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CONTRIBUCION DE LAS
TECNICAS DE BIOLOGIA
MOLECULAR EN LOS
TUMORES METASTATICOS DE
ORIGIN
DESCONOCIDO
Xavier Matias-Guiu
Hospital Universitari Arnau de Vilanova,
Universitat de Lleida, IRBLLEIDA.
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CANCER UNKNOWN PRIMARY
• 3-5 % of diagnosed cancers
• Variability depending of centers
• 50% adenocarcinomas
• Immunohistochemistry helps in 30-70%
• Metastases to liver (25%) and bone (25%)
• Prognosis depends of identification of
primary site.
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MOLECULAR APPROACHES IN
TUMORS OF UNKNOWN ORIGIN
• ONE GENE
• MULTIPLE GENES
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LUNG CANCER AND EGFR
MUTATIONS
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• 83 year old man
• Disseminated cancer (liver and lung). Pleural Effusion
• Pleural Cytology: Positive for malignancy, consistent with adenocarcinoma. TTF-1 negative
Clinical History
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EGFR exon 19 E746-A750 del 15pb
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Diagnosis
Pleural metastasis from pulmonary
adenocarcinoma with EGFR mutations.
Treatment with EGFR inhibitors.
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ASSESSMENT OF PRIMARY
ORIGIN IN PATIENTS WITH A
PREVIOUS HISTORY OF CANCER
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Independent vs Metastatic Tumors
(clonality)
• Cromosome X (HUMARA)
• LOH
• Mutation analysis
• Viral Detection
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• 54 year old woman
• Small cell carcinoma of the lung. Metastatic work-up
negative. A combined treatment with chemotherapy
(cisplatin and VP16) and radiotherapy was
administered. Prophylactic cranial irradiation.
• Left ovarian mass, 3 months ofter finishing treatment
Clinical History
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Diagnosis
Ovarian metastasis of small cell
carcinoma of the lung
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Independent vs Metastatic Tumors
(clonality)
• Cromosome X (HUMARA)
• LOH
• Mutation analysis
• Viral Detection
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• 71 year old woman
• Cervical cancer, two years ago.
• Adrenal Tumor
Clinical History
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Diagnosis
Cervical Carcinoma metastatic to
the adrenal gland
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MOLECULAR APPROACHES IN
TUMORS OF UNKNOWN ORIGIN
• ONE GENE
• MULTIPLE GENES
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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)
• CancerTYPE-bioTheranostics (PCR-based test for 39 cancer
types)
• Rosetta Genomics (PCR-based test on miRNA for 25 cancer
types)
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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)
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Cancer metastático de origen
desconocido
(Analisis con Pathwork en 73 casos)
Patologia Molecular
Total
+ -
I
H
Q
+ 49 11 62
- 10 2 11
Total 59 14 73
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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.
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• 69 year old woman
• Unilateral ovarian tumor
• Colon cancer, several years ago
Clinical History
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CK 7 CK 20CK 7 CK 20
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Villin CDX 2
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Diagnosis
Colon carcinoma metastatic to the
ovary
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• 64 year old woman
• Breast Cancer, several years ago
• Peritoneal Carcinomatosis
Clinical History
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ER WT-1
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Mamoglobin GCDF-15
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Diagnóstico
Metastatic ovarian carcinoma
(serous type)
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• 59 year old man.
• Brain tumor
Clinical History
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TTF-1 CK-7
CK-20
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Diagnosis
Metastatic carcinoma of pancreatic
origin.
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• A 92 year-old man
• No previous history of cancer
• Mass in the thoracic wall
• Biopsy
Clinical History
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TTF-1AE-1-3
a-INHIBINGlypican
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VIMENTIN CD-10
PAX-2
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Diagnosis
Metastatic carcinoma of renal origin.
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• 64 year old woman
• Bilateral ovarian tumors
Clinical History
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• Gastroscopy: negative
• Gastric biopsies: negative
Follow-up
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Diagnosis
Gastric carcinoma metastatic to the
ovaries
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• 50 year old woman.
• Vaginal Bleeding
• Endometrial Biopsy
Clinical History
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AEI-AE3 +
CK7 –
CK 20 +
ER, PR –
Vimentin –
CDX-2 +
Villin +
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CK-20
ER PR CK-7
CDX-2 VILLIN
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• Endometrial bx: Adenocarcinoma (signet-ring features, consistent with gastrointestinal origin
• No evidence of gastrointestinal malignancy
• Hysterectomy and bilateral salpingooforectomy
Clinical History
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Diagnosis
Metastatic adenocarcinoma (signet-
ring features) of unknown origin
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• Antonio Llombart-Cussac
• Ainara Azueta, Maria Santacana, Ana Velasco, Jaime Prat,
• Manuel Mata, J Antonio Lopez Guerrero
Agradecimientos
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Galacidalacidesoxyribonucleicacid, Salvador Dalí, 1963.