Thyroid nodule differential diagnosis

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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]

Thyroid nodule differential diagnosis

In rare cases, a thyroid nodule may reflect one of the hereditary nonmedullary thyroid cancer syndromes such as familial adenomatous polyposis, Werner’s syndrome, Carney complex type 1, or Gardner’s syndrome

Disease		Nodule property	Spread			Nodular growth	Laboratory		Imaging	Pathology	Associated mutation	special consideration
			LN	Vessle	Metastasis		TSH	FT4/T3
Benign	Colloid adenoma	Noncancerous enlargement of thyroid tissue May be painful	-	-	-	Intermediate Slow	NL	NL	Iso- to hypoechoic May have internal cystic or heterogeneous change May have calcification Multiple echogenic foci (of inspissated colloid) with comet tail artifac	Hyperplasia of colloid parenchyma of thyroid gland	---	May progress to carcinoma
	Hashimoto's thyroiditis	Rarely painful	-	-	-	Rapid Intermediate	↓↓	↓	Hypoechoic micronodules (1-6 mm) with surrounding echogenic septations	Massive infiltration of the thyroid gland by lymphocytes and plasma cells Germinal centers Thyroid follicles are usually absent and the few remaining follicles are devoid of colloid Hurthle cells	HLA-A HLA-B	May be accompanied with fever Autoimmune disease of thyroid gland
	Cysts nodule	Most common cause of painful neck lesion	-	-	-	Rapid Intermediate	NL	NL	Cystic non-calcified nodules	Follicular cells Macrophages RBC Colloid	-	Mostly due to degenerating thyroid adenomas
	Follicular adenoma	Rarely painful	-	-	-	Intermediate Slow	↓↓	↑	Thin peripheral halo Predominantly cystic or mixed cystic and solid lesions Isoechoic or predominantly anechoic	---	PAX8-PPAR gamma 1	---
	Hyperplastic nodule		-	-	-	Rapid Intermediate	↓↓	↑
	Macrofollicular adenoma		-	-	-	Intermediate Slow	↓↓	↑
	Microfollicular or cellular adenoma		-	-	-	Intermediate Slow	↓↓	↑
	Hürthle cell adenoma		-	-	-	Intermediate Slow	↑↓	↑↓
Malignant	Papillary carcinoma	Fixed Painless	+	+	Pulmonary Skeletal metastases	Intermediate Slow	NL	NL	Solitary mass usually with an irregular outline, located in the subcapsular region Small punctate regions of echogenicity representing microcalcifications (psammoma bodies)	Unencapsulated and may be partially cystic Papillae consisting of one or two layers of tumor cells surrounding a well-defined fibrovascular core Large, oval, and appear crowded and overlapping nuclei May contain hypodense powdery chromatin, cytoplasmic pseudoinclusions due to a redundant nuclear membrane, or nuclear grooves	RET/PTC NTRK1 RAS BRAF	---
	Follicular carcinoma	Fix Painless	+	+	Bone Lung	Intermediate Slow	↑↓	↑↓	Lesions are typically hypoechoic Usually lacks cystic change	FLUS Tumor capsule Vascular invasion	RAS mutations PAX8-PPAR gamma 1	Most common thyroid cancer in iodine deficient areas
	Medullary carcinoma	Mainly manifest paraneoplastic symptoms: Diarrhea Itching Flushing	+	-/+	Locally to neck Can metastase to all body organ systems	Intermediate Slow	NL	NL	Unifocal May present as multifocal	Hypoechoic Microcalcifications	---	May be associated with other co-existing diseases Associated with high levels of calcitonin
	Anaplastic carcinoma	Dyspnea Metastasis Hoarseness of voice	+	+	Very aggressive Invade directly into adjacent organs, such as the trachea, larynx, esophagus, blood vessel and muscle, resulting in suffocation, vocal cord paralysis, dyspnea or dysphagia	Slow	↓	↑	Microcalcification Infiltrative lesion	Cytologically malignant: Huge nuclear-cytoplasmic ratio Mitoses Presence or absence of necrosis	P53 BRAF	Very malignant, always considered as stage IV
	Primary thyroid lymphoma	Vocal cord paralysis Dyspnea Dysphagia	+	-	MALT lymphoma less aggressive Diffuse large cell lymphomas more aggressive	Intermediate Slow	NL	NL	Nodular (hypoechoic mass), diffuse (mixed echotexture) or mixed Calcifications uncommon	Lymphoepithelial lesion Plasma cells Thyroid parenchyma displaced by lymphocytes	BRAF NRAS MAPK	May be associated with hashimoto thyroiditis
	Metastatic carcinoma	Thyroid and extra thyroid manifestations	+	+	+	Intermediate Slow	↑↓	↑↓	-	-	-	Malignant melanoma Lung cancer breast cancer Renal cancer Gastrointestinal cancer
Thyroglossal duct cyst		Mostly midline Can be painful if get infected	-	-	---	---	NL	NL	Cyst in subhyoid portion or lateral tip of the hyoid bone	---	---	---
Branchial cleft cyst		Cystic mass that develops under the skin in the neck between the sternocleidomastoid muscle and the pharynx	-	+ May adhere to great vessels at the mandibular angle	---	---	NL	NL	Cyst between sternocleidomastoid and pharynx	---	---	---
Neck abscess		Painful mass in the neck, may be accompanied with erythema	+	-	---	Rapid	NL	NL	Cyst with hyperechoic debris containing pus	---	---	---
Parathyroid cyst		Painless mass	-	-	---	Rapid Intermediate	NL	NL	Cystic lesion that is uniformly anechoic	---	---	---
Parathyroid cancer		Lymphadenopathy Palpable lump in the neck	+	+	+ Rarely distant metastases, mainly  thyroid gland, overlying strap muscles, recurrent laryngeal nerve, trachea, or esophagus	Slow Intermediate	NL	NL	Normal thyroid size with a complex echogenic structure May contain hyperechoic solid part and several centrally located anechoic cavities	Tumor cells form branching cord surrounded by fat cells with areas of fibrosis and chronic inflammatory cells or abundant granular eosinophilic cytoplasm	FIHP MEN1	---