• squamous cell carcinoma antigen;
  • anal carcinoma;
  • tumor markers;
  • recurrence;
  • disease-free survival


  1. Top of page
  2. Abstract


The objective of this retrospective study was to investigate the predictive value of pretreatment serum squamous cell carcinoma antigen (SCCAg) levels in 174 patients with squamous cell carcinoma of the anus who received concurrent chemoradiation between 1997 and 2010.


Pretreatment serum SCCAg measurements in patients with histologically diagnosed squamous cell carcinoma of the anal canal and margin who received chemoradiation were compared with clinical tumor classification and lymph node status for prognostic/predictive ability, including 1) tumor response after the completion of chemoradiation treatment, 2) disease recurrence, and 3) overall survival. Clinical measurements and scores were compared using Spearman rank tests, and survival was assessed in both univariate and multivariate survival analyses.


The median pretreatment levels of SCCAg according to clinical tumor classification and clinical lymph node status were 0.8 μg/L in T1 tumors, 1.90 μg/L in T2 tumors, 2.5 μg/L in T3 tumors, 3.8 μg/L in T4 tumors, 1.35 μg/L in patients with N0 status, and 3.05 μg/L in patients with N0+ status (correlation coefficient: T-classification, 0.43; lymph node status, 0.38; both P < .00001). Of the patients who had normal SCCAg levels, 95% achieved a complete response after initial treatment; and, of those who had elevated SCCAg levels, 86% achieved a complete response (P = .05). Overall survival (hazard ratio, 2.5; P = .007) and disease-free survival (hazard ratio, 2.2; P = .058) were worse for those who had elevated pretreatment serum SCCAg concentrations.


Pretreatment SCCAg levels in patients with squamous cell carcinoma of the anal canal and margin were correlated with clinical tumor classification and clinical lymph node status. Elevated levels of SCCAg were associated with a reduced chance of achieving a complete response and an increased chance of recurrence and death. The authors recommend further studies to determine the prognostic value of SCCAg in anal squamous cell carcinoma and suggest the potential use of SCCAg as a stratification factor in future trials. Cancer 2013;119:2391-2398. © 2013 American Cancer Society.


  1. Top of page
  2. Abstract

Squamous cell cancer (SCC) of the anal canal and margin (SCCACM) is a rare malignancy, with approximately 800 cases per year in the United Kingdom.[1] Tumor characteristics and TNM staging affect prognosis.[2] Historically, surgery has been the primary treatment,[3] but this has been replaced by concurrent chemoradiation (CRT).

Five phase 3 trials[4-8] have confirmed that the optimal schedule of CRT is mitomycin C, 5-fluororuacil (5FU), and radiotherapy. Prognostic factors in patients with SCCACM include skin ulceration, site (canal/perianal skin), tumor (T) classification (or tumor size >4 cm), lymph node involvement, and male sex.[9] Alongside clinical and radiologic evaluation, we hypothesized that SCC antigen (SCCAg) levels may help to stage primary disease or offer prognostic information to aid in the selection of treatment options.

SCCAg is a subfraction of TA-4, a tumor-associated antigen[10] characterized as a glycoprotein with a molecular weight of 48,000 Daltons. SCCAg was first obtained from SCC tissues of the uterine cervix[11] and is expressed in serum by several epidermoid tumors, including SCCACM. In cervical cancer, SCCAg has been correlated with initial tumor classification, lymph node involvement, and response to treatment[12] and can diagnose recurrence at an early stage. Individual studies[13-15] and a systematic review[16] have demonstrated a relation between high serum SCCAg levels and poor survival. For these reasons, SCCAg is a useful tumor marker in cervical cancer, but its utility as a tumor marker for SCCACM has been less thoroughly investigated.[17-20]

In our department, pretreatment SCCAg measurement by 1 of the 4 treating radiation oncologists (R.G.-J.) has been part of routine initial diagnostic workup before CRT in SCCACM since 1997. To serve as a reference, a serum sample of SCCAg is routinely taken at the patient's initial visit before the start of CRT. The objectives of our current study were to compare pretreatment serum SCCAg concentrations with clinical tumor (cT) classification and clinical lymph node (cN) status for their ability to predict 1) tumor response after the completion of CRT, 2) disease recurrence, and 3), overall survival (OS).


  1. Top of page
  2. Abstract

The current retrospective study was conducted in line with Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) criteria for the analysis and reporting of marker prognostic studies.[21] Mount Vernon Cancer Center serves a population in the United Kingdom of approximately 1.8 million, but patients with anal cancer are referred from a wider geographic area. We searched our prospectively maintained network database from the period 1997 to June 2010 for all patients who were diagnosed with SCCACM. The date of registration was taken as the date of diagnosis or, if this was unclear, we used the date 3 weeks before the start of treatment. Patients were included in this study if they had histologically confirmed squamous, basaloid, or cloaccogenic carcinoma of the anal canal and margin; an SCCAg measurement taken at the time they met an oncologist and before treatment; received concurrent CRT (defined as receiving at least 30 grays [Gy] in 2 Gy per fraction or less, with at least 1 cycle of concurrent CRT); and had attended at least 1 follow-up visit. We did not include patients who underwent surgical treatment alone, had metastatic disease at presentation, had received prior pelvic radiation, or were known to be positive for the human immunodeficiency virus. Survival was defined as the interval from the day of registration until the detection of recurrence (for disease-free survival [DFS]) or death (for OS). Survival data were censored at last known date of either follow-up or death.

Pretreatment investigations included biopsy, staging according to the 1997 International Union Against Cancer (UICC) staging system,[22] a full blood count, and liver and renal function tests. Evaluation of distant spread included thoracic and abdominopelvic computerized tomography scans. At our institution, magnetic resonance imaging has been used since 2003 and positron emission tomography has been used since 2005 in the initial staging of T2 tumors and more advanced tumors.

Blood samples for SCCAg baseline measurement were taken at the first consultation with an oncologist. Samples were separated within 1 hour and assayed using either the Abbott IMx SCC method for samples that were assayed from 1997 to 2004, or the Abbott Architect SCC method for samples that were assayed from 2004 to 2010 (Abbott Laboratories, Abbott Park, Ill). Both methods are automated immunometric immunoassays with a 2-step type format and are well correlated (r = 0.99).[23] According to the manufacturer, the analytical sensitivity of the Architect SCC assay (calculated as 2 standard deviations above the zero standard) is 0.10 μg/L, and the upper limit of normal for both methods is 1.50 μg/L.[24] Performance was monitored daily, and internal quality control samples ranging from 2 to 50 μg/L yielded interassay coefficients of variation <6%.

Treatment generally was delivered according to the schedule and techniques recommended within the UK Anal Cancer Trial (ACT 2) protocol,[25] which delivered a dose of 50.4 Gy in 28 daily fractions to the International Commission on Radiation Unit (ICRU) intersection point in 5.5 weeks by external-beam irradiation (EBRT) using a shrinking field technique without a gap. Thirty patients received a slightly varied dose and fractionation schedule as part of a pilot study of dose escalation, depending on T-classification.

Tumor response after the completion of CRT was assessed clinically at 6 weeks using magnetic resonance imaging or, if necessary, by an examination under anesthetic with biopsy of suspicious areas. Patients were followed according to clinical protocols, typically at 3-month intervals for the first year and every 6 months thereafter for 5 to 10 years, depending on patient preference. Ethical committee approval for retrospective analysis of samples for evaluation of tumor markers was obtained (LREC no. 07/Q0406/50).

Statistical Methods

We collected and analyzed data on tumor response to treatment and time-to-event analyses (DFS and OS). We conducted prespecified analyses of the relation between baseline SCCAg levels, clinical tumor parameters (T-classification and N status), and these outcomes. A cutoff level of 1.50 μg/L was used as the upper limit of normal for SCCAg. We also conducted exploratory analyses of age and sex and their relation with these outcomes so that we could adjust for the impact of these factors in possible multivariate analyses. A P value < .05 was considered statistically significant in all statistical analyses. All factors that were significant on univariate analysis were included in a subsequent multivariate model.

The predictive value of the clinicopathologic variables and time-to-event outcomes were assessed using univariate (log-rank test) and multivariate (Cox model) survival tests to generate hazard ratios (HRs). Because we could not assume a linear relation between baseline SCCAg levels and cT-classification and cN status, we used the Spearman rank-correlation method to ascertain any correlation between serum SCCAg concentrations and T-classification and N status. We assessed the impact of pretreatment SCCAg levels on the chance of achieving a complete response using the Mann-Whitney-U test and examined whether there was a difference between those who achieved a complete response and those who did not and by constructing a 2 × 2 table and calculating the odds ratio for achieving a complete response.

Following the recommendations of the REMARK group,[21] we used an internal control based on a smaller group of patients who were managed identically except they did not undergo pretreatment SCCAg testing. All statistical analyses were carried out using the open-source statistical software package “R” (R Foundation for Statistical Computing, Vienna, Austria).[26]


  1. Top of page
  2. Abstract

In total, 174 patients were identified from the Mount Vernon Cancer Center database who had received concurrent CRT for histologically proven SCCACM, who also had pretreatment SCCAg measured, and who had at least 1 follow-up visit. These patients included 68 men and 106 women, and their median age was 62 years (range, 30-91 years). Baseline patient characteristics, treatment, and outcomes are summarized in Table 1, and data on combined cT-classification and cN status are provided in Table 2.

Table 1. Baseline Characteristics for all 172 Patients
VariableNo. of Patients
  1. Abbreviations: 5FU, 5-fluororuacil; Cis, cisplatin; CRT, chemoradiotherapy; Gy, grays; MMC, mitomycin C; RT, radiotherapy.

  2. a

    The median RT dose was 50.4 Gy.

Age: Median (range), y62 (30-91)
Anal canal/margin128
Not documented34
Neoadjuvant CRT27
Capecitabine MMC4
Cisplatin alone2
5FU alone5
MMC alone2
RT dose, Gy 
Complete response131
All other responses16
Not documented27
Table 2. Combined Clinical Tumor Classification and Lymph Node Status for All 174 Patients
 Tumor Classification: No. of Patients
Lymph Node StatusT1T2T3T4Tx

All patients received concurrent CRT as primary treatment. One hundred thirty-three patients received 50.4 Gy in 28 fractions according to the ACT II protocol. The remaining patients received between 30 and 55.8 Gy but were treated with a similar technique. Concurrent CRT comprised mitomycin C (12 mg/m2) on day 1 of radiotherapy or cisplatin 60 mg/m2 on days 1 and 29 with 5FU 1000 mg/m2 over days 1 through 4 and days 29 through 32. One hundred forty-six patients received 5FU and mitomycin C, and 47 received cisplatin and 5FU. Further details of radiotherapy doses and chemotherapy regimens are provided in Table 1.

Delays to the start of radiotherapy meant that 28 patients received neoadjuvant chemotherapy followed by CRT, and 2 patients underwent planned surgery followed by CRT. All were included in the subsequent analyses. The median follow-up for patients who remained alive was 61 months (range, 0.46-193 months).

For the entire cohort, the OS rate was 90% at 2 years and 73% at 5 years, and 45 deaths were recorded. The recurrence-free survival (RFS) rate was 84% at 2 years and 71% 5 years. Of all 174 patients, 103 (49%) had an elevated baseline SCCAg level (>1.50 μg/L). The median baseline SCCAg level according to disease stage is provided in Table 3. There was a significant correlation between T-classification and N status and SCCAg level (P < .0001).

Table 3. Median Squamous Cell Carcinoma Antigen Level by Tumor Classification and Lymph Node Status
Disease StageMedian Baseline SCCAg (IQR), ng/dL
  1. Abbreviations: cN, clinical lymph node status; IQR, interquartile range; SCCAg, squamous cell carcinoma antigen.

Clinical tumor classification 
cT180 (42.5-127.5)
cT2190 (87.5-325)
cT3250 (157.5-640)
cT4380 (215-2240)
Clinical lymph node status 
cN0135 (70-265)
cN+305 (160-585)

Baseline Squamous Cell Carcinoma Antigen and Prediction of Response

One hundred forty-six of 174 patients (84%) had a documented response, including 131 patients (75%) who achieved a complete response with primary therapy, as assessed at a median interval of 60 days after the completion of CRT. The odds of failing to achieve a complete response were increased in the presence of a raised baseline SCCAg level (odds ratio, 2.8) (see Table 4), although the increase was not statistically significant (95% confidence interval, 0.96-8.29).

Table 4. Baseline Squamous Cell Carcinoma Antigen Levels in Patients Who Did and Did Not Achieve a Clinical Complete Response
SCCAg StatuscCRNo cCR
  1. Abbreviations: cCR, clinical complete response; SCCAg, squamous cell carcinoma antigen.


Survival Analyses

Primary analyses of DFS and OS were conducted that included clinical tumor classification, lymph node status, and pretreatment SCCAg concentration. We also conducted additional exploratory analyses against age (>65 years) and sex. Kaplan-Meier curves for RFS and OS are provided in Figures 1 and 2, respectively, with patients stratified according to baseline SCCAg. Both OS and RFS were worse for those who had raised baseline SCCAg values compared with those who had normal pretreatment values, although only the difference in OS was statistically significant (OS: HR, 2.46; P = .005; RFS: HR, 2.23; P = .052 for RFS) (Figs. 3, 4). On univariate analysis, higher T-classification (greater than cT2: HR, 2.56; P = .03), positive lymph node status (cN+: HR, 2.61; P = .002), and an elevated baseline SCCAg all had prognostic significance in relation to OS; however, sex (HR, 0.664; P = .17) and age >65 years (HR, 1.73; P = .07) were not significant. None of these factors were related significantly to RFS. However, on multivariate analysis, none were retained as statistically significant variables with respect to OS (all P > .05) (for details, see Table 5), and none were associated with DFS (Table 6).


Figure 1. Overall survival in months.

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Figure 2. Recurrence-free survival in months.

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Figure 3. Overall survival in months, stratified by baseline SCCAg. Red indicates SCCAg > 150 microg/L.

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Figure 4. Recurrence-free survival in months, stratified by baseline SCCAg. Red indicates SCCAg > 150 microg/L.

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Table 5. The Significance of Possible Diagnostic Variables in Relation to Overall Survival
 Univariate Analysis Multivariate Analysis
VariableHR for OSP for OSIncluded in Multivariate Analysis?HR for OSP for OS
  1. Abbreviations: HR, hazard ratio; NA, not available; OS, overall survival; SCCAg, squamous cell carcinoma antigen.

Tumor classification ≥T22.56.002Yes1.93.059
Lymph node-positive disease2.61.001Yes1.23.57
Age >65 y1.73.065NoNANA
SCCAg >150 ng/dL2.46.0049Yes1.8.57
Table 6. The Significance of Possible Prognostic Variables in Relation to Recurrence-Free Survival
 Univariate Analysis Multivariate Analysis
VariableHR for RFSP for RFSIncluded in Multivariate Analysis?HR for RFSP for RFS
  1. Abbreviations: HR, hazard ratio; NA, not available; RFS, recurrence-free survival; SCCAg, squamous cell carcinoma antigen.

Tumor classification ≥T22.52.019NA1.9.13
Lymph node-positive disease0.92.84NoNANA
Age >65 y1.16.7NoNANA
SCCAg >150 ng/dL2.23.0519No1.96.12

For an internal control, we assessed outcomes in patients who did not have SCCAg measurements taken, and OS and RFS did not differ significantly in this group compared with the larger cohort. Thus, there is little evidence to suggest that the patients who had SCCAg measurements recorded formed a group with a better prognosis than all patients with SCCACM who received concurrent CRT.


  1. Top of page
  2. Abstract

To our knowledge, this is the largest published study to date that examines the role of SCCAg in anal cancer. We investigated newly diagnosed patients who received treatment in a consistent fashion.

We have demonstrated that pretreatment SCCAg concentration correlates with cT-classification and cN status, thus also correlating with overall tumor burden. High pretreatment SCCAg levels also increased the likelihood of failing to achieve a complete response, although this difference was not statistically significant. Compared with patients who had normal pretreatment SCCAg levels, DFS and OS were worse for those who had raised serum SCCAg levels, although only OS was significantly lower. Univariate analysis confirmed that, as expected, cT-classification and positive cN status also were significant predictors of OS. All 3 factors had similar predictive power for OS with median HRs ranging from 2.46 to 2.61. We have demonstrated that baseline SCCAg levels are correlated with cT-classification and cN status.

We recognize the limitations of our retrospective study, which was open to chance findings and had a small, unplanned sample size. The current findings will require validation in larger, independent data sets.

Although increased levels of SCCAg have been observed in nonsquamous malignancies and benign conditions,[27] measurement of SCCAg is a reproducible assay.[23] We used the manufacturer's recommended cutoff of <1.5 μg/L, which was derived from a study of 616 healthy volunteers in which 95.6% of individuals had SCCAg values <1.5 μg/L.[24] However, a separate report of SCCAg measurement in cervical cancer argued that a 99% cutoff of 1.9 μg/L should be used to achieve better disease discrimination; and, more recently, an even higher cutoff of 4.5 μg/L[28] was suggested.

In the current study, the pretreatment SCCAg level was correlated with cT-classification and cN status (P < .0001 for both). In a previous study of anal cancer, SCCAg levels were correlated with lymph node invasion (P < .05) but not T-classification (P < .05) and did not offer any prognostic value.[17] In another study that included 60 patients, actuarial survival analyses of patients who had normal versus elevated SCCAg concentrations indicated that the projected 5-year OS rate was 81% for those with normal levels and 43% for those with elevated levels (P = .004). For DSS, the rates were 83% versus 45%, respectively (P = .004).[20] The current study documents levels of SCCAg before the receipt of definitive treatment in a cohort of patients who were treated in a very similar fashion, whereas other reports have included a mixture of patients with primary and recurrent disease, including metastases.[19]

In patients with cervical carcinoma, more advanced tumor classifications are associated with higher levels of serum SCCAg.[29] The reported sensitivity of serum SCCAg in cervical carcinoma is 29% in stage I disease and 89% in stage IV disease.[29] In early stage cervical cancer, the preoperative SCCAg level has been identified as an independent predictor of recurrence and may have prognostic value in deciding on the need for adjuvant radiotherapy.[30] The pretreatment SCCAg level is related to known prognostic markers, such as parametrial invasion and lymph node involvement[31]; and, during follow-up, a rise in SCCAg can precede a clinical manifestation of recurrence.[32] Additional studies have corroborated the clinical utility of SCCAg in cervical carcinoma, identifying a high SCCAg level as an independent sign of a poor prognosis.[13, 33] However, some authors have debated its cost-effectiveness in follow-up.[34, 35]

The correlation of SCCAg levels with more advanced tumor classification also has been observed in other tumor sites, including head and neck sites; and, as in cervical cancer, a rise in SCCAg during follow-up may predate clinical recurrence.[36, 37] The reported sensitivity of SCCAg in head and neck cancer is only 25.7% at diagnosis, although an abnormal level is more common with lymph node involvement.[37]

Lymph node status at diagnosis can be difficult to establish in patients with anal carcinoma. Although cancers of the anal margin tend to drain to the superficial inguinal lymph nodes, more proximal lesions at the dentate line can exhibit a pattern similar to that of rectal cancers, extending either to pararectal lymph nodes or along inferior and middle hemorrhoidal vessels to the obturator lymph nodes.

Approximately 33% of patients have clinically enlarged inguinal lymph nodes; however, if biopsied, only 50% of these will confirm metastatic spread, whereas the remaining patients have lymph nodes enlarged by secondary infection.[38] Some suggest that smaller lymph nodes (4-7 mm) are more likely to harbor metastases than larger lymph nodes.[39] Some patients demonstrate borderline enlarged lymph nodes in pararectal tissues or pelvis on computerized tomography of the pelvis. Hence, the SCCAg level may provide useful supportive evidence when lymph node involvement is suspected. Therefore, currently, it is our practice to encompass borderline or equivocal lymph nodes in our high-dose radiation volume if the SCCAg level is elevated above the expected range for T-classification.

Based on the data available in our study, it is unclear why SCCAg should be associated significantly with OS but not DFS. Previous authors have noted that elevated SCCAg is associated with apparent radioresistance in cervical cancer. In our study, all locoregional recurrences occurred with the phase 1 (30.6 Gy) volume, and almost all primary tumor recurrences were within the high-dose volume. We suspect that, although SCCAg is correlated with both T-classification and N status, clinical lymph node evaluation is less reliable than T-classification; therefore, elevated SCCAg may be a marker of unsuspected lymph node involvement and, thus, may be associated with metastatic (hence fatal) relapse. This is supported by the observation that patients who relapse often have a poor prognosis despite apparently curative surgical salvage There is also the possibility that SCCAg is a marker for patients with other squamous malignancies, and our series included a few patients who had equivocal lung nodules on initial staging and were diagnosed later with lung cancer.

When assessing a possible new prognostic factor, it is important to consider how much additional information it lends. In our study, pretreatment SCCAg was not significant when assessed multivariately with T-classification and N status. However, this may be a function of the relatively small sample size, because, although there is a correlation between SCCAg levels and T-classification and N status at diagnosis, the explanatory power of each is only 10% (measured as R2, where R is the correlation coefficient). This suggests that SCCAg may capture some separate component of the tumor's characteristics aside from that captured by the clinical staging.

Retrospective studies of tumor markers are open to a variety of biases, which we have tried to avoid or control. Our patients were a clinically relevant group that received broadly uniform treatment, thus making interpretation of outcomes easier. We have controlled our time-to-event analyses for known prognostic factors (cT-classification and cN status) as well as age. Because we are measuring levels of a possible marker in a blood sample using a standardized assay, there may be fewer grounds for concern over reproducibility than with more complex and subjective markers, such as histologic parameters, although the ideal cutoff level for SCCAg remains open to debate. Previous studies have used values of 200 ng/dL in anal cancer and 150 to 450 ng/dL in cervical cancer, but the justification for this is unclear. The manufacturer of the test recommends a cutoff of 150 ng/dL on the basis of a large sample of the normal population. For reasons of simplicity and clarity, this value was used in the current study. Although both DFS and OS differed significantly in the presence of raised SCCAg values compared with initial normal values, an examination of the relation between different cutoff levels and outcomes may be a useful part of a further study, and this would be done best in the context of a prospective trial.

The timing and definition of response evaluation in SCCACM is poorly documented in the literature. Early response to CRT determined by conventional radiologic imaging can prove difficult and unreliable because of associated inflammatory changes. Clinical response is usually assessed at 6 to 12 weeks after the completion of CRT treatment, by which time 60% to 85% of patients achieve a complete clinical response. Currently, the reproducibility of assessment remains unclear.

In the future, cytostatic treatments may complicate assessment further. Hence, a robust response marker to facilitate patient stratification would be useful. SCCAg analysis may enable the identification of a group of patients with a high risk of failure after CRT and allow the consideration of alternative therapeutic strategies, such as surgical salvage.

In conclusion, in this series of 174 patients with SCCACM who had an SCCAg assessment before CRT, the initial SCCAg level before treatment was strongly correlated with tumor classification and lymph node status (P < .0001). Patients who had elevated SCCAg levels were less likely to achieve a CR and had a worse prognosis in terms of DFS and OS. Further studies are warranted to determine the strength of SCCAg levels as an independent prognostic factor in patients with SCCACM.


  1. Top of page
  2. Abstract
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