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S100P (Placenta S100) is a 95-amino-acid protein first isolated from the placenta and belongs to the S100 protein family of calcium binding proteins. It is normally present in epithelial cells throughout entire gastrointestinal tract. The highest anti-S100P immunoreactivity is localized in the epithelial cells of the superficial epithelial cuff region, while the reactivity becomes weaker toward the crypts. These immunoreactions are characterized by nuclear/cytoplasmic staining. Normal pancreatic ductal epithelia and liver usually lack the expression of S100P protein. The placenta expresses very high levels of S100P protein in the trophoblastic cells. Lymphoid follicles and smooth muscle of the intestinal wall can also be weakly positive for anti-S100P.1
Applications Anti-S100P in Pancreatic Ductal Adenocarcinoma Pancreatic ductal adenocarcinoma (PDA) and its variants account for 85% to 90% of all pancreatic malignant neoplasms and are currently the fourth leading cause of cancer death in the United States with a 5-year survival rate being less than 5%. Fine needle aspiration (FNA) or small tissue core biopsy is a popular and effective approach to establish the definitive diagnosis of pancreatic cancer. However, interpretation of FNA specimens or small core biopsy specimens is not always straightforward, particularly when the tumor is a well-differentiated adenocarcinoma (WDA), due to the overlapping cytologic and histologic features between neoplastic and reactive ductal epithelium.2 In some instances, the distinction between WDA and reactive changes in these specimens is virtually impossible to make. To improve the diagnostic sensitivity and specificity of FNAs and small tissue core biopsies, attempts have been made to identify specific tumor-associated markers for PDA. Several immunohistochemical markers, such those targeting K-ras, MUC 1, DPC4, mesothelin, prostate stem cell antigen, claudin 4, and KOC (K homology domain containing protein overexpressed in cancer), have been reported to be useful, but the findings were not definitive.2-8 Recent studies have documented that several S100-related proteins are overexpressed in PDA, including S100P, S100A6, and S100A4.9 In addition, overexpression of these proteins has been reported to be associated with a poor clinical outcome. In a recent study on pancreatic benign and malignant lesions2, anti-S100P nuclear or nuclear/cytoplasmic immunoreactivity can be seen in 100% (56/56 cases) of pancreatic ductal adenocarcinoma in fine needle aspiration biopsy with 38 cases showing diffuse and strong nuclear or nuclear/cytoplasmic staining.10 Anti-S100P displays no staining in the benign pancreatic ducts and acinar glands.10 A positive nuclear or nuclear/cytoplasmic immunostaining for anti-S100A6 and anti-S100A4 was seen in 55 of 56 cases (98%) and 41 of 56 cases (73%), respectively. However, compared with anti-S100P, approximately 20% of non-neoplastic ducts were positively stained using antibodies against S100A6 or S100A4. Therefore, anti-S100A6 and anti-S100A4 are less useful antibodies than is anti-S100P in diagnosis of PDA. Another study proved that anti-S100P was completely negative for pancreatic endocrine tumors (0/6 cases).11 The S100P antibody is also able to stain destained and alcohol-fixed FNAB smears with relatively few technical problems. The study also showed that six cases with atypical cytology and that were suspicious for carcinoma did not have cell block tissue for immunohistochemistry study. However, immunostaining performed on the destained smears showed that atypical or suspicious cells in all 6 were positive for anti-S100P. In a follow-up, all 6 patients were proven to have PDA. Therefore, immunodetection of S100P on destained smears may become useful in correctly categorizing atypical and suspicious diagnoses and reducing false-negative diagnoses. Gastrointestinal epithelial contamination, especially from EUS-guided FNAB samples, may significantly influence diagnostic accuracy. Fragments of small-intestinal epithelium are frequently present in specimens from EUS-guided FNAB of the pancreas. Identification of gastrointestinal contaminants may be problematic, even to an experienced cytopathologist; the diagnostic challenge can be even greater when a diagnosis of WDA is considered. One study has reported that anti-S100P showed a membranous staining pattern in normal gastric epithelium.12 However, Deng et al.11 tested S100P expression in 10 surgical specimens including 5 samples of gastric epithelium and 5 samples of duodenal epithelium. The membranous-cytoplasmic staining pattern of anti-S100P was observed in 2 of 5 cases of gastric epithelium, but no nuclear staining was observed.All cases of duodenal epithelium were negative for anti-S100P. Therefore, when gastrointestinal contamination interferes with an interpretation of a WDA specimen, application of nuclear immunostaining for anti-S100P may solve the problem. Since anti-S100P is one of few antibodies that can be applied on alcohol-fixed FNAB smears, it provides broader applications for surgical pathology and cytopathology.
Intraductal papillary mucinous neoplasms of the pancreas are subclassified based on morphological features, and different immunohistochemical profiles have been identified in association with the subtypes. Nakata K et al. investigated the immunohistochemical patterns of anti-S100P in surgical specimens of intraductal papillary mucinous neoplasm obtained from 105 patients. S100P was detected in all intraductal papillary mucinous neoplasm cells (100%) with diffuse nuclear or nuclear/cytoplasmic staining. However, S100P expression was not found in normal pancreatic ductal epithelium. Furthermore, S100P was clearly expressed in the invasive component of intraductal papillary mucinous neoplasms (32/32; 100%), including perineural and lymphatic and minimal invasion. These data suggest that the anti-S100P antibody may be a useful marker for detecting all types of intraductal papillary mucinous neoplasms.14 Histopathologic distinction between benign and malignant bile duct epithelial lesions on endoscopic biopsies can be extremely challenging because of limited material, crush artifact, and compounding inflammatory and/or reactive changes particularly after stent placement. In a study conducted by Levy, M, et al.,15 a total of 72 endoscopic bile duct biopsies, including 40 adenocarcinomas and 32 benign cases, were immunohistochemically examined for the expression of S100P to evaluate its diagnostic value. The results showed that 36 adenocarcinomas (90%) exhibited strong nuclear and cytoplasmic staining for anti-S100P. None of the 32 benign biopsies showed diffuse anti-S100P immunoreactivity. Only eight cases (25%) exhibited focal strong nuclear and cytoplasmic staining, observed in 1% to 20% of the epithelial cells. This differed markedly from that seen in malignant biopsies. Eight benign biopsies (25%) showed focal anti-S100P positivity. In conclusion, an immunohistochemical panel including anti-S100P can be helpful in distinguishing adenocarcinoma from reactive epithelial changes on challenging bile duct biopsies. S100P in Other Benign & Malignant Tumors The morphologic distinction between prostate and urothelial carcinoma can be difficult. Higgins et al. reported by using tissue microarrays, a polyclonal antiserum against S100P protein stained 86% of 295 urothelial carcinomas while only 3% of 260 prostatic adenocarcinomas and 1% of 133 renal cell carcinomas stained. A commercially available monoclonal antibody against S100P stained 78% of 300 urothelial carcinomas while only 2% of 256 prostatic adenocarcinomas and none of 137 renal cell carcinomas stained. The results indicate that the detection of S100P protein expression may help distinguish urothelial carcinomas from other genitourinary neoplasms that enter into the differential diagnosis.16
Technical Investigation Research & Development at Cell Marque: We have evaluated this mouse monoclonal IgG antibody against S100P by using placenta, pancreatic ductal adenocarcinoma, urinary carcinoma, prostatic adenocarcinoma, and renal cell carcinoma with different buffers, reaction conditions, and dilutions. As shown in figure 1, anti-S100P stains strongly in pancreatic ductal carcinoma, however, benign ducts intermixed with malignant ducts are clearly not expressing the marker. Fig. 2 demonstrates that the malignant pancreatic ducts with perineural invasion are strongly stained with anti-S100P. Figure 3 displays that anti-S100P strongly highlights urinary carcinoma. Figure 4 shows hepatocellular cell carcinoma cells do not express S100P. Figure 5 illustrates that S100P is not present in renal cell carcinoma cells. Note occasionally endothelial cells are weakly positive for anti-S100P. The investigation leads us to make the following recommendations:
Conclusion of Technical Investigation: Anti-S100P is a very useful antibody for pancreatic ductal adenocarcinoma and bile ductal adenocarcinoma. It is not only applicable on resected specimens but also good for cytology specimens. Anti-S100P stains cytoplasm and nuclei of tumor cells and is completely negative for benign pancreatic ducts. More importantly, anti-S100P highlights pancreatic ductal mucinous intraepithelial neoplasia. Anti-S100P does not stain prostatic adenocarcinoma, renal cell carcinoma, and hepatocellular carcinoma but is strongly positive in urinary carcinoma of the bladder. When combined with antibodies against uroplakin III and thrombomodulin, it will be useful in detecting urothelial carcinoma. As a negative marker, when combined with renal tumor markers such as anti-PAX8, anti-RCC etc, anti-S100P can be a confirming marker to detect metastatic renal cell carcinoma.
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