### Background - The majority (**75–90%) are nonfunctional**. - ~**90% sporadic / 10% hereditary**; **MEN1** is the most important hereditary association. - Typical imaging: **well-circumscribed, hypervascular pancreatic mass**. - Functional status = **clinical hormone syndrome**, not hormone staining on histo. - Ki-67 is a nuclear protein expressed in actively proliferating cells and serves as a marker of cellular proliferation. In neuroendocrine neoplasms it helps predict tumor biology, prognosis, and treatment response. - Biology - Ki-67 is expressed during the G1, S, G2, and M phases of the cell cycle. - It is largely absent in quiescent (G0) cells. - It is involved in mitotic chromosome organization. - A higher Ki-67 index reflects a greater proportion of actively proliferating tumor cells. - How it is measured - Immunohistochemical staining using an anti-Ki-67 antibody, commonly MIB-1. - Reported as the percentage of viable tumor cells with positive nuclear staining. - Assessment focuses on the most proliferative regions (hot spots), typically counting at least 500 cells. - Intratumoral heterogeneity, specimen sampling, and interobserver variability can affect results. - Clinical significance in NETs - < 3% = G1, typically indolent. Often favors somatostatin analogues, surveillance in selected cases, or other disease-control strategies. - 3-20% = G2, intermediate proliferation. May favor CAPTEM, targeted therapies, PRRT, or other systemic treatments depending on disease characteristics. - >20% = G3, higher proliferation activity. Suggests more aggressive biology and potentially greater sensitivity to cytotoxic chemotherapy. **NET G3 is still well differentiated** and is biologically distinct from poorly differentiated **neuroendocrine carcinoma (NEC)**. - >55% = Often associated with more aggressive biology; particularly relevant in NEC. Generally exhibits greater platinum responsiveness, although survival outcomes remain poor. - **DOTATATE PET = SSTR expression + whole-body staging**, not grade. - Localized functional pNET → generally **resect**. - Nonfunctional pNET: - **<1 cm → usually observe** - **1–2 cm → individualized** - **>2 cm → generally resect** - Recurrence can be late → **long-term surveillance**. --- ### Workup #### Pancreas-Protocol CT / MRI >[!info] > >- pNETs classically demonstrate **avid arterial enhancement**. >- MRI is useful when liver disease is equivocal or repeated surveillance is anticipated. Assess: - Size and location - Arterial enhancement - Main pancreatic duct relationship - Adjacent vascular involvement - Regional nodes - Liver metastases - Multifocality #### EUS + Biopsy Useful when diagnosis or grade will change management: - Lesion >1 cm - Suspected functional tumor - Diagnostic uncertainty - Considering observation where grade matters - Advanced disease requiring treatment selection A very small, radiographically classic nonfunctional pNET being observed does not necessarily require biopsy. --- ### Pathology / Grade First distinction: **Well-differentiated NET** vs **poorly differentiated NEC** For well-differentiated pNETs: |Grade|Ki-67| |---|---| |**G1**|**<3%**| |**G2**|**3–20%**| |**G3**|**>20%**| **Important:** G3 does **not** automatically mean NEC. A well-differentiated **NET G3** and a poorly differentiated **NEC** are different diseases with different biology and treatment. For clinic/case review, always know: - Differentiation - **Ki-67** - Grade - Nodal status - Margin status if previously resected --- ### Somatostatin-Receptor PET **DOTATATE PET** identifies **SSTR-positive disease** and is useful for: - Staging - Detecting occult metastatic disease - Localizing an occult primary - Establishing SSTR status - Determining candidacy for SSTR-directed therapy / PRRT **Common tracers** - **⁶⁸Ga-DOTATATE (Netspot):** standard SSTR PET tracer; short ~68-minute radionuclide half-life. - **⁶⁴Cu-DOTATATE (Detectnet):** same clinical role with a much longer ~12.7-hour half-life, allowing centralized distribution/delayed imaging and a shorter positron range. For practical HPB purposes: **both answer the same question—where is the SSTR-positive disease?** DOTATATE does **not** determine grade. --- ### Biochemical Workup Do **not** shotgun a hormone panel for every incidental pNET. Order biochemical testing according to the clinical syndrome. **Chromogranin A** - Poor specificity - Not diagnostic - Does not determine stage - Limited utility as a routine screening test --- ### Functional pNETs A pNET is **functional only when hormone secretion produces a clinical syndrome**. |Tumor|Think| |---|---| |**Insulinoma**|Hypoglycemia / Whipple triad| |**Gastrinoma**|ZES: ulcer disease, diarrhea, acid hypersecretion| |**VIPoma**|Profuse secretory diarrhea + hypokalemia| |**Glucagonoma**|Diabetes, weight loss, necrolytic migratory erythema| |**Somatostatinoma**|Diabetes, gallstones, steatorrhea| |**Serotonin-secreting pNET**|Flushing, diarrhea, bronchospasm ± carcinoid heart disease| → [[Functional Pancreatic Neuroendocrine Tumors]] --- ### Insulinoma: Quick Recall **Whipple triad** 1. Symptoms of hypoglycemia 2. Documented hypoglycemia during symptoms 3. Resolution with glucose If not captured spontaneously → **supervised fast up to 72 hours**. During hypoglycemia obtain: - Glucose - Insulin - C-peptide - Proinsulin - Beta-hydroxybutyrate - Sulfonylurea screen Think **inappropriate endogenous insulin secretion during hypoglycemia**, not simply an elevated insulin level. **Medical control:** dietary modification ± diazoxide. **SSA caution:** can worsen hypoglycemia through suppression of counter-regulatory glucagon. --- ### Gastrinoma: Quick Recall Think **Zollinger-Ellison syndrome**: - Recurrent/refractory peptic ulcer disease - Diarrhea - Abdominal pain Obtain **fasting gastrin**, but remember: **PPI → hypergastrinemia.** An elevated gastrin alone does not establish gastrinoma. Always consider **MEN1**. --- ### Resect or Observe? #### Functional pNET **Generally resect if localized and operable, regardless of size.** Goals: - Treat the hormone syndrome - Prevent oncologic progression --- #### Nonfunctional <1 cm **Usually observe.** Surveillance with cross-sectional imaging. Reconsider surgery for: - Growth - Symptoms - Higher grade - Concerning imaging features --- #### Nonfunctional 1–2 cm **Gray zone — individualize.** Ask: - Age / operative fitness? - Symptoms? - **Ki-67 / grade?** - Interval growth? - Main duct involvement? - Suspicious nodes? - Invasive features? - Hereditary syndrome? - What operation is required? A **1.5-cm tail lesion amenable to a limited operation** is a different decision from a **1.5-cm head lesion requiring a Whipple**. --- #### Nonfunctional >2 cm **Generally resect.** Risk of malignant behavior, nodal disease, and distant metastasis increases with tumor size. --- ### What Operation? Operation depends on: - Location - Size - Grade - Duct relationship - Nodal risk - Multifocality - Functional status #### Enucleation Best considered for a **small, favorable tumor where pancreatic preservation matters and formal nodal resection is unnecessary**. Classically useful for selected **insulinomas**. Before enucleating, know: - Relationship to the **main pancreatic duct** - Whether nodal staging is necessary - Whether a formal resection would provide meaningful oncologic benefit **Tradeoff:** parenchymal preservation vs **pancreatic fistula risk**. #### Distal Pancreatectomy Body/tail lesion requiring formal resection. Consider whether splenic preservation is oncologically appropriate based on tumor biology and need for lymphadenectomy. #### Pancreaticoduodenectomy Head/uncinate lesion requiring formal oncologic resection. #### Central Pancreatectomy Highly selected low-risk neck/proximal-body lesions when pancreatic preservation is particularly valuable. Tradeoff: preservation of endocrine/exocrine function vs **two pancreatic transection surfaces and substantial POPF morbidity**. --- ### Lymph Nodes Nodal metastatic risk increases with: - Tumor size - Higher grade - More aggressive biology If nodal staging matters, favor an operation that permits **regional lymph-node assessment** rather than simple enucleation. --- ### Before the OR Know: - **Functional or nonfunctional?** - If functional → syndrome controlled? - Sporadic or hereditary? - **MEN1?** - Size? - Location? - Solitary or multifocal? - **Ki-67 / grade?** - Main duct relationship? - Vascular involvement? - Suspicious nodes? - Liver metastases? - DOTATATE avid? - Why are we operating? - Does this require formal resection or can we preserve pancreas? --- ### Advanced / Metastatic Disease Functional status and metastatic status are **independent variables**. A patient with metastatic insulinoma, gastrinoma, VIPoma, etc. needs treatment of both: 1. **Hormone excess** 2. **Tumor burden/progression** Before choosing therapy ask: - Well differentiated NET or NEC? - **Ki-67 / grade?** - SSTR-positive? - Liver-dominant? - Functional? - Indolent or rapidly progressing? - Is rapid cytoreduction needed? Major tools include: - **Somatostatin analogues** - **PRRT** - **CAPTEM / chemotherapy** - **Everolimus** - **Sunitinib** - Liver-directed therapy - Surgery / cytoreduction in selected patients → [[Advanced and Metastatic Pancreatic Neuroendocrine Tumors]] --- ### Surveillance After Resection Recurrence may occur late. - Long-term cross-sectional imaging - CT or MRI - Follow the relevant biochemical marker in functional tumors when useful - Surveillance intensity should reflect tumor biology and recurrence risk - Continue surveillance for **at least 10 years**; longer follow-up may be appropriate --- ### Clinic / OR Pearls - **Incidental pNET ≠ automatic operation.** - Always look for the **Ki-67**. - **G3 NET ≠ NEC.** - Size is useful, but **grade and biology matter**. - Functional status comes from the **syndrome**, not hormone staining. - Don't shotgun hormone markers. - **DOTATATE = SSTR biology/staging; biopsy = histology/grade.** - ⁶⁸Ga and ⁶⁴Cu DOTATATE serve essentially the **same clinical purpose**. - Think hereditary disease with **young age, multifocal tumors, or suggestive history**. - For a 1–2 cm NF-pNET, the **morbidity of the required operation matters**. - Enucleation preserves pancreas but trades this for **POPF risk and limited nodal assessment**. - A functional tumor can absolutely also be metastatic. - pNET recurrence can be late. ### Related Pages - [[Functional Pancreatic Neuroendocrine Tumors]] - [[Advanced and Metastatic Pancreatic Neuroendocrine Tumors]]