Histopathological growth patterns of liver metastases - a retrospective, consecutive, single- center, pilot study and literature review of non-colorectal carcinoma metastasis studies

doi:10.21203/rs.3.rs-4951572/v1

Objective

Histopathological growth patterns (HGPs) in liver metastases have been identified to have prognostic value; however, they currently do not influence therapeutic decisions, and the literature mainly focuses on colorectal adenocarcinoma metastases. Hitherto, they have only been examined in a consecutive setting in 5 studies.

Methods

Patients between 2011 and 2016 were included with the ICD code C7870. General clinicopathological data were obtained from medical charts. Histological slides of the metastases were evaluated by two pathologists with consensus. Statistical analyses were carried out by using the Kruskal-Wallis (continuous variables) and Fisher’s exact test (categorical variables). The Kaplan-Meier method was used to estimate progression-free (PFS) and overall survival (OS), and time-to-progression (TTP) curves, and the logrank test was applied to compare survival curves. All statistical tests were two-sided and p-values less than 0.05 were considered statistically significant.

Results

Altogether 41 patients were included in our study. The majority were diagnosed with secondary colorectal adenocarcinoma (n = 32). Replacement pattern proved to be the most common (n = 22), followed by desmoplastic (n = 15), and pushing (n = 4). There was no significant association found between HGPs and stage (p = 0.105), secondary tumour focality (p = 0.898), largest diameter primary (p = 0.316) and secondary carcinoma (p = 0.441), completeness of resection (p = 0.492), and the presence of venous spread (p = 1). There were no significant results found between HGPs and PFS (p = 0.417), OS (p = 0.297), and TTP (p = 0.267).

Conclusions

Further studies regarding the prognostic utility of HGPs have to be carried out in the future. Our results reflect that HGPs may not be valuable in a consecutive setting.

liver metastasis

histopathological growth pattern

single-center study

literature review

recurrence-free survival

Histopathological growth patterns (HGPs) have been first described by Nakashima et al in 1982. The authors evaluated 60 cases of hepatocellular carcinoma and identified the various HGPs as sinusoidal, replacing, and encapsulated [1]. The first study that presented the utility of HGPs in a metastatic setting was published by Terayama et al in 1996, however, its correlation to prognosis was not yet examined [2]. Currently, in general, HGPs are examined in metastatic colorectal adenocarcinomas, while Vermeulen et al revealed a differing tumour microenvironment of the desmoplastic, the replacement, and the pushing subtypes [3]. Therefore, it has been proposed by van Dam et al, that HGPs should be an indicator of immunomodulatory therapy, including anti-Vascular endothelial growth factor (VEGF), and other medications, as well [4]. The desmoplastic and the replacement types are the most common, and the desmoplastic type has been associated significantly with the best overall survival while pushing is considered the worst. Portal and sinusoid subtypes have been later identified as separate patterns, however, both are rare, therefore, significant data about their effect on prognosis is currently unknown [5]. HGPs are not currently mentioned either in the current World Health Organization (WHO) Classification of Digestive System Tumours, or the American Joint Committee on Cancer’s (AJCC) Cancer Staging Manual, hence, it does not influence therapeutic options [6, 7].

HGPs in non-colorectal cases have been examined by several studies, however, a retrospective, consecutive, single-center study is not yet available. Our study aimed primarily to examine the coherence of HGPs consecutively, regardless of histological subtype. Secondarily we aimed to find an association between HGPs and the features of the primary and secondary tumours. Furthermore, we aimed to provide a literature review of all non-colorectal HGP studies.

Patient selection

This retrospective, consecutive, single-center, pilot study’s database was built from patients with secondary liver cancer, treated at the University of Szeged, between 2011 and 2016. For patient identification, the ICD (International Classification of Diseases) code of C7870 was used, and solely patients with surgical specimens were included. The patients were all operated on at the Department of Surgery, University of Szeged. In all cases, the following data were obtained from medical charts: age, gender, histological subtype, date of diagnosis, largest macroscopic diameter, TNM, clinical stage, and therapy of primary tumour. Regarding the metastases, date of diagnosis, intrahepatic localisation, type of surgery, largest macroscopic diameter, completeness of resection, and presence of venous spread were obtained. Moreover, further metastases, if applicable, and last follow-up data were searched, as well. Progression-free survival (PFS) was defined as the time between the diagnosis of liver metastasis (secondary tumour) and of a further metastatic focus, denominated tertiary tumour, or the patient’s death. Overall survival (OS) was established as the time between the diagnosis of the metastasis and the the patient’s deart. Time-to-progression (TTP) was defined as the time between the metastasis and the tertiary tumour, or tumour progression. The examined clinicopathological parameters and the survival data were consulted with an oncology specialist (BP). After database building, patients’ identifiable data were deleted.

Exclusion criteria

In our retrospective study, only patients were included who were not treated with chemotherapy 6 months before the surgical resection of the liver metastasis. Those cases that did not contain at least 2 Hematoxylin and eosin (HE) slides, were excluded, as well.

Routine pathological assessment

HE-stained slides of the metastases were retrieved from the Department of Pathology’s archive, and all representative slides were chosen, that contained the tumour and the non-tumourous liver tissue. For each case, at least 2 HE slides were essential for the evaluation. Tumours with direct subcapsular localisation have been excluded from the study, to avoid the overdiagnosis of desmoplastic pattern. If necessary, deeper levels were cut.

Assessment of HGPs

HGPs were evaluated by two pathologists (BB, AS) by light microscopy (Olympus BX53F), based on consensus, according to the guidelines of Latacz et al. In all cases, solely a prominent pattern was defined, with its presence of at least 51% of the slide. In discrepant cases, consensus was reached. Desmoplastic HGP was defined by the presence of a desmoplastic border, that clearly separates metastasis from the non-tumourous liver parenchyma, while the replacement subtype was established when the tumour cells represented a continuous transition with the hepatocytes. Pushing HGP was set in cases with expansive tumour borders, with sharp separation from the liver parenchyma. The sinusoidal or portal spread was defined as sinusoidal or portal HGP [5]. Results were registered, and all different HGPs were photographed for illustration. In multiple liver metastasis cases, all foci were separately evaluated, as well.

Statistical analyses

Statistical analyses were carried out by the R statistical software (v4.1.1). To compare more than two groups of independent samples (from non-normally distributed data), the Kruskal-Wallis test was used. The association between categorical variables was examined by Fisher’s exact test. The Kaplan-Meier method was used to estimate RFS/OS curves, and the logrank test was applied to compare survival curves. All statistical tests were two-sided and p-values less than 0.05 were considered statistically significant. Kaplan-Meier curves were created using the R package ‘survminer’ (v0.4.9).

General clinicopathological data and primary tumour characteristics

Altogether 41 patients have been included in our dataset, with a 23:18 male-to-female ratio. Patients’ mean age was 69 years (range: 49-80 years). During this time interval, the majority of secondary liver cancers proved to be of colorectal origin (n=32), however, of the epithelial malignancies, stomach (n=1), small bowel (n=1), gallbladder (n=1), pancreas (n=1), lung (n=1), kidney (n=1) and urinary bladder (n=1) were present, and two cases of malignant melanoma (MM) have been examined. Regarding histology, all colorectal carcinomas were conventional adenocarcinomas, except for one mucinous adenocarcinoma case. The stomach, small bowel, and gallbladder metastases were either neuroendocrine tumours (NETs) or carcinomas (NECs). The stomach and the small bowel NETs proved to be grade 1. The pancreas cancer was histologically ductal adenocarcinoma, the lung was basaloid squamous cell carcinoma, the kidney cancer metastasis was Transcription factor E3 (TFE3) - rearranged renal cell carcinoma, and the urinary bladder cancer proved to be urothelial carcinoma. The melanomas were characterised as superficially spreading and lentigo MM. Table 1 summarises the examined cases with histological phenotype.

Table 1 Summary of the primary tumour’s characteristics

Location of primary tumour	Histological subtype	Number of cases (n)
Colon	Adenocarcinoma	19
Rectum	Adenocarcinoma	11
Rectum	Adenocarcinoma, mucinous subtype	1
Stomach	Neuroendocrine tumour	1
Small bowel	Neuroendocrine carcinoma	1
Gallbladder	Neuroendocrine tumour	1
Pancreas	Ductal adenocarcinoma	1
Lung	Squamous cell carcinoma, basaloid subtype	1
Kidney	TFE3-rearranged renal cell carcinoma*	1
Urinary bladder	Urothelial carcinoma	1
Skin	Malignant melanoma	2

Abbreviations: TFE3 - Transcription factor E3

The average of the largest primary tumour diameter proved to be 29 mm (range: 5-95 mm, standard deviation: 19.45, median: 26). In 9 cases, data were not available. Regarding tumour, node, metastasis (TNM) classification, the majority of cases belonged to the T3 (n=26), and the T2 category (n=12) at the time of primary tumour diagnosis, and 27 cases were diagnosed as N0. Five cases already had distant metastasis (M1) at the time of primary tumour diagnosis and were operated on because of both at the same setting. Complete resection was carried out in 38 cases. The average time between primary and secondary tumour surgery was 21.3 months (range: 0-117). All rectum adenocarcinomas (n=12) were treated beforehand with neoadjuvant therapy. The MM patients received interferon, and radiotherapy, as well. The rest of the patients (n=15) were given chemotherapy, in two cases combined with irradiation.

Follow-up data

During our follow-up, 10 patients died, and 12 were still alive. The follow-up of 19 patients has been suspended, and there is no data available on the cause and the death of the patient in the medical record system. The mean value of PFS proved to be 59 months (range: 1-135 months), and of OS was 55 months (range: 27-135 months), respectively. The mean TTP proved to be 20 months (range: 6-105 months). Tertiary tumours were observed in 15 cases. Solely lung metastases were described in 6, lung and brain metastases in 1, while lung and bone metastases were present also in 3 cases. Omental metastases were present in two cases, sole brain metastases were present in two cases and in a single case a non-regional mediastinal lymph node metastasis, alongside a kidney metastasis, was observed. Complete resection was carried out in 22 cases.

Examination of metastases and assessment of HGPs

Altogether 23 cases were multifocal (range: 2-5), and 74 foci were evaluated. The average largest tumour dimension was 36.9 mm (range: 5-85 mm). Complete resection was carried out in two-thirds of cases (n=27). Segment resection was carried out in all cases, except for 4, when metastasectomy was implemented. During the histological evaluation, the presence of venous invasion in the liver specimen was registered in 8 cases.

Replacement pattern proved to be the most common (n=22) (Figure 1/A), followed by desmoplastic (n=15) (Figure 1/B), and pushing (n=4) (Figure 1/C). In 8 cases, two patterns were present within a single case, however, the ‘dominant pattern’ was present in at least 70% (range: 70-95), therefore, during the evaluation, the dominant pattern was registered. There was no significant association found between HGPs and stage (p=0.105), secondary tumour focality (p=0.898), largest diameter primary (p=0.316) and secondary carcinoma (p=0.441), completeness of resection (p=0.492), and the presence of venous spread (p=1). There were no significant results found between HGPs and PFS (p=0.417), OS (p=0.297), and TTP (p=0.267). Kaplan-Meier curves are demonstrated in Figure 2.

HGPs in liver metastases have been identified to have prognostic value, however, they currently neither influence therapeutic decisions nor have been thoroughly examined widely in a consecutive setting. According to the guideline of Latacz et al, currently, 5 subtypes are differentiated, which are in order of occurrence: desmoplastic, replacement, pushing, sinusoidal, and portal. During our study, we followed the morphological criteria implemented in this scientific paper. While in the case of a desmoplastic pattern, the tumour cells and the liver cells are separated from each other by a band of desmoplastic stromal reaction, in the replacement type, the tumour cells are seen as basically continuous with the hepatocytes. The pushing type represents special morphology since tumour cells are invading expansively, compressing the tumour-free tissue, in the absence of a desmoplastic rim. In the sinusoidal pattern, the tumour cells are invading the hepatic sinusoids, and in the portal pattern the cancer is infiltrating the portal tracts, and/or the biliary branches. The sinusoidal and the portal types are observed rather rarely, therefore, our data are currently limited [5]. Our study contained desmoplastic, replacement, and pushing types of HGP, which are presented in Figure 1.

According to our current knowledge, a pure desmoplastic pattern is associated with the best prognosis, while even a fraction of other patterns (due to occurrence, meaning mainly replacement and pushing patterns) significantly decreases the OS rate by half [5]. Therefore, even some authors recommend the use of a two-tiered system, including desmoplastic and non-desmoplastic. The reason for that may lie in the relationship of HGPs and the tumour microenvironment, because the desmoplastic subtype is associated with intra- and peritumoral lymphoid infiltration, presenting tumour immunity, while the other subtypes do not indicate inflammatory response, therefore, the identification of HGPs may later influence therapeutical decisions on immunotherapy. On the other hand, desmoplastic and pushing subtypes have been associated with the ability to induce angiogenesis, therefore, maintaining vascularisation of the tumour tissue [8]. There is currently no significant data on the prognosis associated with sinusoidal and portal patterns, and there is no specific association found between tumour histological subtype and HGPs [5].

Due to the above-mentioned reasons, there is confusion regarding the true prognostic value of HGPs, whether they should influence therapeutical decisions, and whether they may only be sufficient for colorectal carcinomas, due to differing tumour biology. To get a better understanding of the matter, we aimed to perform a literature review, focusing on non-colorectal carcinoma studies. With a thorough search of PubMed, using keywords “histopathological growth pattern” and “liver” from 1975 to 2023, currently 570 results are available, of which there are only 9 publications involving non-colorectal carcinoma liver metastasis. Table 2 summarises all the currently available publications. Unicenter, retrospective, consecutive studies were carried out by Bohlok et al, Temido et al, and Szczepanski et al [9-11], while multicenter studies were published by Barnhill et al, although, it was not consecutive [12]. Multicenter, retrospective, consecutive studies were Meyer et al in 2022 and 2023, Barnhill et al, and Bohlok et al [13-16].

Table 2 Summary of all non-colorectal carcinoma HGP studies

Author and year of publication	Type of study	Histological subtype of examined tumours	Number of cases	Significant association found with HGPs	HR, CI/SE
Barnhill et al. 2018	Pilot	Uveal MM	41	OS	OS HGP (HR = 6.51, CI: 1.63–25.92 )
Barnhill et al. 2020	Multicenter	Cutaneous MM	42	OS	OS HGP (HR = 3.79, CI: 1.33–10.83)
Bohlok et al. 2020	Unicenter, retrospective, consecutive	NST, lobular carcinoma, other*	36	OS, PFS	OS (HR = 0.20, CI: 0.05 - 0.80) PFS (HR = 0.24; CI: 0.08–0.70)
Temido et al. 2020	Unicenter, retrospective, consecutive	Intestinal, diffuse, and undetermined type gastric adenocarcinoma	19	OS	OS (HR = 0.102, CI: 0.01–0.84; HR = 0.075, CI: 0.01–0.52; HR = 0.1, CI: 0.01–0.69)
Szczepanski et al. 2022	Unicenter, retrospective, consecutive	Uveal MM	54	NA	NA
Meyer et al. 2022	Multicenter, retrospective, consecutive	Anal cancer, adrenocortical carcinoma, cervical carcinoma, endometrial carcinoma, GIST, leiomyosarcoma, liposarcoma, gastric carcinoma, MM, nephroblastoma, renal cell carcinoma, non-seminoma, non-small cell lung cancer, esophageal carcinoma, carcinoma of the ovary, thyroid carcinoma, thymus carcinoma, urothelial cell carcinoma, pancreas carcinoma, small intestine carcinoma, hemangiopericytoma, ORL carcinoma, Vaters ampulla carcinoma, breast carcinoma**	132	OS, RFS	OS (HR = 0.46, CI: 0.25–0.86); RFS (HR = 0.38, CI: 0.21–0.69).
Barnhill et al. 2022	Multicenter, retrospective, consecutive	Uveal MM	72	MSOS, MFS	MSOS (HR = 5, CI: 1,304 - 19,005; HR = 3.5, CI: 0,426 - 29,488; HR = 4.2, CI: 1,067 - 16,739)
Meyer et al. 2023	Multicenter, retrospective, consecutive	NET (pancreatic, gastric, small intestinal, thyroid, colon, lung, mesentery, unknown origin)	63	Not found	OS - grade (HR = 4.43, CI: 1.07–18.29)
Bohlok et al. 2023	Unicenter, retrospective, consecutive	Colorectal adenocarcinoma, anal carcinoma, breast cancer, ORL cancer, esophagus carcinoma, GIST, kidney, leiomyoma, MM, ovary, pancreas, small bowel, testicle, hemangiopericytoma***	263	POOS, PFS	POOS (HR = 0.62, CI: 0.49-0.97); PFS (HR = 0.61, CI: 0.42-0.87)

Abbreviations: CI - Confidence interval; GIST - Gastrointestinal stromal tumour; HGP - Histopathological growth pattern; HR - Hazard ratio; MM - Malignant melanoma; MFS - Metastasis-free overall survival; MSOS - Metastasis-specific survival; NA - Not applicable; NET - Neuroendocrine tumour; NST - No special type carcinoma; ORL - Otolaryngology; OS - Overall survival; PFS - Progression-free survival; POOS - Post-operative overall survival; RFS - Recurrence-free survival; SE - Standard error

* ’Other’ has not been further specified by the authors.

**Histological subtype was not specified in all cases by the authors.

***Histological subtype was not specified in all cases by the authors.

As it is displayed in Table 2, literature research revealed a wide spectrum of examined epithelial tumours. Meyer and coauthors included NETs solely in their work [13]. Regarding non-epithelial cancer metastases, it must be emphasised that MM has been examined in 6 of the publications [11-14, 16, 17]. Peculiarities including gastrointestinal stromal tumour (GIST), leiomyosarcoma, liposarcoma, and hemangiopericytoma were examined by Meyer et al and Bohlok et al. Embryonal neoplasms and germ cell tumours were investigated by the same authors [13, 16]. The average examined case is 80 (range: 19-263).

The earliest non-colorectal HGP pilot study was published in 2018 by Barnhill et al, examining uveal MM liver metastases. Their results were consonant with international data, while with multivariate analysis, HGP proved to have a significant association with OS (Hazard ratio - HR = 6.51; p=0.008) [17].

Statistical analysis was rather unified in these studies, while 6 contained Cox regression, 4 used the logrank test, Kaplan-Meier analysis, and Fisher’s exact test. HGPs’ significant effect on OS was proved by Barnhill et al in 2018 and 2020, Bohlok et al, Temido et al, and Meyer et al [9, 10, 12, 13, 17] Significant association with survival was not found solely by Meyer et al [15], and the statistical analysis was only descriptive in the work of Szczepanski [11]. It has to be emphasised that none of the studies include a literature review.

In our retrospective, consecutive, single-center, pilot study we aimed to investigate the prognostic value of HGPs, regardless of histological subtype. Our cohort included altogether 41 patients over a 6 years’ period, and mainly colorectal adenocarcinomas and other types of gastrointestinal tumours were included, however, two non-epithelial tumours were examined, as well. Statistical analysis did not prove a significant association between HGPs, and stage, secondary tumour focality, largest diameter of primary and secondary carcinoma, completeness of resection, the presence of venous spread, PFS, OS, and TTP.

The limitation of our study is that based on histological subtype, each group consisted of a very different number of cases, therefore, statistical analysis was not ideal to be carried out. Furthermore, it must be emphasised that with the consecutive nature of our study, various tumours with different biological behaviours have been implemented, therefore, our results suggest that the concept of HGPs may not be sufficient for all types of metastatic tumours.

The strength of our work is that it is currently the first study in which a literature review is included, that focuses on non-colorectal carcinoma studies. In the future, our study group plans to expand the database to 2023, and to perform reproducibility examinations, as well, while currently, only two studies investigated the matter [18, 19]. We recommend the use of HGPs primarily in colorectal adenocarcinomas. Even though the presence of liver metastasis represents an advanced stage already, HGPs may have a prognostic or even a therapeutic role in the future.

Acknowledgement

The authors gratefully acknowledge the work of Mihály Dezső for his help in microscopic photographs.

Conflicts of interest

The authors declare no conflict of interest.

Authors’ contributions

Conceptualization: Anita Sejben, Béla Vasas; Methodology: Anita Sejben, Béla Vasas, Tamás Zombori; Formal analysis and investigation: Bence Baráth, Anita Sejben; Writing - original draft preparation: Anita Sejben, Bence Baráth; Writing - review and editing: Anita Sejben, Béla Vasas, Tamás Zombori; Statistical analysis: Tamás Zombori, Tamás Lantos.

Funding

Funding acquisition: Anita Sejben; Resources: New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund (ÚNKP-23-4-SZTE-389). University of Szeged, Faculty of Medicine Research Fund-Hetényi Géza Grant (IV-134-62-1/2024.SZAOK).

Ethical declaration

This study was approved by the Regional and Institutional Research Ethics Committee of the University of Szeged (5462; 170/2023-SZTE) and the Medical Research Council (BM/5299-2/2024).

Data availability

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.

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No competing interests reported.

Histopathological growth patterns of liver metastases - a retrospective, consecutive, single- center, pilot study and literature review of non-colorectal carcinoma metastasis studies

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusions

Figures

Introduction

Materials and methods

Patient selection

Exclusion criteria

Routine pathological assessment

Assessment of HGPs

Statistical analyses

Results

Discussion

Declarations

References

Additional Declarations

Status:

Version 1