Lip Squamous Cell Carcinoma Research Articles

Characteristics of non‐melanoma skin cancers of the cutaneous perioral and vermilion lip treated by Mohs micrographic surgery

The lip and surrounding perioral region are susceptible to non-melanoma skin cancer, but the distribution of basal cell and squamous cell carcinoma on the cutaneous and vermilion lips has not been fully elucidated. To investigate the distribution of cutaneous and vermilion lip non-melanoma skin cancer and to better describe risk factors, anatomic location, treatment characteristics and oncologic outcomes. A retrospective comparative case series of patients undergoing Mohs micrographic surgery (MMS) at a single academic centre for lip and perioral basal cell and squamous cell carcinoma was performed over a 5-year period. Demographics, medical comorbidities, surgical characteristics and recurrence status were extracted. Forty-five vermilion and 116 cutaneous lip cancers were identified. Basal cell carcinoma (BCC) was more common in the cutaneous perioral region, while squamous cell carcinoma (SCC) was more common on the vermilion lip (P<0.001). BCCs were more common on the upper vermilion lip and SCCs were more common on the lower vermilion lip (P<0.001). Within the cutaneous perioral region, both BCCs and SCCs were more common on the upper perioral surface (P=0.002). Male gender was associated with lower lip SCC (P=0.015). Smoking, immunosuppression, anticoagulant use and hydrochlorothiazide use were not associated with cancer type or location. Recurrences were rare, but more common in vermilion lip cancers (6.6%) compared to perioral cutaneous cancers (0.8%). Outcomes for all groups were similar; BCCs of the vermilion lip had significantly greater mean MMS stages (P<0.001) as did SCCs (P=0.05). Basal cell carcinoma is more commonly encountered on the cutaneous lip, whereas SCC is more common on the vermilion lip. Within the vermilion lip, BCC favours the upper lip, while SCC favours the lower lip. Within the cutaneous perioral region, both BCC and SCC favour the upper cutaneous tissue. Early stage lip cancers are curable by Mohs micrographic surgery with rare recurrences.

Immune response and evasion mechanisms in lip carcinogenesis: An immunohistochemical study

ObjectivesProgrammed death ligand-1 (PD-L1) and human leukocyte antigen-G (HLA-G) are considered immune checkpoint molecules that inhibit T-cell effectiveness, contributing to tumor immune escape. This study investigated PD-L1, HLA-G, CD8, and granzyme B (GrB) expression at different stages of lip carcinogenesis. Design and resultsForty cases of lip squamous cell carcinoma (LSCC), 55 actinic cheilitis (AC), and 10 healthy lip mucosa (HLM) were submitted to immunohistochemistry. Semiquantitative (PD-L1, HLA-G), and quantitative (CD8, GrB) analysis were performed. PD-L1 and HLA-G expression in neoplastic cells/keratinocytes and stroma/connective tissue was significantly higher in LSCC and AC, compared to HLM (p<0.05). PD-L1 was not associated with clinicopathological features of the lesions. HLA-G expression by malignant cells was significantly higher in LSCCs with distant metastasis (p = 0.041).CD8+ and GrB+ cell numbers progressively increased from HLMs to LSCC, with AC exhibiting intermediate numbers (p<0.01). Most LSCCs showed coexistence of PD-L1+ and CD8+ cells (72.5%). PD-L1 was directly correlated to CD8+ and GrB+ lymphocytic infiltration in LSCCs (p<0.05). Low cytotoxic immune response was associated with lymph node metastasis in LSCC (p<0.05). ConclusionsPD-L1 and HLA-G-mediated immune evasion mechanisms are likely to occur from early pre-malignant to advanced malignant stages of lip carcinogenesis, which might provide a rationale for therapeutic blockade of these pathways. PD-L1 expression in LSCCs was correlated with the cytotoxic markers, suggesting that PD-L1 may appear as an escape mechanism in response to an active antitumor response.

DNA Methyltransferases and Histone Modifier Proteins in Lip Squamous Cell Carcinoma and Actinic Cheilitis

DNA methylation and histone deacetylation are the most important epigenetic alterations in carcinogenesis. Chronic UVB exposure leads to increased activity of DNA methyltransferases (DNMTs) with recruitment of histone deacetylases (HDACs).

Long term effectiveness of electrochemotherapy for the treatment of lower lip squamous cell carcinoma

PurposeElectrochemotherapy (ECT) is a therapeutic approach based on the local application of electrical pulses that permeabilize cell membranes to enhance the uptake of low-permeant chemotherapeutic agents, thus increasing their cytotoxic effects. Materials and methodsTwenty-one patients with SCC of the lower lip were treated according to the European Standard Operating Procedures of Electrochemotherapy. Bleomycin (15,000 IU/m2 body surface area) was administered intravenously over a 1-min period. Eight electrical pulses (amplitude, 1000 V/cm; duration, 100 μs) were generated and delivered at a repetition frequency of 5 kHz. Changes in tumor volume were used to assess treatment response. ResultsObjective response (OR), complete response (CR), and partial response (PR) rates of 100%, 71.4%, and 28.6% respectively were demonstrated following a single session of ECT. ECT was well tolerated, and no adverse events occurred. ConclusionsIntravenous bleomycin-based ECT is a safe and effective therapy for SCC of the lower lip. ECT improves the quality-of-life of patients by preserving the function and the aesthetic appearance of the affected area. ECT provides a therapeutic option for elderly and frail patients who, due to their state of health, are not suitable for, or refuse surgical interventions.

Participation of hypoxia-inducible factor-1α and lymphangiogenesis in metastatic and non-metastatic lower lip squamous cell carcinoma

This study evaluated the lymphatic density and HIF-1α immunoexpression in lower lip squamous cell carcinoma (LLSCC) and their correlation with clinicopathological (nodal metastasis, clinical stage, histological grade, recurrence and disease outcome) and survival parameters in 20 metastatic and 20 non-metastatic LLSCCs. Lymphatic density was established by counting microvessels (D2-40+) at the tumor core (intratumoral lymphatic density, ILD) and at the invasive front (peritumoral lymphatic density, PLD) and percentages of immunopositive cells for HIF-1α were established. No statistically significant differences in lymphatic densities in relation to clinicopathological parameters were observed (P > 0.05). All cases exhibited nuclear and cytoplasmic HIF-1α immunoexpression, with relatively high percentages of positivity, but this expression was not statistically different in relation to clinicopathological variables (P > 0.05). Positive correlations were observed between ILD and PLD (P = 0.002), and between nuclear HIF-1α immunoexpression at the tumor core and ILD (P = 0.001). The results suggest ILD and PLD are not directly related to the development of lymph node metastasis in LLSCC. The striking expression of HIF-1α suggests the involvement of this protein in the etiopathogenesis of LLSCCs, possibly stimulating lymphangiogenesis at the tumor core. However, this protein does not seem to exert a determining influence on the biological aggressiveness of these tumors.

Immunoexpression of glucocorticoid receptor alpha (GRα) isoform and apoptotic proteins (Bcl-2 and Bax) in actinic cheilitis and lower lip squamous cell carcinoma.

Actinic cheilitis (AC) is a potentially malignant disorder that can progress to squamous cell carcinoma (SCC), but this process is not fully understood. This study evaluated the immunoexpression of glucocorticoid receptor alpha (GRα) isoform and apoptotic proteins (Bcl-2 and Bax) in AC and lower lip SCC (LLSCC). Twenty-two AC and 44 LLSCCs (22 with regional nodal metastasis and 22 without metastasis) were selected. The percentages of nuclear (GRα) and cytoplasmic (GRα, Bcl-2, and Bax) staining in epithelial cells were assessed and correlated with clinical (tumor size/extent and clinical stage) and histopathological parameters (risk of malignant transformation for AC and histopathological grade of malignancy for LLSCCs). Expression of GRα was observed in all cases studied, with relatively high median percentages of positive staining. When compared to AC, LLSCCs exhibited lower nuclear expression and higher cytoplasmic expression of GRα (P < 0.05). Regarding clinicopathological parameters, significant differences were only found for cytoplasmic expression of GRα according to the histopathological grade of LLSCCs (P = 0.036). Higher expression of Bax compared to Bcl-2 was observed in AC and LLSCCs (P < 0.05). In LLSCCs, there was a positive correlation between nuclear and cytoplasmic expressions of GRα (P = 0.006). Reduced nuclear translocation and increased cytoplasmic expression of GRα may be important events in lip carcinogenesis but are not involved in the progression of LLSCC. The role of GRα in lip cancer development does not seem to be primarily related to modulations in the expression of Bcl-2 or Bax.

Expression of stem cell markers Nanog and Nestin in lip squamous cell carcinoma and actinic cheilitis.

To investigate the presence of NANOG, NESTIN, and β-tubulin in lip squamous cell carcinoma (LSCC), actinic cheilitis (AC), and normal epithelium (NE). Thirty cases of LSCC, thirty cases of AC (both analyzed according to the WHO classification and AC according to the binary classification), and twenty cases of NE were submitted to an immunohistochemical study. NANOG was more expressed in the nuclei of AC compared to NE (p=0.007), as well as in high-risk AC cases (p=0.017) and well-differentiated LSCCs (no significance). There was an accumulation of nuclear NANOG from mild to moderate and severe ACs. NESTIN was significantly less present in NE compared to AC (p=0.001) and LSCC (p=0.003). There was a higher expression in severe dysplasia or high-risk AC and well-differentiated LSCC. These results indicate an upregulation of NANOG and NESTIN in the early stages of carcinogenesis. β-tubulin was intensely present in all lesions. The results suggest an upregulation of NANOG and NESTIN in the biological behavior these diseases, mainly in the transformation from AC to LSCC.

Evaluation of epithelial dysplasia adjacent to lip squamous cell carcinoma indicates that the degree of dysplasia is not associated with the occurrence of invasive carcinoma in this site.

We analyzed the different grades of dysplasia in the epithelium adjacent to lip squamous cell carcinoma (LSCC), as a parallel to actinic cheilitis (AC) that suffered malignant transformation. Forty samples of epithelium adjacent to LSCC were histologically graded according to the World Health Organization (WHO) and the binary systems. The expression of mutated p53 was evaluated through immunohistochemistry. According to WHO system, 37.5% of the cases were graded as mild, 45% as moderate and 17.5% as severe dysplasia (P = 0.09). Considering the binary system, 90% of the cases were classified as low-risk and 10% as high-risk lesions. Mutated p53 was present in 73.3% of mild, 88.8% of moderate and 71.4% of severe dysplasia cases. Considering the binary system, 80.5% of the low-risk and 75% of high-risk lesions were immunopositive; 62.5% expressed the protein in both tumor cells and adjacent epithelium; 17.5% in adjacent epithelium only, and 7.5% in LSCC islands only (P = 0.03). We observed heterogeneous grades of epithelial dysplasia in the epithelium adjacent to LSCC, which indicates that the analysis of AC morphological features is insufficient to predict patient's prognosis and to determine a treatment decision. Positive expression of mutant p53 in mild dysplasia reinforces this idea.

Expression of cancer stem cell markers CD44, ALDH1 and p75NTR in actinic cheilitis and lip cancer.

The aim of this work was to evaluate the expression of the cancer stem cell (CSC) markers CD44, ALDH1 and p75NTR in the ultraviolet-induced lesions actinic cheilitis (AC) and lip squamous cell carcinoma (LSCC), and to correlate it with p53 expression. Immunohistochemistry was performed in 4 cases of normal lip (NL), 43 of AC and 20 of LSCC. All cases were positive for CD44, showing a membranous staining without differences between the groups. ALDH1 showed cytoplasmic staining and it was invariable amongst the grades of epithelial dysplasia and between AC and LSCC. p75NTR presented membranous/cytoplasmic staining in the basal and parabasal layer of NL and AC, while LSCC presented cytoplasmic staining in the peripheral layers of the tumor islands. p75NTR showed different expression amongst the dysplasia grades (p < 0.001) but no differences between AC and LSCC. p53 expression was similar amongst the dysplasia grades and between AC and LSCC. CD44, ALDH1 and p75NTR were unrelated amongst themselves and to p53 expression. CSC markers are expressed in potentially malignant and malignant lesions of the lip. Their expressions were invariable between AC and LSCC and unrelated to p53. p75NTR expression increased with the worsening of epithelial dysplasia grade.

Moesin Involvement in Oral Carcinogenesis of the Lower Lip.

This study analyzed moesin immunoexpression in 91 lip squamous cell carcinomas and its influence in patients' prognosis. Moesin immunoexpression was evaluated at the invasive tumor front by a semi-quantitative score method. The association of moesin with the clinicopathological variables was analyzed by the Chi-square test, the survival rates were calculated by Kaplan-Meier and the survival curves compared using the log-rank test. The expression of moesin was strong at the invasive tumor front and weak/negative in differentiated cells such as keratin pearls. There was no association between moesin expression and the clinicopathological variables, but there was a tendency for patients with lip cancer and strong moesin expression to have lower 5- and 10-year overall and disease-free survival rates. Our results confirm the participation of moesin in oral carcinogenesis and suggest that this protein can influence the survival rates of patients with lip squamous cell carcinoma.

Unit Advancement Flap for Lower Lip Reconstruction.

Lower lip reconstruction requires consideration of esthetic and functional outcome in selecting a surgical procedure, and reconstruction with local tissue is useful. The authors reconstructed full-thickness defects with a unit advancement flap. Reconstruction was performed using this method in 4 patients with lower lip squamous cell carcinoma in whom tumor resection with preservation of the mouth angle was possible. The lower lip resection width was 30 to 45 mm, accounting for 50% to 68% of the entire width of the lower lip. The flap was prepared by lateral extension from above the mental unit and matched with the potential wrinkle line of the lower lip in order to design a unit morphology surrounded by the anterior margin of the depressor labii inferioris muscle. It was elevated as a full-thickness flap composed of the orbicularis oris muscle, skin, and mucosa of the residual lower lip from the bilateral sides, and advanced to the defect. Flap transfer was adjusted by small triangular resection of the skin on the lateral side of the mental unit. The postoperative scar was inconspicuous in all patients and there was no impairment of the mouth opening-closing or articulation functions. This was a relatively simple surgical procedure. A blood supply of the flap was stable, and continuity of the orbicularis oris muscle was reconstructed by transferred the residual lower lip advancement flap from the bilateral sides. The postoperative mouth opening-closing function was sufficient, and dentures could be placed from an early phase in elderly patients. The postoperative scar was consistent with the lip unit morphology, being esthetically superior. This procedure may be applicable for reconstruction of defects approximately 1/3 to 2/3 the width of the lower lip where the mouth angle is preserved.

243 Overall risk of primary hematologic malignancies in patients with lip squamous cell carcinoma: A report from the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) program

243 Overall risk of primary hematologic malignancies in patients with lip squamous cell carcinoma: A report from the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) program

The association between immunoexpression levels of oxidant and antioxidant enzymes and lip squamous cell carcinoma.

The aim of this study was to investigate the associations among the immunoexpression levels of manganese superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx), and myeloperoxidase (MPO) in lip squamous cell carcinoma (LSCC) tissues and the clinicopathological characteristics, and prognostic factors in patients with LSCC. The immunoexpression levels of Mn-SOD, GPx, and MPO were examined in 76 LSCC tissue samples using immunohistochemical staining on tissue microarray slides, and compared to those in normal lip mucosa adjacent to venous lakes (normal controls), normal tissue adjacent to corresponding tumors (NTACT), and recurrent tumors. Associations between immunoexpression levels and clinicopathological characteristics were analyzed using the Student's t-test. The prognostic factors were analyzed using Cox regression. The immunoexpression levels of Mn-SOD, GPx, and MPO were significantly different among the normal controls, NTACTs, tumors, and recurrent tumors (Mn-SOD: p=0.001, GPx: p<0.001, MPO: p<0.001). Lower lip cancer was associated with higher Mn-SOD immunoexpression levels (p=0.04) and probably indicated higher oxidative stress. Lymph node involvement with a lower immunoexpression level of MPO (p=0.007) indicated compensatory mechanism to attenuate oxidative damage. A low Mn-SOD immunoexpression level was borderline significantly associated with a worse prognosis for disease-specific survival, and it was probably related to a lower capacity for coping with oxidative stress.

Non-invasive imaging of actinic cheilitis and squamous cell carcinoma of the lip

An early diagnosis is of overwhelming importance for the management and prognosis of mucocutaneous cancer. Actinic cheilitis (AC), defined by the clonal expansion of genomically unstable keratinocytes, is the most common potentially malignant lesion affecting the lips. Squamous cell carcinoma (SCC) is the most frequent oral malignancy, and there is strong evidence that the majority of the SCCs of the lip originate from AC. There is considerable difficulty in discerning between dysplasia and invasive carcinomas solely on a clinical basis. Although dermoscopy has become an essential tool for skin tumor evaluation, reflectance confocal microscopy (RCM) is a non-invasive imaging technology that has proved itself extremely useful in the diagnosis and monitoring of several skin diseases, including AC and SCC. The present study aimed to re-emphasize the usefulness of RCM in the early detection of malignant transformation, using AC and SCC of the lips as working examples. Due to the apparent innocuousness of AC for numerous patients, it is not possible to overstress the importance of a correct and early diagnosis, proper treatment and long-term patient follow-up as being essential for preventing the progression to lip SCC, or for its timely diagnosis.

Management of and risk factors for regional recurrence in upper lip squamous cell carcinoma: Erratum.

Management of and risk factors for regional recurrence in upper lip squamous cell carcinoma: Erratum.

Eosinophilia is a favorable prognostic marker for oral cavity and lip squamous cell carcinoma.

Eosinophils are frequently encountered with squamous cell carcinomas (SCC) and it has been proposed that tumor-associated tissue eosinophilia (TATE) could be of prognostic significance in oral SCC. The aim was to evaluate TATE in 83 oral cavity and 16 lip SCCs as well as the best possible use of TATE as a prognostic marker. The number of eosinophils was counted per high power fields (HPF, ×400) in three different representative areas of the tumor and its stroma. The degree of TATE was analyzed in relation to clinicopathological features of tumors and patients' survival (follow-up mean 40.7months) using Fisher's exact test. TATE was detected in 58 (70%) oral and 8 (50%) lip SCC samples. The median number of eosinophils between oral and lip SCC was different (p=0.028) but TATE was similar per HPF (p=0.085). Totally, 6% of lip and 21% of oral SCC patients died during the follow-up. The patients with the higher TATE had significantly better survival than the patients with the lower TATE (p=0.0136). The best cut-off value predicting the survival was 4 eosinophils/HPF. TATE is a prognostic marker for oral and lip SCC: more than 4 eosinophils/HPF may predict more favorable prognosis.

Lower lip reconstruction using W-plasty

Lower lip squamous cell carcinomas (SCC) correspond to 20-30% of all oral cavity cancers. It mainly affects men over 50 years of age who have previous history of smoking, alcoholism and exposure to the sunlight. The diagnosis is clinical, confirmed by histological analysis. The present paper describes a case of a patient with a SCC affecting more than 1/3 of the lower lip, who underwent resection of the primary lesion and a conservative reconstruction of the lesion’s region, due to the great local mobility, aimed at preserving the functionality without compromising the aesthetic outcome.

Unexpected synchronous diagnosis of papillary thyroid carcinoma in a patient with lower lip squamous cell carcinoma

The presentation of differentiated thyroid carcinoma occurring as a second primary associated with head and neck squamous cell carcinoma is quite unusual. Here, we present an unexpected synchronous diagnosis of two independent head and neck malignancies. A 78‑year‑old male with a rapidly growing, firm, and ulcerated lesion on the lower lip was referred to our clinic. Positron emission tomography‑computed tomography scan performed for systemic screening demonstrated a dense hypermetabolic activity located in the right thyroid lobe, suggesting a second malignancy. Fine‑needle aspiration cytology of the right thyroid gland performed to differentiate the presence of a metastatic lesion, or primary thyroid cancer was compatible with malign cytology related to papillary thyroid carcinoma. Multiple malignancies may be diagnosed synchronously in the head and neck region and these patients with multiple malignant lesions should be evaluated carefully before being accepted as metastatic.

The management of lip squamous cell carcinoma

The management of lip squamous cell carcinoma

Comparison of the histologic risk assessment model between lower lip and oral squamous cell carcinoma.

The histologic risk assessment (HRA) grading system was proposed as a practical measure to predict clinical outcome and its effectiveness has been shown in several studies. It has been suggested that the HRA model might exhibit differences among various oral subsites. The aim of the present study was to compare this system between squamous cell carcinomas (SCCs) of the lower lip (LL) and oral cavity. All primary SCCs located in the LL and oral cavity were retrieved and graded using the HRA model. Data regarding risk score (RS), perineural invasion (PNI), lymphocytic infiltration (LI) and worst pattern of invasion (WPOI) were compared between LL and oral SCCs using χ2 analysis (P<0.05). There were a total of 33 LLSCCs, of which 15, 8 and 10 were categorized as low-risk (RS=0), intermediate-risk (RS=1-2) and high-risk (RS≥3) tumors, respectively. Corresponding values in the 48 oral SCCs were 7, 15 and 26 cases. Significant differences in RS (P=0.00), LI (P=0.01) and WPOI (P=0.01) were observed between LL and oral tumors. The HRA model could be included among the various factors suggested to be different between lip and oral SCCs. Low-risk tumors were more prevalent in the lip which corroborates the less aggressive nature of these cancers. Considering the significantly higher LI in LL SCCs, inflammation may be regarded as an important factor in regulating the invasive behavior of these tumors.