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Metastatic Cutaneous Squamous Cell Carcinoma: An Update
Abstract
Squamous cell carcinoma (SCC) is the second most common type of skin cancer in the United States. Cutaneous SCC has the potential to metastasize and cause morbidity and mortality.
Our purpose was to review and summarize the literature on metastatic cutaneous SCC, including risk factors for metastasis, data from clinical studies, and current management.
Multiple studies confirm that even well-differentiated and small tumors (<2 cm) may metastasize. Over the past two decades, additional literature on the risk factors for metastatic cutaneous SCC, including immunosuppression, has been published. In addition, new staging systems have been proposed that may influence management of these tumors. Chemotherapy regimens are numerous, but remain limited in ability to improve overall survival.
Although we know more about the risk factors, survival for patients with metastatic cutaneous SCC depends on extent of nodal involvement. Therefore, emphasis should remain on prevention and aggressive treatment of cutaneous SCC and vigilant observation for signs and symptoms of metastasis.
... Most patients with CSCC undergo surgery by standard surgical excision or Mohs micrographic surgery [6][7][8]. However, a small percentage of cases of advanced CSCC-which includes distant metastatic disease (tumor has spread to distant organs or lymph nodes) or unresectable locally advanced tumors that are not amenable to curative surgery or radiotherapy-are difficult to treat and are associated with poor prognosis [9][10][11][12]. These advanced cases are often treated with systemic forms of therapy, such as targeted drugs, chemotherapies or immunotherapies. ...
... At 6 years 9.9 (9.8-10.0) 10 Among patients within the incident CSCC cohort and the systemically treated subset, baseline characteristics and demographics were generally similar among patients who were immunocompetent and immunocompromised (Table 1). An exception was the distribution of sex among patients with CSCC who initiated systemic therapy, with the proportion of males 62.0 versus 52.6% among those who were immunocompromised versus immunocompetent, respectively ( Table 1). ...
... Medical writing and editorial support under the direction of the authors was provided by Emmanuel Ogunnowo, PhD and John Facciponte, PhD, of Prime (Knutsford, UK) and funded by Regeneron Pharmaceuticals, Inc., according to Good Publication Practice guidelines (Link). future science group 10.2217/fon-2023-0389 ...
Aim: Since use of major cutaneous surgeries/reconstructions among patients with cutaneous squamous cell carcinoma (CSCC) is not well described, we sought to quantify major cutaneous surgeries/reconstructions among patients with CSCC who were newly diagnosed and for those treated with systemic therapy, stratified by immune status. Methods: We used the Optum ® Clinformatics ® Data Mart database (2013–2020) and Kaplan–Meier estimators to assess risk of surgeries/reconstructions. Results: 450,803 patients were identified with an incident CSCC diagnosis, including 4111 patients with CSCC who initiated systemic therapy. The respective 7-year risks of major cutaneous surgeries/reconstructions were 10.9% (95% CI: 10.7–11.0) and 21.8% (95% CI: 17.6–25.8). Overall risk of major cutaneous surgeries/reconstructions was higher in patients who were immunocompromised than those who were immunocompetent. Conclusion: Approximately one in nine patients with CSCC will undergo ≥1 major cutaneous surgeries/reconstructions within 7 years of diagnosis; the risk increases in patients who initiate systemic therapy and among those who are immunocompromised.
... The prevalence and incidence of SCC is increasing because of longevity and increased UV exposure associated with changes of lifestyle [2]. The larger and the deeper it grows, SCC is more likely to become metastatic [3]. Cutaneous SCC is an invasive and destructive tumor who is associated with a higher risk of disfigurement, local recurrence, and metastasis. ...
... SCC accounts for approximately 20% of cutaneous malignancies [3] and occurs predominantly in elderly fair-skinned men. It has been shown to develop more frequently in chronically precursor lesions, including long-standing ulcers, sinus tracts, burns or osteomyelitis [4]. ...
... Tumor diameter is a major prognosis criterion. Lesion size ≥ 4 cm and histologic evidence of perineural and deep invasion into the deeper tissues were the clinical-pathologic factors associated with higher rates of local recurrence and regional metastasis and lower rates of survival [9], they carry twice the risk for recurrence and 3 times the risk for metastasis [3]. Early studies have shown that whilst both tumour diameter and tumour thickness are independent risk factors for metastatic only the latter is an independent risk factor for local tumour recurrence [10], actually risk factors associated with metastasis include also histologic grade, location, recurrence, and immunosuppressed state [3]. ...
Giant squamous cell carcinomas (SCC) larger than 5 cm in diameter are uncommon; there is no guideline on the size of an SCC that is considered giant. Treatment may be difficult with the need for large tissue resections and complex surgical reconstruction. We report a rare case of giant squamous cell carcinoma of the shoulder attached to deep anatomic planes. The entire mass was removed, resulting in a large defect that was repaired with myocutaneous flap rotation of the latissimus dorsi. Three courses of radiotherapy were performed after surgery. Fifteen months after the operation, the patient is well and working without any local recurrence and metastasis.
... Furthermore, recurrence rates can exceed 50% in patients with high risk factors, such as head andneck localization, perineural involvement, or immunosuppression [3,[5][6][7]. In all these cases, local control by achieving tumor-free margins is paramount in decreasing the risk for metastasis and recurrence [8]. ...
... The TBS method was assessed using EGFR because its utility has already been demonstrated in clinical trials. The median TBS was 12 (8,12) for all tumors (n = 54) and did not differ, particularly between CSCC and HNSCC ( Figure 4B). As both tumor cells and healthy squamous epithelium tissue scored high for EGFR, superficial tumors with mostly superficial margins resulted in a relatively low TBS. Figure 4A shows images of a representative case of SCC from the head and neck region stained for all seven evaluated targets and with their respective TBS. ...
... A moderate TBS was achieved with the uPAR staining, resulting in a median score of 6 (3, 8), mostly because, although uPAR expression was present, it rarely stained intensely. Lastly, αvβ6 integrin resulted in the highest median TBS of 12 (8,12), even though 11% (n = 6) cases did not stain positive in the tumor cells, resulting in a TBS of 0 for these cases ( Figure 4B). ...
R0 resection is paramount in cutaneous squamous cell carcinoma (CSCC) and head and neck squamous cell carcinoma (HNSCC). However, in the setting of recurrence, immunocompromised patients, or non-keratinizing squamous cell carcinoma (SCC) with a spindle growth pattern, tumor borders are difficult, if not impossible, to determine. Fluorescence-guided surgery (FGS) aids in this differentiation. Potential targets for FGS of CSCC and HNSCC were evaluated. Most sections stained intensely for αvβ6 and epidermal growth factor receptor (EGFR) on tumor cells. Normal epithelium stained less for αvβ6 than for EGFR. In addition, soft tissue and stroma stained negative for both, allowing for clear discrimination of the soft tissue margin. Tumor cells weakly expressed urokinase plasminogen activator receptor (uPAR) while expression on stromal cells was moderate. Normal epithelium rarely expressed uPAR, resulting in clear discrimination of superficial margins. Tumors did not consistently express integrin β3, carcinoembryonic antigen, epithelial cell adhesion molecule, or vascular endothelial growth factor A. In conclusion, αvβ6 and EGFR allowed for precise discrimination of SSC at the surgically problematic soft tissue margins. Superficial margins are ideally distinguished with uPAR. In the future, FGS in the surgically challenging setting of cutaneous and mucosal SCC could benefit from a tailor-made approach, with EGFR and αvβ6 as targets.
... The larger the expansion and thickness, the higher the risk of a primary cSCC to metastasise. A total of up to 5% of all cSCC can invade regional lymph nodes and subsequently metastasise to distant tissue, leading to a very poor prognosis with a median survival Dermato 2023, 3 86 of <2 years [1,2,[7][8][9][10]. Although achieving an excellent overall prognosis in most patients with treatment by complete surgical excision, cSCC in advanced stages is usually impossible to treat by surgical excision alone [11]. ...
... The larger the expansion and thickness, the higher the risk of a primary cSCC to metastasise. A total of up to 5% of all cSCC can invade regional lymph nodes and subsequently metastasise to distant tissue, leading to a very poor prognosis with a median survival of <2 years [1,2,[7][8][9][10]. Although achieving an excellent overall prognosis in most patients with treatment by complete surgical excision, cSCC in advanced stages is usually impossible to treat by surgical excision alone [11]. ...
Advanced cutaneous squamous cell carcinoma (cSCC) can be a life-threatening disease for which effective and safe treatment in advanced stages is very limited. GP-2250 has been recently proven to have—in vitro and in vivo—antineoplastic effects on cancer cells. This study aims to investigate the potential anti-neoplastic effects of GP-2250 on the cSCC cell lines SCC13 and A431 through dose finding assessments, MTT cytotoxicity assays, cell migration assays, BrdU proliferation assays and FCM analysis. Our preliminary results have shown for the first time evidence for anti-neoplastic effects of GP-2250 on cSCC cells, enhancing cytotoxicity, attenuating cancer cell proliferation, inducing apoptosis and reducing tumour cell migration. Further investigations evaluating the modes of action of GP-2250 on cSCC cell lines are warranted in order to justify the use in vivo studies.
... The SCC represents a multi-stage progression process from actinic keratosis (SCC in situ) and precancerous lesions to locally advanced SCC, and in very rare cases (about 3-9%) to metastatic SCC [90]. Because of this spectrum of conditions, the therapeutic approaches also vary according to the severity of the stages of SCC. ...
... There is mixed information about using the PD-L1 status of the SCC tumor as a prognostic marker. In the clinical study using nivolumab, it has been shown that the improvement of overall survival observed in the nivolumab group was not associated with the PD-L1 expression [90]. Other studies have also shown no association between PD-L1 expression and immunotherapy efficiency [129,130]. ...
Melanoma and nonmelanoma skin cancers (NMSCs) are recognized as among the most common neoplasms, mostly in white people, with an increasing incidence rate. Among the NMSCs, squamous cell carcinoma (SCC) is the most prevalent malignancy known to affect people with a fair complexion who are exposed to extreme ultraviolet radiation (UVR), have a hereditary predisposition, or are immunosuppressed. There are several extrinsic and intrinsic determinants that contribute to the pathophysiology of the SCC. The therapeutic modalities depend on the SCC stages, from actinic keratosis to late-stage multiple metastases. Standard treatments include surgical excision, radiotherapy, and chemotherapy. As SCC represents a favorable tumor microenvironment with high tumor mutational burden, infiltration of immune cells, and expression of immune checkpoints, the SCC tumors are highly responsive to immunotherapies. Until now, there are three checkpoint inhibitors, cemiplimab, pembrolizumab, and nivolumab, that are approved for the treatment of advanced, recurrent, or metastatic SCC patients in the United States. Immunotherapy possesses significant therapeutic benefits for patients with metastatic or locally advanced tumors not eligible for surgery or radiotherapy to avoid the potential toxicity caused by the chemotherapies. Despite the high tolerability and efficiency, the existence of some challenges has been revealed such as, resistance to immunotherapy, less availability of the biomarkers, and difficulty in appropriate patient selection. This review aims to accumulate evidence regarding the genetic alterations related to SCC, the factors that contribute to the potential benefits of immunotherapy, and the challenges to follow this treatment regime.
... However, certain tumor and patient characteristics increase the risk of metastasis. Prior studies have demonstrated metastasis rates of 3-9%, occurring, on average, one to two years after initial diagnosis [6]. We report an insidious presentation of metastatic primary cSCC appearing as a subcutaneous temporal nodule in a 73-year-old Caucasian man. ...
... Follow up examination at 11 months post-Mohs surgery shows a well-healed scar (black arrow) and no signs of recurrence Since our patient did not have a prior history of skin cancer and since no other cutaneous or systemic SCC was discovered, we speculate that his left helical rim "pre-cancer" may have indeed been an SCC that subsequently metastasized to his temple. The risk of cSCC metastasis is low and has been cited to range between 35 and 9% [6]. When metastasis does occur, the vast majority of metastases are found in the parotid or cervical lymph nodes. ...
Cutaneous squamous cell carcinoma (cSCC) typically arises from a malignant proliferation of keratinocytes. It is the second most common cancer in the United States and typically affects older white men. Risk factors for cSCC include ultraviolet radiation exposure, light skin tone, and immunosuppression. Although metastasis in cSCC is rare, primary tumor characteristics such as location, size, and depth of invasion, among others, can help risk-stratify lesions for local recurrence, metastatic events, and death. We present a case of primary cutaneous metastatic squamous cell carcinoma masquerading as a cyst on the left temple of a 73-year-old Caucasian man following numerous treatments of cryotherapy to an ipsilateral helical lesion.
... Cutaneous squamous cell carcinoma (CSCC), which represents 20% of all cutaneous malignancies, is the second most common skin cancer (1)(2)(3). In addition, the incidence of CSCC is rising in the UK, with the mean annual increase of 5% between 2013 and 2015 (4). ...
... In addition, the incidence of CSCC is rising in the UK, with the mean annual increase of 5% between 2013 and 2015 (4). Although CSCC commonly occurs on the skin of the head and neck (5), there is also a risk of occurrence in the lymph nodes and metastasis to other organs (3,6). Patients with metastatic CSCC have a poor prognosis (6). ...
Avicularin (AL), quercetin-3-α-L-arabinofuranoside, has various pharmacological properties such as anticancer and anti-infective effects. However, the potential molecular mechanism via which AL exerts its anticancer activity is not fully understood. Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer, where metastasis has resulted in in effective clinical treatments. The aim of the present in vitro study was to investigate the anticancer effects and underlying mechanism of AL on human CSCC. The present results suggested that AL dose-dependently inhibited SCC13 cell viability and induced apoptosis. In addition, the present results suggested that AL induced apoptosis via repression of the mitogen-activated protein kinase kinase (MEK)/NF-κB signal pathway, thereby affecting the expression of apoptosis-related genes. Bax expression level was increased, while Bcl-2 expression level was decreased in SCC13 cells following AL treatment. In addition, the MEK/NF-κB signaling pathway-related genes p-MEK and phosphorylated-p65 were also decreased. The present results suggested that AL treatment increased the expression level of E-cadherin, but decreased the expression levels of N-cadherin, matrix metalloproteinase (MMP)-9 and vimentin in SCC13 cells. Collectively, the present results suggested that AL may have an anti-CSCC effect by inhibiting cell viability, inducing apoptosis and inhibiting epithelial-mesenchymal transition (EMT) of CSCC cells. The mechanism of these anti-CSCC effects was suggested to be via the regulation of apoptosis-related genes and EMT-related genes, and the inhibition of the MEK/NF-κB signaling pathway.
... Approximately 5% of patients develop metastases, most commonly to regional lymph nodes (2,3). Previously identified prognostic factors for high-risk cutaneous SCC includes increased tumour diameter, increased depth of invasion, poor differentiation, a desmoplastic growth pattern, the location of the lesion at the site of a scar, perineural invasion and host immunosuppression (2)(3)(4). ...
... Approximately 5% of patients develop metastases, most commonly to regional lymph nodes (2,3). Previously identified prognostic factors for high-risk cutaneous SCC includes increased tumour diameter, increased depth of invasion, poor differentiation, a desmoplastic growth pattern, the location of the lesion at the site of a scar, perineural invasion and host immunosuppression (2)(3)(4). To our knowledge, the reported rate of spread of cutaneous SCC to the leptomeninges and intradural spinal compartment is exceedingly rare, including only three reported cases in the English literature of metastatic dissemination to the cauda equina (5,6). ...
BACKGROUND: Spinal leptomeningeal carcinomatosis from a cutaneous squamous cell carcinoma (SCC) origin is exceedingly rare. Herein, we describe the first report of cauda equina syndrome secondary to drop metastases from a skin SCC. CASE DESCRIPTION: A 69-year-old male with a history of recurrent SCC of the face with known cranial nerve involvement presented with acute onset sphincter and lower extremity symptoms. Neuroimaging revealed a compressive intradural mass at the lumbosacral junction. The patient underwent urgent surgical decompression followed by adjuvant fractionated radiotherapy. Substantial improvement in function and quality of life was reported on postoperative follow-up. CONCLUSION: Cauda equina syndrome manifestations in a patient with a history of cutaneous SCC with perineural spread should raise suspicion for drop metastases. In this case, a relatively straight forward surgical procedure resulted in significant improvement in the quality of life. Therefore, operative intervention should be considered to prevent permanent neurological deficits depending on the patient’s goals of care and overall clinical status.
... Despite its inherent limitations, including the retrospective design and cohort size, our study provides valuable insights into predictive factors for progression in G3-cSCC patients during the median follow-up time of 30 months. This timeframe aligns with previous reports [24], as most recurrences manifest within the initial 1-2 years post-excision [25,27]. As current guidelines acknowledge the challenge of identifying high-risk factors due to the limited and diverse evidence derived primarily from small, heterogeneous, and retrospective studies investigating different outcomes, our study contributes to addressing this knowledge gap [3]. ...
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, depth of infiltration, 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.
... Conversely, SCC is the second most observed subtype of NMSC. Compared to BCC, these have a higher rate of metastasis, which occurs at a rate of 3-9%, as shown by previous studies [15]. The age-adjusted mortality rate for SCC is still relatively low, recently being reported at 1 per 100,000 person-years [16]. ...
Morbidity and mortality from skin cancer continue to rise domestically and globally, and melanoma and non-melanoma skin cancers are a topic of interest in the dermatology and oncology communities. In this review, we summarize the stimulator of interferon genes (STING) pathway, its specific role in the pathogenesis of DNA damage and skin cancer, and STING-specific therapies that may fight both melanoma and non-melanoma skin (NMSC) cancers. Furthermore, we discuss specific portions of the STING pathway that may be used in addition to previously used therapies to provide a synergistic effect in future oncology treatments and discuss the limitations of current STING-based therapies.
... The largest prospective studies involving SLNB in high-risk cSCC of the head and neck only found the number of high-risk features (as compared to specific individual features themselves) to be significant in predicting lymph node metastasis [38]. Studies do reveal metastatic rates of 3-9%, evolving an average of one to two years after initial diagnosis [39]. The anatomic primary site with the highest incidence of lymphatic metastasis is the auricle [40]. ...
Simple Summary
Skin cancer, particularly non-melanoma skin cancer, is the most common malignancy in the world. There are both common and uncommon types that receive treatment every day. Despite their commonality, the management of each is not perfectly defined in the scientific literature. Many require surgical removal, but the management of regional metastasis (such as lymph nodes in the neck) may or may not require surgical removal, or even anything beyond observation. Further complicating matters, some may have microscopic regional metastases that cannot be detected with a physical exam or imaging. This article seeks to summarize the current literature on this topic and to offer specific insight on how to manage non-melanoma skin cancer that has migrated away from the primary site to the regional lymph nodes.
Abstract
Non-melanoma skin cancer (NMSC) represents the most common malignancy in the world, comprising exceedingly common lesions such as basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) and rare lesions such as Merkel cell carcinoma. Risk factors are widely recognized and include ultraviolet (UV) light exposure, radiation exposure, immunosuppression, and many others. As a whole, survival and functional outcomes are favorable, but each histopathological subtype of NMSC behaves differently. Treatment regimens for the primary site usually include wide surgical excision and neck dissection in cases of clinically involved metastatic lymph nodes. The elective management of draining nodal basins, however, is a contested topic. Nearly all subtypes, excluding BCC, have a significant risk of lymphatic metastases, and have been studied with regard to sentinel lymph node biopsy (SLNB) and elective neck dissection. To date, no studies have definitively established a true single standard of care, as exists for melanoma, for any of the NMSCs. As a result, the authors have sought to summarize the current literature and identify indications and management options for the management of the cervical lymphatics for each major subtype of NMSC. Further research remains critically necessary in order to develop complete treatment algorithms.
... It is frequently found in the head and neck region as this area is exposed to sunlight and radiation more often than other areas of the body; thus, the initial spread is observed in the ipsilateral submandibular, sublingual, and intra-parotid lymph nodes. This particular cancer has a metastatic range of 2.3% and 5.2% after considering 5 year and longer follow-ups, respectively [1]. It has been reported that incidence rates of cSCC of the head and neck region are higher in patients with fair skin and continuous intense sun exposure [2]. ...
Non-melanoma skin cancer of the head and neck (NMSCHN) is one of the most common malignancies worldwide, and its incidence is growing at a significant rate. It has been found to be aggressive in its spread and has the capacity to metastasize to regional lymph nodes. Cutaneous squamous cell carcinoma (cSCC) has a considerably high mortality rate. It has remarkable characteristics: diameter >2 cm, depth >5 mm, high recurrence, perineural invasion, and locoregional metastases. Aggressive cSCC lesions most commonly metastasize to the parotid gland. Also, immunocompromised patients have a higher risk of developing this aggressive cancer along with the worst prognostic outcomes. It is very important to discuss and assess the risk factors, prognostic factors, and outcomes of patients with cSCC, which will give clinicians future directives for making modifications to their treatment plans. The successful treatment of aggressive cSCC of the head and neck includes early detection and diagnosis, surgery alone or adjuvant chemotherapy, and radiotherapy as required. Multimodal therapy options should be considered by clinicians for better outcomes of aggressive cSCC of the head and neck.
... Around the world, BCC accounts for around 80% and SCC accounts for about 20% of all diagnosed NMSC cases [1][2][3][4]. While metastasis in cases of BCC is rare, metastasis of SCC is more common and potentially fatal, wherein 20% of all skin cancer related deaths are caused by metastatic SCC [5]. Incidences of NMSC are increasing annually, particularly in the aging Caucasian population, and NMSC is the most frequent acquired cancer and one of the most common malignant cancers [1,3,4]. ...
Five million non-melanoma skin cancers occur globally each year, and it is one of the most common malignant cancers. The dysregulation of the endocannabinoid system, particularly cannabinoid receptor 2 (CB2), is implicated in skin cancer development, progression, and metastasis. Comparing wildtype (WT) to systemic CB2 knockout (CB2-/-) mice, we performed a spontaneous cancer study in one-year old mice, and subsequently used the multi-stage chemical carcinogenesis model, wherein cancer is initiated by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). We found that aging CB2-/- mice have an increased incidence of spontaneous cancerous and precancerous skin lesions compared to their WT counterparts. In the DMBA/TPA model, CB2-/- developed more and larger papillomas, had decreased spontaneous regression of papillomas, and displayed an altered systemic immune profile, including upregulated CD4+ T cells and dendritic cells, compared to WT mice. Immune cell infiltration in the tumor microenvironment was generally low for both genotypes, although a trend of higher myeloid-derived suppressor cells was observed in the CB2-/- mice. CB2 expression in carcinogen-exposed skin was significantly higher compared to naïve skin in WT mice, suggesting a role of CB2 on keratinocytes. Taken together, our data show that endogenous CB2 activation plays an anti-tumorigenic role in non-melanoma skin carcinogenesis, potentially via an immune-mediated response involving the alteration of T cells and myeloid cells coupled with the modulation of keratinocyte activity.
... Similar to BCC, the main reason behind the occurrence of SCC is immoderate exposure to ultraviolet radiation. But, other factors such as human papillomavirus (HPV), chemical carcinogens, genodermatoses, inflammatory conditions, and medicaments (tumor necrosis factor-α inhibitors) also hold responsible for SCC [53,54]. ...
Skin cancer has emerged as the fifth most commonly reported cancer in the world, causing a burden on global health and the economy. The enormously rising environmental changes, industrialization, and genetic modification have further exacerbated skin cancer statistics. Current treatment modalities such as surgery, radiotherapy, conventional chemotherapy, targeted therapy, and immunotherapy are facing several issues related to cost, toxicity, and bioavailability thereby leading to declined anti-skin cancer therapeutic efficacy and poor patient compliance. In the context of overcoming this limitation, several nanotechnological advancements have been witnessed so far. Among various nanomaterials, nanoparticles have endowed exorbitant advantages by acting as both therapeutic agents and drug carriers for the remarkable treatment of skin cancer. The small size and large surface area to volume ratio of nanoparticles escalate the skin tumor uptake through their leaky vasculature resulting in enhanced therapeutic efficacy. In this context, the present review provides up to date information about different types and pathology of skin cancer, followed by their current treatment modalities and associated drawbacks. Furthermore, it meticulously discusses the role of numerous inorganic, polymer, and lipid-based nanoparticles in skin cancer therapy with subsequent descriptions of their patents and clinical trials.
Graphical Abstract
... SCC in OTRs most frequently metastasises to lungs and bones. The survival rate in organ recipients with metastases is 56% after 3 years, and 34% after 5 years, compared to the general population where, surprisingly, it is significantly lower at 25% after 5 years [36]. ...
The occurrence of neoplasms is one of the most common complications and second most frequent cause of death in organ transplant recipients (OTRs). The most frequently occurring neoplasms are skin cancers, predominantly squamous cell carcinoma (SCC). However, the ratio between SCC and basal cell carcinoma (BCC) in OTRs differs in several studies depending on the follow-up time, country, environment and other factors. In this population SCC has a more aggressive course with the presence of metastases and tends to have multifocal growth. The clinical and histopathological picture of SCC in OTRs differs from that observed in immunocompetent patients, which implicates tumour treatment and prognosis. The clinical features and distinctness which pertain to SCC in post-transplantation patients are described in this paper.
... The NCCN guidelines for BCC are extrapolated to SCC with additional consideration of occurrence within a chronic wound, neurologic symptoms, and rapid growth. Because of the increased risk of SCC metastasis (3% to 9%), 15 biopsy and AJCC tumor staging are recommended. The histologic presentation of Bowen disease (SCC in situ) is the presence of atypical keratinocytes throughout the epidermis. ...
Skin cancer is a significant and increasing global health burden. Whilst the current diagnostic workflow is robust and able to provide clinically actionable results, it is subject to notable limitations. The training and expertise required for accurate diagnoses using conventional skin cancer diagnostics is significant and patient access to this workflow can be limited by geographical location or unforeseen events such as COVID-19. Molecular biomarkers have transformed diagnostics and treatment delivery in oncology. With rapid advancements in molecular biology techniques, understanding of the underlying molecular mechanism of cancer pathologies has deepened, yielding biomarkers that can be used to monitor the course of malignant diseases. Herein, commercially available, clinically validated, and emerging skin cancer molecular biomarkers are reviewed. The qualities of an ideal molecular biomarker are defined. The potential benefits and limitations of applying molecular biomarker testing over the course of skin cancer from susceptibility to treatment is explored, with a view to outlining a future model of molecular biomarker skin cancer diagnostics.
... cSCC shows the potential for recurrence and metastasis, making it the main cause of death in NMSC [25]. Previous reports have confirmed that mutations in P53, CDKN2A, RAS, NOTCH1, and NOTCH2 are closely related to cSCC [6][7][8][9]26]; however, the underlying molecular mechanisms behind the aggressive progression of cSCC subpopulations remain to be unveiled, which might account for the high mortality rate of cSCC in NMSC [27]. ...
Background:
Cutaneous squamous cell carcinoma (cSCC) is the leading cause of death in patients with nonmelanoma skin cancers (NMSC). However, the unclear pathogenesis of cSCC limits the application of molecular targeted therapy.
Methods:
Three microarray datasets (GSE2503, GSE45164, and GSE66359) were downloaded from the Gene Expression Omnibus (GEO). After identifying the differentially expressed genes (DEGs) in tumor and nontumor tissues, five kinds of analyses, namely, functional annotation, protein-protein interaction (PPI) network, hub gene selection, TF-miRNA-mRNA regulatory network analysis, and ferroptosis mechanism, were performed.
Results:
A total of 146 DEGs were identified with significant differences, including 113 upregulated genes and 33 downregulated genes. The enriched functions and pathways of the DEGs included microtubule-based movement, ATP binding, cell cycle, P53 signaling pathway, oocyte meiosis, and PLK1 signaling events. Nine hub genes were identified (CDK1, AURKA, RRM2, CENPE, CCNB1, KIAA0101, ZWINT, TOP2A, and ASPM). Finally, RRM2, AURKA, and SAT1 were identified as significant ferroptosis-related genes in cSCC. The differential expression of these genes has been verified in two other independent datasets.
Conclusions:
By integrated bioinformatic analysis, the hub genes identified in this study elucidated the molecular mechanism of the pathogenesis and progression of cSCC and are expected to become future biomarkers or therapeutic targets.
... Multiple SCCs can occur if a new primary SCC is formed elsewhere or the SCC metastasizes. SCC metastasis can be lymphogenic and hematogenic, influenced by several risk factors such as tumor size, tumor depth, and tumor differentiation [6]. ...
Introduction and importance
The incidence of squamous cell carcinoma (SCC) in the population aged under 30 years reaches only 1% of total cases. We report the first case from Papua, Indonesia, with a double primary SCC in a patient aged just 25 years, with albinism as a risk factor. This case report can hopefully enrich existing knowledge of such tumors.
Case presentation
A 25-year-old Papuan female patient came to the oncology clinic of Jayapura Regional General Hospital with a tumor on the left lower lip and a skin tumor on the right temporal side of the face. The patient noticed that the tumor on the lower lip appeared a few weeks earlier than that on the right temporal skin. Both tumors had grown gradually for 5 years. Both tumors were painless, but for the last 3 months, the tumor had bled easily. The patient was born with oculocutaneous albinism (OCA) without other syndromic or systemic disorders.
Clinical discussion and conclusion
In this patient, we suspected double primary SCCs considering the location of the tumor, which theoretically spreads distantly; the size of the lesion at less than 2 cm; the depth of the lesion at less than 4 mm; and the well-differentiated cytology. Another consideration was that patients with OCA have a 1000-fold risk of developing skin cancer and an increased risk of recurrence. Therefore, continual evaluation and screening are necessary.
... reduces the risk of bad prognoses, as well as the costs these pathologies entail on health systems due to their high incidence [1,2]. ...
The early detection of Non-Melanoma Skin Cancer (NMSC) is crucial to achieve the best treatment outcomes. Shape is considered one of the main parameters taken for the detection of some types of skin cancer such as melanoma. For NMSC, the importance of shape as a visual detection parameter is not well-studied. A dataset of 993 standard camera images containing different types of NMSC and benign skin lesions was analysed. For each image, the lesion boundaries were extracted. After an alignment and scaling, Elliptic Fourier Analysis (EFA) coefficients were calculated for the boundary of each lesion. The asymmetry of lesions was also calculated. Then, multivariate statistics were employed for dimensionality reduction and finally computational learning classification was employed to evaluate the separability of the classes. The separation between malignant and benign samples was successful in most cases. The best-performing approach was the combination of EFA coefficients and asymmetry. The combination of EFA and asymmetry resulted in a balanced accuracy of 0.786 and an Area Under Curve of 0.735. The combination of EFA and asymmetry for lesion classification resulted in notable success rates when distinguishing between benign and malignant lesions. In light of these results, skin lesions' shape should be integrated as a fundamental part of future detection techniques in clinical screening.
... плоскоклеточный рак кожи (пКР) (плоскоклеточная карцинома, спиноцеллюлярный рак, плоскоклеточная эпителиома) -злокачественная инвазивная опухоль, развивающаяся из супрабазальных эпидермальных кератиноцитов. Опухоль в большинстве случаев развивается на фоне предраковых заболеваний (актинический кератоз, мышьяковый кератоз, лучевой кератоз, кератоз, вызванный вирусом папилломы человека) или рака in situ (эритроплазия Кейра, болезнь боуэна) и обладает способностью к инвазивному росту и метастазированию [1,2]. за последние годы отмечается стремительный рост заболеваемости злокачественными опухолями кожи. ...
The authors present a clinical case study of squamous cell carcinoma in a psoriasis patient after 24 courses of phototherapy (22 courses of PUVA therapy and two courses of mid-wavelength ultraviolet therapy (311 nm)). The malignant neoplasm developed against the background of signs of a chronic photodamage of the skin: lentigo, actinic elastosis, diffuse hyperpigmentation, spotty skin pigmentation.
... 2 3 However, a small but substantial number of patients present with or subsequently develop metastatic CSCC (mCSCC) or locally advanced CSCC (laCSCC) not amenable to curative surgery or curative radiation (collectively, 'advanced CSCC'), which has a poor prognosis. [4][5][6] Treatment of advanced CSCC, particularly CSCC with a primary site of head and neck, can lead to reduced quality of life (QoL). [7][8][9] Surgery for CSCC can result in considerable morbidity, for example, some patients require orbital exenteration, 10 which significantly reduces QoL, including increased anxiety and depression, difficulty driving, phantom pain, and hallucinations. ...
Background
To provide pooled longer term data from three groups of a phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), and to determine duration of response (DOR) and impact on quality of life (QoL).
Methods
Patients received cemiplimab 3 mg/kg every 2 weeks (group 1, metastatic CSCC [mCSCC], n=59; group 2, locally advanced CSCC, n=78) or cemiplimab 350 mg every 3 weeks (group 3, mCSCC, n=56). Primary endpoint was objective response rate (ORR) per independent central review (ICR). QoL was repeatedly measured at day 1 of each treatment cycle (groups 1 and 2: 8 weeks; group 3: 9 weeks).
Results
Median duration of follow-up was 15.7 months. Overall, ORR per ICR was 46.1% (95% CI: 38.9% to 53.4%). Complete response (CR) rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3, respectively. Median time to CR was 11.2 months. Among patients with partial response or CR, the estimated proportion of patients with ongoing response at 12 months from the first objective response was 87.8% (95% CI: 78.5% to 93.3%), with median DOR not reached. Kaplan-Meier estimated probability of overall survival (OS) was 73.3% (95% CI: 66.1% to 79.2%) at 24 months, with median OS not reached. Global Health Status (GHS)/QoL improvements were observed as early as cycle 2 and were significantly improved and durable until last assessment. Kaplan-Meier estimate of median time to first clinically meaningful improvement for pain was 2.1 (95% CI: 2.0 to 3.7) months and was significantly improved in responders versus non-responders (p<0.0001).
Conclusions
This is the largest (n=193) clinical dataset for a programmed cell death-1 inhibitor against advanced CSCC, confirming the sustained substantial clinical activity of cemiplimab in these patients, including new findings of improved CR rates over time, increasing DOR, and durable pain control and GHS/QoL improvement.
Trial registration number
ClinicalTrials.gov Registry ( NCT02760498 ), https://clinicaltrialsgov/ct2/show/NCT02760498 .
... CSCC is a major public health concern due to its associated medical costs and high incidence (20). The known predisposing factors of CSCC include ultraviolet radiation exposure, chronic immunosuppressed state, inherited genetic conditions, ionizing radiation exposure, human papillomavirus infection and chronic arsenic exposure (21)(22)(23)(24)(25). Moreover, it is necessary to differentiate benign lesions and reactive squamo-proliferative lesions from CSCC (26,27) and to identify the high-risk features associated with invasive tumor progression (28). ...
Cutaneous squamous cell carcinoma (CSCC) is one of the most common types of skin cancer in humans worldwide. The identification and characterization of cancer-associated transmembrane proteins are important for understanding the molecular biology of CSCC. The aim of the present study was to evaluate the expression pattern of transmembrane protein 40 (TMEM40) in CSCC and its clinical significance. The underlying mechanisms were also examined. Reverse transcription-quantitative PCR, western blot and immunohistochemistry analysis were used to determine the relative expression of TMEM40 in CSCC cell lines and clinical tissue samples. The effect of TMEM40 gene silencing on cell proliferation was also evaluated using Cell Counting Kit-8 assays. Wound healing assays, flow cytometry and Transwell assays were used to explore the migration, cell cycle distribution/apoptosis and invasion of CSCC cells following TMEM40 silencing, respectively. In the present study, increased TMEM40 expression was observed in CSCC tissue samples, compared with normal skin, and TMEM40 expression was associated with large tumor size in patients with CSCC. In vitro functional assays indicated that TMEM40 was involved in the regulation of A431 and SCL1 cell growth through its effects on the cell cycle and apoptosis. Silencing TMEM40 in A431 and SCL1 cells resulted in cell cycle arrest at the G0/G1 phase and promoted apoptosis. In addition, migration and invasion were significantly inhibited following silencing of TMEM40 expression in CSCC cells. Taken together, the results of the present study indicated that reduced TMEM40 expression could inhibit CSCC development and that TMEM40 may represent a therapeutic target in CSCC.
... However, it can occasionally metastasize into LNs and to distant organs, as well as spread along nerves. Metastases have been shown to occur in 4-5% of sSCC cases, with the major prognostic factors being the tumor thickness, the increased horizontal tumor size and the immune suppression status of the patient [9][10][11][12]. In addition, the presence of perineural infiltration in the tumor is a bad prognostic factor, which is often associated with increased loco-regional recurrence and decreased patient survival [11,13]. ...
Although tumor-associated lymphangiogenesis correlates with metastasis and poor prognosis in several cancers, it also supports T cell infiltration into the tumor and predicts favorable outcome to immunotherapy. The role of lymphatic vessels in skin squamous-cell carcinoma (sSCC), the second most common form of skin cancer, remains mostly unknown. Although anti-PD-1 therapy is beneficial for some patients with advanced sSCC, a greater understanding of disease mechanisms is still needed to develop better therapies.
Using quantitative multiplex immunohistochemistry, we analyzed sSCC sections from 36 patients. CD8+ T cell infiltration showed great differences between patients, whereby these cells were mainly excluded from the tumor mass. Similar to our data in melanoma, sSCC with high density of lymphatic endothelial cells showed increased CD8+ T cell density in tumor areas. An entirely new observation is that sSCC with perineural infiltration but without metastasis was characterized by low lymphatic endothelial cell density. Since both, metastasis and perineural infiltration are known to affect tumor progression and patients’ prognosis, it is important to identify the molecular drivers, opening future options for therapeutic targeting. Our data suggest that the mechanisms underlying perineural infiltration may be linked with the biology of lymphatic vessels and thus stroma.
... риск развития ПКрК выше для реципиентов после пересадок органов в целом, чем для пациентов после трансплантации гемопоэтических стволовых клеток [22]. Больные с хроническим лимфоцитарным лейкозом, у которых скомпрометирован клеточный и гуморальной иммунитет, также имеют повышенный риск в 8-10 раз для развития ПКрК [23][24][25]. Исходя из этого видно, что ПКрК является иммуногенной опухолью и т-клеточный противоопухолевый ответ может быть особенно полезен в лечении распространенных форм ПКрК. В настоящее время на 2 стадии находится исследование ингибитора PD1 для лечения ПКрК [26]. ...
The incidence of skin cancer is a steady increasing around the world. Tumors of epithelial origin occupy the first place in the structure of all skin malignancy. Epidermoid carcinoma is the most malignant epithelial tumor of the skin and mucous membranes with squamous differentiation. Generally, squamous cell carcinoma is successfully treated by surgical and radiological methods. Often a different kind of plastic defect reconstructions are required after surgical removal. The incidence of epidermoid carcinoma increases with age (average age of patients falls on 65 years) therefore variants of treatment options is limited by comorbidities. However, surgical oncologist do not have enough date and randomized controlled studies on this theme. Minimally invasive methods, especially cryothechnology are increasingly used, but unfortunately their advantage requires additional evidence. We suppose Inclusion in the conventional treatment of new technologies may possibly improve the results of treatment. We reviewed the literature, summarizing data on various methods of treating squamous cell skin cancer. Comprehensive and systematic search was based on MedLine, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus and PubMed among original articles for the period from January 1974 to October 2018.
... CSCC is the second most common skin cancer affecting Japanese and the worldwide population [6][7][8][9]. Until the emergence of PD-1 inhibitors, the prognosis was poor for patients with either locally advanced CSCC not amenable to surgery or metastatic CSCC [10][11][12]. Cemiplimab ("cemiplimab-rwlc" in the US) is the first therapy approved in the US, Europe, Canada, Australia, Brazil, Switzerland, and Israel for the treatment of patients with metastatic or locally advanced CSCC who are not candidates for curative surgery or curative radiation, with an objective response rate (ORR) of 47.2% [13,14]. There is currently no approved therapy for CSCC in Japan. ...
Purpose
Part 1 of this two-part, open-label, Phase 1 study (NCT03233139) assessed the safety, tolerability, pharmacokinetics, immunogenicity, and clinical activity of cemiplimab in Japanese patients with advanced malignancies.
Methods
Patients received cemiplimab 250 mg (n = 6) or 350 mg (n = 7) every 3 weeks intravenously for up to 108 weeks in Part 1. Tumor responses were assessed by investigators every 9 weeks using the Response Evaluation Criteria in Solid Tumors version 1.1.
Results
Of 13 patients enrolled, median age was 62 years (range 33–75) and eight patients were female. Median duration of cemiplimab exposure was 13.1 weeks (range 3.0‒113.6). At the time of data cut-off, 11 patients (84.6%) had discontinued treatment (majority due to disease progression: n = 8, 61.5%). The most common treatment-emergent adverse events (TEAEs) of any grade were contact dermatitis, rash, and viral upper respiratory tract infection (each n = 3, 23.1%). Five grade ≥ 3 TEAEs were reported in four patients: autoimmune colitis, dehydration, hyponatremia, hypophosphatemia, and muscular weakness. No dose-limiting toxicities were reported and no TEAEs led to death. Cemiplimab concentrations in serum were consistent with previously reported pharmacokinetic characteristics of cemiplimab. No anti-drug antibodies were detected in serum. Objective response rate [ORR; complete response + partial response (PR)] was 30.8% (four PR) and disease control rate [ORR + stable disease (SD)] was 46.2% (6/13; two SD).
Conclusion
Cemiplimab exhibited antitumor activity in Japanese patients with advanced malignancies. The safety profile was comparable to those previously reported for cemiplimab and other PD-1 inhibitors.
Trial registration
NCT03233139 at ClinicalTrials.gov.
Graphic abstract
... 1 Cellular atypia specifically describes the variation of the size and shape of cells and nuclei, the absence of intercellular bridges, and the presence of atypical mitotic figures. 1 Squamous cell carcinoma can also arise within mucocutaneous surfaces, including the conjunctiva. 2,3 The conjunctiva is a unique mucous membrane that covers the anterior surface of the eye and is partially exposed to sunlight. 3 In the conjunctiva, particularly in the sun-exposed areas nasally and temporally, SCC can develop and appears as a gelatinous, vascular, or leukoplakic mass typically located at the corneoscleral limbus. ...
Link to video:
https://practicaldermatology.com/videos/conjunctival-scc?c4src=search:feed
... 4 7 Conversely, the prognosis is poor for patients with either locally advanced CSCC (laCSCC) not amenable to curative surgery or curative radiation or metastatic CSCC (mCSCC), collectively referred to as advanced CSCC, treated with cytotoxic chemotherapy or epidermal growth factor receptor inhibitors. [8][9][10] Due to chronic skin damage from ultraviolet light, most CSCCs are hypermutated. 11 12 Patients with high tumor mutational burden (TMB) solid tumors are more likely to derive clinical benefit from inhibition of immune checkpoints, such as programmed cell death (PD)-1. ...
Background
Cemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort ( NCT02383212 ) and the pivotal Phase 2 study ( NCT02760498 ). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study ( NCT02760498 ).
Methods
The primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability.
Results
For Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan–Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%).
Conclusion
In patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses.
Trial registration number
Clinicaltrials.gov, NCT02760498 . Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498
... Global incidence of cSCC is 2.2 million people [1,2] and accounts for most of the ~10,000 annual nonmelanoma skin cancer deaths in the United States [3,4]. cSCC treatments include excision, radiation therapy, photodynamic therapy, and/or topical treatment, including 5-fluorouracil (5FU) [5][6][7]. ...
Cutaneous squamous cell carcinoma (cSCC) causes approximately 10,000 deaths annually in the U. S. Current therapies are largely ineffective against metastatic and locally advanced cSCC. There is a need to identify novel, effective, and less toxic small molecule cSCC therapeutics. We developed a 3-dimensional bioprinted skin (3DBPS) model of cSCC tumors together with a microscopy assay to test chemotherapeutic effects in tissue. The full thickness SCC tissue model was validated using hematoxylin and eosin (H&E) and immunohistochemical histological staining, confocal microscopy, and cDNA microarray analysis. A nondestructive, 3D fluorescence confocal imaging assay with tdTomato-labeled A431 SCC and ZsGreen-labeled keratinocytes was developed to test efficacy and general toxicity of chemotherapeutics. Fluorescence- derived imaging biomarkers indicated that 50% of cancer cells were killed in the tissue after 1μM 5-Fluorouracil 48-hour treatment, compared to a baseline of 12% for untreated controls. The imaging biomarkers also showed that normal keratinocytes were less affected by treatment (11% killed) than the untreated tissue, which had no significant killing effect. Data showed that 5-Fluorouracil selectively killed cSCC cells more than keratinocytes. Our 3DBPS assay platform provides cellular-level measurement of cell viability and can be adapted to achieve nondestructive high- throughput screening (HTS) in bio-fabricated tissues.
... Squamous cell carcinoma (SCC) is the second most common cancer in humans, and its frequency is increasing worldwide (Weinberg et al., 2007). Similarly, SCC is the most common malignant tumour of the skin and oral cavity in cats. ...
Squamous cell carcinoma (SCC) is the most common malignant neoplasm of the skin in cats. Tumour angiogenesis is the pivotal event for tumour progression and metastasis. We assessed protein and gene expression of angiogenic growth factors including bFGF, VEGF-C, TGF-β, PDGF-A, PDGF-C and PDGFR-α that possibly contribute to the angiogenic phenotype of feline SCC (FSCC) and could, therefore, be a good target in the treatment of SCC. In the present study, a total of 27 FSCC cases were investigated. Tumour cases were histopathologically classified as well differentiated (10/27), moderately differentiated (5/27), and poorly differentiated (12/27). The expression levels of the growth factors were detected using immunohistochemistry and assessed semi-quantitatively. Growth factor expression levels were evaluated at different locations: in the oral region, in areas exposed to solar UV radiation including the ears, eyelids and nasal planum, and other miscellaneous locations. Our findings have revealed that FSCC arising from different anatomical sites of the body and showing differences in aggressiveness, metastasis, and prognosis may be angiogenesis dependent, and angiogenic key regulators could play a role in the development of FSCC.
... [3][4][5][6] More than half of HNSCC patients experience relapse and most die from metastatic disease at regional and distant sites, being lymph nodes metastases important adverse prognostic factors. [5][6][7] Therefore, there is an urgent need to better understand the molecular alterations in signaling pathways that contribute to HNSCC tumorigenesis and malignant invasion, in order to develop novel diagnostic and treatment strategies. ...
Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal lining of the upper aerodigestive tract and display few treatment options in advanced stages. Despite increased knowledge of HNSCC molecular biology, the identification of new players involved in triggering HNSCC recurrence and metastatic disease is needed. We uncover that G‐protein‐coupled receptor kinase‐2 (GRK2) expression is reduced in undifferentiated, high‐grade human HNSCC tumors, whereas its silencing in model human HNSCC cells is sufficient to trigger epithelial‐to‐mesenchymal transition (EMT) phenotypic features, an EMT‐like transcriptional program and enhanced lymph node colonization from orthotopic tongue tumors in mice. Conversely, enhancing GRK2 expression counteracts mesenchymal cells traits by mechanisms involving phosphorylation and decreased functionality of the key EMT inducer Snail1. Our results suggest that GRK2 safeguards the epithelial phenotype, whereas its downregulation contributes to the activation of EMT programs in HNSCC.
... Although chemotherapeutic agents such as cisplatin, fluoropyrimidines and bleomycin, doxorubicin are useful, their rate of success is limited (Cranmer, Engelhardt et al. 2010). Also, chemotherapeutic agents such as retinoid and interferons were initially reported to be useful in the treatment of keratinocyte malignancies have unfortunately shown limited success in follow-up studies (Weinberg, Ogle et al. 2007). ...
Cutaneous squamous cell carcinoma (cSCC), premalignant actinic keratosis (AK) and Bowen’s disease (BD) are highly prevalent, heterogeneous keratinocytic skin lesions (KSLs). Discrepancies between clinical presentations and histologic analyses of KSLs frequently lead to misdiagnoses or delayed diagnoses. Biomarkers that can accurately stratify KSLs by their malignant potential are urgently needed to support a paradigm shift in skin cancer care to personalised, precision medicine. In this thesis, a liquid chromatography tandem mass spectrometry (MS) platform was employed to conduct comprehensive proteomic profiling of formalin-fixed and paraffin embedded samples of normal skin and KSLs. Using complementary MS approaches, namely information dependent acquisition (IDA) and sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS), 3574 proteins were quantified overall allowing the identification of novel protein signatures for KSL subtypes. Proteomic findings were further investigated in silico using transcriptome databases, and several interesting targets were confirmed by immunohistochemistry. Distinct proteome profiles corresponding to subcategories of cSCC and precursor lesions were found, demonstrating the potential of MS-based approaches to deliver reliable diagnostics and disease staging. The bioinformatic analysis provided new insights into molecular pathways disrupted in different KSLs. The successful application of a non-invasive tape-stripping method for proteome sampling of KSLs was also demonstrated.
This work represents the most comprehensive proteome study of KSLs to date. The identification of deferentially altered proteins and molecular pathways between subtypes of KSLs will inform the development of diagnostic, therapeutic and disease staging strategies. Further exploration and implementation of the approaches described herein could have a major impact on patient outcomes and reduce the cost burden of KSLs.
... Given its first FDAapproved medication (cemiplimab) was released onto the market, it would be prudent to propose a new definition to help determine which patients are amenable to this treatment. While surgery and a combination of chemotherapy and radiation therapy have been considered the gold standard, other factors such as the general condition of the patient, age, comorbidities, and immunosuppression should be considered as with advanced BCCs [19]. The definition of advanced BCC is relatively new (2014); given the rarity of advanced BCC and cSCC, as well as the recent development of hedgehog inhibitors (HHi) and PD-1 inhibitors, perhaps it was felt there was no need to define advanced disease until recently. ...
Purpose of Review
Advanced cutaneous squamous cell carcinoma (cSCC), though rare, is fatal with an 89% 5-year mortality rate. The diagnostic criteria for advanced basal cell carcinoma were recently redefined with the introduction of hedgehog inhibitors such as vismodegib. Similarly, the authors suggest redefining the diagnostic criteria of advanced cSCC given the introduction of immune checkpoint inhibitors in order to broaden the patient population that can benefit from both new and old treatment options as potential neoadjuvants.
Recent Findings
Cemiplimab is a programmed death-1 (PD-1) inhibitor recently FDA-approved in 2018 for advanced cSCC with improved response rates (47–50%) compared to prior treatments. Given the lack of standardization, we suggest the diagnostic criteria of advanced cSCC to consider the patient condition, age, comorbidities, immunosuppression, and cosmetic outcome when determining a treatment regimen. Patients with diffuse cSCC due to immunosuppression may benefit from acitretin, while lesions on the lip may have a poor cosmetic outcome with surgery and may benefit from neoadjuvant therapy.
Summary
Advanced cSCC does not have standardized diagnostic criteria likely due to the lack of treatment options until now. Additional treatment options may be beneficial to a broader patient population when redefining advanced cSCC to include factors such as immunosuppression and cosmetic outcome from the perspective of the patient.
Objectives:
To describe real-world characteristics and treatment patterns of patients with metastatic cutaneous squamous cell carcinoma (mCSCC).
Methods:
This retrospective observational study used claims data from MarketScan Commercial and Medicare Supplemental databases (1/1/2013-7/31/2019). Adult patients with mCSCC who initiated non-immunotherapy systemic treatment (i.e. index event) between 1/1/2014 - 12/31/2018 were assessed for treatment patterns, allcause and CSCC-related healthcare resource utilization, and costs across settings of care.
Results:
Overall, 207 patients were included in the study. Mean age was 64.8 years, 76.3% were male, 59.4% had prior radiotherapy, and 58.9% had prior CSCC-related surgery. During follow-up, 75.8%, 51.7%, and 35.7% of patients received chemotherapy, radiotherapy, and targeted therapy as first-line treatment, respectively. Cisplatin (32.9%), carboplatin (22.7%), and cetuximab (32.4%) were the most common targeted therapies.Probability of death (95% CI) at month-6, year-1, and year-2 was 24% (16-32%), 50% (40 - 59%), and 67% (56 - 75%), respectively. Average CSCC-related healthcare costs were $5,354 per person per month (PPPM), with outpatient costs being the major cost driver at 96.4% ($5,160 PPPM).
Conclusion:
During 2014-2018, patients with mCSCC were commonly treated with cisplatin and cetuximab; prognosis was generally poor. These results indicate opportunity for new treatments to improve survival outcomes.
Squamous cell carcinoma is the second most commonly detected skin cancer, although presenting low mortality rates, it has a high impact on health economic burden. SCC is mainly detected in the head, neck, limbs, and areas of higher photoexposure. Both extrinsic and intrinsic individual factors account for the development of skin epidermoid carcinoma. Among the main factors, there are ultraviolet radiation exposure, immunosuppression, human papillomavirus, genodermatosis, chronic dermatosis, arsenic exposure, and ionizing radiation. Its subtypes are actinic keratosis, epidermoid carcinoma in situ, and invading epidermoid carcinoma. The main aims of SCC treatment are total removal of the tumor, minimizing the risk for recurrence and metastasis; preservation of function; and provision of the best possible aesthetic outcome.KeywordsSkin epidermoid carcinomaSquamous cell carcinomaSkin cancerNonmelanoma skin cancerKeratinocytic carcinoma
Primary cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with a rising incidence of about 1.8 million in the United States annually. Primary cSCC is usually curable by surgery; however, in some cases, cSCC eventuates in nodal metastasis and death from disease specific death. cSCC results in up to 15,000 deaths each year in the United States. Until recently, non-surgical options for treatment of locally advanced or metastatic cSCC were largely ineffective. With the advent of checkpoint inhibitor immunotherapy, including cemiplimab and pembrolizumab, response rates climbed to 50%, representing a vast improvement over chemotherapeutic agents used previously. Herein, we discuss the phenotype and function of SCC associated Langerhans cells, dendritic cells, macrophages, myeloid derived suppressor cells and T cells as well as SCC-associated lymphatics and blood vessels. Possible role(s) of SCC-associated cytokines in progression and invasion are reviewed. We also discuss the SCC immune microenvironment in the context of currently available and pipeline therapeutics.
Cutaneous squamous cell carcinoma (cSCC) is a skin cancer originating from keratinocytes. Improvements in surgical techniques and the increasingly better management of immunosuppressive therapy has led to very high long-term survival rates of solid organ transplant recipients (SOTR). However, this lifelong immunosuppression to avoid graft rejection confers these patients a higher risk of developing different types of cancer, especially keratinocyte carcinoma. The incidence of cSCC in SOTR is 60–250 times increased compared to the immunocompetent population, and it is very common to develop multiple cSCC during the posttransplant period. Because of the burden of numerous cSCC, the management of skin cancer in SOTR requires a dedicated transplant dermatology clinic with easy access to dermatologic care and more frequent surveillance for high-risk patients. Intervention with regular skin screening examinations may lessen morbidity associated with advanced skin cancer and improve overall quality of life posttransplantation.
Skin carcinomas are the result of the malignant proliferation of epithelial keratinocytes.
The two most common nonmelanoma skin cancers are basal cell carcinoma and squamous cell carcinoma and the latter has the potential to metastasize and cause morbidity and mortality.
During the comprehensive eye exam, clinicians have an opportunity to conduct a visual inspection of the face to detect skin cancers that may be undiagnosed.
The optometrist is trained to detect and describe malignant lesions of the eyelids and periorbital region, and so, extending the exam to include the detection of facial neoplasms can be a life-saving measure.
This article provides a review of the clinical appearances of basal and squamous cell carcinomas of the face and ears and discusses lesion characteristics that warrant dermatologic intervention.
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Recent advances in the understanding and targeting of immune checkpoints have led to great progress in immune therapies against many forms of cancer. While many types of immune checkpoints are currently targeted in the clinic, this review will focus on recent research implicating the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis as an emerging focus for the treatment of keratinocytic tumors. PD-L1 is of particular interest in nonmelanoma skin cancer (NMSC), as it is not only upregulated in these tumors but is stimulated by environmental ultraviolet exposure. This response may also make PD-L1 an excellent target for photochemoprevention using topically applied small molecule inhibitors. Here, we summarize recent investigations on PD-L1 expression and clinically relevant immune checkpoint inhibitor treatment in cutaneous squamous cell carcinoma, basal cell carcinoma, and head and neck squamous cell carcinoma, as well as small molecule agents targeting PD-L1 that may be useful for clinical development aiming at treatment or prevention of NMSC.
Patients with squamous cell carcinoma (SCC) have significantly lower survival upon the development of distant metastases. The extracellular matrix (ECM) is a consistent yet dynamic influence on the metastatic capacity of SCCs. The ECM encompasses a milieu of structural proteins, signaling molecules, and enzymes. Just over 40 years ago, the fibrous ECM glycoprotein laminin was identified. Roughly four decades of research have revealed a pivotal role of laminins in metastasis. However, trends in ECM alterations in some cancers have been applied broadly to all metastatic diseases, despite evidence that these characteristics vary by tumor type. We will summarize how laminins influence the SCC metastatic process exclusively. Enhanced laminin protein deposition occurs at the invasive edge of SCC tumors, which correlates with elevated levels of laminin‐binding β1 integrins on SCC cells, increased MMP‐3 presence, worse prognosis, and lymphatic dissemination. Although these findings are significant, gaps in knowledge of the formation of a premetastatic niche, the processes of intra‐ and extravasation, and the contributions of the ECM to SCC metastatic cell dormancy persist. Bridging these gaps requires novel in vitro systems and animal models that reproduce tumor–stromal interactions and spontaneous metastasis seen in the clinic. These advances will allow accurate assessment of laminins to predict responders to transforming growth factor‐β inhibitors and immunotherapy, as well as potential combinatorial therapies with the standard of care. Such clinical interventions may drastically improve quality of life and patient survival by explicitly targeting SCC metastasis.
Non-melanoma skin cancers (NMSCs) are the fifth most common type of cancer worldwide, affecting both men and women. Each year, more than a million new occurrences of NMSC are estimated, with Squamous Cell Carcinoma (SCC) representing approximately 20% of all skin malignancies. The purpose of this study was to find potential diagnostic biomarkers for SCC by application of eXplainable Artificial Intelligence (XAI) on XGBoost machine learning (ML) models trained on binary classification datasets comprising the expression data of 40 SCC, 38 AK, and 46 normal healthy skin samples. After successfully incorporating SHAP values into the ML models, 23 significant genes were identified and were found to be associated with the progression of SCC. These identified genes may serve as diagnostic and prognostic biomarkers in patients with SCC.
Squamous cell carcinomas (SCC) represent 20% of all nonmelanoma skin cancers, most tumors responding favorably to the conventional therapy. Incisional or excisional biopsy is essential for diagnosis and prognosis evaluation. The study included 103 cases of SCC, following the assessment of some clinical and histopathological aggressivity factors, which were digitally stored and statistically analyzed using comparison tests. The tumor grade was significantly associated with the histological variant, the maximum tumor size, the perineural and lymphovascular invasion, the depth of the invasion and the status of resection limits. The pT category was significantly associated with the location and maximum tumor size, perineural invasion, depth of invasion and status of resection limits. It was observed a significant association of tumor grade and pT category. The evaluation of the clinical and histological characteristics of SCC is an important step in obtaining relevant prognostic information and applying appropriate therapy.
Non-Melanoma skin cancer is one of the most frequent types of cancer. Early detection is encouraged so as to ensure the best treatment, Hyperspectral imaging is a promising technique for non-invasive inspection of skin lesions, however, the optimal wavelengths for these purposes are yet to be conclusively determined. A visible-near infrared hyperspectral camera with an ad-hoc built platform was used for image acquisition in the present study. Robust statistical techniques were used to conclude an optimal range between 573.45 and 779.88 nm to distinguish between healthy and non-healthy skin. Wavelengths between 429.16 and 520.17 nm were additionally found to be optimal for the differentiation between cancer types.
Background
Cutaneous squamous cell carcinoma (cSCC) accounts for nearly a quarter of non‐melanoma skin cancers. Studies reporting Quality of Life (QoL) in this group focus on early stage disease. A small proportion of cSCC patients have high‐risk or advanced disease, with potentially significant QoL impacts, yet are largely overlooked.
Aims
This structured review appraises measures and published QoL outcomes in this group.
Materials & Methods
We conducted searches in MEDLINE, EMBASE, CINAHLplus and PsycInfo in June 2020 (updated in October) to identify publications specifically reporting QoL outcomes in this cohort. Returns were reviewed against a strict set of eligibility criteria.
Results
We identified seven publications for inclusion; three relating to high‐risk cSCC, three to metastatic disease and one to unresectable disease. Publications were appraised for quality using the Mixed Methods Appraisal Tool. Only one fulfilled more than two of the five quality criteria. Studies employed a range of patient reported outcome measures to assess QoL, both generic and disease specific.
Discussion
All studies with multiple time‐points reported stable or improving QoL, however extrapolation of these findings to the cSCC population is not warranted due to study limitations including mixed populations, incomplete data sets or single measurements. We set out to review the QoL literature for high‐risk and advanced cSCC and found a small and disparate body of evidence. Studies varied significantly in terms of study population, design and quality. While the identified studies suggested stable or improving QoL, we question the choice of measures used and highlight the need for further work in this area.
Conclusion
While there are some published reports about quality of life for patients with early stage cutaneous squamous cell carcinoma, these impacts for the high‐risk or advanced cohort are largely unexplored. We conducted a structured review of published measures and outcomes used in this cohort and found a demonstrable need for further, targeted, exploration of patient needs in this area.
Metastatic spread of cutaneous squamous cell carcinoma (cSCC) to the gastrointestinal tract is a rare entity. A 63-year-old woman with a history of poorly controlled HIV and a recurrent cSCC on the right temple presented with functional decline, ascites and shortness of breath. A CT scan showed widespread metastatic malignancy involving lung, pleura, heart, stomach, liver, retroperitoneum and soft-tissue. In the case presented here, an upper endoscopy revealed a submucosal lesion in the stomach. Biopsies described the lesion as a poorly differentiated SCC. Comprehensive genomic profiling yielded striking molecular similarities between the gastric tumour and the patient’s prior cSCC. It confirmed the origin of the disease and excluded spread from an occult primary. This case adds to the limited literature on gastrointestinal metastases of cSCC and serves as a reminder that non-AIDS-defining cancers are on the rise in the HIV-population.
Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in humans and its incidence is both underestimated and on the rise. cSCC is referred to in the literature as high-risk cSCC, locally advanced cSCC, metastatic cSCC, advanced cSCC, and aggressive cSCC. These terms can give rise to confusion and are not always well defined. In this review, we aim to clarify the concepts underlying these terms with a view to standardizing the description of this tumor, something we believe is necessary in light of the new drugs that have been approved or are in development for cSCC.
Resumen
El carcinoma epidermoide cutáneo (CEC) es el segundo tumor más frecuente en humanos y tiene una incidencia creciente e infraestimada. En la literatura nos encontramos con términos como CEC de alto riesgo, CEC localmente avanzado, CEC metastásico, CEC avanzado y CEC agresivo, que pueden dar lugar a confusión y que en algunas ocasiones no se encuentran del todo bien definidos. En esta revisión pretendemos aclarar estos conceptos con la idea de lograr homogeneidad en su descripción, algo que parece necesario a la luz de los nuevos fármacos aprobados y en desarrollo para este tumor.
Inflammatory bowel disease (IBD), both through inherent pathophysiology of the disease and medication effects, influences the risk of development of skin cancer. Evidence suggests that patients with IBD are at an increased risk of developing melanoma, irrespective of therapy, and there is some data that TNFα inhibitors increase this risk. The risk of non-melanoma skin cancers is increased by exposure to thiopurines. Given these associations, it is essential that the IBD practitioner has a good grasp on the most common types of skin cancer and their prevention and management. This chapter covers the pathophysiology of the most common types of skin cancer and provides an overview of data showing associations between skin cancer risk and IBD including various currently available medications. Recommendations are made for skin cancer prevention and management once diagnosed.
The records linkage resources of the Rochester Epidemiology Program Project were used to identify 169 incident cases of invasive squamous cell carcinoma of the skin in the population of Rochester, Minn, between 1976 and 1984. The overall age-standardized incidence was 38.8/100,000 persons (63.1 in men; 22.5 in women). Metastasis occurred in 3.6%, and during an average of 3.8 years of follow-up, recurrence was seen in 3.6% while subsequent new lesions occurred in 12%. The demographics and course of patients with squamous cell carcinoma were different from either those of Bowen's disease or basal cell carcinoma in these population-based data.
A case of cutaneous adenoid squamous cell carcinoma is reported. A 71-year-old man presented with a rapidly growing, hemispheric, asymptomatic nodule on the right face for 3 months. Dermoscopy showed yellow and white keratinized plaque with white halo, keratin plug, linear and helical blood vessels. Histopathological examination showed epidermal atrophy, invasive growth of epithelioid cells in mass or cord-like pattern, forming pseudoglandular structure, in the dermis. Aeantholyt-ic cells and atypical mitoses were also present. There were mixed inflammatory infiltration in and around the tumor tissue. The diagnosis was adenoid squamous cell carcinoma.
The American Joint Committee on Cancer's Cancer Staging Manual is used by physicians throughout the world to diagnose cancer and determine the extent to which cancer has progressed. All of the TNM staging information included in this Sixth Edition is uniform between the AJCC (American Joint Committee on Cancer) and the UICC (International Union Against Cancer).
In addition to the information found in the Handbook, the Manual provides standardized data forms for each anatomic site, which can be utilized as permanent patient records, enabling clinicians and cancer research scientists to maintain consistency in evaluating the efficacy of diagnosis and treatment. The CD-ROM packaged with each Manual contains printable copies of each of the book’s 45 Staging Forms.
Background. Metastases from mucosal and cutaneous carcinomas can present in a delayed fashion, and this late presentation may confer a different prognosis after conventional treatment. Methods. We present a series of patients in which there was a significant time delay between the treatment of a squamous carcinoma of the skin or mucosa of the midface and the detection of regional metastases in 12 of the 13 cases. Primary tumors were located on the lower lip and commissure (n = 3), nasal tip (n = 2), nasal ala (n = 1), columella (n = 1), nasofacial crease (n = 2), maxillary alveolus (n = 3), and mandibular alveolus (n = 1). Metastatic spread manifested by palpable perifacial or submandibular lymph nodes was not evident until greater than 11 months after the treatment of the primary site in 12 of 13 patients (range, 3-45 months). Nine of the patients were clinically staged as N1, whereas there was one each in the N2a, N2b, N2c, and N3 categories. Eleven of the 13 patients were initially seen with palpable disease involving the perifacial nodes within or around the submandibular gland. All patients were treated with neck dissection except one, who refused surgical treatment and underwent a second course of radiotherapy to the cervical region. The nine patients initially seen with clinical stage N1 disease underwent neck dissection with preservation of the sternocleidomastoid, internal jugular vein, and accessory nerve, Results. Of 10 patients with perifacial node metastases who underwent neck dissection, 8 required sacrifice of the marginal mandibular nerve and overlying platysma to gain adequate margin. Extracapsular spread was present in 11 patients, (8 of 9 who were clinically N1). Postoperative radiotherapy was recommended to all patients with extracapsular spread, although only 7 of the 11 received radiotherapy. There were no regional recurrences after a minimum follow-up of 1 year (range, 12-65 months; mean, 31.4 months). Histologic grade appeared to have no influence on prognosis. Conclusions. This cohort demonstrates the ability of midfacial squamous cell carcinoma to manifest regional metastatic disease over a delayed time. This delayed presentation appears to confer a more favorable response to treatment. For midfacial cancers, the perifacial nodes are at greatest risk for metastatic spread. For tumors in this region, primary treatment of the neck is probably not warranted, but careful extended follow-up for the potential of delayed cervical metastasis is prudent. (C) 1998 John Wiley & Sons, Inc.
This is a retrospective analysis of 60 patients with previously untreated metatypical basal cell (3 patients) or squamous cell (57 patients) carcinoma of the skin, metastatic to the parotid area. All patients had a minimum 2-year follow-up, and 43% had a minimum 5-year follow-up. Treatment was surgery alone (8 patients), irradiation alone (16 patients), or planned combined surgery and irradiation (36 patients). The ultimate rates of control of disease in the parotid area were surgery alone, 5 of 8 (63%); irradiation alone, 6 of 13 (46%); planned combined surgery and irradiation, 32 of 36 (89%). In the combined-treated group, all 4 recurrences were in patients who had positive surgical margins and gross involvement of the facial nerve. In patients with negative surgical margins, without involvement of the facial nerve, who had combined treatment, the control rate was 100%. Of the surgery-alone group, only 1 patient ultimately had the disease controlled and retained a functioning facial nerve.
Background: Some patients with invasive cutaneous squamous cell carcinoma are either not adequate surgical candidates or present with lesions in cosmetically sensitive areas in which a surgical procedure might result in an apparent and/or a cosmetically unacceptable scar. Objective: To evaluate the effectiveness of imiquimod 5% cream in the treatment of an invasive squamous cell carcinoma in the nose of a young man. Methods: Imiquimod 5% cream was applied to the lesion five times a week for 12 weeks. Results: Complete clinicopathologic tumor clearance and an excellent cosmetic result were achieved after 12 weeks of imiquimod treatment. Conclusion: Imiquimod 5% cream may represent a reasonably effective alternative for the management of invasive squamous cell carcinoma in selected patients.
Background
Since 1989, 105 patients with squamous head and neck cancer have been treated with combined chemoradiotherapy.Objective
To examine the effectiveness of using combined chemoradiotherapy on patients with squamous head and neck cancer.Design
Eight-year (1989-1997) single-institution evaluation of 105 patients.Methods
Treatment consisted of fluorouracil, 1000 mg/m2 per day, and cisplatin, 20 mg/m2 per day, both given as continuous infusions during 4 days beginning on day 1 and 22 of a concurrent radiotherapy course. Radiation was given in single daily fractions of 1.8 to 2 Gy, to a total dose of 66 to 72 Gy. Salvage surgery was performed for any residual or recurrent locoregional disease. Planned neck dissection was recommended for all patients with N2+ neck disease, irrespective of clinical response.Results
The 105-patient cohort consisted of 79 men and 26 women. The primary site was identified in the oral cavity in 6, oropharynx in 46, larynx in 30, and hypopharynx in 20 patients. Two patients had multiple primaries and 1 patient had an unknown primary. There were 4 patients with stage II, 24 with stage III, and 77 with stage IV disease. Grade 3 and 4 chemoradiotherapy toxic effects included mucositis in 88% of patients, cutaneous reaction in 50%, neutropenia in 49%, thrombocytopenia in 12%, and nausea in 5%. There were no deaths secondary to treatment. The mean weight loss was 12% of initial body weight. To date, primary site persistence or recurrence has occurred in only 14 patients (13%). With a mean follow-up of 39 months, 66 patients (63%) are alive and free of disease. The Kaplan-Meier 4-year projected overall survival is 60% with a disease-specific survival of 74%, a distant metastasis-free survival of 84%, and an overall survival with primary site preserved of 54%.Conclusions
This chemoradiotherapy regimen, although toxic, is tolerable with appropriate supportive intervention. Locoregional and distant control are likely. Primary site conservation is possible in most patients. Chemoradiotherapy appears to have an emerging role in the primary management of head and neck cancer.
• Four hundred fourteen primary cutaneous squamous cell carcinomas were treated by microscopically controlled excision. A five-year mortality-table adjusted cure rate of 93.3% was achieved. The following six parameters were analyzed for correlation with the local recurrence rate: sex, age, lesion diameter, history of previous therapy, anatomic site, and number of stages of Mohs' surgery required for treatment. Only the number of stages correlated significantly with the recurrence rate. However, subpopulations at high risk for recurrent disease could be identified. These consisted of male patients younger than 60 years of age, male patients requiring five or more stages of Mohs' surgery, and patients of either sex with carcinoma of the lower extremity. Modifications of microscopically controlled excision may be warranted in selected patients.
(Arch Dermatol 1982;118:900-902)
BACKGROUND
The prognosis of squamous cell carcinoma (SCC) of the skin is directly related to the development of metastases or local recurrence. This is affected by numerous factors, most of which are independent: clinical tumor size, histopathologic tumor thickness, depth of penetration, degree of cell differentiation, degree of keratinization, location, and immunosuppression. The determination of whether desmoplasia, previously described in only one case of SCC, constitutes an additional prognostic factor was the objective of this study.METHODS
The study was performed prospectively on 594 SCCs from 509 patients. All of the factors mentioned earlier were present. Forty-four SCCs were identified by light microscopy as desmoplastic due to their prominent trabecular growth patterns, narrow columns of atypical epithelial cells, and marked desmoplastic stromal reaction, in some cases with perineural and perivascular invasion. Follow-up ranged from 4 to 10 years (median, 5.3 years).RESULTSAll tumors in the study patient population were treated using the paraffin section method of micrographic surgery. The 44 desmoplastic SCCs were found to metastasize 6 times more often than the remaining 550 tumors (22.7% vs. 3.8%), with 10 times as many local recurrences (27.3% vs. 2.6%).CONCLUSIONS
Desmoplasia is a highly significant (P < 0.001) prognostic factor for SCCs and is associated with the development of metastases or recurrence. Cancer 1997; 79:915-9. © 1997 American Cancer Society.
Background:
Organ transplant recipients receiving immunosuppressive medications are at increased risk of cutaneous malignancies.
Objective:
We sought to determine the complications associated with systemic retinoid therapy in severely affected organ transplant recipients receiving treatment before or during the course of metastatic squamous cell carcinoma.
Methods:
This was a collaborative retrospective study of solid organ transplant recipients treated with systemic retinoids for severe squamous cell carcinoma, with subjective analysis of complications associated with treatment.
Results:
Complications and intolerance of systemic retinoid therapy were common, necessitating discontinuation of therapy in six of eight cases.
Conclusion:
This subset of transplant patients, severely affected by skin cancer, appeared to be less able to tolerate systemic retinoid therapy than patients in formal clinical trials. Intolerance of adverse effects in this context suggests the need for novel approaches with these challenging patients.
The authors treated 14 patients with advanced squamous cell carcinoma (SCC) of the skin or lip with one to four cycles of combination chemotherapy consisting of cisplatin by bolus injection, and 5-fluorouracil (5-FU) and bleomycin by continuous 5-day infusion. Objective responses were seen in 11 of the 13 evaluable patients (84%). Four patients had a complete remission (30%) and seven patients, a partial remission (54%). Local control after definitive complementary radiation and/or surgical treatment was achieved in seven patients. Toxic side effects was acceptable; they consisted of nausea and vomiting in all patients, transient skin changes, hematologic (Grade 3/4) abnormalities in four patients, and pulmonary fibrosis in one elderly patient. These results show that this chemotherapy combination could play a role in reducing the tumor mass and in facilitating definitive treatment to obtain better functional and cosmetic results in advanced SCC of the skin.
These guidelines were commissioned by the British Association of Dermatologists Therapy Guidelines and Audit subcommittee. Members of the committee are: N.H.Cox (Chairman), A.V.Anstey, C.B.Bunker, M.J.D.Goodfield, A.S.Highet, D.Mehta, R.H.Meyrick Thomas, J.K.Schofield. The Multiprofessional Skin Cancer Committee representing the British Association of Dermatologists, the British Association of Plastic Surgeons and members of the Faculty of Clinical Oncology of the Royal College of Radiologists consisted of: N.H.Cox, A.Y.Finlay, B.R.Allen, D.S.Murray, R.W.Griffiths, A.Batchelor, D.Morgan, J.K.Schofield, C.B.Bunker, N.R.Telfer, G.B.Colver, P.W.Bowers, D.L.L.Roberts, A.V.Anstey, R.J.Barlow, J.A.Newton-Bishop, M.E.Gore, N.Kirkham and the authors.
The aims of this study were to investigate the detection of cervical lymph node metastases of head and neck cancer by positron
emission tomographic (PET) imaging with fluorine-18 fluorodeoxyglucose (FDG) and to perform a prospective comparison with
computed tomography (CT), magnetic resonance imaging (MRI), sonographic and histopathological findings. Sixty patients with
histologically proven squamous cell carcinoma were studied by PET imaging before surgery. Preoperative endoscopy (including
biopsy), CT, MRI and sonography of the cervical region were performed in all patients within 2 weeks preceding 18F-FDG whole-body PET. FDG PET images were analysed visually and quantitatively for objective assessment of regional tracer
uptake. Histopathology of the resected neck specimens revealed a total of 1284 lymph nodes, 117 of which showed metastatic
involvement. Based on histopathological findings, FDG PET correctly identified lymph node metastases with a sensitivity of
90% and a specificity of 94% (P<10–6). CT and MRI visualized histologically proven lymph node metastases with a sensitivity of 82% (specificity 85%) and 80% (specificity
79%), respectively (P<10–6). Sonography revealed a sensitivity of 72% (P<10–6). The comparison of 18F-FDG PET with conventional imaging modalities demonstrated statistically significant correlations (PET vs CT, P=0.017; PET vs MRI, P=0.012; PET vs sonography, P=0.0001). Quantitative analysis of FDG uptake in lymph node metastases using body weight-based standardized uptake values
(SUVBW) showed no significant correlation between FDG uptake (3.7±2.0) and histological grading of tumour-involved lymph nodes (P=0.9). Interestingly, benign lymph nodes had increased FDG uptake as a result of inflammatory reactions (SUVBW-range: 2–15.8). This prospective, histopathologically controlled study confirms FDG PET as the procedure with the highest
sensitivity and specificity for detecting lymph node metastases of head and neck cancer and has become a routine method in
our University Medical Center. Furthermore, the optimal diagnostic modality may be a fusion image showing the increased metabolism
of the tumour and the anatomical localization.
Chronic lymphocytic leukemia involves the skin in a small percentage of patients and may portend an ominous prognosis in some patients. We report a series of eight biopsies from seven different patients in which the cutaneous leukemic infiltrate was confined exclusively to the region immediately surrounding primary epithelial neoplasms including squamous cell carcinoma (6), basal cell carcinoma (1) and actinic keratosis (1). The malignant lymphocytes appear to constitute a host response to these neoplasms and do not appear to suggest a rapid downhill course for these patients. These observations serve to 1) suggest a new pattern of cutaneous involvement by leukemic cells and 2) offer some insights into potential cellular trafficking patterns of these neoplastic cells.
We performed a retrospective analysis of all 102 cases of chronic lymphocytic leukemia (CLL) treated by the Hematology Service of the University of Manitoba from Jan 1, 1955, to April 1, 1974. The incidence of secondary cancer was compared with that in the Cancer Registry population of Manitoba of the same age and sex distribution. The risk of all cancers developing in patients with CLL was threefold that for the age- and sex-matched population, eightfold for skin cancers, and twofold for all cancers excluding skin cancer.
Three basal- and four squamous-cell carcinomas in seven patients with chronic lymphocytic leukemia or chronic lymphocytic lymphoma recurred repeatedly after conventional treatment, and grew to large sizes. The squamous-cell carcinomas metastasized in all four of the patients so afflicted. Absolute numbers of circulating T lymphocytes were normal in the seven patients, but they had cutaneous anergy to intradermal tests with common antigens and to dinitrochlorobenzene. The following recommendations for management of cutaneous carcinomas in patients with malignant lymphomatoses are made: 1) closer surveillance than for patients with cutaneous cancers but without malignant lymphomatoses, 2) early treatment of actinic keratoses to prevent possible transformation to malignancy, and 3) microscopically controlled excision of basal- or squamous-cell carcinomas larger than 1 cm in diameter.
The development of microscopically controlled surgery, the use of the fixed-tissue technique for advanced, complicated carcinomas and for malignant melanomas, the use of the fresh-tissue technique for less advanced carcinomas, the five-year results, and plans for the future of the method are discussed.
The incidence of histologically proven perineural invasion in squamous carcinoma of the lower lip is 2%. The 2 year survival in this group of patients is striking low compared to the overall survival with lower lip cancer in general. This may be related to the higher incidence of cervical nodal metastasis in these patients with nerve invasion than those patients without, (80% vs 10%). In addition, no patient survived who presented with a large lesion (greater than 3 cm) nerve invasion and nodal metastasis. In is of interest that 60% of these patient with nerve invasion presented with a history of radiation therapy in the past for a localized lip lesion. Based on the analysis of failures, combined treatment with the judicious use of surgery and radiation in a planned sequential manner hopefully will improved the overall survival in patients with lip cancer and nerve invasion.
This paper presents a review of the literature and a retrospective study of 46 patients with burn scar carcinoma treated from 1945 to 1975. The average patient was 58 years of age and most were males (61%). The average lag period (time from burn to cancer diagnosis) was 42.3 years, with a range from 1.5 to 75 years. Although Marjolin's ulcer generally does not occur in burns that were primarily skin grafted, 11% of these patients had previously undergone skin grafting. The anatomic locations, histopathology, and behavior of these lesions particularly related to the occurrence of metastases are detailed. Of the 16 patients (34.8%) who presented with or developed metastases, 15 expired from the malignancy. The presence or absence of metastases proved to be the most important prognostic indicator. Five patients (10.8%) developed recurrences after treatment, and of these three died from recurrent disease. Five year survival figures ranged from 57% for face and neck lesions to 31% for lower extremity lesions. Specific treatment rendered and mortality are correlated. Although prophylactic node dissections have generally not been recommended, the high percentage of metastases from lower-extremity lesions (53.8%), the poor prognosis associated with such metastases, and the low salvage rate with regional node dissection for positive nodes strongly suggest that prophylactic node dissection be considered, especially for lower-extremity burn scar carcinoma.
Computed tomographic (CT) scans and magnetic resonance (MR) images obtained in 24 patients with cervical lymphadenopathy were retrospectively and blindly evaluated by two readers for the presence of central nodal necrosis (CNN) and extracapsular nodal spread (ENS). The CT studies were all enhanced, and the MR images were obtained with short repetition time (TR)/echo time (TE), long TR/double echo, and enhanced short TR/TE fat-suppressed sequences. Each MR imaging sequence was interpreted separately and then collectively. Sixty lymph nodes were identified with CT. Sensitivity for CNN was 16%-67% with the unenhanced MR pulse sequences, 50% with enhanced sequences, and 83%-100% with CT. The most accurate reading of MR images for CNN was with the unenhanced T1-weighted and T2-weighted images (86%-87%); the accuracy of CT was 91%-96%. The accuracy of MR imaging for detecting ENS was maximal with T1-weighted images (78%-90%). Gadolinium-enhanced, fat-suppressed images did not improve accuracy in evaluating CNN or ENS. CT is currently more accurate than unenhanced or enhanced MR imaging in detecting CNN or ENS.
Positron emission tomography (PET) has been shown to be effective in detecting intracranial malignancies based on cerebral glucose metabolism. To evaluate the ability of PET to detect extracranial head and neck neoplasms and cervical metastases, 16 patients with primary squamous cell carcinomas were examined. All patients received preoperative computerized tomography (CT) and magnetic resonance imaging (MRI) scans and underwent PET evaluation using intravenous 18F-2-fluoro-2-deoxy-D-glucose (FDG). Histopathologic analysis compared tumor invasion and positive lymph nodes with findings on MRI, CT, and PET images. All primary tumors were delineated by PET, while MRI and CT failed to detect one superficial tumor involving the anterior tongue. Ten nodes were detected by CT and MRI versus 12 nodes demonstrated by PET. PET is highly effective in detecting head and neck carcinomas as well as metastatic cervical lymph nodes. In addition, PET may be useful in evaluating postsurgery and postradiotherapy patients for recurrent and new primary tumors.
The striking impression obtained from reviewing the cancer literature is how difficult it is to analyze the data for answers to many important biologic, behavioral, prognostic, and therapeutic questions about squamous cell carcinoma of the skin. This article addresses current concepts, controversies, and management of cutaneous squamous cell carcinoma (excluding the lip and oral mucosa).
We reviewed all studies since 1940 on the prognosis of squamous cell carcinoma (SCC) of the skin and lip. The following variables are correlated with local recurrence and metastatic rates: (1) treatment modality, (2) prior treatment, (3) location, (4) size, (5) depth, (6) histologic differentiation, (7) histologic evidence of perineural involvement, (8) precipitating factors other than ultraviolet light, and (9) host immunosuppression. Local recurrences occur less frequently when SCC is treated by Mohs micrographic surgery. This local recurrence rate differential in favor of Mohs micrographic surgery holds true for primary SCC of the skin and lip (3.1% vs 10.9%), for ear SCC (5.3% vs 18.7%), for locally recurrent (previously treated) SCC (10% vs 23.3%), for SCC with perineural involvement (0% vs 47%), for SCC of size greater than 2 cm (25.2% vs 41.7%), and for SCC that is poorly differentiated (32.6% vs 53.6%).
The role of dermatologists in the diagnosis and treatment of skin cancer continues to increase. Consequently, they will more frequently be involved in the diagnosis, treatment, and management of patients with metastatic or potentially metastatic tumors. Squamous cell carcinomas and malignant melanomas are frequently seen in dermatologic practices and have the capability to metastasize. Metastases are the result of a complex process that is characterized by a sequence of steps, each of which requires acquisition by the malignant cell of key biologic properties. The metastatic sequence can be conceptualized as detachment from the primary tumor followed by invasion, intravasation into a vessel, circulation, stasis within a vessel, extravasation, invasion of the recipient tissue bed, and ultimately proliferation. The basic steps of the metastatic sequence are described as well as how these steps and other tumor cell adaptations can affect the clinical patterns of metastasis. Finally, practical applications of the understanding of these principles of metastasis are discussed.
Retinoids (vitamin A derivatives) and interferon-alpha (IFN-alpha) are potent regulators of malignant cell differentiation and proliferation, and both have immunomodulatory and antiangiogenesis activity. A large body of preclinical and clinical data supports the use of combination therapy with 13-cis-retinoic acid (13-cRA) and IFN-alpha in patients with squamous cell carcinoma of the skin. This carcinoma is an extremely common and frequently severely disfiguring cancer, for which about 10% of patients remain uncured following standard local therapy.
Our purpose was to test whether a 20% or greater complete response rate could be achieved using a combination of these two agents in patients with advanced squamous cell carcinoma of the skin in whom local therapy had failed or was unfeasible or who had regional and/or distant metastases.
Thirty-two patients with heavily pretreated, advanced inoperable cutaneous squamous cell carcinoma of the skin were given a combination of oral 13-cRA (1 mg/kg per day) and subcutaneous recombinant human IFN alpha-2a (3 million units per day) for at least 2 months, unless disease progressed earlier, in a phase II trial.
Nineteen (68%) of the 28 assessable patients responded, seven (25%) of whom had complete responses. Response rates were 93% (13 of 14) in patients with advanced local disease (six complete responses), 67% (four of six) in patients with regional disease (no complete responses), and 25% (two of eight) in patients with distant metastases (one complete response). The relationship between decreased response rate and increased extent of disease was highly statistically significant (P less than .005, chi-square test). The median response duration was greater than 5 months. No life-threatening toxic effects occurred in assessable patients treated with this combination, although dose reductions were required in 18 patients. The major limiting side effect in this elderly patient population (median age, 67 years) was cumulative fatigue.
These results indicate that combined systemic therapy with 13-cRA and IFN alpha-2a is highly effective in patients with advanced squamous cell carcinoma of the skin.
This is a retrospective analysis of 60 patients with previously untreated metatypical basal cell (3 patients) or squamous cell (57 patients) carcinoma of the skin, metastatic to the parotid area. All patients had a minimum 2-year follow-up, and 43% had a minimum 5-year follow-up. Treatment was surgery alone (8 patients), irradiation alone (16 patients), or planned combined surgery and irradiation (36 patients). The ultimate rates of control of disease in the parotid area were surgery alone, 5 of 8 (63%); irradiation alone, 6 of 13 (46%); planned combined surgery and irradiation, 32 of 36 (89%). In the combined-treated group, all 4 recurrences were in patients who had positive surgical margins and gross involvement of the facial nerve. In patients with negative surgical margins, without involvement of the facial nerve, who had combined treatment, the control rate was 100%. Of the surgery-alone group, only 1 patient ultimately had the disease controlled and retained a functioning facial nerve.
The clinical classification of squamous cell carcinoma, which was established primarily by the International Union Against Cancer (UICC), does not permit optimal estimation of expected metastasis. The authors' results indicate that metastasis can be more accurately estimated on the basis of invasion depth, histopathologic grading, and especially tumor thickness. One essential advantage of these criteria is that they can be established by a histopathologist. It is interesting to note that in the authors' collective no carcinoma less than 2 mm thick metastasized, that is, a relatively high percentage of carcinomas (48%) can be graded as no-risk carcinomas. The risk of metastasis for undifferentiated carcinomas greater than 6 mm thick that have infiltrated the musculature, the perichondrium, or the periosteum, however, is quite high. Tumors between 2 and 6 mm thick with moderate differentiation and a depth of invasion that does not extend beyond the subcutis can be classified as low-risk carcinomas.
Elective neck dissection has long been a subject of debate among surgeons. The proponents of elective neck dissection base their rationale on studies that show a 30% incidence of occult disease in those situations for which elective neck dissection is recommended. One hundred eighty-two patients with advanced stages of squamous cell carcinoma of the head and neck were studied. All patients had preoperative computed tomography or magnetic resonance imaging, and all patients had some form of radical neck dissection. The sensitivity of clinical exam was compared with the sensitivity of computed tomography or magnetic resonance imaging in ability to detect nodal disease. The sensitivity of clinical exam alone was 71.7%, while the sensitivity of computed tomography or magnetic resonance imaging was 91.1%. Based on physical exam alone, there would be a 39% rate of occult disease; if computed tomography or magnetic resonance imaging data is combined with physical exam, the occult disease rate would drop to 12%. All centers performing elective neck dissection must reassess their rationale or restudy their occult disease rate with computed tomography or magnetic resonance imaging.
Sixteen of 70 patients with metastatic squamous cell carcinoma (SCC) from the skin had evidence of clinical immunosuppression. In addition to patients with lymphoproliferative disorders or renal failure, those with cicatricial pemphigoid and those undergoing chronic oral corticosteroid therapy were identified as being at high risk. Host immune surveillance appears to play a major role in determining the metastatic potential of cutaneous SCC.
Cutaneous adenoid squamous carcinoma (ASCC) is a distinctive neoplasm featuring tumor cell acantholysis. Because this lesion occasionally may prove troublesome diagnostically, we studied the clinical, histologic, and immunohistochemical features of 55 examples in order to further elucidate its characteristics. ASCC most often occurred in the skin of the head and neck in elderly patients. Of 49 patients in this series, 46 were men and 3 were women; their ages at diagnosis ranged from 25 to 90 yr, with a mean of 71. Six individuals had 2 metachronous neoplasms. ASCC generally behaved in an indolent manner, although 19% of cases did metastasize widely and prove fatal. Tumor size of greater than 1.5 cm appeared to correlate with the risk of an adverse clinical outcome. In addition, 10 patients with ASCC of the skin subsequently developed visceral malignancies. The cutaneous neoplasms were typified by invasive, tubular or pseudoglandular profiles of polygonal cells in the dermis, with glassy eosinophilic cytoplasm and focal squamous pearl formation. Connections to the overlying epidermis were commonly apparent. Immunohistochemically, ASCC demonstrated uniform reactivity for cytokeratin, but lacked markers of specialized glandular cells. These findings militate against the interpretation that such tumors demonstrate partial adnexal differentiation, and show that immunohistology may prove helpful in the differential diagnosis between ASCC and primary or metastatic adenocarcinomas of the skin.
Of 365 consecutive squamous cell carcinomas treated by Mohs surgery, 27 (7.4%) later metastasized. Tumors of the temple, the dorsa of the hands, and the lips were more likely to metastasize than tumors located elsewhere. None of the metastatic lesions developed in antecedent inflammatory or degenerative conditions. No single factor was useful in predicting metastasis, but metastatic lesions, on average, were significantly larger and deeper than nonmetastatic lesions. It was much more difficult to control the primary lesion of patients with metastases. Five of the 27 patients died of metastatic disease despite aggressive surgery, radiation therapy, or both.
The clinicopathologic features of 32 cutaneous squamous cell carcinomas of the head and neck in 12 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma were examined to determine the frequency of clinically aggressive and histologically poorly differentiated carcinomas in this group of patients. Two thirds of the neoplasms were multiple and 56% were high grade (grade 3 or 4). One of the 12 patients had recurrent carcinoma, two patients had recurrent and metastatic disease, and two patients had metastatic tumor without recurrence. Two patients died of tumor, one patient is alive with extensive recurrent and metastatic disease, and one patient died of an uncertain type of carcinoma. An additional patient with squamous cell carcinoma of the face died of cutaneous squamous cell carcinoma that arose on the chest. This study shows that cutaneous squamous cell carcinomas of the head and neck in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma are often high grade and have the potential for recurrence and metastasis.
Bowen's disease (BD) is generally regarded as a premalignant dermatosis.1-3 If untreated, 3% to 5% of patients may develop invasive carcinoma, which is capable of metastasizing and may even cause death.3, 4 Clinically, the lesions of BD present as a scaly, slightly elevated, erythematous plaque with surface fissures and foci of pigmentation. These lesions affect fair-skinned individuals more frequently and are equally distributed on the exposed and nonexposed parts of the body. Microscopically, BD is a form of carcinoma in situ characterized by full-thickness involvement of the epidermis and the pilosebaceous epithelium by atypical keratinocytes. The papillary dermis shows a dense, chronic, inflammatory infiltrate compound of lymphocytes, histiocytes, and plasma cells.
Bowen's disease with invasive carcinoma (BD-CA) is not well recognized by clinicians because of its rarity and lack of specific clinical features. The lesion is often diagnosed as seborrheic keratosis, basal cell carcinoma, squamous cell carcinoma, BD
One hundred eighty-seven squamous cell carcinomas of the lower lip were examined microscopically to identify parameters that might predict metastasis and patient outcome. Excision specimens of 157 nonmetastasizing carcinomas (group I) were compared with specimens from 30 tumors that had metastasized (group II). The following features were recorded: architectural pattern; microscopic thickness (mm); cytologic grade; presence of muscle, nerve, or vessel invasion; inflammatory response; and mitotic rate. The mean thickness was 2.5 mm for group I tumors and 7.5 mm for group II tumors. Seventy-six per cent of the group I tumors were 3 mm thick or less, whereas only one group II lesion (3 per cent) was less than 3 mm thick. Five per cent of the group I neoplasms, compared with 77 per cent of the group II tumors, were at least 6 mm thick. Perineural invasion was seen in 5 per cent of the group I and 41 per cent of the group II lesions. Three per cent of the group I carcinomas had a dispersed pattern, compared with 57 per cent of those in group II. One group I lesion (0.6 per cent) and 37 per cent of the group II tumors were grade 4. Each of these differences was statistically significant (P less than 0.0001). For all lesions studied, metastases had occurred in 60 per cent with perineural invasion, 74 per cent measuring 6 mm or more, 77 per cent with a dispersed pattern, and 92 per cent that were grade 4. These important prognostic variables were best evaluated in the deeper portions of the lesions.
Cutaneous squamous cell carcinomas (SCC) arising in actinically damaged skin, unassociated with chronic inflammation or injury, are generally regarded as nonaggressive lesions. These tumors occasionally recur or metastasize, however, as do de novo SCC. The authors reviewed 63 patients with cutaneous SCC of the trunk or extremities, excluding lesions that developed in known high risk settings, in order to explore the potential of histologic microstaging as a prognostic indicator. Fifty-four patients (86%) were free of recurrence following primary surgical therapy. Nine patients (14%) had either local recurrence or metastases; five of these (8% of the entire series) died of their tumors. Tumor behavior correlated best with the level of dermal invasion and the vertical tumor thickness. All tumors that recurred were 4 mm or more thick and involved the deep half of the dermis or deeper structures. All tumors that proved fatal were at least 10 mm in maximum thickness, and the four lethal lesions that could be evaluated for level of invasion extended into subcutaneous tissue or deeper structures. The thickness and level of invasion of cutaneous SCC appear to represent important prognostic factors and may be relevant indicators for wide field resection and/or elective lymph node dissection.
This report describes an aggressive squamous cell carcinoma of the skin for which we suggest the name acute epithelioma. It is frequently larger than 2 cm and has a characteristic morphology with raised, rolled, vascular but not everted edges. Commonly there is a central crust covering a foul discharge on a papilliferous base. The biopsy is characteristically ambiguous but often that of a well differentiated squamous cell carcinoma. Irrespective of the history, which is usually short, all tumors have a period of rapid growth. Among 193 patients with squamous cell carcinomas of the eyelids or external ear, 24 (12%) of the tumors were designated as being acute epitheliomas. For the eyelids 15/125 (12%) patients were in this group; 10 (67%) had tumors larger than 2 cm, five (33%) developed regional metastases, and three (20%) had tumor related deaths. Irradiation controlled the primary tumor in 15 (100%) patients. Among the 68 ear tumors, nine (13%) were called acute epitheliomas. Eight (89%) were larger than 2 cm, three (33%) developed regional metastases, and two (22%) patients had tumor related deaths. Irradiation controlled the primary tumor in seven (78%) patients. It is postulated that these acute epitheliomas are virus induced tumors that develop in actinicly damaged and immunologically suppressed skin. Following treatment, careful follow-up is recommended because of their metastatic and lethal potential.
Malignant tumors may spread through the perineural and endoneural spaces of the regional nerves. Although the clinical symptoms may be remarkably mild, local neurologic abnormalities should always be considered to be due to neural invasion.
An analysis of 40 cases of head and neck cancers has indicated that this form of metastatic disease is most frequently seen with recurrent or advanced tumors. Initial treatment may be inadequate because neural invasion is unrecognized, or neural involvement may result from an inadequately treated tumor.
Radiologic exploration of the intraosseous portions of the fifth and seventh nerves has proven useful in the diagnosis of perineural and endoneural invasion. An increase in the diameter of the nerve may be reflected by erosion of one or more foramina or canals. In instances of clinically suspected or radiographically demonstrated neural involvement, serial frozen sections should be made during the surgical procedure until disease-free nerve is encountered or evidence of intracranial extension is obtained.
Several of the patients in this series have been salvaged as a result of surgical or radiographic recognition of neural metastases. Undoubtedly, infiltration of the regional nerves will continue to be responsible for some treatment failures. However, we believe that an increasing number of patients may benefit if this form of metastatic disease is appreciated and appropriate diagnostic and therapeutic measures are instituted.
In a series of nearly 7,000 patients with squamous cell epitheliomas, 2% manifested evidence of metastases at the time of diagnosis.
The regional lymph nodes were the most common sites of this extension but far distant viscera were involved in 5% to 10% of the cases.
Metastases may occur early in such cases: 2.5% had been noted for less than one month, 37.8% for less than six months, and 68.1% for less than one year. This indicates that such spread does not occur only in long neglected or inadequately treated instances.
The risk of metastasis of squamous cell carcinoma cannot be determined exactly- It is influenced by several factors. In literature a frequency of metastasis of 2 to 10% is mentioned. In a series of 64 cases of squamous cell carcinoma, treated at our Department of Dermatology with soft X-ray irradiation, dissemination occurred in four cases. In 16 more serious cases, treated by the radiologist or the surgeon, another three cases of metastasis developed. Brief case reports of these seven patients are presented.
The lesions of adenoid squamous cell carcinoma develop in exposed areas, particularly about the head and neck regions in persons with fair skin who spend considerable time outside. The microsocopic features consist of invasion of the corium by proliferating atypical epithelial cells forming an adenoid pattern. The adenoid structure is usually composed of a single peripheral layer of cohesive cuboidal epithelial cells, and toward the center of the lobule there is acantholysis with formation of lumina containing dyskeratotic cells. The precursor stages of adenoid squamous cell carcinoma are classified histopathologically as senile keratosis with acantholysis. The most frequent histologic site of origin in this material was from the upper part of the pilary outer root sheath but some arose from the epidermis. Mucin associated with the adenoid structure showed identical histochemical reactions to those of mucin occurring in the pilary sheath and epidermis (hyaluronic acid) and differed from those of mucin seen in sweat glands (sialomucin). Among 155 patients having 213 lesions of adenoid squamous cell carcinoma there was metastasis in 3 patients (to regional lymph nodes in 2 and to regional lymph nodes and to lung in 1) and direct extension in 2 patients, which led to the death of the 5 patients. Surgical excision is the treatment of choice.
On review of 520 patients with 967 squamous cell carcinomas of the skin of the face treated at The University of Texas M.D. Anderson Hospital and Tumor Institute at Houston during a 10 year period, 14 percent of the patients were noted to have perineural extension of tumor. Study of the patients with perineural tumor demonstrated an increased incidence of spindle cell and adenosquamous cell types, an increased incidence of cervical lymphadenopathy and distant metastasis, and significantly reduced survival curves compared with those of patients with squamous cell skin carcinoma without perineural invasion. Tabulation confirmed that the maxillary and mandibular branches of the trigeminal nerve and the facial nerve were most commonly involved. For patients with squamous cell skin carcinomas with perineural invasion, aggressive therapy is recommended, specifically, resection of involved tissues and nerves and appropriate regional lymphadenectomy followed by postoperative radiotherapy. This plan affords the best opportunity for tumor control. The indications for exploration of the middle fossa of the intracranial portion of the trigeminal nerve deserve further study.