Diagnosing colorectal medullary carcinoma: interobserver variability and clinicopathological implications

Abstract

Colorectal medullary carcinoma, recognized by the World Health Organization as a distinct histologic subtype, is commonly regarded as a specific entity with an improved prognosis and unique molecular pathogenesis. A fundamental but as yet unaddressed question, however, is whether it can be diagnosed reproducibly. In this study, by analyzing 80 colorectal adenocarcinomas whose dominant growth pattern was solid (thus encompassing medullary carcinoma and its mimics), we provided a detailed description of the morphological spectrum from "classic medullary histology" to nonmedullary poorly differentiated histologies and demonstrated significant overlapping between categories. By assessing a selected subset (n=30) that represented the spectrum of histologies, we showed that the interobserver agreement for diagnosing medullary carcinoma by using 2010 World Health Organization criteria was poor; the κ value among 5 gastrointestinal pathologists was only 0.157 (95% confidence interval, 0.127-0.263; P=.001). When we arbitrarily classified the entire cohort into "classic" and "indeterminate" medullary tumors (group 1, n=19; group 2, n=26, respectively) and nonmedullary poorly differentiated tumors (group 3, n=35), groups 1 and 2 were more likely to exhibit mismatch repair protein deficiency than group 3 (P<.001); however, improved survival could not be detected in either group compared with group 3. Our findings suggest that the diagnosis of medullary carcinoma, as currently applied, may only serve as a morphological descriptor indicating an increased likelihood of mismatch-repair deficiency. Additional evidence including a more objective classification system is needed before medullary carcinoma can be regarded as a distinct entity with prognostic relevance. Until such evidence becomes available, caution should be exercised when making this diagnosis, as well as when comparing results across different studies.

Keywords: Colorectal carcinoma; Diagnostic reproducibility; Microsatellite instability; Tumor classification; Tumor histology.

Figure 1

H&E appearances of typical colorectal medullary carcinomas. Note the circumscribed tumor border (A, 40× magnification), the appearance of sheets of cells at low power (B, 40× magnification) imparted by uniform and syncytial tumor cell nests merging with a cellular stroma (C, 100× magnification). Typically, these tumors have abundant tumor-infiltrating lymphocytes (D, 100× magnification).

Figure 2

H&E appearances of high grade colorectal adenocarcinoma with medullary features. Although the tumor cells may appear uniform and are associated with some tumor-infiltrating lymphocytes, they have a cord like growth pattern with a fibrotic stroma (A, 40× magnification), an infiltrative border (B, 40× magnification), or with regions showing solid growth mixed with small but well formed lumina (C, 100× magnification, and D, 200× magnification).

Figure 3

H&E appearances of conventional poorly differentiated colorectal adenocarcinoma. These tumors typically show high grade cytology and a desmoplastic stroma (A–C, each 100× magnification). Tumors may grow in solid sheets; however, the cells show high grade cytological features such as increased nuclear-to-cytoplasmic ratio (D, 100× magnification). Note the lack of apparent tumor infiltrating lymphocytes in these tumors.

Figure 4

Overall survival of high grade colorectal adenocarcinomas with stages II, III, and IV diseases.

Figure 5

Overall survival of high grade colorectal adenocarcinomas of medullary, indeterminate, and conventional poorly differentiated types.