Morphology Matters

Abstract

The 2019 World Health Organization (WHO) classification of colorectal carcinoma (CRC) profoundly reclassified CRC subtypes and introduces tumor budding as a second major grading criterion, while condensing conventional grade into a 2-tiered system. So far it remains largely unexplored how these parameters interact with each other and whether they truly have an independent impact on patient prognosis. We reclassified a large single-center cohort of 1004 CRCs spanning 2 decades for adjusted WHO grade (low vs. high), tumor budding (Bd1/Bd2/Bd3), and CRC subtype (adenocarcinoma not otherwise specified, micropapillary, mucinous, serrated, medullary, adenoma-like, signet-ring cell, mixed adenoneuroendocrine carcinoma/neuroendocrine carcinoma, undifferentiated) according to the criteria of the 2019 WHO classification. We investigated the interaction of these parameters, their connection to stage/microsatellite status, and their significance for patient survival in the different subgroups. Specific subtypes other than adenocarcinoma not otherwise specified represented one third of all CRCs and were unevenly distributed throughout stage and microsatellite subgroups. Subtypes, WHO grade and tumor budding profoundly impacted all survival parameters (P<0.001 for all analyses), with CRC subtypes and tumor budding—but not WHO grade—being stage-independent prognosticators for all survival comparisons. WHO grade had very limited prognostic value in CRC subtypes, while tumor budding retained its strong prognostic impact in most scenarios. Accurate delineation of CRC subtypes introduced in the 2019 WHO classification provides strong stage-independent prognostic information, arguing that they should be considered in pathology reports and in clinical trials. Of the morphology-based grading schemes included in the 2019 WHO, tumor budding outperforms WHO grade.

Neuroendocrine Differentiation in Conventional Colorectal Adenocarcinomas: Incidental Finding or Prognostic Biomarker?

“…There were 581 male patients and 432 female patients. As expected, pTNM/UICC stage, WHO grade and resection status were significantly associated with OS, DSS and DFS (Supplementary Table S1) [4].…”

“…The treatment concepts of included patients followed internal policies, which were based on the given German guidelines at the time of diagnosis, generally meaning that all patients were intended to receive stage-adapted treatment. Most of these tumors were also examined in a recent study on incidence and critical relevance of morphological parameters in colorectal carcinoma subtypes as defined by the 2019 WHO classification of tumors of the digestive system [4].…”

“…The microsatellite status (MSI) was determined in the previous study [4], where all carcinomas were classified and subtyped according to the criteria of the 2019 WHO classification of tumors the digestive system, and pathological staging was reassessed using the current TNM classification of malignant tumors [1,20]. The detailed characteristics of the cohort, including age, sex, TNM, UICC-stage, resection-status, MSI-status, WHO grade, localization and tumor type, are depicted in Supplementary Table S1.…”

“…Full block H&E slides from 1013 colorectal carcinomas that were (mostly) part of a previously published collective were rescreened on full block slides at the beginning of this study [4], where the carcinomas were re-classified in accordance with the subtypes listed in the 2019 WHO classification of tumors of the digestive system. Tumors that were not part of the previous cohort but added to the collective were classified as described previously [4]. The final investigated cohort comprised 1002 colorectal adenocarcinomas of various subtypes that showed no morphologic features suggestive of a neuroendocrine carcinoma (Figure 1).…”

“…However, MANECs differ from conventional colorectal carcinomas in their prognosis. In a recent study of a large cohort of more than 1000 colorectal carcinomas, we found that MANEC patients have a significantly worse clinical outcome than all patients with the other colorectal adenocarcinoma subtypes that are listed in the 2019 WHO Classification of Tumors of the Digestive System (WHO) [4]. They behave more like NECs and are therefore often treated like NECs [5,6].…”