Question 1

A 34-year-old woman presents with a painless neck mass that has been enlarging for 3 months. Fine-needle aspiration is performed. The aspirate shows cohesive clusters of follicular cells arranged in microfollicular and trabecular patterns. The nuclei are round to oval with evenly distributed chromatin, smooth nuclear membranes, and no grooves or intranuclear inclusions. No psammoma bodies are identified. A well-encapsulated follicular neoplasm is subsequently resected. Which of the following additional histological features would most reliably confirm malignancy in this lesion rather than indicating a benign follicular adenoma?

Accepted Answer

Capsular invasion with tumor cells penetrating through the full thickness of the fibrous capsule. ***Capsular invasion with tumor cells penetrating through the full thickness of the fibrous capsule***
- **Follicular carcinoma** and **follicular adenoma** cannot be distinguished by fine-needle aspiration (FNA) or cytology alone; both present as follicular neoplasms with similar cellular features.
- The diagnostic hallmark of **follicular carcinoma** is the presence of **capsular invasion** (full-thickness) or **vascular invasion**, which are absent in benign adenomas.

*Presence of more than three mitotic figures per ten high-power fields within follicular cells*
- While increased **mitotic activity** may be present in malignancies, it is not a reliable or definitive criterion to distinguish follicular carcinoma from adenoma.
- Benign **follicular adenomas** can occasionally show cellular atypia and mitoses without being invasive or malignant.

*Colloid-filled follicles of varying sizes with flattened lining epithelium*
- This description is more characteristic of a **multinodular goiter** or a macrofollicular adenoma, which are typically benign processes.
- **Follicular carcinoma** usually exhibits a microfollicular or solid growth pattern with scant **colloid** rather than large colloid-filled spaces.

*Hurthle cell metaplasia with abundant granular eosinophilic cytoplasm*
- **Hurthle cells** (oncocytes) are found in various conditions, including **Hashimoto thyroiditis**, multinodular goiter, and benign Hurthle cell adenomas.
- The presence of these cells does not confirm malignancy; **Hurthle cell carcinoma** also requires evidence of capsular or vascular invasion for diagnosis.

*Lymphocytic infiltration of the stroma with germinal center formation*
- This is a classic feature of **Hashimoto thyroiditis** (chronic lymphocytic thyroiditis), an autoimmune condition.
- While chronic inflammation is associated with certain thyroid risks, it is not a feature used to diagnose **follicular carcinoma**. [Practice more Pathology questions on OnCourse]

Question 2

A 67-year-old man with a 30-year history of alcohol use disorder presents with jaundice, ascites, and a serum AFP of 620 ng/mL. Abdominal MRI shows a 5 cm arterially enhancing hepatic mass with washout on portal venous phase. A liver biopsy from the mass is performed. The photomicrograph shows trabeculae of large polygonal cells with abundant granular eosinophilic cytoplasm, prominent nucleoli, and intracytoplasmic hyaline globules; adjacent non-tumoral liver shows bridging fibrosis and regenerative nodules. Mallory-Denk bodies are identified in some tumor cells. Which of the following findings, if present, would most specifically distinguish this lesion from a benign hepatocellular adenoma in this biopsy?

Accepted Answer

Stromal or vascular invasion with loss of normal reticulin framework. ***Stromal or vascular invasion with loss of normal reticulin framework***
- The most definitive histological feature of **hepatocellular carcinoma (HCC)** distinguishing it from an adenoma is the presence of **vascular invasion** or stromal infiltration.
- A **reticulin stain** revealing a disrupted or **absent reticulin framework** in trabeculae thicker than three cells is a hallmark of malignancy in the liver.

*Presence of Mallory-Denk bodies within hepatocyte cytoplasm*
- **Mallory-Denk bodies** are inclusions of damaged intermediate filaments commonly seen in **alcoholic liver disease** and can appear in both benign and malignant liver lesions.
- While present in this case of **HCC**, they are not specific for malignancy and can be found in various non-neoplastic conditions like **Wilson's disease**.

*Trabecular growth pattern with sinusoidal vascular channels*
- A **trabecular growth pattern** is a common architecture in normal liver parenchyma and is frequently maintained in **hepatocellular adenomas**.
- While HCC often exhibits wider trabeculae, the mere presence of a trabecular arrangement is not specific enough to exclude a **benign adenoma**.

*Elevated Ki-67 proliferation index above 5% in tumor cells*
- An elevated **Ki-67 index** indicates increased cellular turnover, which can be seen in aggressive **HCC**, but it lacks the specificity to be the sole diagnostic criterion.
- Overlap exists between the proliferation rates of high-grade **adenomas** and well-differentiated carcinomas, making it less reliable than **architectural invasion**.

*Cytoplasmic bile production within the neoplastic hepatocytes*
- The ability to produce **bile** is a functional characteristic of hepatocytes and can be preserved in well-differentiated **HCC**.
- Because **hepatocellular adenomas** are also derived from hepatocytes, they can produce bile, making this feature useless for distinguishing between benign and malignant status. [Practice more Pathology questions on OnCourse]

Question 3

A 67-year-old man with longstanding poorly controlled type 2 diabetes mellitus and hypertension undergoes renal biopsy for nephrotic-range proteinuria and progressive renal insufficiency. He is also known to have longstanding diabetic retinopathy, and immunofluorescence staining for monoclonal light chains is negative. The photomicrograph of a PAS-stained section shows glomeruli with expanded mesangium containing ovoid, homogeneous, PAS-positive nodular deposits situated at the periphery of the glomerular tuft, compressing the adjacent capillary loops. The deposits stain negatively with Congo red. Which of the following best describes the composition and pathogenesis of these nodular deposits?

Accepted Answer

Mesangial matrix glycoprotein accumulation driven by chronic hyperglycemia-induced TGF-β overexpression. ***Mesangial matrix glycoprotein accumulation driven by chronic hyperglycemia-induced TGF-β overexpression***
- The description of **PAS-positive**, **Congo red-negative** nodular deposits at the glomerular periphery is characteristic of **Kimmelstiel-Wilson nodules** seen in **diabetic nephropathy**.
- Chronic hyperglycemia stimulates **TGF-β**, leading to excessive synthesis of **mesangial matrix** proteins like collagen and fibronectin, which eventually form these pathognomonic nodules.
*Amyloid fibril deposition from systemic AL amyloidosis secondary to a plasma cell dyscrasia*
- **Amyloidosis** can present with nodular glomerular deposits, but these would be **Congo red-positive** with apple-green birefringence under polarized light.
- This patient's deposits are specifically noted as **staining negatively with Congo red**, which excludes amyloid.
*Immune complex deposition from circulating anti-GBM antibodies causing membranoproliferative change*
- **Anti-GBM disease** typically presents with a **crescentic glomerulonephritis** and linear IgG staining on immunofluorescence, not peripheral nodules.
- This patient has **nephrotic-range proteinuria** and a classic history of diabetes, making a chronic degenerative process more likely than an acute autoimmune one.
*Fibrin thrombi within mesangial nodules resulting from thrombotic microangiopathy*
- **Thrombotic microangiopathy** involves endothelial injury, microvascular thrombi, and **schistocytes**, often manifesting as acute kidney injury.
- While it can cause basement membrane thickening, it does not typically result in the organized, **PAS-positive nodular glomerulosclerosis** seen here.
*Monoclonal immunoglobulin light-chain deposition disease causing non-amyloid nodular glomerulosclerosis*
- This condition mimics diabetic nodules but is associated with **plasma cell dyscrasias** and would show **monoclonal light chain staining** (kappa or lambda) on immunofluorescence.
- The scenario explicitly states that **immunofluorescence for monoclonal light chains is negative**, and the presence of **diabetic retinopathy** strongly favors a diabetic etiology. [Practice more Pathology questions on OnCourse]

Question 4

A 58-year-old man presents with progressive exertional dyspnea and a dry cough over 8 months. He worked in shipbuilding for 25 years. A chest radiograph shows bilateral lower-lobe reticular opacities and pleural plaques. A transbronchial biopsy is performed. The biopsy reveals dense interstitial fibrosis with golden-brown, beaded, dumbbell-shaped structures within alveolar macrophages that stain positively with Prussian blue. Which of the following best describes the pathological significance of the structures identified in this biopsy?

Accepted Answer

They represent iron-coated mineral fibers and indicate significant fiber burden but do not independently predict malignant transformation. ***They represent iron-coated mineral fibers and indicate significant fiber burden but do not independently predict malignant transformation***
- The description of **golden-brown, beaded, dumbbell-shaped structures** represents **asbestos bodies** (ferruginous bodies), which are asbestos fibers coated with **iron-protein complexes** that stain with **Prussian blue**.
- While they confirm significant exposure and are markers of **asbestosis** when associated with fibrosis, their presence is a marker of **exposure burden** and not a direct cellular predictor of cancer development.

*They are composed of calcium oxalate deposits and are a nonspecific finding in chronic granulomatous lung disease*
- Calcium oxalate crystals are typically associated with **Schäubermann bodies** or found in diseases like **sarcoidosis**, presenting with a different morphology from the dumbbell shapes seen here.
- These deposits are not associated with **shipbuilding** or **Prussian blue-positive** ferruginous coatings.

*They represent inspissated mucus mixed with hemosiderin and are characteristic of allergic bronchopulmonary aspergillosis*
- **Allergic bronchopulmonary aspergillosis (ABPA)** typically presents with **Curschmann spirals** or fungal hyphae, not iron-coated mineral fibers.
- ABPA is associated with **asthma** and **eosinophilia**, which differ from the restrictive pattern and occupational history of this patient.

*They are dystrophic calcifications within necrotic macrophages and indicate prior mycobacterial infection*
- Dystrophic calcification in mycobacterial disease usually forms **Ghon complexes** or scattered calcified granulomas, not microscopic beaded fibers.
- **Prussian blue** specifically stains iron, whereas calcifications are identified with **von Kossa** or Alizarin Red stains.

*They represent fragmented elastic fibers coated with calcium and iron and are pathognomonic for pulmonary sarcoidosis*
- Fragmented fibers coated with iron and calcium are known as **Gamna-Gandy bodies** (seen in the spleen) or **perivascular calcifications**, not dumbbell-shaped alveolar structures.
- **Sarcoidosis** is characterized by **non-caseating granulomas** and **asteroid bodies**, whereas this case fits an occupational history of **asbestos exposure**. [Practice more Pathology questions on OnCourse]

Question 5

A 42-year-old man who recently immigrated from Mexico presents to the clinic with fever, a productive cough streaked with blood, back pain, and night sweats. He was found to be HIV-positive 3 years ago but does not know his most recent CD4+ count. With further questioning, the patient notes that he had previously experienced these symptoms when he was in Mexico, but he has no recollection of taking any treatment. Which of the following characteristics would best describe the histology of a lung biopsy specimen obtained from this patient?

Accepted Answer

Epithelioid cells with caseous necrosis surrounded by multinucleated giant cells and lymphocytes. ***Epithelioid cells surrounded by multinucleated giant cells and lymphocytes***
- The patient's symptoms (fever, productive cough with hemoptysis, back pain, night sweats, HIV-positive status, and history of similar symptoms in Mexico) are highly suggestive of **reactivation tuberculosis (TB)**.
- The characteristic histological finding in **tuberculosis** is **caseating granulomas**, which are composed of epithelioid cells (activated macrophages) surrounded by lymphocytes and multinucleated giant cells (Langhans giant cells), with a central area of **caseous necrosis**.

*Cells with increased nuclear-to-cytoplasmic ratio*
- This description is typical of **malignant cells**, such as those seen in carcinoma, which is not the primary presentation given the historical and symptomatic context pointing towards infection.
- While lung cancer could cause some of these symptoms, the history of previous episodes and HIV points more strongly to an infectious etiology like TB.

*Noncaseating granuloma*
- **Noncaseating granulomas** are characteristic of diseases like **sarcoidosis** or **Crohn's disease**, which typically do not present with the described constitutional symptoms (e.g., night sweats) and hemoptysis in this context, especially with a history of HIV and prior infection.
- The presence of caseous necrosis is a key differentiator for tuberculosis granulomas.

*Cellular debris and macrophages followed by cystic spaces and cavitation*
- This describes the histological features of a **lung abscess** or extensive tissue destruction, which can be a complication of TB but is not the primary defining characteristic of the initial granuloma formation.
- While TB can lead to cavitation, the initial and most specific histological feature in active TB is the granulomatous inflammation.

*Macrophage filled with fungal microorganisms*
- This finding would suggest a **fungal infection** such as histoplasmosis or cryptococcosis, which can occur in HIV-positive individuals and present with similar symptoms.
- However, the strong clinical picture of prior similar illness in Mexico (an endemic area for TB), systemic symptoms, and hemoptysis, makes TB a more probable diagnosis, which is characterized by granulomas rather than direct macrophage colonization by fungi. [Practice more Pathology questions on OnCourse]

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