title: Interobserver variability for the WHO classification of pulmonary carcinoids.
abstract: Pulmonary carcinoids are neuroendocrine tumors histopathologically subclassified into typical (TC; no necrosis, <2 mitoses per 2 mm) and atypical (AC; necrosis or 2 to 10 mitoses per 2 mm). The reproducibility of lung carcinoid classification, however, has not been extensively studied and may be hampered by the presence of pyknotic apoptosis mimicking mitotic figures. Furthermore, prediction of prognosis based on histopathology varies, especially for ACs. We examined the presence of interobserver variation between 5 experienced pulmonary pathologists who reviewed 123 originally diagnosed pulmonary carcinoid cases. The tumors were subsequently redistributed over 3 groups: unanimously classified cases, consensus cases (4/5 pathologists rendered identical diagnosis), and disagreement cases (divergent diagnosis by ≥2 assessors). κ-values were calculated, and results were correlated with clinical follow-up and molecular data. When focusing on the 114/123 cases unanimously classified as pulmonary carcinoids, the interobserver agreement was only fair (κ=0.32). Of these 114 cases, 55% were unanimously classified, 25% reached consensus classification, and for 19% there was no consensus. ACs were significantly more often in the latter category (P=0.00038). The designation of TCs and ACs by ≥3 assessors was not associated with prognosis (P=0.11). However, when disagreement cases were allocated on the basis of Ki-67 proliferative index (<5%; ≥5%) or nuclear orthopedia homeobox immunostaining (+; -), correlation with prognosis improved significantly (P=0.00040 and 0.0024, respectively). In conclusion, there is a considerable interobserver variation in the histopathologic classification of lung carcinoids, in particular concerning ACs. Additional immunomarkers such as Ki-67 or orthopedia homeobox may improve classification and prediction of prognosis.
authors.affiliation: Departments of *Molecular Cell Biology #Pulmonology ∥∥Pathology, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Center, Maastricht **Department of Surgery, Máxima Medical Center, Veldhoven, The Netherlands; CARIM - School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands †Departments of Pathology, Jeroen Bosch Hospital, 's-Hertogenbosch ‡Maasstad Hospital, Rotterdam §Sint Antonius Hospital, Nieuwegein ∥VU University Medical Center, Amsterdam ††Departments of Pulmonology, Atrium Medical Center, Heerlen ‡‡Viecuri Medical Center, Venlo §§Catharina Hospital, Eindhoven, The Netherlands ¶Department of Oncology, Division of Pathology, University of Turin at San Luigi Hospital, Orbassano, Turin, Italy.
authors.forename: Dorian R A
authors.initials: DR
authors.lastname: Swarts
authors.forename: Robert-Jan
authors.initials: RJ
authors.lastname: van Suylen
authors.forename: Michael A
authors.initials: MA
authors.lastname: den Bakker
authors.forename: Matthijs F M
authors.initials: MF
authors.lastname: van Oosterhout
authors.forename: Frederik B J M
authors.initials: FB
authors.lastname: Thunnissen
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.forename: Anne-Marie C
authors.initials: AM
authors.lastname: Dingemans
authors.forename: Marc R M
authors.initials: MR
authors.lastname: Scheltinga
authors.forename: Gerben P
authors.initials: GP
authors.lastname: Bootsma
authors.forename: Harry M M
authors.initials: HM
authors.lastname: Pouwels
authors.forename: Ben E E M
authors.initials: BE
authors.lastname: van den Borne
authors.forename: Frans C S
authors.initials: FC
authors.lastname: Ramaekers
authors.forename: Ernst-Jan M
authors.initials: EJ
authors.lastname: Speel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D002276:Carcinoid Tumor / Q000737:chemistry / Q000145:classification* / Q000401:mortality / Q000473:pathology*; D049109:Cell Proliferation; D032921:Consensus; D005060:Europe; D005260:Female; D018398:Homeodomain Proteins; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D008175:Lung Neoplasms / Q000737:chemistry / Q000145:classification* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D009336:Necrosis; D009419:Nerve Tissue Proteins; D015588:Observer Variation; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D009626:Terminology as Topic; D014944:World Health Organization; D055815:Young Adult
chemical_list: D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; C490261:OTP protein, human