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Expression of S100A9 in adamantinomatous craniopharyngioma and its association with wet keratin formation

  • Authors:
    • Chuan Zhao
    • Wenxin Hu
    • Ning Luo
    • Xingfu Wang
    • Da Lin
    • Zhixiong Lin
  • View Affiliations

  • Published online on: April 26, 2023
  • Article Number: 282
  • Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Wet keratin is a hallmark of adamantinomatous craniopharyngioma (ACP), which is frequently infiltrated by inflammatory cells. S100 calcium‑binding protein A9 (S100A9) has been confirmed to play a decisive role in the development of inflammation. However, the relationship between wet keratin (keratin nodules) and S100A9 in ACP is poorly understood. The objective of the present study was to explore the expression of S100A9 in ACP and its association with wet keratin formation. Immunohistochemistry and immunofluorescence were used to detect the expression of S100A9, β‑catenin and Ki67 in 46 cases of ACP. A total of three online databases were used to analyze S100A9 gene expression and protein data. The results revealed that S100A9 was primarily expressed in wet keratin and some intratumoral and peritumoral cells, and its expression in wet keratin was upregulated in the high inflammation group (P=1.800x10‑3). In addition, S100A9 was correlated with the degree of inflammation (r=0.6; P=7.412x10‑3) and the percentage of Ki67‑positive cells (r=0.37; P=1.000x10‑2). In addition, a significant correlation was noted between the area of wet keratin and the degree of inflammation (r=0.51; P=2.500x10‑4). In conclusion, the present study showed that S100A9 was upregulated in ACP and may be closely associated with wet keratin formation and the infiltration of inflammatory cells in ACP.


Craniopharyngioma (CP) is one type of epithelial tumor originating from embryonic remnants in the sellar region, which most commonly occur in individuals aged 5-14 and 50-74 years (1). Traditionally, CP can be divided into two subtypes: Adamantinomatous CP (ACP) and papillary CP (PCP). The latest World Health Organization classification criteria define ACP and PCP as different types (2). ACP is driven by somatic CTNNB1 mutations, and histologically contains palisade-like basal epithelium, loosely aggregated stellate reticulum, cell clusters composed of cells with nucleocytoplasmic accumulation of β-catenin, nodules of anucleated ghost cells with brightly eosinophilic cytoplasm termed wet keratin, calcification, cholesterol clefts and other structures. In addition, high levels of cytokines and inflammatory markers are frequently discovered in the stroma of ACP (3,4).

The mechanism underlying the formation of the special pathological structures of ACP remains to be elucidated, including wet keratin and calcification. S100 calcium-binding protein A9 (S100A9) is a calmodulin that is closely associated with cellular proliferation, differentiation and apoptosis, and is abundant in inflammatory cells, such as neutrophils. Therefore, S100A9 has also been identified as a crucial inflammatory factor (5). S100A9 is also expressed in keratinocytes in certain skin inflammatory diseases, and is expressed and released by keratinocytes and activated leukocytes during inflammation and bodily injury (6,7). Several genes of the S100 family and proteins involved in epidermal keratinization form the so-called epidermal differentiation complex on human chromosome 1q21(8), and evidence has suggested that S100A9 is closely associated with epithelial differentiation (9). In view of the complex inflammatory microenvironment of ACP, it was hypothesized that epithelial differentiation associated with S100A9 may be involved in the formation of wet keratin. Therefore, the present study investigated the expression of S100A9 in ACP and its association with wet keratin formation, in order to obtain improved insight into the tumor biology of ACP.

Materials and methods

Demographic and clinical data

All sample tissues were obtained from cases that underwent surgery (including radical resection and conservative resection) at Beijing Sanbo Brain Hospital (Beijing, China) between September 2016 and September 2019. Cases were selected that had complete clinical information and histological specimens, and for whom follow-up data could be obtained. Cases were excluded that did not have complete clinical information or enough histological specimens, or follow-up data could not be obtained. A total of 46 eligible cases were included in the present study. The baseline data were collected, including age, sex, radiological images, surgical resection and postoperative recurrence (Table I). Follow-up ended in March 2022, and tumor recurrence or death was considered a progressive event. The patients in the present study provided written informed consent. The present study was designed in accordance with The Declaration of Helsinki and approved by the ethics committee of Sanbo Brain Hospital, Capital Medical University (Beijing, China; ethical approval no. SBNK-YJ-2020-014-01).

Table I

Baseline data of patients.

Table I

Baseline data of patients.

Age, years, median (IQR)11.38 (13.06)
     Predominantly cystic29
     Predominantly solid17
Preoperative status 
     Radical resection42
     Conservative resection4
Postoperative status 
     No recurrence39
Hematoxylin and eosin (H&E) staining

Following surgery, the tissue specimens were immersed in 10% formalin for 24-48 h at room temperature. Then the tissue specimens were placed into molds supplemented with liquid paraffin, cooled and frozen to make the paraffin solid to achieve tissue fixation, and sectioned using a paraffin microtome. The wax blocks were cut into 4-µm sections for H&E staining. Sections were stained with hematoxylin for 0.5-1 min, rinsed with running water, differentiated in 1% hydrochloric acid alcohol for a few seconds, rinsed with running water, then returned to 1% ammonia aqueous solution for 1 min, rinsed with running water for a few seconds, stained in eosin staining solution for a few seconds and sealed after rinsing with running water. All the above experimental procedures were carried out at room temperature. Light field microscopy was used for observation.

Immunohistochemistry and immunofluorescence

Following fixation in 10% formalin for 24-48 h at room temperature, the samples were dehydrated in increasing ethanol concentrations, then samples were embedded in paraffin, the wax blocks were cut into 4-µm sections, deparaffinized in xylene and rehydrated with graded ethanol. Antigen retrieval was performed using Tris-EDTA buffer (pH 9.0) in a 95˚C water bath for 15 min. Endogenous peroxidase was inactivated with 3% H2O2 for 10 min at room temperature. and samples were washed with phosphate-buffered saline (PBS). After blocking using the peroxidase blocking agent for 15 min at room temperature, the sections were incubated with the primary antibody overnight at 4˚C and then rinsed with PBS. Horseradish peroxidase-conjugated secondary antibody was added dropwise and incubated at 37˚C for 30 min and then rinsed with PBS. Samples were placed in diaminobenzidine and rinsed with PBS, and the slides were dehydrated, dried and sealed. Light field microscope was used for observation.

For double immunofluorescence staining, sections (prepared as for immunohistochemistry and immunofluorescence) were subjected to antigen retrieval using Tris-EDTA buffer (pH 9.0) in a 95˚C water bath for 20 min, and were then incubated with immunostaining blocking solution containing 0.1% Triton X-100 for 90 min at room temperature, The diluted primary antibody was then added to the slides and incubated overnight at 4˚C, before being rinsed with PBS containing 0.1% Triton X-100. The diluted fluorescence secondary antibody was added and incubated with the slides for 90 min at room temperature, before being rinsed with PBS containing 0.1% Triton X-100 and incubated with DAPI for 10 min. Immunofluorescence was assessed using a Leica fluorescence microscope (THUNDER Imager Tissue; Leica Microsystems, Inc.) and image analysis was performed using Leica Application suite X software (v3.1.5, Leica Microsystems, Inc.).

The primary antibodies used were S100A9 (Abcam; 1:400; ab92507), Ki67 (OriGene Technologies, Inc.; 1:200; cat. no. ZM-0167) and β-catenin (MAX; 1:200; cat. no. MAB-0754), and the secondary antibodies were conjugated to Alexa Fluor 488 (Abcam; 1:500; cat. no. ab150077) or 647 (Abcam; 1:500; cat. no. ab150115).

Specimen evaluation

Antibody expression was evaluated by two observers and supervised by an experienced pathologist. Tissue samples were divided by H&E staining into a high-inflammation group and a low-inflammation group, according to the degree of inflammatory cell infiltration. Tissues with extensive aggregation of inflammatory cells were included in the high-inflammation group and tissues with scattered distribution of inflammatory cells were included in the low-inflammation group. To assess the degree of inflammation, five areas containing inflammatory cells in the field of vision that could be observed and counted were selected and the percentage of inflammatory cells was counted. For Ki67 staining, brown nuclei were regarded as positive, and five dense areas of positive cells were randomly selected to count the number of positive cells, and the percentage of positive cells was calculated as previously described (10). Expression of S100A9 was evaluated in wet keratin, with brown tissue considered positive; according to the degree of staining, the tissue was classified as strongly positive (3 points), moderately positive (2 points) and weakly positive (1 point) (11). A total of five fields of vision were randomly selected, and the percentage of S100A9-positive areas were estimated for each field; finally, the S100A9 scores of each case were calculated, score=∑ (S100A9 percentage x degree of staining)/5, as previously described (12,13). The percentage of areas of wet keratin was also counted via H&E staining to analyze the relationship between wet keratin and inflammation.

Online databases

The chromosomal location of the S100A9 gene was determined from the Ensembl database (; release 109). The protein-protein interaction was analyzed by STRING ( RNA and protein data were obtained from the pediatric brain tumor online database (The University of Alabama at Birmingham Cancer data analysis portal; Pediatric brain cancer in CBTTC dataset:; RNA and protein data from various pediatric brain tumors, including ACP, were used to assess the RNA and protein expression levels of S100A9.

Data analysis

R (v4.1.1 and GraphPad Prism (v8.0; GraphPad Software; Dotmatics) were used for statistical analysis. Measurement data are shown as the mean ± standard deviation and median (IQR), normally distributed data were assessed using the two-sample unpaired t-test and non-normally distributed data (age comparison of S100A9 high group and low group) were assessed using the Mann-Whitney U test. The χ2 test was used for contingency tables. A linear correlation analysis was performed using Spearman's test. Survival analysis was performed using the Kaplan-Meier test and log-rank test. P<0.05 was considered to indicate a statistically significant difference.


Online databases validate the expression of S100A9 in ACP

Online databases were used to verify the RNA and protein expression levels of S100A9 in ACP. The RNA expression of S100A9 ranked second in ACP among all detected pediatric brain tumors, after teratoma. Protein expression was ranked first (Fig. 1A and B). Several genes of the S100 family and proteins involved in epidermal cornification form a so-called epidermal differentiation complex on human chromosome 1q21(8). The protein-protein interaction between epidermis-related small proline-rich protein genes and S100A family genes was found in the adjacent chromosome location, showing a complex interaction between them (Fig. 1C). These data showed that S100A9 was indeed highly expressed in ACP and played an important role in tumorigenesis.

Inflammatory infiltration and wet keratin evolution detected using H&E staining

The typical pathological structures of ACP are shown in Fig. 2A. Extensive aggregation of inflammatory cells was observed in the high-inflammation group (Fig. 2B), and scattered distribution of inflammatory cells was observed in the low-inflammation group (Fig. 2C). The continuous evolutionary process from tumor cells to wet keratin was observed by H&E staining (Fig. 2D-F). Some tumor cells underwent apoptosis and nucleolysis, and all cells exhibited eosinophilic properties. The dissolved cellular components also fused and eventually calcium deposits appeared, suggesting that wet keratin evolved from dead tumor cells and the calcifications in ACP were the result of calcium salt deposition after wet keratin formation. Additionally, scattered isolated islands of wet keratin were seen in brain tissue (Fig. 2H and I).

Relationship between S100A9 and keratinization

Clusters with nucleocytoplasmic accumulation of β-catenin is characteristic of ACP. Clusters were shown by immunohistochemical staining but wet keratin was negative for β-catenin (Fig. 3A-C; derived from the same sample). Immunohistochemical results showed no obvious dark brown staining of wet keratin on the negative control (ACP tissue without S100A9 antibody) images (Fig. 3D). On the sections stained with the S100A9 antibody, the results showed that S100A9 was expressed in the wet keratin (Fig. 3E and I) and stellate reticulum (Fig. 3G). Some cells in clusters also showed weak positive expression (Fig. 3H) and S100A9 was highly expressed in the tumor stroma (Fig. 3F). In the basal palisades epithelium, S100A9 was partly expressed (Fig. 3H). S100A9 was also highly expressed in wet keratin (Fig. 3I). Immunofluorescence staining showed that S100A9 was expressed in some ACP tumor cells positive for β-catenin. These results indicated that S100A9 was expressed in ACP intratumoral and extratumoral cells, especially in wet keratin (Fig. 3J-L).

Association between S100A9 and wet keratin

S100A9 was expressed in ACP cells, which were eosinophilic in H&E staining (Fig. 4A), and their morphology was from a bulk of normal tumor cells to a shape similar to wet keratin. S100A9 was also expressed in cells are in the process of transitioning from tumor cells to wet keratin (Fig. 4B-F). H&E staining and immunofluorescence showed island-like structures formed by S100A9-positive wet keratin invaded brain tissue around the tumor (Fig. 4G and H; Fig. 2H, upper arrow and Fig. 2I, arrows).

Association between S100A9 in wet keratin and inflammation

Scattered S100A9-positive cells were seen in the brain tissue outside the tumor and these cells became increasingly sparse in areas most distant from the tumor, which was similar to the degree of inflammation produced by the tumor stimulating the brain tissue (Fig. 5A and B). S100A9 was also distributed near the cholesterol cleft, where a large number of inflammatory cells also accumulated (Fig. 5C and D). Areas of wet keratin and the expression of S100A9 in wet keratin was correlated with inflammation in ACP (Fig. 5G and H). The scores of S100A9 in the group with higher inflammation were higher than those in the tumor group with lower inflammation, and the difference was statistically significant (Fig. 5I). The expression difference of S100A9 in the two groups is shown visually in Fig. 5E and F.

Association between S100A9 in wet keratin and proliferation

A number of studies have reported that S100A9 promotes cell proliferation, and inflammation is also an important factor in causing proliferation. No Ki67-positive cells were identified in wet keratin itself, but positive cells were found in scattered regions around wet keratin (Fig. 6A and B). An obvious linear correlation was found between S100A9 scores and percentage of Ki67-positive cells (Fig. 6C).

Association between the expression levels of S100A9 and various clinical factors

The baseline data of patients are shown in Table I. Patients were divided into two groups according to S100A9 score with the median as the cut-off. When the relationships between the expression levels of S100A9 and sex, age, tumor composition, preoperative status, resection and postoperative status were studied, no significant associations were found between S100A9 and various clinical factors (Table II). However, an association between S100A9 and recurrence-free survival was shown, and patients with high S100A9 expression had a poorer prognosis (Fig. 6D). But there was no significant difference between S100A9-High and S100A9-Low.

Table II

Association between S100A9 scores and clinical factors.

Table II

Association between S100A9 scores and clinical factors.

 S100A9 scores 
Clinical factors≤54>54P-value
Sex   6.079x10-1
Age, years, median (IQR)11.96 (21.63)11.08 (7.89) 6.589x10-1
Consistency   5.949x10-1
     Predominantly cystic1613 
     Predominantly solid89 
Preoperative status   1.457x10-1
Resection   9.274x10-1
     Radical resection2220 
     Conservative resection22 
Postoperative status   7.750x10-1
     No recurrence2019 

[i] The median of the S100A9 score was 54. S100A9, S100 calcium-binding protein A9.


In the present study, S100A9 was expressed in some tumor cells and wet keratin. Wet keratin labeled with S100A9 was also hypothesized to be involved in the evolution of keratin. According to the results of the present study, it can be hypothesized that tumor cells expressing S100A9 eventually evolve into wet keratin in ACP.

Wet keratin is a characteristic pathological structure of ACP, but its origin is unclear. Similar structures have been found in calcified odontogenic cysts, an odontogenic tumor histologically similar to ACP (14). Although no direct in vitro experimental study of cell evolution is available, the present study found the evolutionary process of wet keratin was traceable from histological and pathological morphological changes in wet keratin and is associated with ACP stem cell-like cells (15). Therefore, the present study inferred that the evolution of wet keratin was based on the morphological changes in wet keratin. Finally, after the formation of wet keratin, the corresponding metabolic and necrotic substances are deposited; for example, broken organelles, chromatin fragments, proteins and wet keratin deposited these substances may cause non-specific inflammation.

Previous studies have reported that the gene encoding epidermal keratinocyte structural protein and S100 calcium-binding protein form a gene complex (‘epidermal differentiation complex’) on human chromosome 1q21 (8,9). This suggested that S100 calcium-binding proteins are involved in keratinization. The present study also showed that S100A family members have complex interactions with adjacent epidermal differentiation genes.

It is well known that ACP is derived from residual embryonic tissue, which is homologous to the oral epithelium and is a typical epithelial tissue (1). The reason for the presence of wet keratin components in epithelial tumors remains to be elucidated. However, from the results of the present study, it is likely that S100A9 is closely associated with keratinization of cells in ACP to eventually form wet keratin. Wet keratin is common in human ACP but absent in the mouse model of ACP (16,17). Notably, the genomes of mice and rats lack S100A2, S100A12 and two members of the S100A family genes (18,19), This may be the potential biological basis for the lack of wet keratin in the mouse ACP model and not just a coincidence. In addition, S100A family members are calcium ion regulatory proteins (18), which, unsurprisingly, are suspected to be involved in the formation of calcification in ACP.

Enhanced inflammation in the tumor component of ACP is a hallmark of ACP (20-23). Various immune cells, including lymphocytes and myeloid-derived cells, are present in the immune microenvironment in ACP (10,24). Neutrophils contain abundant S100A9, which serves an important role in neutrophil N1-type polarization (25,26), thus S100A9-positive cells in intratumoral and peritumoral brain tissue may include ACP tumor-associated neutrophils. Accordingly, the present study could be the first definitive report on neutrophils in ACP, to the best of the authors' knowledge.

The brain tissue adjacent to the tumor is often infiltrated by inflammatory cells due to the mechanical stimulation of tumor growth and the possible stimulation of biochemical secretions (20). A large number of inflammatory cells has also been shown to infiltrate into the region of cholesterol crystals (20). On the whole, the severity of inflammation was consistent with the overall distribution of S100A9 and wet keratin observed in the present study. The results of the present study also showed that groups with a higher degree of inflammatory infiltration had higher S100A9 expression; in addition, both wet keratin and S100A9 were found to have a significant linear association with inflammation. These results demonstrated a close relationship between inflammation in ACP and both wet keratin and S100A9. S100A9 has also been reported to act through Toll-like receptor 4 and initiates the downstream inflammatory pathway, which is evidently associated with immunity and inflammation (27,28). S100A9 also serves an important role in inflammation of multiple organs and cancer (29,30). The results of the present study are consistent with those of previous studies, showing that S100A9 appears to be a crucial molecule during the inflammatory process of ACP.

The present study also showed a linear correlation between S100A9 and tumor cell proliferation. A previous study showed that S100A family members promote tumor proliferation, and some researchers have used it as a potential target for therapy (31). In the present study, the expression of S100A9 was significantly and linearly correlated with Ki67, reflecting that S100A9 may promote the proliferation of ACP. Notably, S100A9 acts as an inflammation-related factor before tumor metastasis and is associated with tumor metastasis, which suggests that the expression pattern of S100A9 in tumor parenchyma in ACP and the invasiveness of ACP deserve further study (32,33). It is worth mentioning that the present study also found that wet keratin can transcend the tumor boundary and enter the surrounding structures to form island-like structures, which may be a mode of invasive growth of ACP. Given the critical role of S100A9 in ACP related to inflammation, proliferation and metastasis, therapy with drugs such as Tasquinimod or Paquinimod may be a promising direction.

While the present study expanded the understanding of the mechanism underlying wet keratin and its relationship with inflammation in ACP, evidence is still lacking. S100A9 is associated with inflammation in ACP. A limitation of the present study was that it did not have live ACP cells and functional assays related to S100A9 could not be performed, thus the present study lacked evidence of S100A9 interaction with inflammatory cells and it was not possible to prove that S100A9 causes inflammation in ACP. The role played by the S100 protein family in primary tumors and metastases remains to be elucidated and needs further exploration.

The function of S100A9 in ACP may be further demonstrated by animal studies. At the same time, unlike human craniopharyngioma, wet keratin has not been found in mouse models of craniopharyngioma, which some researchers attribute to species differences, but evidence is still insufficient (34). Whether S100A family members are responsible for this difference may be revealed in future studies.

The present study found that wet keratin evolved from some tumor cells in ACP and these tumor cells expressed S100A9. It was hypothesized that S100A9 was involved in the evolution of wet keratin, and S100A9 was associated with inflammation in ACP.


The authors would like to thank Mr. Zhong Ma (Sanbo Brain Hospital, Capital Medical University, Beijing, China), for his excellent assistance.


Funding: The present study was supported by grants from Sanbo Brain Hospital Management Group (grant no. SBJT-KY-2020-002) and Capital's Funds for Health Improvement and Research (grant no. 2022-2-8013).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

ZL conceived and designed the current study. All authors participated in the acquisition of data. Analysis and interpretation of data was performed by CZ, WH, DL, NL and XW. CZ and ZL drafted the manuscript. XW and ZL critically revised the manuscript. ZL reviewed the submitted version of manuscript and approved the final version of the manuscript on behalf of all authors. CZ and XW performed statistical analysis. Administrative, technical and material support was from ZL who also supervised the study. WH and ZL confirm the authenticity of all the raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The patients in the present study provided written informed consent. The present study was designed in accordance with The Declaration of Helsinki and approved by the ethics committee of Sanbo Brain Hospital, Capital Medical University (approval no. SBNK-YJ-2020-014-01).

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.



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Volume 25 Issue 6

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Zhao C, Hu W, Luo N, Wang X, Lin D and Lin Z: Expression of S100A9 in adamantinomatous craniopharyngioma and its association with wet keratin formation. Exp Ther Med 25: 282, 2023
Zhao, C., Hu, W., Luo, N., Wang, X., Lin, D., & Lin, Z. (2023). Expression of S100A9 in adamantinomatous craniopharyngioma and its association with wet keratin formation. Experimental and Therapeutic Medicine, 25, 282.
Zhao, C., Hu, W., Luo, N., Wang, X., Lin, D., Lin, Z."Expression of S100A9 in adamantinomatous craniopharyngioma and its association with wet keratin formation". Experimental and Therapeutic Medicine 25.6 (2023): 282.
Zhao, C., Hu, W., Luo, N., Wang, X., Lin, D., Lin, Z."Expression of S100A9 in adamantinomatous craniopharyngioma and its association with wet keratin formation". Experimental and Therapeutic Medicine 25, no. 6 (2023): 282.