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Sentinel lymph node biopsy for patients with melanoma—introductory comments
Seminars in Diagnostic Pathology (2008) 25, 83-85
Sentinel lymph node biopsy for patients with melanoma—introductory comments Sentinel lymph node (SLN) mapping and biopsy has become “standard of practice” at the majority of cancer centers for patients diagnosed with cutaneous melanoma, if the histologic features of the patient’s tumor meet eligibility criteria. In the words of John Thompson, SLN biopsy “has taken the surgical world by storm over the past decade.”1 It has become an integral part of patient care guidelines issued by the National Comprehensive Cancer Network (www.nccn.org) and other health information resources consulted by patients, such as the Skin Cancer Foundation (www.skincancer.org). Once patient learn about these guidelines, they tend to expect and even request the procedure. SLN biopsy has its strong advocates but also vocal opponents. Advocates emphasize the superior staging and prognostication.2,3 Critics view the procedure as an unnecessary expense and/or source of iatrogenic morbidity,4-6 given the fact that it has not been found to improve overall survival, at least not in the majority of node-negative patients.2 Although improved prognostic information is desirable, concerns about cost versus benefit of expensive tests can appropriately be raised, when resources are limited and patients and society may benefit more convincingly by other health care investments. Even critics, however, generally accept a valuable role of the procedure for patients entering clinical trials.6 This issue of Seminars in Diagnostic Pathology attempts to address key issues related to the procedure. Drs. Aryian and Coit review the clinical aspects, including the historical development of the technique. They emphasize its role as staging procedure for prognostication. Drs. Kayton and La Quaglia review the role of the procedure for pediatric patients. Since diagnostically ambiguous Spitzoid melanocytic proliferation tend to occur in this patient population, they also discuss the role of SLN biopsy in the management of patients with such diagnostically controversial tumors. Drs. Scolyer and colleagues from the Sydney Melanoma Unit describe the pathologic work-up of a node. Dr. Prieto addresses the problems related to frozen sections analysis. Drs. Brennick and Yan point out possible false-positive results, and Dr. Jungbluth reviews the reagents currently used in the 0740-2570/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2008.04.003
analysis of sentinel lymph node. The contributors’ time and effort is greatly appreciated. There are many additional aspects, both clinically and histologically, that one may wish to discuss in more detail. To address some of the issues at least briefly and also as a way to highlight key points discussed by various contributors, I will raise and comment on 5 common questions about SLN biopsy for melanoma (or suspected melanoma). What is the role of SLN biopsy for patients with primary cutaneous melanoma? Its clinical role in the care of cancer patients is that of a staging procedure.1-3 The histologically confirmed status of the sentinel node provides prognostically valuable information superior to other currently available tests. Prognostic information is valuable to the individual patients to assess their risk for recurrence. It is critical for clinical trial design: patients entering treatment protocols need to be stratified into different risk groups so that any potential beneficial effects by the treatment modality can be distinguished from the natural course of the disease. Does the removal of the SLN biopsy have therapeutic value? There is no therapeutic benefit for the majority of patients with a negative sentinel node.2 There is data to suggest improved relapse-free survival as well as improved regional control in patients with a positive SN and subsequent node dissection.1,2,7 However, overall melanoma survival of the majority of patients does not appear to be improved by the removal of the SLN.2 Should SLN be applied to patients with diagnostically ambiguous melanocytic tumors? Kelley and Cockerell proposed in 2001 that sentinel node biopsy may be used for patients with diagnostically controversial melanocytic tumors.8 The proposal implied that patients would be offered the same management as if they had
84
Figure 1 Intranodal melanocytic nevus cell aggregate found incidentally in an axillary lymph node of a patient with mammary carcinoma and no history of melanoma.
melanoma, thereby avoiding “undertreatment.” This rationale has been embraced by many surgeons and cancer centers,9-13 but there are problems with this approach. First, the procedure does not represent therapy: it is a staging tool. Furthermore, there is a risk for applying it too indiscriminately. A surgeon may decide to go ahead with the SLN biopsy whenever a pathologist expresses a lack of confidence and claims that “melanoma cannot be excluded.” It is our opinion that SLN biopsy should only be considered for the staging of a patient, if the primary tumor has been judged as melanoma or at least “highly suspicious” for melanoma by several experts. SLN biopsy is not a substitute for thorough diagnostic workup.9 If the histology of a tumor is ambiguous and experts cannot reach a consensus, it is best to analyze tumor tissue first through ancillary studies, such as comparative genomic hybridization,14,15 whenever possible and not to embark too quickly on a management pathway as if a patient had indeed malignant melanoma.
Seminars in Diagnostic Pathology, Vol 25, No 2, May 2008 tumor, which metastasized to a regional node and later to other sites was, at least in retrospect, anything other than a malignant melanoma. However, not all melanocytes found in a node are malignant, and the presence of melanocytes in lymph nodes does not always prove that an unusual cutaneous melanocytic tumor is a bona-fide malignant melanoma.18-20 There is precedent from other cell types that the spread of benign tissue to lymph nodes and other sites can occur with no adverse clinical consequences (eg, mesothelial cells in lymph node,21 benign metastasizing leiomyomas22). Although pathologists can readily recognize classic appearances of nodal nevi characterized by cytologically bland melanocytes restricted to the fibrous tissue of the nodal capsule and fibrous trabeculae, intraparenchymal nodal nevomelanocytes can on occasion be found (Figures 1 and 2).23 Such a finding may be confused with metastatic melanoma and potentially lead to diagnostic errors of both the node and the tumor on the skin draining to the node.
How extensively should a SLN node be studied? If a pathology laboratory receives a SLN from a patient with melanoma, a decision needs to be made how to process the tissue. Dr. Scolyer and colleagues superbly discuss this issue. I address this question separately, because we are commonly asked about Memorial Sloan-Kettering’s protocol for the workup of SLNs. It is very similar to the protocol used at the Sydney Melanoma Unit except that we use the antibody A103 (to detect Melan-A) instead of HMB-45, since in our hands this antibody has shown better sensitivity for the detection of intranodal melanocytes than HMB-45. We first examine one hematoxylin and eosin (H&E)stained section taken from the inner face of a bivalved node. If metastatic melanoma is found, no further workup is done. If no tumor is seen, five additional sections are taken at defined intervals (for S-100P, H&E, A103, H&E, negative control). Like pathologists at the Sydney Melanoma Unit,
Can the results of a sentinel node be used to reinterpret a diagnostically ambiguous primary tumor? The proposal to offer SLN biopsy to patients with diagnostically ambiguous melanocytic tumors implied also a potential diagnostic benefit.8 If metastatic melanoma was found, the malignant nature of the primary tumor would be confirmed thereby ending any diagnostic controversy.8,16 This underlying rationale “that a melanocytic neoplasm that metastasizes is a melanoma”17 is intuitive. It is a sound argument, if the melanocytes in the node are unequivocally malignant (eg, bulky tumor deposit of melanocytes with enlarged nuclei with prominent nucleoli, mitotic figures and necrosis). We and others have witnessed unfortunate events of misdiagnosed primary tumors (reported, for example as “Spitz nevus,” with or without atypia) with subsequent lymph node metastases and death. In those cases, it makes no sense to deny that an “atypical” primary melanocytic
Figure 2 Intranodal melanocytic nevus cells highlighted by an immunostain for Melan-A, incidentally found in an axillary node of a patient with mammary carcinoma and no history of melanoma.
Busam
SLN-Introductory Comments
85
we have decided against more extensive cutting protocols as practiced or advocated by others24,25 for practical, economical, and medical reasons. As pointed out by Dr. Scolyer, it is impractical to extensively step section SLNs, and it is unlikely that there is any medical benefit from detecting additional cases of rare isolated immunopositive cells in SLNs. Some have suggested to abandon immunohistochemistry altogether and to examine nodes only by H&E.26 This may work well in the majority of SLNs. However, immunostains clearly facilitate detection of small metastatic disease volume. They allow faster detection and make it less likely to miss small tumor deposits.24 Klaus J. Busam, MD Guest Editor
References 1. Thompson JF, Stretch JR, Uren RF, et al: Sentinel node biopsy for melanoma: Where have we been and where are we going? Ann Surg Oncol 11:147S-151S, 2004 2. Morton DL, Thompson JF, Cochran AJ, et al: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 255:1307-1317, 2006 3. Johnson TM, Sondak VK, Bichakjian CK, et al: The role of sentinel lymph node biopsy for melanoma: Evidence assessment. J Am Acad Dermatol 54:19-27, 2006 4. Medalie N, Ackerman AB: Sentinel node biopsy has no benefit for patients whose primary cutaneous melanoma has metastasized to a lymph node and therefore should be abandoned now. Br J Dermatol 151:298-307, 2004 5. Wick MR, Patterson JW: Sentinel lymph node biopsies for cutaneous melanoma. Am J Surg Pathol 29:412-414, 2005 (review) 6. Thomas JM, Patocskai EJ: The argument against sentinel node biopsy for malignant melanoma. BMJ 321:3-4, 2000 7. Sabel MS, Griffith KA, Arora A, et al: Inguinal node dissection for melanoma in the era of sentinel lymph node biopsy. Surgery 141:728735, 2007 8. Kelley SW, Cockerell CJ: Sentinel lymph node biopsy as an adjunct to management of histologically difficult to diagnose melanocytic lesions: A proposal. J Am Acad Dermatol 42:527-530, 2000 9. Lohmann CM, Coit DG, Brady MS, et al: Sentinel lymph node biopsy in patients with diagnostically controversial Spitzoid melanocytic tumors. Am J Surg Pathol 26:47-55, 2002
10. Su LD, Fullen DR, Sondak VK, et al: Sentinel lymph node biopsy for patients with problematic Spitzoid melanocytic lesions: A report on 18 patients. Cancer 97:499-507, 2003 11. Gamblin TC, Edington H, Kirkwood JM, et al: Sentinel lymph node biopsy for atypical melanocytic lesions with Spitzoid features. Ann Surg Oncol 13:1664-1670, 2006 12. Urso C, Borgognoni L, Saieva C, et al: Sentinel lymph node biopsy in patients with “atypical Spitz tumors.” A report on 12 cases. Hum Pathol 37:816-823, 2006 13. Murali R, Sharma RN, Thompson JF, et al: Sentinel lymph node biopsy in histologically ambiguous melanocytic tumors with Spitzoid features (so-called atypical Spitzoid tumors). Ann Surg Oncol 15:302309, 2008 14. Bastian BC, LeBoit PE, Pinkel D: Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol 157:967-972, 2000 15. Bastian BC, Wesselman U, Pinkel D, et al: Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma. J Invest Dermatol 113:1065-1069, 1999 16. Zuckerman R, Maier JP, Guiney WB Jr, et al: Pediatric melanoma: Confirming the diagnosis with sentinel lymph node biopsy. Ann Plast Surg 46:394-399, 2001 17. Mones JM, Ackerman AB: “Atypical” Spitz’s nevus, “malignant” Spitz’s nevus, and “metastasizing” Spitz’s nevus: A critique in historical perspective of three concepts flawed fatally. Am J Dermatopathol 26:310-333, 2004 18. LeBoit PE: What do these cells prove? Am J Dermatopathol 25:255256, 2003 19. Wick M: Melanocytic lesions with features of Spitz nevus. Hum Pathol 37:779-780, 2006 20. Mooi WJ, Krausz T: Spitz nevus versus Spitzoid melanoma. Diagnostic difficulties, conceptual controversies. Adv Anat Pathol 13:147-156, 2006 21. Parkash V, Vidwans M, Carter D: benign mesothelial cells in mediastinal lymph nodes. Am J Surg Pathol 23:1264-1269, 1999 22. Nucci MR, Drapkin R, Cin PD, et al: Distinctive cytogenetic profile in benign metastasizing leiomyoma: pathogenetic implications. Am J Surg Pathol 31:737-743, 2007 23. Biddle DA, Evans HL, Kemp BL, et al: Intraparenchymal nevus cell aggregates in lymph nodes: A possible diagnostic pitfall with malignant melanoma and carcinoma. Am J Surg Pathol 27:673-681, 2003 24. Yu LL, Flotte TJ, Tanabe KK, et al: Detection of microscopic melanoma metastases in sentinel lymph nodes. Cancer 86:617-627, 1999 25. Spanknebel K, Coit DG, Bieligk SC, et al: Characterization of micrometastatic disease in melanoma sentinel lymph nodes by enhanced pathology: Recommendations for standardizing pathologic analysis. Am J Surg Pathol 29:305-317, 2005 26. Wick MR, Patterson JW: Sentinel lymph node biopsies for cutaneous melanoma. Am J Surg Pathol 29(3):412-4, 2005 Mar Review
Sentinel lymph node biopsy for patients with melanoma—introductory comments Sentinel lymph node (SLN) mapping and biopsy has become “standard of practice” at the majority of cancer centers for patients diagnosed with cutaneous melanoma, if the histologic features of the patient’s tumor meet eligibility criteria. In the words of John Thompson, SLN biopsy “has taken the surgical world by storm over the past decade.”1 It has become an integral part of patient care guidelines issued by the National Comprehensive Cancer Network (www.nccn.org) and other health information resources consulted by patients, such as the Skin Cancer Foundation (www.skincancer.org). Once patient learn about these guidelines, they tend to expect and even request the procedure. SLN biopsy has its strong advocates but also vocal opponents. Advocates emphasize the superior staging and prognostication.2,3 Critics view the procedure as an unnecessary expense and/or source of iatrogenic morbidity,4-6 given the fact that it has not been found to improve overall survival, at least not in the majority of node-negative patients.2 Although improved prognostic information is desirable, concerns about cost versus benefit of expensive tests can appropriately be raised, when resources are limited and patients and society may benefit more convincingly by other health care investments. Even critics, however, generally accept a valuable role of the procedure for patients entering clinical trials.6 This issue of Seminars in Diagnostic Pathology attempts to address key issues related to the procedure. Drs. Aryian and Coit review the clinical aspects, including the historical development of the technique. They emphasize its role as staging procedure for prognostication. Drs. Kayton and La Quaglia review the role of the procedure for pediatric patients. Since diagnostically ambiguous Spitzoid melanocytic proliferation tend to occur in this patient population, they also discuss the role of SLN biopsy in the management of patients with such diagnostically controversial tumors. Drs. Scolyer and colleagues from the Sydney Melanoma Unit describe the pathologic work-up of a node. Dr. Prieto addresses the problems related to frozen sections analysis. Drs. Brennick and Yan point out possible false-positive results, and Dr. Jungbluth reviews the reagents currently used in the 0740-2570/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2008.04.003
analysis of sentinel lymph node. The contributors’ time and effort is greatly appreciated. There are many additional aspects, both clinically and histologically, that one may wish to discuss in more detail. To address some of the issues at least briefly and also as a way to highlight key points discussed by various contributors, I will raise and comment on 5 common questions about SLN biopsy for melanoma (or suspected melanoma). What is the role of SLN biopsy for patients with primary cutaneous melanoma? Its clinical role in the care of cancer patients is that of a staging procedure.1-3 The histologically confirmed status of the sentinel node provides prognostically valuable information superior to other currently available tests. Prognostic information is valuable to the individual patients to assess their risk for recurrence. It is critical for clinical trial design: patients entering treatment protocols need to be stratified into different risk groups so that any potential beneficial effects by the treatment modality can be distinguished from the natural course of the disease. Does the removal of the SLN biopsy have therapeutic value? There is no therapeutic benefit for the majority of patients with a negative sentinel node.2 There is data to suggest improved relapse-free survival as well as improved regional control in patients with a positive SN and subsequent node dissection.1,2,7 However, overall melanoma survival of the majority of patients does not appear to be improved by the removal of the SLN.2 Should SLN be applied to patients with diagnostically ambiguous melanocytic tumors? Kelley and Cockerell proposed in 2001 that sentinel node biopsy may be used for patients with diagnostically controversial melanocytic tumors.8 The proposal implied that patients would be offered the same management as if they had
84
Figure 1 Intranodal melanocytic nevus cell aggregate found incidentally in an axillary lymph node of a patient with mammary carcinoma and no history of melanoma.
melanoma, thereby avoiding “undertreatment.” This rationale has been embraced by many surgeons and cancer centers,9-13 but there are problems with this approach. First, the procedure does not represent therapy: it is a staging tool. Furthermore, there is a risk for applying it too indiscriminately. A surgeon may decide to go ahead with the SLN biopsy whenever a pathologist expresses a lack of confidence and claims that “melanoma cannot be excluded.” It is our opinion that SLN biopsy should only be considered for the staging of a patient, if the primary tumor has been judged as melanoma or at least “highly suspicious” for melanoma by several experts. SLN biopsy is not a substitute for thorough diagnostic workup.9 If the histology of a tumor is ambiguous and experts cannot reach a consensus, it is best to analyze tumor tissue first through ancillary studies, such as comparative genomic hybridization,14,15 whenever possible and not to embark too quickly on a management pathway as if a patient had indeed malignant melanoma.
Seminars in Diagnostic Pathology, Vol 25, No 2, May 2008 tumor, which metastasized to a regional node and later to other sites was, at least in retrospect, anything other than a malignant melanoma. However, not all melanocytes found in a node are malignant, and the presence of melanocytes in lymph nodes does not always prove that an unusual cutaneous melanocytic tumor is a bona-fide malignant melanoma.18-20 There is precedent from other cell types that the spread of benign tissue to lymph nodes and other sites can occur with no adverse clinical consequences (eg, mesothelial cells in lymph node,21 benign metastasizing leiomyomas22). Although pathologists can readily recognize classic appearances of nodal nevi characterized by cytologically bland melanocytes restricted to the fibrous tissue of the nodal capsule and fibrous trabeculae, intraparenchymal nodal nevomelanocytes can on occasion be found (Figures 1 and 2).23 Such a finding may be confused with metastatic melanoma and potentially lead to diagnostic errors of both the node and the tumor on the skin draining to the node.
How extensively should a SLN node be studied? If a pathology laboratory receives a SLN from a patient with melanoma, a decision needs to be made how to process the tissue. Dr. Scolyer and colleagues superbly discuss this issue. I address this question separately, because we are commonly asked about Memorial Sloan-Kettering’s protocol for the workup of SLNs. It is very similar to the protocol used at the Sydney Melanoma Unit except that we use the antibody A103 (to detect Melan-A) instead of HMB-45, since in our hands this antibody has shown better sensitivity for the detection of intranodal melanocytes than HMB-45. We first examine one hematoxylin and eosin (H&E)stained section taken from the inner face of a bivalved node. If metastatic melanoma is found, no further workup is done. If no tumor is seen, five additional sections are taken at defined intervals (for S-100P, H&E, A103, H&E, negative control). Like pathologists at the Sydney Melanoma Unit,
Can the results of a sentinel node be used to reinterpret a diagnostically ambiguous primary tumor? The proposal to offer SLN biopsy to patients with diagnostically ambiguous melanocytic tumors implied also a potential diagnostic benefit.8 If metastatic melanoma was found, the malignant nature of the primary tumor would be confirmed thereby ending any diagnostic controversy.8,16 This underlying rationale “that a melanocytic neoplasm that metastasizes is a melanoma”17 is intuitive. It is a sound argument, if the melanocytes in the node are unequivocally malignant (eg, bulky tumor deposit of melanocytes with enlarged nuclei with prominent nucleoli, mitotic figures and necrosis). We and others have witnessed unfortunate events of misdiagnosed primary tumors (reported, for example as “Spitz nevus,” with or without atypia) with subsequent lymph node metastases and death. In those cases, it makes no sense to deny that an “atypical” primary melanocytic
Figure 2 Intranodal melanocytic nevus cells highlighted by an immunostain for Melan-A, incidentally found in an axillary node of a patient with mammary carcinoma and no history of melanoma.
Busam
SLN-Introductory Comments
85
we have decided against more extensive cutting protocols as practiced or advocated by others24,25 for practical, economical, and medical reasons. As pointed out by Dr. Scolyer, it is impractical to extensively step section SLNs, and it is unlikely that there is any medical benefit from detecting additional cases of rare isolated immunopositive cells in SLNs. Some have suggested to abandon immunohistochemistry altogether and to examine nodes only by H&E.26 This may work well in the majority of SLNs. However, immunostains clearly facilitate detection of small metastatic disease volume. They allow faster detection and make it less likely to miss small tumor deposits.24 Klaus J. Busam, MD Guest Editor
References 1. Thompson JF, Stretch JR, Uren RF, et al: Sentinel node biopsy for melanoma: Where have we been and where are we going? Ann Surg Oncol 11:147S-151S, 2004 2. Morton DL, Thompson JF, Cochran AJ, et al: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 255:1307-1317, 2006 3. Johnson TM, Sondak VK, Bichakjian CK, et al: The role of sentinel lymph node biopsy for melanoma: Evidence assessment. J Am Acad Dermatol 54:19-27, 2006 4. Medalie N, Ackerman AB: Sentinel node biopsy has no benefit for patients whose primary cutaneous melanoma has metastasized to a lymph node and therefore should be abandoned now. Br J Dermatol 151:298-307, 2004 5. Wick MR, Patterson JW: Sentinel lymph node biopsies for cutaneous melanoma. Am J Surg Pathol 29:412-414, 2005 (review) 6. Thomas JM, Patocskai EJ: The argument against sentinel node biopsy for malignant melanoma. BMJ 321:3-4, 2000 7. Sabel MS, Griffith KA, Arora A, et al: Inguinal node dissection for melanoma in the era of sentinel lymph node biopsy. Surgery 141:728735, 2007 8. Kelley SW, Cockerell CJ: Sentinel lymph node biopsy as an adjunct to management of histologically difficult to diagnose melanocytic lesions: A proposal. J Am Acad Dermatol 42:527-530, 2000 9. Lohmann CM, Coit DG, Brady MS, et al: Sentinel lymph node biopsy in patients with diagnostically controversial Spitzoid melanocytic tumors. Am J Surg Pathol 26:47-55, 2002
10. Su LD, Fullen DR, Sondak VK, et al: Sentinel lymph node biopsy for patients with problematic Spitzoid melanocytic lesions: A report on 18 patients. Cancer 97:499-507, 2003 11. Gamblin TC, Edington H, Kirkwood JM, et al: Sentinel lymph node biopsy for atypical melanocytic lesions with Spitzoid features. Ann Surg Oncol 13:1664-1670, 2006 12. Urso C, Borgognoni L, Saieva C, et al: Sentinel lymph node biopsy in patients with “atypical Spitz tumors.” A report on 12 cases. Hum Pathol 37:816-823, 2006 13. Murali R, Sharma RN, Thompson JF, et al: Sentinel lymph node biopsy in histologically ambiguous melanocytic tumors with Spitzoid features (so-called atypical Spitzoid tumors). Ann Surg Oncol 15:302309, 2008 14. Bastian BC, LeBoit PE, Pinkel D: Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol 157:967-972, 2000 15. Bastian BC, Wesselman U, Pinkel D, et al: Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma. J Invest Dermatol 113:1065-1069, 1999 16. Zuckerman R, Maier JP, Guiney WB Jr, et al: Pediatric melanoma: Confirming the diagnosis with sentinel lymph node biopsy. Ann Plast Surg 46:394-399, 2001 17. Mones JM, Ackerman AB: “Atypical” Spitz’s nevus, “malignant” Spitz’s nevus, and “metastasizing” Spitz’s nevus: A critique in historical perspective of three concepts flawed fatally. Am J Dermatopathol 26:310-333, 2004 18. LeBoit PE: What do these cells prove? Am J Dermatopathol 25:255256, 2003 19. Wick M: Melanocytic lesions with features of Spitz nevus. Hum Pathol 37:779-780, 2006 20. Mooi WJ, Krausz T: Spitz nevus versus Spitzoid melanoma. Diagnostic difficulties, conceptual controversies. Adv Anat Pathol 13:147-156, 2006 21. Parkash V, Vidwans M, Carter D: benign mesothelial cells in mediastinal lymph nodes. Am J Surg Pathol 23:1264-1269, 1999 22. Nucci MR, Drapkin R, Cin PD, et al: Distinctive cytogenetic profile in benign metastasizing leiomyoma: pathogenetic implications. Am J Surg Pathol 31:737-743, 2007 23. Biddle DA, Evans HL, Kemp BL, et al: Intraparenchymal nevus cell aggregates in lymph nodes: A possible diagnostic pitfall with malignant melanoma and carcinoma. Am J Surg Pathol 27:673-681, 2003 24. Yu LL, Flotte TJ, Tanabe KK, et al: Detection of microscopic melanoma metastases in sentinel lymph nodes. Cancer 86:617-627, 1999 25. Spanknebel K, Coit DG, Bieligk SC, et al: Characterization of micrometastatic disease in melanoma sentinel lymph nodes by enhanced pathology: Recommendations for standardizing pathologic analysis. Am J Surg Pathol 29:305-317, 2005 26. Wick MR, Patterson JW: Sentinel lymph node biopsies for cutaneous melanoma. Am J Surg Pathol 29(3):412-4, 2005 Mar Review