bromochloroacetic-acid and Biliary-Tract-Neoplasms

Liver metastases emerge during the course of colorectal cancer (CRC) in 25-50% of patients. A small proportion of patients present intrabiliary growth. The absence of large series means that little is known about intrabiliary metastasis (IBM), its radiological diagnosis, the most suitable surgical techniques, and its prognostic implications.. A systematic search without limits was performed. The studies selected included patients with a diagnosis of CRC and associated IBM, either synchronous or metachronous.. Of 40 studies selected, 30 were case reports and 10 case series. The median time between diagnosis and IBM was 46.7 months (range 0-180). Most CRC metastases are CK7-/CK20+. Surgical treatment performed ranged from endoscopic resection to major hepatic resections combined with pancreatectomies. It seems that patients with IBM have a better survival than patients without this metastasis.. In a patient with a history of CRC presenting dilatation of the bile duct, IBM should be considered. More studies are needed to determine the most appropriate type of liver resection. It is also necessary to standardize the definition and terminology of this pathology, since the existing definitions may cause confusion and make it difficult to carry out case studies and case series.

Topics: Biliary Tract Neoplasms; Biomarkers, Tumor; Colorectal Neoplasms; Hepatectomy; Humans; Keratins; Prognosis

Tumor cells circulate in low numbers in peripheral blood; their detection is used predominantly in metastatic disease. We evaluated the feasibility and safety of sampling portal venous blood via endoscopic ultrasound (EUS) to count portal venous circulating tumor cells (CTCs), compared with paired peripheral CTCs, in patients with pancreaticobiliary cancers (PBCs).. In a single-center cohort study, we evaluated 18 patients with suspected PBCs. Under EUS guidance, a 19-gauge EUS fine needle was advanced transhepatically into the portal vein and as many as four 7.5-mL aliquots of blood were aspirated. Paired peripheral blood samples were obtained. Epithelial-derived CTCs were sorted magnetically based on expression of epithelial cell adhesion molecules; only those with a proper morphology and found to be CD45 negative and positive for cytokeratins 8, 18, and/or 19 and 4',6-diamidino-2-phenylindole were considered to be CTCs. For 5 samples, CTCs also were isolated by flow cytometry and based on CD45 depletion. ImageStream was used to determine the relative protein levels of P16, SMAD4, and P53. DNA was extracted from CTCs for sequencing of select KRAS codons.. There were no complications from portal vein blood acquisition. We detected CTCs in portal vein samples from all 18 patients (100%) vs peripheral blood samples from only 4 patients (22.2%). Patients with confirmed PBCs had a mean of 118.4 ± 36.8 CTCs/7.5 mL portal vein blood, compared with a mean of 0.8 ± 0.4 CTCs/7.5 mL peripheral blood (P < .01). The 9 patients with nonmetastatic, resectable, or borderline-resectable PBCs had a mean of 83.2 CTCs/7.5 mL portal vein blood (median, 62.0 CTCs/7.5 mL portal vein blood). In a selected patient, portal vein CTCs were found to carry the same mutations as those detected in a metastatic lymph node and expressed similar levels of P16, SMAD4, and P53 proteins.. It is feasible and safe to collect portal venous blood from patients undergoing EUS. We identified CTCs in all portal vein blood samples from patients with PBCs, but less than 25% of peripheral blood samples. Portal vein CTCs can be used for molecular characterization of PBCs and share features of metastatic tissue. This technique might be used to study the pathogenesis and progression of PBCs, as well as a diagnostic or prognostic tool to stratify risk of cancer recurrence or developing metastases.

Topics: Aged; Aged, 80 and over; Biliary Tract Neoplasms; Biomarkers, Tumor; Cell Count; Chicago; Cyclin-Dependent Kinase Inhibitor p16; DNA Mutational Analysis; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Feasibility Studies; Female; Flow Cytometry; Humans; Immunomagnetic Separation; Keratins; Leukocyte Common Antigens; Male; Middle Aged; Mutation; Neoplastic Cells, Circulating; Pancreatic Neoplasms; Portal Vein; Predictive Value of Tests; Proto-Oncogene Proteins p21(ras); Smad4 Protein; Tumor Suppressor Protein p53

Intraductal papillary mucinous neoplasm of the pancreas is a rare but well-established entity in contrast to intraductal papillary mucinous neoplasm of the biliary tract. The aim of this study was to compare the clinicopathologic features of intraductal papillary mucinous neoplasms of the biliary tract and of the pancreas. Twenty patients who underwent resection for intraductal papillary mucinous neoplasm of the biliary tract were compared with 29 cases resected for intraductal papillary mucinous neoplasm of the pancreas. Clinicopathologic characteristics and resection specimens of all patients were reassessed and immunohistochemically screened for expression of a distinct set of tumor markers. Median ages of patients with intraductal papillary mucinous neoplasms of the biliary tract and of the pancreas were 66 and 62 years, respectively (P < .05). Twelve patients with intraductal papillary mucinous neoplasm of the biliary tract (60%) had neoplasms with infiltrating carcinoma, compared with 6 patients with intraductal papillary mucinous neoplasm of the pancreas (21%, P < .05). Cytokeratin 7 and 20 expressions were equal in biliary and pancreatic intraductal papillary mucinous neoplasms. Cytokeratin 20 expression was mainly found in intestinal-type tumors. Gastric, pancreaticobiliary, and oncocytic subtypes were all observed in the intraductal papillary mucinous neoplasm of the biliary tract group. The distribution was significantly different from the intraductal papillary mucinous neoplasm of the pancreas group. The 3-year overall survival rate of malignant biliary and pancreatic intraductal papillary mucinous neoplasm was 63% and 65%, respectively (P = .798). Positive lymph nodes and a high expression of membranous mucin were associated with a significantly shorter overall survival in patients with malignant intraductal papillary mucinous neoplasm. Finally, p53 and Ki67 proliferation index were both associated with the carcinogenesis of intraductal papillary mucinous neoplasm, whereas DPC4 and CDX2 were not. Clinicopathologic features of intraductal papillary mucinous neoplasm of the biliary tract largely resemble those of intraductal papillary mucinous neoplasm of the pancreas, although intraductal papillary mucinous neoplasm of the biliary tract was associated with a higher malignancy rate at the time of surgical treatment. The level of membranous mucin expression and positive lymph nodes are significant prognosticators in patients with malignant intra

Topics: Adult; Aged; Aged, 80 and over; Biliary Tract Neoplasms; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Carcinoma, Papillary; Female; Humans; Keratins; Ki-67 Antigen; Male; Middle Aged; Netherlands; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Survival Rate

The presence of para-aortic lymph node metastasis in biliary cancer has a negative impact on prognosis. The relevance of para-aortic lymph node micrometastasis is unknown.. A total of 546 para-aortic lymph nodes from 49 patients with biliary cancer with positive regional nodes and negative para-aortic nodes were immunostained with epithelial marker CAM5.2 (specific for cytokeratins 7 and 8). Immunostained tumour foci were classified as micrometastases or isolated tumour cells (ITCs) according to their size (larger or smaller than 0.2 mm).. CAM5.2-positive occult carcinoma cells in para-aortic lymph nodes were detected in nine (18 per cent) of 49 patients and in 18 (3.3 per cent) of 546 para-aortic nodes. There was no difference in postoperative survival between patients with and without CAM5.2-positive para-aortic nodes (P = 0.978), but survival for five patients with micrometastases was significantly worse than that for four patients with only ITCs (P = 0.047).. In patients with regional node-positive and para-aortic node-negative biliary cancer, and occult cancer cells in para-aortic lymph nodes, prognosis was significantly worse in those with micrometastases than in patients with only ITCs. An efficient method of intraoperative detection of para-aortic lymph node micrometastases larger than 0.2 mm is needed.

Topics: Adult; Aged; Aged, 80 and over; Aorta; Biliary Tract Neoplasms; Biomarkers; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Keratins; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Time Factors

We describe the histopathologic features of 2 cases of biliary neoplasia with extensive intraductal spread arising in liver cirrhosis. The prevalence of this type of biliary neoplasia may be 0.4% from the review of 468 cases of cirrhotic liver. Histologic analysis revealed that the micropapillary proliferation of the atypical biliary epithelium composed of columnar cells with enlarged nuclei diffusely extended superficially from the septal intrahepatic bile duct to the reactive ductules associated with liver cirrhosis. Both cases exhibited prominent fibrous or sclerotic stroma near the biliary lesion. Immunohistochemical analysis revealed a characteristic cytokeratin and mucin expression pattern (CK7++, CK19++, CK20+, MUC1+/-, MUC2-, MUC5AC+, MUC6-). The tumor cytoplasm was focally positive for laminin gamma2 together with linear staining of the basement membrane. Proliferative activity confirmed by Ki67 staining was relatively high. Both patients were disease-free for 3 years after the operation. We believe that the possibility of biliary neoplasia with extensive intraductal spread should be considered to be a variant of biliary intraepithelial neoplasia.

Topics: Bile Ducts, Intrahepatic; Biliary Tract Neoplasms; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Count; Cell Proliferation; Cholangiocarcinoma; Hepatitis C, Chronic; Humans; Immunoenzyme Techniques; Keratins; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Mucins; Neoplasms, Multiple Primary; Treatment Outcome

To further characterize the immunohistochemical features of hepatobiliary cystadenoma with mesenchymal stroma, a battery of stains was performed on nine typical cases. All nine tumors had been resected from female patients who ranged in age from 30 to 59 years. Freshly cut sections were stained with antibodies to estrogen receptor (ER), progesterone receptor (PR), alpha-smooth muscle actin (SMA), inhibin-alpha, and cytokeratins (CK) 7, 8, 18, and 19. Nuclear staining of the mesenchymal stromal cells for ER and PR was present in all and seven out of nine cases, respectively. A strong cytoplasmic staining of the mesenchymal stromal cells for SMA was seen in all cases. A patchy pale cytoplasmic staining of the tumor epithelium for ER and PR was seen in five out of nine and four out of nine cases, respectively. Immunoreactivity of luteinized stromal cell for inhibin-alpha was documented in three out of nine cases. All tumors (nine out of nine) demonstrated strong cytoplasmic positivity of the epithelial lining of the cysts to CK7, CK8, CK18, and CK19, typical of biliary-type epithelium. The expression of ER, PR, and inhibin-alpha in the ovarian-like stroma supports the likely hormonal dependence of this tumor and probably explains its almost exclusive occurrence in women.

Topics: Actins; Adult; Biliary Tract Neoplasms; Cystadenoma; Cytoplasm; Female; Humans; Immunohistochemistry; Inhibins; Keratins; Liver Neoplasms; Middle Aged; Muscle, Smooth; Receptors, Estrogen; Receptors, Progesterone; Stromal Cells

The recently identified claudins are dominant components of tight junctions, responsible for cell adhesion, polarity and paracellular permeability. Certain claudins have been shown to have relevance in tumor development, with some of them, especially claudin-4, even suggested as future therapeutic target. The aim of the present study was to analyze the expression of claudin-4 in the biliary tree, biliary tract cancers and hepatocellular carcinomas. A total of 107 cases were studied: 53 biliary tract cancers, 50 hepatocellular carcinomas, 10 normal liver and 10 normal extrahepatic biliary duct samples. Immunohistochemical analysis was performed on conventional specimens and on tissue microarrays as well. Claudin-4 was further investigated by Western blot analysis and real-time RT-PCR. Intense membranous immunolabeling was found for claudin-4 in all biliary tract cancers unrelated to the primary site of origin, namely intrahepatic, extrahepatic or gallbladder cancers. Normal biliary epithelium showed weak positivity for claudin-4. In contrast, normal hepatocytes and tumor cells of hepatocellular carcinomas did not express claudin-4. The results of Western immunoblot analysis and real-time RT-PCR were in correlation with the immunohistochemical findings. Cytokeratins, as CK7 (92%) and CK19 (83%) were mostly positive in biliary tract cancers, however, one-third of hepatocellular carcinomas also expressed CK7 (34%). HSA antibody (HepPar1) reacted with the majority of hepatocellular carcinomas (86%), while being positive in a low percentage of the biliary tract cancers (8%). In conclusion, this is the first report of a significantly increased claudin-4 expression in biliary tract cancers, which represents a novel feature of tumors of biliary tract origin. Claudin-4 expression seems to be a useful marker in differentiating biliary tract cancers from hepatocellular carcinomas and could well become a potential diagnostic tool.

Topics: Adenocarcinoma; Biliary Tract Neoplasms; Blotting, Western; Carcinoma, Hepatocellular; Claudin-4; Diagnosis, Differential; Gene Expression; Humans; Immunohistochemistry; Keratin-7; Keratins; Laminin; Liver; Liver Neoplasms; Membrane Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tissue Array Analysis

The incidence of lymph node micrometastases in patients with biliary tract carcinoma is unknown. We evaluated the utility of three antibodies for immunohistochemical (IHC) detection of micrometastatic disease in patients with gallbladder and bile duct carcinoma.. Surgical specimens from 35 patients with biliary tract carcinoma were evaluated. Histologically involved tissues were stained with the following antibodies using standard IHC techniques: cytokeratin (AE1:AE3), CEA (carcinoembryonic antigen), and EMA (epithelial membrane antigen). The antibodies with the greatest degree of positive staining were then used to evaluate the lymph nodes of patients with histologically negative lymph nodes. Micrometastatic disease was defined as clustered atypical cells <2 mm in size detected only with the use of IHC.. All of the primary tumors and histologically positive lymph nodes demonstrated staining with cytokeratin and CEA antibodies, whereas only 83% were positive for EMA. Therefore, cytokeratin and CEA antibodies were used to evaluate histologically negative lymph nodes. Anti-cytokeratin immunostaining detected micrometastatic disease in two patients. Staining with anti-CEA was negative in all specimens. Overall, two of 15 patients with histologically node negative biliary tract carcinoma had occult micrometastases.. Cytokeratin immunostaining enables detection of micrometastases in histologically negative lymph nodes in patients with biliary tract carcinoma. Prospective protocols incorporating cytokeratin staining of the lymph nodes may help determine the incidence and clinical significance of occult micrometastatic disease in these patients.

Topics: Adult; Aged; Biliary Tract Neoplasms; Biomarkers, Tumor; Carcinoembryonic Antigen; Female; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Mucin-1; Neoplasm Metastasis

Hepatobiliary cystadenoma and cystadenocarcinoma of the gall bladder have rarely been reported. An 88-year-old Japanese man was admitted to our clinic because of hypochondralgia and jaundice. Imaging techniques revealed hemobilia and a multilocular cystic tumor in the fundus of the gall bladder, and cholecystectomy was performed. Grossly, the tumor (3.5 x 3 x 3 cm) was multicystic, containing seromucous fluid. The tumor was located in the fibromuscular layer and subserosa of the gall bladder fundus, and protruded into the serosal surface, not into gall bladder lumen. The mucosa appeared free of tumor involvement, and no gall stones were recognized. Microscopically, the tumor was located in the fibromuscular layer, subserosa and tiny focus of the mucosal surface. The tumor consisted of mucin-rich benign columnar cells, dysplastic mucous cells, malignant papillotubular cells and invasive carcinoma cells. Malignant and atypical tumor cells were located in the center of the tumor and in the tiny area of the mucosal surface, while benign tumor cells were located in the peripheral portions of the tumor and in the serosal side. Neither ovarian stroma-like mesenchymal stroma nor an oncocytic change in tumor cells was recognized. Non-tumorous gall bladder showed chronic cholecystitis. Immunohistochemically, benign and carcinoma cells were positive for cytokeratins, epithelial membrane antigen, CA19-9, MUC1, MUC5AC and MUC6, and carcinoma cells were also positive for carcinoembryonic antigen and p53 protein. The present case indicates that hepatobiliary cystadenocarcinoma without mesenchymal stroma may occur in the gall bladder of old men, and suggests that hepatobiliary cystadenoma without mesenchymal stroma may transform into hepatobiliary cystadenocarcinoma in the gall bladder.

Topics: Aged; Aged, 80 and over; Biliary Tract Neoplasms; CA-19-9 Antigen; Carcinoembryonic Antigen; Cystadenocarcinoma; Cystadenoma; Gallbladder Neoplasms; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Male; Mucin 5AC; Mucin-1; Mucin-6; Mucins; Tumor Suppressor Protein p53

Although cytokeratin (CK) phenotyping of metastatic tumors is now routine in many laboratories, the clinical relevance of the procedure has seldom been addressed. We carried out a prospective clinical study of 134 consecutive cases of metastatic adenocarcinoma of the liver diagnosed by needle biopsies stained routinely for CK20 and CK7. The most probable localization of the primary tumor, deduced from this staining pattern, was stated in the original pathology report. The present study compared this assignment with the information available at the time of interpretation of the liver biopsy, to the results of the subsequent clinical investigation, and to the officially reported cause of death as outcome. As expected, the primary tumors were localized in the colon or in the rectum in 85% (34/40) of the CK20+/CK7- metastases. The definite diagnosis remained metastatic colorectal carcinoma in 83% (15/18) of the cases with diagnosed colorectal cancer before the liver biopsy. In the cases without a known primary tumor when the liver biopsy was interpreted, primary colorectal localization was accurately predicted in 86% (19/22) of the patients. Compared to the outcome, 77% (36/47) of the CK20+/CK7+ metastases had the expected pancreaticobiliary primary localization in 83% (30/36) without any primary tumor being known at the time of interpretation of the liver biopsy. In contrast, the majority of CK20- metastatic carcinomas had an unexpected primary localization, 50% (16/32) in the CK20-/CK7+ and 60% (9/15) in the CK20-/CK7- subgroup. In addition, the origin of the liver metastasis remained unknown in 37% (12/32) of CK20-/CK7+ cases. Thus, the CK20+/CK7- phenotype indicates a colorectal origin of the liver metastasis with considerable accuracy and independently of the available clinical information. The same is true for CK20+/CK7+ metastases, which indicate primary tumor localization in the pancreas or in the biliary tree. The results in the CK20- subgroups of the liver metastases are disappointing and cannot substantially help the clinical investigation.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biliary Tract Neoplasms; Biomarkers; Biopsy, Needle; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasms, Unknown Primary; Pancreatic Neoplasms; Phenotype; Retrospective Studies

Immunohistochemistry with different cytokeratin subsets has been successfully used in the differential diagnosis of various human epithelial neoplasms. Cytokeratin 5/6 antibody, which recently became commercially available, has been found useful in the diagnosis of mesothelioma. Studies have reported only infrequent staining in adenocarcinomas. We investigated the pattern of immunoreactivity for cytokeratin 5/6 in hepatobiliary and pancreatic tumors to determine its diagnostic utility in the morphologic evaluation of these neoplasms. Formalin-fixed. paraffin-embedded tissue sections from 10 hepatocellular carcinomas, seven hepatocellular adenomas, 10 cholangiocarcinomas, 10 pancreatic ductal adenocarcinomas, and 13 pancreatic neuroendocrine carcinomas were immunostained with anticytokeratin 5/6 after heat-induced antigen retrieval utilizing a modified avidin-biotin complex technique. Positive and negative controls stained appropriately. Two pathologists evaluated the slides. Strong but focal cytoplasmic immunoreactivity was observed in five of 10 pancreatic ductal adenocarcinomas and two of 10 cholangiocarcinomas. No immunoreactivity was identified in any cases of hepatocellular carcinoma (0/10), hepatocellular adenoma (0/7), or pancreatic neuroendocrine carcinoma (0/13). Additionally, occasional cytokeratin 5/6 immunoreactive benign ductal epithelial cells were seen in the background in some cases. Fifty percent of pancreatic ductal adenocarcinomas and 20% of cholangiocarcinomas are positive with anti-cytokeratin 5/6 immunostaining. For the evaluation of poorly differentiated neoplasms in the liver, immunoreactivity with cytokeratin 5/6 may help to exclude the possibility of hepatocellular carcinoma. Cytokeratin 5/6 may be helpful as a component in the panel of immunostains to differentiate between poorly differentiated neoplasms.

Topics: Biliary Tract Neoplasms; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Pancreatic Neoplasms

We investigated whether a panel of antibodies including WT1 could separate pancreaticobiliary and ovarian carcinomas by staining 64 pancreaticobiliary adenocarcinomas, 41 ovarian serous carcinomas, and 12 primary ovarian mucinous neoplasms with WT1, cytokeratin (CK) 17, CK20, carcinoembryonic antigen (CEA), and CA-125. Moderate or strong intensity reactivity in more than 25% of cells was a positive result. Of the ovarian serous carcinomas, 38 (93%) were WT1 reactive and 22 (54%) WT1 positive, 9 (22%) had CK20 reactivity, and 3 (7%) were CK20 positive in fewer than 50% of cells. All were CK17 or CEA nonreactive. Of the ovarian mucinous neoplasms, all were WT1 and CK17 nonreactive and 11 (92%) were CEA reactive, 8 (67%) CEA positive, 10 (83%) CK20 reactive, and 6 (50%) CK20 positive. Of the pancreaticobiliary adenocarcinomas, 19 (30%) were CK20 positive, 27 (42%) CK17 positive, and 52 (81%) CEA positive. All were WT1 nonreactive. A panel including WT1, CK17, CK20, and CEA is useful to distinguish pancreaticobiliary and ovarian serous carcinomas. Extensive CK17 reactivity is supportive of a pancreaticobiliary adenocarcinoma when the differential diagnosis includes ovarian mucinous neoplasm. None of the antibodies positively identified ovarian mucinous neoplasms.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Antibodies; Biliary Tract Neoplasms; CA-125 Antigen; Carcinoembryonic Antigen; Cystadenocarcinoma; Diagnosis, Differential; DNA-Binding Proteins; Female; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratins; Ovarian Neoplasms; Pancreatic Neoplasms; Transcription Factors; WT1 Proteins

Cytokeratin (CK) patterns and albumin messenger RNA (mRNA) are investigated in 24 patients with benign hepatic lesions (7 patients with focal nodular hyperplasia [FNH], 10 with hepatocellular adenomas [HA], 1 with biliary hamartoma, 4 with biliary cysts, 2 with cystadenomas) and in 8 patients with cystadenocarcinoma, a rare liver malignancy. The lesions and surrounding tissue of the hepatocytic components expressed CK 8 and 18 at immunohistochemistry, whereas the biliary elements evidenced CK 8 and 18 and CK 7 and 19. The albumin mRNA, as detected by in situ hybridization (ISH), revealed different distributions in the hepatocytes of FNH and HA. In the benign biliary lesions, the normal hepatocytes surrounding the tumors expressed albumin mRNA, whereas the biliary structures did not. Interestingly, in the cystadenocarcinomas, albumin mRNA was observed not only in the hepatocytes of residual parenchyma, but also in neoplastic bile duct cells lining the carcinomatous cysts; no signal was identified in the nonneoplastic biliary elements. This indicates that cystadenocarcinomas have a mixed biological phenotype and suggests they could arise either from pluripotent cells or from neoplastic cells that reacquire epigenetic features. Our results suggest two possible diagnostic applications for albumin ISH: on routine sections, it could represent an important tool for distinguishing between cystadenoma and cystadenocarcinoma; and on fine needle biopsy specimens, it could reduce uncertainty between FNH and HA.

Topics: Adenoma; Adolescent; Adult; Aged; Albumins; Biliary Tract Neoplasms; Biomarkers, Tumor; Cell Differentiation; Cystadenocarcinoma; Cystadenoma; Cysts; Diagnosis, Differential; Female; Gene Expression; Hamartoma; Humans; Hyperplasia; Immunoenzyme Techniques; In Situ Hybridization; Keratins; Liver; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Neoplasm Proteins; Phenotype; Protein Isoforms; RNA Probes; RNA, Complementary; RNA, Messenger; RNA, Neoplasm; Stem Cells