ASC and AC share a similar histologic 3
and molecular 41
profile. ASC, however, has long been characterized as having a natural history distinctly more aggressive than that of AC. This has led some to question the role of aggressive treatment strategies for patients with this disease.2
The clinical significance of this rare diagnosis relative to AC is unclear, however, because the oncologic behavior of ASC has been described only by case studies and small, retrospective surgical series reporting patients with early stage cancers (Table ). Moreover, no prior case–control studies or population-based analyses have been performed to definitively establish clinical differences between ASC and AC. In this, the largest study of ASC reported to date, we used a large cancer registry to evaluate the clinical features and oncologic outcomes of patients with this diagnosis. Using a relatively unbiased dataset, we characterize the natural history of ASC and show that ASC is no more inherently aggressive than AC. Indeed, we demonstrate that patients with these two diagnoses have a similar natural history when treated using prevalent patterns of modern clinical practice.
Published case reports and clinical series of patients with pancreatic adenosquamous carcinoma, 1990–2010
ASC has been reported to represent up to 4% of pancreatic neoplasms, but in the largest series of specimens analyzed at autopsy, ASC was identified in only 0.9%.42
In this analysis of a large tumor registry, we found a diagnosis of ASC in approximately 0.4% of 24,604 patients with newly documented pancreatic malignancies recorded between 2000 and 2007. This is remarkably similar to the rate of 0.5% identified in a recent 16-year survey of the State of Michigan Tumor Registry.44
Like patients with AC, most of the patients with ASC presented late in their natural history. Indeed, over 50% of patients analyzed in this study initially presented with synchronous distant metastases. Among patients treated surgically, those with ASC had larger tumors than those with AC; however, a larger proportion of patients with locoregional ASC underwent resection than that with AC, and resected ASC specimens were associated with a similar high rate of regional lymphatic involvement—approximately 60%—as AC tumors. Together, these findings reveal that—although considerably rarer—ASC presents at a similar (albeit advanced) stage as AC and suggest that the two diagnoses share a common biologic behavior prior to diagnosis and treatment.
Stage-specific treatment algorithms for patients with AC are reasonably well-established.45
In contrast, the absolute infrequency of ASC has prohibited the development of standardized treatment protocols for this disease. Indeed, even the treatment of patients with early stage ASC remains controversial, due to reportedly dismal survival rates seemingly regardless of intervention.5
In a recent systematic review of prior reports, 39 patients with ASC who underwent surgery for non-metastatic disease had a median survival duration of 6.8 months (range, 4.6–9) and a 1-year survival rate of 25.5%.6
In two recent single-institution series, overall survival of resected patients was somewhat more favorable. Among 38 resected patients from Johns Hopkins, the median overall survival duration was 10.9 months from diagnosis.27
In another series from the Mayo Clinic, patients who underwent R0 or R1 resection had a median survival duration of 14.4 months and 8 months, respectively, compared to 4.8 months among patients treated without an operation.7
The patients in each group were not described, however, suggesting that patients who did not undergo resection had advanced disease, prior comorbidities, a depressed performance status, or a combination of these factors.
The efficacy of non-operative therapies among patients with ASC has not been rigorously evaluated. Only one prior study has examined the utility of adjuvant chemoradiation for patients with this disease. In that small, retrospective series, 19 (50%) patients who underwent postoperative chemoradiation had a more favorable median overall survival than 19 (50%) patients who did not (13.6 months v. 8.6 months, p
Although adjuvant chemoradiation was found to be the only significant prognostic factor with respect to overall survival on univariate analysis, the analysis suffered from clear selection bias. No studies have specifically studied the effects of systemic chemotherapy when administered in the adjuvant setting, nor its role as palliative therapy for patients with metastatic disease.
In this study, treatment of patients with ASC by surgical resection was associated with a more favorable overall survival relative to no resection, after adjustment for multiple clinical factors including disease stage. Moreover, the overall survival duration of patients with locoregional ASC who underwent surgery was similar to that of patients with locoregional AC who underwent resection in the same time period. Together with the recent single-institution data from high-volume pancreatic treatment centers,7
these data suggest that resection is a reasonable therapeutic approach for patients with ASC in whom a margin-negative resection can be performed safely.
The role of non-operative therapies for patients with ASC is less clear. Although we could demonstrate no association between the administration of adjuvant radiation or chemotherapy on the survival of patients with locoregional ASC following resection, it is interesting that of the only six 5-year survivors with ASC reported to date (four in this series and two in the Johns Hopkins series 27
), all received surgery and adjuvant therapy. Among patients with metastatic ASC, patients who received chemotherapy had a longer overall survival duration (4.5 vs 2 months) than patients who did not. The significance of this finding is uncertain, however, because individual performance status—the most influential factor with regard to the administration of anticancer therapy among patients with advanced pancreatic malignancy—was not recorded in the CCR.46
The absence of recorded performance status represents a fundamental limitation of this and other analyses of pancreatic malignancies using large, population-based datasets.
Two other limitations of this study are particularly noteworthy. Although attempts have been made to identify characteristic molecular fingerprints that may effectively distinguish between ASC and AC, the molecular profile of these two tumors are similar.41
Therefore, ASC must be distinguished from AC histopathologically. A strict diagnosis of ASC requires that a malignant squamous component represent at least 30% of a routinely sectioned adenocarcinoma.3
This arbitrary cutoff has introduced ambiguity to the diagnosis of ASC that reflects both the absence of standardization in histopathologic methods used to process surgical specimens and the subjectivity with which they are evaluated. Indeed, when 38 surgical specimens initially diagnosed as ASC at Johns Hopkins were re-evaluated by a single pathologist, 12 (32%) failed to meet strict criteria for the disease.27
Significantly, although the presence of any squamous component was associated with poor prognosis in the Johns Hopkins study relative to a historic control group of patients with AC, the proportion of the squamous component was not associated with overall survival. The rationale for the strict 30% cutoff is therefore unclear, and several investigators have proposed eliminating this criterion altogether.29
It is also possible that some diagnoses were coded incorrectly in the CCR; however, all diagnoses recorded therein were validated by histopathologic or cytopathologic analysis. Moreover, accuracy of the histopathologic diagnoses recorded in large databases has been evaluated and compared with independent histologic review, with favorable results.47
Nonetheless, the accuracy associated with the diagnosis of ASC may not be as favorable due to the stringent diagnostic requirements for this disease. A further potential for misclassification may exist among patients with advanced cancer treated non-operatively, for whom a large surgical specimen for histopathologic evaluation is absent. The extent to which our conclusions are influenced by this issue is unknown.
In summary, we conclude that ASC is an extremely rare subtype of pancreatic cancer that shares many clinical characteristics—including biologic behavior and overall prognosis—with AC. In this population, the overall survival duration of all patients with ASC and AC were similar after adjustment for multiple clinical factors, including stage at presentation and first treatment strategy. These data therefore refute prior suggestions that ASC is inherently more aggressive than AC and imply that a nihilistic view toward patients with ASC must be avoided. Absent the ability to perform prospective studies to determine the response of ASC to individual therapies, and given the molecular, histopathologic and clinical similarity of these diseases, we recommend the use of aggressive, stage-specific, multidisciplinary treatment protocols developed for AC.