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Insulinoma-Associated Protein 1 (INSM1) Expression in Neuroendocrine Neoplasms: A Newly Discovered Diagnostic Marker
CC BY 4.0 · Indian J Med Paediatr Oncol 2024; 45(04): 306-311
DOI: DOI: 10.1055/s-0043-1774777
Abstract
Introduction Neuroendocrine
neoplasms (NENs) are heterogeneous group of neoplasms with relatively low
incidence. Diagnosis of NENs requires an integrated approach of histology,
immunohistochemistry, and molecular study. In the present study, we evaluated
insulinoma-associated protein 1 (INSM1) expression in NENs and correlated it
with other established neuroendocrine markers.
Materials and Method Retrospective cross-sectional study was conducted
in a tertiary care center. Consecutively, 100 cases from year November 2019 to
January 2021 were enrolled in the study and all relevant data were noted.
Results The
mean (±standard deviation) age of the patients was 55.5 (±10.6) years with a
male preponderance. Total 59%- of the tumors were located in the lung of which
67%- were poorly differentiated neuroendocrine carcinoma. INSM1 were positive
in 97%- cases, while synaptophysin (SYN) in 96%- and chromogranin A (CgA) in 86%-.
Correlation of INSM1 expression with SYN and CgA was statistically significant
(p-value < 0.05).
Mean H-score of INSM1 was significantly higher than SYN and CgA and it was
statistically significant (p-value < 0.001).
Conclusion In
the present study, the expression of INSM1 was seen in 97%- cases of NENs. A
statistically significant association was found between INSM1 and traditional
NE markers. As a nuclear marker it is easy to interpret and it showed higher
H-score. We conclude that INSM1 is a highly sensitive marker and recommend to
incorporate it in the routine practice to aid in the diagnostic workup.
However, a larger cohort is required to establish the organ-specific
sensitivity and specificity of INSM1.
Keywords
neuroendocrine neoplasms - insulinoma-associated protein 1 - immunohistochemistry - traditional neuroendocrine markers - H-score
Supplementary Material
>Supplementary MaterialPublication History
Article published online:
26 September 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
Abstract
Introduction Neuroendocrine neoplasms (NENs) are heterogeneous group of neoplasms with relatively low incidence. Diagnosis of NENs requires an integrated approach of histology, immunohistochemistry, and molecular study. In the present study, we evaluated insulinoma-associated protein 1 (INSM1) expression in NENs and correlated it with other established neuroendocrine markers.
Materials and Method Retrospective cross-sectional study was conducted in a tertiary care center. Consecutively, 100 cases from year November 2019 to January 2021 were enrolled in the study and all relevant data were noted.
Results The mean (±standard deviation) age of the patients was 55.5 (±10.6) years with a male preponderance. Total 59%-of the tumors were located in the lung of which 67%-were poorly differentiated neuroendocrine carcinoma. INSM1 were positive in 97%-cases, while synaptophysin (SYN) in 96%-and chromogranin A (CgA) in 86%. Correlation of INSM1 expression with SYN and CgA was statistically significant (p-value < 0.05). Mean H-score of INSM1 was significantly higher than SYN and CgA and it was statistically significant (p-value < 0.001).
Conclusion In the present study, the expression of INSM1 was seen in 97%-cases of NENs. A statistically significant association was found between INSM1 and traditional NE markers. As a nuclear marker it is easy to interpret and it showed higher H-score. We conclude that INSM1 is a highly sensitive marker and recommend to incorporate it in the routine practice to aid in the diagnostic workup. However, a larger cohort is required to establish the organ-specific sensitivity and specificity of INSM1.
Keywords
neuroendocrine neoplasms - insulinoma-associated protein 1 - immunohistochemistry - traditional neuroendocrine markers - H-scoreIntroduction
Neuroendocrine neoplasms (NENs) are heterogeneous group of disorders with varied histological patterns and nomenclature.[1] Recently, the incidence of NENs has been increased from an estimated 1.09 per 100,000 people in 1973 to 6.98 per 100,000 people in 2012 in the United States.[2] According to the Surveillance, Epidemiology, and End Results[3] and Indian[4] data more than 60%-of neuroendocrine tumors (NETs) arise from the gastroenteropancreatic NETs (GEP-NETs). Clinical course of NENs is different and depends upon the location of the tumor; however, a significant number of patients can present with advanced stage.[5] All NENs share a common neuroendocrine origin and have varied organ-specific characteristics, biological behavior, prognosis, and treatment.[5] Diagnosis of NENs requires an integrated approach of pathological, immunohistochemical, genetic, and molecular markers.[5]
Insulinoma-associated protein 1 (INSM1) is a zinc-finger transcription factor which has a key role in the development of neuroendocrine differentiation in various tissues.[6] Insulinoma-associated-1gene encodes the INSM1, which was first discovered in 1992 at the National Institutes of Health (Bethesda, Maryland, United States) in human pancreatic insulinoma tissue and murine insulinoma cell lines.[7] Rosenbaum et al[8] reported, INSM1 as a robust immunohistochemical marker of neuroendocrine differentiation in normal and neoplastic human tissue. INSM1 is the first and the most widely validated pan-neuroendocrine marker which shows nuclear positivity.
There is a paucity of Indian literature on this new and emerging marker. In the present study, we will investigate the expression of INSM1 in NENs and compare it with the already established neuroendocrine markers.
Materials and Methods
Sample size and study design: This was a retrospective cross-sectional study done at the department of oncopathology in a tertiary cancer center. Consecutive 100 cases of confirmed NENs from November 2019 to January 2021 were enrolled in the study.
Inclusion and exclusion criteria: Immunohistochemically proven cases of NENs were included in the study. Tumors showing neuroendocrine differentiation without immunohistochemical confirmation and inadequate tissue, suspicious lesions, and cytologically diagnosed cases were excluded.
Demographic details were retrieved from the hospital database. All tissues were fixed in 10%-buffered formalin and processed for hematoxylin and eosin and immunohistochemical study. NENs are classified according to the World Health Organization classification.[9] Immunostaining using synaptophysin (SYN) (SP11, monoclonal antibody, Thermoscientific, 1:50), chromogranin A (CgA) (LK2H10, monoclonal antibody, Thermoscientific, 1:100), and INSM1 (clone: MRQ-70, rabbit monoclonal antibody, Cell Marque, 1:50) antibodies were done on all cases. Nuclear immunoreactivity for INSM1 and cytoplasmic stain for SYN and CgA in tumor cells were considered positive. For all markers, both the percentage of cells and intensity of immunoreactivity were noted. H-score assessment was done for INSM1, SYN, and CgA.[10] [11] [12]
Statistical Analysis
Age, sex, location of tumor, histologic type, and histological grade were noted. Associations between categorical variables (location of tumor, tumor subtype, tumor grade) were analyzed using chi-square test. Wilcoxon rank test was used for comparison of H-score value. Two-sided p-values of < 0.05 were considered significant. All statistical analyses were carried out using SPSS 20.
Ethics: The institutional review committee of the Gujarat Cancer and Research Institute approved the study, approval number IRC/35/2019 and date November 14, 2019. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Results
Clinicohistopathological and immunohistochemical characteristics are described in [Table 1]. The mean (±standard deviation [SD]) age was 55.5 (±10.61) years ranging from 25 to 76 years with most of the cases between 51 and 60 years (37%). Male preponderance was noted with male-to-female ratio of 4.2:1. Lung was the most frequently affected organ (59%). Total 67%-cases had poorly differentiated neuroendocrine carcinoma (PD-NEC) of which 65%-had small cell morphology. Total 43%-of cases had a maximum tumor size of > 7 cm. Total 97 cases were positive for INSM1. Of three negative cases, two were PD-NEC of the lung and one was jejunum well-differentiated NET. Of these three negative INSM1 cases, one case was positive for both SYN and CgA, while two were positive of SYN and CgA, respectively.
|
Parameters |
Number of cases (n = 100) |
|---|---|
|
Age |
|
|
< 50> |
33 |
|
≥ 50 y |
67 |
|
Site |
|
|
Lung |
59 |
|
GIT + pancreas |
31 |
|
Others |
10 |
|
Sex |
|
|
Male |
81 |
|
Female |
19 |
|
Types |
|
|
NET |
29 |
|
NEC |
67 |
|
Combined |
4 |
|
Subtypes |
|
|
NET |
|
|
NET 1 |
16 |
|
NET2 |
5 |
|
NET3 |
8 |
|
MINEN |
1 |
|
NEC |
|
|
SMCC |
65 |
|
LCNEC |
2 |
|
Combined |
3 |
|
Immunohistochemistry |
|
|
Synaptophysin |
|
|
Positive |
96 |
|
Negative |
04 |
|
Chromogranin |
|
|
Positive |
86 |
|
Negative |
14 |
|
INSM1 |
|
|
Positive |
97 |
|
Negative |
03 |
|
Variables |
Total cases |
Number of cases (%) |
p-Value[a] |
|
|---|---|---|---|---|
|
INSM1 positive |
INSM1 negative |
|||
|
Histological types |
||||
|
NET NEC Combined |
29 |
28 (96.6) |
1 (3.4) |
00591 |
|
67 |
65 (97.0) |
2 (3.0) |
||
|
4 |
4 (100) |
0 (0) |
||
|
Site |
||||
|
Lung GIT and pancreas Others |
59 |
57 (96.6) |
2 (3.4) |
0.841 |
|
31 |
30 (96.8) |
1 (3.2) |
||
|
10 |
10 (100) |
0 (0) |
||
|
SYN |
||||
|
Positive Negative |
96 |
94 (97.9) |
2 (2.1) |
0.008 |
|
4 |
3 (75) |
1 (25) |
||
|
CgA |
||||
|
Positive Negative |
86 |
83 (96.5) |
3 (3.5) |
0.011 |
|
14 |
14 (100) |
0 (0) |
||
|
Parameters |
Number |
p-Value[a] |
|---|---|---|
|
SYN vs. INSM1 |
||
|
SYN < INSM1 SYN > INSM1 SYN = INSM1 |
79 |
0.001 |
|
18 |
||
|
3 |
||
|
CgA vs. INSM1 |
||
|
CgA < INSM1 CgA > INSM1 SYN = INSM1 |
76 |
0.001 |
|
21 |
||
|
3 |
||
|
SYN vs. CgA |
||
|
SYN < CgA SYN > CgA SYN = CgA |
53 |
0.195 |
|
46 |
||
|
1 |
||
|
Studies |
INSM1 (%) |
SYN (%) |
CgA (%) |
|---|---|---|---|
|
Our study |
97/100 (97) |
96/100 (96) |
86/100 (86) |
|
Fujino et al[16] |
100/102 (98) |
88/102 (86.2) |
84/102 (82.3) |
|
Rosenbaum et al[8] |
27/30 (90) |
29/30 (96.7) |
21/30 (70) |
|
Aldera et al[17] |
59/69 (85.5) |
63/69 (91.3) |
48/69 (69.5) |
|
McHugh et al[13] |
89/110 (82.9) |
109/110 (99.1) |
96/110 (87.3) |
|
Mukhopadhyay et al[6] |
144/152 (95) |
147/150 (98) |
125/149 (84) |
|
Kriegsmann et al[18] |
276/372 (74.2) |
319/372 (85.8) |
289/372 (77.7) |
|
Rooper et al[14] |
99/103 (96.1) |
79/103 (76.7) |
67/103 (65.0) |
|
Sakakibara et al[19] |
120/141 (85.1) |
87/141 (61.7) |
74/141 (52.5) |
|
González et al[20] |
32/32 (100) |
32/32 (100) |
31/32 (97) |
References
- Basu B, Sirohi B, Corrie P. Systemic therapy for neuroendocrine tumours of gastroenteropancreatic origin. Endocr Relat Cancer 2010; 17 (01) R75-R90
- Desari A, Shen C, Halperin D. et al. Trends in incidence, prevalence and survival outcomes in patients with neuroendocrine tumours in the United States. JMMA Oncol 2017; 3 (10) 1335-1342
- Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011; 40 (01) 1-18 , vii
- Amarapurkar DN, Juneja MP, Patel ND, Amarapurkar AD, Amarapurkar PD. A retrospective clinico-pathological analysis of neuroendocrine tumors of the gastrointestinal tract. Trop Gastroenterol 2010; 31 (02) 101-104
- Kyriakopoulos G, Mavroeidi V, Chatzellis E, Kaltsas GA, Alexandraki KI. Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms. Ann Transl Med 2018; 6 (12) 252-264
- Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF. Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol 2019; 32 (01) 100-109
- Goto Y, De Silva MG, Toscani A, Prabhakar BS, Notkins AL, Lan MS. A novel human insulinoma-associated cDNA, IA-1, encodes a protein with “zinc-finger” DNA-binding motifs. J Biol Chem 1992; 267 (21) 15252-15257
- Rosenbaum JN, Guo Z, Baus RM, Werner H, Rehrauer WM, Lloyd RV. Lloyd RV. INSM1: a novel immunohistochemical and molecular marker for neuroendocrine and neuroepithelial neoplasms. Am J Clin Pathol 2015; 144 (04) 579-591
- Rindi G, Klimstra DS, Abedi-Ardekani B. et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 2018; 31 (12) 1770-1786
- McCarty Jr KS, Miller LS, Cox EB, Konrath J, McCarty Sr KS. Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 1985; 109 (08) 716-721
- McCarty Jr KS, Szabo E, Flowers JL. et al. Use of a monoclonal anti-estrogen receptor antibody in the immunohistochemical evaluation of human tumors. Cancer Res 1986; 46 (8, Suppl): 4244s-4248s
- Tadrous P.J.. 2007. “Breast” in Diagnostic Criteria Handbook in HISTOPATHOLOGY: A Surgical Pathology Vade Mecum. John Wiley & Sons; England: pp. 258-266
- McHugh KE, Mukhopadhyay S, Doxtader EE, Lanigan C, Allende DS. INSM1 is highly specific marker of neuroendocrine differentiation in primary neoplasm of the gastrointestinal tract, appendix and pancreas. Am J Clin Pathol 2020; 153 (06) 811-820
- Rooper LM, Sharma R, Li QK, Illei P, Westra WH. INSM1 demonstrates superior performance to the individual and combined use of synaptophysin, chromogranin and CD56 for diagnosing neuroendocrine tumours of the thoracic cavity. Am J Surg Pathol 2017;00:000–000
- Zou Q, Zhang L, Cheng Z, Guo X, Cao D. INSM1 is less sensitive but more specific than synaptophysin in gynaecological high grade neuroendocrine carcinoma: an immunohistochemical study of 75 cases with specificity test and literature review. Am J Surg Pathol 2021; 45 (02) 147-159
- Fujino K, Yasufuku K, Kudoh S. et al. INSM1 is the best marker for the diagnosis of neuroendocrine tumors: comparison with CGA, SYP and CD56. Int J Clin Exp Pathol 2017; 10 (05) 5393-5405
- Aldera AP, Govender D, Locketz ML, Mukhopadhyay S, McHugh K, Allende D. Combined use of INSM1 and synaptophysin is the most sensitive and specific panel to detect neuroendocrine neoplasm in digestive tract. Am J Clin Pathol 2020; 154 (06) 870-871
- Kriegsmann K, Zgorzelski C, Kazdal D. et al. Insulinoma-associated protein 1(INSM1) in thoracic tumour is less sensitive but more specific compared with synaptophysin, chromogranin A and CD56. Appl Immunohistochem Mol Morphol 2020; 28 (03) 237-242
- Sakakibara R, Kobayashi M, Takahashi N. et al. Insulinoma associated protein 1 (INSM1) is a better marker for diagnosis and prognosis estimation of small cell lung carcinoma than neuroendocrine phenotype markers such as chromogranin A, synaptophysin, and CD 56. Am J Surg Pathol 2020; 44 (06) 757-764
- González I, Lu H-C, Sninsky J. et al. Insulinoma-associated protein 1 expression in primary and metastatic neuroendocrine neoplasms of the gastrointestinal and pancreaticobiliary tracts. Histopathology 2019; 75 (04) 568-577
Address for correspondence
Publication History
Article published online:
26 September 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
References
- Basu B, Sirohi B, Corrie P. Systemic therapy for neuroendocrine tumours of gastroenteropancreatic origin. Endocr Relat Cancer 2010; 17 (01) R75-R90
- Desari A, Shen C, Halperin D. et al. Trends in incidence, prevalence and survival outcomes in patients with neuroendocrine tumours in the United States. JMMA Oncol 2017; 3 (10) 1335-1342
- Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011; 40 (01) 1-18 , vii
- Amarapurkar DN, Juneja MP, Patel ND, Amarapurkar AD, Amarapurkar PD. A retrospective clinico-pathological analysis of neuroendocrine tumors of the gastrointestinal tract. Trop Gastroenterol 2010; 31 (02) 101-104
- Kyriakopoulos G, Mavroeidi V, Chatzellis E, Kaltsas GA, Alexandraki KI. Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms. Ann Transl Med 2018; 6 (12) 252-264
- Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF. Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol 2019; 32 (01) 100-109
- Goto Y, De Silva MG, Toscani A, Prabhakar BS, Notkins AL, Lan MS. A novel human insulinoma-associated cDNA, IA-1, encodes a protein with “zinc-finger” DNA-binding motifs. J Biol Chem 1992; 267 (21) 15252-15257
- Rosenbaum JN, Guo Z, Baus RM, Werner H, Rehrauer WM, Lloyd RV. Lloyd RV. INSM1: a novel immunohistochemical and molecular marker for neuroendocrine and neuroepithelial neoplasms. Am J Clin Pathol 2015; 144 (04) 579-591
- Rindi G, Klimstra DS, Abedi-Ardekani B. et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 2018; 31 (12) 1770-1786
- McCarty Jr KS, Miller LS, Cox EB, Konrath J, McCarty Sr KS. Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 1985; 109 (08) 716-721
- McCarty Jr KS, Szabo E, Flowers JL. et al. Use of a monoclonal anti-estrogen receptor antibody in the immunohistochemical evaluation of human tumors. Cancer Res 1986; 46 (8, Suppl): 4244s-4248s
- Tadrous P.J.. 2007. “Breast” in Diagnostic Criteria Handbook in HISTOPATHOLOGY: A Surgical Pathology Vade Mecum. John Wiley & Sons; England: pp. 258-266
- McHugh KE, Mukhopadhyay S, Doxtader EE, Lanigan C, Allende DS. INSM1 is highly specific marker of neuroendocrine differentiation in primary neoplasm of the gastrointestinal tract, appendix and pancreas. Am J Clin Pathol 2020; 153 (06) 811-820
- Rooper LM, Sharma R, Li QK, Illei P, Westra WH. INSM1 demonstrates superior performance to the individual and combined use of synaptophysin, chromogranin and CD56 for diagnosing neuroendocrine tumours of the thoracic cavity. Am J Surg Pathol 2017;00:000–000
- Zou Q, Zhang L, Cheng Z, Guo X, Cao D. INSM1 is less sensitive but more specific than synaptophysin in gynaecological high grade neuroendocrine carcinoma: an immunohistochemical study of 75 cases with specificity test and literature review. Am J Surg Pathol 2021; 45 (02) 147-159
- Fujino K, Yasufuku K, Kudoh S. et al. INSM1 is the best marker for the diagnosis of neuroendocrine tumors: comparison with CGA, SYP and CD56. Int J Clin Exp Pathol 2017; 10 (05) 5393-5405
- Aldera AP, Govender D, Locketz ML, Mukhopadhyay S, McHugh K, Allende D. Combined use of INSM1 and synaptophysin is the most sensitive and specific panel to detect neuroendocrine neoplasm in digestive tract. Am J Clin Pathol 2020; 154 (06) 870-871
- Kriegsmann K, Zgorzelski C, Kazdal D. et al. Insulinoma-associated protein 1(INSM1) in thoracic tumour is less sensitive but more specific compared with synaptophysin, chromogranin A and CD56. Appl Immunohistochem Mol Morphol 2020; 28 (03) 237-242
- Sakakibara R, Kobayashi M, Takahashi N. et al. Insulinoma associated protein 1 (INSM1) is a better marker for diagnosis and prognosis estimation of small cell lung carcinoma than neuroendocrine phenotype markers such as chromogranin A, synaptophysin, and CD 56. Am J Surg Pathol 2020; 44 (06) 757-764
- González I, Lu H-C, Sninsky J. et al. Insulinoma-associated protein 1 expression in primary and metastatic neuroendocrine neoplasms of the gastrointestinal and pancreaticobiliary tracts. Histopathology 2019; 75 (04) 568-577