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Outcomes of Recurrent Head and Neck Cutaneous Squamous Cell Carcinoma

Outcomes of Recurrent Head and Neck Cutaneous Squamous Cell Carcinoma Hindawi Publishing Corporation Journal of Skin Cancer Volume 2011, Article ID 972497, 6 pages doi:10.1155/2011/972497 Clinical Study Outcomes of Recurrent Head and Neck Cutaneous Squamous Cell Carcinoma 1 1 1 1 Nichole R. Dean, Larissa Sweeny, J. Scott Magnuson, William R. Carroll, 1 2 1 Daniel Robinson, Renee A. Desmond, and Eben L. Rosenthal Division of Otolaryngology, Head and Neck Surgery, Department of Surgery, The University of Alabama at Birmingham, Volker Hall G082,1670 University Boulevard, Birmingham, AL 35233, USA Division of Preventive Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 25294, USA Correspondence should be addressed to Eben L. Rosenthal, oto@uab.edu Received 10 March 2011; Accepted 18 April 2011 Academic Editor: S. Ugurel Copyright © 2011 Nichole R. Dean et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Recurrent, advanced stage cutaneous squamous cell carcinoma (cSCC) is uncommon with limited publications on patient outcomes. A retrospective study including patients who underwent surgical resection for recurrent, advanced stage cSCC of the head and neck was performed (n = 72). Data regarding tumor site, stage, treatment, parotid involvement, perineural invasion, positive margins, metastasis, and disease-free survival was analyzed. The majority of patients were male (85%) and presented with recurrent stage III (89%) cSCC. Two-year disease-free survival was 62% and decreased to 47% at 5 years. Parotid involvement, positive margins, nodal metastasis, or the presence of perineural invasion did not correlate with decreased survival (P> .05). Distant metastasis was a strong indicator of poor overall survival (P< .001). Adjuvant postoperative radiotherapy did not improve overall survival (P = .42). Overall survival was poor for patients with advanced recurrent cSCC despite the combined treatment with surgery and radiotherapy. 1. Introduction factors can be applied to determine prognosis in patients with recurrent disease. Nonmelanoma skin cancer (NMSC) is the most common In the present study, we evaluate outcomes in patients diagnosed malignancy in the United States with more than with advanced, recurrent cSCC of the head and neck. In the one million new cases reported each year [1]. Basal cell majority of cases, the treatment recommendations for this (BCC) and cutaneous squamous cell carcinoma (cSCC) patient population are surgery and adjuvant radiotherapy comprise nearly all of the NMSCs. The majority of lesions [7]. Although no single variable can dictate treatment, (80–90%) arise in the sun exposed areas of the head and this study sought to identify further predictive factors and neck [2] and are successfully treated by complete tumor provide guidance for counseling patients with aggressive excision. A small percentage of NMSCs, mostly cSCCs, head and neck cSCC. are refractory to standard surgical resection [1, 3]. Several outpatient-based studies have demonstrated a low incidence 2. Materials and Methods of nodal metastasis (2-3%) in patients with cSCC [4, 5]. Most tertiary care center-referred patients, however, present A retrospective review of all patients (n = 72) who presented with recurrent disease and are at increased risk for neck with recurrent, advanced stage (III or IV) cSCC of the metastasis, poor local control, and further cancer recurrence. head and neck between June 1998 and December 2007 was High risk prognostic indicators include size, anatomic site, performed at The University of Alabama at Birmingham recurrence, history of radiation, immunosuppression, and following Institutional Review Board approval. Tumors were perineural invasion [6]. It is unknown whether the same risk staged according to the American Joint Committee on 2 Journal of Skin Cancer Table 1: Patient characteristics. Cancer (AJCC) guidelines, and histology was confirmed by pathology. Tumors were divided into 5 different anatomic Characteristic n (%) sites: face, neck, ear, periauricular area, and scalp. Lesions Age-years occurring on the face included forehead, periorbital, nose, Mean (range) 71 (42–93) lip, and chin. Periauricular lesions were defined as lesions Gender occurring on the temple, cheek, or postauricular area. Male 61 (85) All patients underwent aggressive surgical resection. This Female 11 (15) included parotidectomy for cases in which parotid involve- ment was suspected on preoperative imaging or clinical Tumor subsite exam. Parotidectomy ranged from superficial to radical Face 19 (27) parotidectomy with sacrifice of the facial nerve. The major- Forehead 5 ity of patients required neck dissection and postoperative Periorbital 4 radiation. Selective, modified, or radical neck dissection was Nose 8 performed at the time of resection or in a staged procedure. Chin 1 Neck dissection was indicated when nodal metastasis was Lip 1 suspected on preoperative imaging or when the patient Periauricular 34 (47) presented with an advanced T classification of their lesion. Cheek 13 Postoperative radiation was recommended for patients with Temple 18 large cutaneous malignancies when more than one positive Postauricular 3 node was identified on neck dissection, when negative surgical margins could not be obtained, or in the presence of Ear 13 (18) perineural or lymphovascular invasion. Histological margins Scalp 3 (4) were defined as negative if the advancing tumor edge was Anterior 2 ≥4 mm from the line of surgical excision and positive if less Posterior 1 than 4 mm. All cutaneous defects were repaired either by Neck 3 (4) primary closure, split thickness skin graft, local or regional T classification flap coverage, or free tissue transfer. T1 1 (1) Demographic characteristics, including patient age, gen- T2 5 (7) der, a history of immunosuppression, previous treatment, T3 4 (6) and time to recurrence, were recorded. Prognostic indicators T4 60 (83) including tumor site, size, perineural invasion, positive mar- gins, or histologic grade were reviewed. Outcomes measured Tx 2 (3) consisted of disease-free survival and cancer recurrence. TMN Stage Descriptive variables are reported as means (±SD) and III 64 (89) categorical variables as percentages. Descriptive statistics IV 8 (11) were compared by general linear models for normally distributed variables or the Kruskal-Wallis test for otherwise. The relationship between patient clinical and treatment factors and disease-specific survival was calculated using the of immune suppression due to lymphoma or leukemia Kaplan-Meier method. Survival time was calculated as the (n = 6), rheumatoid arthritis (n = 1) or were currently interval from date of surgery to date of death or date of maintained on immunosuppressive medications due to prior last followup. Deaths due to other causes were censored for transplant (n = 3). these analyses. A P-value of <.05 was considered statistically No difference in margin status was observed between the significant. Statistical analysis was performed using SAS various tumor sites (P = .48). Perineural invasion, a known Version 9.2 software (SAS Institute Inc., Cary, NC). risk factor for recurrence and metastasis, occurred in 36.9% of patients. Patients with cSCC of the ear and periauricular area were more likely to demonstrate perineural invasion on 3. Results surgical pathology in comparison to all other sites (P = .06). Between 1998 and 2007, there were 72 patients identified Although perineural invasion did not significantly correlate who underwent surgical resection for recurrent, advanced with tumor site or size, patients with this finding were more stage cSCC. The majority of patients were male (84.7%), likely to have parotid involvement (P = .04). A total of presented with stage III disease (88.8%), and had undergone 39 patients (54.1%) underwent superficial (n = 16), total previous surgical resection (76.5%). Median time from pre- (n = 11) or radical (n = 12) parotidectomy. Four patients vious skin cancer diagnosis to presentation with recurrence had undergone previous parotidectomy for positive nodal was 5.7 months (range, 1–41 months). Mean tumor size was metastasis. Parotid involvement, either by direct extension 3.4 cm in largest dimension (±SD 2.07). The majority of or nodal metastasis, was confirmed by surgical pathology in lesions occurred on the ear or periauricular area (65.2%) 92.3% of cases (n = 36). and were classified as T4 lesions (83.3%) invading into deep The majority of patients with parotid involvement extradermal structures (Table 1). Ten patients had a history underwent neck dissection (92.3%). Neck dissection was Journal of Skin Cancer 3 Table 2: Free flaps used for cutaneous defect reconstruction. performed in 66.7% of all patients. The majority (64.5%) underwent selective (n = 31) or modified radical (n = Flap type n 14) neck dissection. One patient required a radical neck ALT 12 dissection. Another patient with a posterior scalp lesion Latissimus 3 had previously undergone an extended posterior triangle Rectus 8 dissection. Three patients had undergone previous neck dissections. Positive nodal metastasis occurred in 43.7% RFFF 13 (n = 21/48) of patients, and nearly all cases occurred in Fibula 2 patients with advanced T classification (83.3%) and those OCRFFF 4 with parotid involvement (85.7%, n = 18/21). The majority ALT: anterolateral thigh; RFFF: radial forearm free flap; OCRFFF: osteocu- of nodes were located in levels I–III (95%). No positive taneous radial forearm free flap. nodes were identified in level IV, and one case of nodal metastasis occurred in level V (Table 3). Nodal metastasis Table 3: Patterns of cervical lymph node metastasis. did not correlate with tumor size, though a larger percentage Level n (%) of patients with cSCC of the ear demonstrated neck disease (66.7%) in comparison to other sites (P = .14). Eight I 6 (25) patients had evidence of distant metastasis at the time of II 12 (50) surgical resection. Distant metastasis did not correlate with III 5 (20) perineural invasion, original tumor site, size, or parotid IV 0 (0) involvement at the time of surgical resection (P> .05). The V1(5) histologic grades of the tumors consisted of 19% (n = 14) well differentiated, 56% (n = 40) moderately differentiated, 8% (n = 6) moderate-poorly differentiated, and 17% (P = .18). Margin status, a history of immunosuppression, (n = 12) poorly differentiated. There was not a statistically and perineural invasion did not predict cancer recurrence. significant relationship found between histologic grade and Two-year disease-free survival was 62.2% and was survival (data not shown). reduced to 47.2% at 5 years (Figure 1). Age greater than All defects were closed either by primary closure or split 65 (P = .34), male gender (P = .06), immunosup- thickness skin graft (n = 23), local or regional flap (n = 7), pression (P = .22), and patients with a previous history or free tissue transfer (n = 42). One patient underwent of radiation (P = .4) tended towards worse survival pectoralis major myocutaneous flap reconstruction, and 6 outcomes. Surprisingly, tumor characteristics including site, patients required local cervicofacial flap coverage. Patients size (greater than 3.4 cm), parotid involvement, perineural with larger defects typically required free flap reconstruction. invasion, or positive margins following resection had no The radial forearm free flap (n = 13) and anterolateral influence on disease-free survival. Two-year disease-free thigh (n = 12) were most commonly utilized for soft tissue survival for patients with positive nodal metastasis was coverage. In cases in which bony reconstruction was also 47.7% versus 72.9% for those without neck disease (P = required, the osteocutaneous radial forearm free flap (n = 4) .14) (Figure 2). Although locoregional metastasis was not and fibula (n = 2) were employed (Table 2). a significant predictor of survival, distant metastasis noted The majority of patients underwent postoperative radi- within 30 days of surgical resection was associated with poor ation (66.7%) as a result of advanced stage disease. Fifteen prognosis (P< .001). No patient with distant metastasis patients had undergone previous radiotherapy, and 3 under- survived beyond 13 months. Most patients required free went both pre- and postoperative radiation. The majority flap reconstruction and postoperative radiation for advanced of patients with positive margins underwent postoperative disease. Patients who underwent free flap reconstruction radiation. Three patients had prior radiation therapy and tended towards worse survival outcomes (P = .24). Despite were unable to tolerate the cytotoxic effects of a second aggressive surgical resection, postoperative radiation was not course of radiation, and two electively declined further ther- shown to affect long term disease-free survival (P = .42) apy. Three patients with perineural invasion did not undergo or repeat cancer recurrence (P = .85) for this patient pop- postoperative radiotherapy based on personal preference. ulation. Although not statistically significant, patients with Mean time to follow up was 18.5 months. Forty percent cervical metastasis who underwent postoperative radiation of patients (n = 28) developed local (67.8%, n = 19), had improved locoregional control (68% versus 25%, P = regional (25%, n = 7) or distant metastasis (14.2%; n = 4) .14) when compared to those who underwent surgery alone. during the followup period. Median time to cancer recur- rence was less than 7 months (6.5, range 1–41 months). One 4. Discussion patient had local recurrence and developed lung metastasis while another patient developed both recurrent neck disease Nonmelanoma skin cancer is the most common malignancy and lung metastasis. Although not statistically significant, worldwide with over 140,000 cases of cSCC diagnosed each patients were more likely to recur if they presented with cSCC year in the United States alone [8]. The incidence of regional of the ear or periauricular area (P = .06), demonstrated metastasis among patients with cSCC ranges from 0.5 to 16% positive nodal metastasis at the time of neck dissection [4] and can result in potentially fatal consequences. Although (P = .14), or did not undergo postoperative radiotherapy a number of factors have been identified as high risk 4 Journal of Skin Cancer series, 5-year disease-free survival was significantly improved for patients undergoing adjuvant radiotherapy following surgical resection (73% versus 18%, P = .001), and 0.8 locoregional control was maintained in 77% of patients [11]. Both studies included patients with parotid or cervical 0.6 metastasis. Nearly 50% of all patients in this study presented with parotid involvement, and 30% had cervical metastasis. All patients underwent surgical resection, and most (66.7%) 0.4 had postoperative radiation. Postoperative radiation did not have an impact on overall disease-free survival (P = .42) 0.2 or cancer recurrence (P = .85). Although not statistically significant, patients who presented with cervical metastasis and received adjuvant radiotherapy in addition to surgical resection had improved locoregional control when compared to those who underwent surgery alone (68% versus 25%, (years) P = .14). Adjuvant radiotherapy appears to provide some Figure 1: Overall disease-free survival for patients with advanced benefit in patients with advanced, recurrent cSCC though recurrent cutaneous squamous cell carcinoma. the risk for repeat recurrence is high given the aggressive nature of these neoplasms. The role for systemic therapy in the treatment of recurrent, advanced stage cSCC remains unknown. Although there have been some case reports citing improved outcomes with the addition of cetuximab [12–14], 0.8 the majority of publications on targeted therapies against EGFR and its tyrosine kinase have demonstrated limited No regional Dz improvement in the mortality of patients with advanced 0.6 disease when used as monotherapy [15–19]. The median time from previous skin cancer diagno- 0.4 sis to presentation with initial recurrence was only 5.7 Regional Dz months (range, 1–41 months). This is likely due to the 0.2 patient population being comprised of advanced, recurrent cutaneous squamous cell carcinomas, and as a result, this cohort of patients had very aggressive disease. The rapid recurrence of the disease reflects the malignant biology of late stage cSCC. In addition, nearly 40% of patients in (years) this series developed a second recurrence with the majority Figure 2: Disease-free survival for patients with and without occurring locally (68%). Distant metastasis noted in the positive nodal metastasis. Two-year disease-free survival for patients immediate postoperative period was associated with poor with regional disease was 47.7% versus 72.9% for those without prognosis (P< .001). Median time to cancer recurrence regional metastasis (P = .14). was 6.5 months, and overall 2-year disease-free survival was 62%. Although not statistically significant, patients from the present study were more likely to recur if they had cSCC prognostic indicators for cancer recurrence and metastasis, of the ear or periauricular area (P = .06), demonstrated most studies to date have only evaluated primary cSCC. In cervical metastasis on surgical pathology (P = .14), or did not undergo postoperative radiotherapy (P = .18). contrast, the majority of patients presenting to a tertiary care center have undergone previous skin cancer treatment and Previous studies have demonstrated a higher incidence of subsequently developed a second primary or recurrence. A nodal metastasis among patients with lesions located on or around the ear as a result of lymphatic drainage to the diagnosis of recurrent cSCC alone confers a more aggressive tumor subtype [9], yet identifying factors associated with parotid gland [20, 21]. In the present study, nearly half poor outcome is essential for patient management and of all patients with parotid involvement either by direct extension or nodal metastasis also demonstrated cervical decision making. In the present study, we review tumor characteristics, disease. Multiple studies have demonstrated that patients prior treatment, and outcomes in patients with recurrent, with parotid involvement are at a high risk for cervical advanced stage cSCC and evaluate the role of postopera- metastasis [9, 22]. In a study by Ying et al., 44% of patients tive radiotherapy. Surgery combined with radiation is the with parotid metastasis also had positive cervical nodes [23]. Therefore it is recommended that all patients with parotid recommended treatment in most cases of advanced disease [7]. In a study by Veness et al., improved locoregional metastasis undergo selective neck dissection. control and disease-free survival (73% versus 54%, P = The majority of patients in this series underwent selective neck dissection which included levels I–III. Fifty percent of .004) were achieved in patients who received adjuvant radiotherapy compared to surgery alone [10]. In another the nodal metastasis were located in level II. This finding is Survival probability Survival probability Journal of Skin Cancer 5 similar to what a recent article published, where nearly 80% Acknowledgments of all positive nodal metastasis from cSCC were located in This work was supported by Grants from the National Insti- level II [24]. Although parotid involvement did not have an tute of Health (NCI K08CA102154 and 2T32 CA091078-06). influence on disease-free survival in this patient population, the 2-year disease-free survival for patients with cervical metastasis was 48% versus 73% for those without neck References disease (P = .14). In the study by Clayman et al., 3-year disease-free survival was 69% for patients with lymph node [1] M. Alam and D. Ratner, “Cutaneous squamous-cell carci- involvement versus 87% for those without nodal disease noma,” New England Journal of Medicine, vol. 344, no. 13, pp. 975–983, 2001. (P = .09) [25]. Cervical metastasis seemingly confers a worse prognosis for patients with recurrent disease. 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Outcomes of Recurrent Head and Neck Cutaneous Squamous Cell Carcinoma

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Hindawi Publishing Corporation
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Copyright © 2011 Nichole R. Dean et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2011/972497
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Hindawi Publishing Corporation Journal of Skin Cancer Volume 2011, Article ID 972497, 6 pages doi:10.1155/2011/972497 Clinical Study Outcomes of Recurrent Head and Neck Cutaneous Squamous Cell Carcinoma 1 1 1 1 Nichole R. Dean, Larissa Sweeny, J. Scott Magnuson, William R. Carroll, 1 2 1 Daniel Robinson, Renee A. Desmond, and Eben L. Rosenthal Division of Otolaryngology, Head and Neck Surgery, Department of Surgery, The University of Alabama at Birmingham, Volker Hall G082,1670 University Boulevard, Birmingham, AL 35233, USA Division of Preventive Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 25294, USA Correspondence should be addressed to Eben L. Rosenthal, oto@uab.edu Received 10 March 2011; Accepted 18 April 2011 Academic Editor: S. Ugurel Copyright © 2011 Nichole R. Dean et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Recurrent, advanced stage cutaneous squamous cell carcinoma (cSCC) is uncommon with limited publications on patient outcomes. A retrospective study including patients who underwent surgical resection for recurrent, advanced stage cSCC of the head and neck was performed (n = 72). Data regarding tumor site, stage, treatment, parotid involvement, perineural invasion, positive margins, metastasis, and disease-free survival was analyzed. The majority of patients were male (85%) and presented with recurrent stage III (89%) cSCC. Two-year disease-free survival was 62% and decreased to 47% at 5 years. Parotid involvement, positive margins, nodal metastasis, or the presence of perineural invasion did not correlate with decreased survival (P> .05). Distant metastasis was a strong indicator of poor overall survival (P< .001). Adjuvant postoperative radiotherapy did not improve overall survival (P = .42). Overall survival was poor for patients with advanced recurrent cSCC despite the combined treatment with surgery and radiotherapy. 1. Introduction factors can be applied to determine prognosis in patients with recurrent disease. Nonmelanoma skin cancer (NMSC) is the most common In the present study, we evaluate outcomes in patients diagnosed malignancy in the United States with more than with advanced, recurrent cSCC of the head and neck. In the one million new cases reported each year [1]. Basal cell majority of cases, the treatment recommendations for this (BCC) and cutaneous squamous cell carcinoma (cSCC) patient population are surgery and adjuvant radiotherapy comprise nearly all of the NMSCs. The majority of lesions [7]. Although no single variable can dictate treatment, (80–90%) arise in the sun exposed areas of the head and this study sought to identify further predictive factors and neck [2] and are successfully treated by complete tumor provide guidance for counseling patients with aggressive excision. A small percentage of NMSCs, mostly cSCCs, head and neck cSCC. are refractory to standard surgical resection [1, 3]. Several outpatient-based studies have demonstrated a low incidence 2. Materials and Methods of nodal metastasis (2-3%) in patients with cSCC [4, 5]. Most tertiary care center-referred patients, however, present A retrospective review of all patients (n = 72) who presented with recurrent disease and are at increased risk for neck with recurrent, advanced stage (III or IV) cSCC of the metastasis, poor local control, and further cancer recurrence. head and neck between June 1998 and December 2007 was High risk prognostic indicators include size, anatomic site, performed at The University of Alabama at Birmingham recurrence, history of radiation, immunosuppression, and following Institutional Review Board approval. Tumors were perineural invasion [6]. It is unknown whether the same risk staged according to the American Joint Committee on 2 Journal of Skin Cancer Table 1: Patient characteristics. Cancer (AJCC) guidelines, and histology was confirmed by pathology. Tumors were divided into 5 different anatomic Characteristic n (%) sites: face, neck, ear, periauricular area, and scalp. Lesions Age-years occurring on the face included forehead, periorbital, nose, Mean (range) 71 (42–93) lip, and chin. Periauricular lesions were defined as lesions Gender occurring on the temple, cheek, or postauricular area. Male 61 (85) All patients underwent aggressive surgical resection. This Female 11 (15) included parotidectomy for cases in which parotid involve- ment was suspected on preoperative imaging or clinical Tumor subsite exam. Parotidectomy ranged from superficial to radical Face 19 (27) parotidectomy with sacrifice of the facial nerve. The major- Forehead 5 ity of patients required neck dissection and postoperative Periorbital 4 radiation. Selective, modified, or radical neck dissection was Nose 8 performed at the time of resection or in a staged procedure. Chin 1 Neck dissection was indicated when nodal metastasis was Lip 1 suspected on preoperative imaging or when the patient Periauricular 34 (47) presented with an advanced T classification of their lesion. Cheek 13 Postoperative radiation was recommended for patients with Temple 18 large cutaneous malignancies when more than one positive Postauricular 3 node was identified on neck dissection, when negative surgical margins could not be obtained, or in the presence of Ear 13 (18) perineural or lymphovascular invasion. Histological margins Scalp 3 (4) were defined as negative if the advancing tumor edge was Anterior 2 ≥4 mm from the line of surgical excision and positive if less Posterior 1 than 4 mm. All cutaneous defects were repaired either by Neck 3 (4) primary closure, split thickness skin graft, local or regional T classification flap coverage, or free tissue transfer. T1 1 (1) Demographic characteristics, including patient age, gen- T2 5 (7) der, a history of immunosuppression, previous treatment, T3 4 (6) and time to recurrence, were recorded. Prognostic indicators T4 60 (83) including tumor site, size, perineural invasion, positive mar- gins, or histologic grade were reviewed. Outcomes measured Tx 2 (3) consisted of disease-free survival and cancer recurrence. TMN Stage Descriptive variables are reported as means (±SD) and III 64 (89) categorical variables as percentages. Descriptive statistics IV 8 (11) were compared by general linear models for normally distributed variables or the Kruskal-Wallis test for otherwise. The relationship between patient clinical and treatment factors and disease-specific survival was calculated using the of immune suppression due to lymphoma or leukemia Kaplan-Meier method. Survival time was calculated as the (n = 6), rheumatoid arthritis (n = 1) or were currently interval from date of surgery to date of death or date of maintained on immunosuppressive medications due to prior last followup. Deaths due to other causes were censored for transplant (n = 3). these analyses. A P-value of <.05 was considered statistically No difference in margin status was observed between the significant. Statistical analysis was performed using SAS various tumor sites (P = .48). Perineural invasion, a known Version 9.2 software (SAS Institute Inc., Cary, NC). risk factor for recurrence and metastasis, occurred in 36.9% of patients. Patients with cSCC of the ear and periauricular area were more likely to demonstrate perineural invasion on 3. Results surgical pathology in comparison to all other sites (P = .06). Between 1998 and 2007, there were 72 patients identified Although perineural invasion did not significantly correlate who underwent surgical resection for recurrent, advanced with tumor site or size, patients with this finding were more stage cSCC. The majority of patients were male (84.7%), likely to have parotid involvement (P = .04). A total of presented with stage III disease (88.8%), and had undergone 39 patients (54.1%) underwent superficial (n = 16), total previous surgical resection (76.5%). Median time from pre- (n = 11) or radical (n = 12) parotidectomy. Four patients vious skin cancer diagnosis to presentation with recurrence had undergone previous parotidectomy for positive nodal was 5.7 months (range, 1–41 months). Mean tumor size was metastasis. Parotid involvement, either by direct extension 3.4 cm in largest dimension (±SD 2.07). The majority of or nodal metastasis, was confirmed by surgical pathology in lesions occurred on the ear or periauricular area (65.2%) 92.3% of cases (n = 36). and were classified as T4 lesions (83.3%) invading into deep The majority of patients with parotid involvement extradermal structures (Table 1). Ten patients had a history underwent neck dissection (92.3%). Neck dissection was Journal of Skin Cancer 3 Table 2: Free flaps used for cutaneous defect reconstruction. performed in 66.7% of all patients. The majority (64.5%) underwent selective (n = 31) or modified radical (n = Flap type n 14) neck dissection. One patient required a radical neck ALT 12 dissection. Another patient with a posterior scalp lesion Latissimus 3 had previously undergone an extended posterior triangle Rectus 8 dissection. Three patients had undergone previous neck dissections. Positive nodal metastasis occurred in 43.7% RFFF 13 (n = 21/48) of patients, and nearly all cases occurred in Fibula 2 patients with advanced T classification (83.3%) and those OCRFFF 4 with parotid involvement (85.7%, n = 18/21). The majority ALT: anterolateral thigh; RFFF: radial forearm free flap; OCRFFF: osteocu- of nodes were located in levels I–III (95%). No positive taneous radial forearm free flap. nodes were identified in level IV, and one case of nodal metastasis occurred in level V (Table 3). Nodal metastasis Table 3: Patterns of cervical lymph node metastasis. did not correlate with tumor size, though a larger percentage Level n (%) of patients with cSCC of the ear demonstrated neck disease (66.7%) in comparison to other sites (P = .14). Eight I 6 (25) patients had evidence of distant metastasis at the time of II 12 (50) surgical resection. Distant metastasis did not correlate with III 5 (20) perineural invasion, original tumor site, size, or parotid IV 0 (0) involvement at the time of surgical resection (P> .05). The V1(5) histologic grades of the tumors consisted of 19% (n = 14) well differentiated, 56% (n = 40) moderately differentiated, 8% (n = 6) moderate-poorly differentiated, and 17% (P = .18). Margin status, a history of immunosuppression, (n = 12) poorly differentiated. There was not a statistically and perineural invasion did not predict cancer recurrence. significant relationship found between histologic grade and Two-year disease-free survival was 62.2% and was survival (data not shown). reduced to 47.2% at 5 years (Figure 1). Age greater than All defects were closed either by primary closure or split 65 (P = .34), male gender (P = .06), immunosup- thickness skin graft (n = 23), local or regional flap (n = 7), pression (P = .22), and patients with a previous history or free tissue transfer (n = 42). One patient underwent of radiation (P = .4) tended towards worse survival pectoralis major myocutaneous flap reconstruction, and 6 outcomes. Surprisingly, tumor characteristics including site, patients required local cervicofacial flap coverage. Patients size (greater than 3.4 cm), parotid involvement, perineural with larger defects typically required free flap reconstruction. invasion, or positive margins following resection had no The radial forearm free flap (n = 13) and anterolateral influence on disease-free survival. Two-year disease-free thigh (n = 12) were most commonly utilized for soft tissue survival for patients with positive nodal metastasis was coverage. In cases in which bony reconstruction was also 47.7% versus 72.9% for those without neck disease (P = required, the osteocutaneous radial forearm free flap (n = 4) .14) (Figure 2). Although locoregional metastasis was not and fibula (n = 2) were employed (Table 2). a significant predictor of survival, distant metastasis noted The majority of patients underwent postoperative radi- within 30 days of surgical resection was associated with poor ation (66.7%) as a result of advanced stage disease. Fifteen prognosis (P< .001). No patient with distant metastasis patients had undergone previous radiotherapy, and 3 under- survived beyond 13 months. Most patients required free went both pre- and postoperative radiation. The majority flap reconstruction and postoperative radiation for advanced of patients with positive margins underwent postoperative disease. Patients who underwent free flap reconstruction radiation. Three patients had prior radiation therapy and tended towards worse survival outcomes (P = .24). Despite were unable to tolerate the cytotoxic effects of a second aggressive surgical resection, postoperative radiation was not course of radiation, and two electively declined further ther- shown to affect long term disease-free survival (P = .42) apy. Three patients with perineural invasion did not undergo or repeat cancer recurrence (P = .85) for this patient pop- postoperative radiotherapy based on personal preference. ulation. Although not statistically significant, patients with Mean time to follow up was 18.5 months. Forty percent cervical metastasis who underwent postoperative radiation of patients (n = 28) developed local (67.8%, n = 19), had improved locoregional control (68% versus 25%, P = regional (25%, n = 7) or distant metastasis (14.2%; n = 4) .14) when compared to those who underwent surgery alone. during the followup period. Median time to cancer recur- rence was less than 7 months (6.5, range 1–41 months). One 4. Discussion patient had local recurrence and developed lung metastasis while another patient developed both recurrent neck disease Nonmelanoma skin cancer is the most common malignancy and lung metastasis. Although not statistically significant, worldwide with over 140,000 cases of cSCC diagnosed each patients were more likely to recur if they presented with cSCC year in the United States alone [8]. The incidence of regional of the ear or periauricular area (P = .06), demonstrated metastasis among patients with cSCC ranges from 0.5 to 16% positive nodal metastasis at the time of neck dissection [4] and can result in potentially fatal consequences. Although (P = .14), or did not undergo postoperative radiotherapy a number of factors have been identified as high risk 4 Journal of Skin Cancer series, 5-year disease-free survival was significantly improved for patients undergoing adjuvant radiotherapy following surgical resection (73% versus 18%, P = .001), and 0.8 locoregional control was maintained in 77% of patients [11]. Both studies included patients with parotid or cervical 0.6 metastasis. Nearly 50% of all patients in this study presented with parotid involvement, and 30% had cervical metastasis. All patients underwent surgical resection, and most (66.7%) 0.4 had postoperative radiation. Postoperative radiation did not have an impact on overall disease-free survival (P = .42) 0.2 or cancer recurrence (P = .85). Although not statistically significant, patients who presented with cervical metastasis and received adjuvant radiotherapy in addition to surgical resection had improved locoregional control when compared to those who underwent surgery alone (68% versus 25%, (years) P = .14). Adjuvant radiotherapy appears to provide some Figure 1: Overall disease-free survival for patients with advanced benefit in patients with advanced, recurrent cSCC though recurrent cutaneous squamous cell carcinoma. the risk for repeat recurrence is high given the aggressive nature of these neoplasms. The role for systemic therapy in the treatment of recurrent, advanced stage cSCC remains unknown. Although there have been some case reports citing improved outcomes with the addition of cetuximab [12–14], 0.8 the majority of publications on targeted therapies against EGFR and its tyrosine kinase have demonstrated limited No regional Dz improvement in the mortality of patients with advanced 0.6 disease when used as monotherapy [15–19]. The median time from previous skin cancer diagno- 0.4 sis to presentation with initial recurrence was only 5.7 Regional Dz months (range, 1–41 months). This is likely due to the 0.2 patient population being comprised of advanced, recurrent cutaneous squamous cell carcinomas, and as a result, this cohort of patients had very aggressive disease. The rapid recurrence of the disease reflects the malignant biology of late stage cSCC. In addition, nearly 40% of patients in (years) this series developed a second recurrence with the majority Figure 2: Disease-free survival for patients with and without occurring locally (68%). Distant metastasis noted in the positive nodal metastasis. Two-year disease-free survival for patients immediate postoperative period was associated with poor with regional disease was 47.7% versus 72.9% for those without prognosis (P< .001). Median time to cancer recurrence regional metastasis (P = .14). was 6.5 months, and overall 2-year disease-free survival was 62%. Although not statistically significant, patients from the present study were more likely to recur if they had cSCC prognostic indicators for cancer recurrence and metastasis, of the ear or periauricular area (P = .06), demonstrated most studies to date have only evaluated primary cSCC. In cervical metastasis on surgical pathology (P = .14), or did not undergo postoperative radiotherapy (P = .18). contrast, the majority of patients presenting to a tertiary care center have undergone previous skin cancer treatment and Previous studies have demonstrated a higher incidence of subsequently developed a second primary or recurrence. A nodal metastasis among patients with lesions located on or around the ear as a result of lymphatic drainage to the diagnosis of recurrent cSCC alone confers a more aggressive tumor subtype [9], yet identifying factors associated with parotid gland [20, 21]. In the present study, nearly half poor outcome is essential for patient management and of all patients with parotid involvement either by direct extension or nodal metastasis also demonstrated cervical decision making. In the present study, we review tumor characteristics, disease. Multiple studies have demonstrated that patients prior treatment, and outcomes in patients with recurrent, with parotid involvement are at a high risk for cervical advanced stage cSCC and evaluate the role of postopera- metastasis [9, 22]. In a study by Ying et al., 44% of patients tive radiotherapy. Surgery combined with radiation is the with parotid metastasis also had positive cervical nodes [23]. Therefore it is recommended that all patients with parotid recommended treatment in most cases of advanced disease [7]. In a study by Veness et al., improved locoregional metastasis undergo selective neck dissection. control and disease-free survival (73% versus 54%, P = The majority of patients in this series underwent selective neck dissection which included levels I–III. Fifty percent of .004) were achieved in patients who received adjuvant radiotherapy compared to surgery alone [10]. In another the nodal metastasis were located in level II. This finding is Survival probability Survival probability Journal of Skin Cancer 5 similar to what a recent article published, where nearly 80% Acknowledgments of all positive nodal metastasis from cSCC were located in This work was supported by Grants from the National Insti- level II [24]. Although parotid involvement did not have an tute of Health (NCI K08CA102154 and 2T32 CA091078-06). influence on disease-free survival in this patient population, the 2-year disease-free survival for patients with cervical metastasis was 48% versus 73% for those without neck References disease (P = .14). In the study by Clayman et al., 3-year disease-free survival was 69% for patients with lymph node [1] M. Alam and D. Ratner, “Cutaneous squamous-cell carci- involvement versus 87% for those without nodal disease noma,” New England Journal of Medicine, vol. 344, no. 13, pp. 975–983, 2001. (P = .09) [25]. Cervical metastasis seemingly confers a worse prognosis for patients with recurrent disease. 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