Mixed epithelial endocrine neoplasms of the colon and rectum – An evolution over time: A systematic review

ARTICLE HIGHLIGHTS

Research background

Mixed tumors of the colon and rectum, composed of a combination of epithelial and endocrine elements of benign and malignant potential are rare neoplasms. These can occur anywhere in the gastrointestinal tract and are often diagnosed incidentally. Though they have been a well-documented entity in the pancreas, recognition and accurate diagnosis of these tumors in the colon and rectum, to date, remains a challenge. This is further compounded by the different terminologies that have been attributed to these lesions over the years adding to increased confusion and misclassification. Therefore, dedicated literature reviews of these lesions in the colon and rectum are inconsistent and are predominantly limited to case reports and case series of limited case numbers.

Though, most of these tumors are high grade and of advanced stage, intermediate and low grade lesions of these mixed tumors are also increasingly been reported. Currently therefore, there are no established independent consensus based guidelines for the therapeutic patient management of these unique lesions: However, as most lesions of clinical significance typically present as high grade, and at an advanced stage, they are usually treated by default as high stage adenocarcinomas of the colon and rectum; though additional specialized targeted therapies for the endocrine elements are emerging with improved understanding.

This manuscript provides a targeted comprehensive literature review of such mixed tumors in the colon and rectum that chronicles the evolution over time with summarization of historical perspectives of terminology and advocates a rationale for the proposal for a new, simple, clinically relevant, non-ambiguous terminology for these lesions to be referred to as mixed epithelial endocrine neoplasms. Discussion of the pathogenesis including genomic landscape, clinicoradiological features, pathology, treatment, prognosis, the current status of the management of the primary lesions, their recurrences and metastases in the context of evidence provides a comprehensive upto date review of these unique colorectal neoplasms.

Research motivation

The key topic of interest is to unravel the varied terminologies that have been attached to these neoplasms ever since its first recognition in 1924 to its current state of World Health Organization 2019. Unfortunately, due to the different terminologies used there is continued lack of clarity and misclassification of these lesions. Therefore, dedicated literature reviews of these lesions in the colon and rectum are inconsistent and are predominantly limited to case reports and case series of limited case numbers.

The detailed review with understanding has resulted in the new proposed terminology that is simple, clinically relevant, non-ambiguous and free of semantic error. Acceptance and utilization of this terminology will facilitate study of identical tumors in larger numbers for improved understanding on their pathogenesis resulting in finding better targeted treatment options and for accurate evaluation of predictive and prognostic factors of these rare and unusual neoplasms.

Research objectives

The main objective of this study was to conduct a targeted review of these complex, rare colorectal neoplasms to further our understanding regarding their pathogenesis, genomic landscape, clinico-radio-pathological features, treatment and prognosis and realize the gaps in our knowledge. Additionally getting the terminology right for these tumors will facilitate future studies of well-designed multi institutional prospective randomized controlled clinical trials to develop and evaluate newer therapeutic strategies for continued improved understanding and personal optimization of clinical management of these rare types of colorectal neoplasms.

Research methods

A comprehensive review of the published English literature was conducted using the search engines PubMed, MEDLINE and GOOGLE scholar. The following search terms (“mixed tumors colon” OR mixed endocrine/neuroendocrine tumor/neoplasm/lesion colon OR adenocarcinoma and endocrine/neuroendocrine tumor colon OR mixed adenocarcinoma and endocrine/neuroendocrine carcinoma colon OR Amphicrine tumors OR Collision tumors) were used. This was repeated for rectal tumors independently using the same search terms. The initial search was conducted in September of 2019. In addition an updated search was conducted in April 2020. Eligibility criteria were defined and all potential relevant items, including full articles and/or abstracts were independently reviewed, assessed and agreed upon items were selected for in-depth analysis. Relevant secondary references were retrieved and reviewed by two of the authors.

Research results

In total 237 full articles/abstracts documents were considered for eligibility of which 45 articles were illegible resulting in a total of 192 articles that were assessed for eligibility of which 139 have been selected for reference in this current review. Therefore this seminal manuscript is a one stop article that provides a detailed outlook on the evolution over time with summarization of historical perspectives, nomenclature, clinicoradiological features, pathology, treatment, prognosis and the current status of the management of both the primary lesions, their recurrences and metastases. Guidelines for therapeutic strategies, patient management and the continued lack of independent consensus guidelines were also explored. An additional feature of this manuscript is the proposal for a new revised terminology for these unique tumors that encompasses all the relevant criteria and is simple, clinically relevant and free of semantic ambiguity. This will solve the biggest hurdle of confusion and misclassification that plagues these rare unique colorectal neoplasms.

Research conclusions

The unique outcome of this targeted review is the proposal for a new revised terminology for these unique tumors that encompasses all the relevant criteria and is simple, clinically relevant and free of semantic ambiguity.

One of the new theories proposed is to report the two components of these tumors-epithelial and endocrine irrespective of their percentages and on their clinical relevance as high grade, intermediate grade and low grade neoplasms.

This manuscript has reviewed the current status of these entities providing a detailed outlook on the evolution over time with summarization of historical perspectives, nomenclature, clinicoradiological features, pathology, treatment, prognosis and the current status of the management of both the primary lesions, their recurrences and metastases. Guidelines for therapeutic strategies, patient management and the continued lack of independent consensus guidelines were also explored. An additional feature of this manuscript is the proposal for a new revised terminology for these unique tumors that encompasses all the relevant criteria and is simple, clinically relevant and free of semantic ambiguity.

Gaps in knowledge that have been identified are threefold that include (1) the pathogenetic pathway are yet to be identified including recognition of the critical carcinogenic “turning point” of this mixed neoplasm in the colon and rectum and answers to the? Why or? How two different neoplastic cells, with different phenotype and different behaviors coexist as one neoplasm. More accessible genomic materials such as circulating tumor cells or deoxyribonucleic acid may prove useful in the future. Such liquid biopsies with genomic profiling of tumor may shed light to the complex genomic landscape of MiNENs/MEENs. Knowledge of unique molecular signatures may serve as the stepping stone to the development of targeted therapeutic options and may facilitate detection of precancerous and early stage lesions which is central to improving patient prognosis. Thus important questions remain that have not yet been addressed by research.

(2) Another area of continued debate is the World Health Organization discriminatory criterion cut off 30% rule for each component for inclusion as a mixed tumor. Most studies have led to the conclusion that it is the degree of component differentiation that influences the prognosis rather than the percentage volume of tumor occupied in the neoplasm. We strongly recommend that there should be continued reporting of any second component especially with poorly differentiated histology or evidence of invasion, regardless of its percentage volume. Further exploration of the minimum percentage of each neoplastic component and their prognostic impact must be revisited.

(3) Finally, recommendations regarding best management strategies for patients with these complex tumors of mixed components are difficult to formulate due to the lack of evidence based guidelines. Clinicopathological risk factors regarding metastatic disease to lymph nodes and distant disease are yet to be explored in detail. The reasons underlying the presence of only one component in the most distant metastases need to be explored. Information regarding synchronous, metachronous metastases, local recurrence, metastases to unusual sites, development of new rapidly growing metastatic lesions while on treatment in otherwise stable disease are stories that needs to be retold and revisited for a deeper understanding of the true biology of this disease.

Research perspectives

MEEN of the colon and rectum are poorly understood rare entities that encompass an extensive range of heterogeneous tumors with a wide variety of combinations leading to tumors of high, intermediate or low grade malignant potential. Morphologically, the two components may present as composite mixed, collision or as amphicrine tumors. Unfortunately, those most commonly encountered in clinical practice are high grade tumors with an epithelial carcinomatous component admixed with a poorly differentiated neuroendocrine component (MANEC) carrying a poor prognosis. These tumors continue to present great histopathological diagnostic challenges on limited biopsy material as in upto one third of the cases only one of the tumor components is identified. Although published cases of these entities are limited, careful dedicated pathological examination of bulky, or locally advanced, poorly differentiated tumors may reveal the true prevalence of this neoplasm. Continued vigilance with methodical detailed examination of the definitive resected specimen with ancillary immunohistochemical studies is required for accurate diagnosis. It is postulated that most pure endocrine cell carcinomas of colon and rectum if examined thoroughly will be associated with a carcinomatous element thus being a MANEC. Variations in morphological characteristics and degrees of cellular differentiation significantly influence the evolution of these cases. Clinical vigilance and histological identification of such tumors is the cornerstone in determining appropriate treatment strategies for these complex lesions. Continued molecular and genetic analysis is crucial for understanding the genetic drivers of this neoplasm as potential for future targeted therapy. Acknowledging, the vital role of the endocrine component in dictating the clinical behavior of this tumor, has led to continued exploration for the use of somatostatin receptors scintigraphy for the diagnosis and follow-up of MANECs. Early referral to a high-volume center with potential multidisciplinary expertise in pathological diagnosis with surgical and medical oncologist multidisciplinary teams in the management of these tumors is an important step in the expectation of improved overall outcomes. Steps to increase clinical and pathological awareness of these rare and complex entities is a key step to better optimize treatment options and lead to the establishment of evidence based guidelines for management. We strongly recommend a multicentric approach with multi institutional collaborative trials of treatment protocols including novel multimodality approach of surgery, chemotherapy, radiotherapy [rectal lesions] and potentially evolving systemic therapy with targeted antineoplastic pharmacological interventions for these unique rare lesions.