What is the management of a neuroendocrine tumor (NET) grade 1 with a Ki-67 index of less than 2%?

Management of Neuroendocrine Tumor Grade 1 with Ki-67 <2%

A neuroendocrine tumor (NET) grade 1 with a Ki-67 index less than 2% is a well-differentiated tumor with low malignant potential that requires specific management based on its location, extent, and functional status. For NETs grade 1 with Ki-67 <2%, surgical resection is the primary treatment of choice for localized disease, while observation may be appropriate for small, incidentally discovered tumors, particularly in the pancreas <2cm without evidence of invasion or metastasis 1.

Classification and Characteristics

NETs grade 1 with Ki-67 <2% are classified according to the WHO classification system as:

• Well-differentiated neuroendocrine tumors (WHO 1)
• Low malignant potential
• Slow-growing tumors with generally favorable prognosis

These tumors demonstrate:

• Positive immunohistochemistry for neuroendocrine markers (chromogranin A, synaptophysin)
• Low proliferative activity (<2% Ki-67 positive cells)
• Fewer than 2 mitoses per 10 high-power fields 1

Diagnostic Workup

1. Histopathological confirmation:

   • Core needle biopsy or surgical specimen
   • Immunohistochemistry for neuroendocrine markers (chromogranin A, synaptophysin)
   • Ki-67 proliferation index assessment (mandatory)

2. Imaging studies:

   • Somatostatin receptor scintigraphy (Octreoscan)
   • CT or MRI depending on tumor location
   • Endoscopic procedures based on tumor location
   • Consider PET scanning with specific tracers (11C-5HTP, 18F-DOPA) 1

3. Biochemical assessment:

   • Plasma chromogranin A (general NET marker)
   • Specific hormone markers based on clinical symptoms and tumor location:
     • Pancreatic NETs: insulin, glucagon, gastrin, VIP
     • Small intestinal NETs: urinary 5-HIAA
     • Rectal NETs: PP, somatostatin, PYY 1

Management Algorithm

For Localized Disease:

1. Pancreatic NETs Grade 1, Ki-67 <2%:

   • Tumors <2cm confined to pancreas: Consider observation with regular imaging surveillance, especially in patients with high surgical risk 1
   • Tumors >2cm or with concerning features: Surgical resection with appropriate margins

2. Gastric NETs Grade 1, Ki-67 <2%:

   • Type I (associated with atrophic gastritis): Endoscopic resection if <1cm
   • Type III (sporadic): Surgical resection due to higher malignant potential

3. Small Intestinal NETs Grade 1, Ki-67 <2%:

   • Surgical resection with regional lymphadenectomy (high rate of nodal metastases even with small primary tumors)

4. Rectal NETs Grade 1, Ki-67 <2%:

   • <1cm without muscularis propria invasion: Endoscopic resection

   • 1cm or with invasion: Surgical resection

5. Appendiceal NETs Grade 1, Ki-67 <2%:

   • <2cm confined to appendix: Simple appendectomy

   • 2cm or with invasion: Right hemicolectomy

For Metastatic Disease:

1. Liver-predominant metastases:

   • Consider surgical resection if complete or near-complete cytoreduction is possible
   • Liver-directed therapies (embolization, ablation) for unresectable disease

2. Widespread metastases:

   • Somatostatin analogs (octreotide, lanreotide) for disease control
   • Monitor for disease progression with regular imaging

Follow-up Recommendations

Despite their low-grade status, NETs require long-term surveillance due to their potential for late recurrence:

• Clinical evaluation every 3-6 months for the first 1-2 years, then annually
• Imaging studies (CT/MRI) every 6-12 months for the first 2-3 years, then annually
• Chromogranin A and specific hormone markers as clinically indicated

Important Considerations

1. Recent research suggests further stratification within Grade 1 NETs may be valuable:

   • NETs with Ki-67 <1% may have significantly better prognosis than those with Ki-67 1-2.99% 2
   • This emerging data suggests patients with Ki-67 1-2.99% may warrant closer surveillance

2. Measurement accuracy matters:

   • "Eyeballed" estimates of Ki-67 are unreliable and can lead to incorrect grading
   • Digital image analysis or manual counting of >2000 cells are preferred methods 3

3. Multidisciplinary approach:

   • Management decisions should involve specialists in endocrinology, surgery, oncology, and nuclear medicine
   • Treatment at centers with expertise in NETs is recommended 1

4. Pitfalls to avoid:

   • Underestimating the metastatic potential of small NETs, particularly in the small intestine
   • Relying solely on Ki-67 for treatment decisions without considering other prognostic factors
   • Inadequate sampling leading to inaccurate Ki-67 assessment

While grade 1 NETs with Ki-67 <2% generally have favorable outcomes, their management should be tailored based on primary site, size, and evidence of invasion, with surgical resection remaining the cornerstone of treatment for most localized tumors.