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AJCC stage grouping (7th edition) in malignant parotid gland tumors
Oral Oncology 49 (2013) 903–910
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Comparison of TNM-based stage grouping versus UICC/AJCC stage grouping (7th edition) in malignant parotid gland tumors Matthias Kreppel a,f,⇑, Martin Scheer a,f, Moritz Meyer b,f, Markus Stenner b,f, Inga Wedemeyer c,f, Uta Drebber c,f, Robert Semrau d,f, Margarete Odenthal c,f, Joachim E. Zöller a,f, Orlando Guntinas-Lichius e, Reinhard Büttner c,f, Dirk Beutner b,f a
Department for Oral and Maxillofacial Plastic Surgery, University of Cologne, Germany Department for Otorhinolaryngology and Head Neck Surgery, University of Cologne, Germany Department of Pathology, University of Cologne, Germany d Department of Radiation Oncology, University of Cologne, Germany e Department for Otorhinolaryngology and Head Neck Surgery, Jena University Hospital, Germany f Center of Integrated Oncology (CIO), Cologne-Bonn, Germany b c
a r t i c l e
i n f o
Article history: Received 9 November 2012 Received in revised form 3 May 2013 Accepted 17 June 2013 Available online 10 July 2013 Keywords: Parotid gland cancer Stage grouping TANIS Prognosis Multivariate analysis
s u m m a r y Background: Although the UICC/AJCC’s TNM staging of the 7th edition was improved in 2002, there are still shortcomings concerning the prognostic quality. Alternative TNM-based stage-groupings such as the T and N Integer Score (TANIS) where shown to have a better prognostic quality for various kinds of head and neck tumors in the past. The aim of the study was to compare the prognostic value of the 7th edition of the UICC/AJCC TNM-classification for carcinoma of the parotid gland with different TNM-based stage groupings. Methods: The retrospective analysis included 180 patients with carcinoma of the parotid gland diagnosed between 1986 and 2007. The stage grouping system of the 7th edition of the UICC/AJCC and TNM-based stage-groupings (TANIS-3, TANIS-8, Snyderman, Berg and Hart) were tested for their prognostic significance. Overall survival (OS) was plotted by Kaplan–Meier analysis. Prognostic factors were identified through univariate and multivariate analysis. Results: In univariate analysis all stage-groupings had a highly significant impact on overall survival (p < 0.05), however in multivariate analysis, only the TANIS-8 scheme (p = 0.008) and Snyderman scheme (p = 0.047) predicted OS, while the UICC/AJCC-classification did not predict OS significantly (p = 0.381). Conclusion: In comparison to other TNM-based stage groupings the UICC/AJCC-classification did not provide significant prediction of OS, while alternative stage-groupings such as the TANIS-8 had a higher prognostic value. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction The TNM classification is a globally accepted classification scheme to describe the anatomic extent of a tumor [1]. It has been developed from the observation that prognosis and treatment modalities are related to the extent of the tumor at the primary site (T-classification), at the regional lymph nodes (N-classification) and the presence or absence of distant metastases (M-classification). Objectives in cancer staging are still the same today as they were more than 40 years ago: Support the planning of treatment, give some indication of prognosis, assist in evaluating treatment ⇑ Corresponding author. Address: Department for Oral and Cranio-Maxillo and Facial Plastic Surgery, University of Cologne, Kerpener Strasse 62, 50931 Cologne, Germany. Tel.: +49 221 478 96564; fax: +49 221 478 7360. E-mail address: [email protected] (M. Kreppel). 1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.06.009
results, allow the unambiguous exchange of information between treatment centers, further the investigation of human cancer and support cancer control activities [2]. TNM-staging for carcinoma of the parotid gland poses some special challenges. Carcinomas of the parotid gland account for 1–3% of all head and neck carcinoma with an annual incidence of 0.4–1.2 per 100,000 persons. Compared to other cancers the relative small number of cases makes it difficult to obtain a sufficient number of patients in order to study and analyze the prognostic quality of the classification [3,4]. Carcinomas of the parotid gland comprise a variety of different histologic types such as mucoepidermoid carcinoma, adenoid cystic carcinoma and adenocarcinoma with different prognosis [5–12]. The various categories of T, N and M offer a detailed description of the anatomic extent of the tumor providing 40 different possible combinations of the T-, N- and M-categories. For purposes of tabulation and analysis,
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a further summarization is needed in order to obtain a reasonable number of homogeneous and distinct categories with respect to survival [13,14]. The T-classification of the UICC/AJCC 4th edition published in 1987 was solely based on the metrical size of the tumor. All T-categories were subdivided into the subgroups a and b, where b denoted local microscopically detectable invasion of the surrounding tissue [6]. In the UICC/AJCC 5th edition, features that reflect the biological behavior of the tumor such as invasion of the facial nerve and local invasion were incorporated to enhance the prognostic quality of the T-classification [12,15–18]. However, there were no significant survival differences between the UICC/ AJCC stages I versus II and III versus IV [19]. The N- and M-classifications of the 6th edition remained unchanged in 2003, while the T-classification was subject to a couple of modifications [20]. In the 7th edition, no changes were made. Changes of the 6th edition yielded only a modest improvement in the predictive value of the stage grouping. The 6th edition still does not provide significant survival differences between the stages I and II, between stages III and IV and no clear separation between the stage IV subgroups IVa, IVb and IVc. [20]. In attempts to a achieve a higher level of discrimation among categories than in the UICC/AJCC-stage classification, various models using the same T and N data have been described [21–24]. The most popular example is the T and N Integer Score (‘‘TANIS’’). The TANIS scheme was first described by Jones et al. in 1993 due to the lack of prognostic relevance of the 4th edition of the UICC/AJCC-stage grouping [22]. This graduation scheme calculates the sum of integer values for the T and N stages, and results in values from 1 to 7. The investigators analyzed a set of 86 patients with stage II–IV head and neck cancer and came to the conclusion that TANIS provides a better prognostic discrimination than UICC/AJCC-stage grouping. The TANIS is based on the assumption that T and N are equally important and independent prognostic factors of survival. Consequently the values of T and N can simply be added. Major advantages of the TANIS are that it is easy to use, its ability to define a reasonable number of groups and the opportunity to be applied retrospectively if the TNM score is known [25]. Other authors have advocated further modifications such as a grouping of the score into 3 or 4 groups [13,21,23,26–28]. The effects of the changes in the UICC/AJCC-staging system of the 6th edition for parotid gland carcinoma have been evaluated in a previous study [20]. However, the prognostic benefit of these alterations could not be confirmed for the split of UICC/AJCC-stage IV. Since no significant improvements of the UICC/AJCC-stage grouping we detectable, we evaluated the prognostic power of other stage groupings previously tested for other head and neck cancers.
Materials and methods Patients The retrospective study included 180 treatment-naive patients with biopsy proven primary malignant tumors of the parotid gland of stages I–IV. All patients were treated at the Department of Otorhinolaryngology, Head and Neck surgery, University of Cologne (tertiary referral center) between 1986–2007. The patients´ clinical characteristics are listed in Table 1. Patients with a tumor of the category T4 were assigned to the categories T4a and T4b using the UICC/AJCC staging criteria of the 7th edition. For all patients pathologic staging (pTNM) was recoded through histopathologic reports after primary surgery. Clinicopathologic parameters were obtained from the medical charts including the histopathologic and surgical reports. Follow-up data were gathered from a
Table 1 Patient and tumor characteristics and 5-year overall survival. Variable N (%)
No. (%)
5-Year OS (%)
All patients
180
70.2
Age 659 years (lower half of median) >59 years (upper half of median)
90 (50%) 90 (50%)
79.9 61.6
Gender Male Female
90 (50%) 90 (50%)
65.2 74.4
T-Classification T1 T2 T3 T4a T4b
37 (20.6%) 35 (19.4%) 33 (18.3%) 68 (37.8%) 7 (3.9%)
87.0 97.0 73.5 49.1 35.7
N-Classification N0 N1 N2 N3
104 (57.8%) 22 (12.2%) 51 (28.3%) 3 (1.7%)
84.6 81.4 38.5 0
M-Classification M0 M1
166 (92.2%) 14 (7.8%)
74.7 0
Treatment Surgery Surgery + adjuvant RT
68 (37.8%) 112 (62.2%)
76.2 66.9
Histopathology Adenocarcinoma Adenoid-cystic carcinoma Mucoepidermoid carcinoma Acinic cell carcinoma Squamous cell carcinoma Undifferentiated carcinoma Miscellaneous
40 34 25 16 14 11 40
59.3 85.0 89.6 80.4 30.5 53.6 52.2
Resection margins R0 R1 & R2
137 (76.1%) 43 (23.9%)
p-value
0.037 0.389
<0.001
<0.001
<0.001
0.092
0.001 (22.2%) (18.9%) (13.9%) (8.9%) (7.8%) (6.1%) (22.2%)
0.052 75.8 54.6
combination of chart review and the local government office for registration of residents. For patients alive, the last follow-up data were solely acquired from clinical chart review. At the time of analysis 48 were deceased. 132 patients were alive. The average follow up time was 51.2 months. Median follow up time was 46.0 months.
Treatment Resection of the tumor and postoperative radiotherapy (RT) were conducted according to the tumor stage. All patients without distant metastases were intended to receive a total parotidectomy and a neck dissection. Radical parotidectomy was performed in cases of facial nerve infiltration. Patients without clinical lymph node involvement were treated with selective neck dissection at least of the levels I–III. Patients with clinically positive cervical lymph nodes or histologically proven cervical lymph node metastases received a radical-modified neck dissection. Adjuvant RT was administered for patients with high-grade carcinoma, adenoid cystic carcinoma, perineural invasion, incomplete resection margins and cervical lymph node metastases. RT was delivered by 6MV photons of a linear accelerator (LINAC) in daily fractions of 1.8–2.0 Gy five-times a week for a total dose of 60–65 Gy. The initial treatment volume included the primary tumor region and the cervical lymph node levels I to V by opposing lateral ports with a dose of 50.4 Gy. After application of 50.4 Gy, coning down and treating with 6-MV photons to the final dose of 60–65 Gy boosted the primary tumor site.
M. Kreppel et al. / Oral Oncology 49 (2013) 903–910
Stage grouping schemes Apart from the UICC/AJCC 7th edition stage grouping various other schemes were tested. For all patients the staging criteria were determined histologically. Since we used the 7th edition of the UICC/AJCC-staging with a split of T4 into T4a and T4b we had to extend the TANIS-7 to 8 subgroups, as T4 is divided into T4a and T4b (TANIS-8). T4a was assigned the value of 4, T4b the value of 5. The groups for TANIS-3 were as follows: 1: 1–3, 2: 4, 3: 5–8 [22,28]. Apart from TANIS-3 and TANIS-8, we tested the schemes proposed by Snyderman, Hart and Berg [21,23,26]. The stage groupings analyzed in this study are shown in Fig. 1 below. Statistical analysis Kaplan–Meier survival analysis was used to estimate the events of interest for overall survival (Overall survival [OS], time interval from beginning of primary therapy until death. Patients, who were alive at their last date of follow-up, were classified as censored observations). A 2-sided log rank test was used to compare overall survival times among patients with different characteristics. P-values of less than 0.05 were considered as statistically significant and printed in bold. For multivariate analysis, a Cox proportional hazard model with forward selection was calculated to estimate the prognostic impact of patient and tumor related factors on survival,
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which were significant in univariate analysis. Furthermore, we used the Cox proportional hazard model to determine the hazard ratio stage groupings by setting up indicator variables for each group. The method was described by Groome et al. to determine relative severity of disease in study groups with different kinds of head and neck cancer [28,29].
Results As shown in Table 1 exactly 50% of our patients were male and female each. Adenocarcinoma was the most frequent histologic type (22.2%) followed by adenoid-cystic carcinoma (19.8%) and mucoepidemoid carcinoma (13.9%). The section ‘‘miscellaneous histopathologic types’’ comprises epithelial–myoepithelial carcinoma, salivary duct carcinoma, basal cell adenocarcinoma, myoepithelial carcinoma and carcinoma arising from pleomorph adenoma. The v2-test showed a highly significant association between the T-classification and the N-classification (p < 0.001). Table 2 shows the distribution of T-, N- and M-categories. Table 3 displays the distribution and the 5-year overall survival rates for the different stage groupings. All patients in UICC/AJCCstage II were alive after 5 years. The UICC/AJCC-stage-grouping scheme had a significant impact on overall survival (p < 0.001) as well as the other stage grouping schemes tested.
Figure 1. Distribution of the different stage groupings.
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Table 2 Distribution of the T- and N-classification of 180 patients.
T1 T2 T3 T4a T4b
Discussion
N0
N1
N2
N3
M1
28 (15.6%) 28 (15.6%) 18 (10.0%) 27 (15.0%) 2 (1.1%)
6 3 5 5 1
2 (1.1%) 2 (1.1%) 9 (5.0%) 25 (13.9%) 2 (1.1%)
1 (0.6%) 0 1 (0.6%) 1 (0.6%) 0
14 (7.8%)
(3.3%) (1.7%) (2.8%) (2.8%) (0.6%)
Table 3 Distribution and overall survival of patients in the different stage groupings. Group (UICC stage)
UICC (7th edition)
TANIS3
TANIS8
Snyderman
Hart
Berg
Group 1 (I) Group 2 (II) Group 3 (III) Group 4 (IVa) Group 5 (IVb) Group 6 (IVc) Group 7
28 (15.6%) 28 (15.6%) 32 (17.8%) 70 (38.9%) 8 (4.4%)
85 (47.2%) 35 (19.4%) 60 (33.3%)
28 (15.6%) 34 (18.9%) 23 (12.8%) 35 (19.4%) 16 (8.9%) 27 (15.0%) 3 (1.7%) 14 (7.8%)
62 (34.4%)
65 (36.1%) 56 (31.1%) 16 (8.9%) 43 (23.9%)
34 (18.9%) 33 (18.3%) 64 (35.6%) 49 (27.2%)
14 (7.8%)
Group 8
23 (12.8%) 37 (20.6%) 58 (32.2%)
Table 4 shows the hazard ratios for the different staging schemes. All 6 staging schemes served as a good predictor for survival in univariate analysis (p < 0.05). The UICC/AJCC-7th edition exhibited a steady increase of risk of death with an increasing stage of disease. Patients in stage II had a smaller risk of death in comparison to patients in stage I (0.477). The difference was not statistically significant (p = 0.42). Stages IVa (p = 0.022), IVb (p = 0.016) and IVc (p < 0.001) were at a significantly higher risk of death than patients with stage I. Multivariate analysis In multivariate analysis we tested 6 models, each containing the factors, which had a significant impact on overall survival in univariate analysis (age, T-classification, N-classification, M-classification and histological tumor type) and one of the stage groupings. Only the schemes proposed by Snyderman (p = 0.047) and the TANIS-8 (p = 0.008) had a significant impact on overall survival in multivariate analysis. The UICC/AJCC-stage grouping (p = 0.381), the TANIS-3 (p = 0.664), the Hart-scheme (p = 0.123) and the Berg-scheme (p = 0.446) failed to reach the 95% significance level.
Correct staging is mandatory in the management of cancer patients in order to assign patients to the best treatment scheme for their individual situation and to evaluate properly effects of different treatment modalities [1,9,13]. This is particularly important for rare tumors like malignant neoplasms of the parotid gland as no prospective randomized controlled trials have been conducted and no standard treatment for the different stages has been defined so far [30]. The aim of the present study was to analyze the prognostic impact of alternative TNM-based stage groupings in comparison to the 7th edition of the UICC/AJCC as the modifications implemented in the 7th edition only yielded modest improvements [20]. The only study so far comparing the prognostic validity of the UICC/AJCC-stage grouping and the TANIS for malignant tumors of the parotid gland was based on the 5th edition of the UICC/AJCC from 1997 [31]. In univariate analysis, all six stage-grouping schemes tested had a highly significant impact on overall survival (Figs. 2–7, p < 0.001). Multivariate analysis, revealed that the TANIS-8 had the strongest prognostic impact of all stage grouping schemes tested on overall survival (p = 0.008). Apart from the TANIS-8 only the Snyderman stage-grouping scheme could be identified as an independent prognostic factor for overall survival (p = 0.047). As shown in Table 4 the categories 2–4 in the Snyderman scheme all are at a significantly higher risk of death than patients in the reference group 1 (p < 0.05). Carinci et al. found that the UICC/AJCC-stage grouping of the 5th edition from 1997 had a higher prognostic value than the TANIS [31]. This is explained by the point that the TANIS assigns equal statistical weight to both the T- and N-classification. In comparison to our study Carinci et al. could not find a significant impact of the nodal status on overall survival in patients with primary epithelial malignancies of the parotid gland. However, the authors did not state, whether each patient received a neck dissection, or whether they used the clinical data of the nodal status [31]. They reported a higher prognostic value for the UICC/AJCC-stage grouping of the 5th edition than for the TANIS. Considering, the changes in the UICC/AJCC-stage grouping from the 5th to the 6th edition of parotid gland carcinoma have led to an improved prognostic validity it seems surprising that the TANIS stage groupings have a higher prognostic quality than the UICC/AJCC-stage grouping of the 7th edition [20]. This may well be explained by the changes made to the T-classification in 2003: The T-classification was revised with special regard to T3. All tumors >4 cm were considered T3, but the maximum size was no longer limited to 6 cm. In accordance to tumors at other head neck sites T4 tumors were subdivided into T4a (lower risk) and T4b (higher risk) in the 6th edition of the UICC/ AJCC staging system for parotid gland cancer, based on the involvement of vital anatomic structures as death is primarily related to locoregional failure [2]. Stage I of the 5th edition, which comprised T1- and T2 tumors without regional lymph node involvement and
Table 4 Relative risk of patients in the different stage groupings. Group (UICC stage)
UICC (6th edition) (p < 0.001)
TANIS-3 (p < 0.001)
TANIS-8 (p < 0.001)
Snyderman (p < 0.001)
Hart (p < 0.001)
Berg (p < 0.001)
Group Group Group Group Group Group Group Group
1.00 0.42 (0.477) 2.26 (0.340) 5.37 (0.022) 8.42 (0.016) 58.33 (<0.001)
1.00 2.98 (0.025) 7.24 (<0.001)
1.00 0.32 (0.349) 3.69 (0.120) 3.69 (0.096) 3.8 (0.117) 7.08 (0.010) 61.19 (<0.001) 66.76 (<0.001)
1.00 6.10 (0.013) 5.97 (0.007) 16.5 (<0.001)
1.00 4.51 (0.008) 5.79 (0.012) 15.74 (<0.001)
1.00 1.53 (0.643) 4.54 (0.045) 14.65 (<0.001)
1 2 3 4 5 6 7 8
(I) (II) (III) (IVa) (IVb) (IVc)
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Figure 2. Overall survival with regard to the UICC/AJCC-classification (7th edition).
Figure 3. Overall survival with regard to TANIS-8.
Figure 4. Overall survival with regard to TANIS-3.
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Figure 5. Overall survival with regard to the Snyderman scheme.
Figure 6. Overall survival with regard to Hart scheme.
Figure 7. Overall survival with regard to Berg scheme.
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distant metastasis was divided into the stages I and II [32]. Stage III has been extended by the inclusion of T3N0M0 and T3N1M0 tumors. Taking into account the N and M stages, the generic stage IV has been split into 3 subcategories in the 6th edition of the UICC/AJCC’s TNM-classification for parotid gland carcinoma: IVa for advanced lower risk tumors, IVb for advanced high risk tumors and IVc with distant metastases, which are definitely incurable and therefore only suitable for palliative treatment. The idea behind this change is that disease without distant metastasis but with dubious prognosis has to be distinguished from an advanced disease that is potentially curable using an aggressive treatment scheme [2,33,34]. No changes to the T- and N- classification have been carried out for the UICC/AJCC’s 7th edition for parotid gland carcinoma [35]. These results differ from previous studies where we could show that the UICC/AJCC-stage grouping schemes of the 6th edition for oral cancer and malignant tumors of the ethmoid sinuses have a similar prognostic quality like TANIS-based stage grouping schemes [32]. This may be due to the point that carcinoma from different sub sites of the head and neck area have a different prognosis. Patients with carcinoma of the salivary glands have a worse overall survival than patients with carcinoma of the oral cavity or the larynx [36]. In comparison to the UICC/AJCC-stage grouping, all staging systems derived from the TANIS carry two major flaws in comparison to the UICC/AJCC-stage grouping: Patients with distant metastases only account for 2–4% of all patients, but it has not been clearly defined how to stage this group in the TANIS [25]. As it had been suggested before we classified these patients in the group of the highest TANIS score but no data are available so far, whether it would be more feasible to create an own group for these patients [27]. The more important problem of the TANIS is that it relies on the assumptions that T- and N-categories are independent and of equal prognostic quality in survival prediction. The prognostic impact of the presence of regional lymph node metastases in patients with parotid gland cancer is not clear. While some studies report that positive lymph node involvement is one of the most adverse prognostic factors [37–39] other studies could not find a significant impact on survival [17]. Secondly, T-classification and N-classification are not independent. We could show a highly significant statistical association between T-classification and N-classification (p < 0.001). A general problem with the alternative staging systems is that each system has its advocates and data to support the contention that makes it difficult to determine, which system should be utilized. The UICC/AJCC’s TNM-classification relies on the assumption that tumors are treated surgically. It does not consider neoadjuvant treatment approaches or molecular therapies such as Cetuximab, which is frequently used in recurrent head and neck cancer [12,42–44]. To incorporate other therapeutic approaches than surgery, the TNM system has to be stratified by therapy. This leads to an exponential increase in stage groups, making it very difficult to evaluate the results because of the small number of patients in every stage group [45]. Both the TNM-classification and the alternative staging systems are not able to address the larger issue of patient, tumor and treatment related factors, which is regarded as an essential part in prognostication today [9,9,12,40,41]. To avoid these problems, nomograms to predict survival after surgery with and without adjuvant chemoradiation for patients with oral squamous cell carcinoma, breast cancer and other malignancies have been developed [46]. For example, in patients with oral squamous cell carcinoma it allows clinicians to estimate the individual risk for a patient The nomogram comprises relevant patient factors beyond the TNM-stages such as age, gender, surgical margin status and tobacco use.
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Our results show that the TNM-system, which only includes information on the anatomic extent of tumor but no biological features is not sufficient to predict prognosis in patients with parotid gland carcinoma. It underlies the assumption that the tumor progresses continuously over time from local to regional to distant sites [40]. Other biological factors that reflect the biological aggressiveness of the disease have proven to be relevant, too [9,47–49]. For example, biomarkers may help to predict the risk of metastases or the treatment response to primary non-surgical approaches such as neoadjuvant radiochemotherapy in an individual patient [48]. Exploring the function of different biomarkers offers the opportunity to move from a tumor model of temporal determinism to one of biological determinism, as carcinogenesis is not defined by what stage the patient is in at detection but rather by molecular characteristics of the tumor and the host. Financial disclosure This study was supported by the Koeln Fortune Program / Faculty of Medicine, University of Cologne. There are no financial disclosures from any of the authors. Conflicts of Interest Statement All authors indicated no potential or actual conflicts of interest. References [1] Greene F, Sobin L. The staging of cancer: a retrospective and prospective appraisal. CA Cancer J Clin 2008;58(3):180–90. ´ Sullivan B, Shap J. New TNM staging criteria for head and neck tumors. Semin [2] O Surg Oncol 2003;21(1):30–42. [3] Bjørndal K, Krogdahl A, Therkildsen M, et al. Salivary gland carcinoma in Denmark 1990–2005: a national study of incidence, site and histology. Results of the Danish Head and Neck Cancer Group (DAHANCA). Oral Oncol 2011;47(7):677–82. [4] Boukheris H, Curtis R, Land C, et al. Incidence of carcinoma of the major salivary glands according to the WHO classification, 1992 to 2006: a population-based study in the United States. Cancer Epidemiol Biomarkers Prev 2009;18(11):2899–906. [5] Stenner M, Weinell A, Ponert T, et al. Cytoplasmatic expression of survivin is an independent predictor of poor prognosis in patients with salivary gland cancer. Histopathology 2010;57(5):699–706. [6] Carinci F, Farina A, Pelucchi S, et al. Parotid gland carcinoma: 1987 and 1997 UICC T classifications compared for prognostic accuracy at 5 years. Eur Arch Otorhinolaryngol 2001;258(3):150–4. [7] Zhou C, Shi D, Ma D, et al. Primary oncocytic carcinoma of the salivary glands: a clinicopathological and immunohistochemical study of 12 cases. Oral Oncol 2010;46(10):73–778. [8] Vékony H, Leemans C, Ylstra B, et al. Salivary gland carcinosarcoma: oligonucleotide array CGH eveals similar genetic profiles in epithelial and mesenchymal components. Oral Oncol 2009;45. 3. [9] Lee A, Ng W, Chan L, et al. The strength/weakness of the UICC/AJCC staging system (7th edition) for nasopharyngeal cancer and suggestions r future improvement. Oral Oncol 2012;48(10):1007–13. [10] van der Schroeff M, Terhaard C, Wieringa M, et al. Cytology and histology have limited predictive value in prognostic value for salivary gland carcinoma. Oral Oncol 2010;46(9):662–6. [11] Akrish S, Peled M, Ben-Izhak O, et al. Malignant salivary gland tumors and cyclo-oxygenase-2: a histothological study and immunohistochemical analysis th implications on histogenesis. Oral Oncol 2009;45(12):1044–50. [12] Yang X, Dai J, Li T, et al. Expression of EMMPRIN in adenoid cystic carcinoma of the salivary glands: correlation with tumor progression and patients’ prognosis. Oral Oncol 2010;46(10):755–60. [13] Hall S, Groome P, Irish J, et al. TNM-based stage groupings in head and neck cancer: application in cancer of the hypopharynx. Head Neck 2009;31(1):1–8. [14] Hermanek P, Sobin L, Fleming I. What do we need beyond TNM? Int J Oral Maxillofac Surg 1999;28(3):203–5. [15] Poorten V, Hart A, Vauterin T, et al. Prognostic index for patients with parotid carcinoma. Cancer 2009;115(3):540–50. [16] Ho K, Lin H, Ann D, et al. An overview of the rare parotid gland cancer. Head Neck Oncol 2011;3:40. [17] Stodulski D, Mikaszewski B, Stankiewicz C. Are all prognostic factors in parotid gland carcinoma well recognized? Eur Arch Otorhinolaryngol 2011;269(3):1019–25. [18] Barrett A, Speight P. Perineural invasion in adenoid cystic carcinoma the salivary glands: a valif prognostic indicator. Oral Oncol 2009;45(11):936–40.
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[19] Numata T, Muto H, Shiba K, et al. Evaluation of the validity of the 1997 International Union Against Cancer TNM classification of major salivary gland carcinoma. Cancer 2000;89(8):1664–9. [20] Schroeder U, Groppe D, Mueller R, et al. Parotid cancer: impact of changes from the 1997 to the 2002 American Joint Committee on Cancer Classification on outcome prediction. Cancer 2008;113(4):758–64. [21] Hart A, Mak-Kregar S, Hilgers F, et al. The importance of correct stage grouping in oncology. Results of a nationwide study of oropharyngeal carcinoma in The Netherlands. Cancer 1995;75(11):2656–62. [22] Jones G, Browman G, Goodyear M, et al. Comparison of the addition of T and N integer scores with TNM stage groups in head and neck cancer. Head Neck 1993;15(6):497–503. [23] Snyderman CH, Wagner RL. Superiority of the T and N integer score (TANIS) staging system for squamous cell carcinoma of the oral cavity. Otolaryngol Head Neck Surg 1995;112(6):691–4. [24] Carinci F, Farina A, Longhini L, et al. Is the new TNM (1997) the best system for predicting prognosis. Int J Oral Maxillofac Surg 1999;28(3):203–5. [25] Lydiatt W, Shah J, Hoffman H. AJCC stage groupings for head and neck cancer: should we look at alternatives? A report of the Head and Neck Sites Task Force. Head Neck 2001;23(8):607–12. [26] Berg H. Die prognostische Relevanz des TNM-Systems für Oropharynxkarzinome. Tumordiagn Ther 1992;13(3):171–7. [27] Carinci F, Pelucchi S, Farina A, et al. A comparison between TNM and TANIS stage grouping for predicting prognosis of oral and oropharyngeal cancer. J Oral Maxillofac Surg 1998;56(7):832–7. [28] Groome P, Schulze K, Boysen M, et al. A comparison of published head and neck stage groupings in carcinomas of the oral cavity. Head Neck 2001;23(8):613–21. [29] Groome P, Schulze K, Mackillop W, et al. A comparison of published head and neck stage groupings in carcinomas of the tonsillar region. Cancer 2001;92(6):1484–894. [30] Al-Mamgani A, van Rooij P, Sewnaik A, et al. Adenoid cystic carcinoma of parotid gland treated with surgery and radiotherapy: long term outcomes, QoL assessment and review of the literature. Oral Oncol 2012;48(3):278–83. [31] Carinci F, Farina A, Pelucchi S, et al. Comparison between TANIS and UICC 1997 stage grouping in parotid gland carcinoma. J Craniofac Surg 2001;12(2):141–4. [32] Kreppel M, Drebber U, Rothamel D, et al. Prognostic impact of different TNMbased stage groupings for oral squamous cell carcinoma. Head Neck 2010;33(10):1467–75. [33] Patel S, Lydiatt W. Staging of head and neck cancers: is it time to change the balance between the ideal and the practical? J Surg Oncol. 2008;97(8):653–7.
[34] van der Schroeff M, Baatenburg de Jong R. Staging and prognosis in head and neck cancer. Oral Oncol 2009;45(4–5):356–60. [35] Wittekindt C, Meyer HJ. Head neck cancer. In: UICC’s TNM-classification of malignant tumors. Berlin: Springer; 2010. p. 23–60. [36] Lavaf A, Genden E, Cesaretti J, et al. Adjuvant radiotherapy improves overall survival for patients with lymph node-positive head and neck squamous cell carcinoma. Cancer 2008;112(3):535–43. [37] Stenner M, Molls C, Klussmann J, et al. Prognosis of surgically treated primary parotid gland cancer – an evaluation of 231 cases. Laryngorhinootologie 2011;90(11):664–71. [38] Walvekar R, Andrade Filho P, Seethala R, et al. Clinicopathologic features as stronger prognostic factors than histology of grade in risk stratification of primary parotid gland malignancies. Head Neck 2011;33(2):225–31. [39] Klussmann J, Ponert T, Mueller R, et al. Patterns of lymph node spread and its influence on outcome in resectable parotid cancer. Eur J Surg Oncol 2008;34(8):932–7. [40] Burke B. Outcome prediction and the future of the TNM staging system. J Natl Cancer Inst 2004;96(19):1408–9. [41] Tang Q, Fan S, Li H, et al. Expression of Cyr61 in primary salivary gland adenoid cystic carcinoma and its relation to Ki-67 and prognosis. Oral Oncol 2011;47(5):365–70. [42] Kreppel M, Eich HT, Brüggenolte C, et al. Preoperative vs. postoperative radiochemotherapy in patients with N2 squamous cell carcinoma of the oral cavity. Oral Oncol 2012;48(10):1019–24. [43] Bonner J, Harari P, Giralt J, et al. Radiotherapy plus cetuximab for squamouscell carcinoma of the head and neck. N Engl J Med 2006;354(6):567–78. [44] Locati L, Bossi P, Perrone F, et al. Cetuximab in recurrent and/or metastatic salivary gland carcinomas: phase II study. Oral Oncol 2009;45(7):574–8. [45] Patel S, Shah J. TNM staging of cancers of the head and neck: striving for uniformity among diversity. CA Cancer J Clin 2005;55(4):242–58. [46] Gross N, Patel S, Carvalho A, et al. Nomogram for deciding adjuvant treatment after surgery for oral cavity squamous cell carcinoma. Head Neck 2008;30(10):1352–60. [47] Stenner M, Demgensky A, Molls C, et al. Prognostic value of survivin expression in parotid gland cancer in consideration of histological subtypes. Eur J Cancer 2011;47(7):1013–20. [48] Kreppel M, Drebber U, Wedemeyer I, et al. Podoplanin expression predicts prognosis in patients with oral squamous cell carcinoma treated with neoadjuvant radiochemotherapy. Oral Oncol 2011;47(9):873–8. [49] Cai B, Xu X, Fu S, et al. Nuclear translocation of MRP-1 contributes to multidrug resistance of mucoepidermoid carcinoma. Oral Oncol 2011;47(12):134–1140.
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Comparison of TNM-based stage grouping versus UICC/AJCC stage grouping (7th edition) in malignant parotid gland tumors Matthias Kreppel a,f,⇑, Martin Scheer a,f, Moritz Meyer b,f, Markus Stenner b,f, Inga Wedemeyer c,f, Uta Drebber c,f, Robert Semrau d,f, Margarete Odenthal c,f, Joachim E. Zöller a,f, Orlando Guntinas-Lichius e, Reinhard Büttner c,f, Dirk Beutner b,f a
Department for Oral and Maxillofacial Plastic Surgery, University of Cologne, Germany Department for Otorhinolaryngology and Head Neck Surgery, University of Cologne, Germany Department of Pathology, University of Cologne, Germany d Department of Radiation Oncology, University of Cologne, Germany e Department for Otorhinolaryngology and Head Neck Surgery, Jena University Hospital, Germany f Center of Integrated Oncology (CIO), Cologne-Bonn, Germany b c
a r t i c l e
i n f o
Article history: Received 9 November 2012 Received in revised form 3 May 2013 Accepted 17 June 2013 Available online 10 July 2013 Keywords: Parotid gland cancer Stage grouping TANIS Prognosis Multivariate analysis
s u m m a r y Background: Although the UICC/AJCC’s TNM staging of the 7th edition was improved in 2002, there are still shortcomings concerning the prognostic quality. Alternative TNM-based stage-groupings such as the T and N Integer Score (TANIS) where shown to have a better prognostic quality for various kinds of head and neck tumors in the past. The aim of the study was to compare the prognostic value of the 7th edition of the UICC/AJCC TNM-classification for carcinoma of the parotid gland with different TNM-based stage groupings. Methods: The retrospective analysis included 180 patients with carcinoma of the parotid gland diagnosed between 1986 and 2007. The stage grouping system of the 7th edition of the UICC/AJCC and TNM-based stage-groupings (TANIS-3, TANIS-8, Snyderman, Berg and Hart) were tested for their prognostic significance. Overall survival (OS) was plotted by Kaplan–Meier analysis. Prognostic factors were identified through univariate and multivariate analysis. Results: In univariate analysis all stage-groupings had a highly significant impact on overall survival (p < 0.05), however in multivariate analysis, only the TANIS-8 scheme (p = 0.008) and Snyderman scheme (p = 0.047) predicted OS, while the UICC/AJCC-classification did not predict OS significantly (p = 0.381). Conclusion: In comparison to other TNM-based stage groupings the UICC/AJCC-classification did not provide significant prediction of OS, while alternative stage-groupings such as the TANIS-8 had a higher prognostic value. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction The TNM classification is a globally accepted classification scheme to describe the anatomic extent of a tumor [1]. It has been developed from the observation that prognosis and treatment modalities are related to the extent of the tumor at the primary site (T-classification), at the regional lymph nodes (N-classification) and the presence or absence of distant metastases (M-classification). Objectives in cancer staging are still the same today as they were more than 40 years ago: Support the planning of treatment, give some indication of prognosis, assist in evaluating treatment ⇑ Corresponding author. Address: Department for Oral and Cranio-Maxillo and Facial Plastic Surgery, University of Cologne, Kerpener Strasse 62, 50931 Cologne, Germany. Tel.: +49 221 478 96564; fax: +49 221 478 7360. E-mail address: [email protected] (M. Kreppel). 1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.06.009
results, allow the unambiguous exchange of information between treatment centers, further the investigation of human cancer and support cancer control activities [2]. TNM-staging for carcinoma of the parotid gland poses some special challenges. Carcinomas of the parotid gland account for 1–3% of all head and neck carcinoma with an annual incidence of 0.4–1.2 per 100,000 persons. Compared to other cancers the relative small number of cases makes it difficult to obtain a sufficient number of patients in order to study and analyze the prognostic quality of the classification [3,4]. Carcinomas of the parotid gland comprise a variety of different histologic types such as mucoepidermoid carcinoma, adenoid cystic carcinoma and adenocarcinoma with different prognosis [5–12]. The various categories of T, N and M offer a detailed description of the anatomic extent of the tumor providing 40 different possible combinations of the T-, N- and M-categories. For purposes of tabulation and analysis,
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a further summarization is needed in order to obtain a reasonable number of homogeneous and distinct categories with respect to survival [13,14]. The T-classification of the UICC/AJCC 4th edition published in 1987 was solely based on the metrical size of the tumor. All T-categories were subdivided into the subgroups a and b, where b denoted local microscopically detectable invasion of the surrounding tissue [6]. In the UICC/AJCC 5th edition, features that reflect the biological behavior of the tumor such as invasion of the facial nerve and local invasion were incorporated to enhance the prognostic quality of the T-classification [12,15–18]. However, there were no significant survival differences between the UICC/ AJCC stages I versus II and III versus IV [19]. The N- and M-classifications of the 6th edition remained unchanged in 2003, while the T-classification was subject to a couple of modifications [20]. In the 7th edition, no changes were made. Changes of the 6th edition yielded only a modest improvement in the predictive value of the stage grouping. The 6th edition still does not provide significant survival differences between the stages I and II, between stages III and IV and no clear separation between the stage IV subgroups IVa, IVb and IVc. [20]. In attempts to a achieve a higher level of discrimation among categories than in the UICC/AJCC-stage classification, various models using the same T and N data have been described [21–24]. The most popular example is the T and N Integer Score (‘‘TANIS’’). The TANIS scheme was first described by Jones et al. in 1993 due to the lack of prognostic relevance of the 4th edition of the UICC/AJCC-stage grouping [22]. This graduation scheme calculates the sum of integer values for the T and N stages, and results in values from 1 to 7. The investigators analyzed a set of 86 patients with stage II–IV head and neck cancer and came to the conclusion that TANIS provides a better prognostic discrimination than UICC/AJCC-stage grouping. The TANIS is based on the assumption that T and N are equally important and independent prognostic factors of survival. Consequently the values of T and N can simply be added. Major advantages of the TANIS are that it is easy to use, its ability to define a reasonable number of groups and the opportunity to be applied retrospectively if the TNM score is known [25]. Other authors have advocated further modifications such as a grouping of the score into 3 or 4 groups [13,21,23,26–28]. The effects of the changes in the UICC/AJCC-staging system of the 6th edition for parotid gland carcinoma have been evaluated in a previous study [20]. However, the prognostic benefit of these alterations could not be confirmed for the split of UICC/AJCC-stage IV. Since no significant improvements of the UICC/AJCC-stage grouping we detectable, we evaluated the prognostic power of other stage groupings previously tested for other head and neck cancers.
Materials and methods Patients The retrospective study included 180 treatment-naive patients with biopsy proven primary malignant tumors of the parotid gland of stages I–IV. All patients were treated at the Department of Otorhinolaryngology, Head and Neck surgery, University of Cologne (tertiary referral center) between 1986–2007. The patients´ clinical characteristics are listed in Table 1. Patients with a tumor of the category T4 were assigned to the categories T4a and T4b using the UICC/AJCC staging criteria of the 7th edition. For all patients pathologic staging (pTNM) was recoded through histopathologic reports after primary surgery. Clinicopathologic parameters were obtained from the medical charts including the histopathologic and surgical reports. Follow-up data were gathered from a
Table 1 Patient and tumor characteristics and 5-year overall survival. Variable N (%)
No. (%)
5-Year OS (%)
All patients
180
70.2
Age 659 years (lower half of median) >59 years (upper half of median)
90 (50%) 90 (50%)
79.9 61.6
Gender Male Female
90 (50%) 90 (50%)
65.2 74.4
T-Classification T1 T2 T3 T4a T4b
37 (20.6%) 35 (19.4%) 33 (18.3%) 68 (37.8%) 7 (3.9%)
87.0 97.0 73.5 49.1 35.7
N-Classification N0 N1 N2 N3
104 (57.8%) 22 (12.2%) 51 (28.3%) 3 (1.7%)
84.6 81.4 38.5 0
M-Classification M0 M1
166 (92.2%) 14 (7.8%)
74.7 0
Treatment Surgery Surgery + adjuvant RT
68 (37.8%) 112 (62.2%)
76.2 66.9
Histopathology Adenocarcinoma Adenoid-cystic carcinoma Mucoepidermoid carcinoma Acinic cell carcinoma Squamous cell carcinoma Undifferentiated carcinoma Miscellaneous
40 34 25 16 14 11 40
59.3 85.0 89.6 80.4 30.5 53.6 52.2
Resection margins R0 R1 & R2
137 (76.1%) 43 (23.9%)
p-value
0.037 0.389
<0.001
<0.001
<0.001
0.092
0.001 (22.2%) (18.9%) (13.9%) (8.9%) (7.8%) (6.1%) (22.2%)
0.052 75.8 54.6
combination of chart review and the local government office for registration of residents. For patients alive, the last follow-up data were solely acquired from clinical chart review. At the time of analysis 48 were deceased. 132 patients were alive. The average follow up time was 51.2 months. Median follow up time was 46.0 months.
Treatment Resection of the tumor and postoperative radiotherapy (RT) were conducted according to the tumor stage. All patients without distant metastases were intended to receive a total parotidectomy and a neck dissection. Radical parotidectomy was performed in cases of facial nerve infiltration. Patients without clinical lymph node involvement were treated with selective neck dissection at least of the levels I–III. Patients with clinically positive cervical lymph nodes or histologically proven cervical lymph node metastases received a radical-modified neck dissection. Adjuvant RT was administered for patients with high-grade carcinoma, adenoid cystic carcinoma, perineural invasion, incomplete resection margins and cervical lymph node metastases. RT was delivered by 6MV photons of a linear accelerator (LINAC) in daily fractions of 1.8–2.0 Gy five-times a week for a total dose of 60–65 Gy. The initial treatment volume included the primary tumor region and the cervical lymph node levels I to V by opposing lateral ports with a dose of 50.4 Gy. After application of 50.4 Gy, coning down and treating with 6-MV photons to the final dose of 60–65 Gy boosted the primary tumor site.
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Stage grouping schemes Apart from the UICC/AJCC 7th edition stage grouping various other schemes were tested. For all patients the staging criteria were determined histologically. Since we used the 7th edition of the UICC/AJCC-staging with a split of T4 into T4a and T4b we had to extend the TANIS-7 to 8 subgroups, as T4 is divided into T4a and T4b (TANIS-8). T4a was assigned the value of 4, T4b the value of 5. The groups for TANIS-3 were as follows: 1: 1–3, 2: 4, 3: 5–8 [22,28]. Apart from TANIS-3 and TANIS-8, we tested the schemes proposed by Snyderman, Hart and Berg [21,23,26]. The stage groupings analyzed in this study are shown in Fig. 1 below. Statistical analysis Kaplan–Meier survival analysis was used to estimate the events of interest for overall survival (Overall survival [OS], time interval from beginning of primary therapy until death. Patients, who were alive at their last date of follow-up, were classified as censored observations). A 2-sided log rank test was used to compare overall survival times among patients with different characteristics. P-values of less than 0.05 were considered as statistically significant and printed in bold. For multivariate analysis, a Cox proportional hazard model with forward selection was calculated to estimate the prognostic impact of patient and tumor related factors on survival,
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which were significant in univariate analysis. Furthermore, we used the Cox proportional hazard model to determine the hazard ratio stage groupings by setting up indicator variables for each group. The method was described by Groome et al. to determine relative severity of disease in study groups with different kinds of head and neck cancer [28,29].
Results As shown in Table 1 exactly 50% of our patients were male and female each. Adenocarcinoma was the most frequent histologic type (22.2%) followed by adenoid-cystic carcinoma (19.8%) and mucoepidemoid carcinoma (13.9%). The section ‘‘miscellaneous histopathologic types’’ comprises epithelial–myoepithelial carcinoma, salivary duct carcinoma, basal cell adenocarcinoma, myoepithelial carcinoma and carcinoma arising from pleomorph adenoma. The v2-test showed a highly significant association between the T-classification and the N-classification (p < 0.001). Table 2 shows the distribution of T-, N- and M-categories. Table 3 displays the distribution and the 5-year overall survival rates for the different stage groupings. All patients in UICC/AJCCstage II were alive after 5 years. The UICC/AJCC-stage-grouping scheme had a significant impact on overall survival (p < 0.001) as well as the other stage grouping schemes tested.
Figure 1. Distribution of the different stage groupings.
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Table 2 Distribution of the T- and N-classification of 180 patients.
T1 T2 T3 T4a T4b
Discussion
N0
N1
N2
N3
M1
28 (15.6%) 28 (15.6%) 18 (10.0%) 27 (15.0%) 2 (1.1%)
6 3 5 5 1
2 (1.1%) 2 (1.1%) 9 (5.0%) 25 (13.9%) 2 (1.1%)
1 (0.6%) 0 1 (0.6%) 1 (0.6%) 0
14 (7.8%)
(3.3%) (1.7%) (2.8%) (2.8%) (0.6%)
Table 3 Distribution and overall survival of patients in the different stage groupings. Group (UICC stage)
UICC (7th edition)
TANIS3
TANIS8
Snyderman
Hart
Berg
Group 1 (I) Group 2 (II) Group 3 (III) Group 4 (IVa) Group 5 (IVb) Group 6 (IVc) Group 7
28 (15.6%) 28 (15.6%) 32 (17.8%) 70 (38.9%) 8 (4.4%)
85 (47.2%) 35 (19.4%) 60 (33.3%)
28 (15.6%) 34 (18.9%) 23 (12.8%) 35 (19.4%) 16 (8.9%) 27 (15.0%) 3 (1.7%) 14 (7.8%)
62 (34.4%)
65 (36.1%) 56 (31.1%) 16 (8.9%) 43 (23.9%)
34 (18.9%) 33 (18.3%) 64 (35.6%) 49 (27.2%)
14 (7.8%)
Group 8
23 (12.8%) 37 (20.6%) 58 (32.2%)
Table 4 shows the hazard ratios for the different staging schemes. All 6 staging schemes served as a good predictor for survival in univariate analysis (p < 0.05). The UICC/AJCC-7th edition exhibited a steady increase of risk of death with an increasing stage of disease. Patients in stage II had a smaller risk of death in comparison to patients in stage I (0.477). The difference was not statistically significant (p = 0.42). Stages IVa (p = 0.022), IVb (p = 0.016) and IVc (p < 0.001) were at a significantly higher risk of death than patients with stage I. Multivariate analysis In multivariate analysis we tested 6 models, each containing the factors, which had a significant impact on overall survival in univariate analysis (age, T-classification, N-classification, M-classification and histological tumor type) and one of the stage groupings. Only the schemes proposed by Snyderman (p = 0.047) and the TANIS-8 (p = 0.008) had a significant impact on overall survival in multivariate analysis. The UICC/AJCC-stage grouping (p = 0.381), the TANIS-3 (p = 0.664), the Hart-scheme (p = 0.123) and the Berg-scheme (p = 0.446) failed to reach the 95% significance level.
Correct staging is mandatory in the management of cancer patients in order to assign patients to the best treatment scheme for their individual situation and to evaluate properly effects of different treatment modalities [1,9,13]. This is particularly important for rare tumors like malignant neoplasms of the parotid gland as no prospective randomized controlled trials have been conducted and no standard treatment for the different stages has been defined so far [30]. The aim of the present study was to analyze the prognostic impact of alternative TNM-based stage groupings in comparison to the 7th edition of the UICC/AJCC as the modifications implemented in the 7th edition only yielded modest improvements [20]. The only study so far comparing the prognostic validity of the UICC/AJCC-stage grouping and the TANIS for malignant tumors of the parotid gland was based on the 5th edition of the UICC/AJCC from 1997 [31]. In univariate analysis, all six stage-grouping schemes tested had a highly significant impact on overall survival (Figs. 2–7, p < 0.001). Multivariate analysis, revealed that the TANIS-8 had the strongest prognostic impact of all stage grouping schemes tested on overall survival (p = 0.008). Apart from the TANIS-8 only the Snyderman stage-grouping scheme could be identified as an independent prognostic factor for overall survival (p = 0.047). As shown in Table 4 the categories 2–4 in the Snyderman scheme all are at a significantly higher risk of death than patients in the reference group 1 (p < 0.05). Carinci et al. found that the UICC/AJCC-stage grouping of the 5th edition from 1997 had a higher prognostic value than the TANIS [31]. This is explained by the point that the TANIS assigns equal statistical weight to both the T- and N-classification. In comparison to our study Carinci et al. could not find a significant impact of the nodal status on overall survival in patients with primary epithelial malignancies of the parotid gland. However, the authors did not state, whether each patient received a neck dissection, or whether they used the clinical data of the nodal status [31]. They reported a higher prognostic value for the UICC/AJCC-stage grouping of the 5th edition than for the TANIS. Considering, the changes in the UICC/AJCC-stage grouping from the 5th to the 6th edition of parotid gland carcinoma have led to an improved prognostic validity it seems surprising that the TANIS stage groupings have a higher prognostic quality than the UICC/AJCC-stage grouping of the 7th edition [20]. This may well be explained by the changes made to the T-classification in 2003: The T-classification was revised with special regard to T3. All tumors >4 cm were considered T3, but the maximum size was no longer limited to 6 cm. In accordance to tumors at other head neck sites T4 tumors were subdivided into T4a (lower risk) and T4b (higher risk) in the 6th edition of the UICC/ AJCC staging system for parotid gland cancer, based on the involvement of vital anatomic structures as death is primarily related to locoregional failure [2]. Stage I of the 5th edition, which comprised T1- and T2 tumors without regional lymph node involvement and
Table 4 Relative risk of patients in the different stage groupings. Group (UICC stage)
UICC (6th edition) (p < 0.001)
TANIS-3 (p < 0.001)
TANIS-8 (p < 0.001)
Snyderman (p < 0.001)
Hart (p < 0.001)
Berg (p < 0.001)
Group Group Group Group Group Group Group Group
1.00 0.42 (0.477) 2.26 (0.340) 5.37 (0.022) 8.42 (0.016) 58.33 (<0.001)
1.00 2.98 (0.025) 7.24 (<0.001)
1.00 0.32 (0.349) 3.69 (0.120) 3.69 (0.096) 3.8 (0.117) 7.08 (0.010) 61.19 (<0.001) 66.76 (<0.001)
1.00 6.10 (0.013) 5.97 (0.007) 16.5 (<0.001)
1.00 4.51 (0.008) 5.79 (0.012) 15.74 (<0.001)
1.00 1.53 (0.643) 4.54 (0.045) 14.65 (<0.001)
1 2 3 4 5 6 7 8
(I) (II) (III) (IVa) (IVb) (IVc)
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Figure 2. Overall survival with regard to the UICC/AJCC-classification (7th edition).
Figure 3. Overall survival with regard to TANIS-8.
Figure 4. Overall survival with regard to TANIS-3.
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Figure 5. Overall survival with regard to the Snyderman scheme.
Figure 6. Overall survival with regard to Hart scheme.
Figure 7. Overall survival with regard to Berg scheme.
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distant metastasis was divided into the stages I and II [32]. Stage III has been extended by the inclusion of T3N0M0 and T3N1M0 tumors. Taking into account the N and M stages, the generic stage IV has been split into 3 subcategories in the 6th edition of the UICC/AJCC’s TNM-classification for parotid gland carcinoma: IVa for advanced lower risk tumors, IVb for advanced high risk tumors and IVc with distant metastases, which are definitely incurable and therefore only suitable for palliative treatment. The idea behind this change is that disease without distant metastasis but with dubious prognosis has to be distinguished from an advanced disease that is potentially curable using an aggressive treatment scheme [2,33,34]. No changes to the T- and N- classification have been carried out for the UICC/AJCC’s 7th edition for parotid gland carcinoma [35]. These results differ from previous studies where we could show that the UICC/AJCC-stage grouping schemes of the 6th edition for oral cancer and malignant tumors of the ethmoid sinuses have a similar prognostic quality like TANIS-based stage grouping schemes [32]. This may be due to the point that carcinoma from different sub sites of the head and neck area have a different prognosis. Patients with carcinoma of the salivary glands have a worse overall survival than patients with carcinoma of the oral cavity or the larynx [36]. In comparison to the UICC/AJCC-stage grouping, all staging systems derived from the TANIS carry two major flaws in comparison to the UICC/AJCC-stage grouping: Patients with distant metastases only account for 2–4% of all patients, but it has not been clearly defined how to stage this group in the TANIS [25]. As it had been suggested before we classified these patients in the group of the highest TANIS score but no data are available so far, whether it would be more feasible to create an own group for these patients [27]. The more important problem of the TANIS is that it relies on the assumptions that T- and N-categories are independent and of equal prognostic quality in survival prediction. The prognostic impact of the presence of regional lymph node metastases in patients with parotid gland cancer is not clear. While some studies report that positive lymph node involvement is one of the most adverse prognostic factors [37–39] other studies could not find a significant impact on survival [17]. Secondly, T-classification and N-classification are not independent. We could show a highly significant statistical association between T-classification and N-classification (p < 0.001). A general problem with the alternative staging systems is that each system has its advocates and data to support the contention that makes it difficult to determine, which system should be utilized. The UICC/AJCC’s TNM-classification relies on the assumption that tumors are treated surgically. It does not consider neoadjuvant treatment approaches or molecular therapies such as Cetuximab, which is frequently used in recurrent head and neck cancer [12,42–44]. To incorporate other therapeutic approaches than surgery, the TNM system has to be stratified by therapy. This leads to an exponential increase in stage groups, making it very difficult to evaluate the results because of the small number of patients in every stage group [45]. Both the TNM-classification and the alternative staging systems are not able to address the larger issue of patient, tumor and treatment related factors, which is regarded as an essential part in prognostication today [9,9,12,40,41]. To avoid these problems, nomograms to predict survival after surgery with and without adjuvant chemoradiation for patients with oral squamous cell carcinoma, breast cancer and other malignancies have been developed [46]. For example, in patients with oral squamous cell carcinoma it allows clinicians to estimate the individual risk for a patient The nomogram comprises relevant patient factors beyond the TNM-stages such as age, gender, surgical margin status and tobacco use.
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Our results show that the TNM-system, which only includes information on the anatomic extent of tumor but no biological features is not sufficient to predict prognosis in patients with parotid gland carcinoma. It underlies the assumption that the tumor progresses continuously over time from local to regional to distant sites [40]. Other biological factors that reflect the biological aggressiveness of the disease have proven to be relevant, too [9,47–49]. For example, biomarkers may help to predict the risk of metastases or the treatment response to primary non-surgical approaches such as neoadjuvant radiochemotherapy in an individual patient [48]. Exploring the function of different biomarkers offers the opportunity to move from a tumor model of temporal determinism to one of biological determinism, as carcinogenesis is not defined by what stage the patient is in at detection but rather by molecular characteristics of the tumor and the host. Financial disclosure This study was supported by the Koeln Fortune Program / Faculty of Medicine, University of Cologne. There are no financial disclosures from any of the authors. Conflicts of Interest Statement All authors indicated no potential or actual conflicts of interest. References [1] Greene F, Sobin L. The staging of cancer: a retrospective and prospective appraisal. CA Cancer J Clin 2008;58(3):180–90. ´ Sullivan B, Shap J. New TNM staging criteria for head and neck tumors. Semin [2] O Surg Oncol 2003;21(1):30–42. [3] Bjørndal K, Krogdahl A, Therkildsen M, et al. Salivary gland carcinoma in Denmark 1990–2005: a national study of incidence, site and histology. Results of the Danish Head and Neck Cancer Group (DAHANCA). Oral Oncol 2011;47(7):677–82. [4] Boukheris H, Curtis R, Land C, et al. Incidence of carcinoma of the major salivary glands according to the WHO classification, 1992 to 2006: a population-based study in the United States. Cancer Epidemiol Biomarkers Prev 2009;18(11):2899–906. [5] Stenner M, Weinell A, Ponert T, et al. Cytoplasmatic expression of survivin is an independent predictor of poor prognosis in patients with salivary gland cancer. Histopathology 2010;57(5):699–706. [6] Carinci F, Farina A, Pelucchi S, et al. Parotid gland carcinoma: 1987 and 1997 UICC T classifications compared for prognostic accuracy at 5 years. Eur Arch Otorhinolaryngol 2001;258(3):150–4. [7] Zhou C, Shi D, Ma D, et al. Primary oncocytic carcinoma of the salivary glands: a clinicopathological and immunohistochemical study of 12 cases. Oral Oncol 2010;46(10):73–778. [8] Vékony H, Leemans C, Ylstra B, et al. Salivary gland carcinosarcoma: oligonucleotide array CGH eveals similar genetic profiles in epithelial and mesenchymal components. Oral Oncol 2009;45. 3. [9] Lee A, Ng W, Chan L, et al. The strength/weakness of the UICC/AJCC staging system (7th edition) for nasopharyngeal cancer and suggestions r future improvement. Oral Oncol 2012;48(10):1007–13. [10] van der Schroeff M, Terhaard C, Wieringa M, et al. Cytology and histology have limited predictive value in prognostic value for salivary gland carcinoma. Oral Oncol 2010;46(9):662–6. [11] Akrish S, Peled M, Ben-Izhak O, et al. Malignant salivary gland tumors and cyclo-oxygenase-2: a histothological study and immunohistochemical analysis th implications on histogenesis. Oral Oncol 2009;45(12):1044–50. [12] Yang X, Dai J, Li T, et al. Expression of EMMPRIN in adenoid cystic carcinoma of the salivary glands: correlation with tumor progression and patients’ prognosis. Oral Oncol 2010;46(10):755–60. [13] Hall S, Groome P, Irish J, et al. TNM-based stage groupings in head and neck cancer: application in cancer of the hypopharynx. Head Neck 2009;31(1):1–8. [14] Hermanek P, Sobin L, Fleming I. What do we need beyond TNM? Int J Oral Maxillofac Surg 1999;28(3):203–5. [15] Poorten V, Hart A, Vauterin T, et al. Prognostic index for patients with parotid carcinoma. Cancer 2009;115(3):540–50. [16] Ho K, Lin H, Ann D, et al. An overview of the rare parotid gland cancer. Head Neck Oncol 2011;3:40. [17] Stodulski D, Mikaszewski B, Stankiewicz C. Are all prognostic factors in parotid gland carcinoma well recognized? Eur Arch Otorhinolaryngol 2011;269(3):1019–25. [18] Barrett A, Speight P. Perineural invasion in adenoid cystic carcinoma the salivary glands: a valif prognostic indicator. Oral Oncol 2009;45(11):936–40.
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