Value of p63 and Cytokeratin 5/6 as Immunohistochemical Markers for the Differential Diagnosis of Poorly Differentiated and Undifferentiated Carcinomas

Institute of Pathology, Charité University Hospital, Berlin, Germany.
American Journal of Clinical Pathology (Impact Factor: 2.51). 01/2002; 116(6):823-30. DOI: 10.1309/21TW-2NDG-JRK4-PFJX
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To facilitate the differential diagnosis of poorly differentiated metastatic carcinomas of unknown primary site, we evaluated p63 and cytokeratin (CK) 5/6 as immunohistochemical markers for squamous cell carcinomas. The study cases were as follows: squamous cell carcinoma of the lungs, head/neck, esophagus, cervix uteri, or anal canal, 73; non-squamous cell carcinomas of various primary sites, 141; and urothelial carcinoma, 20. We also tested 14 malignant mesotheliomas. Immunoreactivity for p63 was as follows: squamous cell carcinomas, 59 (81%); urothelial carcinoma, 14 (70%), most often with diffuse staining patterns; non-squamous cell carcinomas, 20 (14.2%), resulting in a specificity of 0.86 of p63 for squamous cell carcinomas. Coexpression of p63 and CK5/6 had a sensitivity of 0.77 and a specificity of 0.96 for squamous cell carcinomas. Increasing the minimal criterion of positive immunostaining for both markers to more than 50% of immunoreactive tumor cells resulted in a specificity of 0.99, although the sensitivity diminished to 0.66. All malignant mesotheliomas were negative for p63. Our data suggest that positive immunostaining for both p63 and CK5/6 in poorly differentiated metastatic carcinomas is highly predictive of a primary tumor of squamous epithelial origin.

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Available from: Manfred Dietel, Jan 08, 2015
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    • "An accurate method for distinguishing tumor origin to tailor personalized therapies is therefore critical to the successful management of these malignancies. Thus far, there have been a number of studies focused on identifying unique signatures that distinguish among different cancer types, using immunohistochemistry [8] [9] [10] [11], cytogenetic studies [12] [13] [14], comparative microarray analysis [15] [16] [17] [18] [19] [20] [21] [22], combined microarray and quantitative polymerase chain reaction techniques [23] [24], bead-based miRNA profiling [25], and more recently, limited, high-throughput sequencing data combined with microarray [26]. Currently, only qRT-PCR [23] [24] and microarray-based [19] [22] assays are commercially available for use, with diagnostic accuracies ranging from 74 – 85%. "
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    ABSTRACT: Metastatic cancer of unknown primary (CUP) accounts for up to 5% of all new cancer cases, with a 5-year survival rate of only 10%. Accurate identification of tissue of origin would allow for directed, personalized therapies to improve clinical outcomes. Our objective was to use transcriptome sequencing (RNA-Seq) to identify lineage-specific biomarker signatures for the cancer types that most commonly metastasize as CUP (colorectum, kidney, liver, lung, ovary, pancreas, prostate, and stomach). RNA-Seq data of 17,471 transcripts from a total of 3,244 cancer samples across 26 different tissue types were compiled from in-house sequencing data and publically available International Cancer Genome Consortium and The Cancer Genome Atlas datasets. Robust cancer biomarker signatures were extracted using a 10-fold cross-validation method of log transformation, quantile normalization, transcript ranking by area under the receiver operating characteristic curve, and stepwise logistic regression. The entire algorithm was then repeated with a new set of randomly generated training and test sets, yielding highly concordant biomarker signatures. External validation of the cancer-specific signatures yielded high sensitivity (92.0% ± 3.15%; mean ± standard deviation) and specificity (97.7% ± 2.99%) for each cancer biomarker signature. The overall performance of this RNA-Seq biomarker-generating algorithm yielded an accuracy of 90.5%. In conclusion, we demonstrate a computational model for producing highly sensitive and specific cancer biomarker signatures from RNA-Seq data, generating signatures for the top eight cancer types responsible for CUP to accurately identify tumor origin.
    Neoplasia (New York, N.Y.) 11/2014; 16(11). DOI:10.1016/j.neo.2014.09.007 · 4.25 Impact Factor
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    • "We also examined the expression of other mesothelial markers in CC and NBD including WT1, D2-40 and CK5/6 [12,30,47-49]. Not surprisingly, our data showed that WT1 and D2-40 remained highly specific for mesothelial lineage, and should be included in the panel to differentiate mesothelioma from CC. "
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    ABSTRACT: Background Mesothelin, a mesothelial marker, has been found expressed in and as a potential treatment target of cholangioacarcinoma (CC). It is possible that CC may be derived from the cells sharing mesothelial markers. However, the expression of other mesothelial markers in CC is largely unknown. Methods Thirty CC cases (10 extrahepatic and 20 intrahepatic) were retrieved from our institutional archive. The immunohistochemical study of Calretinin (DC8), WT1 (6F-H2), Lymphatic Endothelial Marker (D2-40), CK5/6 (D5/16 B4) and CK19 (b170) was done on formalin fixed paraffin embedded sections for 2–3 blocks of each case. We compared the expression levels between CC and normal bile duct (NBD) on the same block. Results All of the CC and NBD are positive for CK19 (23/23) and negative for WT1 (0/23) and D2-40 (0/23), except one CC positive for D2-40(1/30, 3.3%) and one NBD positive for WT1 (1/23, 4.3%). Calretinin immunoreactivity was detected in 52.2% (12/23) of CC, but none in NBD (0/23). CK5/6 was also detectable in 73.3% (22/30) of CC and all NBD (30/30). Increased expression of calretinin and reduced expression of CK5/6 were more likely associated with CC than NBD (P < 0.001 and P = 0.002, respectively). The sequential staining pattern of positive calretinin and negative CK5/6 in calretinin negative cases has a sensitivity of 69.57% and a specificity of 100% for differentiating CC from NBD. CK5/6 expression was also more likely associated with well-differentiated CC (7/7 versus 12/20 in moderately differentiated, and 9/10 in poorly differentiated, P = 0.019) and extrahepatic CC (10/10 versus 12/20 in intrahepatic, P = 0.029), but there was no association between the calretinin expression and the CC grade or location. Conclusion Calretinin and CK5/6 immunohistochemical stains may be useful for diagnosing a CC. Their immunohistochemical results should be interpreted with caution in the cases with differential diagnoses of mesothelioma and CC. A full mesothelioma panel, including WT1 and/or D2-40, is recommended to better define a mesothelial lineage. The biology of calretinin and CK5/6 expression in CC is unclear, but might shed light on identifying therapeutic targets for CC.
    04/2014; 3:12. DOI:10.1186/2162-3619-3-12
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    • "SCC of the anal canal can show expression of cytokeratin 7 and cytokeratin 5/6 as well [5] [6]. Another immunohistochemical marker that is expressed in both lung and anal SCC is p63, which is expressed in the majority (more than 80%) of SCC from various regions [6]. The marker p16 is a tumor suppressor protein highly expressed in HPV-associated cervical carcinomas and dysplasia as well as anorectal squamous cell carcinoma and dysplasia [4]. "
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    ABSTRACT: Histopathologic techniques are insufficient for distinguishing primary squamous cell carcinoma (SCC) from metastatic SCC, which is clinically important. A patient with SCC of the anus was found to also have SCC of the lung, and the question of metastatic versus synchronous primary diseases was raised. Immunohistochemical and hematoxylin and eosin (H&E) staining on sections of tissue could not discriminate between the two entities. Immunostain for p16 and chromogenic in situ hybridization for human papillomavirus (HPV) type 16 were positive in both tumors. Additionally, allelotyping for loss of heterozygosity displayed similar findings and confirmed the histopathological impression of anal SCC metastasis to the lung. The patient was treated with palliative chemotherapy instead of additional surgical treatment. When multiple tumors are present, determining metastatic versus synchronous primary tumors is necessary for appropriate treatment. Identification can be achieved using allelotyping for loss of heterozygosity.
    02/2014; 2014:608521. DOI:10.1155/2014/608521
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