1. Appendiceal Neuroendocrine Neoplasms (ANENs)
Krystallenia Alexandraki
Endocrinologist
Endocrine Department,
Pathophysiology Clinic,
“Laikon” Hospital,
National and Kapodistrian
University of Athens

2. NEN of the Appendix (ANEN)- Epidemiology
Incidence
0.15 (SEER)/ 106/ yr
/106/ yr
Incidence of appendectomies -
3-9/1000 procedures
ENETS Consensus, 2012 2

3. 27 year-old woman, previously in good health
Patient 1, A. K.
27 year-old woman, previously in good health
2/ abdominal pain
Appendicectomy: Small tumor noted at base of appendix 3

4. Patient 1, A.K. - histopathology
1.1 cm WDNEN.
penetrates the serosa
Do not extend into the mesoappendiceal fat
Not evidence of angioinvasion
Ki-67 < 1%.
Tumour close to the surgical margins
Chromogranin

5. 25 year-old woman, previously in good health.
Patient 2, F. S.
25 year-old woman, previously in good health.
7/05- abdominal pain
Appendicectomy: Small tumor noted at tip of appendix 5

6. Patient 2, F.S. - histopathology
1.2 cm WDNEN.
the tumor penetrates through all layers of the appendix and and invades the mesoappendiceal fat.
Ki-67 = 1%
Surgical margins - free of tumor.
immunohistochemistry:
CgA (+)ve, NSE (+)ve, συναπτοφυσίνη (+)ve, CD56 (+)ve
Tumor
Meso
Mesoappendiceal invasion
Mesoappendiceal invasion

7. 19 year-old woman, previously in good health.
Patient 3, K. T.
19 year-old woman, previously in good health.
7/06- chronic abdominal pain
Appendicectomy: Small tumor noted at the base of appendix and close to the surgical margins 7

8. Patient 3, K.T. - histopathology
0.8 cm WDNEN.
the tumor penetrates through all layers of the appendix and the muscular wall.
Low Ki-67 (few cells)
Surgical margins - free of tumor.
immunohistochemistry:
CgA (+)ve, NSE (+)ve, Synaptophysin (+)ve, CD56 (+)ve
Chromogranin

9. Patients A. K. - F. S. K.T.: What next?
Nothing?
Right hemicolectomy? 9

10. Histopathology characteristics
Feature
Size (cm.)
Penetration to serosa
Mesoappendiceal involvement
lymph/angioinvasion
Perineural involvement
Surgical margins
Ki-67 index (%)
A. K.
1.1
Yes no No
close 1
F. S.
1.2
Free
K. T.
Appendix)
base
Tip
base
0.8
Yes no no no
close
few cells
Alexandraki, J Endocrinol Invest 2011 10

11. Less clear-mets in 10% or none
Histopathology Characteristics in Presented Patients: Tumor Size
“Probability of metastasis in appendiceal NET is related to tumor size”
<10%
5-25%
<1 cm
> 2 cm
1-2 cm
Less clear-mets in 10% or none
% metastasis: ~0
25-40%
Further surgery: No ?
Rt.
Hemicolectomy
Cured by simple appendicectomy; exception: base/ MAI>3mm /incomplete resection 11

12. Histopathology Characteristics in Presented Patients: Penetration to Serosa
“Serosa involvement is demonstrated to be present in up to 70% of all malignant NETs, but is judged to be unrelated to outcome in the published literature”, Stinner and Rothmund, 2005.
“Invasion of the serosa is not correlated with lymph node metastasis and has no impact on survival”, ENETS Consensus, 2008.

13. Histopathology Characteristics in Presented Patients: Localisation
Tip
Mid-appendix
Base
prevalence
60-75%
5-20%
<10%
“Lesions at the base of the appendix are more likely to produce local recurrence than those at the tip if treated only by simple appendicectomy”, Sutton, 2003.
“Incomplete resection after appendicectomy mets NEN at the base: more aggressive therapy in NEN 1-2cm in size”, ENETS Consensus, 2012.

14. Histopathology Characteristics in Presented Patients: Mesoappendiceal invasion (MAI)
“in up to 20% of adults and 40% of children’ Rossi, 2003
“The depth of invasion beyond 3 mm reflects the aggressiveness” ENETS Consensus, 2012.

15. Histopathology Characteristics in Presented Patients: Additional criteria Ki-67 index
“The role of proliferation markers such as Ki-67 and mitotic activity is not precisely defined for appendiceal NETs….it might justified to use these items even for NETs of the appendix regarding the basic biological principles of proliferating tissue, although this reflects a very low level of evidence”, Stinner and Rothmund, 2005
“Additional criteria such as ki-67 of ≥3% or angioinvasion aid decision making”, ENETS Consensus, 2012

16. Histopathology after RHC
A.K.
S.F.
K.T.
Period to RHC (months) 1 2 9
F. S.: 1/10 LN-metastatic NEN
K.T.: 1/14 LN-metastatic NEN
A. K.: 0/36 LNs – persistent disease in proximity of the primary
H & E
SYN LN
Tumor

17. Follow-up
A. K.-34 yrs old
Post-operative complication: ileus – re-operated
abdominal CT and MRI 10 years later free of disease- 1 full-term pregnancy
F. S.:32 yrs old
No post-operative complications
Abdominal ultrasound
and abdominal CT every 5 yrs- 9 yrs free of disease- nulliparous
K. T.: 25 yrs old
Post-operative complication: ileus – re-operated
Abdominal MRI every 2-3 yrs- 8 yrs free of -

18. Pericaecal adhesions and mesenteric lymph nodes
BIOCHEMICAL PROFIL
Α.Κ.
F.S.
K.T.
CgA (ng/ml, 19,4-98,1)
31,5
39.3 40
5-ΗΙΑΑ
(-)
OCTREOSCAN
CT ABDOMEN
Pericaecal adhesions and mesenteric lymph nodes
U/S ABDOMEN
No pathology
MRI ABDOMEN

19. Indium-111-pentetreotide scintigraphy- A.K.
5-HTP PET SCAN A.K. (-)ve
Indium-111-pentetreotide scintigraphy- A.K.
False (+)ve result

20. Three patients summary & Aims:
Three patients with Appendiceal NENs had:
“Grey Zone” tumors with respect to size
Mesoappendiceal invasion (MAI) and base localisation
Regional lymph node metastasis and residual disease
Patients with MAI and 1-2cm in max diameter might have a higher risk of local metastasis than previously considered.
ANEN <1cm, simple appendicectomy is curative and sufficient; only exception NEN at the base of the appendix and incompletely resected or MAI 3 mm

21. Thank you Acknowledgments Prof. D. J. Gross Dr S. Grozinsky-Glasberg
Mrs. D. Barak
Neuroendocrine Tumor Unit Team,
Endocrinology & Metabolism Service, Department of Medicine,
Hadassah-Hebrew University Medical Center,  Jerusalem, Israel
Acknowledgments
Prof. P. Reissman
Department of Surgery, Shaare Zedek Medical Center, Jerusalem, Israel