Insulinoma-associated Protein 1 Research Articles

The Significance of Insulinoma-Associated Protein 1 in the Pathological Diagnosis of Small-Cell Lung Cancer in Biopsy Specimens.

Objective: Our purpose was to investigate the clinicopathological diagnostic value of immunohistochemical antibody for insulinoma-associated protein 1 (INSM1) in biopsy specimens of SCLC. Methods: Biopsy specimens of SCLC diagnosed at the pathology department of Tangshan Gongren Hospital from January 2022 to June 2023 were selected. INSM1 expression was detected and compared with conventional neuroendocrine markers synaptophysin (SYP), chromogranin A (CHGA), and CD56 regarding expression sensitivity and specificity. Results: The sensitivity of INSM1 expression was significantly higher than that of CHGA (95% vs 50%, P = .000), but there was no statistically significant difference in the specificity of INSM1, SYP, CHGA, and CD56 expression (100% vs 94% vs 98% vs 92%, respectively, P = .241, 1.000, .126). Conclusions: INSM1 antibody shows high sensitivity and specificity in the expression of SCLC and serves as a reliable immunohistochemical marker in the clinicopathological diagnosis of SCLC in biopsy specimens.

The role of insulinoma-associated protein 1 in predicting the progression and prognosis of human olfactory neuroblastoma in China

ObjectiveRecent studies have suggested that insulinoma-associated protein 1 (INSM1) is a useful marker for pathological diagnosis of neuroendocrine tumors. In the present study, we investigated the association between INSM1 expression and prognosis in patients with olfactory neuroblastoma (ONB) and assessed the usefulness of INSM1 as a prognostic biomarker in these patients. MethodImmunohistochemistry was performed on 109 ONB patients who underwent endoscopic surgery at Beijing Tong Ren Hospital (Beijing, China) between June 2006 and November 2021 Patient age at the time of surgery ranged from 10 months to 72 years (mean age, 43.55 ± 13.47 years). In total, 63 (57.8%) and 46 (42.2%) tumors occurred in male and female patients, respectively. The percentages of grade I–IV cases were 13.8% (15/109), 36.7% (40/109), 29.4% (32/109) and 20.2% (22/109), respectively. ResultsThe expression rate (moderately/strongly positive) of INSM1 was significantly higher in high-grade (Ⅲ/Ⅳ; 83%; 45/54) than low-grade (Ⅰ/Ⅱ; 27%; 15/55) ONB cases. High expression levels of INSM1 were significantly positively associated with high pathological stage (p < 0.001), local recurrence, and death. Kaplan‑Meier analysis revealed that patients with high INSM1 expression had significantly shorter disease‑free survival (DFS) and mean survival (75.01 ± 10.71 vs. 158.56 ± 10.32) times, and shorter overall survival (OS). Multivariate Cox regression analysis revealed that INSM1 was an independent prognostic factor for DFS (HR: 4.963, 95%CI [2.11–10.84] p < 0.001) and OS (HR: 4.791, 95%CI [2.117–10.485], p < 0.001) after adjusting for sex, age, and tumor grade. In addition, INSM1 was an independent prognostic factor for DFS in patients treated with surgery (HR: 3.714, 95%CI [1.267–10.889], p = 0.017) and chemotherapy (HR: 5.574, 95%CI [1.584–19.612], p = 0.007). ConclusionINSM1 expression had a positive association with the prognosis of patients with ONB and could serve as a prognostic biomarker in these patients.

Musashi-1 Is a Novel Immunohistochemical Marker of Neuroendocrine Carcinoma of the Lung

Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) have recently been grouped as lung neuroendocrine carcinomas (NECs). Because these lung NECs are clinically malignant and their treatment strategies differ from those of non-SCLC, the quality of diagnosis has a significant prognostic impact. The diagnosis of LCNEC requires positive immunohistochemical staining with chromogranin A, synaptophysin, and CD56, along with a morphological diagnosis, and insulinoma-associated protein 1 (INSM1) has been proposed as an additional marker but is still not an ideal or better marker. We investigated Musashi-1 as a novel immunohistochemical marker in 42 patients with SCLCs and 44 with LCNECs who underwent lung resection between 1998 and 2020 at our institution. We found Musashi-1 expression in 98% (41/42) SCLC and in 90% (40/44) LCNEC. These findings were similar to CD56 expression and superior to synaptophysin, chromogranin A, and INSM1. Musashi-1 also tended to show more diffuse and intense staining, especially in LCNEC, with more cases staining &gt; 10% than any other existing markers (Musashi-1, 77%; INSM1, 45%; chromogranin A, 34%; synaptophysin, 41%; and CD56, 66%). In conclusion, we identified Musashi-1 as a novel immunohistochemical staining marker to aid in the diagnosis of lung NEC.

Insulinoma-Associated Protein 1 (INSM1) Expression in Neuroendocrine Neoplasms: A Newly Discovered Diagnostic Marker

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 &lt; 0.05). Mean H-score of INSM1 was significantly higher than SYN and CgA and it was statistically significant (p-value &lt; 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.

High expression of insulinoma-associated protein 1 (INSM1) distinguishes colorectal mixed and pure neuroendocrine carcinomas from conventional adenocarcinomas with diffuse expression of synaptophysin.

Complementary to synaptophysin and chromogranin A, insulinoma-associated protein 1 (INSM1) has emerged as a sensitive marker for the diagnosis of neuroendocrine neoplasms. Since there are no comparative data regarding INSM1 expression in conventional colorectal adenocarcinomas (CRCs) and colorectal mixed adenoneuroendocrine carcinomas/neuroendocrine carcinomas (MANECs/NECs), we examined INSM1 in a large cohort of conventional CRCs and MANECs/NECs. In conventional CRC, we put a special focus on conventional CRC with diffuse expression of synaptophysin, which carry the risk of being misinterpreted as a MANEC or a NEC. We investigated INSM1 according to the immunoreactive score in our main cohort of 1,033 conventional CRCs and 21 MANECs/NECs in comparison to the expression of synaptophysin and chromogranin A and correlated the results with clinicopathological parameters and patient survival. All MANECs/NECs expressed INSM1, usually showing high or moderate expression (57% high, 34% moderate, and 9% low), which distinguished them from conventional CRCs, which were usually INSM1 negative or low, even if they diffusely expressed synaptophysin. High expression of INSM1 was not observed in conventional CRCs. Chromogranin A was negative/low in most conventional CRCs (99%), but also in most MANECs/NECs (66%). Comparable results were observed in our independent validation cohorts of conventional CRC (n = 274) and MANEC/NEC (n = 19). Similar to synaptophysin, INSM1 expression had no prognostic relevance in conventional CRCs, while true MANEC/NEC showed a highly impaired survival in univariate and multivariate analyses (e.g. disease-specific survival: p < 0.001). MANECs/NECs are a highly aggressive variant of colorectal cancer, which must be reliably identified. High expression of INSM1 distinguishes MANEC/NEC from conventional CRCs with diffuse expression of the standard neuroendocrine marker synaptophysin, which do not share the same dismal prognosis. Therefore, high INSM1 expression is a highly specific/sensitive marker that is supportive for the diagnosis of true colorectal MANEC/NEC.

Cutaneous Neuroendocrine Mucinous Carcinomas Are Low-grade But May Be Associated With Other Cancers.

Primary cutaneous mucinous sweat gland carcinoma is said to be prognostically stratifiable by neuroendocrine differentiation, however, this assertion is based on historical data and older staining techniques. We aimed to evaluate the percentage of mucinous and nonmucinous adnexal tumors expressing the newer, more sensitive neuroendocrine marker insulinoma-associated protein 1 (INSM1), and to assess clinicopathologic features in patients cohorted by this phenotype. Of 12 available adnexal/cutaneous adenocarcinomas, 9 were mucinous, 3/9 of which were INSM1-negative, and 2/3 with nodal metastases. Of 3 nonmucinous cases, all were INSM1-negative, 1/3 with nodal metastasis, and 2/3 with lymphovascular invasion. In contrast, of 6 mucinous INSM1-positive cases, no cases had LVI or metastasis, however, 3 patients died during follow-up, 2 from breast or urothelial cancer. A fourth patient developed breast carcinoma. INSM1-positive tumors, from cheek (3), scalp (2), and chin (1) were estrogen receptor and progesterone receptor positive. No cases of apocrine adenoma or hidrocystoma, basal cell, or sebaceous carcinoma labeled with INSM1. While most primary cutaneous mucinous carcinomas are of the neuroendocrine type, our study confirms the presence of occasional non-neuroendocrine mucinous carcinomas. We validate the association of such tumors and nonmucinous non-neuroendocrine adnexal carcinoma with intermediate-grade behavior, including lymph node metastases, but not death. Conversely, neuroendocrine expressing primary cutaneous mucinous carcinoma may represent the well-differentiated neuroendocrine neoplasm/neuroendocrine tumor primary to skin, with low-grade behavior, but attendant risk of germline susceptibility to other aggressive extracutaneous tumors. Routine assessment of cutaneous adnexal carcinoma with INSM1 and longer term follow-up and cancer screening of patients with positive staining is recommended.

Extraskeletal myxoid chondrosarcoma: A study of 17 cases focusing on the diagnostic utility of INSM1 expression and presenting rare morphological variants associated with non-EWSR1::NR4A3 fusions.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain lineage. Insulinoma-associated protein 1 (INSM1) has recently been described as a highly specific and sensitive immunohistochemical marker for EMC. The goal of this study was to evaluate the diagnostic significance of INSM1 immunohistochemistry in EMC. Furthermore, correlations between molecular and morphological findings were performed. Sixteen of 17 EMC cases were stained with the INSM1 antibody. Tumors with at least 5% INSM1-positive cells and any staining intensity were considered positive. Molecular testing was successfully performed in 12/17 cases. The immunohistochemical analysis detected 13 INSM1-positive (81%) and 3 INSM1-negative tumors (19%). The extent of the staining was classified as 1+ in 7 cases (44%), 2+ in 2 cases (13%), 3+ in 2 cases (13%) and 4+ in 2 cases (13%). Intensity of immunostaining was weak in 5 cases (31%), moderate in 2 cases (13%) and strong in 6 cases (38%). Molecular assays revealed 8 EWSR1::NR4A3 positive tumors (67%), 2 TAF15::NR4A3 positive tumors (17%), 1 TCF12::NR4A3 positive tumor (8%) and 1 NR4A3 positive tumor (8%) in which no other gene alteration was identified. Two of them, namely TCF12 positive and one TAF15 positive tumors, were highly cellular and partially associated with pseudopapillary architecture. Our study found that moderate/strong expression of INSM1 in more than 25% of tumor cells was present in only 31% of cases. Thus, the diagnostic utility of INSM1 is rather low. Two morphologically unique cases of non-EWSR1 rearranged EMC with an extremely rare pseudopapillary growth pattern are also reported.

Immunosensitivity and specificity of insulinoma-associated protein 1 (INSM1) for neuroendocrine neoplasms of the uterine cervix.

Previously, we reported that insulinoma-associated protein 1 (INSM1) immunohistochemistry (IHC) showed high sensitivity for neuroendocrine carcinoma of the uterine cervix and was an effective method for histopathological diagnosis, but that its specificity remained to be verified. Therefore, the aim was to verify the specificity of INSM1 IHC for a large number of non-neuroendocrine neoplasia (NEN) of the cervix. RNA sequences were performed for cell lines of small cell carcinoma (TCYIK), squamous cell carcinoma (SiHa), and adenocarcinoma (HeLa). A total of 104 cases of formalin-fixed and paraffin-embedded specimens, 16 cases of cervical NEN and 88 cases of cervical non-NEN, were evaluated immunohistochemically for conventional neuroendocrine markers and INSM1. All processes without antigen retrieval were performed by an automated IHC system. The transcripts per million levels of INSM1 in RNA sequences were 1505 in TCYIK, 0 in SiHa, and HeLa. INSM1 immunoreactivity was shown only in the TCYIK. Immunohistochemical results showed that 15 cases of cervical NEN showed positive for INSM1; the positivity score of the tumor cell population and the stain strength for INSM1 were high. Two of the 88 cases of cervical non-NENs were positive for INSM1 in one case each of typical adenocarcinoma and squamous cell carcinoma. The sensitivity of INSM1 for cervical NEN was 94%; specificity, 98%; the positive predictive value, 88%; and the negative predictive value, 99%. INSM1 is an adjunctive diagnostic method with excellent specificity and sensitivity for diagnosing cervical NEN. Higher specificity can be obtained if morphological evaluation is also performed.

INSM1 Expression in Mesenchymal Tumors and Its Clinicopathological Significance.

Insulinoma-associated protein 1 (INSM1) has been identified as a nuclear marker of neuroendocrine tumors. Although INSM1 appears to be a subtle and specific biomarker for neuroendocrine tumor, its expression and clinicopathological significance in mesenchymal tumors remain unclear. We analyzed INSM1 mRNA level in GEO database and conducted immunohistological staining to detect the expression of INSM1 on 576 mesenchymal tumors from pathology department of Tongji Hospital. At transcription level, INSM1 expression in AITL (angioimmunoblastic T-cell lymphoma) was higher than their adjacent normal tissues as well as Hodgkin's lymphoma. Moreover, INSM1 expression in well-differentiated liposarcoma (WDLPS) was significantly higher than normal fat (P = 0.014) and dedifferentiated liposarcoma (DDLPS) (P = 0.0248). At protein level, the positive rate of INSM1 in AITL was 18/48 (47.4%), while in DDLPS was 9/20 (45%). INSM1 expression in AITL was significantly higher than Hodgkin's lymphoma (P = 0.008). And INSM1 expression in WDLPS was significantly lower than DDLPS (P = 0.015). The combination of GEO data and immunohistochemistry data indicated that the expression level of INSM1 was higher in AITL compared with normal control, suggesting that INSM1 may be involved in pathogenesis of AITL. The abnormal expression of INSM1 was found in WDLPS, and the positive rate of INSM1 was higher in DDLPS than in WDLPS. INSM1 may be involved in the regulation of liposarcoma development. There were significant differences in the expression of INSM1 between AITL and Hodgkin's lymphoma and WDLPS and DDLPS. These findings may assist in the differential diagnosis of these tumors when common markers are difficult to identify, enriching the diagnostic index system of mesenchymal tumors.

Cytological diagnosis of olfactory neuroblastoma at metastatic sites, with emphasis on role of insulinoma-associated protein 1 immunocytochemistry.

Olfactory neuroblastoma (ONB) is a rare neuroectodermal tumor with a propensity for lymph node and distant metastases in a proportion of cases, presenting opportunities for cytological diagnosis. Insulinoma-associated protein 1 (INSM1) is a recently identified marker of neuroendocrine differentiation with higher sensitivity and specificity than traditional neuroendocrine immunostains used in diagnosis of ONB. Archival aspirates diagnosed as metastatic ONB were retrieved and reviewed for described characteristics of ONB. Spare direct smears with sufficient cellular material from each case were selected, if available, and immunocytochemistry for INSM1 was performed on the destained alcohol-fixed smears. INSM1 was also performed on non-neuroendocrine malignant round cell tumors (MRCT). Seven fine needle aspirates (FNA) from five patients were identified, all of which showed a small round cell tumor with fine to coarse granular chromatin. Most cases had moderate to high cellularity, comprised of loosely cohesive clusters and dispersed cells. While two-cell pattern, nuclear streaking and moulding were frequent, background neuropil, fibrillary cytoplasm, and rosettes were uncommon. INSM1 immunostaining performed on spare direct smears showed strong positivity in 30%-100% of tumor cells (mean: 62%) in all aspirates tested (100%). In comparison with other immunostains, INSM1 showed more robust staining, and was easier to interpret. All non-neuroendocrine MRCTs were negative for INSM1. Metatstatic ONB can resemble other small round cell tumors, as all the diagnostic features of ONB may not be readily evident. INSM1 immunocytochemistry has high sensitivity and specificity and can reliably be used as a single marker to support the cytomorphology for a confirmatory diagnosis of ONB, even on direct smears if a cell block is not available.

Co-Expression of Adaptor Protein FAM159B with Different Markers for Neuroendocrine Cells: An Immunocytochemical and Immunohistochemical Study.

Little is known about the adaptor protein FAM159B. Recently, FAM159B was shown to be particularly expressed in neuroendocrine cells and tissues, such as pancreatic islets and neuroendocrine cells of the bronchopulmonary and gastrointestinal tracts, as well as in different types of neuroendocrine tumours. To gain insights into possible interactions of FAM159B with other proteins and/or receptors, we analysed the co-expression of FAM159B and various neuroendocrine-specific markers in the cancer cell lines BON-1, PC-3, NCI-h82, OH-1, and A431 and also in human pancreatic tissues and pancreatic neuroendocrine tumours. The markers included prominent markers of neuroendocrine differentiation, such as chromogranin A (CgA), neuron-specific enolase (NSE), synaptophysin (SYP), insulinoma-associated protein 1 (INSM1), neural cell adhesion molecule 1 (NCAM1), serotonin (5-HT), somatostatin-14/28 (SST), and several receptors that are typically expressed by neuroendocrine cells, such as dopamine receptor 2 (D2R), somatostatin receptor (SSTR) 1, 2, 3, 4 and 5, and regulator of G-protein signalling 9 (RGS9). FAM159B was expressed evenly throughout the cytosol in all five cancer cell lines. Immunocytochemical and immunohistochemical analyses revealed co-expression of FAM159B with SYP, INSM1, RGS9, D2R, SSTR2, SSTR3, SSTR4, and SSTR5 and strong overlapping co-localisation with NSE. Double-labelling and co-immunoprecipitation Western blot analyses confirmed a direct association between FAM159B and NSE. These results suggest the involvement of FAM159B in several intracellular signalling pathways and a direct or indirect influence on diverse membrane proteins and receptors.

Insulinoma-Associated Protein 1 (INSM1): Diagnostic, Prognostic, and Therapeutic Use in Small Cell Lung Cancer

Small cell lung carcinoma (SCLC) is an aggressive and difficult to treat cancer. Although immunohistochemistry is not mandatory for a SCLC diagnosis, it might be required, especially in small samples. Insulinoma-associated protein 1 (INSM1) is expressed in endocrine and nervous tissues during embryogenesis, generally absent in adults and re-expressed in SCLC and other neuroendocrine neoplasms. Its high specificity propelled its use as diagnostic biomarker and an attractive therapeutic target. Herein, we aim to provide a systematic and critical review on the use of INSM1 for diagnosis, prognostication and the treatment of SCLC. An extensive bibliographic search was conducted in PubMed® focusing on articles published since 2015. According to the literature, INSM1 is a highly sensitive (75–100%) and specific (82–100%) neuroendocrine immunohistochemical marker for SCLC diagnosis. It can be used in histological and cytological samples. Although advantageous, its standalone use is currently not recommended. Studies correlating INSM1 expression and prognosis have disclosed contrasting results, although the expression seemed to entail a worse survival. Targeting INSM1 effectively suppressed SCLC growth either as a suicide gene therapy regulator or as an indirect target of molecular-targeted therapy. INSM1 represents a valuable biomarker for a SCLC diagnosis that additionally offers vast opportunities for the development of new prognostic and therapeutic strategies.

Abstract 5252: In colorectal cancer (CRC), neuroendocrine carcinoma (NEC) is contaminated in the cancer given a confirmed diagnosis of poorly differentiated adenocarcinoma (P-ad-ca)

Abstract Background: Most of CRC were well or moderately differentiated adenocarcinoma and P-ad-ca is very rare. In Japan, P-ad-ca was reported to be only 4-6% of all CRC. NEC is also rare. The incidence of that were reported to be less than 1%. One of their points of common is morphological poorly differentiated appearance. In this study, we evaluated the incidence of NEC contaminated in the CRC given a confirmed diagnosis as P-ad-ca. Material and Method: From 2009 to 2019, 816 CRCs were resected in department of Yokohama City University Hospital and 74 cases showing P-ad-ca or having a small region of P-ad-ca with well or moderately differentiated ad-ca (W-ad-ca, M-ad-ca). Among the 74 cases, there were 8 of P-ad-ca, 4 of W-ad-ca with P-ad-ca, 44 of M-ad-ca with P-ad-ca, and 18 W-ad-ca and M-ad-ca with P-ad-ca. Immunohistochemistry (IHC) using neuroendocrine markers (NM) including chromogranin A, synaptophysin and insulinoma-associated protein 1 (INSM1) was performed to identified NEC. Recently, a high incidence of Rb protein loss was reported in NEC of several organs, then IHC using Rb monoclonal antibody was also performed. The cancers showing immunohistochemically positive of at least one of the three NM and negative of Rb were identified as true NEC in this study. Results: At least one of the three NM was positive in the 39 cases. In these 39 cases, 3 cases were also Rb negative. Two of the three cases were region of P-ad-ca. These 2 P-ad-ca regions showed positive of NM. Interestingly, in the other one case, region of W-ad-ca showed positive of NM and negative of Rb. Region of P-ad-ca of the case showed positive of all three NM and Rb. From morphological appearance, this case was quite unlikely to true NEC. Conclusion: In 74 P-ad-ca, 2 cases might be true NEC in our small evaluation. NEC might be contaminated in the P-ad-ca of CRC which is difficult to be distinguished by only pathological findings of HE staining. Citation Format: Yuhan Rong, Yuma Takeda, Naoki Okubo, Akihiro Suzuki, Motohiko Tokuhisa, Noritoshi Kobayashi, Atsushi Ishibe, Ikuma Kato, Shoji Yamanaka, Satoshi Fujii, Itaru Endo, Yasushi Ichikawa. In colorectal cancer (CRC), neuroendocrine carcinoma (NEC) is contaminated in the cancer given a confirmed diagnosis of poorly differentiated adenocarcinoma (P-ad-ca) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5252.

Pulmonary Neuroendocrine Cells and Small Cell Lung Carcinoma: Immunohistochemical Study Focusing on Mechanisms of Neuroendocrine Differentiation.

Neuroendocrine (NE) differentiation has been histochemically detected in normal and cancer tissues and cells. Immunohistochemical analyses have provided a more detailed understanding of NE biology and pathology. Pulmonary NE cells are a rare lung epithelial type, and small cell carcinoma of the lung (SCLC) is a high-grade NE tumor. Pulmonary NE and SCLC cells share common mechanisms for NE differentiation. Neural or NE cell lineage-specific transcription factors, such as achaete-scute homologue 1 (Ascl1) and insulinoma-associated protein 1 (INSM1), are crucial for the development of pulmonary NE cells, and NE differentiation is influenced by the balance between Ascl1 and the suppressive neural transcription factor, hairy-enhancer of split 1, a representative target molecule of the Notch signaling pathway.In this review, we discuss the importance of Ascl1 and INSM1 in identifying pulmonary NE and SCLC cells and introduce Ascl1-related molecules detected by comparative RNA-sequence analyses. The molecular classification of SCLC based on the expression of lineage-specific transcription or co-transcription factors, including ASCL1, NEUROD1, POU2F3, and YAP1, was recently proposed. We attempted to characterize these 4 SCLC subtypes using integrated immunohistochemical studies, which will provide insights into the molecular characteristics of these subtypes and clarify the inter- and intratumor heterogeneities of SCLC.

Diagnostic evaluation of selected granin family proteins and INSM-1 (Insulinoma-associated protein 1) in patients with medullary thyroid carcinoma

Diagnostic evaluation of selected granin family proteins and INSM-1 (Insulinoma-associated protein 1) in patients with medullary thyroid carcinoma

Granin family peptides and INSM-1 (Insulinoma-associated protein 1) in the biochemical diagnosis of pheochromocytoma

Granin family peptides and INSM-1 (Insulinoma-associated protein 1) in the biochemical diagnosis of pheochromocytoma

Utility of Secretagogin as a Novel Marker for the Diagnosis of Lung Neuroendocrine Carcinoma

BackgroundSmall cell lung cancers (SCLC) and large cell neuroendocrine carcinomas (LCNEC) are a subset of high‐grade lung carcinomas with characteristic morphology and molecular profile. Commonly used neuroendocrine markers include synaptophysin, chromogranin A, CD56, and insulinoma‐associated protein 1 (INSM1). However, none of these neuroendocrine markers are perfectly sensitive nor specific. Thus, we examined the utility of a calcium‐binding protein, secretagogin (SCGN), which is found mainly in neuroendocrine cells and neurons for diagnosing high‐grade neuroendocrine carcinomas (NECs) of the lung.Materials and MethodsA total of 71 pulmonary NEC resection specimens were collected from the pathology archive between 2005 and 2021, including 18 SCLCs, 13 combined‐SCLCs (c‐SCLCs), 23 LCNECs, and 17 combined‐LCNECs (c‐LCNECs). Immunohistochemical stains with SCGN were done and compared with synaptophysin, chromogranin A, CD56, and INSM1. The stains were evaluated by Allred scoring system which combined staining intensity and proportion of positive tumor cells. Both intensity score (none =0, mild =1, moderate =2, strong =3) and proportion score (0% =0, &lt;1% =1, 1‐10% =2, 11‐33% =3, 34‐66% =4, 67‐100% =5) were summed up to give a final Allred score between 0 and 8. At least mild staining intensity in at least 1% of the cells was considered positive (Allred score greater than or equal to 2). Clinicopathological parameters such as age, sex, smoking history, tumor size, and tumor stage were also retrieved from the medical chart. Paired T‐test (two‐sided) was used to compare the Allred scores and positive proportions of each stain. Fisher’s exact test was used for categorical variables. A P‐value less than 0.05 was considered statistically significant.ResultsBioinformatic study showed the specific SCGN expression in neuroendocrine cells and NECs. No significant difference was observed among the four NEC categories regarding age, sex, tumor size, and staging. All patients had a history of smoking. SCGN showed diffuse nuclear and cytoplasmic staining in NECs with intra‐tumoral heterogenicity (Figure 1). The non‐neuroendocrine components were negative for SCGN. Sensitivity of SCGN was no better than the other established neuroendocrine markers based on Allred score for all cases combined or LCNECs/c‐LCNECs only. However, the sensitivity of SCGN (71%) was slightly higher than chromogranin A (68%) based on Allred score for SCLCs/c‐SCLCs only. The average percentage of SCGN positive tumor cells was 8% higher than chromogranin A (22% versus 14%, P=0.0332) in all NECs and 18% higher (32% for SCGN versus 13% for chromogranin A, P=0.0054) for SCLC and c‐SCLC cases only.ConclusionSCGN had the lowest sensitivity (55%) among the markers. However, it performed better than chromogranin A (71% versus 68%) in the diagnosis of SCLCs and c‐SCLCs. Its positive tumor cell percentage was significantly higher than chromogranin A in SCLCs and c‐SCLCs (18% higher, P=0.0054). The above data showed that SCGN could be used as a supplemental neuroendocrine marker to diagnose small cell carcinoma.

Utility of secretagogin as a marker for the diagnosis of lung neuroendocrine carcinoma.

Small-cell lung cancers (SCLC) and large-cell neuroendocrine carcinomas (LCNEC) are two types of high-grade pulmonary neuroendocrine carcinomas (NECs). Diagnostic neuroendocrine markers commonly include synaptophysin, chromogranin A, CD56, and insulinoma-associated protein 1 (INSM1). In this study, the utility of secretagogin (SCGN) was examined in the context of pulmonary NEC diagnosis. The study included 71 pulmonary NEC cases (18 SCLCs, 13 combined-SCLCs, 23 LCNECs, and 17 combined-LCNECs). Immunohistochemical stains of SCGN, synaptophysin, chromogranin A, CD56, and INSM1 were performed on whole tumor sections. The stains were evaluated based on combined staining intensity and the proportion of positive tumor cells. At least mild staining intensity in at least 1% of the cells was considered positive. Bioinformatic studies showed specific SCGN expression in neuroendocrine cells and NECs. SCGN showed diffuse nuclear and cytoplasmic staining in NECs with intra-tumoral heterogeneity. The non-neuroendocrine components were negative. The sensitivity of SCGN was no better than the other established neuroendocrine markers based on all NECs combined or LCNECs/c-LCNECs only. However, the sensitivity of SCGN (71%) was higher than chromogranin A (68%) for SCLCs/c-SCLCs only. The average proportion of SCGN positive tumor cells was 8% higher than chromogranin A (22% versus 14%, P = 0.0332) in all NECs and 18% higher for SCLC and c-SCLC cases only (32% versus 13%, P = 0.0054). The above data showed that SCGN could be used as a supplemental neuroendocrine marker to diagnose SCLC.

Immunohistochemical analyses of the expression profiles of INSM1, ATRX, DAXX and DLL3 in solid papillary carcinomas of the breast.

Solid papillary carcinoma (SPC) is a rare but distinct clinicopathological feature of breast cancer characterised by frequent neuroendocrine differentiation. Insulinoma-associated protein 1 (INSM1) is a useful neuroendocrine marker for various neuroendocrine tumours. α-thalassemia/mental retardation syndrome X-linked protein (ATRX) and death domain-associated protein (DAXX) are useful prognostic markers for patients with pancreatic neuroendocrine tumours. However, to the best of our knowledge, few studies have addressed INSM1 expression in SPCs. Although ATRX, DAXX and δ-like canonical notch ligand 3 (DLL3) are frequently expressed in neuroendocrine lung carcinomas, there are no reports on their expression in SPCs. Therefore, the present study aimed to analyse the expression profiles of INSM1, ATRX, DAXX and DLL3 in the largest series of patients with SPC that has been, to the best of our knowledge, studied until now. Immunohistochemical analyses were performed to determine chromogranin A, synaptophysin, INSM1, ATRX, DAXX and DLL3 expression in 39 specimens surgically resected from patients with SPC (18 SPC in situ and 21 SPC invasive). The associations between the expression of these markers and the clinicopathological factors were investigated. Chromogranin A, synaptophysin and INSM1 were expressed in 64.1, 100 and 92.3% of the patients, respectively. Both ATRX and DAXX expression was observed in 28.2% of the patients. No patient expressed DLL3. Lack of INSM1 or chromogranin A expression was significantly associated with advanced pathological stages in patients with SPC (P=0.033) and in patients with invasive SPC (P=0.012), showing a tendency for a high Ki-67 labelling index (LI) and advanced histological grade in patients with invasive SPC. Loss of ATRX or DAXX expression was significantly associated with lymphatic invasion, but not with histological grade, Ki-67 LI or presence of invasive tumours. Thus, INSM1 was demonstrated to be a useful diagnostic marker for SPCs. Overall, detecting the lack of INSM1 or chromogranin A expression may be useful for analysing the characteristics of tumour cells in SPCs.

SOX11 is a sensitive and specific marker for pulmonary high-grade neuroendocrine tumors

BackgroundSynaptophysin (SYN), chromogranin A (CGA), CD56 and insulinoma-associated protein 1 (INSM1) are proposed neuroendocrine (NE) markers used for diagnosis of pulmonary NE tumors. These NE markers have been identified in subsets of non-NE tumors requiring differential diagnosis, thus we sought to explore new NE markers.MethodsWe evaluated the immunohistochemical expression of SOX11, a transcription factor involved in neurogenesis, in pulmonary NE tumors and large cell carcinomas (LCCs).ResultsWe found that SOX11 showed a sensitivity similar to INSM1 and CGA, and less than SYN and CD56 in small cell lung carcinomas (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). While SOX11 is more specific than the other four markers for diagnosis of high-grade neuroendocrine carcinomas (HG-NECs) because 1) None of LCCs (0/63), the most challenging non-NE tumor type for differential diagnosis due to overlapped morphology with LCNECs displayed SOX11 positivity. While expression of at least one of SYN, CGA, CD56 or INSM1 was identified in approximately 60% (18/30) of LCCs. 2) SOX11 was only expressed in 1 of 37 carcinoid tumors in contrast to diffuse expression of SYN, CGA, CD56 and INSM1. In HG-NECs, we noticed that SOX11 was a good complementary marker for SCLC diagnosis as it was positive in 7 of 18 SYN−/CGA−/CD56− SCLCs and 3 of 8 SYN−/CGA−/CD56−/INSM1− SCLCs, and SOX11 positivity in 4 of 6 SYN−/CGA−/CD56− cases previously diagnosed as LCCs with NE morphology provides additional evidence of NE differentiation for reclassification into LCNECs, which was further confirmed by electromicroscopical identification of neurosecretory granules. We also found SOX11 expression cannot predict the prognosis in patients with HG-NECs.ConclusionsTherefore, SOX11 is a useful complementary transcriptional NE marker for diagnosis and differential diagnosis of SCLC and LCNEC.