Expression of SATB2 in Neuroendocrine Carcinomas of the Lung: Frequent Immunopositivity of Large Cell Neuroendocrine Carcinoma with a Diagnostic Pitfall

Abstract

Small cell lung carcinoma (SCLC) and pulmonary large cell neuroendocrine carcinoma (LCNEC) are both classified as lung neuroendocrine carcinoma (NEC). It has recently been reported that the special AT-rich sequence-binding protein 2 (STAB2), known as a colorectal cancer marker, is also expressed in NECs occurring in various organs including the lung. However, few studies have examined any differences of SATB2 immunopositivity between SCLC and LCNEC. We investigated SATB2 expression in 45 SCLC and 14 LCNEC cases using immunohistochemistry as well as the expression of caudal-type homeobox 2 (CDX2) and keratin (KRT) 20. The LCNEC cases were more frequently positive for SATB2 (ten out of 14, 71%) than the SCLC ones (seventeen out of 45, 38%) with a statistically significance (P = 0.035). Furthermore, two LCNEC cases were positive for CDX2 while no positive findings were observed for any SCLC cases, the difference of which, however, was not statistically significant (P = 0.053). KRT20 was negative in all LCNEC and SCLC cases. These results require our attention when we use SATB2 and CDX2 as colorectal cancer markers because their expression in pulmonary NECs can lead to a misdiagnosis that the tumor is of metastatic colorectal adenocarcinoma, especially when the patient has a past history of colorectal cancer. Analyzing the relationship between the demographic/clinical variables and the SATB2 expression in the SCLC cases, just high Brinkman index (≥ 600) was significantly related to the positivity of SATB2 (P = 0.017), which is interesting considering the strong relationship between SCLC and smoking.

Keywords

lung cancer large cell neuroendocrine carcinoma small cell lung carcinoma SATB2 CDX2

Introduction

According to the Surveillance, Epidemiology, and End Results (SEER), the estimated new cases of lung and bronchus cancer is 235,760 in the United States in 2021.¹

The histological classification of the World Health Organization (WHO),² lung cancer has different histological types, such as adenocarcinoma and squamous cell carcinoma, neuroendocrine neoplasms, and metastatic tumors. There are an estimated 20.8/100,000 adenocarcinoma, 9.6/100,000 squamous cell carcinoma, 5.3/100,000 small cell cancer and 0.5/100,000 large cell cancer patients in 2018.¹ For which various treatment options, including surgical resection and radiation therapy as well as anticancer agents, thymidine kinase inhibitors, and immune checkpoint inhibitors, are available. Because therapeutic choices and results differ greatly depending on the histological type and the related genotype, making accurate histopathological diagnosis is of primary importance, for which immunohistochemical marker studies are often useful and considered to be essential.

Neuroendocrine neoplasms of the lung are classified into small cell lung carcinoma (SCLC), large cell neuroendocrine carcinoma (LCNEC), carcinoid tumor, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.² SCLC and LCNEC are collectively referred to as neuroendocrine carcinoma (NEC),^3,4 and noted for the poor prognosis of affected patients, with the positivity of some immunohistochemical neuroendocrine markers being a hallmark for their histopathological diagnosis.

Recent studies have found that some neuroendocrine neoplasms of various organs, including the lung, are immunohistochemically positive for special AT-rich sequence-binding protein 2 (SATB2) and caudal-type homeobox 2 (CDX2), both of which are known as positive markers for colorectal cancer.^5-7

Though they are not essential for establishing neuroendocrine phenotype of a tumor, but they can provide supplementary information to make accurate histopathological diagnosis by combination with neuroendocrine differentiation markers, such as synaptophysin, chromogranin A and Neural cell adhesion molecule 1 (CD56).^8,9

Considering that the most frequent type of metastatic cancer of the lung is of colorectal origin,¹⁰ the expression of STAB2 and/or CDX2 can be a misleading factor for histopathological differential diagnosis between pulmonary NEC and metastatic colorectal adenocarcinoma.

However, their expression in NEC of the lung has not been sufficiently elucidated, and there is no known previous report showing any differences in the positive rate of SATB2 between SCLC and LCNEC, nor any studies that examined the relationship between CDX2 and SATB2 expression in pulmonary NEC. In an attempt to clarify these points, the present investigation was conducted to evaluate the expression of SATB2 and CDX2 in a series of SCLC and LCNEC cases, also with some related immunohistochemical marker studies and some attention to the relationship to demographic and clinical factors of the patients.

Materials and Methods

Patients

The records of 47 cases of pure SCLC treated from January 1, 2016 to July 31, 2019 were obtained from the database of our university's branch hospital. All pathologic specimens associated with those were obtained by transbronchial biopsy. We reviewed all available histologic slides according to the WHO diagnostic criteria.² The samples in which the number of tumor cells was less than 100 or the cells were significantly crushed were considered to be inappropriate for the analysis and excluded. As a result, 45 of those cases of SCLC were enrolled in this study.

Thirteen cases of pure LCNEC treated from January 1, 2015 to July 31, 2019 were also obtained from the same database. After reviewing all available slides obtained for histology, three cases were excluded because a diagnosis of small cell carcinoma was favored. Additionally, four cases of pure LCNEC treated during the same period were obtained from the database of our university hospital, the histopathologic diagnosis of which was confirmed by reviewing all available histologic slides. Thus fourteen LCNEC cases in total were enrolled finally. All LCNEC specimens in those cases were obtained by surgery.

The demographic and clinical data were obtained from the medical record of each patient, including age, sex, smoking habit (Brinkman index [BI]), serum tumor marker values (CEA, carcinoembryonic antigen; CYFRA, cytokeratin fragment 19; NSE, neuron specific enolase; ProGRP, pro-gastrin releasing peptide), the number of times anticancer drugs was administered, ECOG Performance status, and UICC tumor stage.

Immunohistochemistry

All specimens were routinely fixed in 10% buffered formalin with neutral pH and embedded in paraffin. One representative slide was selected from each case, for which immunohistochemistry for SATB2, CDX2, thyroid transcription factor-1 (TTF-1), CD56, synaptophysin, chromogranin A, and keratin 20 (KRT20) was performed. The antibodies used were as follows: SATB2 (SANTA CRUZ, Dallas, TX, USA; clone SATBA4B10, 1:200 dilution), CDX2 (Dako, Santa Clara, CA, USA; clone DAK-CDX2, 1:50 dilution), CD56 (NICHIREI BIOSCIENCES INC., Tokyo, Japan; clone MRQ-42, ready to use), TTF-1 (Dako; clone 8G7G3/1, 1:100 dilution), Chromogranin A (Dako; clone DAK-A3, 1:200 dilution), Synaptophysin (JAPAN TANNER CORPORATION, Osaka, Japan; clone SP11, ready to use), and KRT20 (Dako; clone Ks20.8, ready to use). Immunohistochemistry for KRT20 was performed using Omnis (Dako), while Autostainer Link 48 (Dako) was utilized for the other antibodies, according to the instructions of each manufacturer.

Immunohistochemistry results were evaluated, and the proportion of the positive extent was scored (proportion score) as 0 (negative), 1 (1%-9%), 2 (10%-49%), or 3 (>50%). Proportion scores of 2 and 3 were regarded as positive. The staining intensity was not considered because there existed no ambiguous intensity cases to evaluate.

Statistical Analysis

For the immunohistochemistry with each antibody, the difference of the positivity based on the proportion score between SCLC and LCNEC was tested by Fisher's exact test on 2 × 2 tables.

For the demographic and clinical data of the SCLC cases, each variable was divided into two categories as shown in the following each parenthesis: age (< 65, ≥ 65), sex (male, female), BI (< 600, ≥ 600), CEA (≤5 ng/ml, >5 ng/ml), CYFRA (≤3.5 ng/ml, >3.5 ng/ml), NSE (≤16.3 ng/ml, >16.3 ng/ml), ProGRP (≤81 pg/ml, >81 pg/ml), the number of times anticancer drugs was administered (≥ 4, < 4), ECOG Performance status (0∼1, 2∼4), and UICC tumor stage (I∼III, IV). The relationship between each variable divided into two categories and the SATB2 positivity based on the proportion score was also tested by Fisher's exact test on 2 × 2 tables for the SCLC cases. The comparison of overall survival between SATB2 positive-cases and negative cases in small cell carcinoma was evaluated by the Kaplan-Meier method with the log-rank test.

A P-value < 0.05 was considered to indicate the statistical significance. SPSS for Windows version 27 (IBM, Armonk, NY) was used for all statistical analyses.

Results

Demographics of the Patients

The average age of the 45 SCLC patients at the time of diagnosis was 70.3 years (range 48-84 years), of whom 36 (80%) were male and nine (20%) were female. The fourteen LCNEC patients, thirteen males and one female, had an average age of 73 years (range 65-84 years) at the time of diagnosis.

All SCLC patients were smokers with BI ≥ 600 in 37 out of 45 patients (82%). As for LCNEC, all patients were smokers with BI ≥ 600.

Histopathologic Findings

The tumor cells of SCLC showed scant cytoplasm and finely granular and hyperchromatic nuclei, which formed irregular-shaped sheetlike nests (Figure 1A). Those of LCNEC had abundant eosinophilic cytoplasm and vesicular nuclei with prominent nucleoli, which formed sheetlike nests characterized by the cell arrangement of rosette-like and/or peripheral palisading patterns (Figure 1B).

Immunohistochemical Profiles

Immunohistochemistry results with each antibody are summarized in Table 1. In the SCLC cases, the positive rate of TTF-1, CD56, synaptophysin, and chromogranin A was 64%, 96%, 71%, and 47%, respectively, while in the LCNEC cases, it was 43%, 100%, 64% and 43%, respectively. All except for two SCLC cases were positive for at least one of the three neuroendocrine markers (Figure 1C, D).

Table 1.

Immunohistochemistry Results for SCLC and LCNEC Statistical Analyses Were Performed Using Fisher’s Exact Test. A P-Value < 0.05 was Considered to Indicate the Statistical Significance.

		SCLC			LCNEC
Immunohistochemical marker	Proportion score (0/1/2/3)	Positive/Total	%	Proportion score (0/1/2/3)	Positive/Total	%	P-value
SATB2	20/8/8/9	17/45	38	3/1/3/7	10/14	71	0.035
CDX2	45/0/0/0	0/45	0	11/1/1/1	2/14	14	0.053
TTF-1	14/2/3/26	29/45	64	7/1/0/6	6/14	43	0.214
CD56	1/1/1/42	43/45	96	0/0/5/9	14/14	100	1
Synaptophysin	10/3/0/32	32/45	71	2/4/3/5	9/14	64	0.742
Chromogranin A	17/7/7/14	21/45	47	7/1/1/5	6/14	43	1
KRT20	0/1/0/0	0/45	0	11/3/0/0	0/14	0	NA

Abbreviations: SCLC, small cell lung carcinoma; LCNEC, large cell neuroendocrine carcinoma; SATB2, the special AT-rich sequence-binding protein 2; CDX2, caudal type homeobox 2; TTF-1, thyroid transcription factor-1; KRT20, keratin 20; NA, not available.

Seventeen out of 45 (38%) SCLC cases (Figure 2A) and 10 out of 14 (71%) LCNEC ones (Figure 2B) were positive for SATB2. The positive rate was higher in the LCNEC cases than in the SCLC ones, significant difference was achieved between them statistically (P = 0.035).

All SCLC cases were negative for CDX2 (Figure 2C), whereas two LCNEC cases (14%) were CDX2 positive (Figure 2D), the difference of which was not statistically significant (P = 0.053). Furthermore, one LCNEC case was positive for CDX2 as well as SATB2 (Figure 2B, D).

KRT20 was negative in all SCLC and LCNEC cases.

Relationship Between Demographic/Clinical Variables and SATB2 Expression

For the SCLC cases, the relationship between the demographic/clinical data and the SATB2 expression is shown in Table 2. Of the demographic and clinical variables examined, only high-BI (≥ 600) was significantly related to the positivity of SATB2 (P = 0.017), in which the SATB2 positivity was noticed more frequently in the high-BI cases (17 out of 37, 46%) then in the low-BI ones (0 out of 8, 0%).

Table 2.

Relationship Between the Expression of SATB2 and Demographic/Clinical Variables in the Patients of SCLC Statistical Analyses Were Performed Using Fisher’s Exact Test. A P-Value < 0.05 was Considered to Indicate the Statistical Significance.

		SATB2 (-)	SATB2 ( + )	p-value
Age				0.086
	<65	2	5
	≥65	26	12
Sex				1.000
	female	6	3
	male	22	14
BI				0.017
	<600	8	0
	≥600	20	17
CEA				0.767
	≤5 ng/ml	15	10
	> 5 ng/ml	13	7
Cyfra				0.065
	≤3.5 ng/ml	11	12
	>3.5 ng/ml	17	5
NSE				0.695
	≤16.3 ng/ml	4	4
	>16.3 ng/ml	15	10
PROGRP				1.000
	≤81 pg/ml	9	6
	>81 pg/ml	18	10
Chemo				0.186
	≥4	12	3
	<4	15	11
PS				1.000
	0～1	25	15
	2～4	3	2
Stage				0.530
	I-III	15	11
	IV	11	5

Abbreviations: SATB2, the special AT-rich sequence-binding protein 2; SCLC, small cell lung cancer; BI, Brinkman index; CEA, carcinoembryonic antigen; CYFRA, cytokeratin fragment 19; NSE, neuron specific enolase; ProGRP, pro-gastrin releasing peptide; Chemotherapy, the number of times the anticancer drug was administered; PS, ECOG Performance Status: Stage, UICC tumor stage.

As for the comparison of overall survival between SATB2-positive cases and SATB2-negative cases in SCLC, no statistical difference was found (p = 0.558, Figure 3).

Discussion

The present results confirmed the SATB2 expression in some pulmonary NECs, as noted in 17 out of 45 (38%) SCLC cases and 10 out of 14 (71%) LCNEC ones. The LCNEC cases have a higher positive rate compared with the SCLC cases with statistical difference (P = 0.035). As for CDX2, two LCNEC cases were positive, while all SCLC cases were negative, the LCNEC cases tended to have a positive rate compared with the SCLC cases (P = 0.053), though the sensitivity of CDX2 as a positive marker in the LCNEC cases was low. Thus, the present results suggest that in pulmonary NECs, LCNECs express colorectal markers such as SATB2 and CDX2 more frequently as compared to SCLCs. The positive rates of immunohistochemical markers other than SATB2 and CDX2 in the present study were similar to those noted in previous reports,^11,12 which was considered to demonstrate that the specimens in this study were not extremely biased. Results of other previous studies about immunohistochemical markers expression in pulmonary NECs were summarized in table 3.^5-7,13-21

Table 3.

Positive Rates of SATB2, CDX2, TTF-1 and Neuroendocrine Markers in the Lung for LCNEC, SCLC and Poorly Differentiated Neuroendocrine Carcinoma.

	LCNEC						SCLC
	SATB2	CDX2	TTF1	Synaptophysin	Chromogranin A	CD56	SATB2	CDX2	TTF1	Synaptophysin	Chromogranin A	CD56	PDNCL SATB2
Nicholson (2002)	−	−	−	−	−	−	−	−	−	57% (41/72)	58% (46/80)	−	−
Barbareschi (2003)	−	−	−	−	−	−	−	0% (0/10)	−	−	−−	−	−
Hiroshima (2006)	−	−	−	77% (13/17)	59% (10/17)	53% (9/17)	−	−	−	57% (13/23)	36% (8/22)	96% (21/22)	−
Maleki (2011)	−	−	−	64% (9/14)	28% (4/14)	45% (5/11)	−	−	−	67% (8/12)	54% (7/14)	91% (10/11)	−−
Bari (2014)	−	55.7% (39/70)	−	−	−	−	−	9.5% (7/73)	−	−	−	−	−
Rossi (2014)	−	−	83% (39/43)	55% (26/47)	40% (40/47)	91.5% (43/47)	−	−	−	−	−	−−	−
Yeh (2014)	−	−	−	68.8% (12/17)	41.2% (7/17)	100% (17/17)	−	−	−	71.4% (25/35)	34.3% (12/35)	97% (32/33)	−
Ye (2016)	−	−	−	81.8% (9/11)	9% (1/11)	36.4% (4/11)	−	−	−	83.3% (20/24)	4.2% (1/24)	79.2% (19/24)	−
Fukuhara (2016)	−	−	−	−	−	−	0%(0/4)	−	−	−	−	−	−
Lee (2018)	−	31% (5/16)	56% (9/16)	−	−	−	−	15% (3/20)	85% (17/20)	−	−	−	−
Hoskoppal (2020)	−	−	−	−	−	−	21%(8/39)	−	−	−	−	−	−
Bellizzi (2020)	−	−	−	−	−	−	−	−	−	−	−	−−	33% (10/30)
Vrana (2021)	−	−	−	−	−	−	74.4(29/39)	−	−	−	−	−	−
Our study (2021)	71% (10/14)	14% (2/14)	43% (6/14)	64% (9/14)	43% (6/14)	100% (14/14)	38%(17/45)	0% (0/45)	64% (29/45)	71% (32/45)	47% (21/45)	96% (43/45)	−

Abbreviations: LCNEC, large cell neuroendocrine carcinoma; SCLC, small cell lung carcinoma; PDNCL, poorly differentiated neuroendocrine carcinomas of lung; SATB2, the special AT-rich sequence-binding protein 2; CDX2, caudal type homeobox 2; TTF-1, thyroid transcription factor-1; CD56, Neural cell adhesion molecule 1.

Along with the understanding of the molecular biological mechanism of the lung carcinogenesis in recent years, treatment strategies have become subdivided according to the histopathological diagnosis and the related genetic mutation status, making accurate histopathological diagnosis primarily important. In addition, the lungs represent the most frequent target of metastasis. Of 82,193 cases of chest surgery performed in 2016 in Japan, surgery for metastatic lung tumors accounted for 8497 (10.3%), including colorectal cancer (47.7%), renal cancer (8.5%), and lung cancer metastasis (2.6%), in descending order of frequency.¹⁰ Therefore, it is not an uncommon situation that histopathological differential diagnosis between primary pulmonary cancer and metastatic colorectal cancer is required, especially when the patient have a past history of colorectal cancer. This is also the case for patients with pulmonary NECs.

In general, a pulmonary NEC can be distinguished from a metastatic colorectal adenocarcinoma based on the morphological findings. However, the discrimination could be difficult when typical morphological features of neuroendocrine neoplasms, such as rosette-like and/or nuclear palisading patterns, cannot be recognized. Furthermore, cases with a past history of poorly differentiated colorectal adenocarcinoma present additional challenges. For these confusing situations, the examination of immunohistochemical markers is mandatory. However, the positive staining of SATB2 and CDX2 in pulmonary NEC specimens can lead to a misdiagnosis that the tumor is of metastatic colorectal adenocarcinoma. Therefore, it is important to recognize that some pulmonary NECs, especially LCNECs, are frequently positive for SATB2 and less frequently CDX2, and to understand that the expression of neuroendocrine markers should be concurrently checked. The sufficient positivity of neuroendocrine markers will favor a diagnosis of NEC in spite of the expression of SATB2 and/or CDX2.

SATB2, a protein comprised of 733 amino acids and encoded by the SATB2 gene located on chromosome 2q33.1, binds to DNA, and transcription factors regulate its expression in the nucleus, which have important roles in the developmental process such as facial development, neocortical differentiation, skeletal development, and osteoblast differentiation.^22-25 In normal tissues, the protein is strongly expressed in the epithelium of the lower gastrointestinal tract, cerebral cortex, and hippocampus.²⁶ With regard to the expression in neoplasms, it was initially focused that SATB2 was immunohistochemically positive in a large majority of adenocarcinomas of the lower gastrointestinal tract (86%-97%).^26-28 However, high positive rates of SATB2 have also been reported in rectosigmoid neuroendocrine tumor (NET) (96%-100%), appendiceal NET (79%-100%), and Merkel cell carcinoma (79%) recently.^5-7 Other studies have reported that SATB2 are positive in 53% of Genitourinary small cell carcinoma, 27% of colorectal NECs and 25% of Pancreatic NECs.^7,29 Similarly pulmonary SCLC or pulmonary NEC (details not shown) have shown the positive rate of SATB2 ranging from 21% to 33%.^5,7 Besides, a most recent study has reported the expression of SATB2 in pulmonary and thymic neuroendocrine tumors (carcinoid tumor and NEC), with a higher percentage of expression in SCLC comparing to the previous reports.²¹ Some NET/NECs are positive for SATB2, regardless of their site of origin,^5,7,29 but our study revealed that pulmonary LCNEC tends to have a higher positive rate of SATB2, similar to rectosigmoid NET and Merkel cell carcinoma.

Considering that SATB2 is expressed in the cerebral cortex and hippocampus tissues, it may be plausible that the SATB2 expression is involved in the neural or neuroendocrine differentiation of tumors derived from various organs, which, however, is to be elucidated by further studies.

CDX2 is a protein encoded by the CDX2 gene in chromosome 13q12.2, a homeobox gene that plays a role in differentiation of normal intestinal epithelium and neural tube closure in vertebrates,^30-32 In normal tissues, CDX2 is expressed in the pancreatic duct and pancreatic centroacinar cells, as well as the digestive tract, but not in other organs including the lungs,³³ while another role of CXD2, the suppression of tumor growth, has also been noted.³⁴ As for pulmonary NEC, previous studies have reported that the positive rates of CDX2 are 0% to 15% in SCLC and 31 to 55.7% in LCNEC,^14,17,20 with the same tendency observed in our results.

Although both SATB2 and CDX2 have been regarded as markers for colorectal cancers, the expression of SATB2 and/or CDX2 in pulmonary NEC does not seem to indicate simple intestinal differentiation as discussed above as well as because all cases in the present study were negative for KRT20 that is a well-known intestinal epithelial marker.³⁵ Here, an interesting point to consider is that SATB2 and CDX2 expressions have been observed even in conventional pulmonary adenocarcinomas, with the reported frequency of 3 to 7.2% for SATB2,^26,28,36 and 0 to 11% for CDX2,^14,36,37 respectively. On the other hand, the positive rates in pulmonary adenocarcinomas with an enteric morphology such as pulmonary enteric adenocarcinoma have been shown to be higher, that is, 13 to 15.4% for SATB2,^38,39 and 61.5 to 71.3% for CDX2,^38-41 respectively. These results imply divergent roles of SATB2 and CDX2 in regard to differentiation of pulmonary tumors.

It has been well known that lung carcinogenesis is strongly related to the habit of tabaco smoking, and that is especially the case for SCLC.^42,43 Interestingly, in the present study, all SATB2-positive SCLC cases had a history of heavy smoking (BI ≥ 600), which was significantly more frequent compared to SATB2-negative SCLC cases.

Conclusion

A limitation of the present study is the relatively small number of LCNEC cases, thus additional analysis with a larger cohort will be necessary. Nevertheless, our results showed that some pulmonary NECs, especially LCNEC, are positive for SATB2 in immunohistochemistry findings, which should be kept in mind when SATB2 is used as a marker for diagnosis of metastatic colorectal cancer. Besides, further investigation of the additional expected clinical significance of SATB2 expression in pulmonary NECs might be needed.

Footnotes

Acknowledgments

We thank Takuya Okamura and Chizuru Sunaoka, staff members of the Department of Pathology, Dokkyo Medical University Saitama Medical Center, for their excellent technical assistance.

Conflict of Interest:

None

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions

Hiromichi Inoue: investigation, writing original draft, resources, data curation, and visualization

Jun Matsushima: conceptualization, methodology, investigation, editing, project administration, and supervision

Satoru Kobayashi: resources

Hirokuni Hirata: resources

Masayuki Chida: resources

Toshimi Sairenchi: formal analysis

Satoshi Ota: conceptualization

Shinichi Ban: writing and editing

Yuji Matsumura: writing and editing.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

Ethical Approval

No.1967

Informed Consent

Not applicable, because this article does not contain any studies with human or animal subjects.

ORCID iDs

Jun Matsushima

Shinichi Ban

Trial Registration

This article does not contain any clinical trials.

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