DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer

Abstract

Purpose: Contrary to the extensive data accumulated regarding pancreatic carcinogenesis, the clinical and molecular features characteristic of advanced stage (stage III and IV) disease are unknown. A comprehensive study of pancreatic cancers from patients who have succumbed to their disease has the potential to greatly expand our understanding of the most lethal stage of this disease and identify novel areas for intervention.

Materials and methods: Rapid autopsies were performed on 76 patients with documented pancreatic cancer. The histologic features of end stage disease were determined and correlated to the stage at initial diagnosis, patterns of failure (locally destructive v metastatic disease) and the status of the KRAS2, TP53, and DPC4 genes.

Results: At autopsy, 30% of patients died with locally destructive pancreatic cancer, and 70% died with widespread metastatic disease. These divergent patterns of failure found at autopsy (locally destructive v metastatic) were unrelated to clinical stage at initial presentation, treatment history, or histopathologic features. However, Dpc4 immunolabeling status of carcinoma tissues harvested at autopsy, a sensitive marker of DPC4 genetic status, was highly correlated with the presence of widespread metastasis but not with locally destructive tumors (P = .007).

Conclusion: Pancreatic cancers are represented by distinct genetic subtypes with significantly different patterns of failure. Determinations of DPC4 status at initial diagnosis may be of value in stratifying patients into treatment regimens related to local control versus systemic therapy.

Fig 1.

(A) Example of locally advanced pancreatic cancer found at autopsy. The carcinoma measured 10 cm in greatest dimension and directly invaded the duodenum (d) and occluded the celiac artery (ce). The ultimate cause of death in this patient was bowel ischemia and peritonitis. (B) Example of a patient with limited metastatic burden at autopsy (≤ 10). Similar to that described for the carcinomas in (A), this patient also died of complications of locally advanced carcinoma (ascending cholangitis) even though at initial presentation limited metastatic disease was present. (C) Example of a patient with extensive metastatic burden at autopsy (> 1,000). The cause of death for this patient was hepatic failure secondary to massive tumor burden.

Fig 2.

(A) Frequency of metastatic involvement by pancreatic cancer to various organ sites. The liver is the most common site of metastatic spread, followed by the peritoneum and lung. (B) Total number of target organs involved by metastatic disease. The majority of patients had metastatic disease limited to three or fewer organ sites, although in a subset of patients four or more target organs were affected. LN, lymph node.

Fig 3.

Examples of high grade pancreatic cancer identified at rapid autopsy. (A) Diffusely infiltrative signet ring carcinoma. The single cells contain a prominent mucin vacuole that displaces the nucleus to the cell periphery. Note the lack of a desmoplastic response as is typically seen for conventional infiltrating pancreatic cancer. Signet ring carcinoma was present at initial presentation of this patient. (B) Undifferentiated anaplastic carcinoma. The cells show marked nuclear enlargement and pleomorphism with complete loss of cellular adhesion. This patient underwent surgical resection of a moderately differentiated duct (tubular) adenocarcinoma and completed adjuvant chemoradiotherapy but recurred 21 months postresection with undifferentiated carcinoma. (C) Pancreatic carcinoma showing both differentiated (right side) and undifferentiated (left side) morphologies. Similar to the patient described for (B), this patient also underwent surgical resection of a moderate to poorly differentiated duct (tubular) adenocarcinoma but recurred 4 months postresection. The overall survival for this patient was 23 months. (D) E-cadherin labeling of the carcinoma shown in (C) indicates the loss of E-cadherin expression in the undifferentiated carcinoma, in striking contrast to the moderately differentiated carcinoma present in the same section. (E) Small focus of anaplastic carcinoma (indicated by arrowheads) in an otherwise moderately differentiated adenocarcinoma. An asterisk indicates a focus of moderately differentiated carcinoma present in the same section. (F) E-cadherin labeling of this same region indicates loss of E-cadherin expression in this small focus of undifferentiated carcinoma (≈1% of the cancer volume), whereas E-cadherin expression is retained in the moderately differentiated component.

Fig A1.

(A) Positive Dpc4 immunolabeling in a locally advanced carcinoma that was associated with limited metastatic disease burden (< 10 documented metastase). (B) Loss of Dpc4 immunolabeling in a primary carcinoma associated with widespread metastatic disease (> 1,000 documented metastases).