I will briefly summarize my findings on this issue from a internal review I was commissioned to undertake.

Until recently there have been divergent data on the issue of colorectal cancer (CRC) histologic subtype on the one hand and both prognosis and metastatic pattern on the other.

DUELING STUDIES

Thus a recent retrospective review [1] found that mucinous adenocarcinomas and/or adenocarcinomas with mucinous component were associated independently with a poorer outcome for rectal cancer, but were an independent protective survival indicator in right-sided colon cancer. Mucinous adenocarcinomas exhibited different outcomes relative to different tumor locations for patients with colorectal cancer.

But in contrast, another study [2] found that in multivariable analysis, survival did not differ significantly between adenocarcinomas and mucinous adenocarcinomas after correction for tumor stage, but that signet-ring cell carcinomas remained an independent prognostic factor associated with worse survival. And a recent population study [3] investigated the prognostic value of mucinous histology in two large phase III studies in metastatic CRC, observing a worse overall survival (OS), progression free survival (PFS) and overall response rate (ORR) in patients with mucinous adenocarcinoma compared to patients with adenocarcinoma, with mucinous histology being an independent negative prognostic factor for OS (combined hazard ratio of 1.78) in multivariate analysis. Yet a systematic review and meta-analysis [4] found that the poor prognosis for mucinous adenocarcinoma is only present in rectal cancer; in the adjuvant setting, there was no difference in the efficacy of chemotherapy between mucinous adenocarcinoma and non-mucinous adenocarcinoma.

FINALLY SOME LIGHT

These divergent findings have been clarified only recently. First, it is now widely agreed that

compared with non-mucinous colorectal tumors, Mucinous carcinomas are associated with increased microsatellite instability (MSI) status, CpG island methylation phenotype and BRAF mutation [4,5].

Now, more critically, to understand the intersection with prognostic significance and metastatic pattern, Chinese researchers conducted a retrospective, exploratory study [6] of the prognostic value of MUC in patients stratified by the primary tumor using data from the NCI SEER database and a single institution database. They found that mucinous adenocarcinomas occurred more frequently in patients who exhibited higher pT category, higher pN category, higher TNM stage, higher histological grade, and left-sided colon cancer [7-10] and that based on the SEER data set, mucinous adenocarcinoma was an independent negative survival indicator in rectal cancer (HR 1.125), and while there was no significant association in left-sided colon cancer, mucinous adenocarcinoma was an independent protective survival indicator in right-sided colon cancer (HR 0.925). Thus, mucinous adenocarcinoma was associated independently with poorer outcome for rectal cancer and was an independent protective survival indicator in right-sided colon cancer, exhibiting a different outcome depending on tumor position for patients with colorectal cancer.

Furthermore, a Dutch team found in a population study [11] that the poor prognosis for mucinous adenocarcinoma is only present in rectal cancer, and that in the adjuvant setting, the efficacy of chemotherapy did not differ between mucinous adenocarcinoma and non-mucinous adenocarcinoma. This has been cross-confirmed in a Dutch retrospective review [12] from the same team, who have finally clarified the critical issue of the potential association between histological subtype in CRC and metastatic patterns. They examined differences in metastatic patterns between mucinous adenocarcinoma (MC), signet-ring cell carcinoma (SRCC) and adenocarcinoma (AC) when primary tumor localization was differentiated. What the study found was that:

(1) patients with MC and SRCC

- more frequently had metastatic disease,

- had metastases at multiple sites more often compared with AC patients, and

- more frequently had peritoneal metastases

(2) while AC predominantly metastasized to the liver;

(3) metastatic patterns were modulated by primary tumor site:

- a high rate of abdominal metastases in colon cancer patients

- extra-abdominal metastases were more commonly associated with rectal cancer patients.

LESSONS LEARNED

Thus, metastatic patterns in CRC differ and are dependent on both histological subtypes and the localization of the primary tumor, an insight that helps explains previous contradictory findings which failed to differentiate and control for critical variables:

(1) histological subtype AND

(2) primary tumor localization

and furthermore, prognostic significance also shows dependencies, as discussed and shown above, that must always be considered in the total managment and therapeutics to be deployed in clinical practice.

METHODOLOGY OF THE REVIEW

A search of the PUBMED, Cochrane Library / Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED (Allied and Complimentary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, ISI Web of Science (WoS), BIOSIS, LILACS (Latin American and Caribbean Health Sciences Literature), ASSIA (Applied Social Sciences Index and Abstracts), and SCEH (NHS Evidence Specialist Collection for Ethnicity and Health) was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.

REFERENCES

1. Langner C, Harbaum L, … Rehak P. Mucinous differentiation in colorectal cancer--indicator of poor prognosis? Histopathology 2012; 60(7):1060-72.

2. Nitsche U, Zimmermann A, Späth C, et al. Mucinous and signet-ring cell colorectal cancers differ from classical adenocarcinomas in tumor biology and prognosis. Ann Surg 2013; 258(5):775-82; discussion 782-3.

3. Mekenkamp LJ, Heesterbeek KJ, Koopman M, et al. Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer. Eur J Cancer 2012; 48(4):501-9.

Verhulst J, Ferdinande L, Demetter P, Ceelen W. Mucinous subtype as prognostic factor in colorectal cancer: a systematic review and meta-analysis. J Clin Pathol 2012; 65(5):381-8.

4. Song GA, Deng G, Bell I, Kakar S, Sleisenger MH, Kim YS. Mucinous carcinomas of the colorectum have distinct molecular genetic characteristics. Int. J. Oncol. 2005; 26; 745–750.

5. Tanaka H, Deng G, Matsuzaki K et al. BRAF mutation, CpG island methylator phenotype and microsatellite instability occur more frequently and concordantly in mucinous than non-mucinous colorectal cancer. Int. J. Cancer 2006; 118; 2765–2771.

6. Gao P, Song YX, Xu YY, et al. Does the prognosis of colorectal mucinous carcinoma depend upon the primary tumour site? Results from two independent databases. Histopathology 2013; 63(5):603-15.

7. Leopoldo S, Lorena B, Cinzia A et al. Two subtypes of mucinous adenocarcinoma of the colorectum: clinicopathological and genetic features. Ann. Surg. Oncol. 2008; 15; 1429–1439.

8. Kang H, O'Connell JB, Maggard MA, Sack J, Ko CY. A 10-year outcomes evaluation of mucinous and signet-ring cell carcinoma of the colon and rectum. Dis. Colon Rectum 2005; 48; 1161–1168.

9. Hyngstrom JR, Hu CY, Xing Y et al. Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: analysis from the national cancer data base. Ann. Surg. Oncol. 2012; 19; 2814–2821.

10. Catalano V, Loupakis F, Graziano F et al. Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer. Ann. Oncol. 2011; 23; 135–141.

11. Hugen N, Verhoeven RH, Radema SA, et al. Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma. Ann Oncol 2013; 24(11):2819-24.

12. Hugen N, van de Velde CJ, de Wilt JH, Nagtegaal ID. Metastatic pattern in colorectal cancer is strongly influenced by histological subtype. Ann Oncol 2014; 25(3):651-7.

In my opinion these two articles bring attention to the "vascular" road (not lymphatic) in metastases of adenocarcinoma of the colon (conventional histology). Probably there are phenotypic differences in tumors that prefer this way. These are things that we see in everyday work and I think this is a good area of ​​research.

https://www.researchgate.net/publication/6339513_Pathological_assessment_of_pericolonic_tumor_deposits_in_advanced_colonic_carcinoma_relevance_to_prognosis_and_tumor_staging?ev=prf_pub

https://www.researchgate.net/publication/44650847_TNM_staging_system_of_colorectal_carcinoma_a_critical_appraisal_of_challenging_issues?ev=prf_pub

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