Template for Reporting Results of Biomarker Testing of Specimens From Patients With Thyroid Carcinoma

The College of American Pathologists (CAP) offers these templates to assist pathologists in providing clinically useful and relevant information when reporting results of biomarker testing. The CAP regards the reporting elements in the templates as important elements of the biomarker test report, but the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.The CAP developed these templates as educational tools to assist pathologists in the useful reporting of relevant information. It did not issue them for use in litigation, reimbursement, or other contexts. Nevertheless, the CAP recognizes that the templates might be used by hospitals, attorneys, payers, and others. The CAP cautions that use of the templates other than for their intended educational purpose may involve additional considerations that are beyond the scope of this document.Completion of the template is the responsibility of the laboratory performing the biomarker testing and/or providing the interpretation. When both testing and interpretation are performed elsewhere (eg, a reference laboratory), synoptic reporting of the results by the laboratory submitting the tissue for testing is also encouraged to ensure that all information is included in the patient's medical record and thus readily available to the treating clinical team.Select a single response unless otherwise indicated.Note: Use of this template is optional.___ Adequate___ Inadequate___ Suboptimal (explain): ________________________________ Adequate Estimated tumor cellularity (area used for testing): ______%___ Suboptimal (explain): _____________________________Note: If “Adequate” not selected, please refer to original laboratory report for explanation.___ No mutation detected___ Mutation identified ___ p.V600E, c.1799T>A ___ p.K601E, c.1801A>G ___ Other BRAF mutation (specify): ________________ Indicate mutant allele frequency: ______%___ Cannot be determined (explain): ______________________ No mutation detected___ Mutation identified ___ c.1-124 (C228T) ___ c.1-146 (C250T) ___ Other TERT mutation (specify): ___________________ Cannot be determined (explain): ______________________ No mutation detected___ Mutation identified ___ p.Q61R, c.182A>G ___ p.Q61K, c.181C>A ___ Other NRAS mutation (specify): ___________________ Cannot be determined (explain): ______________________ No mutation detected___ Mutation identified ___ p.Q61R, c.182A>G ___ p.G12V, c.35G>T ___ Other HRAS mutation (specify): ___________________ Cannot be determined (explain): ______________________ No mutation detected___ Mutation identified ___ p.G12D, c.35G>A ___ Other KRAS mutation (specify): ___________________ Cannot be determined (explain): ______________________ No mutation detected___ Mutation identified ___ p.E17K, c.49G>A ___ Other AKT1 mutation (specify): ___________________ Cannot be determined (explain): ______________________ No mutation detected___ Mutation identified (specify): _________________________ Cannot be determined (explain): ______________________ No mutation detected___ Mutation identified ___ p.H1047R, c.3140A>G ___ Other PIK3CA mutation (specify): _________________ Cannot be determined (explain): ______________________ No mutation detected___ Mutation identified ___ p.S33A, c.97T>G ___ Other CTNNB1 mutation (specify): ________________ Cannot be determined___ No mutation detected___ Mutation identified ___ p.M918T, c.2753T>C ___ Other RET mutation (specify): _________________Mutation type ___ Germline (inherited) ___ Somatic (sporadic) ___ Unknown___ Cannot be determined (explain): ______________________ No rearrangement detected___ Rearrangement identified ___ STRN/ALK ___ EML4/ALK ___ Other ALK rearrangement (specify): _______________ Cannot be determined (explain): ______________________ No rearrangement detected___ Rearrangement identified ___ NTRK1/TPM3 ___ NTRK1/TFG ___ Other NTRK1 rearrangement (specify): _____________ Cannot be determined (explain): ______________________ No rearrangement detected___ Rearrangement identified ___ NTRK3/ETV6 ___ Other NTRK3 rearrangement (specify): _____________ Cannot be determined (explain): ______________________ No rearrangement detected___ Rearrangement identified ___ RET/PTC1 ___ RET/PTC3 ___ Other RET rearrangement (specify): _______________ Cannot be determined (explain): ______________________ No rearrangement detected___ Rearrangement identified ___ PAX8/PPARG ___ CREB3L2/PPARG ___ Other PPARG rearrangement (specify): _____________________________________________________ Cannot be determined (explain): ___________________Specify marker: _____________________________________Specify results: _________________________________________ Laser capture microdissection Specify test name*: _________________________________ Manual under microscopic observation Specify test name*: _________________________________ Manual without microscopic observation Specify test name*: _________________________________ Cored from block Specify test name*: _________________________________ Whole tissue section (no tumor enrichment procedure used) Specify test name*: ______________________________* If more than 1 dissection method used, please specify.___ Direct (Sanger) sequencing___ High-resolution melting analysis___ Next-generation (high-throughput) sequencing___ Immunohistochemistry ___ VE1 clone ___ Other (specify): _________________________________ Other (specify): _____________________________________ Direct (Sanger) sequencing___ Next-generation (high-throughput) sequencing___ Other (specify): _____________________________________ Direct (Sanger) sequencing___ High-resolution melting analysis___ Next-generation (high-throughput) sequencing___ Immunohistochemistry ___ Clone (specify): _________________________________ Other (specify): _____________________________________ Codon 12___ Codon 13___ Codon 61___ Other (specify): _____________________________________ Codon 12___ Codon 13___ Codon 61___ Other (specify): _____________________________________ Codon 12___ Codon 13___ Codon 61___ Other (specify): _____________________________________ In situ hybridization___ Reverse transcription–polymerase chain reaction (RT-PCR)___ Immunohistochemistry ___ ALK 5A4 clone ___ ALK D5F3 clone ___ Other (specify): _________________________________ Next-generation (high-throughput) sequencing___ In situ hybridization___ Reverse transcription–polymerase chain reaction (RT-PCR)___ Immunohistochemistry Clone (specify): _____________________________________ Next-generation (high-throughput) sequencing___ In situ hybridization___ Reverse transcription–polymerase chain reaction (RT-PCR)___ Immunohistochemistry Clone (specify): _____________________________________ Next-generation (high-throughput) sequencing___ Direct (Sanger) sequencing___ Next-generation (high-throughput) sequencing___ Immunohistochemistry Clone (specify): ____________________________________ ≥20%___ ≥10%___ ≥5%___ Other (specify): ________%Specify method: __________________________________________________________________________________________________________________Note: Fixative type, time to fixation (cold ischemia time), and time of fixation should be reported if applicable in this template or in the original pathology report.Gene names should follow recommendations of the Human Genome Organisation (HUGO) Nomenclature Committee (www.genenames.org; accessed May 25, 2016).All reported gene sequence variations should be identified following the recommendations of the Human Genome Variation Society (http://varnomen.hgvs.org; accessed May 25, 2016).The collection of material for molecular studies should not affect the morphologic cytologic assessment. For fine-needle aspirates (FNAs), at the time of the FNA procedure, a small portion of the (residual) aspirated material may be collected into nucleic acids preservative. The material may represent a part of the first needle pass or a separate pass dedicated for the molecular analysis.1 The storage and transportation conditions (time, temperature) have to be specified by laboratories.The quantity of isolated nucleic acids is the total amount of extracted nucleic acids. The minimal acceptable amount of nucleic acids will depend on the methodology and should be determined by laboratories. The quality of DNA and RNA can be assessed by amplification of housekeeping genes (eg, GAPDH, PGK1). The troubleshooting procedure for suboptimal specimens should be specified (eg, increasing and decreasing the amount of nucleic acid template).2The proportion of follicular thyroid epithelial cells in an FNA sample can be assessed by comparing the expression of the housekeeping gene and a gene known to be expressed predominantly in thyroid follicular cells (eg, keratin 7, thyroid transcription factor 1 [NK2 homeobox 1]), genes expressed in mimics of thyroid nodule (eg, parathyroid hormone), or genes expressed in medullary thyroid carcinoma (ie, calcitonin).3–5The sensitivity of mutation detection and the method used to establish sensitivity should be established by the laboratory for each methodology (eg, serial dilutions of the positive controls in normal blood/lymphocytes or normal formalin-fixed, paraffin-embedded tissue).Resection specimens may be inadequate owing to improper fixation, decalcification, low tumor content, or small tumor size.The presence of BRAF V600E mutation in a FNA is indicative of about a 99% risk of cancer in the sampled thyroid nodule. When identified alone, BRAF V600E mutation may merely reflect the conventional morphology or tall cell variant of papillary thyroid carcinoma. The combination of BRAF V600E mutation with TERT, AKT1, PIK3CA, or TP53 mutations predicts a more aggressive tumor behavior.6–12 BRAF K601E is an unusual BRAF mutation, which had been reported in follicular variant of papillary thyroid carcinoma and rarely in follicular adenomas.13,14The finding of RAS mutation in a FNA is associated with about a 80% risk of cancer in a given nodule. The most common types of cancer with RAS mutations are the encapsulated follicular variant of papillary carcinoma and follicular carcinoma. The remaining RAS-positive thyroid nodules are usually diagnosed as follicular adenomas. Sporadic medullary thyroid carcinomas with wild-type RET genes may harbor RAS mutations (HRAS or KRAS).2,4,5,8,15,16PIK3CA, AKT1, and TP53 mutations are usually found in advanced thyroid cancer with propensity for dedifferentiation and distant metastasis.8,17The presence of CTNNB1 mutation in a given thyroid nodule is expected to confer a >90% risk of cancer. Point mutations in exon 3 of CTNNB1 stabilize the protein by making it insensitive for adenomatous polyposis coli (APC)–induced degradation, leading to the accumulation of β-catenin in the nucleus. In thyroid tumors, mutations in exon 3 of CTNNB1 were also reported in poorly differentiated and anaplastic carcinomas, but not in well-differentiated carcinomas or benign thyroid nodules.18The presence of RET rearrangements in thyroid FNA is associated with >95% risk of cancer, most frequently classic papillary thyroid carcinoma. Mutations of the RET gene are typically present in sporadic and familial forms of medullary thyroid carcinoma. Among sporadic medullary carcinomas, RET p.M918T mutation accounts for more than 75% of all somatic RET mutations found in medullary carcinomas.19,20Laboratories should disclose whether the test was performed on tissue type (tumor versus normal tissue) that allows distinguishing between germline (inherited) and sporadic (acquired) mutation. Nevertheless, the distinction between sporadic and germline mutation can be reliably made only by testing a nontumorous specimen, preferably patient blood. Clinical management of patients, based on the presence of specific RET mutations, has been defined.19,20The identification of ALK fusions (STRN/ALK or EML4/ALK) in a thyroid FNA is associated with a very high risk of thyroid cancer. ALK fusions were identified in ∼1.5% of papillary thyroid carcinomas and in 4% to 9% of dedifferentiated thyroid cancers.21,22 In advanced papillary thyroid carcinomas and in dedifferentiated thyroid tumors, the presence of an ALK fusion may represent a therapeutic target for crizotinib.21,22Rearrangements of the NTRK1 gene occur in <5% of papillary thyroid carcinomas.23 Different fusion partners of NTRK1 have been described including TPM3 and TPR genes. Some studies reported that NTRK1 fusion–positive papillary thyroid carcinomas may have more aggressive biological behavior and higher rate of local recurrence.24 NTRK3 fusions have been reported in papillary thyroid carcinomas.25,26 In vitro studies showed that ETV6/NTRK3 aberrantly activates phosphatidylinositide 3-kinase signaling pathway. A phase 1a/1b clinical trial of the oral tyrosine kinase inhibitor LOXO-101 is available.The presence of rearrangements involving the PPARG gene, PAX8/PPARG and less frequently CREB3L2/PPARG, correlates with ∼95% risk of cancer, most frequently follicular variant of papillary carcinoma, followed in frequency by follicular carcinoma. Rare cases of follicular adenoma carrying PPARG rearrangements have been reported.27,28 Most of thyroid cancers positive for PPARG rearrangements are low-grade tumors, whereas 5% to 10% of those tumors have aggressive behavior. Of note, PPARG fusions can be exploited as a therapeutic target for advanced thyroid cancer.

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