Division of Surgical, Molecular and Ultrastructural Pathology University of Pisa Pisa University Hospital Research Doctorate in Molecular and Experimental Oncology

UNKNOWN PRIMARY TUMORS a vanishing chapter of pathology

METASTASISPRIMARY ????????

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

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 

 5 % of all metastatic cancer

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

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

??????????? CUP - UPC - UPT - OPT

matter of size CUP - UPC - UPT - OPT

0 mm  few mm  CUP - UPC - UPT - OPT

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

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

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

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

size imaging CUP - UPC - UPT - OPT

PRE – IMAGING ERA

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

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

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

small very aggressive CUP - UPC - UPT - OPT

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        

DUCTALLOBULAR

sexual maturity aging pre-puberal

DCIS LCIS

INFILTRATING DUCTAL CARCINOMA DCIS: FREQUENT

LCIS: RARE INFILTRATING LOBULAR CARCINOMA

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

terminal duct – lobule unit ductal carcinoma lobular carcinoma

DESTRUCTION of the LOBULE

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

invasive cametastasis clones vascular invasion

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

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

PRIMARYMET or  =

PRIMARY MET molecular characterization for molecular therapy