1. Division of Surgical, Molecular and Ultrastructural Pathology University of Pisa Pisa University Hospital g.bevilacqua@med.unipi.it Research Doctorate in Molecular and Experimental Oncology 13431338

2. UNKNOWN PRIMARY TUMORS a vanishing chapter of pathology

3. METASTASISPRIMARY ????????

4. CUP – Carcinoma of Unknown Primary UPC – Unknown Primary Cancer ACUP – Adeno Carcinoma of Unknown Primary    UPT – Unknown Primary Tumor  OPT – Occult Primary Tumor 

5. a biopsy-proven metastatic malignancy this diagnosis requires: after a thorough clinical evaluation that includes physical examination and laboratory and imaging diagnostic tests  no identifiable primary tumor 

6.  5 % of all metastatic cancer

7. CUP - UPC - UPT - OPT source identification:  - molecular profiling: 60 – 85 % - morphology, IHC: 20 – 30 % of cases

8. CUP - UPC - UPT - OPT prognosis:  worst than in cases with known primary

9. ??????????? CUP - UPC - UPT - OPT

10. matter of size CUP - UPC - UPT - OPT

11. 0 mm  few mm  CUP - UPC - UPT - OPT

12. 0 mm: SPONTANEOUS REGRESSION  few mm  CUP - UPC - UPT - OPT

13. SPONTANEOUS REGRESSION of a TUMOR 1 : 60,000 – 100,000 cases ?????????????

14. SPONTANEOUS REGRESSION of a CANCER 1 : 60,000 – 100,000 cases ischemia ????????????? immune response “unofficial” chemical compounds   

15. Hicks AM et al: Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. PNAS 103: 7753–7758, 2006

16. size imaging CUP - UPC - UPT - OPT

17. PRE – IMAGING ERA

18. The lesson of Anatomy of Dott. Nicolaes Tulp Rembrandt, 1632

19. Prof. Rupert A WILLIS 1898 - 1980 in case of CUP - UPC - UPT - OPT LUNG

20. IMAGING & MOLECULAR PROFILING lung pancreas liver / bile ducts kidney / adrenals bowel genital system stomach bladder / ureter breast         

21. small very aggressive CUP - UPC - UPT - OPT

22. ductal; NOS: not otherwise specified; NST: no special type lobular tubular / cribriform medullary mucinous papillary metaplastic apocrine 80% 10% 6%6% 2%2% 2%2% 1% < 1% breast carcinoma        

23. DUCTALLOBULAR

24. sexual maturity aging pre-puberal

25. DCIS LCIS

26. INFILTRATING DUCTAL CARCINOMA DCIS: FREQUENT

27. LCIS: RARE INFILTRATING LOBULAR CARCINOMA

28. LOBULAR early loss of intercellular junctions DUCTAL late loss of intercellular junctions

29. terminal duct – lobule unit ductal carcinoma lobular carcinoma

31. DESTRUCTION of the LOBULE

32. natural history of a carcinoma 1 initiation:2 promotion: 3 progression: normal hyperplastic atypical cancer invasive metastatic

33. invasive cametastasis clones vascular invasion

34. CUP - UPC - UPT - OPT early acquisition of the invasive genotype / phenotype

35. CUP - UPC - UPT - OPT early acquisition of the invasive genotype / phenotype small primary early metastasis bad prognosis

36. PRIMARYMET or  =

37. PRIMARY MET molecular characterization for molecular therapy