Biomarkers in Carcinoma of Unknown Primary

Description

This book aims to examine all immunohistochemical and molecular pathological biomarkers that can be useful and effective in patient diagnosis, prognosis and treatment decision, especially when faced with a carcinoma of unknown primary. For this purpose, epithelial malignancies of all systems and related biomarkers are examined one by one, and to look at the subject through the metastatic regions window, biomarkers that can be used to determine the primary focus for carcinomas seen in the areas most frequently metastasized are emphasized. With this bi-directional perspective, the reader is able to find biomarkers of any type of carcinoma on a system basis, as well as access to which biomarkers can be used when faced with a metastatic carcinoma. The importance of biomarkers in patient follow-up and treatment is also conveyed through the clinician's eye, and so biomarkers are handled with a holistic approach in all aspects. This book primarily targets pathologists, as well as clinicians (oncologists and surgeons) who manage cancer patients. Preface Introduction Contents 1: Definition of “Tissue-Based Biomarker,” its Place in Medicine, and Molecular Pathology 1.1 Definition and Terminology of Biomarker 1.1.1 Diagnostic Biomarker 1.1.2 Prognostic Biomarker 1.1.3 Predictive Biomarker 1.1.4 Monitoring Biomarker 1.1.5 Susceptibility/Risk Biomarker 1.1.6 Pharmacodynamic/Response Biomarker 1.1.7 Safety Biomarker 1.1.8 Digital Biomarker 1.1.9 Validated Surrogate Endpoint 1.2 Methods for Developing Biomarkers 1.2.1 Immunohistochemistry and Finding Specific Antibodies 1.2.2 Finding Molecular Biomarkers 1.2.3 The Challenges of Finding a Biomarker 1.2.4 Defining Biomarker Performance (Validation and Qualification) 1.3 Laboratory Methods for Evaluation of Biomarkers in Pathology 1.3.1 Immunohistochemistry 1.3.2 In Situ Hybridization 1.3.3 Polymerase Chain Reaction (PCR) 1.3.4 Sequencing 1.3.5 Bioinformatics References 2: The Concept and Mechanisms of Metastasis 2.1 Concept of Metastasis 2.2 Mechanisms of Metastasis 2.2.1 Neoplastic Cells 2.2.2 Epithelial-Mesenchymal Transition 2.2.3 Metabolic Changes 2.2.4 Anoikis 2.2.5 Cancer Stem Cells-Cancer-Initiating Cells 2.2.6 Vascular Supply 2.2.7 Immune Modulation 2.2.8 Cancer-Associated Fibroblasts/Tumor Stromal Cells 2.2.9 Extracellular Matrix 2.2.10 Inflammatory Cells 2.2.11 Adhesion Molecules 2.2.12 Invasion of the Vessels 2.2.13 Circulating Tumor Cells 2.2.14 Extravasation 2.2.15 Metastatic Colonization 2.2.16 Tumor Dormancy 2.2.17 Niche Concept 2.2.18 Metastasis-Related Genes and Genetic Pathways 2.2.19 Effect of miRNA on Metastasis 2.2.20 Effects of Long Noncoding RNA on Metastasis 2.2.21 Effects of Microvesicles on Metastasis 2.2.22 Effects of Exosomes on Metastasis 2.2.23 Metastatic Progression Models 2.2.24 Other Routes of Metastasis 2.2.25 Organ Tropism in Metastasis 2.3 Primary Unknown Carcinoma References 3: Biomarkers in Skin Carcinomas 3.1 Skin Carcinomas 3.2 Basal Cell Carcinoma 3.2.1 Diagnostic Biomarkers 3.2.2 Prognostic/Predictive Biomarkers 3.3 Squamous Cell Carcinoma 3.3.1 Diagnostic Biomarkers 3.3.2 Prognostic/Predictive Biomarkers 3.4 Adnexal Tumors 3.4.1 Sebaceous Carcinoma 3.4.1.1 Diagnostic Biomarkers 3.4.1.2 Prognostic/Predictive Biomarkers 3.4.2 Adenoid Cystic Carcinoma (ACC) 3.4.2.1 Diagnostic Biomarkers 3.4.3 Microcystic Adnexal Carcinoma (MAC) 3.4.3.1 Diagnostic Biomarkers 3.4.4 Hidradenocarcinomas 3.4.4.1 Diagnostic Biomarkers 3.4.4.2 Prognostic/Predictive Biomarkers 3.4.5 Porocarcinoma 3.4.5.1 Diagnostic Biomarkers 3.4.5.2 Prognostic/Predictive Biomarkers 3.5 Merkel Cell Carcinoma 3.5.1 Diagnostic Biomarkers 3.5.2 Prognostic/Predictive Biomarkers 3.6 Metastatic Tumors to the Skin 3.6.1 Diagnostic Biomarkers References 4: Biomarkers in Head and Neck Carcinomas 4.1 Nasal Cavity, Paranasal Sinuses and Skull Base 4.1.1 Squamous Cell Carcinoma 4.1.1.1 Diagnostic Biomarkers 4.1.1.2 Prognostic/Predictive Biomarkers 4.1.2 Lymphoepithelial Carcinoma 4.1.2.1 Diagnostic Biomarkers 4.1.3 NUT Carcinoma 4.1.3.1 Diagnostic Biomarkers 4.1.3.2 Prognostic/Predictive Biomarkers 4.1.4 Sinonasal Undifferentiated Carcinoma 4.1.4.1 Diagnostic Biomarkers 4.1.4.2 Prognostic/Predictive Biomarkers 4.1.5 Neuroendocrine Carcinoma 4.1.5.1 Diagnostic Biomarkers 4.1.6 Adenocarcinoma 4.1.6.1 Diagnostic Biomarkers 4.1.7 Emerging Entities 4.1.7.1 HPV-Related Multiphenotypic Sinonasal Cancer 4.1.7.1.1 Diagnostic Biomarkers 4.1.7.2 Renal Cell-like Adenocarcinoma 4.1.7.3 SMARCB1-Deficient Sinonasal Carcinomas 4.1.7.4 SMARCA4-Deficient Sinonasal Carcinoma 4.1.8 Salivary Gland-Type Tumors of the Seromucous Glands 4.1.9 Metastatic Tumors to the Nasal Cavity 4.2 Nasopharynx 4.2.1 Nasopharyngeal Carcinoma 4.2.1.1 Diagnostic Biomarkers 4.2.1.2 Prognostic/Predictive Biomarkers 4.2.2 Nasopharyngeal Papillary Adenocarcinoma 4.2.2.1 Diagnostic Biomarkers 4.2.3 Metastatic Tumors to the Nasopharynx 4.3 Larynx, Hypopharynx, and Oral Cavity 4.3.1 Squamous Cell Carcinoma 4.3.1.1 Diagnostic Biomarkers 4.3.1.2 Prognostic/Predictive Biomarkers 4.3.2 Neuroendocrine Carcinoma 4.3.2.1 Diagnostic Biomarkers 4.3.3 Metastatic Tumors to the Larynx, Hypopharynx, and Oral Cavity 4.4 Oropharynx 4.4.1 Squamous Cell Carcinoma 4.4.1.1 Diagnostic Biomarkers 4.4.1.2 Prognostic/Predictive Biomarkers 4.4.2 Metastatic Tumors to the Oropharynx 4.5 Salivary Glands 4.5.1 Mucoepidermoid Carcinoma 4.5.1.1 Diagnostic Biomarkers 4.5.2 Adenoid Cystic Carcinoma 4.5.2.1 Diagnostic Biomarkers 4.5.2.2 Prognostic/Predictive Biomarkers 4.5.3 Acinic Cell Carcinoma 4.5.3.1 Diagnostic Biomarkers 4.5.4 Secretory Carcinoma 4.5.4.1 Diagnostic Biomarkers 4.5.4.2 Prognostic/Predictive Biomarkers 4.5.5 Polymorphous Adenocarcinoma 4.5.5.1 Diagnostic Biomarkers 4.5.5.2 Prognostic/Predictive Biomarkers 4.5.6 Clear Cell Carcinoma 4.5.6.1 Diagnostic Biomarkers 4.5.7 Basal Cell Adenocarcinoma 4.5.7.1 Diagnostic Biomarkers 4.5.8 Intraductal Carcinoma 4.5.8.1 Diagnostic Biomarkers 4.5.9 Salivary Duct Carcinoma 4.5.9.1 Diagnostic Biomarkers 4.5.9.2 Prognostic/Predictive Biomarkers 4.5.10 Myoepithelial Carcinoma 4.5.10.1 Diagnostic Biomarkers 4.5.11 Epithelial-Myoepithelial Carcinoma 4.5.11.1 Diagnostic Biomarkers 4.5.12 Sebaceous Carcinoma 4.5.12.1 Diagnostic Biomarkers 4.5.13 Lymphoepithelial Carcinoma 4.5.13.1 Diagnostic Biomarkers 4.5.14 Oncocytic Carcinoma 4.5.15 Carcinoma ex-Pleomorphic Adenoma 4.5.15.1 Diagnostic Biomarkers 4.5.16 Emerging Entities 4.5.16.1 Microsecretory Carcinoma 4.5.17 Metastatic Tumors to the Salivary Glands 4.6 Odontogenic and Maxillofacial Bone Tumors 4.6.1 Ameloblastic Carcinoma 4.6.1.1 Diagnostic Biomarkers 4.6.1.2 Prognostic/Predictive Biomarkers 4.6.2 Sclerosing Odontogenic Carcinoma 4.6.2.1 Diagnostic Biomarkers 4.6.3 Clear Cell Odontogenic Carcinoma 4.6.3.1 Diagnostic Biomarkers 4.6.4 Ghost Cell Odontogenic Carcinoma 4.6.5 Metastatic Tumors to Maxillofacial Bone 4.7 Ear 4.7.1 Squamous Cell Carcinoma 4.7.2 Ceruminous Adenocarcinoma 4.7.3 Aggressive Papillary Tumor 4.7.4 Endolymphatic Sac Tumor References 5: Biomarkers in Pulmonary Carcinomas 5.1 Pulmonary Carcinomas 5.1.1 Adenocarcinoma 5.1.1.1 Diagnostic Biomarkers 5.1.1.1.1 Biomarkers Showing Pneumocytic Differentiation (Supporting Adenocarcinoma) in Non-small-Cell Lung Carcinoma 5.1.1.1.2 Immunohistochemical Approach in Histological Typing in Non-small-Cell Lung Carcinomas 5.1.1.2 Prognostic/Predictive Biomarkers 5.1.1.2.1 Epidermal Growth Factor Receptor (EGFR) 5.1.1.2.2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) 5.1.1.2.3 Anaplastic Lymphoma Kinase (ALK) 5.1.1.2.4 ROS Proto-oncogene 1(ROS1) 5.1.1.2.5 BRAF Proto-oncogene, Serine/Threonine Kinase (BRAF) 5.1.1.2.6 MET Proto-oncogene 5.1.1.2.7 Human Epidermal Growth Factor 2 (ERBB2 or HER2) 5.1.1.2.8 RET Proto-oncogene 5.1.1.2.9 Neurotrophic Tyrosine Receptor Kinase (NTRK) 5.1.1.2.10 Programmed Death Ligand 1 Receptor 5.1.1.2.11 Phosphoinositide-3-Kinase Catalytic Alpha Polypeptide (PIK3CA) 5.1.2 Squamous Cell Carcinoma 5.1.2.1 Diagnostic Biomarkers 5.1.3 Neuroendocrine Tumors 5.1.3.1 Diagnostic Biomarkers 5.1.3.1.1 SCLC vs. LCNEC 5.1.3.1.2 HGNEC vs. NSCLC 5.1.3.1.3 SCLC vs. Other Small Round Blue Cell Tumors 5.1.3.1.4 Neuroendocrine Tumors of the Lung vs. Other Primary Organs 5.1.3.2 Prognostic/Predictive Biomarkers 5.1.4 Sarcomatoid Carcinoma 5.1.4.1 Diagnostic Biomarkers 5.1.4.2 Prognostic/Predictive Biomarkers 5.1.5 Salivary Gland-Type Tumors 5.1.5.1 Diagnostic Biomarkers 5.1.6 Other Carcinomas 5.1.6.1 Adenosquamous Carcinoma 5.1.6.1.1 Diagnostic Biomarkers 5.1.6.1.2 Prognostic/Predictive Biomarkers 5.1.6.2 Large-Cell Carcinoma 5.1.6.2.1 Diagnostic Biomarkers 5.1.6.2.2 Prognostic/Predictive Biomarkers 5.1.6.3 Lymphoepithelioma-Like Carcinoma 5.1.6.3.1 Diagnostic Biomarkers 5.1.6.3.2 Prognostic/Predictive Biomarkers 5.1.6.4 NUT Carcinoma 5.1.6.4.1 Diagnostic Biomarkers/Prognostic/Predictive Biomarkers 5.2 Approach to the Materials References 6: Biomarkers in Endocrine Organ Carcinomas 6.1 Thyroid Carcinoma (TC) 6.1.1 Papillary Thyroid Carcinoma (PTC) 6.1.1.1 Diagnostic Biomarkers 6.1.1.2 Prognostic/Predictive Biomarkers 6.1.2 Follicular Thyroid Carcinoma (FTC) 6.1.2.1 Diagnostic Biomarkers 6.1.2.2 Prognostic/Predictive Biomarkers 6.1.3 Poorly Differentiated Thyroid Carcinoma (PDTC) 6.1.3.1 Diagnostic Biomarkers 6.1.3.2 Prognostic/Predictive Biomarkers 6.1.4 Anaplastic Thyroid Carcinoma (ATC) 6.1.4.1 Diagnostic Biomarkers 6.1.4.2 Prognostic/Predictive Biomarkers 6.1.5 Medullary Thyroid Carcinoma (MTC) 6.1.5.1 Diagnostic Biomarkers 6.1.5.2 Prognostic/Predictive Biomarkers 6.2 Metastases to the Thyroid Gland 6.2.1 Diagnostic Biomarkers 6.3 Parathyroid Carcinoma (PC) 6.3.1 Diagnostic Biomarkers 6.3.2 Prognostic/Predictive Biomarkers 6.4 Metastases to the Parathyroid Gland 6.4.1 Diagnostic Biomarkers 6.5 Adrenocortical Carcinoma (ACC) 6.5.1 Diagnostic Biomarkers 6.5.2 Prognostic/Predictive Biomarkers 6.6 Metastases to the Adrenal Gland 6.6.1 Diagnostic Biomarkers References 7: Biomarkers in Gastrointestinal System Carcinomas 7.1 Esophageal Carcinomas 7.1.1 Esophageal Squamous Cell Carcinoma 7.1.1.1 Diagnostic Biomarkers 7.1.1.2 Prognostic and Predictive Biomarkers 7.1.2 Esophageal Adenocarcinoma 7.1.2.1 Diagnostic Biomarkers 7.1.2.2 Prognostic and Predictive Biomarkers 7.1.3 Biomarkers in Other Types of Esophageal Carcinoma 7.1.4 Metastatic Tumors to Esophagus 7.2 Gastric Carcinomas 7.2.1 Gastric Adenocarcinoma 7.2.1.1 Diagnostic Biomarkers 7.2.1.2 Prognostic and Predictive Biomarkers 7.2.2 Biomarkers in Other Types of Gastric Carcinomas 7.2.3 Metastatic Tumors to Stomach 7.3 Small Bowel Carcinomas 7.3.1 Small Bowel Adenocarcinoma 7.3.1.1 Diagnostic Biomarkers 7.3.1.2 Prognostic and Predictive Biomarkers 7.3.2 Metastatic Tumors to Small Bowel 7.4 Colorectal Carcinomas 7.4.1 Colorectal Adenocarcinomas 7.4.1.1 Diagnostic Biomarkers 7.4.1.2 Prognostic and Predictive Biomarkers 7.4.2 Metastatic Tumors to Colorectum 7.5 Appendiceal Carcinomas 7.5.1 Appendiceal Mucinous Neoplasms 7.5.1.1 Diagnostic Biomarkers 7.5.1.2 Prognostic and Predictive Biomarkers 7.5.2 Appendiceal Adenocarcinoma 7.5.2.1 Diagnostic Biomarkers 7.5.2.2 Prognostic and Predictive Biomarkers 7.5.3 Goblet Cell Adenocarcinoma 7.5.3.1 Diagnostic Biomarkers 7.5.3.2 Prognostic/Predictive Biomarkers 7.5.4 Metastatic Tumors to Appendix 7.6 Anal Canal Carcinomas 7.6.1 Squamous Cell Carcinoma 7.6.1.1 Diagnostic Biomarkers 7.6.1.2 Prognostic/Predictive Biomarkers 7.6.2 Adenocarcinoma 7.6.2.1 Diagnostic Biomarkers 7.6.2.2 Prognostic/Predictive Biomarkers 7.6.3 Metastatic Tumors to Anal Canal 7.7 Neuroendocrine Neoplasms of the Gastrointestinal Tract 7.7.1 Diagnostic Biomarkers 7.7.2 Prognostic and Predictive Biomarkers References 8: Biomarkers in Hepatopancreatobiliary Carcinomas 8.1 Liver 8.1.1 Hepatocellular Carcinoma 8.1.1.1 Diagnostic Biomarkers 8.1.1.2 Prognostic and Predictive Biomarkers 8.1.2 Intrahepatic Cholangiocarcinoma 8.1.2.1 Diagnostic Biomarkers 8.1.2.2 Prognostic and Predictive Biomarkers 8.2 Perihilar/Extrahepatic Bile Ducts and Gallbladder 8.2.1 Diagnostic Biomarkers 8.2.2 Prognostic and Predictive Biomarkers 8.2.3 Metastatic Carcinomas in Gallbladder and Extrahepatic Bile Ducts 8.3 Pancreas 8.3.1 Pancreatic Ductal Adenocarcinoma 8.3.1.1 Diagnostic Biomarkers 8.3.1.2 Prognostic and Predictive Biomarkers 8.3.2 Acinar Cell Carcinoma 8.3.2.1 Diagnostic Biomarkers 8.3.2.2 Prognostic and Predictive Biomarkers 8.3.3 Pancreatic Neuroendocrine Neoplasm 8.3.3.1 Diagnostic Biomarkers 8.3.3.2 Prognostic and Predictive Biomarkers 8.3.4 Metastatic Carcinomas in Pancreas 8.4 Ampulla 8.4.1 Diagnostic Biomarkers 8.4.2 Prognostic and Predictive Biomarkers References 9: Biomarkers in Urinary Tract and Male Genital System Carcinomas 9.1 Biomarkers in Kidney Carcinomas 9.1.1 Clear Cell Renal Cell Carcinoma (ccRCC) 9.1.1.1 Diagnostic Biomarkers 9.1.1.2 Prognostic/Predictive Biomarkers 9.1.2 Multilocular Cystic Renal Cell Neoplasm of Low Malignant Potential (MCRCNLMP) 9.1.2.1 Diagnostic Biomarkers 9.1.3 Papillary Renal Cell Carcinoma (PRCC) 9.1.3.1 Diagnostic Biomarkers 9.1.4 Chromophobe Renal Cell Carcinoma (ChRCC) 9.1.4.1 Diagnostic Biomarkers 9.1.5 Collecting Duct Carcinoma (CDC) 9.1.5.1 Diagnostic Biomarkers 9.1.6 Renal Medullary Carcinoma 9.1.6.1 Diagnostic Biomarkers 9.1.7 MiT Family Translocation Renal Cell Carcinoma 9.1.7.1 Diagnostic Biomarkers 9.1.8 Succinate Dehydrogenase (SDH)-Deficient Renal Cell Carcinoma 9.1.8.1 Diagnostic Biomarkers 9.1.9 Mucinous Tubular and Spindle Cell Carcinoma (MTSCC) 9.1.9.1 Diagnostic Biomarkers 9.1.10 Tubulocystic Renal Cell Carcinoma (TC-RCC) 9.1.10.1 Diagnostic Biomarkers 9.1.11 Acquired Cystic Kidney Disease (ACKD)-Associated Renal Cell Carcinoma 9.1.11.1 Diagnostic Biomarkers 9.1.12 Clear Cell Papillary Renal Cell Carcinoma (CCPRCC) 9.1.12.1 Diagnostic Biomarkers 9.1.13 Renal Cell Carcinoma, Unclassified 9.1.14 Metastatic Tumors to the Kidney/Kidney’s Metastases 9.1.14.1 Diagnostic Biomarkers 9.2 Biomarkers in Bladder Carcinomas 9.2.1 Urothelial Carcinoma 9.2.1.1 Diagnostic Biomarkers 9.2.1.1.1 Immunohistochemical Biomarkers in Bladder Cancer 9.2.1.1.2 Molecular Biomarkers in Bladder Cancer 9.2.1.1.3 Molecular Subtyping of NMIBC 9.2.1.1.4 Molecular Subtyping of MIBC UNC Molecular Subtyping System MDA Molecular Subtyping Systems TCGA Molecular Subtyping System Molecular Subtyping Based on Adjuvant Chemotherapy 9.2.1.2 Prognostic/Predictive Biomarkers 9.2.2 Squamous Cell Carcinoma of Urinary Bladder 9.2.2.1 Diagnostic Biomarkers 9.2.2.2 Prognostic/Predictive Biomarkers 9.2.3 Glandular Tumors of the Bladder 9.2.3.1 Adenocarcinoma of Urinary Bladder 9.2.3.1.1 Diagnostic Biomarkers 9.2.3.2 Clear Cell Carcinoma 9.2.3.2.1 Diagnostic Biomarkers 9.2.3.3 Urachal Carcinoma 9.2.3.3.1 Diagnostic Biomarkers 9.2.3.3.2 Prognostic/Predictive Biomarkers 9.2.4 Neuroendocrine Carcinoma 9.2.4.1 Diagnostic Biomarkers 9.2.4.2 Prognostic/Predictive Biomarkers 9.2.5 Metastatic Tumors to the Bladder 9.2.5.1 Diagnostic Biomarkers 9.3 Biomarkers in Prostate Carcinomas 9.3.1 Prostate Adenocarcinoma (PCa) 9.3.1.1 Diagnostic Biomarkers 9.3.1.1.1 Immunohistochemical (IHC) Biomarkers 9.3.1.1.2 Molecular Biomarkers 9.3.1.2 Prognostic/Predictive Biomarkers 9.3.2 Intraductal Carcinoma of the Prostate (IDCP) 9.3.2.1 Diagnostic Biomarkers 9.3.3 Ductal Adenocarcinoma 9.3.3.1 Diagnostic Biomarkers 9.3.4 Urothelial Carcinoma 9.3.4.1 Diagnostic Biomarkers 9.3.5 Squamous Cell Carcinoma 9.3.5.1 Diagnostic Biomarkers 9.3.6 Basal Cell Carcinoma 9.3.6.1 Diagnostic Biomarkers 9.3.7 Neuroendocrine Tumors 9.3.7.1 Diagnostic Biomarkers 9.3.8 Metastatic Tumors to the Prostate 9.3.8.1 Diagnostic Biomarkers 9.3.8.2 Prognostic/Predictive Biomarkers 9.3.9 Molecular Stratification References 10: Biomarkers in Gynecologic Carcinomas 10.1 Ovarian Carcinoma 10.1.1 Diagnostic Biomarkers 10.1.2 Prognostic/Predictive Biomarkers 10.1.3 Metastatic Carcinomas to the Ovary 10.2 Fallopian Tube Carcinoma 10.2.1 Diagnostic Biomarkers 10.3 Endometrial Carcinoma 10.3.1 Diagnostic Biomarkers 10.3.2 Prognostic/Predictive/Therapeutic Biomarkers 10.4 Cervical Carcinomas 10.4.1 Squamous Cell Carcinomas 10.4.1.1 Diagnostic Biomarkers 10.4.2 Adenocarcinomas 10.4.2.1 Diagnostic Biomarkers 10.5 Vulvar Carcinomas 10.5.1 Diagnostic Biomarkers 10.6 Vaginal Carcinomas 10.6.1 Diagnostic Biomarkers 10.7 Neuroendocrine Neoplasia in the Female Genital Tract 10.7.1 Diagnostic Biomarkers 10.7.2 Prognostic/Predictive Biomarkers 10.8 Metastatic Epithelial Tumors to the Female Genital Tract Other than the Ovary References 11: Biomarkers in Breast Carcinomas 11.1 Invasive Breast Carcinoma 11.1.1 Invasive Breast Carcinoma of No Special Type 11.1.1.1 Diagnostic Biomarkers 11.1.1.2 Prognostic/Predictive Biomarkers 11.1.2 Invasive Lobular Carcinoma 11.1.2.1 Diagnostic Biomarkers 11.1.2.2 Prognostic/Predictive Biomarkers 11.1.3 Tubular and Cribriform Carcinoma 11.1.3.1 Diagnostic Biomarkers 11.1.3.2 Prognostic/Predictive Biomarkers 11.1.4 Mucinous Carcinoma 11.1.4.1 Diagnostic Biomarkers 11.1.4.2 Prognostic/Predictive Biomarkers 11.1.5 Invasive Papillary and Micropapillary Carcinoma 11.1.5.1 Diagnostic Biomarkers 11.1.5.2 Prognostic/Predictive Biomarkers 11.1.6 Carcinoma with Apocrine Differentiation 11.1.6.1 Diagnostic Biomarkers 11.1.6.2 Prognostic/Predictive Biomarkers 11.1.7 Metaplastic Carcinoma 11.1.7.1 Diagnostic Biomarkers 11.1.7.2 Prognostic/Predictive Biomarkers 11.2 Rare and Salivary Gland-Type Tumors 11.2.1 Diagnostic Biomarkers 11.2.2 Prognostic/Predictive Biomarkers 11.3 Neuroendocrine Neoplasms 11.3.1 Diagnostic Biomarkers 11.3.2 Prognostic/Predictive Biomarkers 11.4 Metastatic Tumors to the Breast References 12: Diagnostic Approach According to More Frequent Metastatic Sites: Liver, Lung, Bone, and Lymph Nodes 12.1 Diagnostic Approach for Metastatic Carcinomas in the Liver 12.1.1 Diagnostic Approach for Metastatic Adenocarcinomas in the Liver 12.1.2 Diagnostic Approach for Other Types of Metastatic Carcinomas in the Liver 12.1.3 Diagnostic Panel Suggestions for Metastatic Carcinomas in the Liver 12.1.4 Prognostic/Predictive Approach for Metastatic Carcinomas in the Liver 12.2 Diagnostic Approach for Metastatic Carcinomas in the Lung 12.3 Diagnostic Approach for Metastatic Carcinomas in the Bone 12.3.1 General Principles in Diagnostic Approach to Metastatic Lesions in the Bone 12.3.2 Biomarkers in Bone Metastasis of Prostate Carcinoma 12.3.3 Biomarkers in Bone Metastasis of Breast Carcinoma 12.3.4 Biomarkers in Bone Metastasis of Lung Carcinoma 12.3.5 Diagnostic Biomarkers in Other Metastatic Carcinomas 12.4 Diagnostic Approach for Metastatic Carcinomas in Lymph Nodes 12.4.1 Metastasis to Cervical Lymph Nodes 12.4.1.1 Lymph Node Regions of the Neck 12.4.1.2 Head and Neck Carcinomas 12.4.1.2.1 Squamous Cell Carcinoma 12.4.1.2.2 Salivary Gland Carcinomas 12.4.1.2.3 Thyroid Carcinomas 12.4.1.3 Breast Carcinomas 12.4.1.4 Lung Carcinomas 12.4.1.5 Gastrointestinal Carcinomas 12.4.1.6 Hepatocellular Carcinomas 12.4.1.7 Gynecological Carcinomas 12.4.1.8 Urogenital Carcinomas 12.4.2 Metastasis to Mediastinal Lymph Nodes 12.4.3 Metastasis to Axillary Lymph Nodes 12.4.4 Metastasis to Intraabdominal Lymph Nodes References 13: Diagnostic Approach According to Uncovered Metastatic Sites: Mediastinum-Thymus, Peritoneum, Central Nervous System, and Soft Tissue 13.1 Diagnostic Approach for Metastatic Carcinomas in Mediastinum-Thymus 13.2 Diagnostic Approach for Metastatic Carcinomas in the Peritoneum 13.2.1 Prognostic Biomarkers 13.2.2 Predictive Biomarkers 13.3 Diagnostic Approach for Metastatic Carcinomas in the Central Nervous System and Medulla Spinalis 13.3.1 Pathogenesis of Metastasis 13.3.2 Sampling Methods for Biomarkers 13.3.3 Biomarkers for Metastatic Carcinomas 13.4 Diagnostic Approach for Metastatic Carcinomas in Soft Tissue References 14: Management of the Patients with Carcinoma of Unknown Primary and the Role of Biomarkers 14.1 Clinical Approach to the Management of the Patients with Carcinoma of Unknown Primary in General Surgery Practice 14.1.1 Clinical Findings 14.1.2 Laboratory Tests 14.1.3 Radiological Screening 14.1.4 Liver Metastasis 14.1.5 Peritoneal Metastasis 14.1.6 Lymph Node Metastasis 14.1.7 Favorable and Unfavorable Forecast Subgroups 14.1.7.1 Favorable Forecast Subgroups Consulted to General Surgery Clinics 14.1.7.1.1 Papillary Adenocarcinoma of the Peritoneal Cavity in Female Patients 14.1.7.1.2 Axillary Lymph Node Metastasis 14.1.7.1.3 Patients with Colon Cancer Profile 14.1.7.1.4 Patients with Neuroendocrine Neoplasm Metastasis 14.2 Clinical Approach to the Management of the Patients with Carcinoma of Unknown Primary in Pulmonary Medicine Practice 14.2.1 Clinical Findings 14.2.2 Imaging 14.2.3 Cases with Unknown Primary 14.2.4 Adenocarcinoma 14.2.5 Squamous Cell Cancers 14.2.6 Neuroendocrine Cancers 14.3 Metastatic Tumors to the Pleura 14.4 Metastatic Tumors to the Mediastinum References 15: Treatment Approach to Carcinomas of Unknown Primary 15.1 Biomarkers and Treatment 15.2 Tissue of Origin and Treatment 15.3 Comprehensive Molecular Pathologic Profiling and CUP 15.4 Biomarkers and Follow-Up References Appendix I: Biomarkers for Carcinoma of Unknown Primary, Morphological Approach Appendix II: Leading Biomarkers in Current Oncological Pathology Practice ALK Alpha-fetoprotein (AFP) Androgen Receptor (AR) Arginase-1 ATRX BerEP4 BRAF BRCA1 and BRCA2 Calcitonin Caudal-Related Homeobox Gene 2 (CDX2) CEA CD10 CD56 Chromogranin A CK5/6 CK7 CK19 CK20 DAXX EBER E-Cadherin EGFR Estrogen Receptor (ER) Galectin-3 GATA3 GCDFP-15 Glutamine Synthetase Glypican-3 HBME-1 Hepatocyte Paraffin 1 (HepPar1) Human Epidermal Growth Factor Receptor 2 (HER2, c-erbB2, ERBB2, or HER2/neu) INSM-1 Islet-1 KRAS Ki-67 Mammaglobin MET Microsatellite Instability (MSI) MLH1 MOC-31 MSH2 MSH6 MUC1 MUC2 MUC5AC MUC6 Napsin A NKX3.1 NRAS Neurotrophic Tyrosine Receptor Kinase (NTRK) Pancytokeratin (AE1/AE3) Parathyroid Hormone (PTH) PAX2 PAX8 PD1 PDL1 PHH-3 Prostate-Specific Antigen (PSA) PSAP P16 P40 P53 P63 PMS2 Progesterone Receptor (PR) Retinoblastoma Protein (Rb) RET RCC ROS1 SMAD-4 Special AT-Rich Sequence-Binding Protein 2 (SATB2) Synaptophysin TERT TTF-1 Thyroglobulin Villin Vimentin Index