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NCCN Flash Updates: NCCN Guidelines Updated for Thyroid Carcinoma

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), the NCCN Drugs & Biologics Compendium (NCCN Compendium^®),  the NCCN Radiation Therapy Compendium™, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™) for Thyroid Carcinoma. These NCCN Guidelines^® are currently available as Version 1.2024.

Link directly to the Updates section of the NCCN Guidelines: Thyroid Carcinoma

Updates in Version 1.2024 of the NCCN Guidelines for Thyroid Carcinoma from Version 4.2023 include:

THYR-1

• FNA results, top pathway, first column modified: Carcinoma Malignant or suspicious for carcinoma malignancy (Bethesda V or Vl)
• FNA results, middle pathway, removed: High clinical and/or radiographic suspicion of malignancy
• FNA results, lower pathway, first column modified: Atypia of undetermined significance/ Follicular lesion of undetermined significance (AUS/FLUS) (Bethesda III)
• Upper right box modified: Diagnostic categories for FNA results reflect NCI state of the science conference, the Bethesda Classification. Cibas ES, Ali SZ. Thyroid 2017;27:1341-1346. https://www.ncbi.nlm.nih.gov/ pubmed/29091573. Ali SZ, Baloch ZW, Cochand-Priollet B, et al. Thyroid 2023;33:1039-1044. https://pubmed.ncbi.nlm.nih.gov/37427847/. Cytology reports should be interpreted in light of terminology used by local cytopathologists. (Also for THYR-2)
• Footnotes
  • Modified: Alternative term: Suspicious for follicular or oncocytic neoplasm. Estimated risk of malignancy is 15%–40%. Numbers may vary by institution or cytopathologist. Bethesda v3 terminology for Bethesda IV is follicular neoplasm or oncocytic follicular neoplasm, and the estimated risk of malignancy, inclusive of noninvasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP), is mean 30% (range, 23%–34%). (Also for THYR-2)
  • Modified: The diagnosis of follicular carcinoma or oncocytic carcinoma requires evidence of either vascular or capsular invasion, which cannot be determined by FNA. Molecular diagnostics may be useful to allow reclassification of follicular lesions (ie, follicular neoplasm, AUS, FLUS)...
  • Modified: Estimated risk of malignancy is 6%–18% mean 22% (range, 13%–30%) exclusive inclusive of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). (Also for THYR-2)
  • Added: Bethesda V Estimated risk of malignancy, inclusive of noninvasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP), mean 74% (range, 67%–83%); Bethesda VI Estimated risk of malignancy, inclusive of noninvasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP), mean 97% (range, 97%–100%), Ali SZ, et al. Thyroid 2023;33:1039-1044.

THYR-2

• Column 1: AUS/FLUS (Bethesda III) or Follicular neoplasm (Bethesda IV)
• Column 3, middle pathway: Nodule surveillance or Consider lobectomy or total thyroidectomy in select situations for definitive diagnosis/treatment or Consider repeat biopsy

PAP-1

• Diagnostic Procedures, upper pathway
  • Bullet 2: CT/MRI with contrast when suspicious nodes in the neck are detected by US and/ for locally advanced disease or vocal cord paresis
  • Bullet 5 added: Screen for personal and/or family history suggestive of inherited cancer risk (Also for lower pathway) (Also FOLL-1 and ONC-1)
• Preoperative or intraoperative decision-making criteria, upper pathway
  • Bullet removed: Tumor >4 cm in diameter
  • Bullet 4 modified: Poorly differentiated and differentiated high-grade carcinoma
  • Bullet 6 modified: Consider for bilateral nodularity or tumors >4 cm in diameter
• Primary treatment, lower pathway, concerning lymph nodes: Manage as >1 cm (see pathway above)
• Footnote added: Principles of Cancer Risk Assesment and Counseling (THYR-E)

PAP-2

• Clinical Presentation, middle pathway, bullet 3: Poorly differentiated and differentiated high-grade carcinoma
• Footnote added: If histology demonstrates cribriform-morular variant, screen for FAP See Principles of Cancer Risk Assessment and Counseling (THYR-E).

PAP-4

• Clinicopathologic Factors, RAI not typically recommended
  • Bullet 1: Classic Papillary thyroid carcinoma (PTC), classic subtype
  • Bullet 2: Largest primary tumor ≤<2 cm (Also for FOLL-3, ONC-3)
• Clinicopathologic Factors, RAI selectively recommended
  • Bullet 1: Largest Primary tumor >2–4 cm (Also for FOLL-3, ONC-3)
  • Bullet 2: High-risk histology subtypes
• Clinicopathologic Factors, RAI typically recommended
  • Bullet removed: Primary tumor >4 cm (Also for FOLL-3, ONC-3)
  • Bullet 6 added: Differentiated high-grade carcinoma (Also for FOLL-3, ONC-3)
• Footnotes
  • Modified: eg, poorly differentiated tall cell, columnar cell, hobnail variants, diffuse sclerosing, insular.
  • Added: Differentiated high-grade carcinoma includes PTCs with ≥5 mitoses per 2 mm2 and/or tumor necrosis.

PAP-6 (Also for FOLL-5, ONC-5)

• Column 4 modified: At least 4–6 weeks following CT with contrast
• Column 6, upper and lower pathways, bullet added: Consider other local therapies (EBRT, etc) as primary therapy or postoperative for structural metastatic disease.

PAP-7 (Also for FOLL-6, ONC-6)

• Lobectomy, management, no evidence of disease, bullet 2: Neck ultrasound annually, and then as clinically indicated every 3–5 years if stable. Also for Total thyroidectomy without RAI, no evidence of disease.

PAP-8

• Footnote added: Interpretation of rising or new Tg ab is assay dependent and best performed as a radioimmunoassay and with a consistent assay for interpretation of trends. (Also for FOLL-7 and ONC-7)

PAP-10 (Also for PAP-11, PAP-12, FOLL-9, FOLL-10, FOLL-11, ONC-9, ONC-10, and ONC-11)

• Column 2, bullet 2: For advanced, progressive, or threatening disease, genomic somatic ...
• Footnote added: Dabrafenib/trametinib could also be appropriate as a first-line therapy for patients with high-risk disease who are not appropriate for VEGF inhibitors.

FOLL-3

• Footnote added: Differentiated high-grade carcinoma includes follicular thyroid carcinoma with ≥5 mitoses per 2 mm2 and/or tumor necrosis.

FOLL-6

• Footnote added: Follicular thyroid carcinoma does not spread to lymph nodes, but, however, could spread to soft tissue within in the neck.

ONC-1

• FNA Results, Oncocytic follicular neoplasm (Bethesda IV)
• Footnote a modified: The diagnosis of oncocytic carcinoma, formerly known as Hurthle cell carcinoma, requires evidence of either vascular or capsular invasion, which cannot be determined by FNA. Molecular markers should be interpreted with caution and in the context of clinical, radiographic, and cytologic features of each individual patient.

ONC-3

• Footnote added: Differentiated high-grade carcinoma includes oncocytic carcinoma with ≥5 mitoses per 2 mm2 and/or tumor necrosis.

MEDU-1

• Diagnostic procedures
  • Bullet 5: Screen for germline RET proto-oncogene mutations PV (exons 10, 11, 13–16); genetic counseling may be indicated
  • Bullet 8: Additional cross-sectional imaging as indicated for metastatic disease
  • Bullet 8, sub-bullet 2: Consider Ga-68 DOTATATE PET/CT; if not available, consider bone scan and/or skeletal whole body MRI
• Footnotes
  • Removed: Imaging may be indicated based on high burden of disease, calcitonin >500 pg/mL, or elevated CEA levels
  • g modified: Prior to germline testing, all patients should be offered genetic counseling either by their physician or a genetic counselor. Surgical intervention should not be delayed while awaiting test results.

MEDU-2

• Additional workup, bullet 3 modified: Screen for germline RET proto-oncogene mutations PV (exons 10, 11, 13–16); genetic counseling may be indicated
• Footnote i modified: If initial thyroid surgery was less than a total thyroidectomy, additional surgical intervention (eg, completion thyroidectomy ± central neck dissection) may not be necessary unless there is a positive germline RET mutation PV or radiographic evidence of disease (ie, biopsy-proven residual neck disease).

MEDU-3

• Clinical presentation: Germline RET protooncogene PV
• Clinical presentation, upper pathway: Multiple endocrine neoplasia (MEN2B) (RET mutation PV)
• Clinical presentation, lower pathway: MEN2A/Familial medullary thyroid carcinoma (FMTC) (RET mutation PV)
• Additional workup, lower pathway modified
  • Added: See Additional Workup above
  • Bullets removed:
    • Basal serum calcitonin level
    • CEA
    • Pheochromocytoma screening
    • Central and lateral neck compartments ultrasound, if not previously done
    • Consider neck CT with contrast if indicated
• Footnotes
  • k: The timing of prophylactic thyroidectomy generally depends on the aggressiveness of the inherited RET mutation PV. Codon M918T mutations are considered highest risk and codon 634 and A883F mutations are considered high risk, with MTC usually presenting at a younger age, whereas other RET mutation PVs associated with MEN2A or FMTC are generally moderate risk. Prophylactic thyroidectomy may be delayed in patients with less high-risk RET mutations PVs ... (Also for MEDU-4)
  • m: Screening for pheochromocytoma (MEN2A and MEN2B) and hyperparathyroidism (MEN2A) should be performed annually. For some RET mutations PVs (codons 768, 790, 804, or 891), less frequent screening may be appropriate.

MEDU-4

• Clinical presentation: MEN2A/FMTC (RET mutations PV)
• Primary treatment, upper pathway, bullet 1: Prophylactic total thyroidectomy by age 5 based on codon mutation or when mutation identified (if mutation identified at older age)

MEDU-5

• Upper pathway, column 3, bullet 3: Consider bone scan and whole body MRI of axial skeleton in patients with very elevated calcitonin levels
• Footnote added: Imaging may be indicated based on high burden of disease, calcitonin >500 pg/mL, or elevated CEA levels.

MEDU-6

• Column 2 added: somatic testing. (Also for MEDU-7)
• Treatment
  • Bullet 2: EBRT can be should only be considered for unresectable disease or not amenable to targeted systemic therapy, or less commonly, after surgical resection
  • Bullet 3, preferred regimens, tertiary bullet 3: Selpercatinib (positive for RET mutation-positive PV) (category 1). (Also for MEDU-7)
  • Bullet 3, preferred regimens, tertiary bullet 4: Pralsetinib (positive for RET mutation-positive PV) (category 2B). (Also for MEDU-7)
  • Footnote modified: Genomic Somatic testing including TMB or RET somatic genotyping in patients who are germline wild-type or germline unknown. Genomic testing including TMB or RET somatic genotyping in patients who are germline wild-type or germline unknown. (Also for MEDU-7)

ANAP-1

• Diagnostic procedures, bullet 10 added: BRAF IHC testing
• Footnotes modified
  • a: Consider core or open biopsy if FNA is “suspicious” for ATC or is not definitive. Morphologic diagnosis combined with immunohistochemistry is necessary to exclude other entities such as poorly differentiated thyroid cancer, medullary thyroid cancer, squamous cell carcinoma, and lymphoma.
  • b: Molecular testing should include BRAF, NTRK, ALK, RET, MSI, dMMR, and tumor mutational burden. BRAF immunohistochemistry (IHC) testing is recommended due to faster turnaround compared to genetic testing.

ANAP-2

• Stage IVA or IVB, upper pathway
  • Column 1 modified: Resectable (potentially curable with surgery)
  • Column 2 added: Neoadjuvant dabrafenib/ trametinib for BRAF V600E mutated disease may be considered (category 2B)
• Stage IVA or IVB, lower pathway, column 1: Unresectable or borderline resectable

ANAP-3

• Aggressive therapy, treatment
  • Bullet 2: Consider Tracheostomy only if strongly indicated +/- steroid (avoid prophylactic tracheostomy)
  • Bullet 4: Systemic therapy +/- RT (ANAP-A [1 of 3]) and (ANAP-A [2 of 3])

ANAP-A 2 of 3

• Useful in certain circumstances
  • Pembrolizumab (TMB-H [≥10 mut/Mb])
  • Regimen added: Pembrolizumab/lenvatinib, Pembrolizumab 200 mg IV (or 400 mg IV every 6 weeks) + Lenvatinib 20–24 mg, PO daily, Every 3 weeks
  • Regimen added: Nivolumab, 240 mg IV every 2 weeks or 480 mg IV every 4 weeks

ANAP-A 3 OF 3

• References added
  • Dierks C, et al. Phase II ATLEP trial: final results for lenvatinib/pembrolizumab in metastasized anaplastic and poorly differentiated thyroid carcinoma. Ann Oncol 2022;33(Suppl S7):S750-S757.
  • Kollipara R, Schneider B, Radovich M, et al. Exceptional Response with Immunotherapy in a Patient with Anaplastic Thyroid Cancer. Oncologist 2017;22:1149-1151.
  • Ma D, Ding XP, Zhang C, Shi P. Combined targeted therapy and immunotherapy in anaplastic thyroid carcinoma with distant metastasis: A case report. World J Clin Cases 2022;10:3849-3855.
• Footnote added: Pembrolizumab is FDA-approved for patients with TMB-H [≥10 mut/mb] disease.

THYR-A

• Bullet 2, sub-bullet 2: Patients whose TSH levels are chronically suppressed should be counseled to ensure adequate daily intake of elemental calcium (1200 mg/day) and vitamin D (1000 IU).

THYR-C 2 of 5

• Remnant ablasion
  • Sub-bullet 1: 30–50mCi
  • Tertiary bullet 1: If RAI ablation is used in T1b/T2 (1–4 cm), clinical N0 disease, in the absence of other adverse pathologic, laboratory, or imaging features, 30–50 mCi of iodine-131 is recommended (category 1) following either thyrotropin alfa stimulation or thyroid hormone withdrawal. This dose of 30–50 mCi...
• Adjuvant therapy, sub-bullet 1: 5075–150 mCi

THYR-C 4 of 5

• Differentiated, Medullary, or Poorly Differentiated (non-anaplastic) Thyroid Cancer
• Palliative RT, CNS metastases, tertiary bullets removed:
  • ≤4 metastases – consider SRS either following surgical resection or as monotherapy
  • Multiple metastases: Consider enrollment on clinical trial for SRS versus WBRT (with or without hippocampal avoidance), WBRT – 30 Gy in 10 daily fractions; consider 45 Gy in 1.8 Gy daily fractions for good performance status
• Anaplastic Thyroid Cancer, Palliative RT of metastases, CNS metastases, tertiary bullet modified: WBRT – 30 Gy in 10 daily fractions

THYR-C 5 of 5

• References removed:
  • McWilliams RR, Giannini C, Hay ID, et al. Management of brain metastases from thyroid carcinoma: a study of 16 pathologically confirmed cases over 25 years. Cancer 2003;98:256-362.
  • Osborne JR, Kondraciuk JD, Rice SL, et al. Thyroid cancer brain metastases: Survival and genomic characteristics of a large tertiary care cohort. Clin Nucl Med 2019;44:544-549.

THYR-D

• Active Surveillance should not be used in the following scenarios
  • Bullet 2: Tumor characteristics: Aggressive histology histologic subtypes (if noted on FNA) such as tall cell variant; invasion of recurrent laryngeal nerve, trachea, or esophagus; visible extrathyroidal extension; regional or distant metastases; tumor near posterior capsule.
  • Bullet 4: Physician characteristics: Lack of experience and confidence in the use of access to high-quality neck ultrasound.

THYR-E

• Paragraph added: Follicular thyroid cancer is a feature of some inherited cancer syndromes associated with significant clinical implications for the patient and relatives. The most common of these is Cowden Syndrome (CS)/PTEN Hamartoma Tumor Syndrome (PHTS). PHTS should be suspected if the patient also has a personal or family history of breast cancer, endometrial cancer, colorectal cancer/colorectal hamartomas, multiple mucocutaneous lesions, macrocephaly, and/or a wide range of other features as detailed in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic. All patients who meet these criteria for PHTS should receive genetic risk assessment, counseling, and testing. Other patients with two or more first-degree relatives who have also had non-medullary thyroid cancer, or who have a personal or family history of multiple other cancers, may be candidates for genetic testing for germline mutations in other hereditary cancer genes.

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