Thyroid nodule classification

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2]

Bethesda System for Reporting Thyroid Cytopathology

classification	FNA cytology	Predicted risk of malignancy
Benign	Macrofollicular Adenomatoid/hyperplastic nodules Colloid adenomas (most common) Nodular goiter Lymphocytic thyroiditis Granulomatous thyroiditis	0–3 %
Nondiagnostic or Unsatisfactory		1–4 %
Follicular lesion of undetermined significance	Mixed macro- and microfollicular nodules	5–15 %
Atypia of undetermined significance	Atypical cells
Follicular neoplasm	Microfollicular nodules Hurthle cell lesions	15–30 %
Suspicious for a follicular neoplasm	Suspicious for Hurthle cell neoplasm	60–75 %
Malignant	PTC (most common) MTC Anaplastic carcinoma High-grade metastatic cancers	97–99 %

Classification of neoplastic thyroid nodules based on their origin:

		Origin	histologic subtypes
Nonmedullary thyroid cancers (NMTCs)	95% of tumors	thyroid epithelial cells	papillary (85%)	95% are sporadic tumors 5% may be related to inherited genetics due to familial origin Classic varient tall cell variant insular varient columnar variant Hürthle or oxyphilic variant solid or trabecular variant clear cell variant diffuse sclerosing variant cribriform morular variant hobnail variant
			follicular (11%)	Benign follicular adenoma Minimally invasive follicular carcinoma Widely invasive follicular carcinoma Encapsulated follicular variant of papillary thyroid cancer Infiltrative variant of papillary thyroid cancer
			Hürthle cell (3%)
			anaplastic (1%)
Medullary thyroid cancers (MTCs)	5% of all thyroid malignancies	calcitonin-producing parafollicular cells		20% they are familial and occur as part of the multiple endocrine neoplasia (MEN) syndromes

Of the differentiated cancers, papillary cancer comprises about 85% of cases compared to about 10% that have follicular histology, and 3% that are Hu¨rthle cell or oxyphil tumors

Neoplastic thyroid nodules subclassification:

Neoplasm	Subclass	Features
Follicular thyroid lesions	Benign follicular adenoma
	Minimally invasive follicular carcinoma	only invasion of the capsule of the tumor without vascular invasion
	Widely invasive follicular carcinoma	Extensive invasion of the tumor capsule A multinodular tumor without a well-defined capsule invading the normal thyroid surrounding the tumor Extensive vascular invasion (>4 foci of angioinvasion)
	Encapsulated follicular variant of papillary thyroid cancer	minor vascular invasion (≤4 foci of angioinvasion within the tumor or capsule of the tumor) with or without capsular invasion
	Infiltrative variant of papillary thyroid cancer
papillary thyroid cancer	Classic varient
	tall cell variant	more aggressive tumor than classical papillary cancer tumor cells with eosinophilic cytoplasm that are twice as tall as they are wide. The primary tumors tend to be large, they are often invasive, and many patients have both local and distant metastases at the time of diagnosis
	insular varient	solid nests of tumor, often separated by fibrous bands, but the tumor cell nuclei have the same characteristics as do the nuclei of classical papillary cancers.
	columnar variant	elongated cells with palisading nuclei.
	Hürthle or oxyphilic variant	Cellular features of Hürthle cell carcinomas but cells that are arranged in papillary formations.
	solid or trabecular variant
	clear cell variant	must be distinguished from clear cell carcinomas of other organs such as the kidney or colon that have metastasized to the thyroid.
	diffuse sclerosing variant	diffuse involvement of the thyroid, stromal fibrosis, and prominent lymphocytic infiltration
	cribriform morular variant	Prominent cribriform pattern with solid and spindle cell areas as well as squamous morules. This variant is often associated with familial adenomatous polyposis.
	hobnail variant	harbors BRAF V600E mutations and appears to be associated with a high risk of distant metastases and an increased disease-specific mortality

Thyroid nodule classification based on the sonographhic features:

Classification system has been proposed by Horvath et al 3, with a modified recommendation from Jin Kwak et al 4.

TIRADS 1		Normal thyroid gland
TIRADS 2		Benign lesions	Avascular anechoic lesion with echogenic specks (colloid type I) vascular heteroechoic non-expansile, non-encapsulated nodules with peripheral halo (colloid type II) isoechoic or heteroechoic, non-encapsulated, expansile vascular nodules (colloid type III)	0% risk of malignancy
TIRADS 3		Probably benign lesions	Nodule property: Hyperechoic, iso-echoic or hypoechoic nodules, with partially formed capsule and peripheral vascularity, usually in setting of Hashimoto's thyroiditis (Hashimoto's pseudonodule)	<5% risk of malignancy
TIRADS 4	4a	One suspicious feature	Suspicious lesions: solid component high stiffness of nodule on elastography if available markedly hypoechoic nodule microlobulations or irregular margins microcalcifications taller-than-wider shape	5-10% risk of malignancy
	4b	Two suspicious features		10-80% risk of malignancy
	4c	Three/four suspicious features
TIRADS 5		All five suspicious features	Probably malignant lesions (more than 80% risk of malignancy)	>80% risk of malignancy
TIRADS 6		Biopsy proven malignancy

Classification based on TNM

Differentiated and anaplastic thyroid carcinoma TNM staging AJCC UICC 2017

Papillary, follicular, poorly differentiated, Hurthle cell and anaplastic thyroid carcinoma
Primary tumor (T)					Regional lymph nodes (N)		Distant metastasis (M)
T category	T criteria				N category	N criteria	M category	M criteria
TX	Primary tumor cannot be assessed				NX	Regional lymph nodes cannot be assessed	M0	No distant metastasis
T0	No evidence of primary tumor				N0	No evidence of locoregional lymph node metastasis	M1	Distant metastasis
T1	Tumor ≤2 cm in greatest dimension limited to the thyroid				N0a	One or more cytologically or histologically confirmed benign lymph nodes
T1a	Tumor ≤1 cm in greatest dimension limited to the thyroid				N0b	No radiologic or clinical evidence of locoregional lymph node metastasis
T1b	Tumor >1 cm but ≤2 cm in greatest dimension limited to the thyroid				N1	Metastasis to regional nodes
T2	Tumor >2 cm but ≤4 cm in greatest dimension limited to the thyroid				N1a	Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease.
T3	Tumor >4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles				N1b	Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes
T3a	Tumor >4 cm limited to the thyroid
T3b	Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) from a tumor of any size
T4	Includes gross extrathyroidal extension
T4a	Gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size
T4b	Gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels from a tumor of any size