- Email: [email protected]
Combined sentinel lymphadenectomy and Mohs micrographic surgery for high-risk cutaneous squamous cell carcinoma
Combined sentinel lymphadenectomy and Mohs micrographic surgery for high-risk cutaneous squamous cell carcinoma Noah Kawika Weisberg, MD,a Monica M. Bertagnolli, MD,b and David S. Becker, MDa New York, New York Background: There are subgroups of cutaneous squamous cell carcinoma (SCC) that have a higher risk for both regional and distant metastasis. When cutaneous SCC does metastasize, it typically spreads first to local nodal groups. Sentinel lymph node (SLN) localization has been successfully used to evaluate nodal metastasis in breast carcinoma, melanoma, and other select tumors. It may also be useful in certain highrisk cutaneous SCCs. Currently, Mohs micrographic surgery is the treatment of choice for these tumors. Methods: A patient presented with a high-risk recurrent SCC on the forehead. The regional nodal groups were clinically negative and radiographically negative by computed tomographic scan. Sentinel lymphadenectomy was performed by means of technetium 99m–radiolabeled sulfur colloid. The main tumor was resected with Mohs micrographic surgery. Results: A left preauricular SLN was localized by lymphoscintigraphy. The SLN was located intraoperatively by means of a gamma probe and excised. Subsequent pathologic evaluation of the SLN was negative for evidence of metastatic SCC by light microscopy with hematoxylin and eosin, and with immunohistochemical stains for cytokeratins AE1 and AE3. The day after SLN excision, the tumor was removed via Mohs micrographic surgery with clear surgical margins after a total of 8 stages. Aggressive subclinical spread by both subcutaneous “skating” and perineural invasion was noted. Conclusion: The combination of Mohs micrographic surgery and sentinel lymphadenectomy is feasible and has theoretical utility in the management of a subset of cutaneous SCCs at high risk for metastasis. The ability of sentinel lymphadenectomy to identify regionally metastatic cutaneous SCC as well as the additive benefit of SLN and Mohs micrographic extirpation in the treatment of high-risk cutaneous SCC remain to be further clarified. (J Am Acad Dermatol 2000;43:483-8.)
T
here are subgroups of cutaneous squamous cell carcinoma (SCC) that are at increased risk for metastasis. When cutaneous SCC does metastasize, it typically spreads to local nodal groups before distant metastasis occurs. Sentinel lymph node (SLN) localization has been successfully used to evaluate nodal metastasis in breast carcinoma, melanoma, and other select tumors. It is unknown From the Departments of Dermatologya and Surgery,b Weill Cornell Medical School. Accepted for publication Feb 11, 2000. Reprint requests: David S. Becker, MD, Department of Dermatology, Director, Dermatologic and Laser Surgery, Weill Cornell University Medical Center, F-343, New York, NY 10021. E-mail: [email protected]. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/106367 doi:10.1067/mjd.2000.106367
Abbreviations used: LND: SCC: SLN: XRT:
lymph node dissection squamous cell carcinoma sentinel lymph node x-ray therapy
whether SLN localization can be successfully used to screen the nodal basins in high-risk cutaneous SCCs. Currently, Mohs micrographic surgery is the treatment of choice for these tumors.
CASE REPORT The patient is a 73-year-old white man with a history of superficially invasive SCC of the forehead, which had been treated in November 1997 with electrodesiccation and curettage. He is otherwise in 483
484 Weisberg, Bertagnolli, and Becker
J AM ACAD DERMATOL SEPTEMBER 2000
Fig 1. Recurrent SCC of the forehead with clinically distinct inferomedial subcutaneous nodule of SCC.
Fig 2. Preoperative lymphoscintigraphy: Anteroposterior and left lateral static lymphoscintigrams of patient’s head showing 99mTc-radiolabeled sulfur colloid injection site (arrowhead) and left preauricular sentinel nodes (arrows).
good health with no history of radiation therapy to the head and neck or any known immunodeficiency. In May 1999 the patient presented with an illdefined, 6-cm firm tumor on the left side of his upper forehead with central ulceration (Fig 1). The tumor appeared clinically to be adherent to the underlying bone. Slightly inferomedial to this tumor and separated by 1 cm of clinically normal skin was an 8-mm subcutaneous nodule that was clinically suspect as a local metastasis. Biopsy findings of the larger tumor demonstrated poorly differentiated
invasive SCC, and a biopsy specimen of the small nodule revealed SCC invasive to at least 7.5 mm and not in continuity with the epidermis. Locally metastatic SCC could not be ruled out. Clinical examination did not reveal any preauricular, cervical, or submental lymphadenopathy. A computed tomographic scan of his head and neck to evaluate bony tumor invasion and regional metastasis was negative. Factors contributing to the especially high risk of nodal metastasis with this tumor included (1) recurrent tumor, (2) size larger than 2 cm, (3) depth of
Weisberg, Bertagnolli, and Becker 485
J AM ACAD DERMATOL VOLUME 43, NUMBER 3
Fig 3. Perineural invasion of squamous cell carcinoma on Mohs section. (Hematoxylin-eosin stain; original magnification ×20.)
invasion more than 4 mm, and (4) probable satellite cutaneous metastasis. Because of the high risk of this tumor in the setting of a neck with negative clinical and radiographic findings, SLN biopsy followed by Mohs micrographically controlled resection of the tumor was undertaken.
MATERIAL AND METHODS Preoperative lymphoscintigraphy. On the morning of SLN biopsy, 1 mCi filtered technetium 99m (99mTc)–radiolabeled sulfur colloid was injected intradermally at 4 sites around the tumor. Lymphoscintigraphy was performed with a standard largefield-of-view gamma camera immediately after injection to obtain dynamic flow and static images. Intraoperative lymphatic mapping. The patient was positioned, prepared, and draped under conscious sedation. An incision was made over the point of maximum signal; SLN biopsy was performed guided by the gamma probe (Capintec, Gammed IIb, Ramsey, NJ). Histologic examination of the lymph node. After formalin fixation, the SLN was serially sectioned at multiple levels and stained with hematoxylin and eosin. Immunohistochemistry with cytokeratins AE1 and AE3 was also performed. One 4-µm section for each stain was examined at each of the 3 different levels of the sentinel node. Excision of tumor. Extirpation of tumor was performed via the Mohs technique.1
RESULTS After injection of the 99mTc-radiolabeled sulfur colloid, the sentinel node was localized by anteroposterior and lateral images (Fig 2) to the left preauricular position and its position marked on the overlying skin. A second, smaller inferior node located on later images was not marked. A left preauricular incision was made and blunt dissection after the gamma probe signal performed. A single node containing the majority of the radio signal was localized and removed. Subsequent evaluation of the surgical bed with the gamma probe exhibited minimal residual radio signal. Pathologic evaluation of the SLN was negative for evidence of metastatic SCC by both hematoxylin and eosin and by immunohistochemical stains for cytokeratins AE1 and AE3. The day after SLN biopsy the patient returned for Mohs micrographic controlled excision of the tumor. The main tumor mass and the adjacent nodule of subcutaneous SCC were initially approached as two separate lesions. Histologically there was no tumor bridging these two lesions. However, given their close proximity, subsequent Mohs layers encompassed both of these lesions creating one surgical defect. Tumor extended to the periostium. Significant subclinical spread through both subcutaneous “skating” and perineural invasion (Fig 3) was noted, with tumor tracking along the supraorbital nerve and approaching but not entering the
486 Weisberg, Bertagnolli, and Becker
J AM ACAD DERMATOL SEPTEMBER 2000
Fig 4. Final surgical defect. Note extent of subclinical spread in clinically normal skin as well as far inferior extension of surgical defect approaching the supraorbital foramen.
supraorbital foramen. Further subclinical spread occurred inferolaterally towards the preauricular sentinel node. Clear surgical margins were obtained after a total of 8 stages (Fig 4). The surgical defect was temporally covered with a split-thickness skin graft, which will remain in place for at least 1 year as a “window” to monitor for local recurrence. Given the local aggressiveness of the tumor, postoperative radiation therapy to the surgical site is in progress. However, because of the negative status of the SLN, radiation therapy to the draining nodal basins is being deferred. Currently, at 3 months of follow-up, the patient has no clinical evidence of recurrence or metastasis.
DISCUSSION Many studies have attempted to identify factors predictive of locally aggressive biologic behavior and metastasis in cutaneous SCCs. The identification of high-risk patients at the earliest possible stage could facilitate the selection of appropriate therapeutic choices, potentially affecting the survival of this patient population. A meta-analysis on the prognosis of SCCs of the skin and lip since 1940 found that the following variables correlated with local recurrence and metastatic rates: treatment modality, recurrent tumor, tumor location, size (>2 cm), depth (>4 mm), poor histologic differentiation, histologic evidence of perineural involvement, precipitating factors other than ultraviolet light, and host immuno-
suppression.2 Some of these factors have been substantiated in subsequent studies.3-7 Defined subsets of cutaneous SCCs have a significant metastatic potential. The reported incidence of metastatic cutaneous SCC has varied widely depending on the study and its case selection, ranging from 0.5% to 14%.3-5,7-13 One subset, recurrent SCCs, has metastatic rates as high as 25% to 45% if re-treatment is by simple surgical excision.2 The treatment of choice for high-risk tumors is Mohs micrographic surgery.14-17 The majority of metastases of cutaneous SCCs are to the regional lymph nodes, including those within the parotid gland, whereas distant metastases are uncommon.4,7,10,18-24 Cure of such metastases might theoretically be achieved through clearing of these foci in the locoregional nodes. Unfortunately, not all metastases may be clinically apparent at initial presentation. For example, Jackson and Ballantyne21 in a study including 125 SCCs metastatic to the parotid gland noted a 24% incidence of occult metastases in clinically negative nodes. Once cutaneous SCC metastasizes, the treatment options include lymph node dissection (LND), radiation therapy (XRT), and chemotherapy. Studies done to evaluate the efficacy of these therapies in improving long-term survival in this patient group have failed to demonstrate statistically significant improvement with these therapies alone or in combination.6,7,25,26 Even though no prospective randomized study validating the role of combination
J AM ACAD DERMATOL VOLUME 43, NUMBER 3
therapy for metastatic cutaneous SCC exists, surgery and postoperative XRT remain the current standard of care. Survival in patients with regional lymph node metastasis from SCC of the skin remains poor. The 5-year survival for metastatic SCC has been reported as 26%.2 Kraus, Carew, and Harrison6 reported that the clinical stage of the regional metastasis was the only factor predictive of survival and that the identification of regional lymph node metastasis in high-risk patients at an earlier stage may be of benefit. However, in these studies most patients already had clinically and radiographically positive lymph nodes. Theoretically, there would be a survival benefit with removal of the subclinical micrometastases found by SLN biopsy. Palpable regional lymph nodes have often been used to determine whether any further therapy such as LND or XRT, or both, to the nodes was required.21 Elective LND is usually not done in the absence of clinical or radiologic evidence of regional metastatic spread. Consequently, there are few data to predict the number of patients who have subclinical nodal metastases at presentation. However, the study by Jackson and Ballantyne21 suggests that micrometastasis may be more common than expected. It would be optimal to be able to identify this subset of patients while minimizing the morbidities associated with complete LND. The sentinel node is defined as the first lymph node that receives lymph flow from a primary tumor. The histologic status of this node with regard to metastatic disease should theoretically represent the remaining nodes in that lymphatic basin, assuming that metastasis occurs in a systematic fashion. This concept was first described by Cabanas27 in 1977 for SCC of the penis. Morton et al28 popularized SLN biopsy for melanoma in the 1980s and Giuliano et al29 did the same for breast cancer in the mid 1990s. It has been shown that the histopathology of the sentinel node can predict the histology of the downstream nodes in melanoma, breast cancer, and Merkel cell carcinoma.30-34 That is, if the sentinel node is negative for metastatic disease, the downstream nodes will be negative as well. Despite its expanding use in melanoma, studies have not yet demonstrated any survival benefit to patients undergoing SLN biopsy. However, its use has gained favor as a highly accurate and minimally invasive staging technique for the identification of patients who might be candidates for more aggressive therapies. Theoretically, the sensitivity for discovering occult SCC in an SLN might be increased by staining nodal sections for the epithelial antigens AE1 and AE3. The histologic status of the SLN could be important for a variety of reasons: (1) It could assist in staging a
Weisberg, Bertagnolli, and Becker 487
patient, improving assessment of prognosis, and allowing for better stratification of patients for clinical trials; (2) it might identify which patients could benefit from therapeutic LND, XRT, or chemotherapy while minimizing morbidity for lower risk patients; and (3) the removal of clinically invisible micrometastasis may be of some therapeutic benefit in and of itself. The superficial lymphatic system of the head and neck region is marked by inconsistent and unpredictable drainage patterns. It has been previously demonstrated that without preoperative lymphoscintigraphy, elective LNDs may be misdirected in as many as 50% of cases. In melanoma of the head and neck region, lymphoscintigraphically mapped drainage patterns differ from those that would be expected on the basis of classic anatomic teaching by 63%.35 Preoperative lymphoscintigraphy may be utilized to more accurately identify all lymph basins at risk for metastasis, in-transit nodes outside the major lymphatic basins, the number of sentinel nodes, and specifically the location of the sentinel node(s) within the identified basins. The appropriate time to consider the use of lymphatic mapping should be before or simultaneous with the definitive surgical procedure to remove the tumor because surgery can alter lymphatic flow and potentially affect the accuracy of SLN biopsy. The efficacy of SLN for high-risk SCCs is unknown. Even in this patient, metastasis would be unlikely with only 3 months of follow-up, but would likely occur within 2 years.2 Consequently, close follow-up will be necessary to determine whether this procedure is predictive of regional lymph node metastasis in this patient. Currently, SLN for high-risk SCC has only theoretical utility and no benefit can be assured in determining the biologic potential of this individual SCC. Furthermore, no survival benefit for patients can be claimed, even if earlier identification of metastatic SCC is assumed. Adoption of this procedure for individual high-risk SCC should await appropriate clinical trials that demonstrate earlier identification of regional disease and/or an overall survival benefit to this procedure. Some have argued that adoption of SLN (with significant costs) for many melanomas outside the context of appropriately designed clinical trials has been premature. In summary, the combination of Mohs micrographic surgery and SLN is feasible. Optimal management of high-risk cutaneous SCCs involves maximizing the local clearance of the tumor and determining whether the tumor has already metastasized. Mohs surgery can optimize local tumor extirpation. In high-risk cutaneous SCCs with clinically negative nodes, SLN biopsy could theoretically provide useful insight into the
488 Weisberg, Bertagnolli, and Becker
presence of subclinical micrometastasis. Identification of these micrometastases could possibly be used to guide early interventions while the maximum potential gain from these therapies may exist. The expert technical assistance of Vijay Bridgemohansingh is gratefully acknowledged. REFERENCES 1. Cottel WI, Bailin PL, Albom MJ, Gernstein G, Braun M, Hanke CW, et al. Essential of Mohs micrographic surgery. J Dermatol Surg Oncol 1988;14:1:11-3. 2. 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: implications for treatment modality selection. J Am Acad Dermatol 1992;26:976-90. 3. Breuninger H, Schaumburg-Lever G, Holzschuh J. Desmoplastic squamous cell carcinoma of the skin and vermillion surface. Cancer 1997;79:915-9. 4. Dinehart SM, Pollack SV. Metastases from squamous cell carcinoma of the skin and lip: an analysis of twenty-seven cases. J Am Acad Dermatol 1989;21:241-8. 5. Haydon RC. Cutaneous squamous carcinoma and related lesions. Otolaryngol Clin North Am 1993;26:57-71. 6. Kraus DH, Carew JF, Harrison LB. Regional lymph node metastasis from cutaneous squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 1998;124:582-7. 7. Tavin E, Persky M. Metastatic cutaneous carcinoma: squamous cell carcinoma of the head and neck region. Laryngoscope 1996;106:156-8. 8. Brown RO, Osguthorpe JD. Management of the neck in nonmelanocytic cutaneous carcinomas. Otolaryngol Clin North Am 1998;31:841-56. 9. Chuang TY, Popescu NA, Su WD, Chute CG. Squamous cell carcinoma: a population-based incidence study in Rochester, Minn. Arch Dermatol 1990;126:185-8. 10. Epstein E, Epstein NN, Bragg K. Metastases from squamous cell carcinomas of the skin. Arch Dermatol 1968;97:245-51. 11. Levine HL, Ratz JL, Bailin P. Squamous cell carcinoma of the head and neck. Otolaryngol Clin North Am 1985;18:499-503. 12. Lund HZ. How often does squamous cell carcinoma of the skin metastasize? Arch Dermatol 1965;92:635-7. 13. Moller R, Reyman F, Hou-Jensen K. Metastases in dermatological patients with squamous cell carcinoma. Arch Dermatol 1979;115:703-5. 14. Fleming ID, Amonette R, Monaghan T, Fleming MD. Principles of management of basal and squamous cell carcinoma of the skin. Cancer 1995;75;2:699-704. 15. Mohs F, Larson P, Iriondo M. Micrographic surgery for the microscopically controlled excision of carcinoma of the external ear. J Am Acad Dermatol 1988;19:729-37. 16. Roenigk RK. Mohs micrographic surgery. Mayo Clin Proc 1988;63:175-83. 17. Tromovitch TA, Stegman SJ. Microscopic-controlled excision of cutaneous tumors: chemosurgery, fresh tissue technique. Cancer 1978;41:653-8.
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18. Conley J, Arena S. Parotid gland as a focus of metastasis. Arch Surg 1963;87:757-64. 19. Dinehart SM, Nelson-Adesokan P, Cockerell C, Russell S, Brown R. Metastatic cutaneous squamous cell carcinoma derived from actinic keratosis. Cancer 1997;79:920-3. 20. Epstein E. Malignant sun-induced squamous cell carcinoma of the skin. J Dermatol Surg Oncol 1983;9:505-6. 21. Jackson GL, Ballantyne AJ. Role of parotidectomy for skin cancer of the head and neck. Am J Surg 1981;142:464-9. 22. Lazarus HM, Herzig RH, Bornstein R. Metastatic squamous cell carcinoma of the skin. J Natl Med Assoc 1980;72:1196-9. 23. Marvel JB, Schwartz MR, Donovan DT. Metastatic squamous cell carcinoma of the parotid: a case of an occult primary. Head Neck 1990;12:174-7. 24. O’Brien CJ, Malka VB, Mijailovic M. Evaluation of 242 consecutive parotidectomies performed for benign and malignant disease. Aust N Z J Surg 1993;63:870-7. 25. Khurana VG, Mentis DH, O’Brien CJ, Hurst TL, Stevens GN, Packman NA. Parotid and neck metastasis from cutaneous squamous cell carcinoma of the head and neck. Am J Surg 1995;170:446-50. 26. Joseph MG, Zuluetta WR, Kennedy PJ. Squamous cell carcinoma of the skin of the trunk and limbs: the incidence of metastasis and their outcome. Aust N Z J Surg 1992;62:697-701. 27. Cabanas R. An approach for the treatment of penile carcinoma. Cancer 1977;39:456-66. 28. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392-9. 29. Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391-401. 30. Hill ADK, Brady MS, Coit DG. Intraoperative lymphatic mapping and sentinel lymph node biopsy for Merkel cell carcinoma. Br J Surg 1999;86:518-21. 31. Ross MI, Reintgen DS, Balch CM. Selective lymphadenectomy: emerging role for lymphatic mapping and sentinel node biopsy in the management of early stage melanoma. Semin Surg Oncol 1993;9:219-23. 32. Reintgen D, Cruise CW, Wells K, Berman C, Fenske N, Glass F. The orderly progression of melanoma nodal metastases. Ann Surg 1994;220:759-67. 33. Turner RR, Ollila W, Krause DL, Giuliano A. Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg 1997;226:271-8. 34. Wells KE, Rapaport DP, Cruse CW, Payne W, Albertini J, Berman C, et al. Sentinel lymph node biopsy in melanoma of the head and neck. Plast Reconstr Surg 1997;3:591-4. 35. Norman J, Cruse CW, Espinosa C, Cox C, Berman C, Clark R, et al. Redefinition of cutaneous lymphatic drainage with the use of lymphoscintigraphy for malignant melanoma. Am J Surg 1991;162:432-7.
T
here are subgroups of cutaneous squamous cell carcinoma (SCC) that are at increased risk for metastasis. When cutaneous SCC does metastasize, it typically spreads to local nodal groups before distant metastasis occurs. Sentinel lymph node (SLN) localization has been successfully used to evaluate nodal metastasis in breast carcinoma, melanoma, and other select tumors. It is unknown From the Departments of Dermatologya and Surgery,b Weill Cornell Medical School. Accepted for publication Feb 11, 2000. Reprint requests: David S. Becker, MD, Department of Dermatology, Director, Dermatologic and Laser Surgery, Weill Cornell University Medical Center, F-343, New York, NY 10021. E-mail: [email protected]. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/106367 doi:10.1067/mjd.2000.106367
Abbreviations used: LND: SCC: SLN: XRT:
lymph node dissection squamous cell carcinoma sentinel lymph node x-ray therapy
whether SLN localization can be successfully used to screen the nodal basins in high-risk cutaneous SCCs. Currently, Mohs micrographic surgery is the treatment of choice for these tumors.
CASE REPORT The patient is a 73-year-old white man with a history of superficially invasive SCC of the forehead, which had been treated in November 1997 with electrodesiccation and curettage. He is otherwise in 483
484 Weisberg, Bertagnolli, and Becker
J AM ACAD DERMATOL SEPTEMBER 2000
Fig 1. Recurrent SCC of the forehead with clinically distinct inferomedial subcutaneous nodule of SCC.
Fig 2. Preoperative lymphoscintigraphy: Anteroposterior and left lateral static lymphoscintigrams of patient’s head showing 99mTc-radiolabeled sulfur colloid injection site (arrowhead) and left preauricular sentinel nodes (arrows).
good health with no history of radiation therapy to the head and neck or any known immunodeficiency. In May 1999 the patient presented with an illdefined, 6-cm firm tumor on the left side of his upper forehead with central ulceration (Fig 1). The tumor appeared clinically to be adherent to the underlying bone. Slightly inferomedial to this tumor and separated by 1 cm of clinically normal skin was an 8-mm subcutaneous nodule that was clinically suspect as a local metastasis. Biopsy findings of the larger tumor demonstrated poorly differentiated
invasive SCC, and a biopsy specimen of the small nodule revealed SCC invasive to at least 7.5 mm and not in continuity with the epidermis. Locally metastatic SCC could not be ruled out. Clinical examination did not reveal any preauricular, cervical, or submental lymphadenopathy. A computed tomographic scan of his head and neck to evaluate bony tumor invasion and regional metastasis was negative. Factors contributing to the especially high risk of nodal metastasis with this tumor included (1) recurrent tumor, (2) size larger than 2 cm, (3) depth of
Weisberg, Bertagnolli, and Becker 485
J AM ACAD DERMATOL VOLUME 43, NUMBER 3
Fig 3. Perineural invasion of squamous cell carcinoma on Mohs section. (Hematoxylin-eosin stain; original magnification ×20.)
invasion more than 4 mm, and (4) probable satellite cutaneous metastasis. Because of the high risk of this tumor in the setting of a neck with negative clinical and radiographic findings, SLN biopsy followed by Mohs micrographically controlled resection of the tumor was undertaken.
MATERIAL AND METHODS Preoperative lymphoscintigraphy. On the morning of SLN biopsy, 1 mCi filtered technetium 99m (99mTc)–radiolabeled sulfur colloid was injected intradermally at 4 sites around the tumor. Lymphoscintigraphy was performed with a standard largefield-of-view gamma camera immediately after injection to obtain dynamic flow and static images. Intraoperative lymphatic mapping. The patient was positioned, prepared, and draped under conscious sedation. An incision was made over the point of maximum signal; SLN biopsy was performed guided by the gamma probe (Capintec, Gammed IIb, Ramsey, NJ). Histologic examination of the lymph node. After formalin fixation, the SLN was serially sectioned at multiple levels and stained with hematoxylin and eosin. Immunohistochemistry with cytokeratins AE1 and AE3 was also performed. One 4-µm section for each stain was examined at each of the 3 different levels of the sentinel node. Excision of tumor. Extirpation of tumor was performed via the Mohs technique.1
RESULTS After injection of the 99mTc-radiolabeled sulfur colloid, the sentinel node was localized by anteroposterior and lateral images (Fig 2) to the left preauricular position and its position marked on the overlying skin. A second, smaller inferior node located on later images was not marked. A left preauricular incision was made and blunt dissection after the gamma probe signal performed. A single node containing the majority of the radio signal was localized and removed. Subsequent evaluation of the surgical bed with the gamma probe exhibited minimal residual radio signal. Pathologic evaluation of the SLN was negative for evidence of metastatic SCC by both hematoxylin and eosin and by immunohistochemical stains for cytokeratins AE1 and AE3. The day after SLN biopsy the patient returned for Mohs micrographic controlled excision of the tumor. The main tumor mass and the adjacent nodule of subcutaneous SCC were initially approached as two separate lesions. Histologically there was no tumor bridging these two lesions. However, given their close proximity, subsequent Mohs layers encompassed both of these lesions creating one surgical defect. Tumor extended to the periostium. Significant subclinical spread through both subcutaneous “skating” and perineural invasion (Fig 3) was noted, with tumor tracking along the supraorbital nerve and approaching but not entering the
486 Weisberg, Bertagnolli, and Becker
J AM ACAD DERMATOL SEPTEMBER 2000
Fig 4. Final surgical defect. Note extent of subclinical spread in clinically normal skin as well as far inferior extension of surgical defect approaching the supraorbital foramen.
supraorbital foramen. Further subclinical spread occurred inferolaterally towards the preauricular sentinel node. Clear surgical margins were obtained after a total of 8 stages (Fig 4). The surgical defect was temporally covered with a split-thickness skin graft, which will remain in place for at least 1 year as a “window” to monitor for local recurrence. Given the local aggressiveness of the tumor, postoperative radiation therapy to the surgical site is in progress. However, because of the negative status of the SLN, radiation therapy to the draining nodal basins is being deferred. Currently, at 3 months of follow-up, the patient has no clinical evidence of recurrence or metastasis.
DISCUSSION Many studies have attempted to identify factors predictive of locally aggressive biologic behavior and metastasis in cutaneous SCCs. The identification of high-risk patients at the earliest possible stage could facilitate the selection of appropriate therapeutic choices, potentially affecting the survival of this patient population. A meta-analysis on the prognosis of SCCs of the skin and lip since 1940 found that the following variables correlated with local recurrence and metastatic rates: treatment modality, recurrent tumor, tumor location, size (>2 cm), depth (>4 mm), poor histologic differentiation, histologic evidence of perineural involvement, precipitating factors other than ultraviolet light, and host immuno-
suppression.2 Some of these factors have been substantiated in subsequent studies.3-7 Defined subsets of cutaneous SCCs have a significant metastatic potential. The reported incidence of metastatic cutaneous SCC has varied widely depending on the study and its case selection, ranging from 0.5% to 14%.3-5,7-13 One subset, recurrent SCCs, has metastatic rates as high as 25% to 45% if re-treatment is by simple surgical excision.2 The treatment of choice for high-risk tumors is Mohs micrographic surgery.14-17 The majority of metastases of cutaneous SCCs are to the regional lymph nodes, including those within the parotid gland, whereas distant metastases are uncommon.4,7,10,18-24 Cure of such metastases might theoretically be achieved through clearing of these foci in the locoregional nodes. Unfortunately, not all metastases may be clinically apparent at initial presentation. For example, Jackson and Ballantyne21 in a study including 125 SCCs metastatic to the parotid gland noted a 24% incidence of occult metastases in clinically negative nodes. Once cutaneous SCC metastasizes, the treatment options include lymph node dissection (LND), radiation therapy (XRT), and chemotherapy. Studies done to evaluate the efficacy of these therapies in improving long-term survival in this patient group have failed to demonstrate statistically significant improvement with these therapies alone or in combination.6,7,25,26 Even though no prospective randomized study validating the role of combination
J AM ACAD DERMATOL VOLUME 43, NUMBER 3
therapy for metastatic cutaneous SCC exists, surgery and postoperative XRT remain the current standard of care. Survival in patients with regional lymph node metastasis from SCC of the skin remains poor. The 5-year survival for metastatic SCC has been reported as 26%.2 Kraus, Carew, and Harrison6 reported that the clinical stage of the regional metastasis was the only factor predictive of survival and that the identification of regional lymph node metastasis in high-risk patients at an earlier stage may be of benefit. However, in these studies most patients already had clinically and radiographically positive lymph nodes. Theoretically, there would be a survival benefit with removal of the subclinical micrometastases found by SLN biopsy. Palpable regional lymph nodes have often been used to determine whether any further therapy such as LND or XRT, or both, to the nodes was required.21 Elective LND is usually not done in the absence of clinical or radiologic evidence of regional metastatic spread. Consequently, there are few data to predict the number of patients who have subclinical nodal metastases at presentation. However, the study by Jackson and Ballantyne21 suggests that micrometastasis may be more common than expected. It would be optimal to be able to identify this subset of patients while minimizing the morbidities associated with complete LND. The sentinel node is defined as the first lymph node that receives lymph flow from a primary tumor. The histologic status of this node with regard to metastatic disease should theoretically represent the remaining nodes in that lymphatic basin, assuming that metastasis occurs in a systematic fashion. This concept was first described by Cabanas27 in 1977 for SCC of the penis. Morton et al28 popularized SLN biopsy for melanoma in the 1980s and Giuliano et al29 did the same for breast cancer in the mid 1990s. It has been shown that the histopathology of the sentinel node can predict the histology of the downstream nodes in melanoma, breast cancer, and Merkel cell carcinoma.30-34 That is, if the sentinel node is negative for metastatic disease, the downstream nodes will be negative as well. Despite its expanding use in melanoma, studies have not yet demonstrated any survival benefit to patients undergoing SLN biopsy. However, its use has gained favor as a highly accurate and minimally invasive staging technique for the identification of patients who might be candidates for more aggressive therapies. Theoretically, the sensitivity for discovering occult SCC in an SLN might be increased by staining nodal sections for the epithelial antigens AE1 and AE3. The histologic status of the SLN could be important for a variety of reasons: (1) It could assist in staging a
Weisberg, Bertagnolli, and Becker 487
patient, improving assessment of prognosis, and allowing for better stratification of patients for clinical trials; (2) it might identify which patients could benefit from therapeutic LND, XRT, or chemotherapy while minimizing morbidity for lower risk patients; and (3) the removal of clinically invisible micrometastasis may be of some therapeutic benefit in and of itself. The superficial lymphatic system of the head and neck region is marked by inconsistent and unpredictable drainage patterns. It has been previously demonstrated that without preoperative lymphoscintigraphy, elective LNDs may be misdirected in as many as 50% of cases. In melanoma of the head and neck region, lymphoscintigraphically mapped drainage patterns differ from those that would be expected on the basis of classic anatomic teaching by 63%.35 Preoperative lymphoscintigraphy may be utilized to more accurately identify all lymph basins at risk for metastasis, in-transit nodes outside the major lymphatic basins, the number of sentinel nodes, and specifically the location of the sentinel node(s) within the identified basins. The appropriate time to consider the use of lymphatic mapping should be before or simultaneous with the definitive surgical procedure to remove the tumor because surgery can alter lymphatic flow and potentially affect the accuracy of SLN biopsy. The efficacy of SLN for high-risk SCCs is unknown. Even in this patient, metastasis would be unlikely with only 3 months of follow-up, but would likely occur within 2 years.2 Consequently, close follow-up will be necessary to determine whether this procedure is predictive of regional lymph node metastasis in this patient. Currently, SLN for high-risk SCC has only theoretical utility and no benefit can be assured in determining the biologic potential of this individual SCC. Furthermore, no survival benefit for patients can be claimed, even if earlier identification of metastatic SCC is assumed. Adoption of this procedure for individual high-risk SCC should await appropriate clinical trials that demonstrate earlier identification of regional disease and/or an overall survival benefit to this procedure. Some have argued that adoption of SLN (with significant costs) for many melanomas outside the context of appropriately designed clinical trials has been premature. In summary, the combination of Mohs micrographic surgery and SLN is feasible. Optimal management of high-risk cutaneous SCCs involves maximizing the local clearance of the tumor and determining whether the tumor has already metastasized. Mohs surgery can optimize local tumor extirpation. In high-risk cutaneous SCCs with clinically negative nodes, SLN biopsy could theoretically provide useful insight into the
488 Weisberg, Bertagnolli, and Becker
presence of subclinical micrometastasis. Identification of these micrometastases could possibly be used to guide early interventions while the maximum potential gain from these therapies may exist. The expert technical assistance of Vijay Bridgemohansingh is gratefully acknowledged. REFERENCES 1. Cottel WI, Bailin PL, Albom MJ, Gernstein G, Braun M, Hanke CW, et al. Essential of Mohs micrographic surgery. J Dermatol Surg Oncol 1988;14:1:11-3. 2. 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: implications for treatment modality selection. J Am Acad Dermatol 1992;26:976-90. 3. Breuninger H, Schaumburg-Lever G, Holzschuh J. Desmoplastic squamous cell carcinoma of the skin and vermillion surface. Cancer 1997;79:915-9. 4. Dinehart SM, Pollack SV. Metastases from squamous cell carcinoma of the skin and lip: an analysis of twenty-seven cases. J Am Acad Dermatol 1989;21:241-8. 5. Haydon RC. Cutaneous squamous carcinoma and related lesions. Otolaryngol Clin North Am 1993;26:57-71. 6. Kraus DH, Carew JF, Harrison LB. Regional lymph node metastasis from cutaneous squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 1998;124:582-7. 7. Tavin E, Persky M. Metastatic cutaneous carcinoma: squamous cell carcinoma of the head and neck region. Laryngoscope 1996;106:156-8. 8. Brown RO, Osguthorpe JD. Management of the neck in nonmelanocytic cutaneous carcinomas. Otolaryngol Clin North Am 1998;31:841-56. 9. Chuang TY, Popescu NA, Su WD, Chute CG. Squamous cell carcinoma: a population-based incidence study in Rochester, Minn. Arch Dermatol 1990;126:185-8. 10. Epstein E, Epstein NN, Bragg K. Metastases from squamous cell carcinomas of the skin. Arch Dermatol 1968;97:245-51. 11. Levine HL, Ratz JL, Bailin P. Squamous cell carcinoma of the head and neck. Otolaryngol Clin North Am 1985;18:499-503. 12. Lund HZ. How often does squamous cell carcinoma of the skin metastasize? Arch Dermatol 1965;92:635-7. 13. Moller R, Reyman F, Hou-Jensen K. Metastases in dermatological patients with squamous cell carcinoma. Arch Dermatol 1979;115:703-5. 14. Fleming ID, Amonette R, Monaghan T, Fleming MD. Principles of management of basal and squamous cell carcinoma of the skin. Cancer 1995;75;2:699-704. 15. Mohs F, Larson P, Iriondo M. Micrographic surgery for the microscopically controlled excision of carcinoma of the external ear. J Am Acad Dermatol 1988;19:729-37. 16. Roenigk RK. Mohs micrographic surgery. Mayo Clin Proc 1988;63:175-83. 17. Tromovitch TA, Stegman SJ. Microscopic-controlled excision of cutaneous tumors: chemosurgery, fresh tissue technique. Cancer 1978;41:653-8.
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