title: 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.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Lik Hang
authors.initials: LH
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Rhonda K
authors.initials: RK
authors.lastname: Yantiss
authors.affiliation: Department of Surgery, Rabin Medical Center, Petah Tikva 49102, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Sadot
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Marcela Santos
authors.initials: MS
authors.lastname: Calvacanti
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jaclyn F
authors.initials: JF
authors.lastname: Hechtman
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sinisa
authors.initials: S
authors.lastname: Ivelja
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Be
authors.initials: B
authors.lastname: Huynh
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Shitilbans
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Hamza
authors.initials: H
authors.lastname: Guend
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Zsofia K
authors.initials: ZK
authors.lastname: Stadler
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weiser
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.affiliation: Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Mithat
authors.initials: M
authors.lastname: Gönen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: Shiaj@mskcc.org.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D001706:Biopsy; D018276:Carcinoma, Medullary / Q000737:chemistry / Q000145:classification / Q000401:mortality / Q000473:pathology*; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000145:classification / Q000401:mortality / Q000473:pathology*; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015588:Observer Variation; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D009626:Terminology as Topic; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D045643:DNA Repair Enzymes
keywords: Colorectal carcinoma; Diagnostic reproducibility; Microsatellite instability; Tumor classification; Tumor histology