Utility of Secretagogin as a Novel Marker for the Diagnosis of Lung Neuroendocrine Carcinoma
Authors: Baykara Yigit , Xiao Ying , Yang Dongfang , Yakirevich Evgeny , Garcia‐Moliner Maria L. , Maleki Sara , Wang Li J. , Huang Chiung‐Kuei , Lu Shaolei 
Published: May 2022

Background

Small 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 Methods

A 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, <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.

Results

Bioinformatic 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.

Conclusion

SCGN 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.