Carcinoma of Unknown Primary (CUP)

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1 Metasta c Carcinoma of Unknown Primary: Diagnos c Approach Using Immunohistochemistry James R. Conner, MD, PhD Mount Sinai Hospital Toronto, ON Carcinoma of Unknown Primary (CUP) 3-5% of all new malignant diagnoses 7 th or 8 th most common malignant tumor 4 th most common cause of tumor death Slowly declining incidence Improved diagnos c imaging Expanding repertoire of immunohistochemical markers 1

2 Roles of the Pathologist in CUP 1. Dis nguish carcinoma from melanoma, sarcoma, lymphoma 2. Define carcinoma subtype (adenocarcinoma, squamous cell carcinoma, hepatocellular carcinoma, etc) 3. Iden fy site of origin Immunohistochemistry in Workup of CUP Kera ns and their distribu on in carcinomas Lineage specific markers: Cytoplasmic proteins Lineage restricted transcrip on factors Iden fica on of primary liver tumors Squamous cell carcinomas Neuroendocrine tumors 2

3 High and Low Molecular Weight Kera ns LMWKs (CK8, CK18, CAM5.2) expressed by simple epithelium: Glandular epithelium Hepatocytes HMWKs (CK5, CK14, 34βE12) expressed by complex epithelium: Stra fied (squamous, transi onal) epithelium Some ductal epithelium Basal cells CK7 (KRT7) and CK20 (KRT20) Profile CK7+/CK20- CK7+/CK20+ CK7-/CK20+ CK7-/CK20- Most Frequent Primary Sites Breast, Mullerian, Lung, Thyroid Upper GI, Pancreas, Urothelial Colorectal, Merkel Cell Prostate, Hepatocellular, Renal, Adrenal 3

4 Lineage Restricted Markers Cytoplasmic (and Membranous) Markers Primary Site Markers (% Sensi vity) Breast Mammaglobin (60-80), GCDFP-15 (60-80) Lung Napsin A (60-80) Thyroid Thyroglobulin (80-90) Renal RCC (80-90 primary, metasta c) Hepatocellular HepPar1 (70-90), Arginase-1 (80-90) Prostate PSA (85-95), PSAP (85-95) Colorectal Villin (80-90) Adrenal Cortex MelanA/MART-1 (85-95), Inhibin (85-95) Bladder Uroplakin III (15-50), Uroplakin II (50-80) 4

5 Cytoplasmic (and Membranous) Markers In general, sensi vity is high in well-differen ated tumors but decreases substan ally in poorly differen ated tumors GCDFP-15 in Breast Carcinoma 5

6 Mammaglobin in Breast Carcinoma NapsinA in Pulmonary Adenocarcinoma 6

7 Remember Limita ons on Specificity Napsin A Ovarian clear cell carcinoma (80-100%) Papillary renal cell carcinoma (70-90%) Mammaglobin Endometrial carcinoma (10-30%) Inhibin, MelanA/MART-1 Sex cord stromal tumors (>80%) PSA Mammary carcinomas (20-40%) Salivary gland carcinomas (20-40%) Lineage Restricted Transcrip on Factors Expanding repertoire 15 years ago: TTF-1, CDX-2 Now: >50 markers for a wide spectrum of malignancies (NOT limited to carcinoma) Novel insights from developmental biology Essen al for organ specific development Implica on: Expression o en retained even in poorly differen ated tumors 7

8 Commonly Employed Markers in CUP Marker TTF-1 CDX-2 PAX8 GATA3 SATB2 OCT3/4 NKX3.1 SF1 Primary Sites Lung, Thyroid Colorectal, Appendix, Upper GI Mullerian, Kidney, Thyroid Breast, Bladder Colorectal Germ Cell Prostate Adrenal Cor cal, Sex Cord Stromal Poorly Differen ated (Insular) Thyroid Carcinoma TTF-1 PAX8 8

9 Poorly Differen ated Lung Adenocarcinoma TTF-1 PAX8 PAX8 in Ovarian Carcinoma 9

10 CDX-2 in Gastric Adenocarcinoma * Par cularly useful to exclude metasta c lobular breast carcinoma SATB2 in Colorectal Carcinoma 10

11 SATB2 and Osteoblas c Differen a on Dobreva G et al. Cell 2006 SATB2 in Osteosarcoma 11

12 GATA3 in Breast Carcinoma Mammaglobin GATA3 NKX3.1 in Prosta c Adenocarcinoma PSA NKX3.1 12

13 SF1 in Adrenal Cor cal Carcinoma Remember Primary Liver Tumors in the Differen al with CUP Hepatocellular Carcinoma Renal cell carcinoma Adrenal cor cal carcinoma Poorly differen ated carcinoma from any site Cholangiocarcinoma Pancrea c ductal adenocarcinoma Most other adenocarcinomas 13

14 HepPar-1 in Hepatocellular Carcinoma Cau on: HepPar-1 may react with gastric, esophageal, and lung adenocarcinomas, especially hepatoid variants 14

15 Arginase-1 in Hepatocellular Carcinoma Polyclonal CEA in Hepatocellular Carcinoma 15

16 Intrahepa c Cholangiocarcinoma No reliably specific marker O en CK7+, CK20+/-, CDX-2 weak, focal Approximately 50% with loss of SMAD4 Iden cal profile can be seen in metasta c pancrea c adenocarcinoma Dis nc ve Radiographic Features of Intrahape c Cholangiocarcinoma Heterogeneous and delayed enhancement Dilata on of intrahepa c bile ducts Capsular retrac on Satellite nodules Lobar atrophy 16

17 Intrahepa c Cholangiocarcinoma Bahe AD et al Squamous Cell Carcinoma Confirma on p63 (can be focally posi ve in up to 30% of lung adenocarcinomas) p40 (similar sensi vity, greater specificity) HMWKs (second line) Determina on of primary site rarely possible Excep on: virus associated tumors: EBV and nasopharyngeal carcinoma HPV and oropharyngeal carcinomas (tonsil/base of tongue) 17

18 Well Differen ated Neuroendocrine Tumors Increasingly important to determine primary site Pancrea c (but not midgut) NET effec vely treated with Streptozocin, Temozolomide, Everolimus, Suni nib Metasta c WD NETs Midgut (most common): CDX-2 Pancreas: PAX8 (polyclonal) Islet-1 Lung: TTF-1 18

19 ppax8 in Pancrea c WD NET Poorly Differen ated NEC Key: dis nguish visceral from cutaneous tumors Localized Merkel cell carcinoma will be treated surgically All other pa ents will receive pla num-based chemotherapy CK % of Merkel cell carcinomas Rare in other PDNECs TTF-1 Rare in Merkel cell carcinoma Common in PDNEC from most other sites 19

20 What is the site of origin? TTF-1 Key Points Assigning primary site in CUP improves outcomes Expect lower sensi vity in poorly differen ated tumors Lineage specific transcrip on factors increase sensi vity in most cases Knowledge of cross reac vity is cri cal to avoid misdiagnosis Remember to consider primary liver tumors 20

21 Select References Kandala P and Gown A. Arch Pathol Lab Med (2015) Epub ahead of print Conner J and Hornick J. Adv Anat Pathol (2015) 22(3): Bellizzi A. Adv Anat Pathol (2013) 20(5):

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