Cancer of Unknown Primary


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  Notes
 
 
1 : CANCER OF UNKNOWN PRIMARY SITE NICHOLAS PAVLIDIS PROFESSOR OF MEDICAL ONCOLOGY MEDICAL SCHOOL, UNIVERSITY OF IOANNINA GREECE
2 : Histologically confirmed metastatic cancer Detailed medical history Complete physical examination (plus pelvic and rectal exam) Chest radiography Full blood count Biochemistry Urinalysis Stool occult blood testing Histopathology review and use of immunohistochemistry Computed tomography of chest, abdomen and pelvis Mammography or MRI (in certain cases). PET – scan (in certain cases). CLINICAL AND LABORATORY DATA REQUIRED TO DEFINE A PATIENT AS HAVING A CUP
3 : EPIDEMIOLOGY OF CANCER OF UNKNOWN PRIMARY
4 : DON’T FORGET THAT CUP represents the 7th – 8th most frequent type of cancer and the 4th commonest cause of cancer death. It is considered to be more common than non-Hodgkin’s lymphoma
5 : FUNDAMENTAL CHARACTERISTICS Early dissemination Clinical absence of primary at presentation Aggressiveness Unpredictable metastatic pattern
6 : UNPREDICTABLE METASTATIC PATTERN Refers to the differences in the incidence of metastatic sites at diagnosis between known and unknown primary carcinomas E x a m p l e s (1) Lung cancer presenting as CUP involves the bones in 4%, while presenting as a known primary the osseous involvement is 30-50% Pancreatic cancer presenting as CUP has 4-fold higher incidence to affect bones, and 30% incidence to appear with lung metastases. Prostate cancer presenting as CUP has a 3-fold less incidence to affect bones compared to the known primary prostate cancer.
7 : H I S T O L O G Y I N C I D E N C E A d e n o c a r c i n o m a Well to moderately differentiated Poorly or undifferentiated   S q u a m o u s c e l l c a r c i n o m a   U n d i f f e r e n t i a t e d ne o p l a s m s Not specified carcinoma Neuroendocrine tumors Lymphomas Germ cell tumors Melanomas Sarcomas Embryonal malignancies   HISTOLOGICAL CLASSIFICATION 50 % 35 % 10 % 5 %
8 : CLINICOPATHOLOGICAL ENTITIES OF CUP O R G A N H I S T O L O G Y Liver (mainly) and/or other organs AdenoCa M or P diff Lymph nodes Mediastinal – Retroperitoneal (midline distribution) U or P diff Ca Axillary AdenoCa W to P diff Cervical SCC Ca Inguinal U Ca, SCC, mixed SCC / adenoCa W = well, M = moderately, P = poorly, U = undifferentiated
9 : W = well, M = moderately, P = poorly, U = undifferentiated
10 : W = well, M = moderately, P = poorly, U = undifferentiated Bones (solitary or multiple) AdenoCa of various diff Brain (solitary of multiple) AdenoCa of various diff or squamous cell Ca Neuroendocrine tumors P diff Ca with neuroendocrine features (mainly), low-grade neuroendocrine Ca, small cell anaplastic Ca
11 : HOW DO WE SEARCH FOR THE PRIMARY ? By IMAGING By ENDOSCOPY By HISTOPATHOLOGY Immunohisto-chemistry Advanced Molecular Technology Electron Microscopy CT- scans MRIs PET- scans Mammography Ultrasonography Conventional Radiology ENT panendoscopy Bronchoscopy Colonoscopy Proctoscopy Colposcopy
12 : Lysozyme GcDFP-15 (gross cystic disease fluid protein 15) Marker Site of Origin Prostate Lung Breast Colon Ampullary, Colon, Esophageal, Ovarian Lung, Pancreas, Breast, Cholangio, Ovarian PSA (Prostate - specific antigen) TTF1 (Thyroid transcription factor 1) CDX2 CK20 CK7 ER (Estrogen receptor) Breast, Ovarian, Endometrial Mesothelin Ovarian, Cholangio, Mesothelioma, Endometrial CA 125 Ovarian, Endometrial,Cholangio, Pancreas IMMUNOHISTOCHEMISTRY IN CUP DIAGNOSTIC ALGORITHM FOR ADENOCARCINOMA Cholangio, Stomach, Colon, Pancreas, Lung THE 10 MARKERS Clin Cancer Res 11: 3766, 2005
13 : CK7 CK20 CK7 + CK20 + CK7 + CK20 - CK7 - CK20 + CK7 - CK20 - Urothelial tumors Ovarian mucinous adenocarcinoma Pancreatic adenocarcinoma Cholangiocarcinoma Lung adenocarcinoma Breast carcinoma Thyroid carcinoma Endometrial carcinoma Cervical carcinoma Salivary gland carcinoma Cholangiocarcinoma Pancreatic carcinoma Colorectal Carcinoma Merkel cell carcinoma Hepatocellular carcinoma Renal cell carcinoma Prostate carcinoma Squamous cell & small cell lung carcinoma Head & neck carcinoma
14 : MOLECULAR ANALYSIS [Microarray Platforms] around 80% accuracy
15 : IMAGING STUDIES Chest X-ray A presequisite test Barium Studies Non contributory to the detection of 1ry (very low sensitivity) Should only rarely if ever be used
16 : CT - scans Offers an additional diagnostic accuracy of 40% Provides guidance to biopsy procedure Mammography Basic test in women with metastatic adenoCa in axillary nodes However, sensitivity was found to be low
17 : FREQUENCY OF MRI-DETECTED BREAST CA IN PATIENTS WITH CUP AXILLARY ADENOPATHY
18 : FDG - PET SCAN (18 – F – FLUORODEOXYGLUCOSE) Diagnostic accuracy : 26% - 45% More sensitive for occult head – neck and lung tumors J. Nucl. Med. 2003 Meta-analysis (1994-2001) on 298 patients FDG PET showed detection of the primary in 43% of pts Occult : lung 42%, head-neck 36%, GI 6%, Others 17%
19 : ENDOSCOPY Should always be symptoms - or sings oriented investigational procedures ENT panendoscopy : in cervical node involvement Bronchoscopy : in radiographic indications or symptoms Colonoscopy : in relevant symptoms and signs Proctoscopy : in inguinal node involvement Colposcopy : in inguinal node involvement
20 : SERUM TUMOR MARKERS Routine evaluation of current commonly used markers have not been proven of any prognostic or diagnostic assistance A non – specific multiple overexpression of the adenocarcinoma markers (CEA, CA 125, CA 15-3, CA 19-9) has been observed in the majority of CUP patients. Worthwhile to request : PSA in men with bone metastatic adenocarcinoma ?-HCG & AFP in men with an undifferentiated tumor AFP in patients with hepatic tumors CA 125 women with papillary adenocarcinoma of peritoneal cavity. CA 15-3 women with adenocarcinoma involving only axillary lymph nodes.
21 : INVESTIGATIONS FOR THE IDENTIFICATION OF THE PRIMARY TUMOR
22 : IDENTIFICATION OF PRIMARY SITE BY EXTENSIVE DIAGNOSTIC WORK - UP The antemorten frequency of detection of primary site by imaging, endoscopy or immunohistochemistry studies remains around 30%. Pavlidis et al, Eur J Cancer 39: 1990-2005, 2003
23 : IDENTIFICATION OF PRIMARY SITE AT AUTOPSY FROM ALL PUBLISHED SERIES Years of Publications : 1944 - 2000 No of Autopsies : 884 Primary Site Found : 73 % (644 / 884) Genital system 7 % Stomach 6 % Bladder / ureter 0.01 % Breast 0.007 % Other 10 % Lung 27 % Pancreas 24 % Liver/bile duct 8 % Kidney /adrenals 8 % Bowel 7 % Primary Sites Identified :
24 : IDENTIFICATION OF PRIMARY SITE BY GENETIC PROFILING (MICROARRAYS) FROM ALL PUBLISHED CUP SERIES Years of Publications : 2005- 2007 No of Samples : > 500 (cDNA) Biological Assignment of Primaries (Accuracy) : 50 – 87 % Primary Sites Identified : Liver/bile duct 8 % Kidney / adrenals 6 % Bladder / ureter 5 % Stomach 3 % Other 18 % Breast 15 % Pancreas 12.5 % Bowel 12 % Lung 11.5 % Genital system 9 %
25 : WHAT IS THE OPTIMAL THERAPEUTIC APPROACH OF CANCER OF UNKNOWN PRIMARY ?
26 : HISTORICAL OVERVIEW1960 - 2008
27 : FAVOURABLE OR GOOD PROGNOSIS SUBSETS UNFAVOURABLE OR POOR PROGNOSIS SUBSETS CUP
28 : THE FAVOURABLE SUBSETS OR GOOD PROGNOSIS SUBSETS
29 : 1.  Poorly differentiated carcinoma with midline distribution (extragonadal germ cell syndrome). F a v o u r a b l e S u b s e t s 2. Women with papillary adenocarcinoma of peritoneal cavity. 3.  Women with adenocarcinoma involving only axillary lymph nodes. 4.  Squamous cell carcinoma involving cervical lymph nodes 5. Poorly differentiated neuroendocrine carcinomas. 6. Men with blastic bone metastases and elevated PSA (adenocarcinoma). 7. Isolated inguinal adenopathy (squamous carcinoma). 8. Patients with a single, small, potentially resectable tumor.
30 : CHARACTERISTICS OF PATIENTS WITH POORLY DIFFERENTIATED CUP
31 : PERITONEAL CARCINOMATOSIS IN FEMALES
32 : WOMEN WITH PAPILLARY ADENOCARCINOMA OF PERITONEAL CAVILY ( Peritoneal Adenocarcinomatosis )
33 : ISOLATED AXILLARY NODAL METASTASES FROM AN OCCULT PRIMARY BREAST CANCER Cancer 47:2923, 1981 Cancer 66:1461, 1990 Cancer 70: 504, 1992
34 : ISOLATED AXILLARY NODAL METASTASES FROM AN OCCULT PRIMARY BREAST CANCER T H E R A P E U T I C M A N A G E M E N T Axillary Clearance* Simple Mastectomy ** or Local Excision Radical Irradiation ** (breast + axilla) Premenopausal pts : Adjuvant Chemotherapy ? Tamoxifen [ if ER (+) ] Postmenopausal pts : Adjuvant Tamoxifen [ if ER (+) ] Adjuvant Chemotherapy ( ?? ) OR * Type C basis ** Type 3 level P A T I E N T S W I T H N1 (mobile nodes)
35 : PATIENTS WITH N2 (fixed nodes) Preopareative Chemotherapy * ? Axillary Clearance ? Postoperative Chemotherapy ? Radiotherapy ? Tamoxifen Radical Irradiation * ( breast + axilla ) ? Axillary Clearance ( ? ) ? Tamoxifen In non-responding tumors or in elderly pts OR * Type 3 level
36 : ISOLATED AXILLARY NODAL METASTASES FROM AN OCCULT PRIMARY BREAST CANCER S U R V I V A L R A T E S Similar to stage II or III breast cancer Overall survival : 75% at 5yrs, 60% at 10yrs No survival difference between conservative management and mastectomy. N2 disease has worse prognosis than N1. Although adjuvant systemic treatment showed no benefit in the retrospective studies, most patients should be considered for appropriate adjuvant therapy. Male patients have worse prognosis
37 : SQUAMOUS CELL CANCER INVOLVING CERVICAL LYMPH NODES
38 : POORLY DIFFERENTIATED NEUROENDOCRINE CARCINOMAS
39 : OTHER FAVOURABLE CUP SUBSETS Men with adenocarcinoma blastic bone metastases (and elevated PSA) Rx = Treat as metastatic prostate cancer Isolated inguinal lymphadenopathy from squamous cell carcinoma Rx = Dissection ± radiotherapy Single metastatic site Rx = Dissection ± radiotherapy
40 : THE UNFAVOURABLE SUBSETS OR POOR PROGNOSIS SUBSETS
41 : U N F A V O U R A B L E S U B S E T S Adenocarcinoma metastatic to the liver or other organs Non-papillary malignant ascites (adenocarcinoma) Multiple cerebral metastases (adeno or squamous Ca) Multiple lung/pleural metastases (adenocarcinoma) Multiple metastatic bone disease (adenocarcinoma)
42 : Results of Empiric Therapy with Cisplatin - containing Regimens for Adenocarcinoma of Unknown Primary Site
43 : THE SUBSET OF ADENOCARCINOMA METASTATIC TO THE LIVER
44 : HISTOLOGIC SPECTRUM OF LIVER METASTASES
45 : OVERALL RESULTS OF CHEMOTHERAPY IN CUP PATIENTS WITH LIVER METASTASES No of trials : 5 (1991, 1998, 2002, 2005, 2008) No of patients : 711 Response rate : < 20% Median survival : 5.5 months Bull Cancer 1991, J Clin Oncol 1998, Clin Radiol 2002, Gastroent Clin Biol 2005, Cancer Treat Rev 2008
46 : HOW SHOULD WE TREAT PATIENTS WITH UNFAVOURABLE CUP? Patients with relatively young age and good P.S. could offer a chance of platinum - based chemotherapy Alternatively, best supportive care should be recommended.
47 : STEPS IN DIAGNOSTIC AND THERAPEUTIC MANAGEMENT STEP I   SEARCH FOR PRIMARY SITE Complete Medical History and Physical Examination Basic Laboratory Work-up and/or Specific Tests STEP II RULE-OUT POTENTIALLY TREATABLE OR CURABLE TUMORS (Immunohistochemistry, molecular or electron microscopy) i.e. Breast Cancer Germ-cell Tumors Prostate Cancer Ewing Sarcoma Lymphomas PNET Tumors STEP III CHARACTERIZE THE SPECIFIC CLINICOPATHOLOGICAL ENTITY TREAT THE PATIENT FAVOURABLE SUBSETS [ With “Curative ” Intent ] UNFAVOURABLE SUBSETS [ With “Palliative” Intent ] DIAGNOSIS OF METASTATIC CARCINOMA (by histopathology)
48 : ESMO CLINICAL RECOMMENDATIONS C a n c e r o f U n k n o w n P r i m a r y S i t e Briasoulis E, Pavlidis N. Ann Oncology suppl, 2008 www.esmo.org/resources/clinicalquidelines
49 : CANCER OF UNKNOWN PRIMARY THE TAKE HOME MESSAGES
50 : FOR DIAGNOSIS The incidence of CUP is 3-5% CUP carries a different natural history compared to known primary tumors Clinically and histologically CUP consists of more than one diseases Detailed immunohistochemistry study is the cornerstone for CUP diagnosis Molecular analyses ( cDNA or microRNAs ) have high sensitivity in identifying the primary site. The impact however, in patients’ outcome remains questionable. CT- scans offer a 40% accuracy. MRI is sensitive for occult breast cancer (˜ 60% accuracy) PET-scan is very useful in occult head-neck and lung cancer.
51 : FOR TREATMENT Avoid to spend excessive time and money in investigating and treating every CUP patient. Try to identify the favourable subsets : Responsive subsets to locoregional treatments i.e. isolated axillary nodal metastases, SCC of cervical nodes. Responsive subsets to systemic chemotherapy: Poorly differentiated carcinomas of midline distribution Peritoneal adenocarcinomatosis in females Poorly differentiated neuroendocrine carcinomas Platinum with or without taxanes regimens offer 40-70% response rates and long term survival in the favourable subsets. Unfavourable subsets with good P.S> can be treated with platinum – based chemotherapy, but in general carry a dismal prognosis. New agents are warranted.

 

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