A 36-year-old woman comes to the physician for a follow-up visit after she had a PET scan that showed a nodule on the thyroid gland. She has no difficulty or pain while swallowing. She was treated for non-Hodgkin lymphoma at the age of 28 years, which included external beam radiation to the head and neck and 4 cycles of chemotherapy. She appears healthy. Vital signs are within normal limits. Physical examination shows no abnormalities. Serum studies show: Glucose 82 mg/dL Creatinine 0.7 mg/dL Thyroid-stimulating hormone 3 μU/mL Ultrasound of the neck shows a 1.2-cm (0.5-in) nodule on the left lobe of the thyroid with irregular margins and microcalcifications. A fine-needle aspiration biopsy shows Psammoma bodies and cells with clear, ground-glass, empty nuclei. Which of the following is the most appropriate next step in management?

Observation and follow-up in 3 months

A 74-year-old retired female teacher is referred to the endocrinology clinic. She is very concerned about a large mass in her neck that has progressively enlarged over the past 2 weeks. She also reports a 15 pound weight loss over the last 3 months. She now has hoarseness and difficulty swallowing her food, giving her a sensation that food gets stuck in her windpipe when she swallows. There is no pain associated with swallowing. Her speech is monotonous. No other gait or language articulation problems are noted. Testing for cranial nerve lesions is unremarkable. On palpation, a large, fixed and non-tender mass in the thyroid is noted. Cervical lymph nodes are palpable bilaterally. The patient is urgently scheduled for an ultrasound-guided fine needle aspiration to guide management. Which of the following is the most likely gene mutation to be found in this mass?

Inactivating mutation of the p53 tumor suppressor gene

Activating mutation of the Ras protooncogene

A 44-year-old woman comes to the physician for the evaluation of a 1-month history of fatigue and difficulty swallowing. During this period, she has also had dry skin, thinning hair, and rounding of her face. She has type 1 diabetes mellitus and rheumatoid arthritis. Her father had a thyroidectomy for papillary thyroid cancer. The patient had smoked one pack of cigarettes daily for 20 years but quit 3 years ago. She drinks 2–3 glasses of wine daily. Her current medications include insulin, omeprazole, and daily ibuprofen. She appears well. Her temperature is 36.3°C (97.3°F), pulse is 62/min, and blood pressure is 102/76 mm Hg. Examination of the neck shows a painless, diffusely enlarged thyroid gland. Cardiopulmonary examination shows no abnormalities. Further evaluation is most likely to show which of the following?

Positive thyroid peroxidase antibodies and thyroglobulin antibodies in serum

Diffusely increased uptake on a radioactive iodine scan

Increased uptake on radioactive iodine scan in discrete 1-cm area

Large irregular nuclei, nuclear grooves, and Psammoma bodies on thyroid biopsy

Positive immunohistochemical stain for calcitonin on thyroid biopsy

A previously healthy 39-year-old woman comes to the physician because of a slowly enlarging, painless neck mass that she first noticed 3 months ago. During this period, she has also experienced intermittent palpitations, hair loss, and a weight loss of 4.5 kg (10 lb). There is no personal or family history of serious illness. She appears anxious and fidgety. Her temperature is 37.1°C (98.8°F), pulse is 101/min and irregular, respirations are 16/min, and blood pressure is 140/90 mm Hg. Physical examination shows a firm, nontender left anterior cervical nodule that moves with swallowing. Laboratory studies show: TSH 0.4 μU/mL T4 13.2 μg/dL T3 196 ng/dL Ultrasonography confirms the presence of a 3-cm solid left thyroid nodule. A thyroid 123I radionuclide scintigraphy scan shows increased uptake in a nodule in the left lobe of the thyroid gland with suppression of the remainder of the thyroid tissue. Which of the following is the most likely underlying mechanism of this patient's condition?

Gain-of-function mutations of the TSH receptor

Thyroglobulin antibody production

Activation of oncogenes promoting cell division

Persistent TSH stimulation and heterogeneous thyroid tissue hyperplasia

Thyroid peroxidase autoantibody-mediated destruction of thyroid tissue

A 47-year-old woman comes to the physician because of a 2-month history of a lump on her neck and a 1-week history of hoarseness. Examination shows a 3-cm, firm, non-tender nodule on the anterior neck. Further evaluation confirms a thyroid malignancy, and she undergoes thyroidectomy. Histopathologic examination of the surgical specimen shows lymphatic invasion. Genetic analysis shows an activating mutation in the RET/PTC genes. Microscopic examination of the surgical specimen is most likely to also show which of the following?

Calcified spherules and large oval cells with empty-appearing nuclei

Pleomorphic giant cells with numerous atypical mitotic figures

Cuboidal cells arranged spherically around colloid lakes

Hyperplastic epithelium with colloid scalloping

Sheets of polygonal cells surrounding amyloid deposition

Thyroid nodules and cancer for USMLE Step 1: High-Yield Internal Medicine Lessons

Nodule Workup - Spot the Suspect

Initial Test: TSH level. If normal/high → Ultrasound. If low → Radionuclide Scan.
Ultrasound (US): Key for risk stratification. Suspicious features prompting Fine Needle Aspiration (FNA):
- Hypoechogenicity
- Microcalcifications
- Irregular margins
- Taller-than-wide shape
- Chaotic internal vascularity
FNA Biopsy: Most accurate step to rule out cancer for US-suspicious or large nodules.

Ultrasound features of suspicious thyroid nodules

⭐ On a radionuclide scan, "cold" nodules (non-functional) are more likely to be malignant (~15-20% risk) compared to "hot" nodules (hyper-functioning), which are almost always benign.

The Biopsy Guide - Bethesda System

Standardizes reporting of thyroid fine-needle aspiration (FNA) results.

⭐ Papillary thyroid cancer is the most common type, often diagnosed in Bethesda V and VI categories. It has an excellent prognosis.

Cancer Types - The Malignant Quartet

Papillary (Most common, ~85%)
- Prognosis: Excellent.
- Histology: Psammoma bodies, Orphan Annie eye nuclei (intranuclear grooves).
- Spread: Lymphatic.
Follicular (~10%)
- Prognosis: Good.
- Histology: Invasion of capsule and/or blood vessels is key to diagnosis.
- Spread: Hematogenous. 📌 Follicular Follows veins.
Medullary (~3%)
- Prognosis: Fair.
- Histology: Arises from parafollicular C-cells; amyloid stroma (Congo red positive).
- Markers: Produces ↑ Calcitonin.
Anaplastic (<1%)
- Prognosis: Dismal; rapidly fatal.
- Presentation: Older patients, rapidly enlarging neck mass.

⭐ Exam Favorite: Medullary carcinoma is associated with Multiple Endocrine Neoplasia (MEN) types 2A and 2B due to mutations in the RET proto-oncogene.

Thyroid Cancer Histology Composite

Treatment & Monitoring - The Long Game

Surgery: Total or near-total thyroidectomy is the primary treatment.
Radioactive Iodine (RAI): Post-op ablation for remnant tissue, especially in high-risk cases (large tumors, mets).
TSH Suppression: High-dose levothyroxine to suppress TSH, inhibiting growth of potential residual cells. Target TSH is often <0.1 mU/L.
Monitoring: Regular checks of Thyroglobulin (Tg) levels and neck ultrasound.

⭐ Post-total thyroidectomy, Thyroglobulin (Tg) is an excellent tumor marker. A rising Tg level strongly suggests recurrence.

High‑Yield Points - ⚡ Biggest Takeaways

The best initial test for a thyroid nodule is TSH. If low, a radionuclide scan is next to check for a “hot” nodule.

Fine-Needle Aspiration (FNA) is the most accurate test for nodules in euthyroid or hypothyroid patients.

Papillary carcinoma is the most common type, characterized by Orphan Annie eye nuclei and psammoma bodies.

Medullary carcinoma arises from parafollicular C-cells, produces calcitonin, and is associated with MEN 2A/2B.

Anaplastic carcinoma typically affects the elderly, presenting as a rapidly enlarging, firm neck mass.

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