Neuroendocrine tumors of the midgut: Difference between revisions

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==Microscopic evaluation==
==Microscopic evaluation==
Characteristics:<ref name=stanford/>
[[File:Well-differentiated neuroendocrine tumor with salt-and-pepper chromatin.png|thumb|Salt-and-pepper chromatin, seen on H&E, Pap stain and comparison to actual salt and pepper.]]
Characteristics:<ref name=stanford-carcinoids>{{cite web|url=https://surgpathcriteria.stanford.edu/gitumors/ileum-carcinoid-well-differentiated-neuroendocrine-neoplasm-tumor/printable.html|title=Carcinoid / Well Differentiated Neuroendocrine Neoplasm / Tumor of the Ileum, Distal Jejunum and Cecum|website=Stanford University School of Medicine|accessdate=2022-06-18}}</ref>
*Round regular nuclei
*Round regular nuclei
*Stippled (salt and pepper) chromatin
*Stippled to granular (salt and pepper) chromatin
*Moderate to abundant cytoplasm
*Moderate to abundant cytoplasm


===Diagnostic immunohistochemistry===
===Diagnostic immunohistochemistry===
[[File:Synaptophysin immunohistochemistry of neuroendocrine tumor.jpg|thumb|120px|Positive synaptophysin micrograph.]]
If the diagnosis is not clear from light microscopy:
If the diagnosis is not clear from light microscopy:
*'''Synaptophysin''': positive in almost all cases,<ref name=stanford/> and is generally enough for confirmation.
<gallery mode=packed heights=180>
*'''Chromogranin''': mostly positive<ref name=stanford/>
File:Synaptophysin immunohistochemistry of neuroendocrine tumor.jpg|'''Synaptophysin''': positive in almost all cases,<ref name=stanford-carcinoids/> and is generally enough for confirmation.
*'''Argyrophil''': positive in almost all cases<ref name=stanford/>
File:Immunohistochemistry of positive chromogranin in a grade 2 neuroendocrine tumor of the terminal ileum.jpg|'''Chromogranin''': mostly positive<ref name=stanford-carcinoids/>
*'''Argentaffin''' mostly positive<ref name=stanford/>
</gallery>
*'''Neuron specific enolase''', '''PGP9.5''' and '''CD56''' are sensitive but unspecific.<ref name=stanford/>


==Grading==
==Grading==
Line 34: Line 33:
{| class="wikitable"
{| class="wikitable"
|-
|-
! G !! Mitotic count (per 10 HPF) !! Ki-67 index (%)
! G !! Mitotic count (per mm<sup>2</sup>) !! Ki-67 index (%)
|-
|-
| GX || colspan=2 | Grade cannot be assessed
| GX || colspan=2 | Grade cannot be assessed
|-
|-
| G1 || < 2 || < 3%
| G1 || < 1 || < 3%
|-
|-
| G2 || 2 to 20 || 3% - 20%
| G2 || 1 to 10 || 3% - 20%
|-
|-
| G3 || > 20 || > 20%
| G3 || > 10 || > 20%
|}
|}


===Mitotic count===
===Mitotic count===
[[File:Mitoses in neuroendocrine tumor.jpg|thumb|Mitoses in a neuroendocrine tumor.]]
[[File:Mitoses in neuroendocrine tumor.jpg|thumb|Mitoses in a neuroendocrine tumor.]]
At least 40 HPFs should be counted.<ref name="RindiKlöppel2006">{{cite journal|last1=Rindi|first1=G.|last2=Klöppel|first2=G.|last3=Alhman|first3=H.|last4=Caplin|first4=M.|last5=Couvelard|first5=A.|last6=de Herder|first6=W. W.|last7=Erikssson|first7=B.|last8=Falchetti|first8=A.|last9=Falconi|first9=M.|last10=Komminoth|first10=P.|last11=Körner|first11=M.|last12=Lopes|first12=J. M.|last13=McNicol|first13=A-M.|last14=Nilsson|first14=O.|last15=Perren|first15=A.|last16=Scarpa|first16=A.|last17=Scoazec|first17=J-Y.|last18=Wiedenmann|first18=B.|title=TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system|journal=Virchows Archiv|volume=449|issue=4|year=2006|pages=395–401|issn=0945-6317|doi=10.1007/s00428-006-0250-1}}</ref>
The mitotic count should be estimated by counting mitoses over 8 mm<sup>2</sup> (or more), and then dividing that count by 8 (or proportionally more for a larger area).<ref name="mitotic">'''First reference states 40 high power fields (HPFs) and second reference states that one HPF can be assumed to be 0.2 mm<sup>2</sup>''':<br>-{{cite journal|last1=Rindi|first1=G.|last2=Klöppel|first2=G.|last3=Alhman|first3=H.|last4=Caplin|first4=M.|last5=Couvelard|first5=A.|last6=de Herder|first6=W. W.|last7=Erikssson|first7=B.|last8=Falchetti|first8=A.|last9=Falconi|first9=M.|last10=Komminoth|first10=P.|last11=Körner|first11=M.|last12=Lopes|first12=J. M.|last13=McNicol|first13=A-M.|last14=Nilsson|first14=O.|last15=Perren|first15=A.|last16=Scarpa|first16=A.|last17=Scoazec|first17=J-Y.|last18=Wiedenmann|first18=B.|title=TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system|journal=Virchows Archiv|volume=449|issue=4|year=2006|pages=395–401|issn=0945-6317|doi=10.1007/s00428-006-0250-1}}<br>- {{cite journal|last1=Klimstra|first1=David S.|last2=Modlin|first2=Irvin R.|last3=Coppola|first3=Domenico|last4=Lloyd|first4=Ricardo V.|last5=Suster|first5=Saul|title=The Pathologic Classification of Neuroendocrine Tumors|journal=Pancreas|volume=39|issue=6|year=2010|pages=707–712|issn=0885-3177|doi=10.1097/MPA.0b013e3181ec124e}}</ref> {{Further|Evaluation#Counts per mm2}}
 
The mitotic count applies to a HPF area 0.2 mm<sup>2</sup>.<ref name="KlimstraModlin2010">{{cite journal|last1=Klimstra|first1=David S.|last2=Modlin|first2=Irvin R.|last3=Coppola|first3=Domenico|last4=Lloyd|first4=Ricardo V.|last5=Suster|first5=Saul|title=The Pathologic Classification of Neuroendocrine Tumors|journal=Pancreas|volume=39|issue=6|year=2010|pages=707–712|issn=0885-3177|doi=10.1097/MPA.0b013e3181ec124e}}</ref> Thus, calculation of the mitotic count varies for different microscope types:
{|class="wikitable"
! Microscope type !! Area per HPF !! Mitotic count calculation<br>(Mitoses/10HPF)
|-
|
*Olympus BX50, BX40 or BH2 or AO or Nikon with 15x eyepiece || 0.096 mm<sup>2</sup> <ref name=stanford>{{cite web|url=http://surgpathcriteria.stanford.edu/breast/infductcabr/grading.html|title=Infiltrating Ductal Carcinoma of the Breast (Carcinoma of No Special Type)|website=Stanford University School of Medicine|accessdate=2019-10-02}}</ref>
*Olympus BX43 with 10x eyepiece
|| Mitoses in 40 HPFs x 0.52
|-
| AO with 10x eyepiece || 0.12 mm<sup>2</sup> <ref name=stanford/> || Mitoses in 40 HPFs x 0.41
|-
| Nikon Eclipse E400 with 10x eyepiece and 40x objective || 0.25 mm<sup>2</sup> || Mitoses in 40 HPFs x 0.20
|-
| Leitz Ortholux || 0.27 mm<sup>2</sup> <ref name=stanford/> || Mitoses in 40 HPFs x 0.19
|-
| Leitz Diaplan || 0.31 mm<sup>2</sup> <ref name=stanford/> || Mitoses in 40 HPFs x 0.16
|}


===Ki-67 index===
===Ki-67 index===
[[File:Counting Ki-67 index in immunohistochemistry.jpg|thumb|Counting Ki-67 index. To count as positive, a nucleus should be:
[[File:Counting Ki-67 index in immunohistochemistry.jpg|thumb|Counting Ki-67 index. To count as positive, a nucleus should:
<br>- Homogenously darkly stained (not just stippled).
<br>- Not be located in stroma.
<br>- Not be located in stroma.
<br>- Be at least half within the field of view.
<br>- Be at least half within the field of view.
<br>- Be large enough.]]
<br>- Be large enough.<br>Otherwise, even weakly positive nuclei count as positive.]]
The counting is made in areas with the highest concentration of Ki-67 positive cells, called "hot spots".<ref name="ReidBagci2014">{{cite journal|last1=Reid|first1=Michelle D|last2=Bagci|first2=Pelin|last3=Ohike|first3=Nobuyuki|last4=Saka|first4=Burcu|last5=Erbarut Seven|first5=Ipek|last6=Dursun|first6=Nevra|last7=Balci|first7=Serdar|last8=Gucer|first8=Hasan|last9=Jang|first9=Kee-Taek|last10=Tajiri|first10=Takuma|last11=Basturk|first11=Olca|last12=Kong|first12=So Yeon|last13=Goodman|first13=Michael|last14=Akkas|first14=Gizem|last15=Adsay|first15=Volkan|title=Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies|journal=Modern Pathology|volume=28|issue=5|year=2014|pages=686–694|issn=0893-3952|doi=10.1038/modpathol.2014.156}}</ref>
The counting is made in areas with the highest concentration of Ki-67 positive cells, called "hot spots".<ref name="ReidBagci2014">{{cite journal|last1=Reid|first1=Michelle D|last2=Bagci|first2=Pelin|last3=Ohike|first3=Nobuyuki|last4=Saka|first4=Burcu|last5=Erbarut Seven|first5=Ipek|last6=Dursun|first6=Nevra|last7=Balci|first7=Serdar|last8=Gucer|first8=Hasan|last9=Jang|first9=Kee-Taek|last10=Tajiri|first10=Takuma|last11=Basturk|first11=Olca|last12=Kong|first12=So Yeon|last13=Goodman|first13=Michael|last14=Akkas|first14=Gizem|last15=Adsay|first15=Volkan|title=Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies|journal=Modern Pathology|volume=28|issue=5|year=2014|pages=686–694|issn=0893-3952|doi=10.1038/modpathol.2014.156}}</ref>


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==Stage==
==Stage==
Use the AJCC standard, and take both gross and microscopic evaluation into account:<ref>AJCC, 8th edition: {{cite book |editor-last1=Amin |editor-first1=Mahul B. |year=2017 |title=AJCC Cancer Staging Manual |publisher=[[Springer Science+Business Media|Springer]] |isbn=978-3-319-40617-6 |pages=355 | chapter=29 - Neuroendocrine Tumors of the Stomach |edition=8 }}</ref>
Use the AJCC standard, and take both gross and microscopic evaluation into account:<ref>{{AJCC-8|chapter=29 - Neuroendocrine Tumors of the Stomach}}</ref>
{| class="wikitable"
{| class="wikitable"
! scope="col" colspan=2 style="background: #D8F8FB;" | Primary Tumor (T)
! scope="col" colspan=2 style="background: #D8F8FB;" | Primary Tumor (T)
Line 110: Line 90:
! scope="col" | N Criteria
! scope="col" | N Criteria
|-
|-
| NX || Regional lymph nodes cannot be assessed
| NX || Regional lymph nodes cannot be assessed (including no lymph nodes submitted or found)
|-
|-
| N0 || No regional lymph node metastasis
| N0 || No regional lymph node metastasis
Line 119: Line 99:
|-
|-
|}
|}
Mesenteric '''lymph node metastasis''' from neuroendocrine tumors of the midgut:
<gallery mode=packed heights=210>
<gallery mode=packed heights=210>
File:Lymph node metastasis from neuroendocrine tumor.jpg|Mesenterial lymph node metastasis from a neuroendocrine tumor of the midgut.
File:Histopathology of lymph node metastasis from a well differentiated neuroendocrine tumor of the midgut.jpg
File:Lymph node metastasis from neuroendocrine tumor.jpg
</gallery>
</gallery>


Latest revision as of 12:28, 11 December 2023

Author: Mikael Häggström [note 1]

File:Histopathology of small intestinal well-differentiated grade 1 (G1) carcinoid.jpg
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

File:Well-differentiated neuroendocrine tumor with salt-and-pepper chromatin.png
Salt-and-pepper chromatin, seen on H&E, Pap stain and comparison to actual salt and pepper.

Characteristics:[1]

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

Diagnostic immunohistochemistry

If the diagnosis is not clear from light microscopy:

Grading

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 mm2) Ki-67 index (%)
GX Grade cannot be assessed
G1 < 1 < 3%
G2 1 to 10 3% - 20%
G3 > 10 > 20%

Mitotic count

File:Mitoses in neuroendocrine tumor.jpg
Mitoses in a neuroendocrine tumor.

The mitotic count should be estimated by counting mitoses over 8 mm2 (or more), and then dividing that count by 8 (or proportionally more for a larger area).[3] Further information: Evaluation#Counts per mm2

Ki-67 index

File:Counting Ki-67 index in immunohistochemistry.jpg
Counting Ki-67 index. To count as positive, a nucleus should:
- Not be located in stroma.
- Be at least half within the field of view.
- Be large enough.
Otherwise, even weakly positive nuclei count as positive.

The counting is made in areas with the highest concentration of Ki-67 positive cells, called "hot spots".[4]

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.[4]
  • 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.[4] Officially, at least 500 cells should be counted.[5]

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 1] G3 neoplasms are called neuroendocrine carcinomas (NECs).

Stage

Use the AJCC standard, and take both gross and microscopic evaluation into account:[6]

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:

Report

It should include:

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

Notes

  1. ↑ Neuroendocrine tumors of the intestines were formerly called carcinoid tumours
  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.

Main page

References

  1. ↑ 1.0 1.1 1.2 . Carcinoid / Well Differentiated Neuroendocrine Neoplasm / Tumor of the Ileum, Distal Jejunum and Cecum. Stanford University School of Medicine. Retrieved on 2022-06-18.
  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. ↑ First reference states 40 high power fields (HPFs) and second reference states that one HPF can be assumed to be 0.2 mm2:
    -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. 
    - 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. 
  4. ↑ 4.0 4.1 4.2 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. 
  5. ↑ 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. 
  6. ↑ Amin, Mahul (2017). AJCC cancer staging manual (8 ed.). Switzerland: Springer. ISBN 978-3-319-40617-6. OCLC 961218414.  Chapter: 29 - Neuroendocrine Tumors of the Stomach.
    - For access, see the Secrets chapter of Patholines.
    - Copyright note: The AJCC, 8th Ed. is published by a company in Switzerland, and the tables presented therein are Public Domain because they consist of tabular information without literary or artistic innovation, and therefore do not fulfil the inclusion criterion of the Swiss Copyright Act (CopA) which applies to "literary and artistic intellectual creations with individual character" (see Federal Act on Copyright and Related Rights (Copyright Act, CopA) of 9 October 1992 (Status as of 1 January 2022)). edit

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