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 36-year-old woman presents with thyroid swelling. She has been healthy until now and follows all the healthcare precautions except for missing a flu shot this year. On physical examination, the thyroid gland is diffusely enlarged and tender to palpation. Laboratory findings show a decreased serum TSH level and elevated erythrocyte sedimentation rate. Which of the following histopathologic findings would most likely be found in the thyroid gland of this patient?

Mixed cellular infiltration with multinuclear giant cells

Extensive fibrosis of the stroma

Lymphocytic infiltration with germinal centers

Orphan Annie nuclei with psammoma bodies

Sheets of polygonal cells in amyloid stroma

A 55-year-old woman comes to the physician because of a 4-month history of a painless lump on her neck. Examination shows a hard nodule on the left side of her neck. A fine-needle aspiration biopsy shows well-differentiated cuboidal cells arranged spherically around colloid. She undergoes thyroidectomy. Histopathological examination of the surgical specimen shows invasion of the thyroid capsule and blood vessels. Which of the following cellular events is most likely involved in the pathogenesis of this patient's condition?

PAX8-PPAR gamma gene rearrangement

Activation mutation in the BRAF gene

Mutation in the RET proto-oncogene

p53 tumor suppressor gene inactivation

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

A 21-year-old male college student is very anxious about having thyroid cancer as he found a lump in his neck a few days ago. He has also had diarrhea and a feeling of warmth on his face for 3 days now. His father and uncle both have been diagnosed with thyroid cancer. The lump is about 1 cm in diameter and is fixed and nontender on palpation. Physical examination is otherwise unremarkable. Ultrasound shows a non-cystic cold nodule that requires fine needle aspiration for diagnosis. Thyroid functions tests are normal, and his calcitonin level is 346 ug/ml. Which of the following genetic mutations would warrant thyroidectomy in this patient?

Down expression of the Ras protooncogene

Activating mutation of the BRAF gene

A 24-year-old man comes to the physician because of 2 episodes of bleeding from the rectum over the past month. The patient’s father died of colon cancer at the age of 42. The patient has no history of any serious illness and takes no medications. He does not smoke. His vital signs are within normal limits. Physical examination shows a small hard mass over the right mandible that is nontender and fixed to the underlying bone. A similarly hard and painless 5 × 5 mass is palpated over the rectus abdominis muscle. On examination of the rectum, a polypoid mass is palpated at fingertip. Proctosigmoidoscopy shows numerous polyps. Which of the following best explains these findings?

Familial polyposis of the colon

Thyroid neoplasms for USMLE Step 2 CK: High-Yield Pathology Lessons

Thyroid Neoplasms - An Overview

Evaluation: Most nodules require ultrasound-guided Fine-Needle Aspiration (FNA) to rule out malignancy.
Types (most to least common):
- Papillary: Most common, excellent prognosis. Orphan Annie eye nuclei, psammoma bodies.
- Follicular: Hematogenous spread is common.
- Medullary: Arises from parafollicular C-cells; produces calcitonin.
- Anaplastic: Rare, highly aggressive, dismal prognosis.

⭐ High-Yield: Medullary thyroid cancer is associated with RET proto-oncogene mutations and Multiple Endocrine Neoplasia (MEN) syndromes 2A and 2B.

Ultrasound-guided fine-needle aspiration of thyroid nodule

Papillary Carcinoma - Popular Papillae

Most common thyroid cancer (80-85%), excellent prognosis.
Risk factors: Prior radiation exposure (childhood), family history.
Spreads via lymphatics (cervical nodes), but prognosis remains good.

Papillary Thyroid Carcinoma with Orphan Annie Eye Nuclei

Histology:
- Branching papillae with a fibrovascular stalk.
- Orphan Annie eye nuclei: Empty-appearing nuclei, chromatin clearing.
- Psammoma bodies: Laminated, concentric calcifications.
- Nuclear grooves (coffee-bean appearance).

⭐ High-Yield: BRAF V600E mutation is a common driver and is associated with a poorer prognosis.

📌 Mnemonic: "Papi and Moma adopted Orphan Annie" (Papillae, Psammoma bodies, Orphan Annie nuclei).

Follicular Carcinoma - Far-Flung Follicles

Epidemiology: Second most common thyroid cancer; linked to iodine deficiency.
Pathogenesis: Associated with RAS mutations.
Histology: Uniform follicles. Diagnosis requires capsular or vascular invasion; cannot be determined by FNA.
Spread: Hematogenous (bloodstream) spread is characteristic.
- Distant metastases are common (bone, lungs).
- 📌 Follicular Carcinoma Flies Far.
Prognosis: Generally good, but worsens with extensive invasion.

⭐ Fine Needle Aspiration (FNA) cannot distinguish follicular adenoma from carcinoma. The diagnosis requires histologic evidence of capsular or vascular invasion from an excised specimen.

Medullary & Anaplastic - C-Cells & Chaos

Medullary Carcinoma (15-20%)
- From parafollicular C-cells; secretes calcitonin.
- Histo: Nests of polygonal cells in an amyloid stroma (Congo red positive).
- Associated with MEN 2A/2B syndromes (RET proto-oncogene).
- 📌 Medullary = MEN.
Anaplastic Carcinoma (<5%)
- Highly aggressive, undifferentiated tumor in elderly (>65y).
- Dismal prognosis; rapidly fatal.
- Histo: Pleomorphic giant cells.
- Often arises from pre-existing goiter or follicular neoplasm.

⭐ Prophylactic thyroidectomy is recommended for children with RET mutations (MEN2) to prevent aggressive medullary carcinoma.

High‑Yield Points - ⚡ Biggest Takeaways

Papillary carcinoma is the most common thyroid cancer, featuring "Orphan Annie eye" nuclei and psammoma bodies.

Follicular carcinoma spreads hematogenously and is defined by capsular or vascular invasion.

Medullary carcinoma arises from parafollicular C-cells, produces calcitonin, and is linked to MEN 2 (RET oncogene).

Anaplastic carcinoma is a highly aggressive tumor in the elderly with a dismal prognosis.

Fine-needle aspiration (FNA) is the best initial diagnostic test for any thyroid nodule.

Key mutations include BRAF (papillary), RAS (follicular), and RET (medullary).

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