Predicting colorectal cancer liver metastases histological growth patterns: inflammation on the primary tumor is associated with desmoplastic growth pattern

doi:10.21203/rs.3.rs-4376808/v1

Background: More than 50% of patients diagnosed with colorectal cancer (CRC) will develop liver metastases (CRCLM), which is the main cause of death for more than 60% of these patients. The aim of this study was to correlate the clinical and pathological characteristics of the primary CRC and CRCLM, with emphasis in predicting the histological growth pattern of the CRCLM.

Methods: Cohort of seventy-three patients with CRC. Analysis of clinical data and blinded pathological review was performed related with primary tumor and CRCLM features. The analysis was performed in SPSS (version 27) with a significance level of 5%.

Results: A statistically significant association was found between tumor size and metastasis growth pattern (p=0.002), with larger tumors giving rise to metastases with a non-desmoplastic growth pattern. Lymphovascular invasion (LVI) was associated with metachronous CRCLM (p=0.043). In the absence of LVI, the time required for CRCLM to appear was significantly longer (p=0.011). The number of metastases was significantly higher (p=0.049) in tumors without LVI when compared to tumors with LVI. There was a statistically significant association between CRC high-grade inflammation and the desmoplastic metastases growth pattern of the CRCLM (p= 0.017).

Conclusion: The possibility of predicting the CRCLM histological growth pattern resorting to primary CRC characteristics would be useful for proper patient selection for surgery and adapting biological therapies.

colorectal cancer

metastasis

liver

histological growth pattern

Colorectal cancer (CRC) is the third most common type of cancer in the world, ranking second in terms of mortality[1]. This type of tumor is more common in developed countries, more specifically in regions with high-income countries[2]. In recent years, based on the carcinogenesis knowledge and the molecular characteristics of CRC, different factors contributed to the increase in survival, namely, the improvement in screening sensitivity, diagnosis and staging procedures/methodologies; the development and improvement of surgical techniques; as well as the development and optimization of radio and chemotherapy treatment regimens[3]. However, mortality remains high and is higher in patients with advanced disease, such as metastatic disease, being the liver the most frequent organ for the appearance of secondary tumors, due to venous mesenteric drain-age into the portal vein[4].

CRC diagnosis includes a complete evaluation and correct staging, namely through the performance of the analytical study with blood cell count, coagulation study, evaluation of renal and hepatic function as well as the measurement of albumin and CEA (carcinoembryonic antigen). Regarding the imaging study, colonoscopy, ultrasound and, thoracoabdominal-pelvic computed tomography (CT) should be performed[5, 6]. With all this information, tumor staging is defined according to the TNM (tumor node metastasis) classification of the American Joint Cancer Committee/Union for International Cancer Control TNM classification[7]. It is estimated that more than 50% of patients diagnosed with CRC will develop liver metastases, which is the main cause of death for more than 60% of these patients[4].

In recent years, new treatment modalities for advanced CRC have emerged, and different methods are currently available contributing to a curative approach, namely: more effective chemotherapy protocols, predictive biomarkers of chemotherapy response, portal vein embolization, surgical approach with two-step hepatectomy (ALPPS for Associating Liver Partition and Portal vein Ligation for Staged Hepatectomy) and ultrasound-guided parenchyma-sparing liver resection[8–11]. However, regardless of the different therapeutic approaches available, more than 50% of patients experience intrahepatic recurrence even with adjuvant chemotherapy[12]. Furthermore, data from different studies report that more aggressive liver surgeries do not correlate with increased survival, and neoadjuvant chemotherapy has some disadvantages, such as increased morbidity in the post-operative period[13, 14]. Some studies identify worse prognostic factors, such as the size and number of metastases, lobar distribution and tumor progression after chemotherapy or a shorter interval since primary surgery on the primary tumor. However, these characteristics do not represent an absolute contraindication for performing liver surgery[15]. Interventional radiology has been introducing some interesting modalities such as Transarterial Chemoembolization (TACE), Microwave ablation (MWA), radiofrequency ablation (RFA) and selective internal radiation therapy (SIRT) with good results, especially in small lesions, however due to the inflammation-promoting environment they may promote a pro-tumoral environment[16].

A new easily evaluated prognostic factor was recently identified - the histological growth pattern of CRC liver metastases (CRCLM), and some studies demonstrate that different growth patterns influence tumor progression/response[17, 18]. The different growth patterns represent the complexity of the tumor/host interactions, translating probable responses of an angiogenic[19] or inflammatory nature, but they can also be a consequence of the biological characteristics of the primary CRC. However, the main disadvantage is that it is only possible to know the growth pattern of CRCLM after resection, that is, after surgery[20]. The possibility of preoperative characterization of the histological growth pattern would be very interesting and important, as it would allow a therapy adjusted to the biological characteristics and would contribute to an adequate surgical decision when integrated into multidisciplinary therapeutic decision meetings, allowing a more personalized patient follow-up. Thus, in this work, the objective was to study a cohort of patients with CRC and CRCLM and to correlate the primary characteristics of CRC with the features of the CRCLM, in order to identify characteristics that would allow the prediction of the metastases histological growth pattern.

Sample description

Retrospective and observational study included clinical and anatomopathological data from patients undergoing liver surgery for CRCLM, with curative intent, in the surgery department of the Centro Hospitalar e Universitário de Coimbra, between January 2013 and December 2017.

All patients had synchronous or metachronous liver metastases. In this study, 77 patients were selected. All biographical information, namely age (median), gender, and clinical information regarding the characterization of the primary tumor, including size, histology location, TNM classification according to the American Joint Committee on Cancer (AJCC) classification of malignant tumors [18], number of excised nodes, lymphovascular invasion (LVI), neural invasion, presence of inflammatory infiltrate, type of stroma, molecular characterization and degree of tumor regression after neoadjuvant chemotherapy, was obtained. The characterization of metastases was performed considering the number of metastases, size, location and growth pattern.

All information was obtained from the consultation of the clinical file after approval by the ethics committee of the Centro Hospitalar e Universitário de Coimbra (CHUC-137-20), in compliance with the principles of the Declaration of Helsinki.

Histological study

The anatomopathological study was performed using CRC tissue available in paraffin blocks from surgical samples. Samples were analyzed using hematoxylin and eosin (H&E) staining by two trained pathologists. The histopathological review was blinded, with no prior knowledge of patient data or results.

The location of the tumor was defined according to the anatomopathological report, being dichotomized into right and left sides, when the tumor was located proximally or distally to the splenic angle, respectively [19]. The degree of differentiation was established according to the World Health Organization (WHO) Classification as well-differentiated (G1) to undifferentiated (G4)[20]. The histological growth pattern of the primary tumor was defined according to the criteria of Koelzer and Lugli [21]: infiltrative tumor growth, in which there is an invasion of intestinal wall structures by tumor tissue with little or no desmoplastic stromal response; and expansive tumor growth, in which clear demarcation of the invasive front of the tumor and host tissue occurs.

In cases with marked tumoral response to neoadjuvant therapy the type was stroma was not possible to assess, and was considered under the “no data” designation.

The budding tumor was classified according to the consensus recommendations of Lugli et al.[7]: selection of the H&E slide with the highest budding degree on the invasive front and identification of the "hotspot" in 10 fields on the invasive front at 10x magnification. Tumor buds were then counted in the “hot spot” at 20x magnification and the result was expressed as low (Bd1), intermediate (Bd2) and high budding (Bd3), according to the number of buds.

The inflammatory response was also evaluated at the invasive margin of the tumor according to the criteria of Klintrup K et al.[22]: low grade (absence or moderate inflammatory infiltrate) and high grade (moderate or severe inflammatory infiltrate with tumor destruction).

The type of CRC-associated stroma was also characterized, as defined by Ueno H et al.[23] into three categories: immature, intermediate or mature based on the existence of myxoid stroma or keloid-type collagen in the tumor stroma, in slides stained with H&E. Myxoid stroma is defined as a stroma with an amorphous mucinous substance, typically composed of vacuolated and slightly basophilic or amphophilic extracellular material in collagen fibres. Keloid-type collagen is characterized by thick hyalinized bundles of hyalinized hypocellular collagen. Tumors with myxoid stroma were designated as immature. If there was no myxoid stroma that met the criteria for an immature desmoplastic reaction, the desmoplastic reaction was designated as intermediate or mature, depending on whether the fibrotic stroma contained keloid-type collagen or not, respectively. Typically, the mature desmoplastic reaction is composed of thin mature collagen fibers stratified in several layers in all fibrous reactive zones. Stromal areas around microscopic abscesses were not considered in the analysis.

In cases with marked tumoral response to neoadjuvant therapy the type was stroma was not possible to assess, and was considered under the “no data” designation.

In patients undergoing neoadjuvant chemotherapy for liver metastases, the degree of tumor regression (TRG) was evaluated. The TRG consists of an ordinal scale used to estimate the response to neoadjuvant therapy in the surgical specimen. In this study, the Rubbia-Brandt et al was adopted [24]. The scale includes 5 degrees: TRG5 characterized by the absence of tumor response; TRG4 characterized by the existence of viable tumor in about 75%; TRG3 characterized by the existence of viable tumor in about 50%; TRG2 characterized by the existence of viable tumor in about 25% and in the periphery of the le-sion; and TGR1 characterized by the absence of viable tumor [25].

For the molecular characteristics, the study of microsatellite instability/stability by immunohistochemistry, and the evaluation of the presence of mutations in the KRAS genes (Kirsten rat sarcoma viral oncogene homolog), NRAS (Viral neuroblastoma RAS (v-ras) oncogene homolog) and BRAF by polymerase chain reaction (PCR). Due to the restrospective nature of the study not all of the CRC had the immunohistochemistry or molecular assessment.

Regarding the analysis of samples of CRCLM, the growth pattern in the tumor periphery of the liver metastasis was evaluated, as described by Van den Eyden et al. [26]: desmoplastic growth pattern when the metastasis presents a border of connective tissue between the tissue and liver parenchyma; expansive growth pattern when liver cell plaques at the interface are compressed by the tumor; and replacement growth pattern when infiltrating tumor cells replace hepatocytes in liver cell plaques. The pattern must represent more than 75% of the interface. In cases of two different patterns, each presenting more than 25% of the invasive front of the tumor, the growth pattern is called a mixed pattern [16]. The growth pattern was further dichotomized as desmoplastic versus non-desmoplastic, reflecting its biological behavior [27]. All slides were observed using a light microscope - Nikon Eclipse 50i, and the images were obtained using a Nikon-Digital Sight DS-Fi1 cam-era.

Statistical analysis

The sample was characterized through the presentation of the mean with standard deviation - mean (OD) - and the median with the quartiles of the distribution - Median [Q1, Q3] - when the variables were quantitative and the absolute and relative frequencies - n (%) - when they were quantitative. The quantitative characteristics of metastases or primary tumors were compared between categories of qualitative variables, respectively, of primary tumors and metastases using the Mann-Whitney and Kruskal-Wallis tests, de-pending on whether two groups or at least three groups of categories were compared. The association between categorical variables was performed using Fisher's exact test and between quantitative variables using Spearman's correlation coefficient. The option for non-parametric tests was based on the lack of adjustment of the sample quantitative distributions to normal distributions, and this assumption was evaluated by the Shapiro-Wilk test. The analysis was performed using SPSS, version 27 and analyzed at a significance level of 5%.

3.1. Sample characterization

The selected sample included 77 patients (Table 1), 29 female patients (37.7%) and 48 male patients (62.3%), with a median age of 66.5 years [Interquartile range (IQR) 59-73.8]. The mean time from diagnosis between primary tumor and metastases was 6.0710.59 months, ranging from 13 to 53 months.

Table 1. Data from the total of patients (Age, tumor size, number of nodes with metastasis and the total nodes number).

	n	Min-Max		Avg (Std Dev)		Median [Q1 - Q3]
Age	77		42 - 88		65.5 (9.9)		66.5 [59 – 73.8]
Size (cm)	40		2 - 15		4.3 (2.5)		4 [2.5 – 5.8]
Lymph nodes with metastasis	77		0 - 49		4.3 (6.6)		3 [0.3 - 6]
Total number of lymoh nodes	77		4 - 71		21.5 (14.7)		19 [11 – 29.3]

Of the total sample, 68.8% did not undergo neoadjuvant chemotherapy. Regarding the 31.2% who underwent neoadjuvant therapy for primary CRC, tumor regression (modified Ryan's TRG) was observed in all patients, namely: TRG1 in 16.7% of patients, TRG2 in 45.8% of patients and TRG3 in 37.5% of patients.

Since some of these patients were submitted to neoadjuvant therapy for the primary tumor we excluded those patients and constitute a final cohort of 53 patients. This final cohort is depicted in table 2 and the characteristics can be seen in table 3.

	n	Min-Max		Avg (Std Dev)		Median [Q1 - Q3]
Age	53		43 - 89		67 (10.4)		67.7 [59.7 – 76.3]
Size (cm)	28		2 - 15		4.9 (2.7)		4.5 [3 - 6]
Lymph nodes with metastasis	53		0 - 49		4.7 (7.6)		3 [0.3 – 6.8]
Total number of lymph nodes	53		6 - 71		24.9 (15.8)		21 [12.3 – 32.8]
Time between primary tumor and metastases	53		-1 - 54		9.1 (11)		6.7 [0 - 11.5]
Number of metastases	51		1 - 10		2.5 (1.8)		2 [1 - 3]
Diameter (larger, cm)	51		0 - 8		2.6 (1.8)		2.3 [1.2 – 3.5]

		n (%)
Primary Tumor	Cecum	4 (7.5%)
	Ascending colon	8 (15.1%)
	Hepatic angle	5 (9.4%)
	Transverse colon	3 (5.7%)
	Splenic angle	1 (1.9%)
	Descendent colon	3 (5.7%)
	Sigmoid	23 (43.4%)
	Rectosigmoid transition	1 (1.9%)
	Rectum	5 (9.4%)
Morphology	Adenocarcinoma	44 (83%)
	Adenocarcinoma with areas of mucus production	5 (9.4%)
	Micropapillary adenocarcinoma	1 (1.9%)
	Mucinous adenocarcinoma	1 (1.9%)
	Serrated adenocarcinoma	1 (1.9%)
Laterality	Right	18 (34%)
Laterality	Left	35 (66%)
Tumor classification	1	1 (1.9%)
	2	1 (1.9%)
	3	29 (54.7%)
	4a	20 (37.7%)
	4b	2 (3.8%)
Tumor classification simplified	T1	1 (1.9%)
	T2	1 (1.9%)
	T3	29 (54.7%)
	T4	22 (41.5%)
Node classification	0	13 (24.5%)
	1a	7 (13.2%)
	1b	12 (22.6%)
	2	2 (3.8%)
	2a	8 (15.1%)
	2b	11 (20.8%)
Node classification simplified	N0	13 (24.5%)
	N1	19 (35.8%)
	N2	21 (39.6%)
Node positive	N0	13 (24.5%)
Node positive	N+	40 (75.5%)
TRG	1	4 (5.2%)
	2	11 (14.3%)
	3	9 (11.7%)
	No neoadjuvant therapy	53 (68.8%)
Lymphovascular Invasion	Absence	4 (7.5%)
Lymphovascular Invasion	Presence	49 (92.5%)
Perineural Invasion	Absence	9 (17%)
Perineural Invasion	Presence	44 (83%)
Primary Growth Pattern	Infiltrative	41 (77.4%)
Primary Growth Pattern	Expansive	11 (20.8%)
Budding	Bd1	36 (67.9%)
	Bd2	10 (18.9%)
	Bd3	7 (13.2%)
Inflammatory Infiltrate	Absent	8 (15.1%)
	Mild	18 (34%)
	Moderate	19 (35.8%)
	Severe	7 (13.2%)
Inflammatory infiltrate type	Low grade	26 (49.1%)
Inflammatory infiltrate type	High grade	27 (50.9%)
Stroma	Immature	30 (56.6%)
Stroma	Mature	23 (43.4%)
Grading	2	50 (94.3%)
Grading	3	3 (5.7%)
MMR	MSS	5 (9.4%)
MMR	No data	48 (90.6%)
*KRAS*	Wild-type	6 (11.3%)
*KRAS*	Mutation	19 (35.8%)
	No data	28 (52.8%)
*BRAF*	Wild-type	7 (13.2%)
*BRAF*	No data	46 (86.8%)

Concerning the location of the primary tumor and its influence on the type of unilobar or bilobar hepatic metastasis, the data showed that there is a tendency when the location of the primary tumor is at the splenic angle (100%), hepatic angle (100%), ascending ( 87.5%), sigmoid (90.5%) that the metastasis are unilobar; when the preferential location of the primary tumor is in the rectosigmoid zone (100%) or in the transverse colon (66.7%), the metastasis tend to be bilobar. With regard to the size of the primary tumor, a statistically significant association was found between the size of the tumor and the pattern of metastasis growth (p=0.002). Larger tumors (68.4%) give rise to metastases with a non-desmoplastic growth pattern (Figure 1).

The LVI can predict the type of metastasis to be synchronous or metachronous (p=0.043) revealing in this study that when there is no LVI, it is certain that the metastasis must arise in a metachronous way (p=0.011), while when LVI is present the metastasis must be synchronous, with 57.1% probability. Regarding the number of metastases, this is significantly higher (p=0.049) in tumors without LVI compared to tumors with LVI.

It is also observed that (p=0.082) primary tumors with a high-grade inflammatory infiltrate type tend to develop CRCLM with a desmoplastic growth pattern (66.7%) whereas primary tumors where low-grade inflammatory infiltrate is present, exhibit more frequently a non-desmoplastic pattern of liver metastasis (62.5%). This relation gains statistical significance, when we add the patients with neoadjuvant chemotherapy/radiotherapy, but with poor response, namely TRG3 for the primary tumor (n=9). When added the 9 patients there is a significant correlation (p=0.017) between CRC with high-grade inflammation and desmoplastic pattern of CRCLM, and between primary CRC with low-grade inflammation and non-desmoplastic pattern of CRCLM (Figure 2).

The process of CRC and CRCLM carcinogenesis is multifactorial and complex. Understanding carcinogenesis, a process that includes different actors, plays a crucial role in the development of new therapeutic strategies[21].

According to the literature, there has been a decline in the incidence of CRC in older age groups, coinciding with an increase in the incidence in younger individuals. Thus, the median age at diagnosis decreased from 72 years to 66 years, maintaining the similarity of incidence in both genders, which is in line with the studied sample[22]. Regarding the location of the primary tumor, the studied cohort revealed a predominance of tumors studied in the left colon, that is, in the distal colon, which agrees with the literature. In half of all CRCs in individuals aged 65 years or older, CRC occurs in the proximal colon, however, in individuals younger than 50 years, rectal tumors are more common, followed by tumors located in the distal colon[22]. Depending on the location, CRC presents different evolution, conditioning the overall survival. The difference can be attributed to the anatomical and developmental location, or to the factors that participate in carcinogenesis, such as differences in the distinct bacterial flora on the two sides of the colon, exposure to different nutrients and bile acids, or even a combination of both[23]. Thus, and considering the sample consisting solely of tumors with liver metastases, there are data in the literature that point to a higher probability of liver and lung metastases in CRC tumors located on the left colon, which is in line with the characteristics of studied sample since all individuals included had liver metastases and most of the primary tumors were lo-cated on the left colon[24,25].

Currently, the criteria for therapy and assessment of prognosis and recurrence of CRC are mainly based on anatomopathological information, that is, on the TNM classification[26]. Regarding the histological analysis of the tumor, different parameters were evaluated such as tumor size, histological grade, perineural invasion and LVI, budding, type of stroma, presence and type of inflammatory infiltrate, of tumor regression, the number of resected nodes and the number of invaded nodes.

The major cause of death in patients diagnosed with CRC is disseminated disease. About two-thirds of those with CRC develop distant recurrence. The liver is the most common organ in which metastatic disease occurs in CRC. When tumor cells escape from the primary site through the bloodstream, the most likely place where they will become lodged is the liver. About 25% of patients have a synchronous disease and about 70% of patients develop metachronous liver metastases[27]. Although the overall survival of patients with metastatic CRC was low about three decades ago, there has been a significant improvement in recent years[28]. Despite innovation in terms of treatments as well as the deepening of the understanding of the biological behavior of the tumor, much remains to be done. Several published retrospective studies analyzing cohorts of patients with liver metastases identified worse prognostic factors such as the size of the largest lesion, the number of lesions and the response after chemotherapy or time interval since resection of the primary tumor[15]. However, it should be noted that none of these factors constitutes a contraindication for liver surgery and does not reflect the tumor/host interaction, a fundamental aspect to take into account when customizing therapy. Furthermore, it is also important to add that more aggressive liver surgeries do not translate into increased survival and the performance of neoadjuvant chemotherapy is associated with a significant increase in postoperative morbidity[13,14].

In this context, the main objective of this work emerged, namely to correlate the histological characteristics of the primary CRC tumor with the histological characteristics of liver metastases to contribute to a personalized approach to the patient. In this cohort, it was also found that there is a tendency for characteristics such as the location of the primary tumor to influence the type of lobar or bilobar CRCLM and the fact that LVI is verified is a factor that influences whether the metastasis is synchronous or metachronous. In primary CRC, histological factors such as extramural venous invasion, perineural growth, lymphatic invasion, angioinvasion, diffuse growth pattern and synchronous metastasis have been associated with worse survival outcomes[7]. Thus, the fact that the appearance of synchronous metastasis is associated with the observation of LVI may constitute a factor of worse prognosis[29,30].

With regard to the characterization of the CRCLM growth pattern, there are some studies that described that the growth pattern has relevant prognostic and clinical implications, with an influence also on patient survival, but also on the response to chemotherapy treatment, emphasizing therefore its importance[31].

Thus, the use of this histological parameter in clinical practice should be a reality. In this study, we proved that smaller primary tumors and the presence of high-grade inflammatory infiltrate are associated with a desmoplastic pattern. The inflammatory characteristic is highly reproducible, especially when dichotomized as low and high-grade. Knowing that the desmoplastic growth pattern is associated with an inflammatory microenvironment[32] it is rather logic that a primary tumor associated with a more severe inflammation, also triggers an inflammatory response in a secondary location. This is a very interesting finding and could allow for histological growth pattern prediction, alone or in combination with imaging findings[33,34]. The inflammation may even be applied to other tumors that metastasize to the liver, exhibiting the same patterns, such as gastric[35], and breast cancer[36] and melanoma[37,38]. Studies correlating primary tumor characteristics in those cases would add value, and assess that possibility, of a “one marker for all tumors” or if it would be necessary to adapt the feature considering the primary tumor.

The addition of tumors with neoadjuvant therapy with poor response (such as in this work) may also be feasible since due to the poor response is rather logical that the microenvironment is not disturbed.

A very promising hypothesis of research would be to compare the inflammatory population of the liver metastases and circulating inflammatory cells. This would allow for a blood sample prevision of the histologic growth patterns. Multiplex methodology could a very important role in this field, by studying in detail the composition of the inflammatory infiltrate and isolating one or two major subpopulations of inflammatory cells[39].

However, this leave us with the question of how to predict the histological growth pattern in tumors that had a major response to neoadjuvant chemotherapy or radiotherapy. In these cases, the profound changes in the tumoral microenvironment would not allow to use inflammatory density as a predictor feature, with molecular and radiology findings as the only options. Some studies have been recently published highlight the possibilities of predicting the histological growth pattern of the CRCLM with very interesting results[40–42]. Probably an algorithm combining several modalities would be a viable option in a near future.

The study of MSI status should also provide valuable answers regarding CRC biological behavior and the relation with CRCLM growth patterns. Little is known about CRCLM histological growth patterns and MSI status since the routine study for the defects in mismatch repair proteins (MMR) is rather recent (in our department it only started in 2018). The massive search for MMR defects will probably provide some insight on this feature and the ability to use MSI status as a predicting tool for CRCLM growth patterns[20,43].

A previous study from Wu JB et al[44]. showed that primary carcinoma with desmo-plastic liver metastasis had mutations in APC, TP53, KRAS, PIK3CA, and FAT4, while primary carcinoma with replacement liver metastasis showed mutations in APC and TP53 KRAS, FAT4, DNH5, SMAD, ERBB2, ERBB3, LRP1, and SDK1. However, this was based on whole exome sequencing, which is a very expensive method and it was only performed in five patients. Nevertheless, this states that mutation profile may have a role in the histological growth patterns, and in the future, the integration of KRAS/NRAS/BRAF and microsatellite instability may have a role in the characterization of the histological growth patterns.

A more recent study from Höppener et al[45], in 2022, addressed this topic of primary CRC histology and its association with CRCLM growth pattern. They studied only treatment naïve patients and the results were similar to the one obtained in this study, namely a less dense inflammation in the primary tumor and a non-desmoplastic pattern.

The ESMO guidelines for patients diagnosed with metastatic CRC highlight the importance of a multidisciplinary approach that includes specialties such as oncology, surgery, imaging and pathology[10]. The most used biomarkers in clinical practice are molecular, and include RAS, BRAF and MSI. Regarding the current histopathological characteristics, the dimension of the metastasis, the percentage of necrosis and fibrosis, the possibility (state) of resection and the degree of tumor regression are included[7,46]. However, being able to predict information about metastasis based on information from the primary tumor would be extremely valuable and would be an asset in the initial approach of the patient diagnosed with CRC.

With this work, it was possible to prove that there is a possibility, through the characteristics of the primary tumor (size, location, LVI and density of inflammatory infiltrate), to be able to infer about the characteristics of CRCLM, with an impact on the disease and consequently on therapeutic approaches. Primary CRC with more dense inflammation is associated with desmoplastic growth patterns in CRCLM, with consequent better prognosis, and this may extremely useful in multidisciplinary meeting, allowing for a better selection of patients for therapy and surgical intervention.

Author Contributions: All authors contributed to the study conception and design. Data collec-tion was performed by A.M.A.and R.C.O. Material preparation, analysis, and interpretation were performed by R.C.O., M.A.C. and J.G.T. Statistical analysis were performed by B.O.The first draft of the manuscript was written by A.M.A. and all authors commented, participated in the writing, and approved its final version.

Funding: This research received no external funding.

Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Centro Hospitalar e Uni-versitário de Coimbra (CHUC-140-20).

Informed Consent Statement: Patient consent was waived.

Data Availability Statement: All data generated or analyzed during this study are included in this published article (and its Supplementary Materials).

Conflicts of Interest: The authors declare no conflict of interest

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No competing interests reported.

Predicting colorectal cancer liver metastases histological growth patterns: inflammation on the primary tumor is associated with desmoplastic growth pattern

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Abstract

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Introduction

Materials and Methods

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Discussion

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Additional Declarations

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