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Patterns of regional and distant metastasis in patients with eyelid and periocular squamous cell carcinoma
Patterns of Regional and Distant Metastasis in Patients with Eyelid and Periocular Squamous Cell Carcinoma Misha Faustina, MD, Roxana Diba, MD, M. Amir Ahmadi, MD, Brett F. Gutstein, Bita Esmaeli, MD Purpose: To determine the frequency and location of regional lymph node metastasis in patients with squamous cell carcinoma (SCC) of the eyelid and periocular skin. Patterns of distant metastasis were also investigated. Design: Retrospective case series. Patients: One hundred eleven patients treated at The University of Texas M. D. Anderson Cancer Center for SCC of the eyelid and periocular skin between 1952 and 2000. Methods: The clinical records of the 111 patients were retrospectively reviewed. The clinical characteristics analyzed included age, gender, location of lesion, treatment modalities, patterns of regional nodal and distant metastasis, and perineural invasion. Follow-up time ranged from 6 to 484 months (median, 76.6). Main Outcome Measure: Incidence of regional lymph node metastasis. Results: The most common sites of SCC were the lower eyelid (54 patients [48.6%]), the medial canthus (40 patients [36.0%]), and the upper eyelid (25 patients [22.5%]). Local treatment of SCC consisted of wide local excision with frozen section analysis to ensure negative margins in 96 patients (86.4%), radiotherapy (without surgery) in 7 patients, and primary exenteration because of extensive tumor in 7 patients. Local recurrence occurred in 41 patients (36.9%). Twenty-seven patients (24.3%) had regional nodal metastasis during the study period. Sixteen of these patients had regional lymph node metastasis at the time of the initial presentation to M. D. Anderson Cancer Center. Eleven developed regional nodal disease later. Seven patients (6.2%) had distant metastasis during the study period. Nine patients (8.1%) had perineural invasion. Conclusion: This study indicates that the overall rate of regional lymph node metastasis in patients with SCC of the eyelid or periocular skin may be as high as 24%. Thus, careful surveillance of the regional lymph nodes is an important aspect of the initial management of eyelid or periocular skin SCC. Consideration could be given to studying sentinel lymph node biopsy as a technique to stage SCC of the eyelid or periocular skin more accurately, especially in patients with recurrent, large, or highly invasive lesions or with perineural invasion. Ophthalmology 2004;111:1930 –1932 © 2004 by the American Academy of Ophthalmology.
Squamous cell carcinoma (SCC) is the second most common malignancy of the eyelid skin.1–3 It occurs in the eyelid much less frequently than basal cell carcinoma, but it is biologically more aggressive than basal cell carcinoma.4,5 Regional lymph nodes are generally believed to be the most common first site of metastasis of SCC of the eyelid.6 – 8 The sentinel lymph node mapping and biopsy technique has been used for early detection of microscopic nodal disease in patients with cutaneous malignancies, and our group has previously shown that this technique is feasible in patients with eyelid and conjunctival tumors.9 –13 Originally received: November 7, 2003. Accepted: February 10, 2004. Manuscript no. 230751. From the Section of Ophthalmology, Department of Plastic Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Correspondence to Bita Esmaeli, MD, Section of Ophthalmology, Department of Plastic Surgery, Unit 443, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: [email protected].
1930
© 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
The goal of this study was to determine the frequency and location of regional lymph node metastasis in patients with eyelid and periocular skin SCC, to determine the potential utility of sentinel lymph node biopsy in the management of such tumors.
Materials and Methods Appropriate institutional review board approval was obtained for this retrospective review. The patients included in this study were identified through a search of the Tumor Registry database at The University of Texas M. D. Anderson Cancer Center. One hundred eleven patients with eyelid and periocular skin SCC treated between 1952 and 2002 and for whom at least 6 months of follow-up data were available were identified. The clinical records were reviewed retrospectively. Information analyzed included age, gender, location of lesion (as outlined in Fig 1),14 treatment modalities, perineural invasion, local recurrence, patterns of regional nodal and distant metastasis, and overall survival. ISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2004.02.009
Faustina et al 䡠 Eyelid and Periocular Skin Squamous Cell Carcinoma
Figure 1. Eyelid and periocular skin zones used to classify tumors in this study. Reprinted with permission from Spinelli HM, Jelks GW, Periocular reconstruction: a systemic approach, Plastic and Reconstructive Surgery, 91(6), 1017–24.
Results Patient characteristics and patterns of recurrence are summarized in Table 1. The age of diagnosis ranged from 31 to 91 years (median, 64). Eighty-nine men and 22 women were affected. The follow-up time ranged from 6 to 484 months (median, 76.6) after the exclusion of 2 patients who had a follow-up time of ⬍6 months but were included in this study because they had regional nodal metastasis (the main outcome measure for this study) when the SCC was initially diagnosed. One hundred seven patients were Caucasian, and 4 were Hispanic. Sixty-eight patients (61.2%) had a history of chronic sun exposure. Sixty-two patients (55.8%) had a history of actinic keratosis in the same zone as the SCC. Fortyone patients (36.9%) had previously undergone local irradiation. Zone II, the lower eyelid, was the most common tumor location (54 patients [48.6%]). The distribution of tumors by zone for the remaining 57 patients was as follows: zone III, the medial canthus (40 patients [36.0%]); zone I, the upper eyelid (25 patients [22.5%]); zone IV, the lateral canthus (18 patients [16.2%]); and Table 1. Patient Characteristics and Patterns of Recurrence Characteristic Gender Male Female Tumor zone* I II III IV V Multiple zones Local recurrence Regional nodal metastasis Distant metastasis *See Figure 1.
zone V, the contiguous periocular skin (3 patients [2.7%]). Thirtythree patients (29.7%) had lesions involving more than one zone. One hundred seven patients (96.3%) had invasive SCC, and 4 patients (3.6%) had carcinoma in situ. Local treatment of SCC consisted of wide local excision in 96 patients (86.4%); 18 of these patients received external beam radiotherapy after surgery. External beam radiotherapy was used as the primary modality for local destruction of tumor (without surgery) in 7 patients because of the large area of involvement prohibiting useful reconstruction after excision, or in patients whose tumor had recurred despite a previous surgical resection. Seven patients had primary exenteration at the time of initial presentation to M. D. Anderson Cancer Center because of the extensive nature of their tumor, involving anterior orbital structures or large areas of multiple zones. One patient had evidence of regional lymph node and distant metastasis at the time of presentation to our hospital and was treated with chemotherapy. Four patients, 3 initially treated with wide local excision with radiotherapy and 1 initially treated with wide local excision, had exenteration as a secondary procedure after experiencing local recurrence. Local recurrence occurred in 41 patients (36.9%); 21 had it before referral to our center. The median time from diagnosis of SCC to referral to M. D. Anderson was 19 months. Twenty-seven patients (24.3%) had regional nodal metastasis during the study period. The diagnosis of regional nodal involvement was made on the basis of clinical palpation of the regional nodes and was confirmed via fine needle aspiration. Sixteen of these patients had regional lymph node metastasis at the time of initial presentation to M. D. Anderson; the other 11 patients developed regional nodal metastasis after the initial presentation. The involved lymph node basins included the parotid/preauricular (12 patients), submandibular/submental (9 patients), submaxillary (3 patients), cervical (3 patients), and subdigastric (2 patients). Two patients had metastasis to more than one regional nodal basin. All patients with regional lymph node metastasis underwent completion neck dissection, followed by radiation therapy to the involved nodal basins. Seven patients had distant organ metastasis during the study period. One patient had distant metastasis to the lung at the time of initial diagnosis; 6 additional patients developed distant metastasis after initial diagnosis. Nine patients (8.1%) had histologic documentation of perineural invasion. All 9 of these patients received external beam radiotherapy after surgical ablation of the tumor. Five of these patients developed regional lymph node metastasis, and 2 had distant metastasis. Five patients died of tumor-related causes (from metastatic SCC) during the study period; 3 of these patients had pulmonary metastasis alone, 1 had brain metastasis alone, and 1 had metastasis to both sites.
No. (%) of Patients
Discussion 89 (80.2) 22 (19.8) 25 (22.5) 54 (48.6) 40 (36.0) 18 (16.2) 3 (2.7) 33 (29.7) 41 (36.9) 27 (24.3) 7 (6.2)
The incidence of regional lymph node metastasis secondary to eyelid and periocular SCC in the present study (24.3%) is relatively high compared with the incidence previously reported.1,3,5,15 The previously reported incidences of regional lymph node metastasis associated with SCC of the eyelid and periocular skin have varied widely, from as low as 10% to as high as 21.4% in different retrospective series.1,8 The current study represents one of the largest series of eyelid and periocular skin SCC reported to date and has a relatively long follow-up time compared with those of previously published reports. The relatively high rate of regional nodal involvement in our study may be partly the result of
1931
Ophthalmology Volume 111, Number 10, October 2004 selection bias: the proportion of patients with more advanced disease is higher at our cancer center than in other settings. We found that the parotid/preauricular nodes were the regional lymph nodes most often involved. This finding agrees with our previous observations in patients who underwent sentinel lymph node biopsy for conjunctival, eyelid, or periocular malignancies10 and with recent observations in a lymphoscintigraphy study of normal subjects in which the lymphatic drainage in most patients who were injected with technetium in the periocular region was to the parotid/preauricular nodes (Najawahan N, personal communication, 2003). The submandibular/submental nodes were the second most frequently involved regional nodes, and the lower cervical lymph nodes were often involved as secondorder lymph nodes draining the eyelid or periocular tumor. Most of the other findings in this retrospective study were also consistent with previously reported observations. About a third of the patients in this study had at least one local recurrence, underscoring the importance of initial aggressive wide local excision and complete surgical extirpation with frozen section analysis to ensure negative margins.7,16 –18 Distant metastasis was seen in only 7 patients, and there were only 5 tumor-related deaths, indicating that regional nodal metastasis is a far more common event associated with SCC of the eyelid and periocular skin than is distant organ metastasis. The use of sentinel lymph node biopsy in SCC of the head and neck has previously been explored.19 –22 Our group has published several reports of a modification of the usual technique of sentinel lymph node biopsy for eyelid and conjunctival tumors, which can successfully identify the sentinel nodes.9 –13 Given the significant rate of regional lymph node metastasis observed in the current study, it seems that sentinel node biopsy should be further studied as an adjunct to the current management of SCC of the eyelid and periocular skin in patients at high risk for regional metastasis. These high-risk features may include large lesions wider than 2 cm, those that are locally recurrent, or those with perineural invasion.
References 1. Reifler DM, Hornblass A. Squamous cell carcinoma of the eyelid. Surv Ophthalmol 1986;30:349 – 65. 2. Tanenbaum M, Grove AS Jr, McCord CD Jr. Eyelid tumors: diagnosis and management. In: McCord CD Jr, Tanenbaum M, Nunery WR, eds. Oculoplastic Surgery. 3rd ed. New York: Raven Press Ltd.; 1995:145–74. 3. Doxanas MT, Iliff WJ, Iliff NT, Green WR. Squamous cell carcinoma of the eyelids. Ophthalmology 1987;94:538 – 41.
1932
4. Dailey JR, Kennedy RH, Flaharty PM, et al. Squamous cell carcinoma of the eyelid. Ophthal Plast Reconstr Surg 1994; 10:153–9. 5. Loeffler M, Hornblass A. Characteristics and behavior of eyelid carcinoma (basal cell, squamous cell, sebaceous gland, and malignant melanoma). Ophthalmic Surg 1990;21:513– 8. 6. McCord CD Jr, Cavanagh HD. Microscopic features and biologic behavior of eyelid tumors. Ophthalmic Surg 1980; 11:671– 81. 7. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. J Am Acad Dermatol 1992;26:976 –90. 8. Cook BE Jr, Bartley GB. Treatment options and future prospects for the management of eyelid malignancies: an evidence-based update. Ophthalmology 2001;108:2088 –100. 9. Esmaeli B, Eicher S, Popp J, et al. Sentinel lymph node biopsy for conjunctival melanoma. Ophthal Plast Reconstr Surg 2001;17:436 – 42. 10. Amato M, Esmaeli B, Ahmadi MA, et al. Feasibility of preoperative lymphoscintigraphy for identification of sentinel lymph nodes in patients with conjunctival and periocular skin malignancies. Ophthal Plast Reconstr Surg 2003;19:102– 6. 11. Esmaeli B. Advances in the management of malignant tumors of the eyelid and conjunctiva: the role of sentinel node biopsy. Int Ophthalmol Clin 2002;42:151– 62. 12. Esmaeli B. Sentinel node biopsy as a tool for accurate staging of eyelid and conjunctival malignancies. Curr Opin Ophthalmol 2002;13:317–23. 13. Esmaeli B, Reifler D, Prieto VG, et al. Conjunctival melanoma with a positive sentinel lymph node. Arch Ophthalmol 2003; 121:1779 – 83. 14. Spinelli HM, Jelks GW. Periocular reconstruction: a systemic approach. Plast Reconstr Surg 1993;91:1017–24. 15. Lund RZ. How often does squamous cell carcinoma metastasize? Arch Dermatol 1965;92:635–7. 16. Donaldson MJ, Sullivan TJ, Whitehead KJ, Williamson RM. Squamous cell carcinoma of the eyelids. Br J Ophthalmol 2002;86:1161–5. 17. Soparkar CN, Patrinely JR. Eyelid cancers. Curr Opin Ophthalmol 1998;9:49 –53. 18. Reifler DM, Hornblass A. Surgical management of squamous cell carcinoma of the lid. Ophthal Plast Reconstr Surg 1986; 2:75– 82. 19. Shoaib T, Souter DS, Prosser JE, et al. A suggested method for sentinel node biopsy in squamous cell carcinoma of the head and neck. Head Neck 1999;21:728 –33. 20. Bilchik AJ, Giuliano A, Essner R, et al. Universal application of intraoperative lymphatic mapping and sentinel lymphadenectomy in solid neoplasms. Cancer J Sci Am 1998;4:351– 8. 21. Pitman KT, Ferlito A, Devaney KO, et al. Sentinel lymph node biopsy in head and neck cancer. Oral Oncol 2003;39: 343–9. 22. Ross GL, Shoaib T, Soutar DS, et al. The First International Conference on Sentinel Node Biopsy in Mucosal Head and Neck Cancer and adoption of a multicenter trial protocol. Ann Surg Oncol 2002;9:406 –10.
Squamous cell carcinoma (SCC) is the second most common malignancy of the eyelid skin.1–3 It occurs in the eyelid much less frequently than basal cell carcinoma, but it is biologically more aggressive than basal cell carcinoma.4,5 Regional lymph nodes are generally believed to be the most common first site of metastasis of SCC of the eyelid.6 – 8 The sentinel lymph node mapping and biopsy technique has been used for early detection of microscopic nodal disease in patients with cutaneous malignancies, and our group has previously shown that this technique is feasible in patients with eyelid and conjunctival tumors.9 –13 Originally received: November 7, 2003. Accepted: February 10, 2004. Manuscript no. 230751. From the Section of Ophthalmology, Department of Plastic Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Correspondence to Bita Esmaeli, MD, Section of Ophthalmology, Department of Plastic Surgery, Unit 443, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: [email protected].
1930
© 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
The goal of this study was to determine the frequency and location of regional lymph node metastasis in patients with eyelid and periocular skin SCC, to determine the potential utility of sentinel lymph node biopsy in the management of such tumors.
Materials and Methods Appropriate institutional review board approval was obtained for this retrospective review. The patients included in this study were identified through a search of the Tumor Registry database at The University of Texas M. D. Anderson Cancer Center. One hundred eleven patients with eyelid and periocular skin SCC treated between 1952 and 2002 and for whom at least 6 months of follow-up data were available were identified. The clinical records were reviewed retrospectively. Information analyzed included age, gender, location of lesion (as outlined in Fig 1),14 treatment modalities, perineural invasion, local recurrence, patterns of regional nodal and distant metastasis, and overall survival. ISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2004.02.009
Faustina et al 䡠 Eyelid and Periocular Skin Squamous Cell Carcinoma
Figure 1. Eyelid and periocular skin zones used to classify tumors in this study. Reprinted with permission from Spinelli HM, Jelks GW, Periocular reconstruction: a systemic approach, Plastic and Reconstructive Surgery, 91(6), 1017–24.
Results Patient characteristics and patterns of recurrence are summarized in Table 1. The age of diagnosis ranged from 31 to 91 years (median, 64). Eighty-nine men and 22 women were affected. The follow-up time ranged from 6 to 484 months (median, 76.6) after the exclusion of 2 patients who had a follow-up time of ⬍6 months but were included in this study because they had regional nodal metastasis (the main outcome measure for this study) when the SCC was initially diagnosed. One hundred seven patients were Caucasian, and 4 were Hispanic. Sixty-eight patients (61.2%) had a history of chronic sun exposure. Sixty-two patients (55.8%) had a history of actinic keratosis in the same zone as the SCC. Fortyone patients (36.9%) had previously undergone local irradiation. Zone II, the lower eyelid, was the most common tumor location (54 patients [48.6%]). The distribution of tumors by zone for the remaining 57 patients was as follows: zone III, the medial canthus (40 patients [36.0%]); zone I, the upper eyelid (25 patients [22.5%]); zone IV, the lateral canthus (18 patients [16.2%]); and Table 1. Patient Characteristics and Patterns of Recurrence Characteristic Gender Male Female Tumor zone* I II III IV V Multiple zones Local recurrence Regional nodal metastasis Distant metastasis *See Figure 1.
zone V, the contiguous periocular skin (3 patients [2.7%]). Thirtythree patients (29.7%) had lesions involving more than one zone. One hundred seven patients (96.3%) had invasive SCC, and 4 patients (3.6%) had carcinoma in situ. Local treatment of SCC consisted of wide local excision in 96 patients (86.4%); 18 of these patients received external beam radiotherapy after surgery. External beam radiotherapy was used as the primary modality for local destruction of tumor (without surgery) in 7 patients because of the large area of involvement prohibiting useful reconstruction after excision, or in patients whose tumor had recurred despite a previous surgical resection. Seven patients had primary exenteration at the time of initial presentation to M. D. Anderson Cancer Center because of the extensive nature of their tumor, involving anterior orbital structures or large areas of multiple zones. One patient had evidence of regional lymph node and distant metastasis at the time of presentation to our hospital and was treated with chemotherapy. Four patients, 3 initially treated with wide local excision with radiotherapy and 1 initially treated with wide local excision, had exenteration as a secondary procedure after experiencing local recurrence. Local recurrence occurred in 41 patients (36.9%); 21 had it before referral to our center. The median time from diagnosis of SCC to referral to M. D. Anderson was 19 months. Twenty-seven patients (24.3%) had regional nodal metastasis during the study period. The diagnosis of regional nodal involvement was made on the basis of clinical palpation of the regional nodes and was confirmed via fine needle aspiration. Sixteen of these patients had regional lymph node metastasis at the time of initial presentation to M. D. Anderson; the other 11 patients developed regional nodal metastasis after the initial presentation. The involved lymph node basins included the parotid/preauricular (12 patients), submandibular/submental (9 patients), submaxillary (3 patients), cervical (3 patients), and subdigastric (2 patients). Two patients had metastasis to more than one regional nodal basin. All patients with regional lymph node metastasis underwent completion neck dissection, followed by radiation therapy to the involved nodal basins. Seven patients had distant organ metastasis during the study period. One patient had distant metastasis to the lung at the time of initial diagnosis; 6 additional patients developed distant metastasis after initial diagnosis. Nine patients (8.1%) had histologic documentation of perineural invasion. All 9 of these patients received external beam radiotherapy after surgical ablation of the tumor. Five of these patients developed regional lymph node metastasis, and 2 had distant metastasis. Five patients died of tumor-related causes (from metastatic SCC) during the study period; 3 of these patients had pulmonary metastasis alone, 1 had brain metastasis alone, and 1 had metastasis to both sites.
No. (%) of Patients
Discussion 89 (80.2) 22 (19.8) 25 (22.5) 54 (48.6) 40 (36.0) 18 (16.2) 3 (2.7) 33 (29.7) 41 (36.9) 27 (24.3) 7 (6.2)
The incidence of regional lymph node metastasis secondary to eyelid and periocular SCC in the present study (24.3%) is relatively high compared with the incidence previously reported.1,3,5,15 The previously reported incidences of regional lymph node metastasis associated with SCC of the eyelid and periocular skin have varied widely, from as low as 10% to as high as 21.4% in different retrospective series.1,8 The current study represents one of the largest series of eyelid and periocular skin SCC reported to date and has a relatively long follow-up time compared with those of previously published reports. The relatively high rate of regional nodal involvement in our study may be partly the result of
1931
Ophthalmology Volume 111, Number 10, October 2004 selection bias: the proportion of patients with more advanced disease is higher at our cancer center than in other settings. We found that the parotid/preauricular nodes were the regional lymph nodes most often involved. This finding agrees with our previous observations in patients who underwent sentinel lymph node biopsy for conjunctival, eyelid, or periocular malignancies10 and with recent observations in a lymphoscintigraphy study of normal subjects in which the lymphatic drainage in most patients who were injected with technetium in the periocular region was to the parotid/preauricular nodes (Najawahan N, personal communication, 2003). The submandibular/submental nodes were the second most frequently involved regional nodes, and the lower cervical lymph nodes were often involved as secondorder lymph nodes draining the eyelid or periocular tumor. Most of the other findings in this retrospective study were also consistent with previously reported observations. About a third of the patients in this study had at least one local recurrence, underscoring the importance of initial aggressive wide local excision and complete surgical extirpation with frozen section analysis to ensure negative margins.7,16 –18 Distant metastasis was seen in only 7 patients, and there were only 5 tumor-related deaths, indicating that regional nodal metastasis is a far more common event associated with SCC of the eyelid and periocular skin than is distant organ metastasis. The use of sentinel lymph node biopsy in SCC of the head and neck has previously been explored.19 –22 Our group has published several reports of a modification of the usual technique of sentinel lymph node biopsy for eyelid and conjunctival tumors, which can successfully identify the sentinel nodes.9 –13 Given the significant rate of regional lymph node metastasis observed in the current study, it seems that sentinel node biopsy should be further studied as an adjunct to the current management of SCC of the eyelid and periocular skin in patients at high risk for regional metastasis. These high-risk features may include large lesions wider than 2 cm, those that are locally recurrent, or those with perineural invasion.
References 1. Reifler DM, Hornblass A. Squamous cell carcinoma of the eyelid. Surv Ophthalmol 1986;30:349 – 65. 2. Tanenbaum M, Grove AS Jr, McCord CD Jr. Eyelid tumors: diagnosis and management. In: McCord CD Jr, Tanenbaum M, Nunery WR, eds. Oculoplastic Surgery. 3rd ed. New York: Raven Press Ltd.; 1995:145–74. 3. Doxanas MT, Iliff WJ, Iliff NT, Green WR. Squamous cell carcinoma of the eyelids. Ophthalmology 1987;94:538 – 41.
1932
4. Dailey JR, Kennedy RH, Flaharty PM, et al. Squamous cell carcinoma of the eyelid. Ophthal Plast Reconstr Surg 1994; 10:153–9. 5. Loeffler M, Hornblass A. Characteristics and behavior of eyelid carcinoma (basal cell, squamous cell, sebaceous gland, and malignant melanoma). Ophthalmic Surg 1990;21:513– 8. 6. McCord CD Jr, Cavanagh HD. Microscopic features and biologic behavior of eyelid tumors. Ophthalmic Surg 1980; 11:671– 81. 7. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. J Am Acad Dermatol 1992;26:976 –90. 8. Cook BE Jr, Bartley GB. Treatment options and future prospects for the management of eyelid malignancies: an evidence-based update. Ophthalmology 2001;108:2088 –100. 9. Esmaeli B, Eicher S, Popp J, et al. Sentinel lymph node biopsy for conjunctival melanoma. Ophthal Plast Reconstr Surg 2001;17:436 – 42. 10. Amato M, Esmaeli B, Ahmadi MA, et al. Feasibility of preoperative lymphoscintigraphy for identification of sentinel lymph nodes in patients with conjunctival and periocular skin malignancies. Ophthal Plast Reconstr Surg 2003;19:102– 6. 11. Esmaeli B. Advances in the management of malignant tumors of the eyelid and conjunctiva: the role of sentinel node biopsy. Int Ophthalmol Clin 2002;42:151– 62. 12. Esmaeli B. Sentinel node biopsy as a tool for accurate staging of eyelid and conjunctival malignancies. Curr Opin Ophthalmol 2002;13:317–23. 13. Esmaeli B, Reifler D, Prieto VG, et al. Conjunctival melanoma with a positive sentinel lymph node. Arch Ophthalmol 2003; 121:1779 – 83. 14. Spinelli HM, Jelks GW. Periocular reconstruction: a systemic approach. Plast Reconstr Surg 1993;91:1017–24. 15. Lund RZ. How often does squamous cell carcinoma metastasize? Arch Dermatol 1965;92:635–7. 16. Donaldson MJ, Sullivan TJ, Whitehead KJ, Williamson RM. Squamous cell carcinoma of the eyelids. Br J Ophthalmol 2002;86:1161–5. 17. Soparkar CN, Patrinely JR. Eyelid cancers. Curr Opin Ophthalmol 1998;9:49 –53. 18. Reifler DM, Hornblass A. Surgical management of squamous cell carcinoma of the lid. Ophthal Plast Reconstr Surg 1986; 2:75– 82. 19. Shoaib T, Souter DS, Prosser JE, et al. A suggested method for sentinel node biopsy in squamous cell carcinoma of the head and neck. Head Neck 1999;21:728 –33. 20. Bilchik AJ, Giuliano A, Essner R, et al. Universal application of intraoperative lymphatic mapping and sentinel lymphadenectomy in solid neoplasms. Cancer J Sci Am 1998;4:351– 8. 21. Pitman KT, Ferlito A, Devaney KO, et al. Sentinel lymph node biopsy in head and neck cancer. Oral Oncol 2003;39: 343–9. 22. Ross GL, Shoaib T, Soutar DS, et al. The First International Conference on Sentinel Node Biopsy in Mucosal Head and Neck Cancer and adoption of a multicenter trial protocol. Ann Surg Oncol 2002;9:406 –10.