Mucinous Colorectal Cancer

Mucinous cancer is a distinct form of colorectal cancer (CRC) found in 10–15% of patients with CRC. Mucinous cancer differs from adenocarcinoma in terms of clinical and histopathological characteristics. It has long been associated with an inferior response to treatment compared with adenocarcinoma. The debate concerning the prognostic implications of mucinous tumour in patients with CRC is ongoing and it 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 management of patients with mucinous cancer. A review article, published recently in the Nature Reviews Clinical Oncology, provides insight into advances that have been made in the care of patients with mucinous cancer.

In their article, the authors describe the prognostic implications for patients with colon or rectal mucinous cancers separately; moreover, the predictive implications of mucinous cancer 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. They also described how responses to treatment differ from those of patients with CRC adenocarcinoma. Other important issues are also covered, including the potential to tailor management strategies to best suit the needs of individual patients, the value of early recognition of mucinous cancer subtype using magnetic resonance imaging (MRI), and the implications of the aberrant metastatic pattern of mucinous cancer observed in most patients.

Distinct characteristics

Mucinous cancer is more commonly found in patients with colon cancer than in those with rectal cancer (15% versus 9% of patients, respectively). The infrequent occurrence of mucinous cancer relative to adenocarcinoma renders results from randomised controlled trials using unselected populations of patients with CRC inappropriate. 

Mucinous cancer is distinguished as a subtype of CRC that is more frequently found in female patients and is predominantly, but not exclusively, located in the proximal colon. The aetiology of mucinous cancer is not well understood. Observations from clinical studies have shown that mucinous cancer is less common in patients in Asian countries, and higher rates of mucinous cancer have been reported in Europe, North America and Australia. Furthermore, mucinous cancer is more commonly diagnosed in patients with inflammatory bowel diseases (IBD), such as Crohn's disease or ulcerative colitis, and in patients with a history of pelvic or abdominal radiotherapy, are also more likely to be diagnosed with mucinous cancer.

Mucinous adenocarcinoma is characterised by abundant mucous secretion comprising at least 50% of the tumour volume. The designation of a tumour as mucinous is arbitrary and is often dependent on the individual pathologist's subjective assessment and level of experience. Mucinous cancer is considered poorly differentiated (grade 3). Nevertheless, grade assignment is largely subjective, with no or few defined criteria. The extent to which histopathological characteristics, such as growth pattern, tumour border aspect, location of mucous, and tumour cell:mucous ratio, influence outcomes is currently unknown. Furthermore, the presence of a signet-ring cell component in patients with mucinous cancer has been associated with poor outcome, but the exact clinical importance of this factor needs to be further investigated.

Compared with adenocarcinoma, mucinous cancer is more commonly diagnosed at an advanced stage of disease. A few possible explanations for this phenomenon exist. Firstly, mucinous cancer has a tendency to be located in the proximal colon and mucinous cancers are of a less firm consistency than adenocarcinomas, causing detectable symptoms to arise only when the disease reaches a more-advanced stage. In addition, mucinous cancer has a different molecular signature to adenocarcinoma, which might cause faster disease progression. The exact molecular aberrations that are responsible for this pattern of disease progression, and the sequence of any alterations, is currently unknown.

Various molecular aberrations have been described in patients with mucinous cancer. Compared with adenocarcinoma, mucinous cancers more often have microsatellite instability (MSI). Whenever mucinous cancers are microsatellite stable, however, they are characterised by a markedly reduced rate of copy-number aberrations when compared with adenocarcinoma. BRAF mutations are also commonly found in patients with mucinous cancer and are associated with an infiltrative pattern of tumour growth. An increased rate of KRAS and PIK3CA mutations has also been observed in patients with mucinous cancer. The MUC2 gene, which encodes mucin-2 (MUC-2), a protein that coats the epithelia of the intestines, airways and other mucous-membrane-containing organs is frequently overexpressed in patients with mucinous cancer, although this molecular feature is not exclusive to this form of disease. Overexpression of MUC-2 might protect against antitumour immune effectors by forming a mucous layer, thus promoting tumour development.

Mucinous cancer can be diagnosed preoperatively and high-resolution MRI, being more accurate than analysis of initial biopsy samples, has an important role in this regard. Documenting mucinous cancer using findings of both imaging and analysis of pathological specimens is important and has direct clinical implications.

Established mechanisms exist that might explain the relative resistance to chemotherapy and radiotherapy of patients with mucinous cancer compared with those with adenocarcinoma. This resistance to treatment is probably caused by a combination of a different molecular signature and the markedly different physical properties of mucin-containing tumours compared with adenocarcinomas, which gives rise to unique patterns of spread, and substantially different patterns of vascularity and tumour cellularity.

Despite a relatively poor prognosis, advances have been made in survival rates by careful en bloc removal of such tumours through improved standards of total mesorectal excision (TME) surgery. This removal strategy avoids intraoperative spillage and rupture of gelatinous mucinous cancers into the abdominal cavity. Awareness of the diagnosis of this disease subgroup, which has a poor prognosis, is important for surgical planning and follow-up surveillance of these patients.

Future improvements in adjuvant and neoadjuvant therapy might be achievable by using different approaches that take into account both the unique physical properties as well as molecular profiles of these tumours. Advances in tumour characterisation will also have an important role in the future, and will possibly enable further tailoring of treatment.

When mucinous cancer is diagnosed in the metastatic setting, the prognosis of the patients is generally worse than that of patients diagnosed with metastatic adenocarcinoma.

A multimodality approach has become the standard of care for the management of patients with CRC, and multidisciplinary team meetings should aim to raise awareness of the importance of histological subtypes where patients are managed using such an approach. For mucinous colorectal cancers, next considerations for different members of the multidisciplinary team have been suggested:

Radiologist

• Rectal mucinous cancer can be identified on T2-weighted MRI screening
• Rectal mucinous cancer response to chemoradiotherapy cannot be accurately evaluated with MRI screening
• After a pathological complete response to preoperative therapy, MRI screening might be the only way to determine tumour hytology
• Extensive metastatic pattern of mucinous cancer demands appreciation of subtype during follow-up study or assessment

Pathologist

• Mucinous cancer can be easily missed on preoperative biopsy
• Preoperative therapies might hamper histopathological assessment
• Grade assignment is unreliable in mucinous cancer
• The impact of a positive CRM might be altered in rectal mucinous cancer following preoperative chemoradiotherapy

Surgeon

• Mucinous cancer tumours are larger and therefore more at risk of incomplete removal
• Incomplete resection is the most important prognostic factor in patients with rectal mucinous cancer
• The impact of a positive circumferential resection margin might be altered in patient with rectal mucinous cancer following preoperative chemoradiotherapy
• High rate of peritoneal metastases should raise awareness in case of tumour spillage
• Mucinous cancer is an adverse prognostic factor in patients undergoing resection of liver metastasis

Radiation oncologist

• Rectal mucinous cancer shows poorer tumour downstaging by chemoradiotherapy than adenocarcinoma
• Rectal mucinous cancer benefits from short-term radiotherapy

Medical oncologist

• Patient with rectal mucinous cancer have poorer tumour downstaging responses to chemoradiotherapy than patients with adenocarcinoma
• Mucinous cancer has a poorer response to palliative systemic therapy than adenocarcinoma
• Mucinous cancer benefits from adjuvant chemotherapy for stage III colon cancer equally to adenocarcinoma

Reference

Hugen N, Brown G, Glynne-Jones R, et al. Advances in the care of patients with mucinous colorectal cancer. Nature Reviews Clinical Oncology 2015; Published online 1 September. doi:10.1038/nrclinonc.2015.140