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.

CANCER UNKNOWN ORIGIN

(Pathology)

• Adenocarcinoma (50%)

• Poorly Differentiated Carcinomas(35%)

• Squamous Cell Carcinoma (10%)

• Undifferentiated Carcinoma (5%)

CANCER UNKNOWN ORIGIN

(Immunohistochemistry)

• Cytokeratins

• Organo-specific markers (PSA,

Thyroglobuline, GCDFP-15)

• Non-organ-specific markers (CEA, p63,

ER/PR)

CANCER UNKNOWN ORIGIN

(Cytokeratins 7 + 20 -)

• Breast Ca

• Lung, nonsmall cell ca (90%)

• Ovarian serous ca (90%)

• Mesothelioma

• Endometrial Ca

CANCER UNKNOWN ORIGIN

(Cytokeratins 7 - 20 +)

• Colon Ca (75-95%)

CANCER UNKNOWN ORIGIN

(Cytokeratins 7 + 20 +)

• Transitional Cell Ca

• Ovarian mucinous ca

• Pancreatic Ca

CANCER UNKNOWN ORIGIN

(Cytokeratins 7 - 20 -)

• Hepatocellular Ca (70- 90%)

• Renal cell ca (70 – 90%)

• Prostatic Ca

• Neuroendocrine Ca

• Squamous cell Ca

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)

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, PRGCDF-15Mamoglobin

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

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

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)

MOLECULAR APPROACHES IN

TUMORS OF UNKNOWN ORIGIN

• ONE GENE

• MULTIPLE GENES

• 83 year old man

• Disseminated cancer (liver and lung). Pleural Effusion

• Pleural Cytology: Positive for malignancy, consistent with adenocarcinoma. TTF-1 negative

Clinical History

EGFR exon 19 E746-A750 del 15pb

Diagnosis

Pleural metastasis from pulmonary

adenocarcinoma with EGFR mutations.

Treatment with EGFR inhibitors.

MOLECULAR APPROACHES IN

TUMORS OF UNKNOWN ORIGIN

• ONE GENE

• MULTIPLE GENES

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)

Estudio Molecular Cancer Origen Desconocido

Last generation sequenciacing

(Ion Torrent, Miseq)

Actionable genomic alteration rather than site of origin for

personalized therapy

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)

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.

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)

• 64 year old woman

• Breast Cancer, several years ago

• Peritoneal Carcinomatosis

Clinical History

ER WT-1

Mamoglobin GCDF-15

Diagnóstico

Metastatic ovarian carcinoma

(serous type)

• 59 year old man.

• Brain tumor

Clinical History

TTF-1 CK-7

CK-20

Diagnosis

Metastatic carcinoma of pancreatic

origin.

• 64 year old woman

• Bilateral ovarian tumors

Clinical History

CK 7 negative; CK 20 positive

• Gastroscopy: negative

• Gastric biopsies: negative

Follow-up

Diagnosis

Gastric carcinoma metastatic to the

ovaries

• 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.

Take Home Messages