title: A detailed clinicopathologic study of ALK-translocated papillary thyroid carcinoma.
abstract: Pathogenic ALK translocations have been reported in papillary thyroid carcinoma (PTC). We developed and validated a screening algorithm based on immunohistochemistry (IHC), followed by fluorescence in situ hybridization (FISH) in IHC-positive cases to identify ALK-rearranged PTC. IHC and FISH were performed in a cohort of 259 thyroid carcinomas enriched for aggressive variants. IHC was positive in 8 cases, 6 confirmed translocated by FISH (specificity 75%). All 251 IHC-negative cases were FISH negative (sensitivity 100%). Having validated this approach, we performed screening IHC, followed by FISH in IHC-positive cases in an expanded cohort. ALK translocations were identified in 11 of 498 (2.2%) of all consecutive unselected PTCs and 3 of 23 (13%) patients with diffuse sclerosing variant PTCs. No ALK translocations were identified in 36 PTCs with distant metastases, 28 poorly differentiated (insular) carcinomas, and 20 anaplastic carcinomas. All 14 patients with ALK translocations were female (P=0.0425), and translocations occurred at a younger age (mean 38 vs. 48 y, P=0.0289 in unselected patients). ALK translocation was an early clonal event present in all neoplastic cells and mutually exclusive with BRAF mutation. ALK translocation was not associated with aggressive clinicopathologic features (size, stage, metastasis, vascular invasion, extrathyroidal extension, multifocality, risk for recurrence, radioiodine resistance). We conclude that 2.2% of PTCs are ALK-translocated and can be identified by screening IHC followed by FISH. ALK translocations may be more common in young females and diffuse sclerosing variant PTC but do not connote more aggressive disease.
authors.affiliation: *Cancer Diagnosis and Pathology Research Group §§Sydney Vital Translational Research Centre, Kolling Institute of Medical Research §University of Sydney Endocrine Surgical Unit **Hormones and Cancer Group, Cancer Genetics Laboratory, Kolling Institute of Medical Research Departments of ¶Anatomical Pathology #Endocrinology, Royal North Shore Hospital, St Leonards †Department of Anatomical Pathology SYDPATH, St Vincent's Hospital ‡Kinghorn Cancer Centre and Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst ∥Histopath Pathology, North Ryde ††Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown ‡‡University of Sydney, Sydney, NSW, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Chou
authors.forename: Sheila
authors.initials: S
authors.lastname: Fraser
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Toon
authors.forename: Adele
authors.initials: A
authors.lastname: Clarkson
authors.forename: Loretta
authors.initials: L
authors.lastname: Sioson
authors.forename: Mahtab
authors.initials: M
authors.lastname: Farzin
authors.forename: Carmen
authors.initials: C
authors.lastname: Cussigh
authors.forename: Ahmad
authors.initials: A
authors.lastname: Aniss
authors.forename: Christine
authors.initials: C
authors.lastname: O'Neill
authors.forename: Nicole
authors.initials: N
authors.lastname: Watson
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Clifton-Bligh
authors.forename: Diana L
authors.initials: DL
authors.lastname: Learoyd
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Robinson
authors.forename: Christina I
authors.initials: CI
authors.lastname: Selinger
authors.forename: Leigh W
authors.initials: LW
authors.lastname: Delbridge
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Sidhu
authors.forename: Sandra A
authors.initials: SA
authors.lastname: O'Toole
authors.forename: Mark
authors.initials: M
authors.lastname: Sywak
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000077548:Anaplastic Lymphoma Kinase; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D002291:Carcinoma, Papillary; D002648:Child; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012680:Sensitivity and Specificity; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology*; D046888:Tissue Array Analysis; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases