1. Describe the major challenge in the treatment of thyroid nodules.

2. List findings in the patient’s history and physical examination that suggest malignancy in a thyroid nodule.

3. Differentiate fine needle aspiration results by category and discuss categorization changes proposed by the National Cancer Institute.

4. Determine how to best approach patients with asymptomatic hyperparathyroidism, based on recommendations from the National Institutes of Health.

5. Compare technetium Tc99m sestamibi scans to ultrasonography for preoperative parathyroid localization.

Gerard M. Doherty, MD
Norman Thompson Professor of Surgery, Chief, Division of Endocrine Surgery, Head, Section of General Surgery, and Program Director, Department of Surgery, University of Michigan Medical School, Ann Arbor

Evaluation of Thyroid Nodules

Epidemiology: prevalence 4% to 7% (palpable) in adult clinical population, but 50% in autopsy or ultrasonography (US) series; incidence of thyroid cancer 4/100,000 persons per year; challenge to identify cancers without overtreating benign nodules

Evaluation

Fine needle aspiration (FNA): good test; low rate of false positives; rate of false negatives slightly higher, depending on aspiration and cytology assessment techniques used

Clues to malignancy detected via history and physical examination: patient’s age and sex; history of head and neck irradiation; family history of thyroid carcinoma; presence of solitary dominant nodules, as opposed to nodules associated with multinodular goiter; hardness or irregularity of nodule; presence of palpable lymph nodes; recurrent laryngeal nerve palsy; symptoms of local pressure, especially if disproportionate to nodule size

Nuclear scan (123 I scintigraphy; scintiscan): only appropriate indication hyperthyroidism (thyrotropin [TSH] suppression); cancer rare in these cases (suspect if palpable lymph nodes also present)

Diagnostic US: permits characterization of nodule before FNA; extension of physical examination; provides accurate size measurements when following patients over time; differentiates nodule characteristics (cystic, solid, or complex); allows assessment of nodule size and shape; guides FNA; axis of benign nodules usually follows lobular axis; also shows microcalcification and other suspicious features; US more accurate than physical examination, which is “not nearly as sensitive and as specific as we would like”

Fine needle aspiration

Cytology results: 4 categories; inadequate specimen—requires repeat FNA or other assessment, such as operative removal; malignant results—require operative removal; benign results—require follow-up; ≤5% risk for false negative; reassess patient at 6 and 12 mo; if lesion stable, primary care physician can follow patient; indeterminate results—most challenging; cytologist’s judgment should figure prominently in treatment plan; nuclear scan may eliminate ≈10% of patients with “hot” nodules; proportion of nodules found to be malignant increasing, due in part to greater use of US; 8% to 15% risk that nodule >1 cm malignant; unclear whether all thyroid cancers require treatment

National Cancer Institute (NCI) recommendations: based on year-long effort to develop standard criteria for describing thyroid nodular cytology; concluded that FNA indicated for any nodule with suspicious features on US; also consider for FNA lesions with mean diameter >1 to 1.5 cm; for patients with multiple nodules, speaker suggests aspirating dominant one plus ≥1 other most suspicious nodules; risk for malignancy ≈10% among incidentalomas found via US; US indicated whenever nodule suspected; sonographically suspicious features include microcalcifications, hypoechoic solid nodules, irregular or lobulated margins, intranodular vascularity, and nodal metastases

Incidental nodules: ≈1 in 3 incidental nodules found on positron emission tomography (PET) are papillary thyroid cancers; seen on 2% to 3% of PET performed for other reasons; risk for malignancy 14% to 50% in published literature; usually primary rather than metastatic disease; focal uptake suspicious, but diffuse uptake is not; US indicated for incidentalomas found on computed tomography (CT) or magnetic resonance imaging (MRI); incidentalomas detected on 16% of CT or MRI of neck (10% of those malignant)

FNA guidance: US usually recommended over palpation; “almost no reason” to perform palpation-guided FNA of thyroid nodules; US associated with lower risk for nondiagnostic FNA; contraindications to palpation guidance— nonconfirmatory US; presence of large cystic component; previous nondiagnostic result; altered neck anatomy due to previous illness or surgery

Proposed NCI changes for reporting FNA results (Bethesda terminology): definitions unchanged for nondiagnostic, benign, and malignant results; cyst fluid findings—may be diagnostic of benign cyst; follicular cells of undetermined significance—associated with low-risk lesion; Hürthle cells present with other cell types suggestive of Hashimoto’s disease; follicular neoplasm—sheets of follicular cells with no inflammatory cells; risk for malignancy, 20% to 30%; Hürthle cell neoplasm—diagnosed when only or mostly Hürthle cells present; risk for malignancy, 20% to 33%; suspicious for malignancy—some features of papillary or medullary cancer present, but not enough for definitive diagnosis; risk for malignancy at least as high as 20% to 33%; implies need for measuring calcitonin; suspicious for follicular neoplasm—follicular cells appear atypical but not malignant; lobectomy usually required for definitive diagnosis; risk for malignancy low, but higher than for benign lesions; repeat FNA often changes classification (recommended before diagnostic lobectomy)

Primary Hyperparathyroidism

Causes of hypercalcemia: most common causes primary hyperparathyroidism or humoral hypercalcemia of malignancy; only causes of simultaneous hypercalcemia and hyperparathyroidemia are primary hyperparathyroidism and familial hypocalciuric hypercalcemia (FHH); all other causes of hyperparathyroidism associated with low levels of parathyroid hormone (PTH; gland normal but hypercalcemia suppresses activity); 24-hr urine calcium may determine if patient has FHH; other helpful tests include measurements of serum creatinine and serum levels of vitamin D, and bone mineral density (BMD); today, diagnosis easier than it was 15 to 20 yr ago, due to availability of reliable serum PTH test

Primary hyperparathyroidism: defined as inappropriately high level of PTH in setting of normal or high level of ionized calcium; combination diagnostic; incidence 50-100/100,000 people per year; ≈50,000 new cases in United States annually; more common in women than men; risk increases after menopause to 2/1000 women >60 yr of age; most cases now detected with routine multichannel blood tests before symptoms develop; natural history of untreated asymptomatic hyperparathyroidism—in study of 121 patients, 61 eventually underwent surgery; serum calcium, PTH levels, and urinary calcium normal at 1- and 10-yr follow-up; patients experienced prompt sustained increase in bone density; of 52 unoperated patients who were followed, 8 developed kidney stones; serum hypercalcemia and hyperparathyroidemia persisted but did not worsen; hypercalciuria improved when managed with bisphosphonates; 14 patients developed symptoms requiring surgery; 11 patients experienced BMD decrease >10%; conclusion—without surgical intervention, patients’ conditions worsen (but not markedly and without dramatic effect on quality of life); some (but not all) develop indications requiring surgery

Case: 69-yr-old man; 5-yr history of biochemical hypoparathyroidism; recent history—diagnosed and followed by primary care physician; complaints of hip pain and weakness in legs; 1 mo before presentation, patient developed kidney stone, which passed spontaneously; status upon presentation—patient exhibits “diseases of the well- cared-for” (hypercholesterolemia, hypertension, gastroesophageal reflux disease [GERD], and depression); minimal past surgical history; no family history of hyperparathyoidism; no unhealthy habits; physical examination— unrevealing (no palpable neck mass); laboratory studies—elevated serum calcium (10.9 mg/dL); elevated intact PTH levels (235 pg/mL); elevated C-terminal PTH (630 pg/mL); calculated creatinine clearance (65 mL/min); decision on whether to treat—in this case, need for surgical intervention clear, due to evidence of kidney stone

Recommended approach to asymptomatic patient: guidelines developed in 1990 at consensus conference held at National Institutes of Health (NIH); these guidelines updated in 2002 at NIH state-of-the-science conference; indications for intervention include significant hypercalcemia (≥1 mg/dL above normal for given laboratory); 24-hr urine calcium >400 mg/day (surrogate for bone loss); 30% reduction in creatinine clearance; abnormal serum creatinine; BMD indicative of osteoporosis (T-score [bone density compared to population with peak BMD {people in their twenties}; good correlation with fracture risk] <-2.5); age <50 yr, due to concerns about long-term effects (eg, risk to bones, cardiovascular disease, potential malignancies) of untreated hyperparathyroidism; guidelines for nonoperative follow-up—semiannual measurement of calcium; annual measurements of serum creatinine and BMD

Treatment: conventional parathyroidectomy associated with failure rate of 4% to 10%, as well as low rate of complications; today, preferred treatment directed parathyroidectomy (takes advantage of advances in preoperative localization, and ability to measure PTH intraoperatively [helps determine when to conclude surgery] and makes procedure less invasive]); speaker’s practice to measure PTH just before surgery, then 10 and 15 min after gland removal; he considers decline in PTH of 50% and into normal range predictive of postoperative normocalcemia (various algorithms can be used; speaker considers his fairly conservative); most patients have single adenoma and can be treated with local anesthetic in outpatient surgery center; advantages over open surgery—fewer frozen sections, decreased hospital costs, and smaller incision; resolution of hyperparathyroidism physiologic marker for cure; patients prefer less invasive surgery

Preoperative localization of parathyroid gland: technetium Tc99m sestamibi scan most common technique; however, less accurate when abnormal glands small; when scan definitive, median weight of abnormal glands 920 mg; if scan indeterminate, median weight 426 mg; with negative scan, median weight 340 mg; therefore, smaller the gland, less likely the results of sestamibi scan positive; high -resolution US also used; visible gland sufficient indication for surgery; sensitivity of both techniques 70% to 80%; US misses large glands that slide posteriorly along esophagus or under sternum (but good for finding smaller glands); sestamibi misses smaller glands that remain next to thyroid (good for detecting ectopic glands)

Case (continued): definitive imaging—sestamibi scan (delayed image) detects clear left-sided parathyroid gland; via US, large hypoechoic parathyroid gland visible at lower end of left lower pole of thyroid; operative course— typical; patient taken to OR, sedated, and given superficial cervical block; surgeon makes 1-in incision in lower midline (part of thyroid incision); very large (≈2 g) left lower parathyroid gland removed; patient’s baseline PTH 335 pg/mL, and after 10 min dropped to 29 pg/mL; take-home points—resolution of parathyroid disease expected; surgeon does not have to look at 3 other glands to know they are normal; pathology results show benign hypercellular parathyroid gland