Scientific Papers

Invasive stratified mucin-producing carcinoma of the colorectum: expanding the morphologic spectrum of large bowel cancer | Diagnostic Pathology

It is common knowledge that epithelial-lined organs such as the GI, respiratory and the genitourinary systems can develop both adenocarcinomas and squamous cell carcinomas or combinations thereof. One of the hallmarks of squamous cell carcinoma is epithelial stratification. What is not as well-known is the phenomenon of epithelial stratification with intracytoplasmic mucin as has recently been described in the cervix, anus, penis and prostate [1,2,3,4,5,6,7,8,9]. The current study shows that this phenomenon can also occur in the colorectum. It is different from squamous differentiation in that [16,17,18,19] it is a cohesive group of stratified epithelial cells with variable amounts of intracytoplasmic mucin dispersed through the entirety of the lesion but without overt gland formation.

Colorectal ISMC differs from the well and moderately differentiated (low-grade) adenocarcinomas (NOS) in that there are no well-formed conventional glands found in this tumor. With poorly differentiated conventional adenocarcinomas (NOS), the glands are still present though they are highly irregular and more difficult to discern compared to low-grade tumors. Furthermore, these tumors are often quite desmoplastic with irregular infiltrative margins/high tumor-budding scores [22, 25,26,27], and lack the trans-lesional stratified pattern with peripheral palisading of ISMCs [1,2,3,4,5,6,7,8,9].

Colorectal ISMC is different from the mucinous adenocarcinoma in its histologic architecture and constituent cells. Mucinous adenocarcinomas generally have conventional glands (Fig. 4a) admixed with (extracellular) mucinous pools (> 50% of the tumor) though there can be variable numbers of signet ring cells (intracellular mucin) [22, 25,26,27].

Fig. 4
figure 4

a Mucinous adenocarcinoma showing a few profiles of conventional malignant colonic acini associated with pools of extracellular mucin. (H&E; original magnification × 40). b Medullary carcinoma showing groups of polygonal cells with vesicular nuclei, prominent nucleoli and abundant cytoplasm arranged in a diffuse or nesting pattern. (H&E; original magnification × 40). c Signet ring cell carcinoma showing a predominance of dyscohesive cells with prominent intracytoplasmic mucin and a crescentic nucleus that is displaced to one side. (H&E; original magnification × 40). d Goblet cell carcinoma (grade 1) composed of small well-defined nests of goblet-like cells. Immunohistochemistry showed scattered neuroendocrine cells within the goblet cell clusters. Other areas showed Paneth cell differentiation. (H&E; original magnification × 40)

ISMC also has to be distinguished from medullary carcinoma [20,21,22, 25,26,27] which is largely composed of polygonal cells with vesicular nuclei, prominent nucleoli, and abundant cytoplasm (Fig. 4b). The tumor cells are mostly arranged in sheets, nests or trabeculae with at the most very few isolated glands or mucin. The immunohistochemical profile of these tumors is aberrant (CK7 + /CK20-/CDX2-), thus differing from ISMCs which have a typical CRC immunoprofile (CK20 + /CDX2 + /CK7-). Medullary carcinoma is an important category because, despite its seemingly undifferentiated appearance, it has less frequent lymph node metastasis and a relatively favorable prognosis [20,21,22, 25,26,27]. In contrast, 8 of 9 CRC ISMCs in this limited series had lymph node metastases.

Unlike CRC ISMC, undifferentiated carcinomas show no glandular structures or any other features that are indicative of definite differentiation [21, 22, 25, 27]. It is possible that some of the cases originally designated as undifferentiated CRCs may in fact represent medullary carcinoma [20,21,22,23, 27].

Another important differential diagnosis is signet ring cell carcinoma (Fig. 4c) or discohesive carcinoma which is mostly seen in the stomach [28,29,30,31]. This gastric adenocarcinoma, even in its early stages, appears to begin de novo as signet ring cell carcinoma [29,30,31]. In fact, since its early stages can mimic mucin neck cells, recent genetic studies and follow up have helped to better recognize and define this entity. In contrast, it has been noted that the origin of colorectal signet ring cell carcinoma is quite confounding with the exception of those tumors that clearly have an origin in the more conventional mucinous adenocarcinomas associated with an overlying adenoma [27]. Tumors meeting the strict definition of CRC signet ring cell carcinoma (> 50% of isolated tumor cells having prominent intracytoplasmic mucin) are rare [27, 32]. They tend to be fairly homogeneous with little if any glandular formation and present at advanced stages with a rapid downward course. In the case of CRC ISMC, the signet ring cells appear to be a product of tumor progression i.e. they are seen admixed with mucinous pools and other cohesive irregularly shaped tumor cell clusters rather than the relatively more homogeneous diffusely infiltrative individual signet ring cells seen in the stomach or colorectum [27,28,29,30,31,32].

ISMC should also to be distinguished from goblet cell carcinoma (Fig. 4d). This is a tumor of appendiceal origin that characteristically shows discrete tubules or clusters of goblet-like mucinous cells admixed with variable numbers of neuroendocrine cells and Paneth-like cells [33,34,35]. With progression, there is an increase in the number of signet ring cells, mucinous pools and architectural complexity. Indeed, the recently proposed idea of grading goblet cell carcinomas was meant to address this phenomenon [33,34,35]. Colorectal ISMC, however, differs from goblet cell carcinoma in that it is neither located in the appendix nor does it demonstrate the amphicrine composition that includes goblet cell nests, neuroendocrine cells and Paneth cells.

All in all, our findings show that CRCs with the histology of ISMC do exist. The study suggests that, with tumor progression, CRC ISMCs develop a more prominent mucinous and signet ring cell component in a manner similar to the increase in complexity and histologic grade that occurs with goblet cell carcinomas [29,30,31] and other tumors. The importance of this entity is that it highlights the phenotypic plasticity of colorectal progenitor cells, and provides another pathway for the genesis of signet ring cells besides conventional mucinous CRC adenocarcinoma [27]. The experience with these tumors in other organs is still limited, but various authors suggest that it is an aggressive neoplasm [1,2,3,4,5], which is in accord with our study. Further investigations are warranted to learn more about this tumor, focusing on the early lesions that are easier to recognize before tumor progression/dedifferentiation efface the prototypical morphology. In this way, ISMC could be enlisted together with other CRC morphologic subtypes such as micropapillary, adenoma-like, serrated, mucinous, poorly cohesive, signet ring cell, medullary, adenosquamous and sarcomatoid carcinoma [21, 22, 25,26,27]. Ultimately, all these histologic patterns are a manifestation of the phenotypic plasticity of the progenitor cells. The resultant diversity of carcinoma types does, however, have clinicopathologic and prognostic utility. At the same time, it is increasingly being recognized that there is value to combining the histologic classification with the clinical profile and molecular signatures. For CRC ISMCs, to the extent that they tend to be right-sided, mucinous, lymphoplasmacytic, MLH1/PMS2 deficient with BRAF mutations, they seem to be aligned with the hypermutated molecular phenotype [36,37,38]. Future studies, both prospective and retrospective, are required to better characterize these tumors.

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