1. Annals of Oncology 23: 298–304, 2012 종양혈액내과 R4 김태영 / prof. 김시영

2. Introduction Cancer of unknown primary (CUP) : metastatic cancer in the absence of a clinically detectable anatomically defined primary tumor site after an ‘adequate’ diagnostic evaluation A summary of the first global conference on CUP organized by the CUP Foundation to share understanding of the biology and treatment of patients with CUP The emphasis on newer diagnostic techniques and developments with the aim of standardizing and improving patient care and stimulating further CUP research

3. definition, epidemiology, biology, prognosis CUP : metastatic cancer without an anatomically defined primary tumor - In the first group a strong suspicion of the primary tumor site of origin based on clinical and pathologic features. - In the second group even after substantial evaluation, the primary tumor site remains uncertain - Improving diagnostic technologies ( IHC, molecular profiling assays )

4. definition, epidemiology, biology, prognosis Incidence of CUP : 2%–10% of all cancer USA - CUP accounts for 2.3% of all cancers. 30 000 patients / year Some CUP patients are treated as ‘known primaries’. recent analysis carried out by Tong et al: as many as 100 000 CUP patients per year in Europe and a similar number in the United States.

5. definition, epidemiology, biology, prognosis The biology and pathogenesis of CUP is poorly understood In the majority of patients, the primary tumor site is very small and clinically undetectable yet clinically detectable metastases In 25% of patients, the primary is not evident even at autopsy stem cell and embryologic migration Hypotheses : some genetic changes, particularly mutations early in the development of the primary tumor

6. definition, epidemiology, biology, prognosis CUP as a whole has a poor prognosis present with adenocarcinomas and poorly differentiated carcinomas Distinct subsets of patients (20% of the whole group) have an improved survival after appropriate therapy Patients not favorable subsets : a median survival of 8–12 months, 1-year survival from 15% to 35% no uniform treatment standard many patients are currently being treated on a probability of primary tumor site diagnosis

8. diagnostic approaches to CUP At autopsy, an occult primary can anatomically be found in 75% the most common primary tumor sites : pancreas and lung, followed by liver/bile ducts, kidney/adrenal Use of a panel of multiple IHC stains, molecular profiling assays Accurate diagnosis of the primary tumor site is first step to testing the clinical outcome to site-specific therapeutic regimens now and in the future

9. pathologic evaluation The pathologic investigation – systematic approach 1. cancer is present in the tissue sample ? 2. describe the broad cancer type carcinoma, melanoma, lymphoma, or sarcoma 3. subtype of carcinoma: squamous, adenocarcinoma, solid carcinoma (thyroid, liver, renal) neuroendocrine, germ-cell tumors, or mesothelioma 4. predict the primary site from the histopathology and IHC staining

10. pathologic evaluation GCDFP-15, mammoglobulin in breast TTF-1 with (CK-7+, CK-20 - ) in lung HEPAR-1 in hepatocellular thyroglobulin/TTF-1 in thyroid, placental alkaline phosphatase/OCT-4 in germ-cell tumors, CDX-2 with (CK-7-, CK-20+) in colorectal WT-1/PAX-8 in ovary Synaptophysin and chromogranin in neuroendocrine tumors Panels of IHC markers superior to single biomarkers Dennis et al. panel using 10 different marker stains, can correctly classify the site of origin in 88% of adenocarcinomas

11. pathologic evaluation Horlings et al. 38 patients with CUP with IHC staining In 16 out of 38 (42%) a single primary site was suspected. In 15 of these 16 patients (94%), molecular assay diagnosis in agreement with the IHC diagnosis. Greco and Hainsworth 171 patients with CUP, most having fairly comprehensive IHC. In 59 (35%) of 171 patients, a single primary tumor site diagnosed molecular profile assay diagnosis agreed in 40 of 52 (77%). State-of-the-art IHC staining predict in 35%–40% of CUP molecular profile assays are in agreement most of the time

12. clinical evaluation Morphologic exam of a biopsy specimen -a critical first step All patients - complete history, physical examination a full-body CT, CBC, LFT, renal function tests, and UA Women - mammography, Men- PSA PET scanning can be helpful - SqCC presenting in cervical LNs - a single site of metastatic disease before local therapy The pattern of metastasis in CUP is an important part

13. molecular profiling and classification of human cancers malignant tissues still retain some of signature gene expression genetic signatures in CUP not always same as known primary cancers Molecular approaches could determine targeted treatment pathways the diagnostic and treatment-predictive pathways could integrated in one process. A clinically viable test needs to be compatible with : formalin-fixed paraffin-embedded (FFPE) tissues low numbers of tumor cells, discriminate large number of tumor types

15. new technologies in practice A retrospective study : molecular profiling assay (RT-PCR) by bioTheranostics biopsy specimen of 20 patients with CUP latent known primary sites found between 2 and 54 months The molecular profile assay prediction :accurate in 15 of the 20 (75%) Recent prospective study compared the molecular profiling of 89 CUP patients using the Rosetta Genomics–Prometheus assay results correlated with clinicopathologic features in 84% of cases

18. Conclusions A single definition of CUP - difficult : CUP is not a single neoplasm but a clinicopathologic syndrome with a range of neoplasms and clinical presentations Better understanding of their primary site of origin, the molecular biolopy of neoplastic process => personalized treatment The performance of molecular assays appears broadly similar to optimal IHC The comparison of optimal pathology and molecular assays in CUP patients remains an important question Clinical and costeffectiveness studies