Comment
However, they show the safety of adjuvant aromatase inhibitor treatment for women with osteopenia or osteoporosis, when used concomitantly with bisphosphonates, calcium, and vitamin D. MA.27B puts the onus of choosing between steroidal and nonsteroidal aromatase inhibitors back on the oncologist and empowered patients.
3
4
5
6
Aju Mathew, *Adam Brufsky Division of Hematology and Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15232, USA [email protected] We declare that we have no competing interests. 1
2
Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010; 28: 509–18. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007; 369: 559–70.
7
8 9
Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010; 11: 1135–41. Thurlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005; 353: 2747–57. Goss PE, Ingle JN, Pritchard KI, et al. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27—a randomized controlled phase III trial. J Clin Oncol 2013; 31: 1398–404. Goss PE, Hershman DL, Cheung AM, et al. Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial. Lancet Oncol 2014; published online March 11. http://dx.doi. org/10.1016/S1470-2045(14)70035-X. Goss PE, Hadji P, Subar M, Abreu P, Thomsen T, Banke-Bochita J. Effects of steroidal and nonsteroidal aromatase inhibitors on markers of bone turnover in healthy postmenopausal women. Breast Cancer Res 2007; 9: R52. Coleman RE, Marshall H, Cameron D, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 2011; 365: 1396–405. Valachis A, Polyzos NP, Coleman RE, et al. Adjuvant therapy with zoledronic acid in patients with breast cancer: a systematic review and meta-analysis. Oncologist 2013; 18: 353–61.
In The Lancet Oncology, Aimilios Lallas and colleagues1 investigated sentinel lymph node status and outcome in patients with atypical Spitz tumours. There is a consensus among experts who diagnose atypical Spitz tumours and those who treat these patients that sentinel lymph node status is neither prognostic nor diagnostic. Lallas and colleagues’ work disseminates this information more widely in the oncology literature. Atypical Spitz tumours commonly metastasise to regional lymph nodes; however, they are rarely associated with further clinical progression. The histopathological diagnosis of cutaneous melanocytic tumours is straightforward in most cases; however, in the realm of spindled and epithelioid cell neoplasms, some cases are particularly diagnostically challenging. Described by Sophie Spitz more than 65 years ago, even benign melanocytic tumours might resemble melanoma.2 Recent tumour classifications for this category of melanocytic proliferations range from the wholly benign spindled and epithelioid cell naevus (Spitz naevus), to atypical Spitz tumour (with an overall histopathological resemblance to Spitz naevus but a few atypical features), to spitzoid melanoma (sharing some features described by Spitz but also with characteristics meeting criteria for a diagnosis of melanoma).3,4 www.thelancet.com/oncology Vol 15 April 2014
Important work by many groups worldwide has shown that atypical Spitz tumour is associated with a fairly high rate of metastasis to sentinel lymph nodes, paradoxically without disease progression beyond the nodal basin.5,6 Over the past two decades, sentinel lymphadenectomy has become an established low morbidity staging procedure with possible therapeutic benefits for patients with cutaneous melanoma. It is important to distinguish the diagnostic, staging (prognostic), and therapeutic roles, if any, of sentinel lymph node sampling. For patients with atypical Spitz tumour, sentinel lymph node status was used in past years as a diagnostic remedy: if tumour cells were found in the lymph node, the ambiguous cutaneous spitzoid tumour was judged to be a melanoma. However, it is now clear that atypical Spitz tumours are associated with sentinel lymph node metastasis in more than 30% of cases, yet 5-year survival exceeds 99%.7 By contrast, about 15% of patients with melanoma undergoing sentinel lymphadenectomy have metastases; death within 5 years of diagnosis occurs in more than 20% of patients.8,9 Clearly, sentinel lymph node status is not useful in the diagnosis of melanocytic tumours; sentinel lymph node metastasis does not always indicate the
Dr P Marazzi/Science Photo Library
Atypical Spitz tumours and sentinel lymph nodes
See Review page e178
377
Comment
tumour is malignant melanoma. Likewise, sentinel lymphadenectomy is not useful for staging disease in the management of atypical Spitz tumours because metastases from these tumours are not prognostic. The results of Lallas and colleagues’ study establish that sentinel lymph node metastasis is not of diagnostic or prognostic significance in patients with atypical Spitz tumours. What has not been determined is the therapeutic usefulness, if any, of sentinel lymphadenectomy. This question is important because some investigators suggest that sentinel lymphadenectomy is an unnecessary test if there is no prognostic significance. Additionally, some would argue against sentinel lymphadenectomy since no action will be taken if there is a positive sentinel lymph node (completion lymphadenectomy and adjuvant therapy are no longer recommended in patients with atypical Spitz tumour and sentinel lymph node metastases). Continued use of sentinel lymphadenectomy in the setting of atypical Spitz tumour is supported by the hypothesis that removal of any lymph node harbouring metastatic disease is therapeutic and prolongs the disease-free interval. There is not enough data to prove or disprove this hypothesis; however, in the current study, six of 541 patients died from complications of metastatic disease and only one of these patients had been treated with sentinel lymphadenectomy. However, no patient had disease progression in a recent report of children with atypical Spitz tumours who were not treated with sentinel lymphadenectomy.10 Overall the small number of patients and absence of 20 years of follow-up in these studies does not support a specific conclusion; the possibility that sentinel lymphadenectomy is of therapeutic benefit in patients with atypical Spitz tumours remains. Interestingly, molecular staging of the primary tumour might have a role in atypical Spitz tumour. In a landmark study by Gerami and colleagues, a subset
of patients with atypical Spitz tumours was identified as having chromosomal copy number aberration and homozygous 9p21 deletions. In atypical Spitz tumours these specific molecular abnormalities in the primary cutaneous tumour correlate with progression beyond the sentinel lymph node.11 Although the presence of lymph node metastases is not a sign of poor prognosis in patients with atypical Spitz tumours, it is unknown whether removing these metastases is of therapeutic benefit. Ultimately, this might be an arena where molecular analysis provides the best staging data. Lyn McDivitt Duncan Pathology Service, Harvard Medical School, Dermatopathology Unit, Massachusetts General Hospital, Boston, MA, USA (LMD) [email protected] I declare that I have no competing interests. 1 2 3
4
5
6
7
8
9 10
11
Lallas A, Kyrgidis A, Ferrara G, et al. Atypical Spitz tumours and sentinel lymph node biopsy: a systematic review. Lancet Oncol 2014; 15: 178–83. Spitz S. Melanomas of childhood. Am J Pathol 1948; 24: 591–609. Barnhill RL. The Spitzoid lesion: rethinking Spitz tumors, atypical variants, ‘Spitzoid melanoma’ and risk assessment. Mod Pathol 2006; 19 (suppl 2): S21–33. Cerroni L, Barnhill R, Elder D, et al. Melanocytic tumors of uncertain malignant potential: results of a tutorial held at the XXIX Symposium of the International Society of Dermatopathology in Graz, October 2008. Am J Surg Pathol 2010; 34: 314–26. Hung T, Piris A, Lobo A, et al. Sentinel lymph node metastasis is not predictive of poor outcome in patients with problematic spitzoid melanocytic tumors. Hum Pathol 2013; 44: 87–94. Ludgate MW, Fullen DR, Lee J, et al. The atypical Spitz tumor of uncertain biologic potential: a series of 67 patients from a single institution. Cancer 2009; 115: 631–41. Gershenwald JE, Soong SJ, Balch CM, American Joint Committee on Cancer Melanoma Staging C. 2010 TNM staging system for cutaneous melanoma...and beyond. Ann Surg Oncol 2010; 17: 1475–77. Gershenwald JE, Andtbacka RH, Prieto VG, et al. Microscopic tumor burden in sentinel lymph nodes predicts synchronous nonsentinel lymph node involvement in patients with melanoma. J Clin Oncol 2008; 26: 4296–303. Gershenwald JE, Ross MI. Sentinel-lymph-node biopsy for cutaneous melanoma. N Engl J Med 2011; 364: 1738–45. Cerrato F, Wallins JS, Webb ML, McCarty ER, Schmidt BA, Labow BI. Outcomes in pediatric atypical spitz tumors treated without sentinel lymph node biopsy. Pediatr Dermatol 2012; 29: 448–53. Gerami P, Cooper C, Bajaj S, et al. Outcomes of atypical spitz tumors with chromosomal copy number aberrations and conventional melanomas in children. Am J Surg Pathol 2013; 37: 1387–94.
The need to expand global access to radiotherapy The escalating global tide of cancer cases and deaths, and the increasing burden of disease in low-income and middle-income countries (LMIC), is a major global health challenge. To respond to this challenge, in 2012 the World Oncology Forum endorsed an urgent plan 378
of action—to lessen cancer deaths by 25% by 2025, achieving a worldwide reduction of 1·5 million deaths from cancer per year.1 A comprehensive cancer management strategy is needed to achieve this target, especially in LMIC, and to www.thelancet.com/oncology Vol 15 April 2014
However, they show the safety of adjuvant aromatase inhibitor treatment for women with osteopenia or osteoporosis, when used concomitantly with bisphosphonates, calcium, and vitamin D. MA.27B puts the onus of choosing between steroidal and nonsteroidal aromatase inhibitors back on the oncologist and empowered patients.
3
4
5
6
Aju Mathew, *Adam Brufsky Division of Hematology and Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15232, USA [email protected] We declare that we have no competing interests. 1
2
Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010; 28: 509–18. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007; 369: 559–70.
7
8 9
Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010; 11: 1135–41. Thurlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005; 353: 2747–57. Goss PE, Ingle JN, Pritchard KI, et al. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27—a randomized controlled phase III trial. J Clin Oncol 2013; 31: 1398–404. Goss PE, Hershman DL, Cheung AM, et al. Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial. Lancet Oncol 2014; published online March 11. http://dx.doi. org/10.1016/S1470-2045(14)70035-X. Goss PE, Hadji P, Subar M, Abreu P, Thomsen T, Banke-Bochita J. Effects of steroidal and nonsteroidal aromatase inhibitors on markers of bone turnover in healthy postmenopausal women. Breast Cancer Res 2007; 9: R52. Coleman RE, Marshall H, Cameron D, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 2011; 365: 1396–405. Valachis A, Polyzos NP, Coleman RE, et al. Adjuvant therapy with zoledronic acid in patients with breast cancer: a systematic review and meta-analysis. Oncologist 2013; 18: 353–61.
In The Lancet Oncology, Aimilios Lallas and colleagues1 investigated sentinel lymph node status and outcome in patients with atypical Spitz tumours. There is a consensus among experts who diagnose atypical Spitz tumours and those who treat these patients that sentinel lymph node status is neither prognostic nor diagnostic. Lallas and colleagues’ work disseminates this information more widely in the oncology literature. Atypical Spitz tumours commonly metastasise to regional lymph nodes; however, they are rarely associated with further clinical progression. The histopathological diagnosis of cutaneous melanocytic tumours is straightforward in most cases; however, in the realm of spindled and epithelioid cell neoplasms, some cases are particularly diagnostically challenging. Described by Sophie Spitz more than 65 years ago, even benign melanocytic tumours might resemble melanoma.2 Recent tumour classifications for this category of melanocytic proliferations range from the wholly benign spindled and epithelioid cell naevus (Spitz naevus), to atypical Spitz tumour (with an overall histopathological resemblance to Spitz naevus but a few atypical features), to spitzoid melanoma (sharing some features described by Spitz but also with characteristics meeting criteria for a diagnosis of melanoma).3,4 www.thelancet.com/oncology Vol 15 April 2014
Important work by many groups worldwide has shown that atypical Spitz tumour is associated with a fairly high rate of metastasis to sentinel lymph nodes, paradoxically without disease progression beyond the nodal basin.5,6 Over the past two decades, sentinel lymphadenectomy has become an established low morbidity staging procedure with possible therapeutic benefits for patients with cutaneous melanoma. It is important to distinguish the diagnostic, staging (prognostic), and therapeutic roles, if any, of sentinel lymph node sampling. For patients with atypical Spitz tumour, sentinel lymph node status was used in past years as a diagnostic remedy: if tumour cells were found in the lymph node, the ambiguous cutaneous spitzoid tumour was judged to be a melanoma. However, it is now clear that atypical Spitz tumours are associated with sentinel lymph node metastasis in more than 30% of cases, yet 5-year survival exceeds 99%.7 By contrast, about 15% of patients with melanoma undergoing sentinel lymphadenectomy have metastases; death within 5 years of diagnosis occurs in more than 20% of patients.8,9 Clearly, sentinel lymph node status is not useful in the diagnosis of melanocytic tumours; sentinel lymph node metastasis does not always indicate the
Dr P Marazzi/Science Photo Library
Atypical Spitz tumours and sentinel lymph nodes
See Review page e178
377
Comment
tumour is malignant melanoma. Likewise, sentinel lymphadenectomy is not useful for staging disease in the management of atypical Spitz tumours because metastases from these tumours are not prognostic. The results of Lallas and colleagues’ study establish that sentinel lymph node metastasis is not of diagnostic or prognostic significance in patients with atypical Spitz tumours. What has not been determined is the therapeutic usefulness, if any, of sentinel lymphadenectomy. This question is important because some investigators suggest that sentinel lymphadenectomy is an unnecessary test if there is no prognostic significance. Additionally, some would argue against sentinel lymphadenectomy since no action will be taken if there is a positive sentinel lymph node (completion lymphadenectomy and adjuvant therapy are no longer recommended in patients with atypical Spitz tumour and sentinel lymph node metastases). Continued use of sentinel lymphadenectomy in the setting of atypical Spitz tumour is supported by the hypothesis that removal of any lymph node harbouring metastatic disease is therapeutic and prolongs the disease-free interval. There is not enough data to prove or disprove this hypothesis; however, in the current study, six of 541 patients died from complications of metastatic disease and only one of these patients had been treated with sentinel lymphadenectomy. However, no patient had disease progression in a recent report of children with atypical Spitz tumours who were not treated with sentinel lymphadenectomy.10 Overall the small number of patients and absence of 20 years of follow-up in these studies does not support a specific conclusion; the possibility that sentinel lymphadenectomy is of therapeutic benefit in patients with atypical Spitz tumours remains. Interestingly, molecular staging of the primary tumour might have a role in atypical Spitz tumour. In a landmark study by Gerami and colleagues, a subset
of patients with atypical Spitz tumours was identified as having chromosomal copy number aberration and homozygous 9p21 deletions. In atypical Spitz tumours these specific molecular abnormalities in the primary cutaneous tumour correlate with progression beyond the sentinel lymph node.11 Although the presence of lymph node metastases is not a sign of poor prognosis in patients with atypical Spitz tumours, it is unknown whether removing these metastases is of therapeutic benefit. Ultimately, this might be an arena where molecular analysis provides the best staging data. Lyn McDivitt Duncan Pathology Service, Harvard Medical School, Dermatopathology Unit, Massachusetts General Hospital, Boston, MA, USA (LMD) [email protected] I declare that I have no competing interests. 1 2 3
4
5
6
7
8
9 10
11
Lallas A, Kyrgidis A, Ferrara G, et al. Atypical Spitz tumours and sentinel lymph node biopsy: a systematic review. Lancet Oncol 2014; 15: 178–83. Spitz S. Melanomas of childhood. Am J Pathol 1948; 24: 591–609. Barnhill RL. The Spitzoid lesion: rethinking Spitz tumors, atypical variants, ‘Spitzoid melanoma’ and risk assessment. Mod Pathol 2006; 19 (suppl 2): S21–33. Cerroni L, Barnhill R, Elder D, et al. Melanocytic tumors of uncertain malignant potential: results of a tutorial held at the XXIX Symposium of the International Society of Dermatopathology in Graz, October 2008. Am J Surg Pathol 2010; 34: 314–26. Hung T, Piris A, Lobo A, et al. Sentinel lymph node metastasis is not predictive of poor outcome in patients with problematic spitzoid melanocytic tumors. Hum Pathol 2013; 44: 87–94. Ludgate MW, Fullen DR, Lee J, et al. The atypical Spitz tumor of uncertain biologic potential: a series of 67 patients from a single institution. Cancer 2009; 115: 631–41. Gershenwald JE, Soong SJ, Balch CM, American Joint Committee on Cancer Melanoma Staging C. 2010 TNM staging system for cutaneous melanoma...and beyond. Ann Surg Oncol 2010; 17: 1475–77. Gershenwald JE, Andtbacka RH, Prieto VG, et al. Microscopic tumor burden in sentinel lymph nodes predicts synchronous nonsentinel lymph node involvement in patients with melanoma. J Clin Oncol 2008; 26: 4296–303. Gershenwald JE, Ross MI. Sentinel-lymph-node biopsy for cutaneous melanoma. N Engl J Med 2011; 364: 1738–45. Cerrato F, Wallins JS, Webb ML, McCarty ER, Schmidt BA, Labow BI. Outcomes in pediatric atypical spitz tumors treated without sentinel lymph node biopsy. Pediatr Dermatol 2012; 29: 448–53. Gerami P, Cooper C, Bajaj S, et al. Outcomes of atypical spitz tumors with chromosomal copy number aberrations and conventional melanomas in children. Am J Surg Pathol 2013; 37: 1387–94.
The need to expand global access to radiotherapy The escalating global tide of cancer cases and deaths, and the increasing burden of disease in low-income and middle-income countries (LMIC), is a major global health challenge. To respond to this challenge, in 2012 the World Oncology Forum endorsed an urgent plan 378
of action—to lessen cancer deaths by 25% by 2025, achieving a worldwide reduction of 1·5 million deaths from cancer per year.1 A comprehensive cancer management strategy is needed to achieve this target, especially in LMIC, and to www.thelancet.com/oncology Vol 15 April 2014
