Neuroendocrine tumors of the midgut

Jump to navigation Jump to search

Author: Mikael Häggström [notes 1]

Well-differentiated grade 1 (G1) neuroendocrine tumor (carcinoid)

The processing of neuroendocrine tumors (NET) of the midgut includes:

  • Gross processing
  • Microscopic evaluation
  • Immunohistochemistry
  • For diagnosis if not clear from initial microscopy
  • Grading

Gross processing

See Intestine with tumor

Microscopic evaluation


  • Round regular nuclei
  • Stippled (salt and pepper) chromatin
  • Moderate to abundant cytoplasm

Diagnostic immunohistochemistry

If the diagnosis is not clear from light microscopy:

  • Argyrophil: positive in almost all cases[1]
  • Argentaffin mostly positive[1]
  • Neuron specific enolase, PGP9.5 and CD56 are sensitive but unspecific.[1]


Neuroendocrine lesions are graded histologically according to markers of cellular proliferation, rather than cellular polymorphism. For this purpose, it is recommended that mitotic count and Ki-67 index is determined for all gastroenteropancreatic neuroendocrine neoplasms:[2]

G Mitotic count (per 10 HPF) Ki-67 index (%)
GX Grade cannot be assessed
G1 < 2 < 3%
G2 2 to 20 3% - 20%
G3 > 20 > 20%

Mitotic count

Mitoses in a neuroendocrine tumor.

At least 40 HPFs should be counted.[3]

The mitotic count applies to a HPF area 0.2 mm2.[4] Thus, calculation of the mitotic count varies for different microscope types:

Microscope type Area per HPF Mitotic count calculation
  • Olympus BX50, BX40 or BH2 or AO or Nikon with 15x eyepiece
  • Olympus BX43 with 10x eyepiece
0.096 mm2 [1] Mitoses in 40 HPFs x 0.52
AO with 10x eyepiece 0.12 mm2 [1] Mitoses in 40 HPFs x 0.41
Nikon Eclipse E400 with 10x eyepiece and 40x objective 0.25 mm2 Mitoses in 40 HPFs x 0.20
Leitz Ortholux 0.27 mm2 [1] Mitoses in 40 HPFs x 0.19
Leitz Diaplan 0.31 mm2 [1] Mitoses in 40 HPFs x 0.16

Ki-67 index

Counting Ki-67 index. To count as positive, a nucleus should be:
- Homogenously darkly stained (not just stippled).
- Not be located in stroma.
- Be at least half within the field of view.
- Be large enough.

The counting is made in areas with the highest concentration of Ki-67 positive cells, called "hot spots".[5]

The main methods are:

  • 'Eye-balling' , which is apparently the most common method for determining the Ki-67 index. In 'eye-balling', an impression is made without actually counting individual cells. It can be done on one single view intermediate power (× 10 objective), or by scrolling at higher magnification.[5]
  • Manual counting, which is indicated if eye-balling is within a factor of 2 from any grading limit (such as between 1.5% and 6%). It should be done by photographing (and perhaps printing) the slide so that cells can be marked as they are counted.[5] Officially, at least 500 cells should be counted.[6]

If the mitotic count and Ki-67 index are discordant, the figure which gives the highest grade is used.

G1 and G2 neuroendocrine neoplasms are called neuroendocrine tumors (NETs).[notes 2] G3 neoplasms are called neuroendocrine carcinomas (NECs).


Use the AJCC standard, and take both gross and microscopic evaluation into account:[7]

Primary Tumor (T)
T Category Tumor Criteria
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Invades the lamina propria or submucosa, and less than or equal to 1 cm in size
T2 Invades the muscularis propria, or greater than 1 cm in size
T3 Invades through the muscularis propria into subserosal tissue without penetration of overlying serosa
T4 Invades visceral peritoneum (serosal) or other organs or adjacent structures
Regional Lymph Node (N)
N Category N Criteria
NX Regional lymph nodes cannot be assessed (including no lymph nodes submitted or found)
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis less than 12 nodes
N2 Large mesenteric masses (> 2 cm) and / or extensive nodal deposits (12 or greater), especially those that encase the superior mesenteric vessels

Mesenteric lymph node metastasis from neuroendocrine tumors of the midgut:


It should include:

  • Diagnosis of neuroendocrine tumor
  • Grade
  • T and N stage by AJCC standard
  • Whether the resection is radical


  1. For a full list of contributors, see article history. Creators of images are attributed at the image description pages, seen by clicking on the images. See Patholines:Authorship for details.
  2. Neuroendocrine tumors of the intestines were formerly called carcinoid tumours

Main page


  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 . Infiltrating Ductal Carcinoma of the Breast (Carcinoma of No Special Type). Stanford University School of Medicine. Retrieved on 2019-10-02.
  2. >WHO Classification of Tumours of the Digestive System (4 ed.). Lyon: International Agency for Research on Cancer. 2010. pp. 13–14. ISBN 978-92-832-2432-7. 
  3. Rindi, G.; Klöppel, G.; Alhman, H.; Caplin, M.; Couvelard, A.; de Herder, W. W.; Erikssson, B.; Falchetti, A.; et al. (2006). "TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system ". Virchows Archiv 449 (4): 395–401. doi:10.1007/s00428-006-0250-1. ISSN 0945-6317. 
  4. Klimstra, David S.; Modlin, Irvin R.; Coppola, Domenico; Lloyd, Ricardo V.; Suster, Saul (2010). "The Pathologic Classification of Neuroendocrine Tumors ". Pancreas 39 (6): 707–712. doi:10.1097/MPA.0b013e3181ec124e. ISSN 0885-3177. 
  5. 5.0 5.1 5.2 Reid, Michelle D; Bagci, Pelin; Ohike, Nobuyuki; Saka, Burcu; Erbarut Seven, Ipek; Dursun, Nevra; Balci, Serdar; Gucer, Hasan; et al. (2014). "Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies ". Modern Pathology 28 (5): 686–694. doi:10.1038/modpathol.2014.156. ISSN 0893-3952. 
  6. Basile, Maíra Leite; Kuga, Fábio Seiji; Del Carlo Bernardi, Fabíola (2019). "Comparation of the quantification of the proliferative index KI67 between eyeball and semi-automated digital analysis in gastro-intestinal neuroendrocrine tumors ". Surgical and Experimental Pathology 2 (1). doi:10.1186/s42047-019-0045-8. ISSN 2520-8454. 
  7. AJCC, 8th edition: "29 - Neuroendocrine Tumors of the Stomach". AJCC Cancer Staging Manual (8 ed.). Springer. 2017. pp. 355. ISBN 978-3-319-40617-6.