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. 2015 May;39(5):652-9.
doi: 10.1097/PAS.0000000000000368.

A detailed clinicopathologic study of ALK-translocated papillary thyroid carcinoma

Angela Chou  1 , Sheila Fraser, Christopher W Toon, Adele Clarkson, Loretta Sioson, Mahtab Farzin, Carmen Cussigh, Ahmad Aniss, Christine O'Neill, Nicole Watson, Roderick J Clifton-Bligh, Diana L Learoyd, Bruce G Robinson, Christina I Selinger, Leigh W Delbridge, Stanley B Sidhu, Sandra A O'Toole, Mark Sywak, Anthony J Gill
Affiliations

A detailed clinicopathologic study of ALK-translocated papillary thyroid carcinoma

Angela Chou et al. Am J Surg Pathol. 2015 May.

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.

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Conflict of interest statement

Conflicts of Interest and Source of Funding: Supported by the Cancer Institute NSW through the Sydney Vital Translational Research Centre. S.O.T. and A.J.G. report receiving honoraria from lectures from Pfizer, manufacturers of crizotinib. S.O.T. was also supported by the Sydney Breast Cancer Foundation for this study. For the remaining authors none were declared.

Figures

FIGURE 1
FIGURE 1
A, ALK-translocated PTC with a follicular and solid architecture. Although this tumor was considered insufficiently infiltrative to be classified as diffuse sclerosing variant, numerous psammoma bodies are noted in the thyroid away from the main tumor mass, indicating a tendency to lymphovascular invasion. B, ALK IHC on a diffuse sclerosing variant PTC arising in the setting of Hashimoto thyroiditis. ALK highlights small groups of malignant cells (arrows) in lymphatics or the interstitium associated with psammoma bodies. C, ALK-translocated PTC with a follicular and solid architecture. D, ALK shows strong diffuse cytoplasmic staining in all neoplastic cells. Although there is some nonspecific staining of colloid, non-neoplastic cells are negative (A and C, hematoxylin and eosin; B and D, ALK IHC).
FIGURE 2
FIGURE 2
A, Unencapsulated follicular variant papillary carcinoma was one of the more common patterns demonstrated by ALK-translocated PTC. B, Follicular and solid architectures appeared to be overrepresented in ALK-translocated PTC. C, In some areas this ALK-translocated carcinoma demonstrated a solid and almost morula architecture reminiscent of a solid cell rest. D, Serial sections of this area demonstrates diffuse strong positive staining for ALK (A–C, hematoxylin and eosin; D, ALK IHC).
FIGURE 3
FIGURE 3
FISH studies from ALK-translocated cases. A, Using the break-apart probe ALK-rearranged PTC with >15% of tumor nuclei showing splitting of the orange (3′) and green (5′) signals. B, Using the Tricheck probe, the splitting of orange and green signals is still evident; however, an extra “split” blue signal is now present and colocalizes with the split orange and green signals, suggesting that the translocation partner is EML4.
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