The biology of pancreatic cancer morphology

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal of all human malignancies. PDAC precursor lesions, invasive primary PDAC, and metastatic PDAC each display distinct morphologies that reflect unique biology. This 'biomorphology' is determined by a complex neoplastic history of clonal phylogenetic relationships, geographic locations, external environmental exposures, intrinsic metabolic demands, and tissue migration patterns. Understanding the biomorphological evolution of PDAC progression is not only of academic interest but also of great practical value. Applying this knowledge to surgical pathology practice facilitates the correct diagnosis on routine H&E stains without additional ancillary studies in most cases. Here I provide a concise overview of the entire biomorphological spectrum of PDAC progression beginning with initial neoplastic transformation and ending in terminal distant metastasis. Most biopsy and resection specimens are currently obtained prior to treatment. As such, our understanding of untreated PDAC biomorphology is mature. The biomorphology of treated PDAC is less defined but will assume greater importance as the frequency of neoadjuvant therapy increases. Although this overview is slanted towards pathology, it is written so that pathologists, clinicians, and scientists alike might find it instructive for their respective disciplines.

Keywords: Pancreatic cancer; biology; morphology; pancreatic ductal adenocarcinoma; pathology.

Fig. 1

Biomorphology of PDAC precursor lesions. (A) At low magnification acinar to ductal metaplasia (ADM) maintains a lobular architecture surrounded by a fibroinflammatory stroma. Metaplastic ducts are seen on the periphery and residual acinar units on the interior. (B) At high magnification metaplastic ducts show morphology that overlaps with malignancy including luminal necrosis, nuclear atypia, and jagged glandular outlines. (C) The ADM ductal units in B are more atypical than this bland-appearing PDAC that is infiltrating adjacent to a large vessel. (D–F) Dysplasia increases as genetic drivers accumulate during precursor progression. (G) Gene:environment positive feedback maintains precursor lesions.

Fig. 2

Biomorphology of neoplastic surface spread. (A) Periampullary ducts from the pancreas are situated within the ampullary wall muscle bundles. (B) Intraductal spread of invasive PDAC into the periampullary lumens. (C) An intestinal type intraductal papillary mucinous neoplasm (IPMN) has spread through the periampullary ducts and colonised the surface of the ampullary mucosa. This will mimic an ampullary villous adenoma on a biopsy. (D) Invasive PDAC has invaded directly through the wall of the duodenum (arrows) and colonised the duodenal mucosal surface. This may also simulate a surface adenoma on a biopsy. (E) High power magnification shows focal perineural invasion (arrows) in otherwise normal appearing pancreatic parenchyma. This was a grossly negative resection margin located 1 cm from the primary tumour mass. (F) Low power magnification of peripancreatic fibroadipose tissues shows a large nerve (outlined) with perineural invasion (arrows). This was a frozen section of a resection margin with no grossly identified tumour mass.

Fig. 3

Biomorphology of primary PDAC and the hallmark desmoplastic stroma. (A) An intraductal papillary mucinous neoplasm (IPMN) has grown into a large nerve (flanked by arrows). The neoplastic epithelium has anchored onto the nerve. Is this an event that facilitates malignant transformation? (Slide kindly shared by M. Garcia-Buitrago.) (B) The schematic depicts secretory matrix opposition between myofibroblast-type cancer-associated fibroblasts (myCAFs) and PDAC that occurs within the tumour stroma. (C) The schematic depicts secretory matrix cooperation between inflammatory-type cancer-associated fibroblasts (iCAFs) and PDAC that occurs within the tumour stroma. (D) Low power magnification shows a large PDAC gland encased within densely fibrotic stroma. (E) High power magnification of CAFs residing in fibrotic areas. These could represent myCAFs. (F) Low power magnification shows PDAC glands encased within a partially fibromyxoid stroma. (G) High power magnification of CAFs residing in fibromyxoid areas. Patrols of inflammatory cells are also often in fibromyxoid stroma, although they are ineffective at controlling the PDAC invaders.

Fig. 4

Biomorphology of subclonal evolution. (A) Low power magnification shows a well-differentiated (classic) glandular subclone on the left and a poorly differentiated squamous-like subclone on the left. Note the sharp boundary between them. (B) Low power magnification of a large duct subclone. The ducts are often as large as the main pancreatic duct. (C) Low power magnification of a small duct subclone. The ducts are so small they may be difficult to see at low power. (D) High power magnification of a clear/foamy gland subclone with characteristic pale cytoplasm and raisinoid nuclei. (E) High power magnification of a poorly differentiated subclone. Note small clusters and single cells infiltrating in the stroma. (F) High power magnification of a squamous-like subclone. The tumour in this example grows as sheets of poorly differentiated pink cells with little intervening stroma. These subclones usually express patchy p63 by immunohistochemistry. (G) High power magnification of an undifferentiated subclone. The cells are discohesive and do not form glands or nests. (F) High power magnification of a pleomorphic liposarcoma (PLS)-like subclone. This is a variant I have occasionally noticed in practice. (G) High power magnification of a sarcomatoid subclone. The overtly malignant spindle cells are tightly packed with little intervening stroma.

Fig. 5

The biomorphology of metastatic PDAC. (A) Low power magnification shows that metastatic peritoneal implants resemble stellate scars. (B) Some peritoneal PDACs are encased within densely fibrotic stroma. (C) Others are encased within fibrofibromyxoid stroma. (D) Schematic illustrating positive feedback loops between nutrient transport systems and pro-tumourigenic biosynthetic enzymes that produce anabolic metabolites and/or reprogram chromatin for metastasis. (E) High power magnification of a distant metastatic PDAC with ‘biosynthetic’ morphology and an underdeveloped ‘delicate’ stroma. (F) Masson trichrome stain highlights the delicate pericellular fibrosis. (G) A liver metastasis seeded by a well-differentiated clear/foamy gland subclone forms back-to-back glands with delicate intervening stroma. (H) Likewise, a liver metastasis seeded by a poorly differentiated subclone is highly cellular with a delicate stroma. (I) In many instances, half of the core biopsy of a liver metastasis is viable tumour while the other half is necrotic. (J) Liver metastases may show well-developed fibrosis beneath the liver capsule. Such metastases are usually implants on the liver surface rather than true haematogenous metastases. (K) Low power magnification of a metastatic PDAC to the lung shows ‘lepidic’ growth within alveoli. (L) Like liver metastases, lepidic metastases develop a delicate stroma and glands are adjacent to native vessels (arrows).