ORIGINAL RESEARCH. Chance Matthiesen & Spencer Thompson & Salahuddin Ahmad & Elizabeth Syzek & Daniel Zhao & Terence Herman & Carl Bogardus

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1 J Radiat Oncol (2013) 2:79 85 DOI /s ORIGINAL RESEARCH A comparison of the sixth and seventh editions of the AJCC TNM systems for T classification and predicting the outcomes of advanced (T2 T4) non-melanoma skin cancers treated with radiotherapy Chance Matthiesen & Spencer Thompson & Salahuddin Ahmad & Elizabeth Syzek & Daniel Zhao & Terence Herman & Carl Bogardus Received: 23 May 2012 / Accepted: 12 September 2012 / Published online: 6 December 2012 # Springer-Verlag Berlin Heidelberg 2012 Abstract Objectives In 2009, the AJCC released the seventh edition staging manual. We aimed to retrospectively apply this updated staging criteria to a cohort of previously treated NMSC treated with radiation therapy (RT) and compare outcomes between the two editions in regard to T classification. Methods Seventy-two lesions were identified. By the sixth edition, there were 38 T2 (52.7 %), 16 T3 (22.2 %), and 18 T4 lesions (25.0 %). We restaged the 72 lesions according to the seventh edition criteria and applied an analysis to determine outcome changes as related to stage. Results Twenty-nine lesions (40.3 %) had their tumor category restaged. Thirteen (72.2 %) of 18 T4 and all (100 %) T3 lesions were downstaged. Cumulatively, there are now 65 T2 (90.3 %), 2 T3 (2.8 %), and 5 T4 lesions (6.9 %). These restaged lesions showed changes in CR and DFS following RT for T2 (84.2 and 93.1 % to 87.7 and 92.2 %, p<0.0001), T3 (81.3 and 85.7 % to 0 and 0 %, p<0.0001), and T4 lesions (66.7 and 72.2 % to 40.0 and 40.0 %, p<0.0001). Conclusions The AJCC seventh edition potentially results in a poorer outcome prediction in advanced lesions treated with radiation therapy. The elimination of size and the requirement of specific bone invasion location as a staging C. Matthiesen (*) : S. Thompson : S. Ahmad : E. Syzek : T. Herman : C. Bogardus Stephenson Oklahoma Cancer Center, Department of Radiation Oncology, University of Oklahoma Health Sciences Center, 800 N.E. 10th Street, OKCC L100, Oklahoma City, OK 73104, USA chance-matthiesen@ouhsc.edu D. Zhao Department of Biostatistics and Epidemiology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma, USA criterion have substantially changed the staging pattern and outcome analysis. Keywords Non-melanoma skin cancer. American Joint Committee on Cancer Staging System. AJCC. Radiation therapy Introduction Staging plays an integral and pivotal role in the treatment decision process of cancer. Cancer staging provides a benchmark for patients and physicians for defining prognosis and determining the most appropriate treatment algorithm, modality, and approach [1]. The American Joint Committee on Cancer (AJCC) staging manual has been an accepted and established reference for primary tumor, regional, and systemic disease staging. In 2009, the AJCC released its revised seventh edition, which included staging revisions for several malignancies including non-melanoma skin cancer (NMSC) when compared with the prior AJCC sixth edition [2]. The AJCC sixth and seventh edition versions for the staging of NMSC are shown in Tables 1 and 2. NMSC is the most common of all cancers, with over one million cases diagnosed and treated annually [3]. Basal cell carcinoma (BCC) accounts for approximately 80 % of NMSC, with the remainder predominantly squamous cell carcinoma (SCC) [4]. Most patients diagnosed with NMSC are treated at an early tumor stage (T1N0M0) with great success. Large and locally advanced (T2 T4) NMSC lesions however often present a treatment challenge depending upon the lesion location, size, depth of invasion, histology, and patient characteristics.

2 80 J Radiat Oncol (2013) 2:79 85 Table 1 AJCC sixth edition staging manual for non-melanoma skin cancer Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor 2 cm in greatest dimension T2 Tumor >2 cm but not <5 cm in greatest dimension T3 Tumor >5 cm in greatest dimension T4 Tumor invades deep extradermal structures (i.e., bone, muscle, and cartilage) Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis In a prior report, we reviewed and analyzed our experiences treating T2 T4 NMSC according to the AJCC sixth edition with radiotherapy (RT) [5]. Given the revised changes from the previous AJCC sixth edition to the updated seventh edition staging manual, we proposed to apply the updated version to our previous report regarding the use of RT for large and locally advanced (T2 T4) NMSC. We aimed to evaluate how these changes in staging criteria would affect these lesions in regard to T classification and outcome. Methods After approval from our Institutional Review Board (IRB), we retrospectively reviewed the records of 70 nonconsecutive and selected stage T2 T4 NMSC patients treated in our clinic with RT from 2004 to NMSC patients not receiving RT were excluded. Eighty-five lesions were identified that were staged T2 T4 according to the AJCC sixth edition staging criteria. A complete and detailed report regarding these 70 patient and 85 lesion characteristics, research methodology, RT techniques, RT dose ranges, and post RT treatment outcomes been previously reported [5]. In this previous analysis, we identified 56 previously untreated lesions, 17 recurrent, and 12 post-operative lesions [5]. In this subsequent investigation, our aim was to evaluate the staging changes following the application of the AJCC seventh edition criteria and the ensuing outcome differences between the staging systems. Patients and lesions which were previously untreated or recurrent were included, but post-operative lesions were excluded in this analysis to be Table 2 AJCC seventh edition staging manual for non-melanoma skin cancer Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor 2 cm or less in greatest dimension with less than 2 high-risk features** T2 Tumor >2 cm in greatest dimension or tumor of any size with two or more high-risk features* T3 Tumor with invasion of the maxilla, mandible, orbit, or temporal bone T4 Tumor with invasion of the skeleton (axial or appendicular) or perineural invasion of skull base Excludes NMSC of the eyelid* High risk features** Depth/invasion >2 mm thickness Clark level IV Perineural invasion Anatomic Primary site ear Location Primary site non-hair-bearing lip Differentiation Poorly differentiated or undifferentiated Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but <6 cm in dimension N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N3 Metastasis in a lymph node, more than 6 cm in greatest dimension Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis more consistent with previous reports [6 9]. One untreated T2 lesion and patient from our previous analysis was excluded because further data acquisition revealed that the lesion was a post-operative lesion misclassified at treatment presentation. Patient and lesion characteristics from our previous investigation which were used as the cohort for this comparative analysis included 72 total NMSC lesions in 58 patients staged according to the AJCC sixth edition for primary T classification. The results of this staging criteria resulted in 38 T2 lesions (52.8 %), 16 T3 lesions (22.2 %), and 18 T4

3 J Radiat Oncol (2013) 2: lesions (25.0 %). These lesions were categorized separately into previously untreated (n055) and recurrent (n017) lesions. Histologies included 34 SCC (47.2 %) and 38 BCC (52.8 %). The skin of the head and neck was the most commonly involved site of disease origination in 84.7 % of all lesions. Nine lesions had nodal metastasis at presentation, and nine lesions had bone involvement. Patients included nine female and 49 male patients, with a median age of 72 years (range years). RT techniques for treatment included electron therapy (n048, 66.7 %), 3D conformal photons (n09, 12.5 %), and intensity modulated radiation therapy (IMRT) (n015, 20.8 %). Three previously untreated T4 lesions received chemotherapy: two (one BCC and one SCC) concurrently and one (SCC) following RT completion. We then utilized this collected cohort of patients described above and retrospectively restaged the primary tumor T classification of the 72 lesions according to the AJCC seventh edition staging criteria shown in Table 2. We subsequently applied the same analysis as described in our previous report [5] regarding tumor T classification to determine outcomes following RT in regard to the achievement of complete response (CR), partial response (PR), local recurrence (LR), and disease free survival (DFS). A CR was defined as a complete resolution of disease determined clinically and/or radiographically at RT completion. A PR is defined as a clinical and/or radiographic determination of residual tumor at RT completion. A LR is defined as a clinically or radiographically detected tumor after radiotherapy completion and initial achievement of CR. Statistical analysis was performed using Chi-square comparison methods. Results The outcomes in this second analysis following the restaging of the lesions and the results following the completion RT were of interest. Figure 1 illustrates the cumulative changes resulting in this lesion cohort when staged according to the two AJCC staging editions. Patients had a median follow-up of 20.0 months (range 2 52 months). After restaging, the 72 lesions according to the AJCC seventh edition staging criteria, 29 lesions (40.3 %) had their primary tumor stage re-classified. All 29 lesions were subsequently downstaged, no upstaging occurred. To be more specific regarding these restaging outcomes, no T2 lesion was restaged. However, of the initial 18 T4 lesions, 13 (72.2 %) were downstaged. Eleven of these 13 T4 lesions (84.6 %) were downstaged to T2, and two (15.4 %) were downstaged to T3. Of the initial sixteen T3 lesions, all (100 %) were downstaged to T2. Therefore, following restaging according to the AJCC seventh edition criteria, Fig. 1 Lesion classifications by primary tumor T classification according to the AJCC sixth and seventh edition manuals there are cumulatively now 65 T2 lesions (90.3 %), two T3 lesions (2.8 %), and five T4 lesions (6.9 %). The results following restaging and outcomes analysis for this cohort of now AJCC seventh edition staged lesions with respect to achievement CR following RT and patient DFS are shown in Table 3. These results more thoroughly discussed below according to T classification category. T2 lesions By AJCC sixth edition criteria, there were 38 T2 lesions in 29 patients. Our data following RT completion showed an initial achievement of a CR in 32 lesions (84.2 %). One lesion (2.6 %) achieved a PR. Three lesions (7.9 %) experienced a LR following RT. All three recurrences were managed surgically and no evidence of disease was ultimately achieved. Two patients

4 82 J Radiat Oncol (2013) 2:79 85 Table 3 Summary of lesion category changes between the AJCC sixth and seventh editions, and the subsequent changes to achievement of complete response (CR) and disease free survival (DFS) Number of lesions Achievement of CR % DFS % P value< AJCC sixth edition lesion T T T AJCC seventh edition lesion T T T experienced systemic progression. DFS by the AJCC sixth edition for these T2 patients was 93.1 %. Following restaging according to the AJCC seventh edition, there are now 65 T2 lesions in 51 patients. This resulted in an increase of approximately 60.0 % in T2 lesions when compared to the staging results according to the AJCC sixth edition criteria. Following the same analysis as above, an overall lesion achievement of CR now occurred in 57 lesions (87.7 %). A PR resulted in three lesions (4.6 %), and ten lesions experienced a LR (15.4 %). DFS for these patients is now 92.2 %. T3 lesions There were 16 T3 lesions in 14 patients according to the AJCC sixth edition staging criteria. Thirteen (81.3 %) of these AJCC sixth edition lesions achieved a CR. Three LRs (18.8 %) occurred at follow-up. DFS for this patient group was 85.7 %. Following restaging of these lesions according to the AJCC seventh edition criteria, there were now only two T3 lesions. There was no achievement of CR following RT in these two patients. Both patients lesions experienced a PR and subsequently progressed locally and systemically. Both patients ultimately died as a result of disease progression. T4 lesions There were 18 T4 lesions in 18 patients according to the AJCC sixth edition criteria. Achievement of CR was in 12 lesions (66.7 %), a PR occurred in six lesions (33.3 %), and four LR (22.2 %) occurred at follow-up. All PR lesions progressed. DFS for this group was 72.2 %. Following AJCC seventh edition restaging of these lesions, there are now five T4 lesions in five patients. Overall achievement of CR was in two lesions (40.0 %) and a PR in three lesions (60.0 %). DFS was reduced in these patients to 40.0 %. Discussion In this report, we compare the application of the AJCC seventh edition NMSC modifications to a cohort of patients and lesions previously analyzed according the AJCC sixth edition. The purpose of this review is to ascertain if these updated seventh edition staging revisions would more accurately predict prognosis, become more predictive of treatment outcomes, and ultimately be more informative to the development of a treatment algorithm. Following a review of the results as detailed above, several observations are readily noted. Regarding T2 lesions, none of the AJCC sixth edition T2 lesions in this cohort had their primary tumor T classification modified. This would have been expected since they had already met the AJCC sixth edition criteria for a tumor diameter greater than 2 cm. The revisions which resulted in the downstaging of the AJCC sixth edition T3 and T4 lesions to the AJCC seventh edition T2 lesions had a minimal and insignificant effect following re-analysis for the ability of the lesion to achieve a CR at RT completion (84.2 versus 87.7 %) or in DFS (93.1 versus 92.2 %). This is clinically significant in that the AJCC seventh edition staging modifications resulted in successfully identifying many of the previously higher staged and more advanced lesions according to the sixth edition. These restaged lesions had an overall improved prognosis than the AJCC sixth edition primary tumor T classification had indicated. All of the AJCC sixth edition T3 lesions were downstaged to T2 lesions according to the AJCC seventh edition criteria. This was the direct result of the changes to the definition of a T3 lesion between the two staging guidelines. In the AJCC sixth edition, size alone was the inclusion criteria, and included any lesion greater than 5 cm in greatest diameter. In contrast, the AJCC seventh edition definition specifies that a T3 lesion must contain bony involvement of specific facial bones (maxilla, mandible, orbit, or temporal) and is entirely independent of tumor diameter. Therefore, dramatic differences in lesion categorization between the two guidelines to T3 restaging were found in our series. Many would agree, however, that a lesion that is clinically

5 J Radiat Oncol (2013) 2: locally advanced and biologically aggressive enough to invade these bones would likely be of a larger diameter, perhaps approaching or exceeding the previous 5 cm threshold, but not necessarily. The two T4 lesions which were downstaged to T3 in this series were a result of this specific facial bone invasion criteria, however the resulting prognosis became very poor (CR and DFS 81.3 and 85.7 % versus 0 and 0 %). T4 lesions according to the AJCC sixth edition were vaguely and cumulatively grouped under the definition of invasion of extradermal structures, regardless of size or location. As we noted in a prior report [10], these lesions could be small lesions invading the shallow extradermal structures of the ear or nose to very large erosive lesions involving the entire hemi-face. Most would conclude that such a dramatic difference in the definition of a T4 lesion would not carry the same prognosis or treatment approach. The AJCC seventh edition T4 lesions are limited by definition to lesions involving the axial or appendicular skeleton or perineural invasion of the skull base. As we noted in the Results section, these modifications resulted in 11 lesions being downstaged to T2 lesions due to the lack of bone involvement. The two T4 lesions downstaged to T3 were the result of facial bone involvement. The data supporting the AJCC seventh edition revisions were primarily based upon other head and neck studies demonstrating a poor prognosis of SCC in advanced lymph node disease involving the skull base [11 13], and a consensus of the NMSC task force that extension of NMSC to the axial skeleton also merits a T4 designation [1]. As reported in the Results section, many of the AJCC sixth edition T4 lesions which were downstaged to T2 lesions had an overall improved prognosis. This is indicated by the fact that their restaging and inclusion into the T2 category did not significantly alter this lesion s prognosis in terms of CR or DFS (84.2 and 93.1 % to 87.7 and 92.2 %). A significant factor which resulted in this improvement was the downstaging of lesions which lacked bone erosion, which has been shown to be an independent poor prognostic factor in other studies [8, 10, 14]. The depth of invasion, involvement of muscle, cartilage, or other deep extradermal tissue excluding bone did not seem to factors into the overall disease prognosis in this series. Understanding the significance of the presence of bone erosion to the prognosis of NMSC lesion involving the head and neck, the location, or the specification of bone involvement appears less important as the AJCC seventh edition distinguishes. Others have agreed with the changes that the seventh edition modification allows for clearer discrimination between T3 and T4 lesions in the head and neck region [15]. We suggest that if prognostically there is little difference clinically, then the T3 versus T4 staging definitions seem arbitrary. When analyzed, the T4 CR and DFS outcomes changed from 66.7 and 72.2 % to 40.0 and 40.0 % respectively between the AJCC sixth and seventh editions. When one considers the outcome modifications in the T3 lesions (CR and DFS 81.3 and 85.7 % vs. 0 and 0 %), the significance of the bone erosion is prominent. Based on this series, and likely other series if analyzed, it would appear logical that the overall prognostic differences would be trivial between the AJCC seventh edition T3 and T4 lesions by their stated definitions. In the AJCC seventh edition, the size threshold remained at 2 cm for the distinction between T1 and T2 lesions. In the AJCC sixth edition, a size criterion of >5 cm was used as a separation between a T2 and T3 lesion. The AJCC cutaneous SCC task force determined that there was a lack of evidence to support a 5-cm separation [1]. Warner [15] commented that few lesions were graded as T3 according to the AJCC sixth edition due to the likely presence of extension of extradermal structures and would therefore be upstaged to a T4 lesion in this prior edition. While this rationale seems logical, our respectable but limited series did account for 16 T3 lesions (22.2 %) by AJCC sixth edition criteria. Other advanced NMSC series have shown numbers and percentages of cohorts that are similar [7, 9]. In our present series, the AJCC sixth edition T3 CR rate and DFS of our patient cohort was 81.3 and 85.7 %. In addition, three AJCC sixth edition T3 lesions experienced a LR (18.8 %). This is in contrast to the AJCC sixth edition T2 lesion LR rate (7.9 %). While the AJCC cutaneous SCC Task Force ultimately decided that insufficient evidence was available to support a 5-cm cutoff for T classification upstaging, our series data suggests otherwise. Other reports have supported size thresholds for tumor upstaging as well [16]. While our series does not provide uncontested definitive evidence to support the previous 5-cm threshold, it does add to the evidence that a size factor is significant, does occur in a respectable number of patients, and should be considered for primary tumor upstaging. The AJCC seventh edition staging criteria primarily focuses on SCC s poor prognostic factors including poor differentiation, perineural invasion, extension >2-mm depth, tumor diameter, and anatomic site. However, BCC constitutes approximately 80 % of all NMSC [4]. In previous reports [5 7, 10, 14], it has been well established that BCC histology alone carries an improved prognostic difference and differing natural disease progression compared to SCC, regardless of the staging criteria. Therefore, we suggest that BCC and SCC should be staged and treated as two different disease entities. Merkel cell carcinoma is separated due to its known difference in clinical behavior and prognosis, therefore it seems logical that a separation of BCC

6 84 J Radiat Oncol (2013) 2:79 85 would appropriately follow such a separation as well, albeit for a more benign and favorable prognostic rationale. This especially seems appropriate given that BCC constitutes the overwhelming majority of all NMSC, and far more diagnoses than SCC or Merkel cell. The acknowledgement of the AJCC regarding the focus of the seventh edition guidelines to the more poor prognostic factors primarily pertinent to SCC indirectly provides support for this stance. The potential separation of BCC from SCC in regard to NMSC staging could further separate and clarify prognostic components of these two entities in regard to T classification. This could further assist the stratification and study of cutaneous SCC in regard to clinical trials and investigations. As the current model stands, BCC is staged and included in the pool of NMSC, regardless that it comprises a greater majority of diagnoses and likely falsely elevates prognostic percentages in regard to primary tumor T classification, especially in regard to advanced primary tumor stages. The seventh edition nodal staging has been updated to be more consistent with other SCC nodal staging involving the head and neck. As was shown in our previous series [5], all lesions which included nodal involvement were SCC histology. It is well-known that BCC rarely involves regional or distant lymphatic spread [4, 17]. We agree with the proposed changes, as they are more reflective of other SCC nodal staging of the head and neck, and therefore consistency has been accomplished. Limitations of this review include the size of the included cohort, length of follow-up, the fact that this investigation reflects a single institution perspective derived from patients treated with RT, and our clinical experience with such lesions which could have geographical as well as patient population implications. These limitations, however, do not negate the apparent findings presented when the AJCC seventh edition staging guidelines were applied. Further review and investigation is necessary and warranted regarding these findings, as NMSC remains the most common of all cancers and these diagnoses continue to rise at a rate of 3 8 % per year [18]. Conclusions The AJCC seventh edition staging of NMSC potentially results in a poorer outcome prediction for T3 and T4 lesions treated with radiation therapy when compared with the AJCC sixth edition (p<0.0001). The elimination of size and the requirement of specific bone invasion location as a staging criterion for advanced NMSC have significantly changed the staging pattern and outcome analysis for these advanced lesions. We propose that in view of such changes in outcome analysis that the AJCC considers reinstating a size criterion for upstaging larger lesions, and that all bone invasions be considered T4. Furthermore, BCC should be considered to be staged separately from SCC, as these are clearly different disease entities which clinically behave differently and have different prognoses. Such changes would more accurately reflect the clinical findings and improve accuracy to the staging of advanced NMSC. Conflict of interest References None declared, none to disclose. 1. Edge SB, American Joint Committee on Cancer (2010) AJCC cancer staging manual, 7th edn. Springer, New York, p 648, xiv 2. 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