Immunohistochemical profiling of liver metastases and matched-pair analysis in patients with metastatic pancreatic ductal adenocarcinoma
Introduction
The worldwide incidence of pancreatic cancer amounts to approximately 430,000 cases per year and appears to be increasing [1]. Reflecting its poor prognosis, pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related death in Europe, and the 5-year overall survival (OS) rate of approximately 8% is among the lowest of all solid cancers [2]. Radical resection is the only potentially curative treatment, but the prognosis remains poor and relapse is frequent. Because of its late presentation, PDAC often results in a medical emergency requiring immediate intervention [3].
Metastatic spread occurs rather late in the genetic evolution of PDAC [4] suggesting that early detection of PDAC could improve the clinical outcome [5]. However, because there are few and unspecific symptoms, the disease is usually detected late, and around 80% of patients already have locally advanced tumor growth or distant metastasis at initial diagnosis, with the liver being the most frequent metastatic site [6]. Although previous studies on the feasibility of resecting pancreatic metastases in selected patients reported promising results [7,8], the therapeutic options in stage IV pancreatic cancer remain limited. While most studies on the immunohistochemical profile of PDAC focus on the primary tumor, systematic histopathological investigation of LM is uncommon. The histopathological classification of PDAC in a pancreatobiliary (PB) and intestinal (INT) type has been reported previously [[9], [10], [11]]. Immunohistochemical (IHC) staining with a panel including cytokeratin (CK) 7, CK20, mucin (MUC) 1, MUC2, and CDX2 further aids in distinguishing between both histopathological types (PB-type: CK7+ MUC1+; INT-type: CK20 + MUC2+ CDX2+) [10]. PDAC with an INT-type in the primary tumor was reported as an independent predictor for better OS [12], but the impact of this type in LM has not been investigated.
Epithelial-mesenchymal transition (EMT), accompanied by loss of E-cadherin and expression of mesenchymal markers such as vimentin, has been associated with invasive tumor growth and metastatic spread in several solid cancers [13]. Furthermore, the EMT program is known to induce cancer stem cell formation and enhance chemoresistance in PDAC [14]. The presence and potential prognostic impact of EMT in LM of PDAC has not been investigated.
Somatic mutation of SMAD4 through deletion or intragenic mutation occurs in around 55% of PDAC patients [15]. The loss of SMAD4 expression is associated with distant metastasis and poor prognosis in patients with PDAC by altering cellular signaling in the transforming growth factor (TGF) β pathway [6]. CDX2 functions as a major transcriptional regulator of intestinal cell differentiation and is used as a marker to assign adenocarcinomas of unknown primary to colorectal lineage [16]. The reported prognostic implications of positive CDX2 staining in PDAC are unclear [16,17].
As previously reported [18], different morphological patterns of LM are associated with different prognosis in patients with colorectal cancer. The infiltrative front at the LM tumor periphery has been classified as replacing, pushing, or desmoplastic [19]. However, the incidence and prognostic impact of different LM infiltration patterns in PDAC have yet to be investigated.
Previous studies suggested limited molecular divergence between primary tumors and distant metastases in an unpaired analysis [20]. To understand underlying factors of metastatic spread in patients with PDAC, comparison of paired patient samples is essential but severely limited because sufficient tissue from both the primary tumor and LM is rarely available.
The purpose of the current study was to use immunostaining to characterize LM in patients with PDAC adenocarcinoma to identify prognostic factors. In a separate subgroup analysis, paired samples (primary tumor and LM) from the same patient were evaluated to identify differences in the IHC profile.
Section snippets
Patients and tissues
Following approval by the regional ethics committee in Stockholm, data were screened from 427 patients who had histologically confirmed LM of metastatic adenocarcinoma and who were included in the cancer register at the Karolinska Institute, Stockholm, Sweden. All patients who met the following criteria were included in this retrospective study: (i) diagnosis of metastatic PDAC on imaging (CT, PET-CT, MRI or EUS); (ii) histomorphology of the LM that is consistent with metastatic PDAC; and (iii)
Clinicopathologic assessment
Most tumors were located in the pancreatic head (n = 28, 40.6%), followed by the pancreatic body (n = 21, 30.4%) and tail (n = 20, 28.9%). Most tumors were in advanced stages (T3/4, n = 53, 76.8%) and had spread to regional lymph nodes. The median level of carbohydrate-antigen 19-9 (CA19-9) at initial diagnosis was 2223 kU/L (range, 6–1044000 kU/L). Surgical resection was performed in only seven patients (9.1%) without distant metastasis at the initial diagnosis. However, all seven patients
Discussion
PDAC has a poor prognosis because of aggressive, locally invasive tumor growth and frequent metastatic spread. Metastases were previously shown to develop late in the lengthy genetic evolution of PDAC [4], but recent studies suggest that distant tumor spread may occur much earlier than anticipated [29]. Because of occult clinical symptoms and late presentation, only around 20% of patients with PDAC are eligible for surgical resection with curative intent [6]. To date, research, particularly
Author contributions
T. H.: Data curation, statistical analysis, investigation, validation, methodology, visualization, writing-original draft, writing-review, editing. C. S. V. (Caroline S. Verbeke): Data curation, pathology review, statistical analysis, investigation, validation, methodology, project administration, writing-review, editing. O. S., M. B. and R. H.: Data curation, validation, methodology, project administration, writing-review, funding, editing. W. R.: Data curation, investigation, visualization,
Funding
This current analysis was supported by grants from the Stockholm County Council, the Swedish Cancer and Allergy Foundation, and by the research funds of the Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska University Hospital, Stockholm, Sweden.
Conflicts of interest
The authors declare they have no conflict of interest.
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