Neuroendocrine tumors of the midgut

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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

Positive synaptophysin micrograph.

If the diagnosis is not clear from light microscopy:

  • Synaptophysin: positive in almost all cases,[1] and is generally enough for confirmation.
  • Chromogranin: mostly positive[1]
  • 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[1] Mitotic count calculation
Olympus BX50, BX40 or BH2 or AO or Nikon with 15x eyepiece 0.096 mm2 Mitoses in 40 HPFs x 0.52
AO with 10x eyepiece 0.12 mm2 Mitoses in 40 HPFs x 0.41
Olympus with 10x eyepiece 0.16 mm2 Mitoses in 40 HPFs x 0.31
Nikon Eclipse E400 with 10x eyepiece and 40x objective 0.25 mm2 Mitoses in 40 HPFs x 0.20
Leitz Ortholux 0.27 mm2 Mitoses in 40 HPFs x 0.19
Leitz Diaplan 0.31 mm2 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
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


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


  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Unless otherwise specified in boxes, reference is: . 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.