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C ANCER OF U NKNOWN P RIMARY S ITE

C ANCER OF U NKNOWN P RIMARY S ITE. N ICHOLAS P AVLIDIS, MD, PhD, FRCP (Edin). PROFESSOR OF MEDICAL ONCOLOGY MEDICAL SCHOOL, UNIVERSITY OF IOANNINA GREECE. Barcelona , June 2012. CANCER OF UNKNOWN PRIMARY ( CUP ). 1) DEFINITION EPIDEMIOLOGY BIOLOGY

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C ANCER OF U NKNOWN P RIMARY S ITE

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  1. CANCER OFUNKNOWNPRIMARYSITE NICHOLAS PAVLIDIS, MD, PhD, FRCP (Edin) PROFESSOR OF MEDICAL ONCOLOGY MEDICAL SCHOOL, UNIVERSITY OF IOANNINA GREECE Barcelona , June 2012

  2. CANCER OF UNKNOWN PRIMARY ( CUP ) 1) DEFINITION EPIDEMIOLOGY BIOLOGY 4) PATHOLOGY 5) NATURAL HISTORY 6) DIAGNOSTIC APPROACH 7) TREATMENT

  3. IS THERE A DEFINITION FOR CANCER OF UNKNOWN PRIMARY ORIGIN ?

  4. In1970’s THE DEFINITION All patients presented with histologically confirmed metastatic carcinoma in whom a complete medical history, careful physical examination, chest x-ray, full blood count, stool occult blood testing and urinalysis did not identify the primary site.

  5. CLINICAL ANDLABORATORYDATAREQUIRED TO DEFINE A PATIENT AS HAVING ACUP • Histologically confirmed metastatic cancer • Detailed medical history • Complete physical examination (plus pelvic and rectal exam) • Chest radiography • Full blood count • Biochemistry • Urinalysis • Stool occult blood testing • Histopathology review and use of immunohistochemistry • Computed tomography of chest, abdomen and pelvis • Mammography or MRI (in certain cases). • PET – scan (in certain cases).

  6. WHAT IS THE INCIDENCE OF CANCER OF UNKNOWN PRIMARY SITE ?

  7. EPIDEMIOLOGY OF CANCER OF UNKNOWN PRIMARY

  8. THE BIOLOGY OF CANCER OF UNKNOWN PRIMARY

  9. Hypothesis A CUP does not undergo type 1 progression (from a premalignant lesion to malignant) b u t Follows a type 2 progression (malignant at the onset of the disease without forming a primary site) Frost P et al, Cancer Bull 1989, 41, 139-141

  10. Hypothesis B CUP follows the parallel progression model where metastases can arise early in the development of a malignancy … I n c o n t r a s t t o the linear progression model where stepwise progression of accumulating genetic and epigenetic alterations accompanying cancer development Klein C, Nature Reviews Cancer 9: 302-312, 2009

  11. TRANSLATIONAL RESEARCH ON CUP BIOLOGY • Chromosomal Instability • Oncogenes – Oncoproteins • Tumour and Metastasis Suppressor Genes • Angiogenesis • Metalloproteinases • Hypoxia • Epithelial Mesenchymal Transition and Stemness • Signaling Pathways

  12. TRANSLATIONAL RESEARCH IN CUP

  13. Adverse prognostic factor in squamous cervical CUP 25 % -

  14. THE NATURAL HISTORY OF CANCER OF UNKNOWN PRIMARY SITE

  15. FUNDAMENTAL CHARACTERISTICS • Early dissemination • Clinical absence of primary at presentation • Aggressiveness • Unpredictable metastatic pattern

  16. UNPREDICTABLE METASTATIC PATTERN • Refers to the differences in the incidence of metastatic sites at diagnosis between known and unknown primary carcinomas E x a m p l e • Pancreatic cancer presenting as CUP has 4-fold higher incidence to affect bones, and 30% incidence to appear with lung metastases.

  17. Cancer of Unknown Primary Site : One or more Diseases ?

  18. HISTOLOGICAL CLASSIFICATION I N C I D E N C E H I S T O L O G Y A d e n o c a r c i n o m a Well to moderately differentiated Poorly or undifferentiated 50 % 35 % S q u a m o u s c e l l c a r c i n o m a 10 % U n d i f f e r e n t i a t e d ne o p l a s m s Not specified carcinoma Neuroendocrine tumors Lymphomas Germ cell tumors Melanomas Sarcomas Embryonal malignancies 5 %

  19. CLINICOPATHOLOGICAL ENTITIES OF CUP O R G A N H I S T O L O G Y Liver(mainly) and/or other organs AdenoCa M or P diff Lymph nodes Mediastinal – Retroperitoneal (midline distribution) U or P diff Ca Axillary AdenoCa W to P diff Cervical SCC Ca Inguinal U Ca, SCC, mixed SCC / adenoCa W = well, M = moderately, P = poorly, U = undifferentiated

  20. W = well, M = moderately, P = poorly, U = undifferentiated

  21. Bones (solitary or multiple) AdenoCa of various diff Brain (solitary of multiple) AdenoCa of various diff or squamous cell Ca Neuroendocrine tumorsP diff Ca with neuroendocrine features (mainly), low-grade neuroendocrine Ca, small cell anaplastic Ca W = well, M = moderately, P = poorly, U = undifferentiated

  22. WHAT IS THE OPTIMAL INVESTIGATIONAL DIAGNOSTIC APPROACH FOR THE IDENTIFICATION OF THE PRIMARY TUMOR ?

  23. HOW DO WE SEARCH FOR THE PRIMARY ? By HISTOPATHOLOGY By IMAGING By ENDOSCOPY Immunohisto-chemistry ENT panendoscopy Conventional Radiology PET- scans Advanced Molecular Technology Bronchoscopy Mammography Colonoscopy Ultrasonography Proctoscopy CT- scans MRIs Colposcopy

  24. By HISTOPATHOLOGY

  25. STEPS OF IMMUNOHISTOCHEMICAL DIAGNOSTIC APPROACH FOR CUP Carcinoma AE 1/3 pancytokeratin Lymphoma Common leucocyte antigen (CLA) Melanoma S100, HMB45 Sarcoma S100, Vimentin STEP 1 (Detects broad type of cancer)

  26. STEP 2(Detects subtype of carcinoma) Adenocarcinoma CK 7/20, PSA Germ cell tumour PLAP, OCT4, AFP, HCG Hepatocellular Carcinoma Hepar 1, canalicular pCEA/CD10/CD13 Renal cell carcinoma RCC, CD10 Thyroid carcinoma TTF1, thyroglobulin Neuroendocrine carcinoma Chromogranin, synaptophysin, PGP 9.5, CD56 Squamous carcinoma CK 5/6, p63

  27. STEP 3 (Detects origin of an adenocarcinoma) Prostate PSA, PAP Lung TTF1 Breast GCDFP-15, mammaglobulin, ER Colon CD X 2, CK 20 Pancreas/Biliary CD X 2, CK 20, CK7 Ovary ER, Ca 125, mesothelin

  28. CYTOKERATINS (CKS) Monoclonal antibodies against cytokeratin polypeptides CK7 and CK20

  29. CK7 CK20 CK7 - CK20 + CK7 - CK20 - CK7 + CK20 + CK7 + CK20 - Urothelial tumors Ovarian mucinous adenocarcinoma Pancreatic adenocarcinoma Cholangiocarcinoma Lung adenocarcinoma Breast carcinoma Thyroid carcinoma Endometrial carcinoma Cervical carcinoma Salivary gland carcinoma Cholangiocarcinoma Pancreatic carcinoma Colorectal Carcinoma Merkel cell carcinoma Hepatocellular carcinoma Renal cell carcinoma Prostate carcinoma Squamous cell & small cell lung carcinoma Head & neck carcinoma

  30. MOLECULAR ANALYSIS [Microarray Platforms] > 80 – 90 % accuracy

  31. Gene expression profiling A s s a y s

  32. Accuracy of microRNA-based classification of metastases of unknown primary. Nicholas Pavlidis, George E. Pentheroudakis, et al ASCO, May 2012 A b s t r a c t We used a microarray-based test that uses the expression of 64 microRNAs to retrospectively evaluate tumors from CUP patients. Methods: A cohort of resected metastatic lesions from patients diagnosed with CUP was studied blindly on the microRNA-based test. The cohort included 93 samples (from 92 patients) with tissue adequate for the test. Results: The test results were fully concordant with the diagnosis based on all the clinical and pathological information available including follow-up and outcome in 92% of patients compared to ~70% agreement with the patients’ diagnosis at initial presentation, before additional data gathered throughout patient management. Conclusions: In a retrospective, well studied cohort of metastases from CUP patients, a previously developed test based on the expression profile of 64 microRNAs allowed accurate identification of tissue of origin in 92% of the cases. This study validates the high accuracy of the test on real CUP patients.

  33. By IMAGING

  34. IMAGING STUDIES IN CUP Imaging Study Diagnostic Value Prerequisite test Useless 40% accuracy / Guidance to biopsy Low sensitivity 60% accuracy 43% accuracy / more sensitive for occult H+N and Lung Ca Chest X-ray Barium studies CT-scans Mammography MRI (breast) FDG-PET SCAN

  35. By ENDOSCOPY

  36. ENDOSCOPY • Should always be symptoms - or sings oriented investigational procedures • ENT panendoscopy: in cervical node involvement • Bronchoscopy: in radiographic indications or symptoms • Colonoscopy : in relevant symptoms and signs • Proctoscopy: in inguinal node involvement • Colposcopy : in inguinal node involvement

  37. SERUM TUMOR MARKERS • Routine evaluation of current commonly used markers have not been proven of any prognostic or diagnostic assistance • A non – specific multiple overexpression of the adenocarcinoma markers (CEA, CA 125, CA 15-3, CA 19-9) has been observed in the majority of CUP patients. • Worthwhile to request : PSA in men with bone metastatic adenocarcinoma Β-HCG & AFP in men with an undifferentiated tumor AFP in patients with hepatic tumors CA 125 women with papillary adenocarcinoma of peritoneal cavity. CA 15-3women with adenocarcinoma involving only axillary lymph nodes.

  38. HOW OFTEN CAN THE PRIMARY TUMOR BE INDENTIFIED ?

  39. IDENTIFICATION OF PRIMARY SITE BY EXTENSIVE ROUTINE DIAGNOSTIC WORK - UP The antemortem frequency of detection of primary site by imaging, endoscopy or immunohistochemistry studies remains around 30%. Pavlidis et al, Eur J Cancer 39: 1990-2005, 2003

  40. IDENTIFICATION OF PRIMARY SITE AT AUTOPSY FROM ALL PUBLISHED SERIES No of Autopsies : 884 Years of Publications : 1944 - 2000 Primary Site Found : 73 % (644 / 884) Primary Sites Identified : Lung 27 % Pancreas 24 % Liver/bile duct 8 % Kidney /adrenals 8 % Bowel 7 % Genital system 7 % Stomach 6 % Bladder / ureter 0.01 % Breast 0.007 % Other 10 %

  41. IDENTIFICATION OF PRIMARY SITE BY GENETIC PROFILING (MICROARRAYS) FROM ALL PUBLISHED CUP SERIES No of Samples : > 500 (cDNA) Years of Publications : 2005- 2007 Biological Assignment of Primaries (Accuracy) : 50 – 87 % Primary Sites Identified : Breast 15 % Pancreas 12.5 % Bowel 12 % Lung 11.5 % Genital system 9 % Liver/bile duct 8 % Kidney / adrenals 6 % Bladder / ureter 5 % Stomach 3 % Other 18 %

  42. WHAT IS THE OPTIMAL THERAPEUTIC APPROACH OF CANCER OF UNKNOWN PRIMARY ?

  43. Overall comparative results of chemotherapy in CUP patients. A review of all phase II non –randomized studies

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