Metastatic cutaneous squamous cell carcinoma accounts for nearly all squamous cell carcinomas of the parotid gland.

Primary squamous cell carcinoma of the parotid gland (pSCCP) has long been recognized as a separate entity and is included in the WHO classifications of salivary gland tumors. However, it is widely accepted among head and neck pathologists that pSCCP is exceptionally rare. Yet, there are many publications describing series of pSCCP and data from SEER and other cancer register databases indicate erroneously an increasing incidence of pSCCP. Importantly, pSCCP and metastatic (secondary) squamous cell carcinoma to the parotid gland (mSCCP) have nearly identical histological features, and the diagnosis of pSCCP should only be made after the exclusion of mSCCP. Moreover, all of the histological diagnostic criteria proposed to be in favor of pSCCP (such as, for example, dysplasia of ductal epithelium) can be encountered in unequivocal mSCCP, thereby representing secondary growth along preexistent ducts. Squamous cell differentiation has also been reported in rare genetically defined primary parotid carcinomas, either as unequivocal histological squamous features (e.g., NUT carcinoma, mucoepidermoid carcinoma), by immunohistochemistry (e.g., in NUT carcinoma, adamantinoma-like Ewing sarcoma, basal-type salivary duct carcinoma, mucoepidermoid carcinoma), or a combination of both. Another major issue in this context is that the International Classification of Diseases (ICD) coding system does not distinguish between primary or metastatic disease, resulting in a large number of patients with mSCCP being misclassified as pSCCP. Immunohistochemistry and new molecular biomarkers have significantly improved the accuracy of the diagnosis of many salivary gland neoplasms, but until recently there were no biomarkers that can accurately distinguish between mSCCP and pSCCP. However, recent genomic profiling studies have unequivocally demonstrated that almost all SCCP analyzed to date have an ultraviolet light (UV)-induced mutational signature typical of mSCCP of skin origin. Thus, mutational signature analysis can be a very useful tool in determining the cutaneous origin of these tumors. Additional molecular studies may shed new light on this old diagnostic and clinical problem. This review presents a critical view of head and neck experts on this topic.

Case Series: Cemiplimab and Nivolumab Immunotherapy as Promising Treatment in Advanced or Metastatic Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer. Surgery is usually curative; however, some locally advanced or metastatic CSCC may be unresectable. Current novel therapeutic options with immune checkpoint inhibition (ICI) of programmed-death receptor 1 (PD-1) such as cemiplimab and nivolumab have demonstrated promising and sustained results with good tolerability in patients with CSCC. This study looks at 2 cases of CSCC treated with cemiplimab and nivolumab, respectively, demonstrating dramatic response within 2 cycles with significant reduction in tumour size and minimal toxicities or adverse outcomes reported. Immunotherapy has shown positive results as an effective treatment option for unresectable, recurrent, or metastatic CSCC. It is currently approved for use in the USA and Europe.

Real-world analysis of cost, treatment patterns, and outcomes of patients with metastatic cutaneous squamous cell carcinoma in the US.

OBJECTIVES: To describe real-world characteristics and treatment patterns of patients with metastatic cutaneous squamous cell carcinoma (mCSCC). METHODS: This retrospective observational study used MarketScan Commercial and Medicare Supplemental claims databases (1/1/2013-7/31/2019). Adult patients with mCSCC who initiated non-immunotherapy systemic treatment (i.e. index event) between 1 January 2014 and 31 December 2018 were assessed for treatment patterns, all-cause and CSCC-related healthcare resource utilization, costs, and mortality . RESULTS: Overall, 207 patients were included in the study(mean age 64.8 years, 76.3% 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%) and carboplatin (22.7%) were the most common chemotherapy agents, and cetuximab (32.4%) was the most common targeted therapy during the first-line.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.

Surgical factors affecting regionally metastatic cutaneous squamous cell carcinoma to the parotid gland.

BACKGROUND: Understanding the impact of surgical treatment on regionally metastatic cutaneous squamous cell carcinoma (cSCC). METHODS: Retrospective series of 145 patients undergoing parotidectomy and neck dissection for regionally metastatic cSCC to the parotid. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) analyzed over 3 years. Multivariate analysis was completed using Cox proportional hazard models. RESULTS: OS was 74.5%, DSS was 85.5% and DFS was 64.8%. On multivariate analysis, immune status (HR = 3.225[OS], 5.119[DSS], 2.071[DFS]) and lymphovascular invasion (HR = 2.380[OS], 5.237[DSS], 2.595[DFS]) were predictive for OS, DSS, and DFS. Margin status (HR = 2.296[OS], 2.499[DSS]) and ≥18 resected nodes (HR = 0.242[OS], 0.255[DSS]) were predictive of OS and DSS, while adjuvant therapy was predictive of DSS (p = 0.018). CONCLUSIONS: Immunosuppression and lymphovascular invasion portended worse outcomes in patients with metastatic cSCC to the parotid. Microscopically positive margins and <18 nodes resected are associated with worse OS and DSS, while patients receiving adjuvant therapy had improved DSS.

Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: The Current and Future Role of Radiation Therapy in the Era of Immunotherapy.

Radiation therapy (RT) is an effective therapeutic option for small localized cutaneous squamous cell carcinoma (cSCC) among patients who are not eligible for or refuse surgery. RT also has a defined role as an adjuvant treatment in cases of adverse features that predispose to tumor recurrence after local excision. Since the development of cSCC is often a late consequence of chronic sun exposure, its occurrence is more common among elderly patients whose comorbidities may contraindicate surgical procedures. These could be impeded not only by frail medical conditions but also by technical issues. Indeed, an aggressive locoregional behavior of cSCC may culminate in unresectability due to widespread invasion of neighboring tissues. Moreover, cSCC could develop distant metastases. Both locally advanced and metastatic cSCCs carry a poor prognosis. In these scenarios, recent discoveries of tumor molecular targets are promoting the use of promising systemic therapies, especially immunotherapy, over RT. However, the results from using immunotherapy and, even more so, of chemotherapy are still not optimal. By contrast, advances in radiation delivery equipment can safely treat even large and complex-shaped cSCC targets in challenging body sites. In addition, RT could also have a role in metastatic cSCC settings by enhancing the effectiveness of concomitant immunotherapy. The aim of this review is to summarize and comment on the body of literature about the use of radiotherapy for operable and inoperable locally advanced cSCCs and for metastatic ones in an attempt to define its current and future role.

Treatment of advanced cutaneous squamous cell carcinoma: a Mohs surgery and dermatologic oncology perspective.

Locally advanced or metastatic cutaneous squamous cell carcinoma no longer amenable to surgical resection or primary radiation therapy requires an alternative approach to treatment. Until 2018, management consisted of limited systemic chemotherapies, which carried marginal clinical benefit. The introduction of immunotherapy with anti-PD-1 antibodies resulted in alternative treatment options for advanced cutaneous squamous cell carcinoma with substantial antitumor activity, durable response and acceptable safety profile. The field of immunotherapeutics continues to expand with adjuvant, neoadjuvant and intralesional studies currently in progress. Herein, the authors discuss their approach for the treatment of advanced cutaneous squamous cell carcinoma from the perspective of a Mohs surgeon and a dermatologic oncologist.

Cancer Stem Cell Subpopulations Are Present Within Metastatic Head and Neck Cutaneous Squamous Cell Carcinoma.

Cancer stem cells (CSCs) have been identified in many cancer types including primary head and neck cutaneous squamous cell carcinoma (HNcSCC). This study aimed to identify and characterize CSCs in metastatic HNcSCC (mHNcSCC). Immunohistochemical staining performed on mHNcSCC samples from 15 patients demonstrated expression of the induced pluripotent stem cell (iPSC) markers OCT4, SOX2, NANOG, KLF4, and c-MYC in all 15 samples. In situ hybridization and RT-qPCR performed on four of these mHNcSCC tissue samples confirmed transcript expression of all five iPSC markers. Immunofluorescence staining performed on three of these mHNcSCC samples demonstrated expression of c-MYC on cells within the tumor nests (TNs) and the peri-tumoral stroma (PTS) that also expressed KLF4. OCT4 was expressed on the SOX2+/NANOG+/KLF4+ cells within the TNs, and the SOX2+/NANOG+/KLF4+ cells within the PTS. RT-qPCR demonstrated transcript expression of all five iPSC markers in all three mHNcSCC-derived primary cell lines, except for SOX2 in one cell line. Western blotting showed the presence of SOX2, KLF4, and c-MYC but not OCT4 and NANOG in the three mHNcSCC-derived primary cell lines. All three cell lines formed tumorspheres, at the first passage. We demonstrated an OCT4+/NANOG+/SOX2+/KLF4+/c-MYC+ CSC subpopulation and an OCT4+/NANOG-/SOX2+/KLF4+/c-MYC+ subpopulation within the TNs, and an OCT4+/NANOG+/SOX2+/KLF4+/c-MYC+ subpopulation within the PTS of mHNcSCC.

A Rare Case of Synchronous Waldenström's Macroglobulinemia and Cutaneous Squamous Cell Carcinoma with a Lung Mass: A Diagnostic and Management Dilemma.

Cutaneous squamous cell carcinoma has presented an increasing burden globally, with the occurrence of metastatic cutaneous squamous cell carcinoma being a relatively rare event but presenting with significant challenges in management, and a paucity of treatment options. Waldenström's macroglobulinemia is similarly an infrequent diagnosis. We present a rare case of a synchronous diagnosis of cutaneous squamous cell carcinoma and Waldenström's macroglobulinemia with an associated lung mass with squamous differentiation. The considered origin of the lung mass was either metastatic cutaneous squamous cell carcinoma or a primary squamous cell carcinoma of the lung, representing a third primary malignancy. The report highlights complexities in diagnosis and management, particularly in a patient with multiple synchronous malignancies. It further emphasizes the need for expanded global availability of specific therapies, including PD-1 inhibitors.

Prolonged Response to Pembrolizumab in Spindle Cell Squamous Cell Carcinoma Metastatic to the Central Nervous System.

BACKGROUND: Cutaneous squamous cell carcinoma is a common type of skin cancer, with aggressive metastatic or locally advanced disease representing an uncommon minority of presentations. Emerging data have supported the Food and Drug Administration approval of the anti-PD1 human monoclonal antibody cemiplimab in select patients with advanced disease. However, there is limited data regarding durability of effect and generalizability of anti-PD1 effectiveness across therapies. Additionally, information regarding applicability of these regimens to the rare spindle cell variant and to central nervous system metastases for cutaneous squamous cell carcinoma is unfortunately limited. CASE PRESENTATION: A 72-year-old gentleman presented with facial neurological deficits and a dermal nodule and was diagnosed with spindle cell squamous cell carcinoma with perineural invasion. His course was notable for early intracranial metastasis with progressive neurological deficits despite recurrent radiation therapy with intermittent response. When progressive left-sided weakness prompted imaging evaluation that was concerning for disease recurrence after exhaustion of radiation therapy options, the patient was started on systemic therapy with the anti-PD-1 monoclonal antibody treatment prior to the approval of cemiplimab. Pembrolizumab was chosen due to the fact that the patient was ineligible for clinical trials and for its every 21-day dosing. With this treatment, he has achieved a durable clinical response, resulting in near resolution of neurological deficits and more than a year of progression-free survival to date, despite aggressive intracranial disease. CONCLUSIONS: This case suggests that anti-PD-1 therapy with pembrolizumab may represent an effective and well-tolerated treatment for patients with metastatic spindle cell squamous cell carcinoma including patients with metastatic disease to the central nervous system.

Metastatic squamous cell carcinoma of the skin with clinical response to lapatinib.

BACKGROUND: Lapatinib is a tyrosine kinase inhibitor that blocks the HER2 receptor and is typically used in the setting of metastatic breast cancer. Both ERBB2 (HER2) and ERBB3 (HER3) belong to the same family of receptor tyrosine kinases. Dimerization of these receptors leads to activation of cell proliferation and survival pathways, granting oncogenic potential to dysregulated ERBB/HER receptors. Next generation sequencing (NGS) of tumors has ushered in a new era of personalized oncology therapy and has the ability to detect mutations in ERBB receptors. CASE PRESENTATION: We present a patient with metastatic cutaneous squamous cell carcinoma who failed surgery, radiation, and anti-PD1 therapy, but showed clinical response to a drug targeting an ERBB3 mutation identified with NGS. Following initiation of the drug lapatinib, this patient exhibited dramatic tumor regression in the skin, soft tissue, bone and nerves. CONCLUSIONS: Cutaneous squamous cell carcinoma is the 2nd most common skin cancer in humans and future investigation of ERBB2 targeted therapies may provide an effective treatment strategy for patients with mutations in the ERBB2/3 pathway.

Age is not a predictor of prognosis in metastatic cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: Metastatic cutaneous squamous cell carcinoma of the head and neck (cHNSCC) is more common in older patients. It is postulated that the age-related decline in immunity plays a role in cancer predisposition and prognosis. We aimed to investigate the effect of age on outcomes in cHNSCC and compare these with the outcomes of patients with cHNSCC and known immunosuppression. METHODS: Patients with metastatic cHNSCC treated with curative intent were identified from a prospectively collated database of head and neck cancers at the Sydney Head and Neck Cancer Institute. Patients with cHNSCC with known immunosuppression provided a comparison group for analysis of disease-specific outcomes. RESULTS: The study cohort includes 418 immunocompetent patients with metastatic cHNSCC (median age: 73 years (interquartile range: 65-81 years)) and the control cohort includes 24 patients with metastatic cHNSCC and immunosuppression (median age: 51 years (interquartile range: 42-62 years)). Increasing age was not associated with poorer disease-free or disease-specific survival. Patients in older age groups (70 years and over) had better disease-specific outcomes than patients with long-term immunosuppression. Patterns of disease failure did not differ between different age groups. The number of positive nodes and extra-capsular spread were the only significant prognostic variables in multivariable analysis. CONCLUSION: In the context of metastatic cHNSCC, age should not be considered as a marker of poor prognosis. Age should not be considered a surrogate marker of immune function considering the poorer outcomes seen in patients with immunosuppression. Older patients with metastatic cHNSCC should be considered candidates for standard treatment if otherwise medically fit.

Fatal metastatic cutaneous squamous cell carcinoma evolving from a localized verrucous epidermal nevus.

A malignant transformation is known to occur in many nevi such as a sebaceous nevus or a basal cell nevus, but a verrucous epidermal nevus has only rarely been associated with neoplastic changes. Keratoacanthoma, multifocal papillary apocrine adenoma, multiple malignant eccrine poroma, basal cell carcinoma and cutaneous squamous cell carcinoma (CSCC) have all been reported to develop from a verrucous epidermal nevus. CSCC has also been reported to arise from other nevoid lesions like a nevus comedonicus, porokeratosis, a sebaceous nevus, an oral sponge nevus and an ichthyosiform nevus with CHILD syndrome. Here we report a case of progressive poorly differentiated CSCC arising from a localized verrucous epidermal nevus, which caused both spinal cord and brain metastasis.