Endocrine
// Review Sections

Thyroid Anatomy

Embryology

  1. Thyroid AnatomyMedial anlage of thyroid
    1. The medial anlage of the thyroid gland forms at the foramen cecum of the tongue
    2. During the 4th week of gestation, a ventral diverticulum of the foramen cecum is formed from the 1st and 2nd pharyngeal pouches
    3. This diverticulum descends in the midline of the neck as the thyroglossal tract to the normal position of the thyroid (by 7th week of gestation)
      1. Path of descent is usually anterior to hyoid bone, but may be posterior or through it
    4. Lateral anlage of thyroid
      1. Consisting of the C-cell precursors, which arise from the neural crest portion of the 4th pharyngeal pouch
      2. Fuses with the descended medial anlage

Anatomy of the Thyroid Gland

  1. Thyroid lobes
    1. 2 lobes connected at isthmus (2nd and 3rd tracheal ring)
    2. Each lobe: 4 x 2 x 2cm, weight: 20g
    3. Pyramidal lobe
      1. Extends superiorly from the isthmus (variable size, may extend to hyoid bone)
      2. The obliterated thyroglossal duct extends from pyramidal lobe to the hyoid bone
        1. May harbor a thyroglossal duct cyst
      3. Tubercle of Zuckerkandl
        1. Variably present
        2. Posterolateral projection of thyroid tissue at point of fusion of medial and lateral anlages of the thyroid
    4. Recurrent laryngeal nerve usually traverses posterior aspect of the tubercle
      1. May help facilitate identification of the RLN
      2. Rarely, recurrent laryngeal nerve runs lateral to tubercle of Zuckerkandl – increased risk of damage during dissection.
  1. Ectopic thyroid tissue
    1. Present in ~ 7 – 10% of the population
    2. ~90% of ectopic thyroid tissue is found in the base of the tongue as lingual thyroid
    3. Lateral aberrant thyroid: thyroid tissue found in the lateral cervical lymph nodes
      1. Considered malignant thyroid tumor until proven otherwise (most often represents metastatic papillary carcinoma)
    4. Anatomical relationships
      1. Anterior: strap muscles (sternohyoid, sternothyroid, thyrohyoid, omohyoid)
        1. Innervation: ansa cervicalis
      2. Posterior: tracheaanatomy of a thryoid gland
      3. Ectopic thyroid tissue
        1. Present in ~ 7 – 10% of the population
        2. ~90% of ectopic thyroid tissue is found in the base of the tongue as lingual thyroid
        3. Lateral aberrant thyroid: thyroid tissue found in the lateral cervical lymph nodes
          1. Considered malignant thyroid tumor until proven otherwise (most often represents metastatic papillary carcinoma)
        4. Anatomical relationshipsAnatomical relationships
          1. Anterior: strap muscles (sternohyoid, sternothyroid, thyrohyoid, omohyoid)
            1. Innervation: ansa cervicalis
          2. Posterior: trachea
          3. Posterolateral: common carotid arteries, internal jugular veins, vagus nerve
            1. Thyroid lobes
              1. 2 lobes connected at isthmus (2nd and 3rd tracheal ring)
              2. Each lobe: 4 x 2 x 2cm, weight: 20g
              3. Pyramidal lobe
                1. Extends superiorly from the isthmus (variable size, may extend to hyoid bone)
                2. The obliterated thyroglossal duct extends from pyramidal lobe to the hyoid bone
                  1. May harbor a thyroglossal duct cyst
                3. Tubercle of Zuckerkandl
                  1. Variably present
                  2. Posterolateral projection of thyroid tissue at point of fusion of medial and lateral anlages of the thyroid
              4. Recurrent laryngeal nerve usually traverses posterior aspect of the tubercle
                1. May help facilitate identification of the RLN
                2. Rarely, recurrent laryngeal nerve runs lateral to tubercle of Zuckerkandl – increased risk of damage during dissection.
                3. Posterolateral: common carotid arteries, internal jugular veins, vagus nerve

Common Cartoid Arteries

Vasculature

  1. Arterial supply
    1. Superior thyroid artery (on each side)
      1. First branch of the external carotid artery at the level of the carotid bifurcation
      2. With thyroidectomy need ligation of the superior thyroid arteries close to thyroid gland to avoid injury to superior laryngeal nerve (superior thyroid artery runs with superior laryngeal nerve until approximately 1cm from the superior thyroid pole)
    2. Inferior thyroid artery (on each side)
      1. From thyrocervical trunk of subclavian artery
      2. With thyroidectomy, need ligation of the inferior thyroid arteries close to thyroid gland to avoid injury to parathyroid glands (devascularized) and recurrent laryngeal nerve
    3. Ima (3%)From aortic arch or innominate artery

transfixing sutureAortic Arch

  1. Venous drainage
    1. Superior thyroid vein (on each side)
      1. Drain to internal jugular
    2. Middle thyroid vein (on each side)
      1. Drain to internal jugular
    3. Inferior thyroid vein (on each side)
      1. Drain to brachiocephalic vein

Nerves

  1. Recurrent laryngeal nerve
    1. LocationLymphatic Nerve Diagram
      1. Originates from Vagus nerve in superior mediastinum
      2. Recurs around vessel
        1. Left recurrent laryngeal nerve: loops around aorta
        2. Right recurrent laryngeal nerve: loops around right subclavian or innominate artery
    2. In tracheoesophageal groove (posterior to thyroid)
      1. Right: more oblique course to tracheoesophageal grove. Left: vertical course
  1. Runs with inferior thyroid artery, lateral or deep to the ligament of Berry and enters the larynx at the 1st tracheal ring
    Nerve Diagram 3 Nerve Diagram 4 Nerve Diagram 2
  2. Non-recurrent laryngeal nerveUsually posterior to the inferior thyroid artery in tracheoesophageal groove (but may occasionally be anterior)
    1. 5 – 0.7% on the right
    2. Risk of injury during thyroid surgery
  3. A direct nerve is the consequence of the formation of the arteria lusoria vascular abnormality
    1. Innominate artery is absent
    2. Right common carotid and right subclavian arteries originate directly from the aortic arch
    3. Subclavian artery takes a retroesophageal course
  4. Left non-recurrent laryngeal nerve: much more rare, may occur with situs inversus
  1. Innervation
    1. Motor to entire larynx (except cricothyroid muscle)
      1. Lateral and posterior cricoarytenoid, thyroarytenoid, and interarytenoid muscles
    2. Superior laryngeal nerveSuperior Laryngeal Nerve
      1. Introduction
        1. External branch of superior laryngeal nerve is the most commonly injured nerve with total thyroidectomy
      2. Location
        1. Originates from Vagus nerve as it exits the base of the skull
        2. Runs superior and lateral to thyroid lobes
        3. May run with superior thyroid artery at upper pole of thyroid until about 1cm before the artery enters the capsule
  1. Divides into internal and external branches
  2. Enters larynx
  1. Innervation
    1. External branch
      1. Motor to cricothyroid muscle and inferior pharyngeal constrictor muscles
    2. Internal branch
      1. Sensory to larynx

Lymphatics

    1. Node levels of the necklymphatic diagram 1
      1. Node level I
        1. Submental and submandibular nodes cephalic to hyoid bone and anterior to posterior aspect of submandibular gland
      2. Level II, III, IV
        1. Includes nodes along internal jugular vein bordered by lateral edge of carotid sheath (level VI) anteromedially and posterior border of sternocleidomastoid muscle (posterior)
          1. Level III: bordered by hyoid bone (superior) and cricoid cartilage (inferior)
          2. Level II and level IV are cephalid and caudal to level III respectively
            1. IIa and IIb: subdivided by spinal accessory nerve
          3. Level Vlymphatic diagram 2
            1. Nodes of posterior triangle of neck
              1. Va and Vb: subdivided by inferior border of cricoid cartilage
                1. Va: nodes surrounding spinal accessory nerve
                2. Vb: transverse cervical and supraclavicular nodes
              2. Level VI
                1. Includes nodes in area from hyoid bone (superior) to innominate artery (inferior) and laterally to carotid sheath
              3. Node level VII
                1. Mediastinal nodes
              4. Drainage pattern/nodal metastasis pattern of the thyroid
                1. Nodal metastasis in thyroid cancer generally follows an orderly progression
                  1. Generally, metastasize to level VI nodes first
                    1. Prelaryngeal (Delphian), pretracheal, and right and left paratracheal nodes
                      1. Retropharyngeal and retroesophageal nodes – less commonly involved
                    2. Followed by node levels II – V
                      1. Lateral node involvement is less common, but associated with a worse prognosis
                    3. Level I and level VII nodes are rarely involved
                  2. Intracapsular lymphatics provide communication from lobe to lobe across the isthmus

Physiology and Thyroid Function Testing

Physiology

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Thyroid Function Testing

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Lingual Thyroid

Thyroglossal Duct Cyst

Thyroiditis

Hypothyroidism

Hypothyroidism

  1. Introduction
    1. Decrease basal metabolic rate, decrease β-receptor/LDL receptor synthesis
    2. Etiology
      1. Thyroiditis
        1. Hashimoto’s thyroiditis (90%)
        2. Subacute painless lymphocytic thyroiditis
      2. Iodine deficiency, enzyme deficiency
  • Medications
    1. Amiodarone, lithium, sulfonamides, phenylbutazone
  1. Hypothalamic/pituitary dysfunction
  2. Congenital (Cretinism)
  1. Clinical and laboratory findings
    1. Clinical findings in adult hypothyroidism
      1. General
        1. Weight gain
        2. Fatigue, cold intolerance
        3. Periorbital puffiness, hoarse voice, nonpitting edema,
          1. Due to increase hyaluronic acid and water in interstitial tissue
        4. Macroglossia
      2. Neurologic
        1. Diminished reflexes
        2. Mental slowness, dementia
  • Cardiovascular
    1. Diastolic hypertension
    2. Dilated cardiomyopathy
    3. Atherosclerotic coronary artery disease
    4. Bradycardia
  1. Gastrointestinal
    1. Constipation
  2. Musculoskeletal
    1. Proximal muscle myopathy
      1. Increase serum creatinine kinase
  • Patients who are hypothyroid have increased risk of myopathy from statin use
    1. Carpal tunnel syndrome
  1. Integumentary
    1. Coarse hair, loss of outer 1/3 of eyebrow
    2. Coarse, yellow skin
      1. Decrease conversion of β-carotenes into retinoic acid
  • Gynecologic
    1. Menstrual irregularities
      1. Menorrhagia (most common)
    2. Clinical findings in pediatric hypothyroidism
      1. Delayed puberty, delayed menarche
      2. Growth retardation
    3. Laboratory findings
      1. Decrease serum T4, increased serum TSH
      2. Antimicrosomal, antiperoxidase, and antithyroglobulin antibodies
  • Hypercholesterolemia
  1. Myxedema coma
    1. Introduction
      1. Typically occurs in elderly patients with history of hypothyroidism following precipitating event
        1. Precipitating events
          1. Surgery, trauma
          2. Cold exposure
          3. Use of sedatives/opiates
          4. Infection
          5. CHF, stroke
        2. Clinical findings
          1. Change in mental status, somnolence
          2. Hypothermia
  • Bradycardia, hypoventilation
  1. Hypotension
  1. Laboratory findings
    1. Increased TSH, low or undetectable FT4
    2. Metabolic acidosis
  • Hypoglycemia, hypocortisolism (10%), SIADH (hyponatremia)
  1. Management
    1. ABC’s
      1. Ventilatory support (airway support in obtunded patient)
      2. IV fluids +/- vasopressors
    2. Hydrocortisone
  • IV Levothyroxine
    1. Give after hydrocortisone (LT4 may increase cortisol clearance)
  1. Passive warming
    1. Active rewarming is avoided (unless core temperature is < 28° C) due to increase in oxygen consumption and peripheral vasodilation (hypotension) caused by active rewarming
      1. Core temperature < 28° C: increase risk of ventricular fibrillation
    2. Prognosis
      1. Mortality rate may be as high as 60%

 

Euthyroid Sick Syndrome

Thyroid Hormone Excess

Nontoxic Goiter

Thyroid Nodule

Benign and Malignant Tumors

Benign Tumors of the Thyroid

  1. Follicular adenoma
    1. Introduction
      1. Most common benign tumor
      2. ~ 10% progress into follicular carcinoma
    2. Tumor characteristics
      1. Presents as a solitary “cold” nodule
      2. Completely surrounded by a capsule
  • No vascular invasion
  1. Management
    1. FNA is not diagnostic
    2. Requires lobectomy to differentiate from cancer
      1. The diagnosis of follicular carcinoma or Hürthle cell carcinoma requires either evidence of vascular and/or capsular invasion which cannot be determined by FNA

Malignant Tumors of the Thyroid

  1. Malignant tumor classification
    1. Differentiated thyroid cancers of follicular cell origin:
      1. Papillary thyroid carcinoma and its variants
      2. Follicular thyroid carcinoma
  • Hürthle cell carcinoma
  • Ionizing radiation is a risk factor for all differentiated thyroid cancers of follicular cell origin
    1. Differentiated thyroid cancers of parafollicular cell origin:
      1. Medullary thyroid carcinoma
    2. Undifferentiated
      1. Anaplastic thyroid cancers (derived from follicular cell origin)
    3. Dedifferentiated thyroid cancers of follicular cell origin
      1. Spectrum of dedifferentiation that exists between differentiated tumors and undifferentiated anaplastic thyroid cancer
    4. Familial syndromes of thyroid disease
Syndrome Thyroid Disease Gene/Tumor Marker
MEN type IIA and IIB Medullary thyroid cancer RET/calcitonin
Carney complex Differentiated thyroid cancer PRKAR1A
Cowden disease Follicular thyroid cancer PTEN
Peutz-Jeghers Syndrome Differentiated thyroid cancer STK 11 or LKB 1
Familial adenomatous polyposis Papillary thyroid cancer APC
  1. Papillary thyroid cancer (PTC)
    1. Introduction
      1. Most common thyroid cancer (80%)
      2. Women > men (3:1)
  • Usually in the 4th and 5th decades
  1. Risk factors
    1. Radiation exposure (5 – 40+ years after exposure)
      1. Particularly in children (low risk in adults)
        1. Beginning within 5 years of irradiation during childhood, new nodules develop at a rate of about 2% annually, reaching a peak incidence within 30 years of irradiation but remaining high at 40 years (NCCN)
      2. Radiation induced PTC
        1. More aggressive histology
        2. Higher recurrence rates
  • Overall survival is similar to spontaneous forms
  1. Family history
  2. Long-standing goiter (> 5 years)
  1. Pathogenesis and gross and microscopic findings
    1. Usually multifocal
    2. Papillary fronds intermixed with follicles
  • Psammoma bodies
    1. Dystrophically calcified cancer cells
  1. Orphan Annie nuclei
    1. Empty-appearing nuclei
  2. Lymphatic invasion
  3. Variants
    1. Follicular variant
      1. Histologic and architectural appearance of follicular tumors
      2. Cytologic features of papillary carcinoma (behaves in same manner as classic PTC)
    2. More aggressive variants (dedifferentiated)
      1. Tall cell variant
        1. Higher incidence of lymph node metastasis
        2. Lower overall survival (higher mortality rate)
      2. Columnar cell
      3. Diffuse sclerosing type
    3. Thyroid cancer staging (thyroid cancer of follicular cell origin)
      1. TNM staging
        1. T staging
          1. T1: tumor ≤ 2cm
          2. T2: tumor 2 – 4cm
          3. T3: tumor > 4cm
          4. T4: extra-thyroid extension (beyond thyroid capsule)
            1. T4a: tumor extends into subcutaneous tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve
            2. T4b: tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels
          5. N staging
            1. N1: regional lymph node metastasis
              1. N1A: metastasis to level VI nodes
              2. N1B: metastasis to level I, II, III, IV, V, or VII nodes
            2. M staging
              1. M1: distant metastasis
            3. Staging
              1. Stage I
                1. Age < 45: Any T, Any N, M0
                2. Age ≥ 45: T1N0M0
              2. Stage II
                1. Age < 45: Any T, Any N, M1
                2. Age ≥ 45: T2N0M0
              3. Stage III
                1. Age ≥ 45
                  1. T3N0M0,
                  2. T1-3N1AM0
                2. Stage IV
                  1. Age ≥ 45
                    1. IVa: T4a or N1B
                    2. IVb: T4b
  • IVc: M1
  1. Disease spread
    1. Cervical nodes
      1. Level VI is most common site
      2. 20 – 90% (depending on method of detection) have regional lymph node metastasis at time of diagnosis (ATA)
        1. In one review, nodal metastases were found in 36% of 8029 adults with papillary carcinoma, in 17% of 1540 patients with follicular thyroid carcinoma, and in up to 80% of children with papillary carcinoma (NCCN)
      3. Distant metastasis: lungs (most common), bone
    2. Preoperative evaluation of differentiated thyroid cancer of follicular cell origin
      1. Neck ultrasound and FNA of nodule and suspicious lymph nodes (ATA)
        1. Biopsy all suspicious lymph nodes, all nodes > 1cm in IIb – Vb, and all nodes > 1.5cm in I and IIa
          1. Nodes < 5 – 8mm, especially without worrisome features may be observed rather than attempting FNA
          2. Inaccessible node on FNA
            1. Observed for growth with serial ultrasound
            2. If node demonstrates growth, attempt repeat FNA
  • If still inaccessible, perform open biopsy
  1. Cytology and IHC stain of FNA samples for thyroglobulin
  1. +/- preoperative laryngoscopy (prior to any thyroid surgery)
    1. Indicated for patients with vocal complaints, audible vocal abnormalities, and prior neck operation or radiation
  • Routine use of other imaging studies (CT, MRI, PET) and measurement of preoperative serum thyroglobulin is not recommended preoperatively (ATA)
  1. Management of papillary thyroid cancer
    1. Surgical management of papillary thyroid cancer
      1. Total thyroidectomy +/- lymph node dissection
        1. Most now advocate total thyroidectomy for all patients in whom the diagnosis of PTC is assigned preoperatively (Greenfield)
        2. Benefits of total thyroidectomy v. lobectomy in management of differentiated thyroid cancers of follicular origin
          1. Removes multicentric lesions
            1. PTC ≥ 1 cm: 50% have additional cancer in the contralateral thyroid lobe (NCCN)
          2. Allows use of radioiodine to localize and treat residual thyroid tissue
  • Allows postoperative serum thyroglobulin to be used as a marker of recurrent or persistent disease
  1. Thyroid lobectomy may be sufficient in low-risk patients with papillary microcarcinoma
    1. Papillary microcarcinoma: small (< 1cm), unifocal, unilobar tumor with no capsular or vascular invasion
    2. Contraindications to lobectomy (perform total thyroidectomy) in patients in which PTC is diagnosed preoperatively (NCCN and ATA)
      1. Age > 45 (ATA)
      2. Tumor > 1cm (ATA) or > 4cm (NCCN)
  • Gross extra-thyroidal extension
  1. Cervical lymph node or distant metastasis
    1. N1a micrometastasis (≤ 5 metastatic lymph nodes with no lesion > 5mm in largest dimension) …
  2. Vascular invasion
  3. Multifocal disease or bilateral nodularity
  • History of radiation to head or first-degree relative with differentiated thyroid cancer
  • Poorly differentiated/aggressive variant
  1. Completion thyroidectomy indicated in the following patients diagnosed with PTC found post lobectomy (NCCN)
    1. Any of the above stated indications
    2. Positive margins
  • Microscopic multicentric disease
  1. Lymph node dissection
    1. Central neck dissection
  • Prophylactic neck dissection: nodal metastasis is not detected clinically or by imaging (clinically N0)
  • Therapeutic neck dissection: nodal metastasis is apparent clinically (preoperatively or intraoperatively) or by imaging (clinically N+)
    1. Prophylactic central neck dissection
      1. Emerging standard of care in patients with papillary thyroid cancer and Hürthle cell cancer
      2. Especially in patients with high risk histology (i.e. tall cell variant) and/or patients > 45-years-old who may be up-staged by the presence of nodal metastasis
  • Difficult to image due to intact thyroid
    1. Therapeutic central neck dissection
      1. Recommended in biopsy-proven cervical nodal metastasis
  • Procedure
    1. Includes at least prelaryngeal, pretracheal, and at least one paratracheal lymph node basin
    2. May be extended to include removal of additional central nodal basins (retropharyngeal, retroesophageal, paralaryngopharyngeal and/or superior mediastinal)
  1. Lateral neck dissection
    1. Prophylactic lateral neck dissection
      1. Not indicated
    2. Therapeutic lateral neck dissection
      1. Recommended in biopsy-proven lateral cervical nodal metastasis
  • Classification (comprehensive v. selective lateral neck dissection) (ATA)
    1. Comprehensive lateral neck dissection (MRND) – removal of nodal basins I – V with preservation of one or more of the following: spinal accessory nerve (CN XI), internal jugular vein (IJV), or sternocleidomastoid muscle (SCM)
    2. Selective lateral neck dissection – removal of < all 5 nodal basins (directed by patterns of lymphatic drainage of the primary tumor) with preservation of CN XI, IJV, and SCM
  1. Procedure
    1. Selective lateral neck dissection of levels IIa, III, IV, and Vb (ATA)
      1. Include I or IIb: if biopsy-proven involvement of basin
      2. Include Va when US evaluation shows suspicious Va nodes
    2. Complications
      1. Chronic pain and numbness
        1. Numbness of lateral neck and ear (most common permanent complication)
          1. Due to injury to greater auricular nerve and sensory cervical rootlets
        2. Postoperative hypoparathyroidism
          1. Lateral neck dissection doubles the risk of transient postoperative hypoparathyroidism
        3. CN XI injury
          1. Risk is increased when level IIb and Va are dissected
        4. Chyle leak (3.6%)
      2. Radiotherapy with 131I
        1. Introduction
          1. For residual thyroid tissue and/or metastatic disease
          2. Done 6 – 12 weeks after surgery
        2. Tumors responsive to RAI
          1. Papillary and follicular thyroid cancer are typically highly responsive to 131I
          2. Hürthle cell carcinoma is less likely to concentrate 131I
          3. Medullary thyroid cancer does not concentrate 131I
        3. Typical indications for 131I therapy (any of the following) (NCCN)
          1. Tumor > 4cm
            1. Papillary tumor < 1cm or follicular carcinoma < 2cm: no radioiodine therapy
          2. Gross extra-thyroidal disease
          3. Postoperative unstimulated thyroglobulin level > 5 – 10ng/mL
          4. Known distant metastasis (susceptible to RAI)
          5. Selectively indicated in patients with primary papillary tumor 1 – 4cm or follicular carcinoma 2 – 4cm and high risk for recurrence:
            1. High risk histology
            2. Lymphovascular invasion
  • Lymph node metastasis
    1. N1A with < 5 metastatic lymph nodes with 2 – 5mm of focus of cancer in node – RAI ablation is not indicated, particularly if the postoperative thyroglobulin is < 1ng/mL
  1. Multifocal (with at least one focus > 1cm)
  2. Persistence of anti-thyroglobulin antibodies
  3. Postoperative unstimulated thyroglobulin < 5 – 10ng/mL (> 1ng/mL)
  1. Thyroid hormone replacement pre- and post- RAI
    1. Thyroid hormone replacement prior to RAI
      1. Introduction
        1. Residual thyroid tissue or differentiated thyroid cancer must be stimulated by elevated levels of TSH to take up RAI
          1. TSH should be at least 30mIU/mL
        2. Regimen options
          1. Cytomel [liothyronine (LT3)] given immediately postoperatively prior to radiotherapy. Allow withdrawal x 2 weeks prior to ablation
            1. T3 has a much shorter half-life (8 – 12 hours) in comparison to T4 (7 – 10 days)
          2. Levothyroxine [thyroxine (T4)] given immediately postoperatively prior to radiotherapy. Allow withdrawal x 3 weeks prior to ablation
          3. Levothyroxine given immediately postoperatively with no withdrawal but thyrogen (recombinant TSH) x 2 days then ablation on day 3
        3. Thyroid hormone replacement following RAI
          1. Thyroxine (with or without LT3 for 7 days) may be resumed on day 2 after RAI
  • Levothyroxine (post-RAI ablation if performed)
    1. Tumor is TSH dependent
    2. General goal: TSH < 1mU/L, preferably 1 – 0.5mU/L and patient mildly thyrotoxic
      1. Goal TSH dependent on risk of recurrence and presence of persistent disease
    3. Adjuvant radiation therapy
      1. May be indicated in unresectable locoregional disease not responsive to 131I or used in conjunction with 131I for unresectable locoregional disease
    4. Follow-up surveillance following resection and management of metastatic disease
      1. Follow-up surveillance following resection (for well-differentiated thyroid cancers)
        1. Ultrasound, thyroglobulin and TSH every 6 months for 2 years and then annually
      2. Management of metastatic disease (general statements)
        1. Surgical resection (if appropriate)
          1. Resection of isolated symptomatic metastases has been associated with improved survival
        2. 131I radiotherapy (if tumor concentrates 131I)
          1. May consider pretreatment 123I diagnostic imaging with TSH stimulation (or low-dose 131I) prior to 131I radioablation to identify remnant tissue or metastatic foci
        3. +/- radiation therapy
        4. +/- systemic therapy
          1. Sorafenib (kinase inhibitor)
            1. Demonstrate clinically significant activity in randomized, placebo-controlled clinical trials in locally recurrent unresectable and metastatic medullary thyroid cancer and in radioiodine-refractory differentiated thyroid cancer
          2. Prognosis
            1. Poor prognostic factors
              1. Male
              2. Tumor size > 4cm
              3. History of radiation
              4. Age > 45 years old (age is most important prognostic factor)
              5. Aggressive variant/dedifferentiated
              6. Extracapsular invasion
              7. Lymph node or distant metastasis
            2. Overall 5-year survival is 95%
  • Local invasion is most common cause of death
  1. Follicular carcinoma (FTC)
    1. Introduction
      1. 10 – 15% of thyroid cancers
      2. Female dominant (3:1)
  • Age: > 50-years-old
  1. Risk factors
    1. Radiation
    2. Low iodine
      1. Low iodine is a risk factor for follicular and anaplastic thyroid cancers
    3. Pathogenesis and gross and microscopic findings
      1. Gross and microscopic findings
        1. Unifocal (most common thyroid cancer presenting as a solitary cold nodule)
        2. Encapsulated or invasive
        3. Neoplastic follicles invade blood vessels (spreads hematogenously)
        4. Must demonstrate invasion through the capsule and/or vascular invasion
      2. Pathogenesis
        1. Most contain either RAS mutations or a PAX8-PPAR gamma 1 rearrangement but not both
      3. Disease spread
        1. Spreads hematogenously; lymph node metastasis is less common
        2. Distant metastasis
          1. Lung, bone, CNS, skin
          2. 10 – 15% of patients with FTC have distant metastasis; 50% if both extensive capsular and vascular invasion are present (widely invasive follicular cancer) (Uptodate)
        3. Management
          1. Perform lobectomy + isthmusectomy and send for frozen section and permanent
          2. If pathology shows adenoma or follicular cell hyperplasia: nothing else needed
  • If pathology shows follicular cancer: manage like papillary thyroid cancer
    1. Completion thyroidectomy indicated if invasive follicular carcinoma is present
    2. Completion thyroidectomy v. observation if minimally invasive follicular carcinoma
      1. Minimally invasive follicular carcinoma
        1. Well-defined tumor with microscopic capsular invasion and/or few foci of vascular invasion
        2. Excellent prognosis – if found after thyroid lobectomy, completion thyroidectomy may not be necessary
      2. Differences in management of papillary and follicular thyroid cancer
        1. Follicular thyroid cancer is less likely to have lymph node metastasis; thus prophylactic central neck dissection is not typically indicated
      3. Prognosis
        1. Overall 10-year survival is 70%
      4. Hürthle cell tumor (oxyphilic or oncocytic cell carcinoma)
        1. Introduction
          1. Considered a variant of follicular carcinoma (via World Health Organization)
          2. Comparison to follicular carcinoma
            1. Often multifocal and bilateral
            2. Less likely to concentrate 131I
            3. More often associated with lymph node metastases and distant metastases (lower overall survival)
          3. Histology
            1. Oncocytic (askanazi cell): mostly eosinophilic cells with abundant cytoplasm, closely packed mitochondria, round nuclei with prominent nucleoli
          4. Management
            1. Managed similar to follicular cell carcinoma
              1. Less likely to concentrate 131I
              2. More often associated with lymph node metastasis and thus may consider prophylactic central neck dissection at completion thyroidectomy for histologically confirmed Hürthle cell carcinoma
            2. Medullary carcinoma (MTC)
              1. Introduction
                1. 1 – 2% of thyroid cancers
                2. Sporadic v. familial
                  1. Sporadic (80%)
                    1. Sporadic form typically presents in 5th or 6th decade
                    2. Solitary, unilateral
                  2. Familial (20%)
                    1. Familial type has an overall better prognosis than sporadic type
                    2. Presents earlier in comparison to sporadic form (3rd or 4th decade)
                    3. Multicentric, bilateral
  • Familial type
    1. MEN IIa syndrome (60%)
      1. Medullary carcinoma, hyperparathyroidism, pheochromocytoma
      2. 4 variants
        1. MEN IIa
        2. MEN IIa with cutaneous lichen amyloidosis
          1. Presents with intense pruritus in the scapular region of the back that improves with sun exposure
          2. Hyperpigmented lesion develops later (secondary to scratching)
          3. Manage with phototherapy, corticosteroids, moisturizing lotions, and antihistamines
  • MEN IIa with Hirschprung’s disease
  1. Familial medullary thyroid cancer (FMTC)
  1. MEN IIb syndrome (5%)
    1. Medullary carcinoma, mucosal neuroma, pheochromocytoma, marfanoid body habitus
      1. Mucosal neuroma: hyperpigmentation of lips, eyelids, etc – earliest sign
    2. Familial medullary thyroid cancer (35%)
      1. Autosomal dominant, often considered a variant of MEN IIa
      2. Mutation in cysteine codons of extracellular or transmembrane domains of RET
  • Prevalence of MTC in FMTC and MEN II: 100%
  • Medullary carcinoma: most aggressive when associated with MEN IIb and most indolent when associated with familial medullary thyroid cancer
    1. Pathogenesis
      1. Associated with RET oncogene mutation
        1. Sporadic: ~ 50% have somatic RET mutation
          1. Those lacking RET mutation have somatic mutations of HRAS, KRAS or NRAS
        2. Relationship of common RET mutations to risk of aggressive MTC in MEN IIa and IIb (ATA)
          1. Highest risk: M918T
          2. High risk: codon 634 (high association with pheochromocytoma), A883
        3. Derived from parafollicular C cells
          1. Synthesize calcitonin
            1. Converted into amyloid
          2. C cell hyperplasia is a precursor lesion (in familial forms)
  • Ectopic hormone
    1. ACTH
      1. Management with somatostatin analogues may be useful in patients with symptoms from excess ACTH
    2. Disease spread
      1. In patients with palpable disease > 70% have nodal metastasis and 10% have distant metastasis
      2. Distant metastasis
        1. Lung, bone, liver
      3. Diagnosis/preoperative evaluation
        1. Ultrasound/FNA
          1. IHC staining of FNA sample: calcitonin, chromogranin, CEA. Absence of thyroglobulin
          2. Amyloid (non-diagnostic)
        2. Additional imaging studies
          1. Neck, chest, abdomen CT scan and axial MRI and bone scintigraphy
            1. Indicated if signs/symptoms of regional or distant metastasis or calcitonin > 500pg/mL
  • Additional laboratory evaluation
    1. Serum calcitonin (basal)
      1. Gastrin (pentagastrin): used to confirm elevated calcitonin (causes an increase in calcitonin in patients with medullary thyroid cancer) – pentagastrin no longer used
    2. Serum CEA
      1. Useful in evaluating disease progression
      2. CEA level out of proportion to calcitonin or low levels of CEA and calcitonin indicate poorly differentiated MTC
    3. Test to exclude pheochromocytoma and hyperparathyroidism
      1. Pheochromocytoma: if present, pheochromocytoma must be resected prior to thyroidectomy
      2. Hyperparathyroidism: if present, resection at time of thyroidectomy
    4. Genetic screening for familial cases
      1. Test for RET proto-oncogene (10q11.2)
      2. Children with RET germline mutation (ATA)
        1. MEN IIa (ATA-MOD): total thyroidectomy when serum calcitonin level becomes elevated
          1. May consider total thyroidectomy earlier in childhood if the parents do not wish to embark on a lengthy period of evaluation which might last years
        2. MEN IIa (ATA-H): total thyroidectomy by age 5
          1. In the absence of suspicious lymph nodes, central neck dissection if calcitonin > 40pg/mL
        3. MEN IIb (ATA-HST): total thyroidectomy by age 1 (or first months of life)
          1. In the absence of suspicious lymph nodes, central neck dissection based on whether the parathyroid glands can be identified and left in situ or autotransplanted
        4. Adults with RET germline mutation
          1. Annual serum calcitonin
            1. Normal serum calcitonin: continue annual testing
            2. Elevated serum calcitonin: total thyroidectomy (central neck dissection based on ultrasound findings and preoperative calcitonin levels)
          2. Must exclude pheochromocytoma prior to thyroidectomy
        5. Management
          1. Surgical management
            1. Total thyroidectomy and central neck dissection
            2. Modified radical neck dissection (ATA)
              1. Modified radical neck dissection indicated for clinically or radiologically identifiable disease in lateral neck or gross disease in adjacent central neck
              2. Contralateral lateral neck dissection should also be considered if preoperative imaging is positive in the ipsilateral neck and negative in the contralateral neck but basal calcitonin level is > 200pg/mL
            3. Patient with pheochromocytoma and medullary thyroid cancer
              1. Resect pheochromocytoma prior to MTC
              2. Pheochromocytoma may be resected by laparoscopic or retroperitoneoscopic adrenalectomy
            4. Patients with hyperparathyroidism and medullary thyroid cancer
              1. Only visibly enlarged parathyroid glands should be resected.
              2. If all four glands are enlarged, remove four glands with autotransplantation in brachioradialis
            5. Adjuvant treatment
              1. Radiotherapy with 131I
                1. No value for 131I
              2. External beam radiation therapy
                1. EBRT to neck and mediastinum should be considered in patients at high risk for local recurrence (residual MTC, extrathyroidal extension, or extensive lymph node metastasis)
              3. Systemic therapy
                1. Oral kinase inhibitors may be indicated in locally recurrent unresectable and metastatic medullary thyroid cancer
  • Surgical management of metastatic disease
    1. Bone metastasis
      1. Spinal cord compression: urgent glucocorticoids and surgical decompression
      2. Fractures or impending fractures: surgery, thermoablation (RFA or cryotherapy)
      3. Painful osseous metastasis: denosumab or bisphosphonates
    2. Lung and mediastinal metastasis
      1. Surgical resection if large, solitary lung metastasis
      2. RFA for peripheral, small metastasis
      3. Systemic therapy if multiple, progressively enlarging metastasis
    3. Hepatic metastasis
      1. Surgical resection: large isolated hepatic metastasis
      2. Chemoembolization: disseminated tumor less than 30mm in size involving less than 1/3 of the liver
    4. Follow-up surveillance and management
      1. Annual calcitonin and CEA
        1. Patients with detectable basal calcitonin or elevated CEA
          1. Neck chest, abdomen CT scan,
          2. Possible bone scan and MRI of axial skeleton if levels are markedly elevated
        2. Levothyroxine is indicated in all patients
          1. C cells lack TSH receptors –TSH suppression is not necessary. Keep TSH in normal range
        3. Prognosis
          1. 50% 5-year survival rate for MEN IIa (based on distant metastasis)
          2. 10% 5-year survival rate for MEN IIb
        4. Primary thyroid lymphoma (PTL)
          1. Introduction
            1. 1 – 2% of thyroid malignancies
            2. 1% of extranodal lymphomas arise in the thyroid
  • Nearly all are Non-Hodgkin’s type
    1. 75% are diffuse large B cell lymphomas
    2. 25% are MALT tumors (better prognosis)
  1. Most often develop from Hashimoto’s thyroiditis (only known risk factor for PTL)
  1. Clinical
    1. Most commonly presents as a rapidly enlarging goiter but may present as a solitary nodule
  2. Diagnosis
    1. FNA
      1. May suggest thyroid lymphoma but often is nondiagnostic
    2. Large bore needle biopsy or excisional biopsy
      1. Conducted when FNA suggests lymphoma or clinical suspicion for lymphoma is high in the presence of non-diagnostic FNA
    3. Staging (Lugano modification of Ann Arbor staging classification)
      1. IE: disease limited to the thyroid gland (50%)
      2. IIE: disease limited to thyroid gland and locoregional nodes (45%)
  • IIIE: disease with lymph node involvement on both sides of the diaphragm
  1. IV: diffuse organ involvement
  • 50% of patients present with stage IE and 45% of patients present with stage IIE
    1. Management
      1. Diffuse large B cell lymphoma
        1. Chemotherapy (R-CHOP) followed by radiation
          1. R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
        2. Patient presents with severe airway compromise (Uptodate)
          1. Establish airway
          2. Tissue biopsy to establish diagnosis followed by R-CHOP (tumors shrink within hours of starting R-CHOP)
        3. MALT Lymphoma
          1. Limited (stage I – II): radiation
          2. Advanced (stage III – IV): immunotherapy or chemoimmunotherapy
          3. Limited MALT of the thyroid diagnosed after thyroid resection
            1. Observation may be appropriate if no evidence of residual disease
            2. If positive margins are present, adjuvant radiation therapy is recommended
          4. Anaplastic thyroid cancer
            1. Epidemiology
              1. Most often occur in elderly (median age is 7th decade) women with long-standing goiters
              2. Risk factors
                1. Low iodine
                2. Multinodular goiter
                3. History of follicular cancer or papillary thyroid cancer
                  1. ~50% had previous or concurrent thyroid malignancy
                4. Pathogenesis
                  1. Terminal dedifferentiation of preexisting carcinoma of thyroid follicular cells
                  2. Associated with loss of p53 tumor suppressor gene
                5. Clinical
                  1. Presents as rapidly growing neck mass (85%)
                6. Staging
                  1. All are considered stage IV cancers
                7. Management
                  1. Tumor localized to thyroid or locally advanced resectable tumors
                    1. Complete resection followed by chemotherapy and radiation
                    2. Nearly all present with advanced disease and surgery is not typically indicated
                  2. Locally advanced inoperable disease
                    1. Chemotherapy and radiation (in patients who desire active therapy rather than palliative therapy)
                    2. Locoregional resection may be necessary for palliation of airway or esophageal obstruction
                      1. Death is usually due to upper airway obstruction (often despite tracheostomy)
  • Distant metastasis
    1. No effective therapy
  1. Prognosis
    1. Rapidly aggressive and uniformly fatal (most are fatal within 6 months)
  2. Metastasis to thyroid
    1. Tumor of origin
      1. Renal (most common), breast, lung
    2. Management
      1. When the thyroid is the sole site of metastatic disease, thyroidectomy (lobectomy v. total thyroidectomy) may be appropriate
      2. Palliative resection is typically not indicated

 

 

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Quiz 2

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