Why is pancreatic cancer so deadly? The pathologist's view

Hruban, Ralph H.; Gaida, Matthias M.; Thompson, Elizabeth D.; Hong, Seung Mo; Noë, Michaël; Brosens, Lodewijk A.A.; Jongepier, Martine; Offerhaus, G. Johan A.; Wood, Laura D.

doi:10.1002/path.5260

Cited by 85 publications

(80 citation statements)

References 161 publications

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“…Pancreatic ductal adenocarcinoma develops through sequential genetic and epigenetic alterations in a number of driver genes, including KRAS , TP53 , SMAD4 , and CDKN2A . Accumulating evidence from engineered mouse models attests to the importance of PanIN as a precursor of PDAC .…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

et al. 2020

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There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co‐occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next‐generation sequencing of 50 cancer‐related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis.

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Section: Introductionmentioning

confidence: 99%

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

et al. 2020

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“…Several factors have been shown to have predictive or prognostic value for disease free or overall survival in resected PDA patients, including a high ratio of involved to total resected lymph nodes, larger tumor size, high tumor grade, the presence of vascular and perineural invasion, or variably positive margins (7)(8)(9). Venous invasion is very common in pancreatic cancer and may contribute to the aggressiveness of this disease (10). Molecular features of PDA have also been attributed to worse outcome after surgery.…”

Section: Introductionmentioning

confidence: 99%

“…Samples that did not contain more than 20 variant loci after applying this filter were excluded. In patient PAM41, a large cluster of highly related liver metastases (PT4,8,9,10,11) were simplified by including only sample PT9 to improve runtime. The resulting mutations and associated major and minor copy numbers were clustered with PyClone using default settings.…”

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confidence: 99%

Evolutionary Origins of Recurrent Pancreatic Cancer

Sakamoto

Attiyeh

Gerold

et al. 2019

Preprint

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Surgery is the only curative option for Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that adjuvant or first-line platinum therapy corresponds to an increased mutational burden of recurrent disease. Recurrent disease is enriched for mutations that activate Mapk/Erk and PI3K/AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings advocate for combination therapies with immunotherapy and routine post-treatment sampling as a component of management of recurrent pancreatic cancer.

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“…Die Prognose ist durch die späte Diagnose und durch die Tumoraggressivität bestimmt, welche multifaktoriell bedingt ist [1]. Diese Faktoren sind in der frühen venösen und perineuralen Invasion, der desmoplastischen Stromareaktion, dem "Tumor Immune Microenvironment" und den spezifischen genetischen Alterationen geschuldet [4,6].…”

Section: Prognose Und Nachsorgeunclassified

Pankreaskarzinom – Chirurgie im Wandel der multimodalen Therapiemöglichkeiten

Belyaev¹,

Uhl²

2019

Allgemein- und Viszeralchirurgie up2date

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Why is pancreatic cancer so deadly? The pathologist's view

Cited by 85 publications

References 161 publications

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

Evolutionary Origins of Recurrent Pancreatic Cancer

Pankreaskarzinom – Chirurgie im Wandel der multimodalen Therapiemöglichkeiten

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