Insulinoma classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]

Overview

Insulinoma may be classified according to their malignant potential into 2 sub-types: Benign (90%) and malignant (10%). It is also classified into 2 subtypes based on the number: solitary (90%) and multiple (10%). Previously insulinoma was classified into 2 subtypes based on hormonal level as determined by radioimmunoassay into group A and group B. The staging of malignant insulinoma is based on the AJCC 2010, ENETS and modified ENETS staging classification.

Classification

Classification of insulinoma
Criteria	Classification	Features
Malignancy potential	Benign	90% of insulinomas are benign in nature.
Malignancy potential	Malignant	10% of Insulinomas have a malignant potential to invade adjacent soft tissues or structures. The malignant type is mostly associated with MEN 1 syndrome. They also have a recurrence rate which is higher in those with MEN1 (21% at 10 and 20 years) than without it (5% at 10 and 7% at 20 years).^[1] In one of the recent research papers, the recurrence was described as 4 times more common in individuals with MEN 1.^[2]
Based on number	Solitary	90% of insulinomas are solitary.
Based on number	Multiple	10% of insulinomas can be multiple in number.
Based on the functionality (clinical manifestations)	Functional	According to WHO, functioning pancreatic endocrine tumors are classified as: Well-differentiated endocrine tumors, with benign or uncertain behavior. Well-differentiated endocrine carcinomas with low-grade malignant behavior. Poorly differentiated endocrine carcinomas with high-grade malignant behavior. Note: Most insulinomas are classified as well-differentiated endocrine tumors (WHO 1) but occasionally they belong to WHO 2 or 3. ^[3]^[4]^[5]^[6]
	Non-functional^[7]
Based on hormonal level determined by radioimmunoassay^[8] (previously used)	Group A	Abundant B cells with a trabecular arrangement and uniform insulin immunofluorescence.
	Group B	Scarce B cells with a medullary arrangement and irregular immunofluorescence.

American Joint Cancer Committee (AJCC) 7th edition 2010 calssification

The staging of malignant insulinoma being a pancreatic neuroendocrine tumor may be classified into several subtypes based on American Joint Cancer Committee (AJCC) 7th edition 2010: ^[9]^[10]

Stage	T	N	M
IA	T1	N0	M0
IB	T2	N0	M0
IIA	T3	N0	M0
IIB	T1-3	N1	M0
III	T4	Any N	M0
IV	Any T	Any N	M1

AJCC 2010
T	T1	<2 cm in greatest dimension
	T2	>2 cm in greatest dimension
	T3	Beyond the pancreas but without involvement of the superior mesenteric artery
	T4	Involvement of the celiac axis or superior mesenteric artery (unresectable tumor)
N	N0	No regional lymph node metastasis
N	N1	Regional lymph node metastasis
M	M0	No distant metastasis
M	M1	Distant metastasis

European Neuroendocrine Tumor Society (ENETS) classification:

Being a pancreatic neuroendocrine tumor, it is also staged by European Neuroendocrine Tumor Society (ENETS) as: ^[9]^[10]

Stage	T	N	M
I	T1	N0	M0
IIA	T2	N0	M0
IIB	T3	N0	M0
IIIA	T4	N0	M0
III B	Any T	N1	M0
IV	Any T	Any N	M1

ENETS
T	T1	Tumor limited to pancreas, <2 cm
	T2	Tumor limited to pancreas, 2-4 cm
	T3	>4cm, or invading the duodenum or common bile duct
	T4	Tumor invades adjacent structures
N	N0	No regional lymph node metastasis
N	N1	Regional lymph node metastasis
M	M0	No distant metastasis
M	M1	Distant metastasis

WHO 2010 classification system

WHO classification system combined differentiation and grading characteristics to classify the belligerence of a pancreatic neuroendocrine tumor.
The aggressiveness of tumor was expressed in form of mitotic count and staining of a nuclear antigen called Ki-67: ^[11]^[6]

Grade of tumor	Mitotic Count(Mitoses per 10 high powerfields)	Expression of Ki 67
Grade 1	<2	≤3%
Grade 2	2-10	3-20%
Grade 3	>20	>20%

Grade 1 and 2 tumors were classified as neuroendocrine neoplasm (NET) and grade 3 were classified as neuroendocrine carcinoma (NEC).

In its new 8th edition of AJCC which is planned to be published on January 1, 2018; AJCC had developed a modified ENETS (mENETS) staging classification:^[9]

Stage	T	N	M
IA	T1	N0	M0
IB	T2	N0	M0
IIA	T3	N0	M0
IIB	T1-3	N1	M0
III	T4	Any N	M0
IV	Any T	Any N	M1

mENETS
T	T1	Tumor limited to pancreas, <2 cm
	T2	Tumor limited to pancreas, 2-4 cm
	T3	>4cm, or invading the duodenum or common bile duct
	T4	Tumor invades adjacent structures
N	N0	No regional lymph node metastasis
N	N1	Regional lymph node metastasis
M	M0	No distant metastasis
M	M1	Distant metastasis

References

↑ F. J. Service, M. M. McMahon, P. C. O’Brien & D. J. Ballard (1991). “Functioning insulinoma–incidence, recurrence, and long-term survival of patients: a 60-year study”. Mayo Clinic proceedings. 66 (7): 711–719. PMID 01677058.
↑ Ahmad N, Almutawa AM, Abubacker MZ, Elzeftawy HA, Bawazir OA (2017). “Recurrent insulinoma in a 10-year-old boy with Down’s syndrome”. Endocrinol Diabetes Metab Case Rep. 2017. doi:10.1530/EDM-16-0155. PMC 5445445. PMID 28567298.
↑ de Herder, Wouter W.; Niederle, Bruno; Scoazec, Jean-Yves; Pauwels, Stanislas; Klöppel, Günter; Falconi, Massimo; Kwekkeboom, Dik J.; Öberg, Kjel; Eriksson, Barbro; Wiedenmann, Bertram; Rindi, Guido; O’Toole, Dermot; Ferone, Diego (2007). “Well-Differentiated Pancreatic Tumor/Carcinoma: Insulinoma”. Neuroendocrinology. 84 (3): 183–188. doi:10.1159/000098010. ISSN 0028-3835.
↑ Schott M, Klöppel G, Raffel A, Saleh A, Knoefel WT, Scherbaum WA (2011). “Neuroendocrine neoplasms of the gastrointestinal tract”. Dtsch Arztebl Int. 108 (18): 305–12. doi:10.3238/arztebl.2011.0305. PMC 3103981. PMID 21629514.
↑ Bosman, F. T. (2010). WHO classification of tumours of the digestive system. Lyon: International Agency for Research on Cancer. ISBN 978-9283224327.
↑ ^6.0 ^6.1 Sun J (2017). “Pancreatic neuroendocrine tumors”. Intractable Rare Dis Res. 6 (1): 21–28. doi:10.5582/irdr.2017.01007. PMC 5359348. PMID 28357177.
↑ Mittendorf EA, Liu YC, McHenry CR (2005). “Giant insulinoma: case report and review of the literature”. J Clin Endocrinol Metab. 90 (1): 575–80. doi:10.1210/jc.2004-0825. PMID 15522939.
↑ Berger M, Bordi C, Cüppers HJ, Berchtold P, Gries FA, Münterfering H; et al. (1983). “Functional and morphologic characterization of human insulinomas”. Diabetes. 32 (10): 921–31. PMID 6311653.
↑ ^9.0 ^9.1 ^9.2 Luo G, Javed A, Strosberg JR, Jin K, Zhang Y, Liu C; et al. (2017). “Modified Staging Classification for Pancreatic Neuroendocrine Tumors on the Basis of the American Joint Committee on Cancer and European Neuroendocrine Tumor Society Systems”. J Clin Oncol. 35 (3): 274–280. doi:10.1200/JCO.2016.67.8193. PMID 27646952.
↑ ^10.0 ^10.1 Yang M, Zeng L, Zhang Y, Wang WG, Wang L, Ke NW; et al. (2015). “TNM staging of pancreatic neuroendocrine tumors: an observational analysis and comparison by both AJCC and ENETS systems from 1 single institution”. Medicine (Baltimore). 94 (12): e660. doi:10.1097/MD.0000000000000660. PMC 4554009. PMID 25816036.
↑ Bosman, F. T. (2010). WHO classification of tumours of the digestive system. Lyon: International Agency for Research on Cancer. ISBN 978-9283224327.

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[1] F. J. Service, M. M. McMahon, P. C. O’Brien & D. J. Ballard (1991). “Functioning insulinoma–incidence, recurrence, and long-term survival of patients: a 60-year study”. Mayo Clinic proceedings. 66 (7): 711–719. PMID 01677058.

[pmid28567298-2] Ahmad N, Almutawa AM, Abubacker MZ, Elzeftawy HA, Bawazir OA (2017). “Recurrent insulinoma in a 10-year-old boy with Down’s syndrome”. Endocrinol Diabetes Metab Case Rep. 2017. doi:10.1530/EDM-16-0155. PMC 5445445. PMID 28567298.

[de_HerderNiederle2007-3] Herder, Wouter W.; Niederle, Bruno; Scoazec, Jean-Yves; Pauwels, Stanislas; Klöppel, Günter; Falconi, Massimo; Kwekkeboom, Dik J.; Öberg, Kjel; Eriksson, Barbro; Wiedenmann, Bertram; Rindi, Guido; O’Toole, Dermot; Ferone, Diego (2007). “Well-Differentiated Pancreatic Tumor/Carcinoma: Insulinoma”. Neuroendocrinology. 84 (3): 183–188. doi:10.1159/000098010. ISSN 0028-3835.

[pmid21629514-4] Schott M, Klöppel G, Raffel A, Saleh A, Knoefel WT, Scherbaum WA (2011). “Neuroendocrine neoplasms of the gastrointestinal tract”. Dtsch Arztebl Int. 108 (18): 305–12. doi:10.3238/arztebl.2011.0305. PMC 3103981. PMID 21629514.

[5] Bosman, F. T. (2010). WHO classification of tumours of the digestive system. Lyon: International Agency for Research on Cancer. ISBN 978-9283224327.

[pmid28357177-6] 6.0 ^6.1 Sun J (2017). “Pancreatic neuroendocrine tumors”. Intractable Rare Dis Res. 6 (1): 21–28. doi:10.5582/irdr.2017.01007. PMC 5359348. PMID 28357177.

[pmid15522939-7] Mittendorf EA, Liu YC, McHenry CR (2005). “Giant insulinoma: case report and review of the literature”. J Clin Endocrinol Metab. 90 (1): 575–80. doi:10.1210/jc.2004-0825. PMID 15522939.

[pmid6311653-8] Berger M, Bordi C, Cüppers HJ, Berchtold P, Gries FA, Münterfering H; et al. (1983). “Functional and morphologic characterization of human insulinomas”. Diabetes. 32 (10): 921–31. PMID 6311653.

[pmid27646952-9] 9.0 ^9.1 ^9.2 Luo G, Javed A, Strosberg JR, Jin K, Zhang Y, Liu C; et al. (2017). “Modified Staging Classification for Pancreatic Neuroendocrine Tumors on the Basis of the American Joint Committee on Cancer and European Neuroendocrine Tumor Society Systems”. J Clin Oncol. 35 (3): 274–280. doi:10.1200/JCO.2016.67.8193. PMID 27646952.

[pmid25816036-10] 10.0 ^10.1 Yang M, Zeng L, Zhang Y, Wang WG, Wang L, Ke NW; et al. (2015). “TNM staging of pancreatic neuroendocrine tumors: an observational analysis and comparison by both AJCC and ENETS systems from 1 single institution”. Medicine (Baltimore). 94 (12): e660. doi:10.1097/MD.0000000000000660. PMC 4554009. PMID 25816036.

[11] Bosman, F. T. (2010). WHO classification of tumours of the digestive system. Lyon: International Agency for Research on Cancer. ISBN 978-9283224327.

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