Prognostic factors based on histological categorization of desmoplastic reactions in pancreatic cancer.

BACKGROUND/PURPOSE: In colorectal cancer, the morphological categorization of fibrotic cancer stroma in the invasive frontal zone of the primary tumor is well reflected in the prognosis. Conversely, the histological characteristics of pancreatic cancer (PC) reveal fibrotic hyperplasia of stroma known as desmoplasia; however, its characterization is unknown. Therefore, this study aimed to evaluate the prognostic factors according to the histological categorization of desmoplastic reactions in PC. METHODS: We retrospectively enrolled 167 patients who underwent curative resection for PC. The desmoplastic pattern was histologically classified as mature, intermediate, or immature. Clinicopathological features were evaluated, and disease-free and overall survival (OS) were analyzed in the three groups. Prognostic factors were assessed using univariate and multivariate analyses. RESULTS: In total, 19 mature, 87 intermediate, and 61 immature desmoplastic patterns were evaluated. Jaundice decompression, white blood cell count, and platelet/lymphocyte ratio were significantly different among the groups. The mature group had a better disease-free survival (DFS) prognosis than the other two groups; however, OS did not differ between the groups. Desmoplastic patterns showed significant differences between the three groups for DFS. CONCLUSIONS: Desmoplastic patterns are a prognostic factor of DFS for PC, with mature desmoplastic reactions associated with good prognosis. Thus, they may aid in individualized therapeutic approaches in patients with PC.

Cancer-associated fibroblasts at the unfavorable desmoplastic stroma promote colorectal cancer aggressiveness: Potential role of ADAM9.

The tumor microenvironment plays a key role in cancer aggressiveness. Desmoplastic reaction (DR), morphologically classified as Mature, Intermediate and Immature types, has previously been shown to be highly prognostic in colorectal cancer (CRC) and it consists to a large extent of cancer-associated fibroblasts (CAFs). The aim of our study was to characterize the molecular background of DR and understand the effects of CAFs in tumor aggressiveness. The prognostic significance of DR was initially examined in 1497 patients. Then CAFs originating from patient tissues with different DR types were isolated and their impact on tumor growth was examined both in vitro and in vivo. DR was shown to be highly prognostic, with patients within the Immature DR group conferring the worst relapse-free survival. The conditioned media of CAFs from tumor with Immature-type DR (CAFsImmature ) significantly increased proliferation and migration of CRC cell lines and growth of CRC-derived organoids compared to that of CAFs from Mature-type DR (CAFsMature ). Subcutaneous or orthotopic implantation of CRC cells together with CAFsImmature in mice significantly promoted tumor growth and dissemination compared to implantation with CAFsMature . Systematic examination of the expression of "a disintegrin and metalloproteinases" (ADAMs) in CAFs isolated from CRC tissues showed that the secreted isoform of ADAM9 (ADAM9s) was significantly higher in CAFsImmature than in CAFsMature . Knockdown of ADAM9s in CAFsImmature abrogated the promoting effects on CRC cell proliferation and migration. CAFs-derived ADAM9s is implicated in deteriorating survival in CRC patients with Immature-type DR by increasing tumor cell proliferation and dissemination.

Histological categorisation of the desmoplastic reaction is a predictor of patient prognosis in oesophageal squamous cell carcinoma.

AIMS: Histological categorisation of the desmoplastic reaction (DR) is an independent prognostic factor in colorectal cancer. However, it is unknown whether DR categorisation is predictive of oesophageal squamous cell carcinoma (OSCC) outcomes. This study aimed to evaluate the prognostic value of DR categorisation in OSCC patients. METHODS AND RESULTS: Data were collected from 118 patients with OSCC who underwent a curative oesophagectomy with T2 or deeper wall invasion. The DR in each tumour was classified as mature, intermediate or immature based on the presence or absence of keloid-like collagen and myxoid stroma. We identified 49 mature DR tumours, 41 intermediate DR tumours and 28 immature DR tumours. The 5-year overall survival (OS) rate was highest in the mature DR group (42.8%), followed by the intermediate DR group (25.0%) and the immature DR group (19.9%) (P = 0.022, log-rank test; P = 0.006, log-rank trend test). The 5-year disease-specific survival (DSS) rate was also highest in the mature DR group (48.5%), followed by the intermediate DR group (30.8%) and the immature DR group (26.8%) (P = 0.031, log-rank test; P = 0.010, log-rank trend test, respectively). Multivariate analysis revealed that an immature DR was an independent poor prognostic factor of OS and DSS (P = 0.002 and P = 0.004). CONCLUSIONS: DR categorisation of OSCC stroma following oesophagectomy is a useful diagnostic tool and an independent prognostic marker.

Expression and Function of a Disintegrin and Metalloproteinases in Cancer-Associated Fibroblasts of Colorectal Cancer.

BACKGROUND: Cancer tissues consist of cancer cells and stroma, the latter of which dictates cancer tissue microenvironment. We recently reported that the desmoplastic reaction (DR) pattern at the invasive front in colorectal cancer (CRC) is a promising prognostic indicator. However, the molecular mechanisms of DR formation and contribution to patients' prognosis remain unclear. SUMMARY: The tumor tissue microenvironment composed of extracellular matrix (ECM), soluble factors (growth factors/cytokine/cytokine), and stromal cells controls tumor growth and spread. Among stromal cells, cancer-associated fibroblasts (CAFs) play a key role in development of the cancer tissue microenvironment, and they are responsible for DR formation. CAFs express a disintegrin and metalloproteinases (ADAMs), which modulate cancer tissue microenvironmental factors. We isolated CAFs and normal fibroblasts from colon tissues of patients with CRC and characterized them. CAFs showed the increased expression of several ADAM species including ADAM9, ADAM10, ADAM12, and ADAM17, and the expression was further increased on the ECM-coated plates. Our in vitro and in vivo studies using CAFs and CRC cells suggest that ADAM expression is associated with the morphological DR category, and ADAMs may affect cancer malignancy through tumor proliferation in CRC. Key Message: This review summarizes the present knowledge on ADAMs in cancer and describes our recent findings regarding the molecular biological background of DR mainly by focusing on ADAMs.

Cancer-induced spiculation on computed tomography: a significant preoperative prognostic factor for colorectal cancer.

PURPOSE: Cancer-induced spiculation (CIS) on computed tomography, which is reticular or linear opacification of the pericolorectal fat tissues around the cancer site, is generally regarded as cancer infiltration into T3 or T4, but its clinicopathological significance is unknown. This study examines the correlation between CIS and clinicopathological findings to establish its prognostic value. METHODS: The subjects of this retrospective study were 335 patients with colorectal cancer (CRC), who underwent curative surgery between January, 2010 and December, 2011, at the National Defense Medical College Hospital in Saitama Prefecture, Japan. RESULTS: The level of interobserver agreement in the evaluation of CIS was substantial (83%; kappa value, 0.65). The presence of CIS was specific for T3/T4 disease (positive predictive value, 88.3%), and was significantly associated with tumor size and venous invasion. The 5-year relapse-free survival rate was significantly lower in patients with CIS than in those without CIS (68.6% and 84.0%, respectively, p = 0.001). Subgroup analysis revealed remarkable prognostic differences in patients with stage III and T3 disease. Multivariate analysis revealed that CIS was a significant independent prognostic factor. CONCLUSIONS: CIS was a significant preoperative prognostic factor and could be useful in the selection of preoperative therapy for patients with CRC.

Morphological consistency of desmoplastic reactions between the primary colorectal cancer lesion and associated metastatic lesions.

Some preceding studies show that a desmoplastic reaction (DR) at the invasive front of a primary tumor (DRprimary) is a promising prognostic indicator, and its histologic classification is an independent prognostic factor in patients with colorectal cancer (CRC). Although DR is observed in metastatic lesions, such as those in lymph nodes (DRLN) and the liver (DRliver), the association between DRprimary and DR of metastatic lesions is unclear. We investigated whether DRLN and DRliver could be categorized in the same manner as DRprimary and examined the features and prognostic implications of DRLN and DRliver. In this study, we evaluated 363 patients with metastases to lymph nodes and 45 patients with synchronous liver metastases who underwent curative resection. DRLN and DRliver statuses were classified as mature, intermediate, or immature, based on keloid-like collagen and myxoid stroma appearances in the metastatic lesions. Overall, 109, 106, and 148 patients had mature, intermediate, and immature DRLN, respectively; in total, 5, 21, and 19 patients had mature, intermediate, and immature DRliver, respectively. DRLN and DRprimary (spearman's rho = 0.43, P < 0.0001) and DRliver and DRprimary (spearman's rho = 0.40, P = 0.0069) were each significantly correlated. The 5-year relapse-free survival (RFS) after surgery was 67.7% for mature/intermediate DRLN and 52.9% for immature DRLN; the 5-year RFS after hepatectomy was 11.5% for mature/intermediate DRliver and 5.6% for immature DRliver. In conclusion, DRLN and DRliver may be classified in the same manner as DRprimary; morphological consistency of DR was observed between primary and metastatic lesions.

Prognostic significance of histological categorization of desmoplastic reaction in colorectal liver metastases.

Desmoplastic reaction (DR) involves the growth of fibrous or connective tissues around a tumor and has recently attracted attention as an indicator of malignant potential. Previous studies have confirmed that histological categorization of DR in the primary tumor is an independent prognostic factor in patients with colorectal liver metastases (CRLM). However, it remains unclear whether the DR status of the metastatic liver lesion (DRliver) is a useful prognostic factor. This pathological review evaluated records from 204 patients who underwent hepatectomy for CRLM at the National Defense Medical College Hospital in Japan. Each case's DRliver was classified as mature, intermediate, or immature based on the presence of keloid-like collagen and myxoid stroma in the metastatic liver lesion. This resulted in 12 cases of mature DRliver, 101 cases of intermediate DRliver, and 91 cases of immature DRliver. There was a significant correlation between the DR statuses of the primary tumor and the metastatic liver lesion (Spearman's rho = 0.3, P = 0.0001). The 5-year relapse-free survival rates after hepatectomy were 33.8% for mature/intermediate DRliver and 16.7% for immature DRliver (P = 0.0021). The 5-year overall survival rate after hepatectomy was higher in the mature/intermediate DRliver group (64.8%) than in the immature DRliver group (35.0%; P = 0.0012). The multivariate analysis confirmed that DRliver categorization could independently predict relapse-free survival and overall survival. In conclusion, DRliver categorization may be valuable for predicting prognosis after hepatectomy among patients with CRLM.

Prognostic Value of Poorly Differentiated Clusters in Liver Metastatic Lesions of Colorectal Carcinoma.

Colorectal liver metastasis (CRLM) is the most common pattern of metastases or recurrence in colorectal carcinoma; however, no robust pathologic prognostic factors have been identified. This study aimed to verify the prognostic value of poorly differentiated clusters (PDC) in liver metastatic lesions and to clarify the correlation between PDC in liver metastatic lesions (PDC) and the primary tumor histology. Consecutive patients who underwent resection for CRLM were pathologically reviewed. PDC was defined as cancer clusters comprising ≥5 cancer cells and lacking glandular formation and was quantifiably graded as G1 (<5 clusters), G2 (5 to 9 clusters), and G3 (≥10 clusters) based on the highest number of clusters observed under ×20 magnification. The cohort comprised 204 patients. PDC was classified as G1, G2, and G3 for 68, 69, and 67 patients, respectively, and it was significantly associated with PDC grade in the primary tumor (P<0.001). Among the potential prognostic factors, tumor budding in the primary tumor, PDC in the primary tumor, the number of liver metastases, extrahepatic metastasis, and PDC significantly influenced overall survival (OS) after CRLM resection. According to the PDC grade, the 5-year OS rates were 68.9%, 48.3%, and 39.5% for G1, G2, and G3 (P<0.001), respectively. Multivariate analysis for OS showed that PDC grade, tumor budding in the primary tumor, the number of liver metastasis and extrahepatic metastasis were independent prognostic factors. In conclusion, there is a correlation in the PDC grade between the primary tumor and liver metastatic lesion, and PDC grade could be a promising new prognostic factor after CRLM resection.