Why is there a name change from ‘desmoplastic’ to ‘encapsulated’ occurring when referring to liver metastases surrounded by a strip of fibrous tissue?

Recent research has linked the formation of the perimetastatic capsule to a benign-like fibrotic reaction that is part of a reparative hepatic process, rather than being tumour-induced “desmoplasia” in its narrower sense and as seen within tumours such as pancreatic adenocarcinoma or primary colorectal cancer

References:

Fernández Moro, C. et al. (2023). An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver. Nature communications, 14(1), 5024. https://doi.org/10.1038/s41467-023-40688-x

Fernández Moro, C et al. (2023). What’s in a name? Refining the nomenclature of liver metastases growth patterns by changing “desmoplastic” to “encapsulated”. BJC reports, 1(1), 19. https://doi.org/10.1038/s44276-023-00018-6

Can the growth patterns only be identified in liver metastases?

No, histopathological growth patterns are also recognisable in primary lung tumours and lung metastases. The alveolar growth pattern is the equivalent of the replacement growth pattern seen in liver metastases. Tumour cells fill the alveolar spaces and use or co-opt the capillary blood vessels of the alveoli.

The nomenclature and definitions of growth patterns of lung metastases are not yet standardized, but the following publications perhaps represent the most elaborate attempt to perform standardization: Bridgeman, V. L. et al. (2017). Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. The Journal of pathology, 241(3), 362–374. https://doi.org/10.1002/path.4845

Why is it taking so long for the histopathological growth patterns of liver metastases to be implemented in clinical practice?

Since the (re)description of the growth patterns of liver metastases in 2001 (Vermeulen, P. B. et al. (2001). https://doi.org/10.1002/path.966), it has taken a long time before prognostic studies were carried out with large patient numbers. These studies are now widely available and unequivocally demonstrate the association of the encapsulated growth pattern with a favourable disease course after resection of a liver metastasis in patients with colorectal cancer (Buisman, F. E. et al. (2022). https://doi.org/10.1016/j.ejca.2022.01.012; Höppener, D. J. et al. (2021). https://doi.org/10.1093/jncics/pkab026). In line with this, EORTC has recently integrated the use of the growth patterns in its consensus recommendations on the optimal management of colorectal cancer liver metastases (Bregni, G. et al. (2025). https://doi.org/10.1016/j.ctrv.2025.102926), and also the International Collaboration on Cancer Reporting is considering including the histopathological growth patterns as an element of the pathology reporting of a liver metastasis resection.

An important barrier to clinical implementation is that the histopathological growth patterns are currently only assessed postoperatively, which obviously restricts their use in preoperative treatment planning. Although imaging-based prediction models are being developed, they require further validation before they can be routinely used for preoperative decision-making.

Moreover, the molecular and cellular mechanisms of both growth patterns have not yet been elucidated. Although clinical studies can already be envisaged in which the growth patterns would serve as a decisive factor for one or another study arm, a better understanding of the biology of the growth patterns will likely lead to the identification of new, growth pattern-specific therapeutic targets which can then be exploited in randomized clinical trials.

Are the cut-off values for assigning a patient to one or the other growth pattern group unequivocally established?

They are not. Nevertheless, for patients with a liver metastasis from colorectal carcinoma that is completely surrounded by a capsule, all large retrospective studies show that there is a clear survival advantage compared to patients with any proportion of the interface displaying a replacement growth pattern. About 20 to 30% of patients with colorectal liver metastases belong to this improved outcome group. Some research teams have however demonstrated that, when the section with the largest diameter of a metastasis is completely and carefully evaluated, the proportion of replacement growth does matter when it comes to predicting survival. For metastases from other primary tumour types, such as breast cancer or melanoma, the cut-off values still are to be established. Probably, this will need studies with more patients than included in the published studies.

Do you need stains in addition to the H&E stain to determine the HGPs?

Other stains are not needed to assess the HGPs. In less straightforward cases, for example when there is a lot of inflammation at the interface (such as after chemotherapy prior to surgery), it may be useful to perform a limited set of immunohistochemical analyses. Antibodies directed at the cancer cells (cytokeratin 20, CDX2 or SATB2 for CRC liver metastases) and at the hepatocytes (Hep Par 1, also called HSA, or cytokeratin 7 for more primitive, bi-potent liver progenitor cells at the interface) might in difficult cases help to detect cancer cell-hepatocyte contact, suggestive of replacement growth.

What is meant by the ‘escape’ phenotype of liver metastases?

The “escape phenotype” of liver metastases refers to a situation where, after pre-operative systemic treatment (such as chemotherapy), the liver metastases exhibit features that indicate tumour cells have managed to evade or “escape” the effects of the therapy. This phenotype is characterised by a combination of signs: there is evidence of a pathological response to treatment (such as tumour regression or necrosis), but also areas where viable tumour cells persist, often at the periphery of the metastasis. These surviving tumour cells almost always adopt the replacement growth pattern, allowing them to resist further therapy and continue to proliferate. A set of morphological criteria is being developed so that ‘escape’ can be determined unambiguously and reproducibly in H&E-stained tissue sections.

Is there an animal model that allows the study of the growth patterns of liver metastases and that mimics patient conditions as closely as possible?

The CMT93-model is a syngeneic and immunocompetent model of adenocarcinoma (large intestine: carcinoma of the rectum). Liver metastases in this model express both the encapsulated and the replacement growth pattern, often within the same metastasis. The encapsulated component is well differentiated (pseudoglandular structures) while in the replacement component, cancer cells are arranged in small solid nests that invade the liver parenchyma while replacing the hepatocytes. A manuscript that describes this model is in the making.

Is there going to be a third edition of the international consensus guidelines for scoring the growth patterns of liver metastases?

Yes. Given the ongoing worldwide research into the biological mechanisms underlying the growth patterns, studies on ‘escape’, on a more detailed characterisation of the fibrotic capsule, efforts to teach self-learning algorithms to score the growth patterns on H&E sections, studies focusing on the growth patterns in metastases of other tumour types than colorectal and breast cancer, the characterisation of a suitable mouse model, as well as all the efforts being made to identify the growth patterns through medical imaging, it is likely that the writing of the new consensus guideline will begin in 2025.