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Incisional biopsy and melanoma prognosis: Facts and controversies
Clinics in Dermatology (2010) 28, 316–318
Incisional biopsy and melanoma prognosis: Facts and controversies Annette Pflugfelder, MD, Benjamin Weide, MD, Thomas Kurt Eigentler, MD, Andrea Forschner, MD, Ulrike Leiter, MD, Laura Held, MD, Friedegund Meier, MD, Claus Garbe, MD ⁎ Center for Dermatooncology, Department of Dermatology, University Hospital Tübingen, Liebermeisterstr 25, 72076 Tübingen, Germany
Abstract Facing the increasing number of melanoma patients is the controversial question of whether an incisional biopsy is associated with an unfavorable patient prognosis. Results of nine studies that occurred during the last four decades were reviewed. One of these studies was a large, prospective randomized controlled trial. Evidence from this trial and from most other studies is that incisional biopsies were not associated with an unfavorable prognosis for melanoma patients. Incisional biopsies are currently recommended for the histopathologic diagnosis of large tumors in facial, mucosal, and acral locations. Complete excisional biopsies are the generally recommended standard for melanoma surgery. Incisional biopsies of malignant melanoma do not negatively influence prognosis. Complete excision of primary melanoma is still the recommended standard of care and is a precondition for accurate histopathologic diagnosis. © 2010 Elsevier Inc. All rights reserved.
Introduction Melanoma incidence is increasing worldwide in the last decades, but the mean tumor thickness is decreasing.1 It involves an increasing number of excisions of thin melanomas and simultaneously a high number of dysplastic nevi and other pigmented lesions suspicious of melanoma. This raises the question of whether time-consuming total excisions could be replaced in some cases by incisional biopsies, which are easier to handle and more cost-effective.
⁎ Corresponding author. Tel.: +49 7071 29 83768; fax: +49 7071 29 5187. E-mail address: [email protected] (C. Garbe). 0738-081X/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2009.06.013
A disadvantage of incisional biopsies is a less reliable histopathologic diagnosis,2 but another question is still of concern to physicians as well as patients and is still discussed worldwide: Will cutting into the tumor cause harm?
Type of biopsy and prognosis of melanoma Whether cutting into a tumor leads to an inferior prognosis for the patient has been debated for decades. A noli me tangere (“do not touch me”) strategy is still often considered as appropriate. Complete excisions are performed to obtain a better histologic result and are still preferred by some surgeons to avoid displacing tumor cells and possibly causing tumor seeding. There is still concern that incomplete
Incisional biopsy and melanoma prognosis Table 1
317
Recurrence and overall survival after excisional vs incisional biopsies
First author, year
8
Molenkamp, 2007 Martin,4 2005 Bong,5 2002 Austin,9 1996 Lees,6 1991 Lederman,3 1985 Griffiths,7 1985 Rampen,10 1980 Epstein,11 1969
Study design
Retrospective Prospective RCT Matched controls Retrospective Retrospective Prospective Retrospective Retrospective Retrospective
Evaluable patients
Biopsy type, No.
Recurrences, No. (%)
Overall survival, No. (%)
No.
EB/IB
EB
IB
EB
IB
471 1776 761 127 1086 472 258 76 193
388/83 1139/637 496/265 79/48 990/96 353/119 208/50 62/14 55/115
62 (16) 117 (10) 134 (27) … 82 (16) … 20 (10) … …
17 (21) 72 (11) 76 (30) … 13 (14) … 6 (12) … …
… … 403 (81) 63 (80) 617 (62) 310 (88) 126 (61) … 31 (56)
… … 213 (80) 27 (56) 52 (51) 98 (82) 28 (56) … 75 (65)
P
NS NS NS b.001 NS NS … .006 NS
EB, excisional biopsy; IB, incisional biopsy; NS, not significant; RCT, randomized controlled trial.
excisions or punch biopsies will harm patients, although several recent studies showed no negative influence on patient survival.3-8 We present and discuss nine of the studies in this field in the last four decades. An overview of the different studies is given in Table 1.3-11 One of the first studies regarding this topic was published in 1969.11 A total of 193 patients were recorded by the Californian Tumor Registry and were surgically treated between 1950 and 1954. Initial biopsies were performed in 115 patients, and 55 were radically excised. The 10-year overall survival was 65.4% in the biopsy group vs 55.8% for those with initially complete excision. Limitations of the study were lack of tumor thickness data because this prognostic variable was not yet known, although the diameter of the lesions was recorded.11 Other authors12 advised against incisional biopsies and hypothesized that tumor cells could be displaced to the deep dermis or the subcutaneous structures. This assumption was based on a small series of 76 patients in which a clearly negative effect on prognosis was demonstrated in the incisional group.12 Several later studies demonstrated no negative effect of incisional biopsies. A retrospective investigation 13 of 258 patients found no difference in survival rates if tumor thickness was balanced between the two groups. In a prospective study of 472 patients, 353 had total excisional biopsies and 119 had punch biopsies or partial excisions. All patients were grouped by four tumor thickness categories. Within these categories there was no significant survival difference between the incisional and the excisional group. Because the authors found no increased risk associated with incisional biopsies, they recommended incisional biopsies for large lesions or for lesions located in cosmetically sensitive areas.3 A large retrospective study in 1991 included 1086 patients. Of these, 990 received a complete excision, and 96 were initially treated with incisional biopsy. After stratification for age, gender, and tumor thickness, there was no difference in mortality rates during a 5-year period.6
In an analysis of 127 patients with melanoma of the head and neck region, the 48 patients in the incisional biopsy group had significantly reduced survival but no significant difference in regional recurrence.9 Because the skin in head and neck region has little subcutaneous fat, the authors postulated that cutting into the tumor could seed cells directly into the blood circulation, causing an increased risk for distant metastases and a worse overall survival in the biopsy group. An important fact in this study was that the patients in the incisional biopsy group were significantly older than in the excision group, and the median follow-up was only 36 months. A retrospective case-control study published in 2002 included 265 patients with incisional biopsy who were each matched against two excision patients, controlling for sex, age, site, and tumor thickness. This large, controlled study found no difference in survival between the groups.5 The largest study was a prospective randomized controlled trial in 2164 patients that was published in 2005. Differences were tested between complete surgical excision, incisional biopsy, and shave biopsy. No significant differences were observed in the incidence of sentinel lymph node metastases, locoregional recurrences, disease-free survival, distant disease-free survival, and overall survival.4 Another retrospective study, which was published 2007, investigated 471 patients. An interesting finding was even a slightly better overall survival and disease-free survival in patients with initially positive excision margins. The stimulation of the immune system through residual tumor cells was considered as possible explanation for this trend; however, the authors favored complete excisions for a better histopathologic diagnosis.8
Discussion Most retrospective and prospective studies did not show an influence on patient outcome after incisional or excisional biopsies. Limitations of the older studies were small numbers of patients and lack of control of well-established prognostic
318 factors such as tumor thickness, ulceration, localization, and age. Because recent large studies have not shown any significant difference in prognosis after different types of biopsies, there is currently no evidence that incisional biopsies could alter the clinical course or promote metastatic growth. The concept that mechanical manipulation, such as by fine needle puncture or by biopsies, could cause seeding of tumor cells is old and has been discussed in different types of cancer.14,15 The concern is that seeding of tumor cells could induce spread of metastases. In fear of displacing melanoma cells, for example, patients are often advised not to get manual lymphatic drainage of a benign lymphoedema.16 In contrast to this mechanical concept, there are considerations that molecular characteristics of tumor cells, including the presence of adhesion molecules, matrix metalloproteinases, and vascular growth factors, give the tumor cells the ability to migrate and induce vascularization. Only tumor cells that possess complete molecular equipment seem to be capable of initiating metastatic spread.17 As long as certain components of this molecular equipment are lacking, mechanical stimuli may not be sufficient to promote metastases.
Conclusions Incisional biopsies or incomplete primary excisions do not seem to influence patient prognosis in any way. Nevertheless, a complete primary excision of suspicious lesions should generally be performed to conserve the total architecture of the lesion whenever it is possible. This is a precondition to achieve an accurate histopathologic diagnosis comprising a proper evaluation of tumor thickness and ulceration. Some basic indications have been established for incisional biopsies of suspicious lesions. These are, in general, extensive pigmented lesions with unclear dignity, extensive facial lentigo maligna, pigmented lesions in acral regions, and pigmented lesions in mucosal areas.
A. Pflugfelder et al.
References 1. Lens MB, Dawes M. Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 2004; 150:179-85. 2. Karimipour DJ, Schwartz JL, Wang TS, et al. Microstaging accuracy after subtotal incisional biopsy of cutaneous melanoma. J Am Acad Dermatol 2005;52:798-802. 3. Lederman JS, Sober AJ. Does biopsy type influence survival in clinical stage I cutaneous melanoma? J Am Acad Dermatol 1985;13:983-7. 4. Martin RC, Scoggins CR, Ross MI, et al. Is incisional biopsy of melanoma harmful? Am J Surg 2005;190:913-7. 5. Bong JL, Herd RM, Hunter JA. Incisional biopsy and melanoma prognosis. J Am Acad Dermatol 2002;46:690-4. 6. Lees VC, Briggs JC. Effect of initial biopsy procedure on prognosis in stage 1 invasive cutaneous malignant melanoma: review of 1086 patients. Br J Surg 1991;78:1108-10. 7. Griffiths RW, Briggs JC. Biopsy procedures, primary wide excisional surgery and long term prognosis in primary clinical stage I invasive cutaneous malignant melanoma. Ann R Coll Surg Engl 1985;67:75-8. 8. Molenkamp BG, Sluijter BJ, Oosterhof B, Meijer S, van Leeuwen PA. Non-radical diagnostic biopsies do not negatively influence melanoma patient survival. Ann Surg Oncol 2007;14:1424-30. 9. Austin JR, Byers RM, Brown WD, Wolf P. Influence of biopsy on the prognosis of cutaneous melanoma of the head and neck. Head Neck 1996;18:107-17. 10. Rampen FH, van Houten WA, Jop WC. Incisional procedures and prognosis in malignant melanoma. Clin Exp Dermatol 1980;5:313-20. 11. Epstein E, Bragg K, Linden G. Biopsy and prognosis of malignant melanoma. JAMA 1969;208:1369-71. 12. Rampen FH, van der Esch EP. Biopsy and survival of malignant melanoma. J Am Acad Dermatol 1985;12:385-8. 13. Griffiths RW, Briggs JC. Biopsy procedures, primary wide excisional surgery and long term prognosis in primary clinical stage I invasive cutaneous malignant melanoma. Ann R Coll Surg Engl 1986;68:58. 14. Fentiman IS, Millis RR, Chaudary MA, King RJ, Miller KJ, Hayward JL. Effect of the method of biopsy on the prognosis of and reliability of receptor assays in patients with operable breast cancer. Br J Surg 1986; 73:610-2. 15. Davies HE, Musk AW, Lee YC. Prophylactic radiotherapy for pleural puncture sites in mesothelioma: the controversy continues. Curr Opin Pulm Med 2008;14:326-30. 16. Godette K, Mondry TE, Johnstone PA. Can manual treatment of lymphedema promote metastasis? J Soc Integr Oncol 2006;4:8-12. 17. Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature 2001;411:342-8.
Incisional biopsy and melanoma prognosis: Facts and controversies Annette Pflugfelder, MD, Benjamin Weide, MD, Thomas Kurt Eigentler, MD, Andrea Forschner, MD, Ulrike Leiter, MD, Laura Held, MD, Friedegund Meier, MD, Claus Garbe, MD ⁎ Center for Dermatooncology, Department of Dermatology, University Hospital Tübingen, Liebermeisterstr 25, 72076 Tübingen, Germany
Abstract Facing the increasing number of melanoma patients is the controversial question of whether an incisional biopsy is associated with an unfavorable patient prognosis. Results of nine studies that occurred during the last four decades were reviewed. One of these studies was a large, prospective randomized controlled trial. Evidence from this trial and from most other studies is that incisional biopsies were not associated with an unfavorable prognosis for melanoma patients. Incisional biopsies are currently recommended for the histopathologic diagnosis of large tumors in facial, mucosal, and acral locations. Complete excisional biopsies are the generally recommended standard for melanoma surgery. Incisional biopsies of malignant melanoma do not negatively influence prognosis. Complete excision of primary melanoma is still the recommended standard of care and is a precondition for accurate histopathologic diagnosis. © 2010 Elsevier Inc. All rights reserved.
Introduction Melanoma incidence is increasing worldwide in the last decades, but the mean tumor thickness is decreasing.1 It involves an increasing number of excisions of thin melanomas and simultaneously a high number of dysplastic nevi and other pigmented lesions suspicious of melanoma. This raises the question of whether time-consuming total excisions could be replaced in some cases by incisional biopsies, which are easier to handle and more cost-effective.
⁎ Corresponding author. Tel.: +49 7071 29 83768; fax: +49 7071 29 5187. E-mail address: [email protected] (C. Garbe). 0738-081X/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2009.06.013
A disadvantage of incisional biopsies is a less reliable histopathologic diagnosis,2 but another question is still of concern to physicians as well as patients and is still discussed worldwide: Will cutting into the tumor cause harm?
Type of biopsy and prognosis of melanoma Whether cutting into a tumor leads to an inferior prognosis for the patient has been debated for decades. A noli me tangere (“do not touch me”) strategy is still often considered as appropriate. Complete excisions are performed to obtain a better histologic result and are still preferred by some surgeons to avoid displacing tumor cells and possibly causing tumor seeding. There is still concern that incomplete
Incisional biopsy and melanoma prognosis Table 1
317
Recurrence and overall survival after excisional vs incisional biopsies
First author, year
8
Molenkamp, 2007 Martin,4 2005 Bong,5 2002 Austin,9 1996 Lees,6 1991 Lederman,3 1985 Griffiths,7 1985 Rampen,10 1980 Epstein,11 1969
Study design
Retrospective Prospective RCT Matched controls Retrospective Retrospective Prospective Retrospective Retrospective Retrospective
Evaluable patients
Biopsy type, No.
Recurrences, No. (%)
Overall survival, No. (%)
No.
EB/IB
EB
IB
EB
IB
471 1776 761 127 1086 472 258 76 193
388/83 1139/637 496/265 79/48 990/96 353/119 208/50 62/14 55/115
62 (16) 117 (10) 134 (27) … 82 (16) … 20 (10) … …
17 (21) 72 (11) 76 (30) … 13 (14) … 6 (12) … …
… … 403 (81) 63 (80) 617 (62) 310 (88) 126 (61) … 31 (56)
… … 213 (80) 27 (56) 52 (51) 98 (82) 28 (56) … 75 (65)
P
NS NS NS b.001 NS NS … .006 NS
EB, excisional biopsy; IB, incisional biopsy; NS, not significant; RCT, randomized controlled trial.
excisions or punch biopsies will harm patients, although several recent studies showed no negative influence on patient survival.3-8 We present and discuss nine of the studies in this field in the last four decades. An overview of the different studies is given in Table 1.3-11 One of the first studies regarding this topic was published in 1969.11 A total of 193 patients were recorded by the Californian Tumor Registry and were surgically treated between 1950 and 1954. Initial biopsies were performed in 115 patients, and 55 were radically excised. The 10-year overall survival was 65.4% in the biopsy group vs 55.8% for those with initially complete excision. Limitations of the study were lack of tumor thickness data because this prognostic variable was not yet known, although the diameter of the lesions was recorded.11 Other authors12 advised against incisional biopsies and hypothesized that tumor cells could be displaced to the deep dermis or the subcutaneous structures. This assumption was based on a small series of 76 patients in which a clearly negative effect on prognosis was demonstrated in the incisional group.12 Several later studies demonstrated no negative effect of incisional biopsies. A retrospective investigation 13 of 258 patients found no difference in survival rates if tumor thickness was balanced between the two groups. In a prospective study of 472 patients, 353 had total excisional biopsies and 119 had punch biopsies or partial excisions. All patients were grouped by four tumor thickness categories. Within these categories there was no significant survival difference between the incisional and the excisional group. Because the authors found no increased risk associated with incisional biopsies, they recommended incisional biopsies for large lesions or for lesions located in cosmetically sensitive areas.3 A large retrospective study in 1991 included 1086 patients. Of these, 990 received a complete excision, and 96 were initially treated with incisional biopsy. After stratification for age, gender, and tumor thickness, there was no difference in mortality rates during a 5-year period.6
In an analysis of 127 patients with melanoma of the head and neck region, the 48 patients in the incisional biopsy group had significantly reduced survival but no significant difference in regional recurrence.9 Because the skin in head and neck region has little subcutaneous fat, the authors postulated that cutting into the tumor could seed cells directly into the blood circulation, causing an increased risk for distant metastases and a worse overall survival in the biopsy group. An important fact in this study was that the patients in the incisional biopsy group were significantly older than in the excision group, and the median follow-up was only 36 months. A retrospective case-control study published in 2002 included 265 patients with incisional biopsy who were each matched against two excision patients, controlling for sex, age, site, and tumor thickness. This large, controlled study found no difference in survival between the groups.5 The largest study was a prospective randomized controlled trial in 2164 patients that was published in 2005. Differences were tested between complete surgical excision, incisional biopsy, and shave biopsy. No significant differences were observed in the incidence of sentinel lymph node metastases, locoregional recurrences, disease-free survival, distant disease-free survival, and overall survival.4 Another retrospective study, which was published 2007, investigated 471 patients. An interesting finding was even a slightly better overall survival and disease-free survival in patients with initially positive excision margins. The stimulation of the immune system through residual tumor cells was considered as possible explanation for this trend; however, the authors favored complete excisions for a better histopathologic diagnosis.8
Discussion Most retrospective and prospective studies did not show an influence on patient outcome after incisional or excisional biopsies. Limitations of the older studies were small numbers of patients and lack of control of well-established prognostic
318 factors such as tumor thickness, ulceration, localization, and age. Because recent large studies have not shown any significant difference in prognosis after different types of biopsies, there is currently no evidence that incisional biopsies could alter the clinical course or promote metastatic growth. The concept that mechanical manipulation, such as by fine needle puncture or by biopsies, could cause seeding of tumor cells is old and has been discussed in different types of cancer.14,15 The concern is that seeding of tumor cells could induce spread of metastases. In fear of displacing melanoma cells, for example, patients are often advised not to get manual lymphatic drainage of a benign lymphoedema.16 In contrast to this mechanical concept, there are considerations that molecular characteristics of tumor cells, including the presence of adhesion molecules, matrix metalloproteinases, and vascular growth factors, give the tumor cells the ability to migrate and induce vascularization. Only tumor cells that possess complete molecular equipment seem to be capable of initiating metastatic spread.17 As long as certain components of this molecular equipment are lacking, mechanical stimuli may not be sufficient to promote metastases.
Conclusions Incisional biopsies or incomplete primary excisions do not seem to influence patient prognosis in any way. Nevertheless, a complete primary excision of suspicious lesions should generally be performed to conserve the total architecture of the lesion whenever it is possible. This is a precondition to achieve an accurate histopathologic diagnosis comprising a proper evaluation of tumor thickness and ulceration. Some basic indications have been established for incisional biopsies of suspicious lesions. These are, in general, extensive pigmented lesions with unclear dignity, extensive facial lentigo maligna, pigmented lesions in acral regions, and pigmented lesions in mucosal areas.
A. Pflugfelder et al.
References 1. Lens MB, Dawes M. Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 2004; 150:179-85. 2. Karimipour DJ, Schwartz JL, Wang TS, et al. Microstaging accuracy after subtotal incisional biopsy of cutaneous melanoma. J Am Acad Dermatol 2005;52:798-802. 3. Lederman JS, Sober AJ. Does biopsy type influence survival in clinical stage I cutaneous melanoma? J Am Acad Dermatol 1985;13:983-7. 4. Martin RC, Scoggins CR, Ross MI, et al. Is incisional biopsy of melanoma harmful? Am J Surg 2005;190:913-7. 5. Bong JL, Herd RM, Hunter JA. Incisional biopsy and melanoma prognosis. J Am Acad Dermatol 2002;46:690-4. 6. Lees VC, Briggs JC. Effect of initial biopsy procedure on prognosis in stage 1 invasive cutaneous malignant melanoma: review of 1086 patients. Br J Surg 1991;78:1108-10. 7. Griffiths RW, Briggs JC. Biopsy procedures, primary wide excisional surgery and long term prognosis in primary clinical stage I invasive cutaneous malignant melanoma. Ann R Coll Surg Engl 1985;67:75-8. 8. Molenkamp BG, Sluijter BJ, Oosterhof B, Meijer S, van Leeuwen PA. Non-radical diagnostic biopsies do not negatively influence melanoma patient survival. Ann Surg Oncol 2007;14:1424-30. 9. Austin JR, Byers RM, Brown WD, Wolf P. Influence of biopsy on the prognosis of cutaneous melanoma of the head and neck. Head Neck 1996;18:107-17. 10. Rampen FH, van Houten WA, Jop WC. Incisional procedures and prognosis in malignant melanoma. Clin Exp Dermatol 1980;5:313-20. 11. Epstein E, Bragg K, Linden G. Biopsy and prognosis of malignant melanoma. JAMA 1969;208:1369-71. 12. Rampen FH, van der Esch EP. Biopsy and survival of malignant melanoma. J Am Acad Dermatol 1985;12:385-8. 13. Griffiths RW, Briggs JC. Biopsy procedures, primary wide excisional surgery and long term prognosis in primary clinical stage I invasive cutaneous malignant melanoma. Ann R Coll Surg Engl 1986;68:58. 14. Fentiman IS, Millis RR, Chaudary MA, King RJ, Miller KJ, Hayward JL. Effect of the method of biopsy on the prognosis of and reliability of receptor assays in patients with operable breast cancer. Br J Surg 1986; 73:610-2. 15. Davies HE, Musk AW, Lee YC. Prophylactic radiotherapy for pleural puncture sites in mesothelioma: the controversy continues. Curr Opin Pulm Med 2008;14:326-30. 16. Godette K, Mondry TE, Johnstone PA. Can manual treatment of lymphedema promote metastasis? J Soc Integr Oncol 2006;4:8-12. 17. Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature 2001;411:342-8.