Chapter 095. Carcinoma of Unknown Primary (Part 4) ppt

Chapter 095. Carcinoma of Unknown Primary (Part 4) There are 20 subtypes of cytokeratin (CK) intermediate filaments with different molecular weights and differential expression in various cell types and cancers. Monoclonal antibodies to specific CK subtypes have been used to help classify tumors according to their site of origin; commonly used CK stains in CUP are CK7 and CK20. CK7 is found in tumors of the lung, ovary, endometrium, and breast and not in those of the lower gastrointestinal tract, whereas CK20 is normally expressed in the gastrointestinal epithelium, urothelium, and Merkel's cells. CK20+/CK7– strongly suggest a primary tumor of the colon; 75–95% of colon tumors show this pattern of staining. CK20–/CK7+ suggests cancer of the lung, breast, ovary, endometrium, and pancreaticobiliary tract; some of these can also be CK20+. The nuclear CDX-2 transcription factor, which is the product of a homeobox gene necessary for intestinal organogenesis, is often used to aid in the diagnosis of gastrointestinal adenocarcinomas. Thyroid transcription factor 1 (TTF-1) is a 38-kDa homeodomain- containing nuclear protein that plays a role in transcriptional activation during embryogenesis in the thyroid, diencephalon, and respiratory epithelium. TTF-1 nuclear staining is typically positive in lung and thyroid cancers. Approximately 68% of adenocarcinomas and 25% of squamous cell lung cancers stain positive for TTF-1, which helps differentiate a lung primary tumor from metastatic adenocarcinoma in a pleural effusion, the mediastinum, or the lung parenchyma. Distinguishing pleural mesothelioma from lung adenocarcinoma can be challenging. Calretinin, Wilms' tumor gene-1 (WT-1), and mesothelin have been suggested as useful markers for mesothelioma. Gross cystic disease fibrous protein-15, a 15-kDa monomer protein, is a marker of apocrine differentiation that is detected in 62–72% of breast carcinomas. UROIII, high-molecular-weight cytokeratin, thrombomodulin, and CK20 are the markers used to diagnose lesions of urothelial origin. Role of DNA Microarray and Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) in CUP In the absence of a known primary, developing therapeutic strategies for CUP is challenging. The current diagnostic yield with imaging and immunochemistry is ~20–30% for CUP patients. The use of gene expression studies holds the promise of substantially increasing this yield. Gene expression profiles are most commonly generated using quantitative RT-PCR or DNA microarray. Neural network programs have been used to develop predictive algorithms from the gene expression profiles. Typically, a training set of gene profiles from known cancers (preferably from metastatic sites) are used to train the software. The program can then be used to predict the origin of a test tumor, and presumably of true CUP. Comprehensive gene expression databases that have become available for common malignancies may also be useful in CUP. Investigators have used expression data from normal differentiated tissues to identify conserved expression profiles found in malignant tissue as a basis for predicting the tissue of origin. These approaches have been effective in blind testing against known primary cancers and their metastasis. However, because, by definition, the primary tumor site is not identifiable in CUP, validation of site prediction in this setting can be challenging, and any predictions currently must be supported by clinical and pathologic correlation. Prospective validation trials are currently evaluating the role of molecular studies in CUP. Carcinoma of Unknown Primary: Treatment General Considerations The treatment of CUP continues to evolve, albeit slowly. The median survival duration of most patients with disseminated CUP is ~6–10 months. Systemic chemotherapy is the primary treatment modality in most cases, but the careful integration of surgery, radiation therapy, and even periods of observation are important in the overall management of this condition (Figs. 95-2 and 95-3). Prognostic factors include performance status, site and number of metastases, response to chemotherapy, and serum lactate dehydrogenase (LDH) levels. Culine and colleagues developed a prognostic model using performance status and serum LDH levels, which allowed the assignment of patients into two subgroups with divergent outcomes. Future prospective trials using this prognostic model are warranted. Clinically, several CUP diagnoses fall into a favorable prognostic subset. Others, including those with disseminated CUP, have a more unfavorable prognosis. Figure 95-2 Treatment algorithm for adenocarcinoma and poorly differentiated adenocarcinoma CUP. C, chemotherapy; IHC, immunohistochemistry; GI, gastrointestinal; CRT, chemoradiation; RT, radiation; PSA, prostate- specific antigen; MRI, magnetic resonance imaging. . Chapter 095. Carcinoma of Unknown Primary (Part 4) There are 20 subtypes of cytokeratin (CK) intermediate filaments with different. role of molecular studies in CUP. Carcinoma of Unknown Primary: Treatment General Considerations The treatment of CUP continues to evolve, albeit slowly. The median survival duration of most. a primary tumor of the colon; 75–95% of colon tumors show this pattern of staining. CK20–/CK7+ suggests cancer of the lung, breast, ovary, endometrium, and pancreaticobiliary tract; some of