CANCER UNKNOWN PRIMARY

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María Rosa Quintana Pinto
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2 CANCER UNKNOWN PRIMARY 3-5 % of diagnosed cancers Variability depending of centers 50% adenocarcinomas Immunohistochemistry helps in 30-85% Gene expression assays help in 75-90% Both methods solve > 95% Prognosis depends of identification of primary site.

4 CANCER UNKNOWN ORIGIN (Pathology) Adenocarcinoma (50%) Poorly Differentiated Carcinomas(35%) Squamous Cell Carcinoma (10%) Undifferentiated Carcinoma (5%)

5 CANCER UNKNOWN ORIGIN Cytokeratins (Immunohistochemistry) Organo-specific markers (PSA, Thyroglobuline, GCDFP-15) Non-organ-specific markers (CEA, p63, ER/PR)

6 CANCER UNKNOWN ORIGIN Breast Ca (Cytokeratins ) Lung, nonsmall cell ca (90%) Ovarian serous ca (90%) Mesothelioma Endometrial Ca

7 CANCER UNKNOWN ORIGIN (Cytokeratins ) Colon Ca (75-95%)

8 CANCER UNKNOWN ORIGIN (Cytokeratins ) Transitional Cell Ca Ovarian mucinous ca Pancreatic Ca

9 CANCER UNKNOWN ORIGIN (Cytokeratins ) Hepatocellular Ca (70-90%) Renal cell ca (70 90%) Prostatic Ca Neuroendocrine Ca Squamous cell Ca

10 CANCER UNKNOWN ORIGIN (Tumor Specific Markers) Cytoplasmic / Membranous (differenciation) (Differentiated cells; Expression related to degree of differentiation; Expression may be focal) Nuclear Transcription Factors (Sensitive and specific; Expression not necessarily related to degree of differentiation; Expression on entire tumor cell population)

11 CANCER UNKNOWN ORIGIN (Breast cancer markers) GCDFP-15 (sensitivity, 55%; highest in lobular and apocrine; independent of grade, ER status, mitotic index; also expressed in vulva, eyelid; never expressed in lung, colon, ovary) Mamaglobin (sensitivity 46,6%, combined with GCDFP-15, sensitivity 69%) ER, PR Mamoglobin GCDF-15

12 CANCER UNKNOWN ORIGIN (GI tract markers) Villin (sensitive for colon ca; 5% lung adenoca) CDX-2 (sensitive for colon ca; occasionally positive in mucinous ovarian or bladder adenoca) CK7 / CK20

13 TTF-1 38 kd member of the NKx-2 family of transcription factors Thyroid, respiratory epithelium and diencephalon Lung tumors (highest in neuroendocrine and bronchioloalveolar; lowest in squamous and mucinous) Occasional rectal and ovarian adenoc. Positive in thyroid and neuroendocrine tumors

14 WT-1 Tumor suppressor gene in 11p13 Mesangial cells, Sertoli cells, ovarian stroma and surface epithelium, mesothelium Marker of serous ovarian cancer (97% specificity, 91% sensitivity)

16 MOLECULAR APPROACHES IN TUMORS OF UNKNOWN ORIGIN ONE GENE MULTIPLE GENES

17 Clinical History 83 year old man Disseminated cancer (liver and lung). Pleural Effusion Pleural Cytology: Positive for malignancy, consistent with adenocarcinoma. TTF-1 negative

19 EGFR exon 19 E746-A750 del 15pb

20 Diagnosis Pleural metastasis from pulmonary adenocarcinoma with EGFR mutations. Treatment with EGFR inhibitors.

21 MOLECULAR APPROACHES IN TUMORS OF UNKNOWN ORIGIN ONE GENE MULTIPLE GENES

22 Commercial Tests for Cancer of Unknown Origin Quest-Lab Corp (92 gene PCR test for 39 cancer types) Agendia (microarray-based test for 43 cancer types) Pathworks Diagn (microarray-based test for 15 cancer types, representing 60 different morphologies) Veridex ( PCR-based test for 6 cancer types) Epitype ( Methylation-based assay) CancerTYPE-bioTheranostics (PCR-based test for 39 cancer types) Rosetta Genomics (PCR-based test on mirna for 25 cancer types)

25 Estudio Molecular Cancer Origen Desconocido Last generation sequenciacing (Ion Torrent, Miseq) Actionable genomic alteration rather than site of origin for personalized therapy

27 Cancer metastático de origen desconocido (Inmunohistoquímica versus Patología Molecular en 73 casos) 73 casos, que se presentan como metástasis de cáncer de origen incierto o controvertido (103 casos evaluados) Pathwork Tissue of Origin Test en tejido congelado Immunohistoquímica (CK7, CK20, CK19, PSA, Thyrogl, TTF1, GCDF-15, Mamoglobin, ER, PR, WT1, CDX2, villin, PAX2, HepPar 1, Glypican, CD-10, Inhibin, S-100, Melan-A, HMB-45)

28 Cancer metastático de origen desconocido (Inmunohistoquímica versus Patología Molecular en 73 casos) Los principales problemas a los que se plantea la técnica molecular son: 1) Dificultades técnicas inherentes al sistema de microarrays 2) Dificultad de trabajar con muestras congeladas 3) Problemas de ruido de fondo por la población normal acompañante 4) Metástasis de cánceres primarios, que no están incluidos entre los que el sistema evalúa 5) Problemas específicos en tipos histológicos precisos.

29 Cancer metastático en ovario y peritoneo (Inmunohistoquímica versus Patología Molecular en 32 casos) 29 con origen conocido tras follow-up: IHQ : 22/ 29 Pathwork: 25/29 IHQ + Pathwork: 26/ 29 3 casos sin origen aclarado tras follow-up: En los 3 casos concordancia IHQ y Pathwork ( colon, estomago, y colon versus estómago)

31 Clinical History 64 year old woman Breast Cancer, several years ago Peritoneal Carcinomatosis

33 ER WT-1

34 Mamoglobin GCDF-15

36 Diagnóstico Metastatic ovarian carcinoma (serous type)

37 Clinical History 59 year old man. Brain tumor

39 TTF-1 CK-7 CK-20

41 Diagnosis Metastatic carcinoma of pancreatic origin.

42 Clinical History 64 year old woman Bilateral ovarian tumors

44 CK 7 negative; CK 20 positive

45 Follow-up Gastroscopy: negative Gastric biopsies: negative

47 Diagnosis Gastric carcinoma metastatic to the ovaries

48 Take Home Messages Conventional pathology and IHC solves 70% of cases Combination of Conventional pathology, IHC and gene expression assays solves more than 95% of cases Gene expression tests should be interpreted in the appropriate pathological context.

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