Dermatol. 2018;78(2):237–47.
Stratigos AJ, Garbe C, Dessinioti C, Lebbe C, Bataille V, Bastholt L, 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.
Moreno-Ramírez D, Silva-Clavería F, Fernández-Orland A, Eiris N, Ruiz de Casas A, Férrandiz L. Surgery for cutaneous squamous cell carcinoma and its limits in advanced disease. Dermatol Pract Concept. 2021;11(Suppl 2):e2021167S.
Ribero S, Stucci LS, Daniels GA, Borradori L. Drug therapy of advanced cutaneous squamous cell carcinoma: is there any evidence. Curr Opin Oncol. 2017;29(2):129–35.
Haug K, Breuninger H, Metzler G, Eigentler T, Eichner M, Häfner HM, et al. Prognostic impact of perineural invasion in cutaneous squamous cell carcinoma: results of a prospective study of 1,399 tumors. J Invest Dermatol. 2020;140(10):1968–75.
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):419–28.
Stratigos AJ, Garbe C, Dessinioti C, Lebbe C, Bataille V, Bastholt L, et al. European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 2. Treatment. Eur J Cancer. 2020;128:83–102.
Likhacheva A, Awan M, Barker CA, Bhatnagar A, Bradfield L, Brady MS, et al. Definitive and postoperative radiation therapy for basal and squamous cell cancers of the skin: executive summary of an American society for radiation Oncology clinical Practice guideline. Pract Radiat Oncol. 2020;10(1):8–20.
Protocol for the examination of specimens from patients with cutaneous squamous cell carcinoma of the head and neck. College of American Pathologists. September 2022 version. Available from:
Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R, McCarthy SW, et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol. 2012;30(21):2678–83.
Protocol for the examination of excision specimens from patients with melanoma of the skin. College of American Pathologists. March 2022 version. Available from:
Bozdogan H. Model selection and Akaike’s Information Criterion (AIC): the general theory and its analytical extensions. Psychometrika. 1987;52(3):345–70.
Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93–9.
Karia PS, Jambusaria-Pahlajani A, Harrington DP, Murphy GF, Qureshi AA, Schmults CD. Evaluation of American joint committee on cancer, international union against cancer, and brigham and women’s hospital tumor staging for cutaneous squamous cell carcinoma. J Clin Oncol. 2014;32(4):327–34.
Burton KA, Ashack KA, Khachemoune A. Cutaneous squamous cell carcinoma: a review of high-risk and metastatic disease. Am J Clin Dermatol. 2016;17(5):491–508.
Friedman HI, Cooper PH, Wanebo HJ. Prognostic and therapeutic use of microstaging of cutaneous squamous cell carcinoma of the trunk and extremities. Cancer. 1985;56(5):1099–105.
Szewczyk M, Pazdrowski J, Golusiński P, Dańczak-Pazdrowska A, Marszałek S, Golusiński W. Analysis of selected risk factors for nodal metastases in head and neck cutaneous squamous cell carcinoma. Eur Arch Otorhinolaryngol. 2015;272(10):3007–12.
Genders RE, Marsidi N, Michi M, Henny EP, Goeman JJ, van Kester MS. Incomplete excision of cutaneous squamous cell carcinoma; systematic review of the literature. Acta Derm Venereol. 2020;100(6):adv00084.
National Comprehensive Cancer Network. Squamous cell skin cancer Version 1.2021. Medlin Med Encycl. 2021. Available from: [accessed 13 July 2021].
Kerns MJ, Darst MA, Olsen TG, Fenster M, Hall P, Grevey S. Shrinkage of cutaneous specimens: formalin or other factors involved?J Cutan Pathol. 2008;35(12):1093–6.
Sevray M, Brenaut E, Grangier Y, Misery L, Poizeau F, Staroz F. Retraction of cutaneous specimens: tumours and margins after surgical excision. J Clin Pathol. 2020;73(1):42–6.
Schmults CD, Karia PS, Carter JB, Han J, Qureshi AA. Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study. JAMA Dermatol. 2013;149(5):541–7.
Eigentler TK, Leiter U, Häfner HM, Garbe C, Röcken M, Breuninger H. Survival of patients with cutaneous squamous cell carcinoma: results of a prospective cohort study. J Invest Dermatol. 2017;137(11):2309–15.
Zakhem GA, Pulavarty AN, Carucci J, Stevenson ML. Association of patient risk factors, tumor characteristics, and treatment modality with poor outcomes in primary cutaneous squamous cell carcinoma: a systematic review and meta-analysis. JAMA Dermatol. 2023;159(2):160–71.
Barnes TA, Amir E. HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer. Br J Cancer. 2017;117(4):451–60.
Weinberg AS, Ogle CA, Shim EK. Metastatic cutaneous squamous cell carcinoma: an update. Dermatol Surg. 2007;33(8):885–99.
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