Current Pathology Model of Pancreatic Cancer

Abstract

Pancreatic cancer (PC) is one of the most aggressive and lethal malignant neoplasms, ranking in seventh place in the world in terms of the incidence of death, with overall 5-year survival rates still below 10%. The knowledge about PC pathomechanisms is rapidly expanding. Daily reports reveal new aspects of tumor biology, including its molecular and morphological heterogeneity, explain complicated "cross-talk" that happens between the cancer cells and tumor stroma, or the nature of the PC-associated neural remodeling (PANR). Staying up-to-date is hard and crucial at the same time. In this review, we are focusing on a comprehensive summary of PC aspects that are important in pathologic reporting, impact patients' outcomes, and bring meaningful information for clinicians. Finally, we show promising new trends in diagnostic technologies that might bring a difference in PC early diagnosis.

Keywords: morphological subtyping; pancreatic adenocarcinoma; pancreatic cancer heterogeneity; pancreatic cancer spectroscopy; pancreatic neural remodeling; pathology reporting.

Figure 2

Selected WHO and non-WHO morphological subtypes of PDAC: (A)—clear cell subtype, (B)—colloid subtype, (C)—foamy gland pattern, (D)—PDAC derived from IPMN, invasive component, (E)—large duct/cystic papillary pattern, (F)—large duct/cystic papillary pattern negative for elastic stain, (G)—high-grade squamous differentiation, (H)—low-grade squamous differentiation—reproduced with permission from Kalimuthu et al., Gut, published by BMJ, 2020 [17], (I)—vacuolated cell pattern—reproduced with permission from Samad et al., Diagnostic Cytopathology, published by Wiley Periodicals, Inc., 2014 [79]; PDAC, pancreatic ductal adenocarcinoma; IPMN, intraductal papillary mucinous neoplasm; (A–F) orcein stain; original magnification (A,C,D,G–I) 100×, (B,E,F) 40×.

Figure 1

Main trends in PDAC pathology and research that are expected to improve survival. Poor PDAC patients’ prognosis is multifactorial—no sensitive and specific early diagnostic methods is one of the reasons. Another is the resistance to available therapeutic options, which is caused, among other things, by the tumor’s molecular and morphological heterogeneity. Detailed pathological reporting is crucial for targeted and personalized therapy. The development of new diagnostic methods, combined with a proper pathologic evaluation and spectroscopic profiling, leads to effective treatment. Altogether, this will increase PDAC patients’ survival rates. PDAC, pancreatic ductal adenocarcinoma; LIF, leukemia inhibitory factor; IL-6, interleukin-6; cfDNA, cell-free DNA; FTIR, Fourier transform infrared spectroscopy; Raman, Raman spectroscopy; SERS, surface-enhanced Raman spectroscopy; NGS, next-generation sequencing; ICB, immune checkpoint blockers; NRF2, nuclear factor-erythroid 2–related factor 2; GEM, gemcitabine; PANR, PDAC-associated neural remodeling; CAFs, cancer-associated fibroblasts; CSCs, cancer stem cells; EGFR, epithelial growth factor receptor.

Figure 3

Morphological classifications: (A)—proposed by Kalimuthu et al. [17], and (B)—proposed by Sántha et al. [18]. See the text (Section 6) for further details on the topic. Images are reproduced with permission from Kalimuthu et al., Gut, published by BMJ, 2020 [17] and from Sántha et al., Cancers, published by MDPI, 2021 [18].

Figure 4

Direct lymph node involvement by PDAC (NI): Almost the whole left part (A) and more than an upper two-thirds (B) are occupied by solid PDAC growth, which directly invades the remnants of a lymph node (asterisks). This form of NI in PDAC has a different prognostic significance compared to a true metastatic spread (arrows in (C,D)). See the text (Section 12) for further details on the topic. (H&E stain, original magnification ×4).

Figure 5

Spectroscopic mapping of ampullary adenocarcinoma: A hematoxylin-eosin slide image of ampullary cancer tissue with superimposed FTIR and Raman hyperspectral maps treated with hierarchical cluster analysis, and averaged spectra with corresponding second derivatives from each cluster; spectroscopic maps cover both cancerous (red circle) and noncancerous—stroma (green circle) tissue fragments. Reproduced with permission from Szymonski et al., Clinical Spectroscopy, published by Elsevier B.V, 2021 [251]. FTIR, Fourier transform infrared spectroscopy.