Relevance of the primary lesion in the prognosis of metastatic cutaneous squamous cell carcinoma

ORIGINAL ARTICLE Relevance of the primary lesion in the prognosis of metastatic cutaneous squamous cell carcinoma Sydney Ch ng, MBBS, FRACS, 1 Jonathan R. Clark, MBBS, FRACS, 1 Markus Brunner, MD, 1 Carsten E. Palme, MBBS, FRACS, 2 Gary J. Morgan, MBBS, FRACS, 2 Michael J. Veness, MBBS, MD, FRANZCR 2 1 The Sydney Head & Neck Cancer Institute, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, New South Wales, Australia, 2 Head & Neck Cancer Service, Westmead Hospital, University of Sydney, Westmead, Sydney, New South Wales, Australia. Accepted 28 November 2011 Published online 16 March 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.22941 ABSTRACT: Background. It remains unclear how primary tumor factors impact on prognosis in patients with nodal metastasis in head and neck cutaneous squamous cell carcinoma (SCC). The purpose of this study was to assess whether primary tumor characteristics are independent prognostic factors. Methods. Patients treated for metastatic cutaneous SCC from 1978 to 2010 were identified (n ¼ 239). A proportional hazards model was used to assess the effect of primary tumor variables. Results. On multivariable analysis, tumor differentiation (hazard ratio [HR], 0.2; 95% confidence interval [CI], 0.1 0.8; p ¼.03) was found to be significantly associated with disease-specific survival (DSS), unlike margin status (p ¼.23), tumor size (p ¼.21), and thickness (p ¼.11). Patient, treatment, and nodal factors were confirmed to be important predictors of survival. Conclusion. This article suggests that pathological features of the primary lesion bear little importance in the presence of established nodal metastasis, other than tumor differentiation. It validates the grouping of T1--3N1 as stage III under the current American Joint Committee on Cancer (AJCC) TNM staging system. VC 2012 Wiley Periodicals, Inc. Head Neck 35: 190 194, 2013 KEY WORDS: staging, cutaneous squamous cell carcinoma, tumor factor, tumor differentiation INTRODUCTION Cutaneous squamous cell carcinoma (SCC) is a major burden on healthcare resources in countries such as Australia. In more than 98% of cases, the risk of death due to cutaneous SCC is minimal. In the small minority of metastatic cases, however, it can be life threatening, and treatment can be potentially debilitating and disfiguring. Certain characteristics of cutaneous SCC that confer increased metastatic potential are recognized in the latest American Joint Committee on Cancer (AJCC) TNM staging system (Table 1). 1,2 This represents a significant improvement over prior AJCC staging systems by allowing for T (primary lesion) upstaging if any unfavorable pathological feature is present, and by also stratifying nodal metastasis by size and number (Table 1). Despite this improvement, it remains unclear how primary tumor factors impact on prognosis in patients with proven nodal metastasis. The primary purpose of this study was to determine whether primary tumor characteristics are independent prognostic factors in patients with metastatic nodal cutaneous SCC of the head and neck. *Corresponding author: S. Ch ng, The Sydney Head & Neck Cancer Institute, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, New South Wales, Australia. E-mail: snchng@xtra.co.nz PATIENTS AND METHODS Patients Patients who had undergone treatment for metastatic cutaneous SCC from 1978 to 2010 were identified from the Westmead Cancer Center Head & Neck database. Patients without a clearly defined index lesion were excluded from analysis. Information on patient demographics, treatment, follow-up and survival, the index lesion, and the metastatic nodal disease was obtained from this prospectively maintained database. A total of 239 patients fulfilled the inclusion criteria. There were 193 male and 45 female patients, and median age at diagnosis was 68 years. Median follow-up was 3.1 years. Statistical analysis Statistical analysis was carried out with SPSS 19 (IBM Corp., Armonk, NY). The end points for analysis included disease-specific survival (DSS) and overall survival (OS). Survival was calculated from the date of surgery (for regional metastasis) to date of death or last follow-up. Differences in survival were determined using the log-rank test and survival curves were generated using the Kaplan Meier method. A Cox proportional hazards model was used to adjust for the effect of other significant covariates and potential confounders to determine the independent effect of primary tumor-related variables. Primary tumor variables with a p value <.25onunivariable 190 HEAD & NECK DOI 10.1002/HED FEBRUARY 2013

TUMOR FACTORS IN METASTATIC CUTANEOUS SCC TABLE 1. AJCC seventh edition TNM staging for cutaneous squamous cell carcinoma and other cutaneous carcinomas. T1 T2 T3 T4 N1 N2 N3 Anatomical stage groups Stage I Stage II Stage III Stage IV AJCC prognostic groups Stage I* Stage II Stage III and IV 2 cm >2 cm Deep: muscle, bone, cartilage, jaws, orbit Skull base, axial skeleton Single <3cm Single 3 to 6 cm, mu ltiple 6 cm >6 cm T1 N0 T2 N0 T3 N0 T1, 2, 3 N1 T1, 2, 3 N2 T4 or N3 or M1 T1 N0 T2 N0 Same as anatomical above *High risk factors (AJCC) >4 mm thickness, Clark IV, perineural invasion, lymphovascular incasion, ear, nonglabrous lip, poorly or undifferentiated *Stage I with >1 high risk factor ¼ stage II Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, http:// www.springerlink.com analysis were included in the initial model and a (nonautomated) backward stepwise selection technique was used to construct the final multivariable survival models. Missing values were imputed, in particular where a pathological variable was not reported, it was imputed as being absent (as the usual practice of pathologists was to only report adverse features when present), and for continuous variables, the mean or median was imputed as appropriate. A p value of <.05 was considered statistically significant. Treatment philosophy Treatment philosophy evolves over time, differs in minor aspects between treating physicians, and is adapted to the individual patient. However, overall it is standard practice at our institution to routinely perform selective neck dissection for patients undergoing therapeutic parotidectomy with a clinically and radiologically negative neck because of the high incidence (20% to 30%) of occult metastasis. Adjuvant radiotherapy (range, 50 60 Gy to the primary and nodal sites) is recommended if indicated by close or involved surgical margin, multiple nodal involvement, extracapsular spread, and perineural or vascular invasion. RESULTS One hundred twenty-nine patients underwent both parotidectomy and neck dissection, 91 patients had neck dissections alone (49 selective and 42 comprehensive), and the remaining 19 patients had parotidectomy alone. Two hundred five patients were treated with surgery and radiotherapy, 28 with surgery alone, and the remaining 6 had multimodality treatment of surgery, postoperative adjuvant radiotherapy, and chemotherapy (carboplatin) as part of a Trans-Tasman Radiation Oncology Group (TROG) trial. Clinical and pathological variables are summarized in Table 2. During follow-up, 41 patients died of cutaneous SCC and 46 patients died from other causes. The impact of various patient, primary lesion, and metastatic disease parameters on DSS and OS are presented in Table 3. The only primary tumor factor on univariable analysis with a significant association with DSS was tumor differentiation (well-differentiated vs the rest; p ¼.03) as shown in Figure 1A. No primary tumor factor was significantly associated with OS. Primary tumor factors selected for inclusion in the initial multivariable model were margin status (p ¼.23), tumor size (p ¼.21 for linear trend), and thickness (p ¼.11 for linear trend), as shown in Figures 1B to 1D. The final multivariable models for DSS and OS are shown in Table 4. The only primary tumor factor with evidence for significant association with DSS after adjusting for effect of other clinical and pathological factors was tumor differentiation (hazard ratio [HR], 0.2; 95% confidence interval [CI], 0.1 0.8; p ¼.03), with weak evidence for an association with OS (HR, 0.6; 95% CI, 0.3 1.0; p ¼.08). In contrast, nodal factors, including margin status (HR, 2.7; 95% CI, 1.4 5.2; p ¼.004 for DSS; HR, 2.3; 95% CI, 1.4 3.7; p <.001 for OS), invasion of adjacent structures (HR, 2.4; 95% CI, 1.2 4.7; p ¼.013 for DSS; HR, 1.9; 95% CI, 1.2 3.0; p ¼.008 for OS), and N1S3 stage 3 based on node size and number (HR, 1.8; 95% CI, 1.0 3.1; p ¼.041) were significantly associated with survival. In addition, patient factors including immunosuppression (HR, 3.7; 95% CI, 1.6 8.6; p ¼.003 for DSS; HR, 3.0; 95% CI, 1.5 5.9; p ¼.002 for OS), disease-free interval less than 9 months (HR, 3.5; 95% CI, 1.7 7; p ¼.001 for DSS; HR 1.9, 95% CI 1.2 3.1, p ¼ 0.010 for OS), and treatment with adjuvant radiotherapy (HR, 0.4; 95% CI, 0.2 0.9; p ¼.020 for DSS; HR, 0.6; 95% CI, 0.3 1.1; p ¼.13 for OS) were also significant predictors of survival (Table 4). DISCUSSION Epidemiologic studies worldwide have consistently shown that the incidence of cutaneous SCC has steadily increased over the last 4 decades, possibly due to a combination of depletion of the ozone layer, an aging population, increasing use of immunosuppression, and changing social trends. 3,4 Less than 5% of cutaneous SCC metastasize, but given that 75% of cutaneous SCC arise in the head and neck, the parotid and cervical lymph nodes are the most common nodal basins involved with metastasis. Many studies have investigated adverse prognostic factors for cutaneous SCC so that a more targeted approach in management and surveillance can be recommended. 5 10 The seventh edition of the AJCC TNM staging system has taken into consideration much of the growing literature regarding these prognostic factors. Primary tumor characteristics recognized in this edition include size >2 cm, depth >2 mm, invasion into subcutaneous fat or bone, poor differentiation, perineural invasion (PNI), and anatomic site on the ear or nonglabrous lip. These unfavorable characteristics impart their adverse effect by reducing local control and also increasing the rate of metastasis. The current TNM staging system implies that primary tumor factors play little role in overall patient prognosis in the presence of established nodal metastases by grouping T1, T2, and T3 together when combined with N1 disease under stage HEAD & NECK DOI 10.1002/HED FEBRUARY 2013 191

TABLE 2. Clinicopathologic parameters. Parameters No. of patients of 239 % Parameters No. of patients of 239 % Patient factor Ear 44 18 Immunosuppression Lip 34 14 Yes 33 14 Other 6 3 No 71 30 Size Unknown 135 56 <20 mm 105 44 Gender <50 mm 65 27 Male 194 81 50 mm 10 4 Female 45 19 Unknown 59 25 Disease-free interval Lesion thickness Short (<9 mo) 143 60 <10 mm 90 38 Long 96 40 <20 mm 25 10 Adjuvant radiotherapy 20 mm 11 5 Yes 211 88 Unknown 113 47 No 28 12 Margin Adjuvant chemotherapy Clear 103 43 Yes 11 5 Close/involved 106 44 No 219 92 Unknown 30 13 Unknown 9 4 Nodal disease factor Invasion of adjacent structures Histologic grade Yes 43 18 Well 38 16 No 183 77 Moderate 85 36 Unknown 13 5 Poor 78 33 Involved node margin Undifferentiated 2 1 Clear 94 39 Unknown 36 15 Involved 132 55 Vascular invasion Unknown 13 5 Yes 10 4 N1S3* No 85 36 1 92 38 Unknown 144 60 2 110 46 Perineural invasion 3 36 15 Yes 36 15 Size of nodes No 93 39 <30 mm 147 62 Unknown 109 46 <60 mm 70 29 Site 60 mm 8 3 Anterior scalp 22 9 Unknown 14 6 Posterior scalp 20 8 Number of nodes Frontotemporal 48 20 1 116 49 Cheek 37 15 >1 122 51 Neck 13 5 Unknown 1 <1 Nose 15 6 * N1S3 stage I, single lymph node measuring 3 cm; II, single lymph node measuring >3 cm or multiple lymph nodes measuring 3 cm; III, multiple lymph nodes measuring >3 cm. TABLE 3. Univariable association between various parameters and DSS and OS (log-rank test and log-rank test for trend). Parameters DSS p value OS p value Patient factor Immunosuppression.01.01 Disease-free interval.01.03 Radiotherapy.11.07 Tumor differentiation.03.24 Perineural invasion.38.44 Site.32.30 Size.21.09 Margin.22.50 Thickness.11.51 Vascular invasion.62 Metastasis factor Stage (N1S3).12.25 Extracapsular spread.01.02 Invasion of adjacent structures.01.01 Margin of node.04.01 Abbreviations: DSS, disease-specific survival; OS, overall survival. III. However, to our knowledge, there is no literature to validate this grouping. Although primary tumor factors are proven to predict an increased likelihood of metastasis, they cease to be relevant in prognosis once nodal metastasis is present, with the exception of tumor differentiation (Table 4). Unfortunately, we did not have data on skull base and axial skeleton invasion to determine whether T4 should be separated from T1 to 3 as stage IV disease. Given that this still represents resectable disease in many patients, it is unlikely to have a similar prognosis to patients with distant metastases (M1). Well-differentiated tumor variants, by Broder's classification, consist of less than 25% of undifferentiated cells. 11 They tend to have abundant keratinization, often with keratin pearl formation in the central portion, lowgrade nuclear pleomorphism, and generous cytoplasm. Well-differentiated tumors generally have large aggregates or large cohesive cords of tumor cells at their invading front, which are less likely to penetrate lymphatic or blood vessels. It is, therefore, not surprising that in only 15.9% (38 of 239) of our cases the index lesion was found to be 192 HEAD & NECK DOI 10.1002/HED FEBRUARY 2013

TUMOR FACTORS IN METASTATIC CUTANEOUS SCC FIGURE 1. (A-D) Tumor differentiation was the only primary tumor factor that was significantly associated with disease-specific survival. Margin, primary tumor size, and thickness had no significant association. of this highly favorable histologic grade. With an 80% reduction in disease-specific death, it is a strong independent prognostic factor in patients with cutaneous SCC regional metastasis. How closely the histologic grade correlates between primary lesion and nodal disease, however, is unclear. It is interesting that poorly differentiated tumors did not have a significantly different prognosis to moderately differentiated tumors, whereas the AJCC staging system considers poorly or undifferentiated cutaneous SCC to be an adverse factor. It is likely that the predominant effect of poor differentiation lies in its association with nodal metastases and, therefore, once nodal metastases are present, the balance shifts toward better prognosis for the exceptional group of well-differentiated tumors. This study suggests that management of patients with metastatic cutaneous SCC should be focused largely on patient and nodal factors. Treatment and surveillance regimes may need to be intensified in immunosuppressed patients, those with a short disease-free interval from primary tumor to the development of nodal disease (less than 9 months), and the presence of extracapsular extension of tumor to involve adjacent structures, particularly where a clear surgical margin cannot be obtained. Deintensification is likely to be appropriate for well-differentiated index HEAD & NECK DOI 10.1002/HED FEBRUARY 2013 193

CH'NG ET AL. TABLE 4. Multivariable analysis of predictors of DSS and OS. Parameter DSS OS HR (95% CI) p value HR (95% CI) p value Patient factor Immunosuppression 3.7 (1.6 8.6).003 3.0 (1.5 5.9).002 Disease-free interval <9 mo 3.5 (1.7 7.3).001 1.9 (1.2 3.1).010 Radiotherapy 0.4 (0.2 0.9).020 0.6 (0.3 1.1).13 Age 1.04 (1.021 1.066) <.001 Grade (well-differentiated vs others) 0.2 (0.1 0.8).027 0.6 (0.3 1.0).084 Nodal disease factor Invasion of adjacent structures 2.7 (1.4 5.2).004 2.3 (1.4 3.7) <.001 Involved node margin 2.4 (1.2 4.7).013 1.9 (1.2 3.0).008 Stage (N1S3) 1.8 (1.0 3.1).041 Abbreviations: DSS, disease-specific survival; OS, overall survival; HR, hazard ratio; CI, confidence interval. lesions with a long disease-free interval where the nodal disease is isolated, small (<3 cm), and contained within the lymph node. However, until there is prospective evidence, rationale for deintensification is open to debate. In addition, there are as yet undefined molecular markers that are likely to predict biologic behavior of the tumor. Inherent limitations with data collection and pathology reporting have to be acknowledged. One shortcoming of our data is the incomplete data on PNI. The pathologic diagnosis of PNI is defined as the presence of cancer cells within the perineural space, with partial or complete encircling of the enclosed nerve. Histologically, the diagnosis of PNI may be overlooked due to selective specimen sectioning, skip pattern, and subtlety of the sign (scanty lymphocytic infiltration may be the only indication). 12 The inconsistent documentation of PNI, particularly before the introduction of synoptic reporting systems, further compounds the analysis of this parameter. PNI encompasses a wide spectrum of presentation with varying prognosis; the nerve involved may be a major nerve or an unnamed minor nerve in the vicinity of the tumor, and the degree of involvement may be clinically obvious or subclinical, macroscopic, or microscopic. 13,14 Cutaneous SCC of the head and neck can gain access to the skull base and intracranial structures through the extensive neural system and skull base foramina (T4). Although not supported by this study, we believe that, in some subsets of patients, PNI in the index lesion is likely to be a major prognostic factor even in the setting of metastatic nodal disease. Our data certainly supports that direct nodal invasion of nerves (included under nodal invasion of adjacent structures) has an independent adverse effect. The survival benefit of adjuvant radiotherapy cannot be measured precisely in a retrospective study of this nature because of patient selection bias. 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