Part 2: 5 Advanced-Level MCQs
Below are five more challenging MCQs integrating multiple advanced concepts from the excerpt. Each MCQ has at least two answer choices that are “close” or tricky.
MCQ 1 (Scenario + Critical Analysis)
Question
A 58-year-old patient with a known low-grade (G2) pancreatic neuroendocrine tumor (PNET) presents with slowly enlarging liver metastases. Imaging confirms somatostatin receptor (SSTR) avid lesions on 68Ga-DOTATATE PET/CT, and the patient has mild flushing symptoms that began a few weeks ago. The patient has never received systemic therapy. Based on current understanding and guidelines, which of the following best reflects the initial treatment approach to slow disease progression and address mild symptoms?
Answer Choices
A. Start sunitinib plus high-dose proton-pump inhibitors (PPIs).
B. Begin octreotide LAR or lanreotide to address both symptoms and tumor growth.
C. Administer platinum-based chemotherapy (cisplatin/etoposide).
D. Proceed immediately with liver transplantation due to metastatic disease.
Correct Answer: B. Begin octreotide LAR or lanreotide to address both symptoms and tumor growth.
Explanation
- Why B is correct: Somatostatin analogs (SSAs) such as octreotide LAR or lanreotide are first-line in well-differentiated, SSTR-positive PNETs. They can help control hormone-mediated symptoms and have shown antiproliferative benefits in low- and intermediate-grade disease.
- Why A is incorrect: Sunitinib is an approved targeted therapy for advanced PNETs, but SSAs are typically introduced earlier, particularly in patients with functional symptoms and SSTR-avid tumors. PPIs alone target gastric acid hypersecretion (more relevant in gastrinomas or Zollinger-Ellison syndrome), not mild flushing.
- Why C is incorrect: Platinum-based chemotherapy is more common in high-grade neuroendocrine carcinomas or poorly differentiated disease. This patient has a G2 well-differentiated tumor.
- Why D is incorrect: Liver transplantation is rarely performed as initial therapy in PNET metastatic disease due to limited donor availability and the possibility of other effective medical or surgical interventions.
Key Takeaways (4–5 sentences)
Somatostatin analog therapy is often the first-line approach for SSTR-positive, low- to intermediate-grade PNETs when symptomatic or progressive disease arises. These agents can stabilize tumor growth and alleviate clinical symptoms of hormone excess. For well-differentiated PNETs, other therapies like targeted agents (e.g., sunitinib, everolimus) or peptide receptor radionuclide therapy (PRRT) may be considered in subsequent lines. High-grade or poorly differentiated neuroendocrine carcinomas usually require platinum-based chemotherapy.
Reference
Blumgart's Surgery of the Liver, Biliary Tract and Pancreas, 7th edition,
Chapter 65: "Pancreatic neuroendocrine tumors: Classification, clinical picture, diagnosis, and therapy,"
Subtopic: "Nonsurgical Management / Somatostatin Analogs," pp. 903–912
MCQ 2 (All are true EXCEPT…)
Question
All of the following statements regarding surgical management of pancreatic neuroendocrine tumors (PNETs) with familial syndromes are true EXCEPT:
Answer Choices
A. In MEN1, multiple small tumors often necessitate a combined approach with distal pancreatectomy and enucleation of head lesions.
B. Aggressive resection of a gastrinoma larger than 2 cm in MEN1 is generally recommended to reduce the risk of liver metastases.
C. In von Hippel-Lindau (VHL), surgical resection is indicated for pancreatic lesions ≥3 cm or showing significant growth.
D. In MEN1, complete pancreatectomy is always indicated to prevent any possibility of PNET recurrence.
Correct Answer: D. In MEN1, complete pancreatectomy is always indicated to prevent any possibility of PNET recurrence.
Explanation
- Why D is incorrect (and the correct choice in an “EXCEPT” question): Complete pancreatectomy is not always performed in MEN1 patients because it leads to significant morbidity (brittle diabetes, exocrine insufficiency). A more selective approach—distal resection and enucleation of any head lesions—is often used instead.
- Why A is correct: In MEN1 with multiple small PNETs, surgeons frequently remove the distal pancreas and enucleate smaller tumors in the head/uncinate process, balancing oncologic control with the risk of endocrine insufficiency.
- Why B is correct: MEN1 gastrinomas larger than 2 cm carry a higher risk of metastases, prompting more aggressive resection such as pancreaticoduodenectomy or wide local excision plus lymphadenectomy.
- Why C is correct: VHL-associated PNETs ≥3 cm or with rapid growth are generally resected to prevent metastatic spread; smaller stable lesions can be observed.
Key Takeaways (4–5 sentences)
Familial syndromes require a nuanced surgical approach for PNETs. MEN1 often involves multiple pancreatic lesions; thus, a combination of distal pancreatectomy and enucleation of smaller head lesions is frequently employed. Very aggressive surgery such as total pancreatectomy is avoided when possible due to its associated endocrine and exocrine complications. In contrast, VHL management relies on tumor size (commonly ≥3 cm) or growth rate to decide on resection, given the risk of metastatic spread.
Reference
Blumgart's Surgery of the Liver, Biliary Tract and Pancreas, 7th edition,
Chapter 65: "Pancreatic neuroendocrine tumors: Classification, clinical picture, diagnosis, and therapy,"
Subtopic: "Surgical Management & Familial Syndromes," pp. 903–912
MCQ 3 (Scenario + Controversy/Guidelines)
Question
A 66-year-old patient is diagnosed with a nonfunctional PNET in the tail of the pancreas measuring 1.5 cm, discovered incidentally on imaging for nonspecific abdominal pain. There is no evidence of lymph node involvement or distant metastases, and the Ki-67 index is 2%. The patient has significant comorbidities (including poorly controlled coronary artery disease). According to the latest controversies and data on small, nonfunctional PNETs, which of the following would be the most appropriate next step?
Answer Choices
A. Immediate distal pancreatectomy with splenectomy
B. Surveillance imaging at regular intervals and resect only if growth or symptoms develop
C. Start chemotherapy (temozolomide + capecitabine)
D. Endoscopic ultrasound-guided ablation of the lesion
Correct Answer: B. Surveillance imaging at regular intervals and resect only if growth or symptoms develop
Explanation
- Why B is correct: Current evidence suggests that nonfunctional PNETs under 2 cm, especially if low-grade (Ki-67 ≤2–3%), can be safely observed if the patient has significant surgical risks. Surveillance is reasonable, with resection reserved for tumors that show enlargement or become symptomatic.
- Why A is incorrect: While surgical resection is an option for small PNETs, immediate surgery in this patient with notable comorbidities may pose unnecessary risk if the lesion is clinically indolent.
- Why C is incorrect: Low-grade, small, nonfunctional PNETs are not routinely treated with chemotherapy unless they demonstrate progression or more aggressive features.
- Why D is incorrect: EUS-guided ablation is not standard for small nonfunctional PNETs; resection or observation are more common, evidence-based approaches.
Key Takeaways (4–5 sentences)
The management of small, nonfunctional PNETs is controversial; however, multiple studies suggest a watchful waiting approach is safe for stable lesions below 2 cm in low-risk patients. Surgery is still considered for larger or growing tumors. Treatment decisions hinge on tumor biology (grade, Ki-67), patient comorbidities, and the presence of any symptoms or progression. Surgical intervention must be balanced against operative risks, especially in older patients with significant comorbidities.
Reference
Blumgart's Surgery of the Liver, Biliary Tract and Pancreas, 7th edition,
Chapter 65: "Pancreatic neuroendocrine tumors: Classification, clinical picture, diagnosis, and therapy,"
Subtopic: "Surgical Management of Nonfunctional PNETs <2 cm," pp. 903–912
MCQ 4 (Interpretation / Genetics + Therapy)
Question
Next-generation sequencing (NGS) of a well-differentiated PNET in a 50-year-old patient reveals alterations in MEN1 and TSC2, as well as a high SSTR2 expression on functional imaging. After failing first-line somatostatin analog therapy (disease progression), the physician is deciding between a targeted mTOR inhibitor and peptide receptor radionuclide therapy (PRRT). Which factor would most strongly favor starting everolimus (an mTOR inhibitor) rather than proceeding to PRRT?
Answer Choices
A. A documented loss of MEN1 gene function
B. Multiple small liver metastases with a borderline low creatinine clearance
C. High SSTR2 expression on 68Ga-DOTATATE PET/CT
D. A Ki-67 index of <5% on tumor biopsy
Correct Answer: B. Multiple small liver metastases with a borderline low creatinine clearance
Explanation
- Why B is correct: PRRT can pose a significant risk of renal toxicity, and patients with reduced renal function (borderline low creatinine clearance) are at higher risk for long-term kidney damage. In such a scenario, an mTOR inhibitor like everolimus might be chosen over PRRT to avoid further compromising renal function.
- Why A is incorrect: Loss of MEN1 gene function is frequently seen in sporadic PNETs and does not specifically dictate a stronger need for everolimus over PRRT.
- Why C is incorrect: High SSTR2 expression typically supports the utility of PRRT because it indicates strong receptor targeting on the tumor cells.
- Why D is incorrect: A low Ki-67 index (<5%) does not exclude the use of PRRT; in fact, low/intermediate grade disease often responds well to PRRT if there is good SSTR expression.
Key Takeaways (4–5 sentences)
Target selection in advanced PNETs can be influenced by tumor biology, genetic alterations, and patient comorbidities—particularly renal function. PRRT can be very effective for tumors with high SSTR expression but may carry risks of long-term hematologic and kidney toxicity. Everolimus, an mTOR inhibitor, is a valuable alternative when PRRT risks are high or if tumor genetic profiles (e.g., TSC2 mutations) suggest a potential benefit. Treatment choices must be individualized, weighing efficacy, genetic drivers, side-effect profiles, and overall patient health.
Reference
Blumgart's Surgery of the Liver, Biliary Tract and Pancreas, 7th edition,
Chapter 65: "Pancreatic neuroendocrine tumors: Classification, clinical picture, diagnosis, and therapy,"
Subtopic: "Molecular Biology, Somatic Alterations & Treatment Considerations," pp. 903–912
MCQ 5 (Scenario + Grading & Management)
Question
A 64-year-old with a Grade 3 pancreatic neuroendocrine neoplasm and poorly differentiated histology presents with rapidly progressive disease in the liver and retroperitoneal lymph nodes. Immunohistochemistry reveals TP53 and Rb mutations. Which of the following management strategies is most appropriate for this patient?
Answer Choices
A. Initiate a platinum-based chemotherapy regimen (e.g., cisplatin/etoposide).
B. Administer somatostatin analog therapy for cytostatic control.
C. Refer for peptide receptor radionuclide therapy (PRRT) as the first step.
D. Attempt resection of both the primary tumor and all metastatic deposits immediately.
Correct Answer: A. Initiate a platinum-based chemotherapy regimen (e.g., cisplatin/etoposide).
Explanation
- Why A is correct: Poorly differentiated, Grade 3 pancreatic neuroendocrine carcinomas (PNECs) with TP53 and Rb mutations typically resemble small-cell lung cancer biology. The standard first-line regimen is a platinum-based combination (e.g., cisplatin/etoposide) to address the aggressive behavior.
- Why B is incorrect: Somatostatin analog therapy is primarily used for well-differentiated NETs, especially G1–G2. This patient’s tumor is poorly differentiated, G3, and rapidly progressing, making an SSA monotherapy insufficient.
- Why C is incorrect: PRRT can be effective for well-differentiated SSTR-avid tumors. However, high-grade, poorly differentiated neuroendocrine carcinomas often have low SSTR expression and respond better to cytotoxic chemotherapy.
- Why D is incorrect: Surgical resection is not typically pursued initially in extensive, rapidly progressive, poorly differentiated G3 disease. The metastatic burden is often too high for curative surgery.
Key Takeaways (4–5 sentences)
Poorly differentiated, high-grade (G3) neuroendocrine carcinomas of the pancreas are clinically and genetically distinct from well-differentiated NETs. Tumors harboring TP53 and Rb gene mutations behave aggressively and parallel small-cell lung carcinoma management. First-line platinum-based chemotherapy (e.g., cisplatin/etoposide) is used to achieve tumor cytoreduction. Understanding histological grade, differentiation, and molecular mutations is critical in guiding appropriate therapy.
Reference
Blumgart's Surgery of the Liver, Biliary Tract and Pancreas, 7th edition,
Chapter 65: "Pancreatic neuroendocrine tumors: Classification, clinical picture, diagnosis, and therapy,"
Subtopic: "Pathology and Staging & Nonsurgical Management of High-Grade Disease," pp. 903–912
Key Takeaways for the Entire Topic
- PNET Spectrum: Pancreatic neuroendocrine tumors range from low-grade, well-differentiated indolent lesions to highly aggressive, poorly differentiated carcinomas.
- Functional vs. Nonfunctional: About 30% are functional, presenting with hormone-excess syndromes; nonfunctional tumors may be incidentally detected or present with mass effect.
- Management Decisions: Tumor grade, size, functional status, and patient comorbidities dictate treatment—ranging from surveillance in select small, low-grade lesions to aggressive chemotherapy in high-grade disease.
- Familial Syndromes: MEN1, VHL, NF1, and tuberous sclerosis each require careful screening and may involve multiple pancreatic lesions and multidisciplinary care.
- Advanced Therapies: Somatostatin analogs (SSAs), targeted agents (mTOR inhibitors, tyrosine kinase inhibitors), peptide receptor radionuclide therapy (PRRT), and chemotherapy (particularly platinum-based in G3 disease) form essential parts of the treatment armamentarium.