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Cumulative incidence function curves for (A) local recurrence, (B) nodal metastasis, and (C) disease-specific death and (D) Kaplan-Meier survival curves for overall survival by Brigham and Women's Hospital (BWH) tumor stage.
Source publication
To compare American Joint Committee on Cancer (AJCC), International Union Against Cancer (UICC), and Brigham and Women's Hospital (BWH) tumor (T) staging systems for cutaneous squamous cell carcinoma and validate BWH staging against prior data.
Primary tumors diagnosed from 2000 to 2009 at BWH (n = 1,818) were analyzed. Poor outcomes (local recurre...
Context in source publication
Citations
... BWH T2a also appears to be low risk. BWH classifications of T2b and T3 offer a risk of nodal metastases that surpasses 20%, but metastatic risk evaluation in the AJCC-8 system remains limited [53]. ...
Simple Summary
Incidence rates of cutaneous squamous cell carcinoma (cSCC) are projected to increase due to rising exposures to risk factors. While surgical removal continues to be the mainstay of treatment for low-risk cSCC, management of high-risk cases remains complex and lacks uniformity. This article serves as an up-to-date review of cSCC, especially highlighting high-risk patients. Topics reviewed include pathogenesis, molecular markers, and histologic subtypes, with a particular emphasis on diagnosis and management.
Abstract
Representing the second most common skin cancer, the incidence and disease burden of cutaneous squamous cell carcinoma (cSCC) continues to increase. Surgical excision of the primary site effectively cures the majority of cSCC cases. However, an aggressive subset of cSCC persists with clinicopathological features that are indicative of higher recurrence, metastasis, and mortality risks. Acceleration of these features is driven by a combination of genetic and environmental factors. The past several years have seen remarkable progress in shaping the treatment landscape for advanced cSCC. Risk stratification and clinical management is a top priority. This review provides an overview of the current perspectives on cSCC with a focus on staging, treatment, and maintenance strategies, along with future research directions.
... Consistent with cancer management in general, treatment pathways for cSCC are based upon population-based estimates of risk. Available risk classification systems for cSCC based on clinicopathologic features include National Comprehensive Cancer Network (NCCN) risk groups, Brigham and Women's Hospital (BWH) staging and American Joint Committee on Cancer Staging Manual, 8th edition (AJCC8) [7][8][9]. BWH and AJCC8 use tumor characteristics to classify a patient's risk of disease progression by T-stage, while NCCN includes both patient-specific and tumor factors to stratify risk to offer treatment options for prevention of local recurrence, metastasis or disease specific death. Unfortunately, several of these risk factors are subjective or difficult to measure (i.e., rapidly growing, clinical extent of tumor, neurologic symptoms) or have documented intra-and inter-rater histopathologic variability (grade of differentiation [10] and depth of invasion [11,12]) equating to limited accuracy in determining metastatic risk [13,14]. ...
The validated 40-gene expression profile (40-GEP) test independently stratifies risk of regional or distant metastasis for cutaneous squamous cell carcinoma (cSCC) tumors with high-risk clinicopathologic features. This study evaluated the stratification of risk by the 40-GEP test in a large cohort of tumors with one or more high-risk factors and in clinically relevant subgroups, including tumors within National Comprehensive Cancer Network (NCCN) high- and very-high-risk groups, lower-stage BWH T1 and T2a tumors, and patients > 65 years old.
This multicenter (n = 58) performance study of the 40-GEP included 897 patients. Kaplan-Meier analyses were performed to assess risk stratification profiles for 40-GEP Class 1 (low), Class 2A (higher) and Class 2B (highest) risk groups, while nested Cox regression models were used to compare risk prediction of clinicopathologic risk classification systems versus risk classification systems in combination with 40-GEP.
Patients classified as 40-GEP Class 1, Class 2A, or Class 2B had significantly different metastatic risk profiles (p < 0.0001). Integrating 40-GEP results into models with individual clinicopathologic risk factors or risk classification systems (Brigham and Women’s Hospital, American Joint Committee on Cancer Staging Manual, 8th Edition) and NCCN demonstrated significant improvement in accuracy for prediction of metastatic events (ANOVA for model deviance, p < 0.0001 for all models).
The 40-GEP test demonstrates accurate, independent, clinically actionable stratification of metastatic risk and improves predictive accuracy when integrated into risk classification systems. The improved accuracy of risk assessment when including tumor biology via the 40-GEP test ensures more risk-aligned, personalized patient management decisions.
... Main characteristics and classifications of BCC and cSCC[1,2,14,30,31,[33][34][35].Table 1. Cont. ...
Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) are the most frequently occurring non-melanocytic skin cancers. The objective of our study is to present the pathophysiology of BCC and cSCC and its direct relationship with the histopathological diagnostics and the differential diagnostics of these types of cancer, based on the morphological characteristics, immunohistochemical profile, and genetic alterations. The qualitative study was based on emphasizing the morphological characteristics and immunohistochemistry profiles of BCC and cSCC and the differential diagnostics based on the tissue samples from the Clinical Pathology Department of Mures Clinical County Hospital between 2020 and 2022. We analyzed the histopathological appearances and immunohistochemical profiles of BCC and cSCC in comparison with those of Bowen disease, keratoacanthoma, hyperkeratotic squamous papilloma, metatypical carcinoma, pilomatricoma, trichoblastoma, Merkel cell carcinoma, pleomorphic dermal sarcoma (PDS), and melanoma. Our study showed the importance of the correct histopathological diagnosis, which has a direct impact on the appropriate treatment and outcome for each patient. The study highlighted the histopathological and morphological characteristics of NMSCs and the precursor lesions in HE and the immunohistochemical profile for lesions that may make the differential diagnosis difficult to establish.
... Several staging and risk stratifcation systems were discussed, including NCCN risk stratifcation [12], the American Joint Committee on Cancer (AJCC) Staging Manual-8 th edition [21], and Brigham and Women's Hospital (BWH) tumor classifcation [22,23]. AAD and NCCN used low-and high-risk criteria as defned by NCCN to give their recommendations. ...
... In 2013, Brigham and Women's Hospital's (BWH) tumor classifcation system was proposed and later validated [22,23] for the management of cSCC due to the poor prognostic value of AJCC staging. However, BWH classifcation lacks the inclusion of lymph node and distant metastases, which are included in the AJCC classifcation. ...
Background. This study presents a comparative analysis of recently published guidelines to manage cutaneous squamous cell carcinoma (cSCC) and cutaneous basal cell carcinoma (cBCC) within the United States (US). Methods. A PubMed database search was performed for the time period between June 1, 2016, and December 1, 2022. A comprehensive comparison was performed in the following clinical interest areas: staging and risk stratification, management of primary tumor and regional nodes with curative intent, and palliative treatment. Results. Guidelines from 3 organizations were analyzed: the American Academy of Dermatology (AAD), the National Comprehensive Cancer Network (NCCN), and the American Society for Radiation Oncology (ASTRO). The guidelines used different methodologies to grade evidence, making comparison difficult. There was agreement that surgery is the preferred treatment for curative cBCC and cSCC. For patients ineligible for surgery, there was a consensus to recommend definitive radiation. AAD and NCCN recommended consideration of other topical modalities in selected low-risk cBCC. Postoperative radiation therapy (PORT) was uniformly recommended in patients with positive margins that could not be cleared with surgery and in patients with nerve invasion. The definition and extent of nerve invasion varied. All guidelines recommended surgery as the primary treatment in patients with lymph node metastases in a curative setting. The criteria used for PORT varied; NCCN and ASTRO used lymph node size, number of nodes, and extracapsular extension for recommending PORT. Both NCCN and ASTRO recommend consideration of systemic treatment along with PORT in patients with extracapsular extension. Conclusion: US guidelines provide contemporary and complementary information on the management of cBCC and cSCC. There are opportunities for research, particularly in the areas of staging, indications for adjuvant treatment in curative settings, extent of nerve invasion and prognosis, and the role of systemic treatments in curative and palliative settings.
... cSCC reportedly metastasizes in up to 5% of patients and kills as many people annually as melanoma [4]. Current staging systems, American Joint Committee on Cancer (AJCC)-8 and Brigham Women's Hospital (BWH), use clinical and histopathological risk factors to assess risk of recurrence or metastasis [5][6][7]. Both staging systems have defined intermediate to high-risk tumors as T2 or higher. ...
... Other GEP derivations were inclusive of large numbers of low-risk tumors unlikely to metastasize, only controlling for age, sex, and tumor location, neglecting to control for stage [18]. Intermediate to high-risk tumors (BWH T2a & T2b) are known to have more outcome variability, making prediction and risk-stratification increasingly difficult [5]. Our primary tumors were phenotypically similar but were stage-and immunosuppression-matched to identify the molecular and genetic differences underlying their behavior and outcomes. ...
Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in humans and kills as many people annually as melanoma. The mutational and transcriptional landscape of cSCC has identified driver mutations associated with disease progression as well as key pathway activation in the progression of pre-cancerous lesions. The understanding of the transcriptional changes with respect to high-risk clinical/histopathological features and outcome is poor. Here, we examine stage-matched, outcome-differentiated cSCC and associated clinicopathologic risk factors using whole exome and transcriptome sequencing on matched samples. Exome analysis identified key driver mutations including TP53 , CDKN2A , NOTCH1 , SHC4 , MIIP , CNOT1 , C17orf66 , LPHN22 , and TTC16 and pathway enrichment of driver mutations in replicative senescence, cellular response to UV, cell-cell adhesion, and cell cycle. Transcriptomic analysis identified pathway enrichment of immune signaling/inflammation, cell-cycle pathways, extracellular matrix function, and chromatin function. Our integrative analysis identified 183 critical genes in carcinogenesis and were used to develop a gene expression panel (GEP) model for cSCC. Three outcome-related gene clusters included those involved in keratinization, cell division, and metabolism. We found 16 genes were predictive of metastasis (Risk score ≥ 9 Met & Risk score < 9 NoMet). The Risk score has an AUC of 97.1% (95% CI: 93.5% - 100%), sensitivity 95.5%, specificity 85.7%, and overall accuracy of 90%. Eleven genes were chosen to generate the risk score for Overall Survival (OS). The Harrell’s C-statistic to predict OS is 80.8%. With each risk score increase, the risk of death increases by 2.47 (HR: 2.47, 95% CI: 1.64-3.74; p<0.001) after adjusting for age, immunosuppressant use, and metastasis status.
... The risk of LNM in cSCC is relatively low [21] and indiscriminate imaging could lead to a considerable number of false positives and unnecessary additional procedures [123,124]. However, it is well established that tumors with higher T scores in staging systems have a higher risk of LNM [28], and there are studies suggesting that early detection of LNM when fewer lymph nodes are affected [125], or where nodes are smaller and there is no extracapsular invasion [126], may lead to a better prognosis. Some studies have shown a trend towards larger lymph nodes in patients with clinically detected LNM compared to those routinely screened with ultrasound [127]. ...
Simple Summary
Cutaneous squamous cell carcinoma is the second most common subtype of skin cancer. The scalp is one of the most frequently affected locations and is associated with a higher risk of complications, compared to other locations. In addition, it has a characteristic thickness and anatomical structure that may influence both growth pattern and treatment of primary cutaneous squamous cell carcinoma; while clinical peripheral margins may be easily achieved during surgery, vertical excision of the tumor is limited by the skull. Despite having a unique anatomy, current guidelines do not offer specific recommendations for cutaneous squamous cell carcinoma of the scalp, which may lead to inconsistent decision-making in multidisciplinary committees when discussing tumors with some risk factors or with close histological margins. Thus, more data are needed to improve its management and assist multidisciplinary teams in shared decisions.
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common subtype of skin cancer. The scalp is one of the most frequently affected locations and is associated with a higher rate of complications, compared to other locations. In addition, it has a characteristic thickness and anatomical structure that may influence both growth pattern and treatment of primary cSCC; while clinical peripheral margins may be easily achieved during the surgery, vertical excision of the tumor is limited by the skull. Despite having a unique anatomy, current guidelines do not contemplate specific recommendations for scalp cSCC, which leads to inconsistent decision-making in multidisciplinary committees when discussing tumors with high risk factors or with close margins. This article provides specific recommendations for the management of patients with scalp cSCC, based on current evidence, as well as those aspects in which evidence is lacking, pointing out possible future lines of research. Topics addressed include epidemiology, clinical presentation and diagnosis, imaging techniques, surgical and radiation treatments, systemic therapy for advanced cases, and follow-up. The primary focus of this review is on management of primary cSCC of the scalp with localized disease, although where relevant, some points about recurrent cSCCs or advanced disease cases are also discussed.
... For risk stratification of cSCC, tumours with a size of > 20 mm, depth of > 2 mm or Clark level of IV or V were considered high-risk (20). Tumour classification (Brigham and Women's Hospital tumour classification system) was based on clinical and pathological risk factors (20,21). All patients were Chinese and only accepted surgical treatment. ...
Retinal G protein-coupled receptor (RGR), a photosensitive protein, functions as a retinal photoisomerase under light conditions in humans. Cutaneous squamous cell carcinoma (cSCC) is linked to chronic ultraviolet exposure, which suggests that the photoreceptor RGR may be associated with tumorigenesis and progression of squamous cell carcinoma (SCC). However, the expression and function of RGR remain uncharacterized in SCC. This study analysed RGR expression in normal skin and in lesions of actinic keratosis, Bowen’s disease and invasive SCC of the skin with respect to SCC initiation and development. A total of 237 samples (normal skin (n = 28), actinic keratosis (n = 42), Bowen’s (n = 35) and invasive SCC (n = 132) lesions) were examined using immunohistochemistry. Invasive SCC samples had higher expression of RGR protein than the other samples. A high immunohistochemical score for RGR was associated with increased tumour size, tumour depth, Clark level, factor classification, and degree of differentiation and a more aggressive histological subtype. In addition, RGR expression was inversely correlated with involucrin expression and positively correlated with proliferating cell nuclear antigen (PCNA) and Ki67 expression. Furthermore, RGR regulates SCC cell differentiation through the PI3K-Akt signalling pathway, as determined using molecular biology approaches in vitro, suggesting that high expression of RGR is associated with aberrant proliferation and differentiation in SCC.
... Human specimens, immunohistochemistry, and RPPA Human tumor samples and skin biopsies were obtained under protocols approved by the University of Arizona institutional review board (institutional review board number 1807818073), all samples were deidentified, and written informed consent was documented. Samples were classified as normal SP skin (n ¼ 20), low-risk cSCC (n ¼ 39), or high-risk cSCC (n ¼ 30) using clinical evaluation and verification from pathological analysis according to the Brigham and Women's Hospital staging system (Karia et al, 2014). IHC staining of human skins for PD-L1 was performed as described previously using the SP263 kit (Ventana Medical Systems) . ...
The immune checkpoint ligand PD-L1 has emerged as a molecular target for skin cancer therapy and might also hold promise for preventive intervention targeting solar UV light–induced skin damage. In this study, we have explored the role of PD-L1 in acute keratinocytic photodamage testing the effects of small-molecule pharmacological inhibition. Epidermal PD-L1 upregulation in response to chronic photodamage was established using immunohistochemical and proteomic analyses of a human skin cohort, consistent with earlier observations that PD-L1 is upregulated in cutaneous squamous cell carcinoma. Topical application of the small-molecule PD-L1 inhibitor BMS-202 significantly attenuated UV-induced activator protein-1 transcriptional activity in SKH-1 bioluminescent reporter mouse skin, also confirmed in human HaCaT reporter keratinocytes. RT-qPCR analysis revealed that BMS-202 antagonized UV induction of inflammatory gene expression. Likewise, UV-induced cleavage of procaspase-3, a hallmark of acute skin photodamage, was attenuated by topical BMS-202. NanoString nCounter transcriptomic analysis confirmed downregulation of cutaneous innate immunity- and inflammation-related responses, together with upregulation of immune response pathway gene expression. Further mechanistic analysis confirmed that BMS-202 antagonizes UV-induced PD-L1 expression both at the mRNA and protein levels in SKH-1 epidermis. These data suggest that topical pharmacological PD-L1 antagonism using BMS-202 shows promise for skin protection against photodamage.
... Early staging systems for cSCC were criticized due to a lack of discriminatory ability with regard to determining risk of progression, but more recent iterations have shown improved correlation with outcome. [23][24][25][26] While earlier schemes focused predominantly on size and features of advanced spread (such as bony invasion), more recent schemes have included histological parameters such as depth of invasion, poor differentiation, and perineural invasion. 15 While these schemes show broad correlation with outcome in organ transplant recipients, 8,18 a background of immunosuppression is in itself a ''high-risk'' feature, 16 and some have suggested that it should be included as such in formal staging schemes. ...
Background
Cutaneous squamous cell carcinoma is a significant cause of morbidity for immunosuppressed patients such as organ transplant recipients; however, histological parameters which predict the likelihood of tumor progression are typically based on general population studies in which immunosuppressed patients represent only a small fraction of cases.
Objectives
To determine the histological parameters which have independent prognostic value for cutaneous squamous cell carcinoma arising in renal transplant recipients.
Methods
Case-control study incorporating a retrospective blinded histological review of 70 archived specimens of cutaneous squamous cell carcinoma diagnosed in renal transplant recipients, comprising 10 cases where the tumor had progressed and 60 controls.
Results
Progression was significantly associated with head and neck location, size, depth, poor histological grade, perineural invasion (including small caliber perineural invasion), lymphovascular invasion, and a desmoplastic growth pattern.
Limitations
The retrospective nature and the low number of cases compared to controls.
Conclusion
In immunosuppressed patients both small caliber perineural invasion and a desmoplastic growth pattern may also have prognostic significance in addition to other histological parameters already recognized in formal staging schemes.
... The most commonly used systems include the individual risk factor-based National Comprehensive Cancer Network (NCCN) system, American Joint Committee on Cancer Eighth Addition (AJCC8) staging system, and the Brigham and Women's Hospital (BWH) classification. [15][16][17] These systems are based on clinical and/or pathological features, such as tumor size and thickness, perineural invasion, cell differentiation, and tumor location. However, these factors may be limited in their utility, as biopsy specimens are often transected, precluding accurate measurement of tumor depth. ...
... 18 The combination of these limitations have resulted in a low sensitivity (23-46%) and positive predictive value (PPV) (12-13%) for these staging systems. 16,17,21,22 Given these relatively low sensitivity and PPV values, more precise methods of predicting the risk of recurrence, metastasis, and mortality are needed for skin cancer. Precision medicine has already become commonplace throughout many specialties, including dermatology. ...
Background:
Cutaneous squamous cell carcinoma (cSCC) is a growing health concern with a rapidly increasing incidence. Disease-specific mortality is typically preceded by a metastasis, but current staging systems have significant limitations in predicting this event. The 40-gene expression profile (40-GEP) test is a validated method of further stratifying patients based on the risk of regional or distant metastasis, but limited guidelines exist for incorporating this test into clinical practice.
Objective:
To review the available literature on the use of gene expression profile (GEP) testing to assess prognosis in cSCC and create consensus statements to guide dermatology clinicians on its use.
Methods:
A comprehensive literature search of PubMed, EMBASE, and Scopus was completed for English-language original research articles on the use of GEP testing to assess cSCC prognosis. A panel of 8 dermatologists with significant expertise in diagnosing and managing cSCC gathered to review the articles and create consensus statements. A modified Delphi process was used to approve each statement and a strength of recommendation was assigned using the Strength of Recommendation Taxonomy (SORT) criteria.
Results:
The literature search produced 157 articles that met the search criteria. A thorough screening of the studies for relevance to the research question resulted in 21 articles that were distributed to the panelists for review prior to the roundtable discussion. The panel unanimously voted to adopt 7 consensus statements and recommendations, 6 of which were given a strength of "A" and 1 of which was given a strength of "C".
Conclusion:
The 40-GEP test provides accurate and independent prognostic information beyond standard staging systems that only incorporate pathologic data. Incorporation of GEP testing into national guidelines can help further stratify patients based on risk of metastasis and thus may improve morbidity and mortality. J Drugs Dermatol. 2023;22(12): doi:10.36849/JDD.7691e.
