Dragomir Mihnea P, Popovici Vlad, Schallenberg Simon, Čarnogurská Martina, Horst David, Nenutil Rudolf, Bosman Fred, Budinská Eva
Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
J Pathol Clin Res. 2025 Jul;11(4):e70034. doi: 10.1002/2056-4538.70034.
The intertumoral and intratumoral heterogeneity of colorectal adenocarcinoma (CRC) at the morphologic level is poorly understood. Previously, we identified morphological patterns associated with CRC molecular subtypes and their distinct molecular motifs. Here we aimed to evaluate the heterogeneity of these patterns across CRC. Three pathologists evaluated dominant, secondary, and tertiary morphology on four sections from four different FFPE blocks per tumor in a pilot set of 22 CRCs. An AI-based image analysis tool was trained on these tumors to evaluate the morphologic heterogeneity on an extended set of 161 stage I-IV primary CRCs (n = 644 H&E sections). We found that most tumors had two or three different dominant morphotypes and the complex tubular (CT) morphotype was the most common. The CT morphotype showed no combinatorial preferences. Desmoplastic (DE) morphotype was rarely dominant and rarely combined with other dominant morphotypes. Mucinous (MU) morphotype was mostly combined with solid/trabecular (TB) and papillary (PP) morphotypes. Most tumors showed medium or high heterogeneity, but no associations were found between heterogeneity and clinical parameters. A higher proportion of DE morphotype was associated with higher T-stage, N-stage, distant metastases, AJCC stage, and shorter overall survival (OS) and relapse-free survival (RFS). A higher proportion of MU morphotype was associated with higher grade, right side, and microsatellite instability (MSI). PP morphotype was associated with earlier T- and N-stage, absence of metastases, and improved OS and RFS. CT was linked to left side, lower grade, and better survival in stage I-III patients. MSI tumors showed higher proportions of MU and TB, and lower CT and PP morphotypes. These findings suggest that morphological shifts accompany tumor progression and highlight the need for extensive sampling and AI-based analysis. In conclusion, we observed unexpectedly high intratumoral morphological heterogeneity of CRC and found that it is not heterogeneity per se, but the proportions of morphologies that are associated with clinical outcomes.
结直肠癌（CRC）在形态学水平上的瘤间和瘤内异质性目前尚不清楚。此前，我们确定了与CRC分子亚型相关的形态学模式及其独特的分子基序。在此，我们旨在评估这些模式在整个CRC中的异质性。三名病理学家在一组22例CRC的试点研究中，对每个肿瘤的四个不同FFPE块中的四个切片的主要、次要和三级形态进行了评估。基于人工智能的图像分析工具在这些肿瘤上进行训练，以评估一组161例I-IV期原发性CRC（n = 644张苏木精-伊红染色切片）的形态学异质性。我们发现，大多数肿瘤有两种或三种不同的主要形态类型，复杂管状（CT）形态类型最为常见。CT形态类型没有组合偏好。促结缔组织增生性（DE）形态类型很少占主导地位，也很少与其他主导形态类型组合。黏液性（MU）形态类型大多与实性/小梁状（TB）和乳头状（PP）形态类型组合。大多数肿瘤表现出中等或高度异质性，但未发现异质性与临床参数之间存在关联。较高比例的DE形态类型与较高的T分期、N分期、远处转移、美国癌症联合委员会（AJCC）分期以及较短的总生存期（OS）和无复发生存期（RFS）相关。较高比例的MU形态类型与较高的分级、右侧以及微卫星不稳定性（MSI）相关。PP形态类型与较早的T和N分期、无转移以及改善的OS和RFS相关。CT与左侧、较低分级以及I-III期患者更好的生存率相关。MSI肿瘤中MU和TB的比例较高，而CT和PP形态类型的比例较低。这些发现表明，形态学变化伴随肿瘤进展，并突出了广泛取样和基于人工智能分析的必要性。总之，我们观察到CRC的瘤内形态学异质性出乎意料地高，并且发现与临床结果相关的并非异质性本身，而是形态学的比例。
