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Time to rethink TNM staging in cutaneous SCC
Reflection and Reaction
Time to rethink TNM staging in cutaneous SCC See Articles page 713
Non-melanoma skin cancer (NMSC) is the most common malignancy worldwide, with about 20% of NMSC classified as squamous-cell carcinoma (SCC). Most arise on the sun-exposed head and neck in older white men as a consequence of chronic, often occupational, sun exposure. In countries such as Australia, these cancers are at an epidemic rate and associated with morbidity and mortality. Although only a few (<5%) patients with cutaneous SCC will ever develop metastases, usually to regional lymph nodes, the absolute number of patients worldwide treated with a SCC makes this a major (and growing) publichealth issue. Patients developing nodal metastases need major surgery and adjuvant radiotherapy, and despite this treatment many (20–25%) will subsequently die from their disease.1 As such, identifying patients with high-risk SCC is important both for the management of these patients and also for future research. In the past, many putative variables have been suggested as being associated with the development of nodal metastases (panel).2 However, much of this evidence has been based on small retrospective series, and, to my knowledge, high-quality data from a large prospective cohort are not available. The current American Joint Committee on Cancer (AJCC)3 Tumour, Node, Metastasis (TNM) staging system for NMSC is flawed and inadequately prognosticates outcome for patients with a primary SCC4 and also those with metastatic nodal SCC.5 In patients with a primary SCC, and excluding those with stage T4 disease (extradermal invasion, such as muscle, bone or cartilage), the only variable deemed important in
Panel: Suggested high-risk factors for the development of nodal metastases* • • • • • • • • • •
Large size (>20 mm) Thick or deeply invasive lesion (>4–5 mm) Incomplete excision Recurrent setting High-grade or desmoplastic growth Presence of perineural invasion Presence of lymphovascular invasion Located near the parotid gland (eg, ear, temple, forehead, or anterior scalp) Immunosuppressed state (eg, transplant recipient or haematological malignancy) Rapid growth
*Patients often have many high-risk factors present
702
assigning T stage is horizontal dimension (T1 ≤20 mm, T2 >20 mm and ≤50 mm, and T3 >50 mm). Important other variables, such as tumour thickness, location, or immunosuppression, are not considered. In this issue of the The Lancet Oncology, Brantsch and colleagues6 present the findings of a large prospective study of 615 German patients diagnosed with cutaneous SCC and treated with three-dimensional excision (2–10mm excision margins). Only a few patients (31 of 615 [5%]) were immunosuppressed. With an adequate median follow-up of 43 months, the researchers report 26 of 615 (4%) patients developing nodal metastases with most (19 of 26 [73%]) occurring within the first 12 months. Local recurrence occurred in 20 of 615 (3%) patients and, of note, six of 20 (30%) of these patients also had concomitant nodal metastases. This latter point highlights the association between local recurrence and the high occurrence of nodal metastases, which is well documented in the published work.7 Thus, achieving local control after treatment, usually surgery, for any SCC is important. The study by Brantsch and colleagues6 builds on extensive previous work from these researchers, which suggests important pathological variables, such as tumour thickness and desmoplasia, are significantly associated with the development of nodal metastases from cutaneous SCC.8,9 Furthermore, recent evidence from an Australian study of 266 patients with metastatic cutaneous SCC of the head and neck, suggested that horizontal tumour dimension was not strongly associated with the development of nodal metastases.10 In this study, the median tumour size was only 15 mm (70% T1 lesions), but the median tumour thickness was 6 mm (65% ≥5 mm). There was a significant correlation between tumour thickness and size. Brantsch and colleagues6 report that tumour thickness greater than 6·0 mm is the only highly significant factor for metastases (p<0·0001) based on a Cox regression model of an internal validation sample of 415 patients. A total of 14 of 90 (16%) patients with tumours greater than 6·0 mm in thickness developed nodal metastases and no patient with a tumour 2·0 mm or less in thickness developed nodal metastases. Horizontal growth (T size) and tumour grade dropped out of the model. The researchers also noted a correlation between tumour thickness and size (p<0·0001). With regards to local recurrence, both tumour thickness greater www.thelancet.com/oncology Vol 9 August 2008
Reflection and Reaction
than 6·0 mm (p=0·0010) and desmoplastic growth (p<0·0001) predicted for recurrence. Desmoplastic growth was only seen in 51 of 615 (8%) patients and the findings of perineural invasion or perivascular invasion were always associated with desmoplasia. Brantsch and colleagues6 have therefore proposed a modified TNM staging system on the basis of their findings (T1 ≤2·0 mm thick, T2 2·1–6·0 mm thick, and T3 >6·0 mm thick). The presence of desmoplasia and immunosuppression will be denoted by adding “d” or ”i”. Despite their findings, they acknowledge the need for larger studies to validate their data. Even so, there is now compelling evidence that tumour thickness, and not horizontal size, as used in the AJCC TNM staging system, should be considered one of the most important variables for defining a patient with a high-risk cutaneous SCC. Other variables, such as location, immunosuppression, desmoplastic growth, and a recurrent primary, will all contribute to this risk. Future research aimed at better managing these high-risk patients seems the next logical step with regards to the role of sentinel-lymph-node biopsy, elective nodal treatment, or close observation and regular investigations.
Michael J Veness Westmead Hospital, University of Sydney, Sydney, NSW, Australia [email protected] The author declared no conflicts of interest. 1
2 3
4 5
6
7
8 9
10
Veness MJ, Porceddu S, Palme CE, Morgan GJ. Cutaneous head and neck squamous cell carcinoma metastatic to parotid and cervical lymph nodes. Head Neck 2007; 29: 621–31. Veness MJ. Defining patients with high-risk cutaneous squamous cell carcinoma. Australas J Dermatol 2006; 47: 28–33. Greene FL, Page ID, Fleming ID, et al, eds. AJCC cancer staging handbook: TNM classification of malignant tumours, 6th edn. New York, USA: Springer, 2002. Yoav PT. Problems in the current TNM staging of nonmelanoma skin cancer of the head and neck. Head Neck 2007; 29: 525–27. O’Brien CJ, McNeil EB, McMahon JD, Pathak I, Lauer CS, Jackson MA. Significance of clinical stage, extent of surgery and pathological findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head Neck 2002; 24: 417–22. Brantsch KD, Meisner C, Schönfisch B, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol 2008; 9: 713–20. Rowe DE, Carroll RJ, Day CL. 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. Breuninger H, Black B, Rassner G. Microstaging of squamous cell carcinomas. Am J Clin Pathol 1990; 94: 624–27. Breuninger H, Schaumburg-Lever G, Holzschuh J, Horny HP. Desmoplastic squamous cell carcinoma of the skin and vermilion surface: a highly malignant subtype of skin cancer. Cancer 1997; 79: 915–19. Veness MJ, Palme CE, Morgan GJ. High-risk cutaneous squamous cell carcinoma of the head and neck: results from 266 treated patients with metastatic lymph node disease. Cancer 2006; 106: 2389–96.
Income matters: reducing the mortality gap The My Child Matters programme is one of the most comprehensive, international cooperative projects related to paediatric oncology and represents an original alliance between industry, scientific institutions, and society. In this month’s issue of The Lancet Oncology, Ribeiro and colleagues1 present findings of a survey done in the ten countries where the first 14 approved field projects from the My Child Matters programme have been launched to provide essential information on the quality of the existing health-care delivery systems for children with cancer. Besides useful descriptive data, the report highlights the association between very low per capita investment in health and unfavourable prognosis for children with cancer, for whom in five out of the ten countries survival is estimated to be as low as 10% over 5 years. A careful assessment of the data and of the discussion informs the reader on paediatric cancer care worldwide, and highlights the complex challenge of putting the care of a numerically small population at www.thelancet.com/oncology Vol 9 August 2008
the centre of attention in countries where competing priorities for health investments are numerous and quantitatively more relevant. One of the more interesting contributions of the report is its focus on the importance of epidemiology as a way of highlighting the needs of the countries, not simply in terms of continents, but by concentrating the attention on the specific conditions of each country. Along the same lines, it is worth underlining that the paucity of reliable data has been considered positively by the authors as an impetus for developing strategies that involve supervisory staff recognising the issues and subsequently identifying the causes and possible solutions. The well-established strategies of twinning between advanced centres in high-income countries and those in low-income countries are appropriately deemed by stakeholders as a mandatory, and often effective, strategy, but only if they are one of several interventions, which should be the responsibility of
See Articles page 721
703
Time to rethink TNM staging in cutaneous SCC See Articles page 713
Non-melanoma skin cancer (NMSC) is the most common malignancy worldwide, with about 20% of NMSC classified as squamous-cell carcinoma (SCC). Most arise on the sun-exposed head and neck in older white men as a consequence of chronic, often occupational, sun exposure. In countries such as Australia, these cancers are at an epidemic rate and associated with morbidity and mortality. Although only a few (<5%) patients with cutaneous SCC will ever develop metastases, usually to regional lymph nodes, the absolute number of patients worldwide treated with a SCC makes this a major (and growing) publichealth issue. Patients developing nodal metastases need major surgery and adjuvant radiotherapy, and despite this treatment many (20–25%) will subsequently die from their disease.1 As such, identifying patients with high-risk SCC is important both for the management of these patients and also for future research. In the past, many putative variables have been suggested as being associated with the development of nodal metastases (panel).2 However, much of this evidence has been based on small retrospective series, and, to my knowledge, high-quality data from a large prospective cohort are not available. The current American Joint Committee on Cancer (AJCC)3 Tumour, Node, Metastasis (TNM) staging system for NMSC is flawed and inadequately prognosticates outcome for patients with a primary SCC4 and also those with metastatic nodal SCC.5 In patients with a primary SCC, and excluding those with stage T4 disease (extradermal invasion, such as muscle, bone or cartilage), the only variable deemed important in
Panel: Suggested high-risk factors for the development of nodal metastases* • • • • • • • • • •
Large size (>20 mm) Thick or deeply invasive lesion (>4–5 mm) Incomplete excision Recurrent setting High-grade or desmoplastic growth Presence of perineural invasion Presence of lymphovascular invasion Located near the parotid gland (eg, ear, temple, forehead, or anterior scalp) Immunosuppressed state (eg, transplant recipient or haematological malignancy) Rapid growth
*Patients often have many high-risk factors present
702
assigning T stage is horizontal dimension (T1 ≤20 mm, T2 >20 mm and ≤50 mm, and T3 >50 mm). Important other variables, such as tumour thickness, location, or immunosuppression, are not considered. In this issue of the The Lancet Oncology, Brantsch and colleagues6 present the findings of a large prospective study of 615 German patients diagnosed with cutaneous SCC and treated with three-dimensional excision (2–10mm excision margins). Only a few patients (31 of 615 [5%]) were immunosuppressed. With an adequate median follow-up of 43 months, the researchers report 26 of 615 (4%) patients developing nodal metastases with most (19 of 26 [73%]) occurring within the first 12 months. Local recurrence occurred in 20 of 615 (3%) patients and, of note, six of 20 (30%) of these patients also had concomitant nodal metastases. This latter point highlights the association between local recurrence and the high occurrence of nodal metastases, which is well documented in the published work.7 Thus, achieving local control after treatment, usually surgery, for any SCC is important. The study by Brantsch and colleagues6 builds on extensive previous work from these researchers, which suggests important pathological variables, such as tumour thickness and desmoplasia, are significantly associated with the development of nodal metastases from cutaneous SCC.8,9 Furthermore, recent evidence from an Australian study of 266 patients with metastatic cutaneous SCC of the head and neck, suggested that horizontal tumour dimension was not strongly associated with the development of nodal metastases.10 In this study, the median tumour size was only 15 mm (70% T1 lesions), but the median tumour thickness was 6 mm (65% ≥5 mm). There was a significant correlation between tumour thickness and size. Brantsch and colleagues6 report that tumour thickness greater than 6·0 mm is the only highly significant factor for metastases (p<0·0001) based on a Cox regression model of an internal validation sample of 415 patients. A total of 14 of 90 (16%) patients with tumours greater than 6·0 mm in thickness developed nodal metastases and no patient with a tumour 2·0 mm or less in thickness developed nodal metastases. Horizontal growth (T size) and tumour grade dropped out of the model. The researchers also noted a correlation between tumour thickness and size (p<0·0001). With regards to local recurrence, both tumour thickness greater www.thelancet.com/oncology Vol 9 August 2008
Reflection and Reaction
than 6·0 mm (p=0·0010) and desmoplastic growth (p<0·0001) predicted for recurrence. Desmoplastic growth was only seen in 51 of 615 (8%) patients and the findings of perineural invasion or perivascular invasion were always associated with desmoplasia. Brantsch and colleagues6 have therefore proposed a modified TNM staging system on the basis of their findings (T1 ≤2·0 mm thick, T2 2·1–6·0 mm thick, and T3 >6·0 mm thick). The presence of desmoplasia and immunosuppression will be denoted by adding “d” or ”i”. Despite their findings, they acknowledge the need for larger studies to validate their data. Even so, there is now compelling evidence that tumour thickness, and not horizontal size, as used in the AJCC TNM staging system, should be considered one of the most important variables for defining a patient with a high-risk cutaneous SCC. Other variables, such as location, immunosuppression, desmoplastic growth, and a recurrent primary, will all contribute to this risk. Future research aimed at better managing these high-risk patients seems the next logical step with regards to the role of sentinel-lymph-node biopsy, elective nodal treatment, or close observation and regular investigations.
Michael J Veness Westmead Hospital, University of Sydney, Sydney, NSW, Australia [email protected] The author declared no conflicts of interest. 1
2 3
4 5
6
7
8 9
10
Veness MJ, Porceddu S, Palme CE, Morgan GJ. Cutaneous head and neck squamous cell carcinoma metastatic to parotid and cervical lymph nodes. Head Neck 2007; 29: 621–31. Veness MJ. Defining patients with high-risk cutaneous squamous cell carcinoma. Australas J Dermatol 2006; 47: 28–33. Greene FL, Page ID, Fleming ID, et al, eds. AJCC cancer staging handbook: TNM classification of malignant tumours, 6th edn. New York, USA: Springer, 2002. Yoav PT. Problems in the current TNM staging of nonmelanoma skin cancer of the head and neck. Head Neck 2007; 29: 525–27. O’Brien CJ, McNeil EB, McMahon JD, Pathak I, Lauer CS, Jackson MA. Significance of clinical stage, extent of surgery and pathological findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head Neck 2002; 24: 417–22. Brantsch KD, Meisner C, Schönfisch B, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol 2008; 9: 713–20. Rowe DE, Carroll RJ, Day CL. 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. Breuninger H, Black B, Rassner G. Microstaging of squamous cell carcinomas. Am J Clin Pathol 1990; 94: 624–27. Breuninger H, Schaumburg-Lever G, Holzschuh J, Horny HP. Desmoplastic squamous cell carcinoma of the skin and vermilion surface: a highly malignant subtype of skin cancer. Cancer 1997; 79: 915–19. Veness MJ, Palme CE, Morgan GJ. High-risk cutaneous squamous cell carcinoma of the head and neck: results from 266 treated patients with metastatic lymph node disease. Cancer 2006; 106: 2389–96.
Income matters: reducing the mortality gap The My Child Matters programme is one of the most comprehensive, international cooperative projects related to paediatric oncology and represents an original alliance between industry, scientific institutions, and society. In this month’s issue of The Lancet Oncology, Ribeiro and colleagues1 present findings of a survey done in the ten countries where the first 14 approved field projects from the My Child Matters programme have been launched to provide essential information on the quality of the existing health-care delivery systems for children with cancer. Besides useful descriptive data, the report highlights the association between very low per capita investment in health and unfavourable prognosis for children with cancer, for whom in five out of the ten countries survival is estimated to be as low as 10% over 5 years. A careful assessment of the data and of the discussion informs the reader on paediatric cancer care worldwide, and highlights the complex challenge of putting the care of a numerically small population at www.thelancet.com/oncology Vol 9 August 2008
the centre of attention in countries where competing priorities for health investments are numerous and quantitatively more relevant. One of the more interesting contributions of the report is its focus on the importance of epidemiology as a way of highlighting the needs of the countries, not simply in terms of continents, but by concentrating the attention on the specific conditions of each country. Along the same lines, it is worth underlining that the paucity of reliable data has been considered positively by the authors as an impetus for developing strategies that involve supervisory staff recognising the issues and subsequently identifying the causes and possible solutions. The well-established strategies of twinning between advanced centres in high-income countries and those in low-income countries are appropriately deemed by stakeholders as a mandatory, and often effective, strategy, but only if they are one of several interventions, which should be the responsibility of
See Articles page 721
703