【A rare hardcore, predicting the growth pattern of liver metastasis tumor (1/2)】

【Tomorrow 10-11 o'clock】

The tissue growth pattern (HGP) of colorectal cancer liver metastasis (Crclm) is one of the latest research and exciting prognostic factors in modern oncology. By reflecting the interactions between tumor hosts, i.e. angiogenesis, apoptosis and immune responses, they provide an easily accessible, inexpensive and reproducible prognostic information. However, this feature is precisely their main disadvantage, as this highly relevant knowledge can only be obtained after pathological examination of surgical specimens. Whether it is possible to accurately predict that HGP will provide valuable clinically relevant information for multidisciplinary treatment of Crclm patients.

In this article, we will review the main HGP and its role as a prognostic biomarker. Then, before making any multidisciplinary treatment decisions, we will digress on the potential clinical implications of predicting major HGP. We will then review the currently available patterns of predicting HGP with a focus on four possible pathways. First, we will explore the characteristics of primary tumors. Second, the role of modern imaging will be reviewed. Third, for patients who have previously relapsed after hepatic resection due to CRCCLM, we will detail how the initial HGP can help predict HGP in new liver metastasis. Finally, we will review the status of tumor biopsy, liquid biopsy, and molecular analysis in predicting HGP.

Although hgp is undoubtedly an exciting topic from a clinical and research perspective, there are still many areas to be explored. Two specific pathways of progress include the prognostic value of hgp in liver metastasis in non-colorectal cancer and the prognostic value of hgp in extrahepatic metastasis.

Finally, since HGP reflects important tumor-host interactions, they should not be regarded as biomarkers themselves but as a tissue phenotype. In an era of rapid advances in molecular classification of cancer using molecular targets, we will briefly review the possible biological drivers behind each particular HGP. Ultimately, this may offer the possibility for the development of novel therapies designed to regulate tumor-host interactions, thereby advantageously affecting the prognosis of the major causes of cancer-related deaths.

Colorectal cancer (crc) is a highly occasional tumor with 500,000 new cases in Europe in 2018, the second most common cancer. In terms of mortality, colorectal cancer accounts for 9.2% of all cancer-related deaths, ranking second among cancer-related deaths. Despite efforts to promote a healthy lifestyle and prevent colorectal cancer campaign, the incidence of colorectal cancer is still increasing, especially among young patients, which may be related to the "Western lifestyle". It is expected that by 2030, colorectal cancer will increase by as much as 60%, with more than 2 million new cases and 1 million deaths.

Despite colorectal cancer screening and early detection, most patients still experience distant metastasis, and disseminated disease is the main cause of death in these patients. Most colorectal cancer metastasis is located in the liver, with up to 25% of patients presenting synchronous disease and up to 70% of patients developing metachronous liver metastasis.

For patients with localized liver disease, surgery is the only treatment option, with very good results in 5 and 10 years, with an overall survival rate of 40% and 25%, respectively. In the cohort of patients with liver metastasis (crclm) with strict selection of colorectal cancer, the survival rate after surgical removal of crclm was as high as 97%. Despite this, not all patients are suitable for surgery.

With the development of better and more effective systemic chemotherapy, the development of targeted therapeutic drugs, and the improvement of surgical technology, more patients have been cured.

However, the importance of choosing the right patient should be pursued more actively. Not all patients can gain long-term survival benefits from surgical interventions, as liver recurrence of crclm is very common in the first two years after surgery. In addition, liver surgery is at risk for perioperative morbidity and mortality and may also affect quality of life. This is especially important when there are less invasive and less pathological alternative hepatic resections, such as thermal ablation that may compete with the survival outcomes of hepatic resections.

Therefore, the need for personalized treatment of CRCM is the most important. The fourth stage of CRC management should always be carried out by a multidisciplinary team based on knowledge in different medical fields. The decision on surgical resection should not only be based on technical resectability, but also the specific biological characteristics of the patient. This requires accurate prediction of biomarkers to help make multidisciplinary decisions.

Assessment of disease scope and aggressiveness has long shown prognostic value and remains highly correlated in treatment decisions. Elevated tumor serum markers, i.e., carcinoembryonic antigen (CEA), is associated with poor prognosis. The size of maximum liver metastasis, the number of nodules, evidence of extrahepatic disease, i.e., the time between lung and/or peritoneum, primary colorectal carcinoma and Crclm and synchronous disease, the location of the primary tumor (right hemicolon and left hemicolon) is also considered to be a feature of prognosis. As research on ras mutations becomes more frequent, patients with Kras mutations have lower overall survival after Crclm resection.

However, the isolated values ​​for each factor are limited, and different systems have been designed to provide risk assessment. In fact, prognostic scores, while useful, have limited roles in individualized decision-making in patients.

Despite all interest and prognosis, the above factors reflect only tumor biology and invasiveness and may not really represent the interaction between tumor and host, which is necessary to establish crosstalk between tumor and non-tumor environments, which are marked by individualized drugs.

In recent years, a very interesting prognostic factor has emerged in the medical literature - the tissue growth pattern of Crclm (HGP). This simple and reproducible property was established by routine pathological examination of hematoxylin-eosin-stained slides and does not require further testing. Proper naked eye examination and sampling is required, and sometimes complete lesions are sampled for nodules less than 3 cm.

After examination, pathologists should classify HGP as a connective tissue proliferation type according to recent consensus - when there is a thick interstitial band rich in lymphocytes and blood vessels between the tumor and the non-tumor parenchyma; propulsion type - tumor cells grow and compress nearby hepatocyte plates; and replacement type - tumor components grow in a less clear way to penetrate non-tumor hepatocytes

HGP has attracted attention in recent years because they are not just a different tissue phenotype. In fact, several studies have shown that HGP is predictive for overall survival. Promoting HGP is associated with poor overall survival, a characteristic also described in alternative growth types, while connective tissue hyperplasia HGP is a good predictor of overall survival.

Hepatectomy is the gold standard treatment method for patients with crclm and is also the treatment method for patients with liver metastasis in other primary sites. Although most patients develop initially unresectable diseases due to tumor burden, many patients can successfully degrade through preoperative chemotherapy, making hepatectomy feasible and low incidence.

Over the years, several technical methods for resection of Crclm have emerged, ranging from two-stage radical resection to first-stage surgery that retains parenchymal, with or without thermal ablation, but the latter is recommended for smaller subcapsular lesions. In larger and central lesions, the number of nodules, involved anatomical segments and residual liver volume after surgery will be the main drivers of determining first-stage resection or second-stage resection. The overall condition of the patient is also extremely important, as age and the presence of complications may impair the surgical approach.

Recently, liver transplantation has also been included in the treatment library. In reality, surgical science is mainly divided into two strategies for Crclm. On the one hand, supporters of radical two-stage technologies that accelerate liver hypertrophy, such as combined liver segmentation and portal vein ligation staged hepatic resection (alpps). This strategy suggests that metastases near the vascular bile duct pedicle should undergo complete R0 resection, inevitably sacrificing a large amount of liver parenchyma, which usually requires portal and hepatic vein blood flow regulation techniques. Although this approach is conceptually attractive, it is also full of several problems, namely the increase in morbidity and mortality, and

The rate of rescue rehepatic reexcitation is reduced in the case of intrahepatic recurrence. On the other hand, others support first-stage radical, retaining parenchymal resection, even at the cost of positive margin resection. This strategy retains more liver parenchymal, allowing for first-stage surgery, with a lower incidence and increasing the chance of resection of the liver again when liver metastasis recurs. In fact, several studies have shown that resection of Crclm accompanied by vascular bile duct structure tumor shedding has the same survival results as R0 radical resection, challenging a long-standing surgical dogma, that is, Crclm should be clear at the edge of resection, ideally exceeding 1 mm.

However, although the two strategies are conceptually different, none of them exhibits obvious superiority and the overall survival results are comparable. This may indicate that it is not surgical techniques that determine the prognosis, but the biological behavior of the tumor, and its interaction with the host.

Some specific biological features, such as ras and braf mutations, or the origin of the midgut and hindgut of primary tumors, have been shown to be closely related to prognosis. Although these features have clear therapeutic implications for the choice of targeted therapy, the relationship between mutation status and specific surgical techniques has not been determined until recently. However, a recent study showed that non-anatomical resection was associated with poor prognosis in patients carrying Kras mutations. In addition, the presence of Kras mutations was higher with a higher risk of local recurrence after R1 resection than Kras wild-type states.

This challenges the idea that liver metastasis is nothing more than a group of bland cells that have little or no interaction with the surrounding parenchyma except the cells caused by their growth. Biological processes such as angiogenesis, vascular selection, paracrine and autocrine of growth factors, as well as interactions with immune cells, occur at the tumor-host interface. These events explain different HGPs and are likely to have different implications for surgical treatment.

In line with this, another recent study showed that the R0 resection rate of Crclm with pro-connective tissue hyperplasia type was increased. This suggests that the presence of a fiber-free interstitial mass around liver metastases may have a protective effect on the positive resection of the margin. However, if such interstitial mass is not present, as is the case with replacement and pushing HGP, patients may face the risk of marginal resection, increasing the risk of liver recurrence. We speculate that in this case, resection should expand the margin. However, this remains to be demonstrated. In any case, accurate prediction of preoperative growth patterns can make the surgical plan more personalized.

Another rather interesting clinical significance of HGP is the relationship between connective tissue hyperplasia HGP and relapse-free survival and recurrence patterns. In a thought-provoking study by Nierop et al., the authors described that patients with connective tissue hyperplasia HGP had more liver localized recurrences than those with non-connective tissue hyperplasia HGP showed more multi-site recurrences. In the latter HGP, the chance of resection was also lower. Similarly, preoperative prediction of HGP could help

Resolve the risk of recurrence in individual patients. For example, for patients with non-connective tissue hyperplasia HGP, if appropriate, it can avoid potential pathological resection and switch to less invasive techniques such as thermal ablation, which can lead to earlier and more aggressive recurrence risks. Local ablation has the added benefit of not delaying the recovery of tumor treatment, which is an adverse event after active surgical resection that can affect the prognosis. In addition, patients with non-connective tissue hyperplasia HGP may also benefit from more active perioperative chemotherapy regimens.

Despite all the data on the Human Genome Project, one challenge for optimization is the reduction of chemotherapy samples. Most patients with liver metastasis in colorectal cancer have received preoperative treatment, in which case liver metastasis may exhibit a different profile than Crclm that was not treated before surgery, and the histomorphological phenotype of Crclm may change during treatment. Nevertheless, the data obtained in the original article are solid and interesting. Most reviews and meta-analysis of HGP combine different sample treatments and are difficult to coordinate. Prospective and controlled studies should be the main assets in this field, redirecting to imaging during treatment, evaluating modifications, and stratifying HGP based on treatment.

HGP may also have an impact on liver transplantation of Crclm. This surgical approach has gained interest in selected cases and may be an effective option when partial hepatectomy is not feasible. Some criteria must be met to consider the treatment of patients, i.e. the primary tumor has been removed, the patient responds to systemic chemotherapy, and the presence of liver-only diseases. HGP may play a role in predicting prognosis here, and patients with liver disease can be selected that are more likely to develop liver disease, especially those with connective tissue hyperplasia.

However, to our knowledge, there is no research report on Crclm liver transplantation. Therefore, the authors recommend that the study of publishing liver transplant results on Crclm report HGP in explants specimens and their effects on the results. Furthermore, since we do not know the effect of HGP on immunosuppression, it would be interesting to report the role of HGP in liver relapse if HGP occurs.
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