Upper and Lower Eyelid Malignancies: Differences in Clinical Presentation, Metastasis, and Treatment.

Approximately 5-15% of all dermatologic malignancies manifest in the upper and lower eyelids. The primary types include basal cell carcinoma, squamous cell carcinoma, and sebaceous cell carcinoma, with Merkel cell carcinoma and melanoma following closely behind. Basal cell carcinoma predominantly affects the lower eyelid, yet various other carcinomas, melanomas, metastases, and neoplasms of diverse origins can arise on both upper and lower eyelids. Risk factors such as advanced age, smoking, and notably, exposure to UV light significantly contribute to the development of these eyelid lesions. Despite the increasing incidence, research on dermatologic eyelid malignancies remains limited. However, such study is imperative given that many systemic oncologic malignancies initially present as metastatic eyelid lesions. This paper provides an in-depth exploration of eyelid anatomy, clinical presentation, diagnosis, and treatment management.Key Points: Eyelid metastases represent less than one percent of all eyelid cancers, yet they often serve as the initial indication of an underlying systemic malignancy. Early detection and treatment is crucial in improving prognosis and quality of life for patients. Treatment options encompass a range of modalities, with Mohs surgery as the gold standard for the removal of ocular tumors. Additional treatment options include local excision as well as non-surgical interventions such as radiotherapy, cryotherapy, immunotherapy, and topical medications.

Accidental discovery of metastasized basal cell carcinoma.

INTRODUCTION: Metastasis of basal cell carcinoma (BCC) is a very rare finding because the disease is mostly discovered early in development and treated immediately. Moreover, the metastasis percentage is less than 0.5%. PATIENT AND METHODS: A 66-year-old man presented to the emergency department after a fall from his bike. He sustained fractures, and a 40-year-old skin lesion was discovered on his back. Histological analysis of a biopsy from the primary lesion, a CT scan, and bone biopsy were performed. RESULTS: The three tests combined confirmed BCC with metastasis to the liver, lung, and bone. We also systematically eliminated the possibility of other skin lesions, such as squamous cell carcinoma, angiosarcoma, cutaneous lymphoma, and melanoma. CONCLUSION: We report an accidental discovery of a rare case of a 40-year-old BCC with multiple distant metastases, resulting in stage IV disease.

Molecular testing in metastatic basal cell carcinoma.

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a very rare entity, and diagnosis can be challenging. Therapeutic options are limited, and response to targeted therapy is poor. OBJECTIVE: To demonstrate a clonal relationship between BCCs and their metastases and to explore which hedgehog pathway-related mutations are involved in mBCC. METHODS: Genetic analysis was conducted in 10 primary BCCs and their metastases. Genes relevant for BCC development were analyzed in tumor and metastasis material with small molecule molecular inversion probes (smMIPs) for PTCH1, PTCH2, SMO, SUFU, GLI2, and TP53 or with targeted next generation sequencing of the same genes and CDKN2A, CDKN2B, CIC, DAXX, DDX3X, FUBP1, NF1, NF2, PTEN, SETD2, TRAF7, and the TERT promoter. RESULTS: In 8 of 10 patients, identical gene mutations could be demonstrated in the primary tumors and their metastases. A broad spectrum of mutations was found. Four patients had SMO mutations in their tumor or metastasis, or both. All SMO mutations found were known to cause resistance to targeted therapy with vismodegib. LIMITATIONS: In 2 patients there was insufficient qualitative DNA available for genetic analysis. CONCLUSIONS: Molecular testing can help to identify the origin of a BCC metastasis and may be of prognostic and therapeutic value.

Metastasizing basal cell carcinoma: A clinicopathologic and immunohistochemical study of 22 cases.

Basal cell carcinomas metastasize rarely, and there have been limited studies of potential drivers for this metastasis. Epithelial-mesenchymal transition (EMT) may play a role, although this has not been investigated in detail. We reviewed clinicopathologic features of 22 patients with metastasizing basal cell carcinoma (MBCC). Immunohistochemical markers of EMT, including CD44, E-cadherin, claudin, smooth muscle actin, beta-catenin, Twist1, and Oct 3/4, were evaluated on 10 MBCC (primary and metastases) and 18 non-metastasizing BCC. Primary sites included the head and neck, trunk, and extremity, while metastatic sites included lymph nodes, lung, bone, and soft tissue. Of 19 cases with follow-up, the range of follow-up after diagnosis of metastasis was 5 to 248 months (median: 50 months). Two cases were of unknown primary, nine metastases were diagnosed concurrently with primary tumors, and remaining cases showed a median latency between diagnosis of primary and metastatic tumors of 27.5 months (range: 3-81 months). Median survival was 66 months. Compared to non-metastasizing BCC, MBCC demonstrated reduced CD44 expression (primary [P = .0036], metastatic [P = .011]) and increased Twist1 expression (primary, P = .0017). MBCC shows variably aggressive behavior, and reduced CD44 and increased Twist1 expression may indicate significant EMT in metastasizing tumors and signify a metastatic phenotype.

Metastatic head and neck cutaneous basal cell carcinomas: a retrospective observational study.

Cutaneous basal cell carcinoma is usually an indolent and slow-growing tumor with potential for local invasion and recurrence; however, metastatic events are exceedingly rare. The annual incidence of metastasis is estimated to range between 0.00281 and 0.05%. A retrospective search in the pathology database of a single tertiary institution was performed in the period between 1999 to 2019. Primary cutaneous metastatic basal cell carcinomas had paraffin blocks and glass slides retrieved. A total of 8673 cases was identified. The overall prevalence of metastatic tumors was 0.05% (4/8673). The median patient's age at diagnosis was 61 years old (range 52-79). The most common primary site of tumor was nose (2/4) and the most common histological subtype was infiltrative. The sampled lymph nodes were identified during primary tumor resection, except for 1 patient who had a sentinel lymph node biopsy performed as a surgeon individual decision. One patient had hematogenous spread to the pleura, diagnosed 5 years after diagnosis. In summary, this study adds new data to the current literature in metastatic primary cutaneous basal cell carcinomas and highlights the importance of early diagnosis and appropriate surgical excision in an effort to prevent local advanced disease, recurrence and lymphovascular dissemination.

Metastatic Basal Cell Carcinoma of the Skin: A Comprehensive Literature Review, Including Advances in Molecular Therapeutics.

Basal cell carcinoma (BCC) of the skin is the most common type of malignant human tumor. In Europe, the incidence of BCC ranges from 44.6 to 128 cases per 100,000 inhabitants annually, whereas in the United States, the yearly incidence rate ranges between 500 and 1500. The global incidence has been calculated to be as high as 10 million cases of BCC per year. There are 2 main clinical patterns of BCC-the familial BCC in basal cell nevus syndrome and sporadic BCC. The etiology of cutaneous BCC is usually the result of the interaction between solar ultraviolet radiation and genetic factors. Somatic or germline mutations in the effector components of the hedgehog signaling pathway (ie, PTCH1, PTCH2, SMO or SUFU genes) are responsible for ∼90% of the cases of both sporadic and familial BCC, all causing a constitutive activation of the hedgehog pathway. Cutaneous BCC very rarely metastasizes, and diagnosis in metastatic sites can be very difficult. Metastatic BCC has weakly effective therapeutic options with a poor prognosis until few years ago. In 2012, small-molecule therapies, involving inactivation of the hedgehog signaling pathway, and capable of reducing tumor growth and progression have been introduced into clinical practice for advanced (locally advanced or metastatic) BCC. We performed a comprehensive literature review on metastatic BCC and found at least 915 cases reported to date. In addition, we extensively discussed the differential diagnosis of metastatic BCC, and outlined the advances in clinical therapeutics involving these small molecules.

MST1R (RON) expression is a novel prognostic biomarker for metastatic progression in breast cancer patients.

PURPOSE: This study evaluates the prognostic significance of MST1R (RON) expression in breast cancer with respect to disease progression, long-term survival, subtype, and association with conventional prognostic factors. METHODS: The approach includes interrogation of survival and tumor staging with paired MST1R RNA expression from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Protein expression evaluation was performed using immunohistochemistry (IHC) staining of MST1R on breast cancer tissue samples from the Cancer Diagnosis Program Breast Cancer Progression tissue microarray and locally obtained breast tumor tissue samples analyzed with paired survival, metastasis, and subtype. RESULTS: Data from TCGA (n = 774) show poorer relapse-free survival (RFS) in patients with high MST1R expression (P = 0.32) and no difference in MST1R expression based on tumor stage (P = 0.77) or nodal status (P = 0.94). Patients in the GEO-derived Kaplan-Meier Plotter microarray dataset demonstrate the association of MST1R and poorer overall survival (n = 1402, P = 0.018) and RFS in patients receiving chemotherapy (n = 798, P = 0.041). Patients with high MST1R expression display worse overall survival (P = 0.01) and receiver operator characteristic (ROC) analysis demonstrate the predictive capacity of increased MST1R with early death (P = 0.0017) in IHC-stained samples. Paired IHC-stained breast tumor samples from the primary versus metastatic site show MST1R expression is associated with metastatic progression (P = 0.032), and ROC analysis supports the predictive capacity of MST1R in metastatic progression (P = 0.031). No associations of MST1R with estrogen receptor (ER), progesterone receptor (PR), both ER and PR, HER2 positivity, or triple-negativity were found (P = 0.386, P = 0.766, P = 0.746, P = 0.457, P = 0.947, respectively). CONCLUSIONS: MST1R expression has prognostic value in breast cancer with respect to survival and metastatic progression. MST1R expression is not associated with tumor stage, nodal status, or subtype.

Rare basal cell metastasis of a basal-squamous skin collision tumour to the lung and axillary lymph node.

We report a case of a 60-year-old man who was a former cigar smoker with a slow-growing, large exophytic left shoulder mass (15 cm in diameter) and later found to have left axillary lymphadenopathy. Fine needle aspirate biopsy of the left shoulder mass revealed squamous cell carcinoma (SCC). However, pathology of the enlarged left axillary lymph node was reported as metastatic adenocarcinoma. The patient underwent surgical resection of the shoulder mass which comprised of SCC (>95%) and adenoid basal cell carcinoma (BCC) as a second component of the tumour. The BCC had identical histology as the metastatic carcinoma in the left axillary lymph node. Therefore, diagnosis was revised as cutaneous collision tumour with metastatic BCC. Six months later following adjuvant radiation therapy, the patient was diagnosed with metastatic BCC in the right lung. Stereotactic body radiation therapy (SBRT) and a selective hedgehog pathway inhibitor vismodegib were given with only limited efficacy. Clinical trial registration number NCT03132636.

Emerging Nonsurgical Therapies for Locally Advanced and Metastatic Nonmelanoma Skin Cancer.

BACKGROUND: Locally advanced and metastatic nonmelanoma skin cancer (NMSC) not amenable to surgical resection requires a different approach to therapy. OBJECTIVE: To review the efficacy and adverse effects of emerging treatment options for locally advanced and metastatic NMSC. MATERIALS AND METHODS: A comprehensive search on PubMed was conducted to identify relevant literature investigating the role of program cell death 1 (PD-1) inhibitor, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, epidermal growth factor receptor (EGFR) inhibitor, and Hedgehog pathway inhibitors in the treatment of NMSC. RESULTS: PD-1 inhibitor and CTLA-4 inhibitor have shown promising efficacy with tolerable side-effect profiles in the treatment of NMSC, although the number of cases reported is limited. Currently, 3 larger-scale clinical trials are investigating PD-1 inhibitor therapy for NMSC. Similarly, EGFR inhibitor demonstrated marginal success in unresectable cutaneous squamous cell carcinomas. Hedgehog pathway inhibitors were approved by the US FDA for treatment of locally advanced and metastatic basal cell carcinomas and have shown favorable efficacy. Common adverse effects included muscle spasm, alopecia, and dysgeusia. CONCLUSION: Systemic therapies including PD-1 inhibitors and CTLA-4 inhibitors have demonstrated early promising results for difficult-to-treat NMSC. Future studies are necessary to optimize treatment outcome.

Efficacy, safety, and comparison of sonic hedgehog inhibitors in basal cell carcinomas: A systematic review and meta-analysis.

BACKGROUND: Sonic hedgehog inhibitors (SHHis) provide an additional treatment option for basal cell carcinomas (BCCs), especially for metastatic or locally advanced BCC. However, studies have been heterogeneous and lacked direct comparisons between molecules. OBJECTIVE: To determine the efficacy and safety of the class of molecules SHHi for treating BCC and to compare them individually. METHODS: We performed a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-compliant systematic review of studies followed by a meta-analysis. RESULTS: Eighteen articles were included in our meta-analysis; 16 articles were combined for efficacy and 16 for safety. In locally advanced BCC, overall response rates (ORRs) were similar for vismodegib and sonidegib (69% vs 57%, respectively) but not complete response rates (31% vs 3%, respectively). In metastatic disease, the ORR of vismodegib was 2.7-fold higher than the ORR of sonidegib (39% vs 15%, respectively). For side effects affecting a majority of patients, prevalences for muscle spasms (67.1%), dysgeusia (54.1%), and alopecia (57.7%) were in similar proportions for sonidegib and vismodegib. Patients receiving sonidegib experienced more upper gastrointestinal distress than patients receiving vismodegib. CONCLUSION: SHHis induce a partial response to locally advanced BCC disease. Side effects are common, similar across molecules, associated with high discontinuation rates, and warrant discussion beforehand.

Low recurrence rate of head and neck basal cell carcinoma treated with Mohs micrographic surgery: A retrospective study of 1021 cases.

OBJECTIVE: Mohs micrographic surgery (MMS) is the treatment of choice for high-risk primary basal cell carcinoma (BCC) and recurrent BCC of the head and neck, showing fewer recurrences compared with surgical excision (SE). The objectives of this study were to determine the recurrence rate of head and neck BCC after MMS and to develop a prediction model with significant risk factors for recurrence. DESIGN: A retrospective study of patient records. METHODS: All BCCs treated with MMS between 1 January 1995 and 1 July 2013 at the University Medical Center Groningen (UMCG) were selected retrospectively. Recorded parameters were patient characteristics, tumour size, tumour location, histopathological subtype, previous treatment, the number of stages until microscopic clearance, defect size, adverse events, follow-up time and recurrence after MMS. RESULTS: The study covered 1021 MMS operations conducted on primary BCCs (57.4%), residual BCCs (25.6%) and recurrent BCCs (17.0%). The median follow-up time was 54.0 months (ranging from 1 to 221 months). The 5-year cumulative probability of recurrence was 3.3%: 2.6% for primary BCCs, 5.4% for residual BCCs and 2.9% for recurrent BCCs. An aggressive histopathological subtype, residual BCCs and recurrent BCCs were significant risk factors for predicting a higher risk of recurrence after MMS. CONCLUSION: This large-scale retrospective study showed low recurrence rates after MMS for primary and recurrent BCCs. Residual BCCs treated with MMS had relatively higher recurrence rates. The risk of recurrence for MMS-treated residual aggressive BCCs was more than four times higher than that for primary non-aggressive BCCs.

Characterization and survival of patients with metastatic basal cell carcinoma in the Department of Veterans Affairs: a retrospective electronic health record review.

Available descriptive statistics for patients with metastatic basal cell carcinoma (mBCC) are limited. To describe disease characteristics, treatment patterns, survival outcomes, and prognostic factors of patients with mBCC, we conducted a retrospective review of electronic health records in the Department of Veterans Affairs (VA). The primary outcome was survival. Data were also collected on demographics, comorbidities, medications, and procedures. Median (IQR) age of patients with mBCC (n = 475) was 72.0 (17.0) years; 97.9% of patients were male. Almost two-thirds of patients received no initial therapy for mBCC. Median overall survival was 40.5 months [95% CI (confidence interval) 4.8-140.0], and was shorter in patients with distant metastases (17.1 months; 95% CI 2.8-58.0) than in those with regional metastases (59.4 months; 95% CI 17.6-140.0). Because the VA mBCC population is largely male and elderly, the generalizability of these results in other populations is limited and must be interpreted cautiously. Data from this large cohort add valuable information on a rare and poorly researched disease and refine previously wide estimates of overall survival for mBCC.

Vismodegib and the Hedgehog Pathway Inhibitors: A Historical Perspective to Current Clinical Application.

Vismodegib (Erivedge, Genentech-Roche) is the first in class of Hedgehog pathway inhibitors approved for treatment of metastatic basal cell carcinoma (BCC), or locally advanced BCC that has recurred after surgery or is not amenable to surgery or radiation. Its path to discovery has been unique and traces its origin to corn lilies, sheep, Drosophila flies, and the Hedgehog signaling pathway. J Drugs Dermatol. 2018;17(5):506-508.

Guidelines of care for the management of basal cell carcinoma.

Basal cell carcinoma (BCC) is the most common form of human cancer, with a continually increasing annual incidence in the United States. When diagnosed early, the majority of BCCs are readily treated with office-based therapy, which is highly curative. In these evidence-based guidelines of care, we provide recommendations for the management of patients with BCC, as well as an in-depth review of the best available literature in support of these recommendations. We discuss biopsy techniques for a clinically suspicious lesion and offer recommendations for the histopathologic interpretation of BCC. In the absence of a formal staging system, the best available stratification based on risk for recurrence is reviewed. With regard to treatment, we provide recommendations on treatment modalities along a broad therapeutic spectrum, ranging from topical agents and superficially destructive modalities to surgical techniques and systemic therapy. Finally, we review the available literature and provide recommendations on prevention and the most appropriate follow-up for patients in whom BCC has been diagnosed.

Radiotherapy regimens in patients with nonmelanoma head and neck skin cancers.

BACKGROUND: To assess the effectiveness and outcomes of adjuvant radiotherapy regimens for nonmelanoma skin cancers (NMSC) of the head and neck, particularly for elderly patients. METHODS: A retrospective review of patients with head and neck NMSC was conducted. Radiotherapy dose per fraction regimens included ≤200, 240-250, 300-400, and 500-600 cGy. Demographics, tumor characteristics, local control (LC), regional control (RC), and survival outcomes were analyzed. RESULTS: Of the 90 patients with 140 disease sites, 76.6% were squamous cell carcinoma, 15.5% were basal cell carcinoma, and 7.7% were other histologies. The mean age at diagnosis was 72.1 years old. The most common location was preauricular (20.0%), followed by temple, scalp, cheek, and forehead. The overall LC and RC rates were 88.8% and 88.8%, respectively by patients, and 92.8% and 86.4%, respectively by treatment sites. Age, primary tumor location, T classification, N classification, overall stage, perineural invasion, comorbid disease, skull base invasion, and radiotherapy subgroup were significantly associated with disease-free and overall survival (P < 0.05). LC and RC were not significantly different among the radiotherapy dose subgroups. The mean survival was longer in patients treated with 240-250 cGy/fraction (50.3 months). There was no significant difference in radiotherapy toxicity between the subgroups. CONCLUSION: Short-term radiotherapy regimens for patients with locally or regionally advanced head and neck NMSC appear feasible and effective, particularly in elderly patients or those that cannot tolerate the length of standard regimens.