Niek Hugen

Metastatic pattern in colorectal cancer is strongly influenced by histological subtype

BACKGROUND Clinical studies regarding colorectal cancer (CRC) have suggested differences in metastatic patterns between mucinous adenocarcinoma (MC), signet-ring cell carcinoma (SRCC) and the more common adenocarcinoma (AC). The current study systematically evaluates metastatic patterns of different histological subtypes in CRC patients and analyzes metastatic disease upon primary tumor localization. PATIENTS AND METHODS A nationwide retrospective review of pathological records of 5817 patients diagnosed with CRC who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch pathology registry (PALGA). To substantiate clinical relevance, metastatic patterns were compared with the prospective randomized multicenter Total Mesorectal Excision (TME) trial, which investigated efficacy of preoperative radiotherapy in rectal cancer patients. RESULTS In the autopsy study, 1675 patients had metastatic disease. MC and SRCC patients more frequently had metastatic disease (33.9% and 61.2% versus 27.6%; P < 0.0001) and had metastases at multiple sites more often compared with AC patients (58.6% and 70.7% versus 49.9%; P = 0.001). AC predominantly metastasized to the liver, and MC and SRCC more frequently had peritoneal metastases. Metastatic patterns were also related to the primary tumor site, with a high rate of abdominal metastases in colon cancer patients, whereas rectal cancer patients more often had metastases at extra-abdominal sites. Results from the TME trial confirmed findings in rectal cancer patients from the autopsy study. CONCLUSION There are profound differences in metastatic patterns between histological subtypes and the localization of the primary tumor in CRC. Findings from this study should encourage to take these factors into account for follow-up strategies and future studies.BACKGROUND Clinical studies regarding colorectal cancer (CRC) have suggested differences in metastatic patterns between mucinous adenocarcinoma (MC), signet-ring cell carcinoma (SRCC) and the more common adenocarcinoma (AC). The current study systematically evaluates metastatic patterns of different histological subtypes in CRC patients and analyzes metastatic disease upon primary tumor localization. PATIENTS AND METHODS A nationwide retrospective review of pathological records of 5817 patients diagnosed with CRC who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch pathology registry (PALGA). To substantiate clinical relevance, metastatic patterns were compared with the prospective randomized multicenter Total Mesorectal Excision (TME) trial, which investigated efficacy of preoperative radiotherapy in rectal cancer patients. RESULTS In the autopsy study, 1675 patients had metastatic disease. MC and SRCC patients more frequently had metastatic disease (33.9% and 61.2% versus 27.6%; P < 0.0001) and had metastases at multiple sites more often compared with AC patients (58.6% and 70.7% versus 49.9%; P = 0.001). AC predominantly metastasized to the liver, and MC and SRCC more frequently had peritoneal metastases. Metastatic patterns were also related to the primary tumor site, with a high rate of abdominal metastases in colon cancer patients, whereas rectal cancer patients more often had metastases at extra-abdominal sites. Results from the TME trial confirmed findings in rectal cancer patients from the autopsy study. CONCLUSION There are profound differences in metastatic patterns between histological subtypes and the localization of the primary tumor in CRC. Findings from this study should encourage to take these factors into account for follow-up strategies and future studies.

Colorectal signet-ring cell carcinoma: benefit from adjuvant chemotherapy but a poor prognostic factor

Colorectal signet‐ring cell carcinoma (SRCC) has been associated with poor survival compared with mucinous adenocarcinoma (MC) and the more common adenocarcinoma (AC). Efficacy of adjuvant chemotherapy in SRCC has never been assessed. This study analyzes the prognostic impact of SRCC and determines whether colonic SRCC patients benefit from adjuvant chemotherapy equally compared with MC and AC patients. Data on 196,757 colorectal cancer (CRC) patients in the period 1989–2010 was included in this Dutch nationwide population‐based study. Five‐year relative survival estimates were calculated and multivariate relative survival analyses using a multiple regression model of relative excess risk (RER) were performed. SRCC was found in 1,972 (1.0%) patients. SRCC patients presented more frequently with stage III or IV disease than AC patients (75.2% vs. 43.6%, p < 0.0001) and SRCC was more frequently found in the proximal colon (57.7 vs. 32.0%, p < 0.0001). SRCC patients had a poor 5‐year relative survival of 30.8% (95% CI 28.1–33.6%) in the colon and 19.5% (95% CI 14.7–24.8%) in the rectum compared with 56.8% (95% CI 56.4–57.1%) and 58.5% (95% CI 57.9–59.1%) for AC. This survival difference was found in stage II, but was most prominent in stage III. Compared with AC, there was no significant interaction between SRCC and adjuvant chemotherapy (RER 1.10, 95% CI 0.81–1.51), suggesting a comparable benefit from adjuvant chemotherapy in AC and SRCC. In conclusion, the prognostic impact of SRCC is dismal in both colon and rectal cancer patients, but adjuvant chemotherapy is associated with improved survival in AC, MC, and SRCC patients.

Advances in the care of patients with mucinous colorectal cancer

The majority of colorectal cancers (CRCs) are classified as adenocarcinoma not otherwise specified (AC). Mucinous carcinoma (MC) is a distinct form of CRC and is found in 10–15% of patients with CRC. MC differs from AC in terms of both clinical and histopathological characteristics, and has long been associated with an inferior response to treatment compared with AC. The debate concerning the prognostic implications of MC in patients with CRC is ongoing and MC is still considered an unfavourable and unfamiliar subtype of the disease. Nevertheless, in the past few years epidemiological and clinical studies have shed new light on the treatment and management of patients with MC. Use of a multidisciplinary approach, including input from surgeons, pathologists, oncologists and radiologists, is beginning to lead to more-tailored approaches to patient management, on an individualized basis. In this Review, the authors provide insight into advances that have been made in the care of patients with MC. The prognostic implications for patients with colon or rectal MC are described separately; moreover, the predictive implications of MC regarding responses to commonly used therapies for CRC, such as chemotherapy, radiotherapy and chemoradiotherapy, and the potential for, and severity of, metastasis are also described.

Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis.

Purpose Colorectal cancer (CRC) treatment is largely determined by tumor stage. Despite improvements made in the treatment of various types of metastatic disease, staging has not been refined. The role of tumor deposits (TDs) in staging remains debated. We have assessed the relation of TDs with metastatic pattern to evaluate whether TDs might add significant new information to staging. Methods We performed a systematic literature search that was focused on the role of TDs in CRC. Studies with neoadjuvant-treated patients were excluded. Data on stage, histologic factors, and outcome were extracted. Data from four large cohorts were analyzed for the relevance of the presence of TDs, lymph node metastases (LNMs), and extramural vascular invasion (EMVI) on the pattern of metastases and outcomes. Results Of 10,106 included patients with CRC, 22% presented with TDs. TDs are invariably associated with poor outcome. Presence of TDs was associated with presence of LNMs and EMVI. In a pairwise comparison, effects of TD were stronger than those of both LNMs and EMVI. In the logistic regression model, TDs in combination with LNMs is the strongest predictor for liver (odds ratio [OR], 5.5), lung (OR, 4.3) and peritoneal metastases (OR, 7.0). Presence of EMVI adds information for liver and lung metastases, but not for peritoneal metastases. Conclusion We have shown that TDs are not equal to LNMs or EMVI with respect to biology and outcome. We lose valuable prognostic information by allocating TDs into nodal category N1c and only considering TDs in the absence of LNMs. Therefore, we propose that the number of TDs should be added to the number of LNMs to derive a final N stage.

The Increasing Relevance of Tumour Histology in Determining Oncological Outcomes in Colorectal Cancer.

Colorectal cancer is not just one type of cancer. Differences in outcome and reaction to treatment can at least be partly explained by different histological and molecular subtypes. Recognition of these differences may influence treatment decisions. However, there is huge variation in the amount of information that is available. Several tumour types such as mucinous carcinoma, signet ring cell carcinoma, neuroendocrine carcinoma and adenosquamous carcinoma have such a distinct phenotype that they are readily recognised. However, due to the rarity of signet ring cell carcinoma and adenosquamous carcinoma, limited data are available. More recently defined subtypes, like medullary carcinoma, serrated adenocarcinoma and micropapillary carcinoma, are not adequately diagnosed, which limits research possibilities using large-scale data from registries. In the current review, we systematically describe the histologic subtypes with the clinical and molecular background. We evaluate their prognosis compared to adenocarcinoma not otherwise specified and speculate about the clinical relevance.

Limited effect of lymph node status on the metastatic pattern in colorectal cancer

Regional lymph node metastases in colorectal cancer (CRC) decrease outcome. Whether nodal metastases function as a biomarker, i.e. as a sign of advanced disease, or are in fact involved in the metastatic process is unclear. We evaluated metastatic patterns of CRC according to the lymph node status of the primary tumor. A retrospective review of 1393 patients with metastatic CRC who underwent autopsy in the Netherlands was performed. Metastatic patterns of regional lymph node positive and negative CRC were compared and validated by population-based data from the Eindhoven Cancer Registry (ECR). Patients with regional lymph node positive CRC more often developed peritoneal metastases (28% vs. 21%, p=0.003) and distant lymph node metastases (25% vs. 15%, p <0.001). Incidences of liver and lung metastases were comparable. Data from the ECR confirmed our findings regarding peritoneal (22.4% vs. 17.0%, p=0.003) and distant lymph node metastases (15.8% vs. 9.7%, p <0.001). Regional lymph node positive CRC show a slightly different dissemination pattern, with higher rates of peritoneal and distant lymph nodes metastases. Comparable incidences of liver and lung metastases support the hypothesis that dissemination to distant organs occurs independently of lymphatic spread.

The molecular background of mucinous carcinoma beyond MUC2

The increasing interest of the oncology community in tumour classification and prediction of outcome to targeted therapies has put emphasis on an improved identification of tumour types. Colorectal mucinous adenocarcinoma (MC) is a subtype that is characterized by the presence of abundant extracellular mucin that comprises at least 50% of the tumour volume and is found in 10–15% of colorectal cancer patients. MC development is poorly understood, however, the distinct clinical and pathological presentation of MC suggests a deviant development and molecular background. In this review we identify common molecular and genetic alterations in colorectal MC. MC is characterized by a high rate of MUC2 expression. Mutation rates in the therapeutically important RAS/RAF/MAPK and PI3K/AKT pathways are significantly higher in MC compared with non‐mucinous adenocarcinoma. Furthermore, mucinous adenocarcinoma shows higher rates of microsatellite instability and is more frequently of the CpG island methylator phenotype. Although the majority of MCs arise from the large intestine, this subtype also develops in other organs, such as the stomach, pancreas, biliary tract, ovary, breast and lung. We compared findings from colorectal MC with tumour characteristics of MCs from other organs. In these organs, MCs show different mutation rates in the RAS/RAF/MAPK and PI3K/AKT pathways as well, but a common mucinous pathway cannot be identified. Identification of conditions and molecular aberrations that are associated with MC generates insight into the aetiology of this subtype and improves understanding of resistance to therapies.

Advances in organ preserving strategies in rectal cancer patients

Treatment of rectal cancer patients has been subjected to change over the past thirty years. Total mesorectal excision is considered the cornerstone of rectal cancer treatment, but is also associated with significant morbidity resulting in an impaired quality of life. The addition of neoadjuvant chemoradiotherapy to surgery has shown to improve survival and local control and may lead to a partial or even complete response (CR). This raises questions regarding the necessity for subsequent radical surgery. After careful patient selection local excision and wait-and-see approaches are explored, aiming to improve quality of life without compromising oncological outcome. A multimodality diagnostic approach for optimal staging is crucial in determining the appropriate neoadjuvant treatment regimen. Adequate endoscopic restaging of rectal tumours after multimodality treatment will aid in selecting patients who are eligible for an organ preserving approach. The role and accuracy of imaging in the detection of the primary tumour, residual rectal cancer or local recurrence seems vital. Alternative neoadjuvant regimens are currently explored to increase the rate of clinical CRs, which may support organ preserving approaches. This review aims to generate insight into the advances in diagnostics and treatment modalities in all stages of rectal cancer and will highlight future studies that may support further implementation of organ preservation treatment in rectal cancer.

Reduced rate of copy number aberrations in mucinous colorectal carcinoma

Background Mucinous carcinoma (MC) is found in 10%–15% of colorectal cancer (CRC) patients. It differs from the common adenocarcinoma (AC) in histopathological appearance and clinical behavior. Methods Genome-wide DNA copy number and survival data from MC and AC primary CRC samples from patients from two phase III trials (CAIRO and CAIRO2) was compared. Chromosomal copy number data from The Cancer Genome Atlas (TCGA) was used for validation. Altogether, 470 ACs were compared to 57 MCs. Results MC showed a reduced amount of copy number aberrations (CNAs) compared with AC for the CAIRO/CAIRO2 cohort, with a median amount of CNAs that was 1.5-fold lower (P = 0.002). Data from TCGA also showed a reduced amount of CNAs for MC. MC samples in both cohorts displayed less gain at chromosome 20q and less loss of chromosome 18p. A high rate of chromosomal instability was a strong negative prognostic marker for survival in MC patients from the CAIRO cohorts (hazard ratio 15.60, 95% CI 3.24–75.05). Conclusions Results from this study indicate that the distinct MC phenotype is accompanied by a different genetic basis when compared with AC and show a strong association between the rate of chromosomal instability and survival in MC patients.

Does pelvic radiation increase rectal cancer incidence? – A systematic review and meta-analysis

BACKGROUND One of the late complications associated with radiation therapy (RT) is a possible increased risk of second cancer. In this systematic review, we analysed the incidence of rectal cancer following primary pelvic cancer irradiation. METHODS A literature search was conducted using the PubMed and EMBASE libraries. Original articles that reported on secondary rectal cancer after previous RT for a primary pelvic cancer were included. Sensitivity analyses were performed by correcting for low number of events, high risk of bias, and outlying results. RESULTS A total of 5171 citations were identified during the literature search, 23 studies were included in the meta-analyses after screening. A pooled analysis, irrespective of primary tumour location, showed an increased risk for rectal cancer following RT (N = 403.243) compared with non-irradiated patients (N = 615.530) with a relative risk (RR) of 1.43 (95% confidence interval [CI] 1.18-1.72). Organ specific meta-analysis showed an increased risk for rectal cancer after RT for prostate (RR 1.36, 95%CI 1.10-1.67) and cervical cancer (RR 1.61, 95% CI 1.10-2.35). No relation was seen in ovarian cancer patients. The modality of RT did not influence the incidence of rectal cancer. CONCLUSIONS This review demonstrates an increased risk for second primary rectal cancer in patients who received RT to the pelvic region. This increased risk was modest and could not be confirmed for all primary pelvic cancer sites. The present study does not provide data to change guidelines for surveillance for rectal cancer in previously irradiated patients.