Presentation on theme: "Cancer of Unknown Primary"— Presentation transcript:
1 Cancer of Unknown Primary Dr Lucy WalkingtonOctober 2013
2 CUP/UKP/MUOPatients who present with metastatic malignancy without an identified primary source…..Important to distinguish between cancers where the 10 will be identified after investigation and the true CUP
3 Background 9,778 new cases of CUP registered in England, 2006 2.7% of total cancers in England, 20063-5% overallF>M (54% V 46%)Median age at diagnosis is 65 years10% < 50 age group30% - multiple metastases at diagnosisLiver, bone (+ marrow), lung & LNscommonest metastatic sitesOften rapidly progressing4th most common cause of cancer death(NICE guidance July 2010)
4 BackgroundIt is a heterogeneous group of tumours which 1st present with metastases and not the primary.A work-up does not identify primary site at the time of diagnosisIn 15-25% PM doesn’t reveal the primaryOccult primary is said to turn out to be colorectal, lung or pancreas in approx 60%
5 Background The term CUP in practice may cover: Patients ‘referred’ where absolutely no work-up/assessment has been done;Patients who are too poorly to be investigatedPatients where investigations eventually identify the primaryA true Unknown Primary!
6 Who to Investigate Patients should only be investigated if: the result is likely to affect treatment decisionthe patient understands why the investigations are being carried out, their risks and benefitsthey are prepared to accept the treatment.
7 Decreasing in incidence WHY?Improved diagnosisChange in cancer registry codesChanges in clinical practice due to MDT working
8 CUP patients – don’t come “packaged” Process is complex & labour intensiveMedian survival ranges from 4 to 11 monthsNo change in survival between 1992 – 2006Compare general cancer survival1, 3 & 5-year survivals are 23%, 11% & 6% respectivelyMost do not benefit from chemo
9 What do these patients need? A thorough history and examinationBasic bloods esp U+E, LFTs, bone profile.Needs to include:Any symptoms/signsAny FHxOccupational/smoking historySignificant comorbidityPerformance StatusInc head & neck, rectal, pelvic, testicles, and breast examination.
10 What do these patients need? (Chest Xray)(CT abdo & pelvis (+/- chest))(U/S testes)(Mammogram)(FOB, urinalysis, myeloma screen)(Symptom directed Endoscopy).(Tumour Markers –AFP, HCG, PSA, CA125, CEA)(Biopsy)Myeloma screen (if isolated or multiple lytic lesions)Cancer antigen (CA) 125 (serum) in women with peritoneal malignancy or ascitesAFP & hCG (especially if mid line nodal disease)Testicular ultrasound in men with presentation compatible with germ-cell tumoursBiopsy & standard histological examination with IHC to distinguish carcinoma from other malignant processesMammographyShould not be done routinely but directed by disease pattern e.g. axillary LAN or pathological featuresPET-CT scan (18FDG)Cervical LAN with no 10 tumour on panendoscopy of ENT region if radical treatment is an option
11 Overview of management Know when to investigatePatient fit for treatmentMaximise identification of treatable conditionsMinimise over-investigationEarly identification of patientsEarly expert assessment/involvement by an appropriate oncologistRelevant investigations in a rational orderInitial investigations (high yield) e.g. CT scanSecondary specialist investigationsL Gaspa et al (2002) yield of basic tests 62% and additional tests was 29%Know when to stop investigations
12 Tumour markers Do not measure except for: Not recommended for diagnosisLow sensitivity & specificityInappropriate requesting often leads to unnecessary, costly & potentially harmful investigationsDo not measure except for:AFP & hCG if presentation compatible with germ cell tumoursMediastinal or retroperitoneal masses & in young men (<50)AFP if presentation compatible with HCCPSA if presentation compatible with prostate cancerCA125 in women with presentation compatible with ovarian cancer (including inguinal node, chest, pleural, peritoneal or retroperitoneal presentations)
13 Important factor to consider initially is the CELL TYPEepithelial V non-epithelial
14 Pathology Heterogeneous collection of tumour types Includes CarcinomasPoorly differentiated malignanciesSophisticated pathologic evaluationIdentify certain histologiesAllow appropriate therapyTechniquesLight microscopyImmunohistochemical stainingElectron microscopyMolecular genetics
15 Histological types in CUP Histological SubtypeProportion of CasesAdenocarcinoma(Incl G1 & 2 differentiated Ca)45-61%Undifferentiated Carcinoma24-39%Squamous Cell Carcinoma4-15%Small cell Carcinoma (neuroendocrine carcinoma)3-4%Souhami et al, Oxford Textbook of Oncology, 2nd Ed, 2002
16 Immunohistochemistry Basic haemotoxylin & eosin (H&E) – high diagnostic rateoften insufficient to determine cell origin in adeno’sFor CUP – panel of IHC is needed to exclude:MelanomaLymphomaSarcomaGerm CellExpression of cytokeratin 20 (CK20) & 7 (CK7)important in determining tissue of origin for adenocarcinomasThyroid Transcription Factor 1(TTF-1)used to increase or reduce probability of bronchial carcinomaOestrogen receptor (ER)breast, esp in conjunction with CK20 & 7Must be guided by clinical features
17 Immunohistochemistry IHC markers help to define tumour lineageperoxidase-labeled antibodies are used against specific tumour antigensSelect appropriate set of antibodiescannot be replaced by using a universal battery of markersNo IHC test is 100% specificE.g. PSA can be positive in salivary gland carcinomaIHC markers are for guidance to be used in conjunction with the patient's presentation & imaging studies to guide management
20 Why Gene Expression Profiling Can Classify Cancers Types Cancers from different origins are derived from cells from different developmental processesGene expression is distinct between different developmentally- derived cell types
21 Promising molecular targets and targeting compounds in CUP MoleculeRasHER2EGFRC-KITPDGFRBCL2P53VEGFVEGFRTherapeutic ModFarnesyl-transferase inhAntibodies, TKI’sTKI’sAntisense oligonucleotidesGene Rx, degradation inhAntibodiesDeveloped agentsTipifarnib, lonafarnibTrastuzumab, lapatinibCetuximab, gefitinib, erlotinibImatinib, sunitinibOblimersen G3139ONYX015, INGN201, MI63BevacizumabZD6474, sorafenib, sunitinibPentheroudakis and Pavlidis, Cancer Treat Rev, 2006
22 FAVOURABLE SUBSETS Women with isolated axillary adenopathy Women with papillary serous adenocarcinoma of the peritoneal cavitySquamous cell carcinoma (SCC) involving cervical lymph nodesIsolated inguinal adenopathy from SCCMen with bone metastases, elevated serum PSA, or PSA positive on tumor stainingMen with poorly differentiated carcinoma of midline distributionPoorly differentiated neuroendocrine carcinomaSingle, small & potentially resectable metastatic site
23 UNFAVOURABLE SUB-SETS Adenocarcinoma metastatic to the liver or other organsNon-papillary malignant ascites (adeno)Multiple cerebral metastases (adeno or squamous carcinoma)Multiplelung/pleuralmetastases (adeno)Multiple metastatic bone disease (adeno)
24 Prognostic factors Majority have a limited life expectancy weeks to monthsSubsets with better prognosisSome achieve survival rates of yearsGroups that have responded well to empirical chemowith the advent of IHC some tumours have been found to be extragonadal GCTs and LymphomasOther CUP groups with better than average prognosiswomen with axillary LAN (adenoCa)patients with cervical LAN (SCC)
25 SCF LN Rarely H&N primaries Commonly from sites below the clavicles oesophagus, lung, breast, GI, prostateUsually adenocarcinoma(R) SCF – breast & lung primaries(L) SCF – intra-abdominal malignanciesspread via thoracic duct
26 Metastatic Cervical LNs Cervical node metastases of squamous cell carcinoma from occult primary constitute about 2-5% of all patients with CUPMets in upper & mid neckattributed to H&N cancersLower neck (SCF)associated with 10 below the clavicles e.g. lung or GI tract
27 TREATMENT FAVORABLE SUBSETS Squamous cell carcinoma of the cervical lymph nodesDespite aggressive diagnostic approach, the primary site is not found in the majority of patientsIpsilateral tonsillectomy is often performed since the primary can be found in 10 to 25% of cases - Small tumors may originate in the deep crypts and not be detected by superficial biopsyTreat as locally advanced head and neck cancerLow stage (N1) – Surgery RT or RT aloneHigh stage (N2-N3) - Chemoradiotherapy
28 Inguinal LN Rare presentation of CUP May arise from Skin malignancy of leg or lower trunkOccult melanomaPerineal & pelvic malignancyHistology may direct investigationsmixed squamous/adenoCa – signifies a ‘cloacogenic’ primary that may be occultexamination of anorectal regiongynaecological examcystoscopyRegional RT can prolonged responses (esp. if SCC)If LN mets only site & occult melanoma excluded
29 TREATMENT FAVORABLE SUBSETS Isolated inguinal squamous cell carcinomaTumour is usually located in the genital or anorectal areaPatients without an identifiable primary tumour may benefit from inguinal lymphadenectomy, +/- adjuvant RTRole for chemotherapy in the adjuvant setting is not well definedSurgery ± RT, ? chemotherapy
30 TREATMENT FAVORABLE SUBSETS Men with bone metastases, elevated serum PSA, or PSA positive on tumor stainingProstate cancer is the most likely diagnosis1. Elderly men with adenocarcinoma of unknown primary & predominantly blastic bone metastases2. Patients with increased PSA or positive PSA staining on the biopsy specimen despite atypical presentationHormonal therapy
31 TREATMENT FAVORABLE SUBSETS Women with isolated axillary adenopathyLymph nodes should be tested for ER, PR & HER-2In cases of negative mammogram, the primary may be seen on MRI or after mastectomyPrognosis is similar to lymph node positive breast cancerMobile lymph nodes (N1) - Treat as stage IIA breast cancerFixed lymph nodes (N2) - Treated as stage IIIA breast cancerMRM + AND chemotherapy ± hormonal therapy/RTNeoadjuvant chemotherapy for N2 disease
32 TREATMENT FAVORABLE SUBSETS Women with papillary serous adenocarcinoma of the peritoneal cavityGerminal epithelium of the ovary & peritoneal mesothelium share the same embryological originMore common in women with BRCA-1 mutation and may also be seen after prophylactic oophorectomyOutcomes are similar to ovarian cancer at equivalent stagePatients should be treated as stage III ovarian carcinomaSurgical debulking followed by chemotherapy
33 TREATMENT FAVORABLE SUBSETS Poorly differentiated neuroendocrine carcinomaIHC usually stains positive for chromogranin or NSEPatients frequently present with diffuse metastases to the liver or bonesPlatinum-based chemotherapy (platinum + etoposide)
34 TREATMENT FAVORABLE SUBSETS Men with poorly differentiated carcinoma of midline distributionYoung males with tumours of predominant midline distribution (mediastinum & retroperitoneum) should be treated as extragonadal germ cell tumorsCisplatin-based chemotherapy (BEP)
35 TREATMENT FAVOURABLE SUBSETS Single metastatic siteAlthough other metastatic sites may become evident within a short period, some patients may achieve a prolonged disease-free interval with local therapies such as surgery or radiotherapyAdjuvant chemotherapy may also be consideredSurgery or RT
37 Bone MetastasesBetween % patients present with bone symptoms due to metsSouhami et al 2002In CUP patientsw/o skeletal symptomsbone scan + ve in 50 %with symptomsbone scan + ve in 90 %
38 Bone mets from different primaries cause different radiological appearances Blastic lesionsprostateHodgkin's & NHLthyroidcarcinoidSCLCLytic lesionsmyelomamelanomarenal cell carcinomaNSCLCIn CUP, bone appearances are of limited value in directing a search for a primary tumour
40 Current Clinical Practice Diagnosis of metastatic cancerSearch for primary siteRule out non-carcinoma hx - Lymphoma, melanoma, sarcomaIdentify favourable subgroupsUnfavourable subgroupPoor PSGood PSClinical trialPlatinum-taxane chemotherapyBest Supp Care
42 Who should be involved with the care of CUP patients?
43 Who gets involved with a potential CUP? ?All CliniciansNeed to be able to assess for any potential primary and refer then to appropriate team.When primary not obvious, early advice from OncologyDirect which testsDirect appropriateness of InvestigationsLarge Input expected from Palliative CareMajority of cases are too poorly for Treatment and need palliation
44 What about dealing with patients who require admission? Whoever is on call at that time??Admit patient under an appropriate team eg named General Medicine firm, named General surgery team, named orthopaedics team? ie Each area would have a responsible team!Should they be admitted directly under an Oncologist?Should they be admitted directly under Palliative Care?
45 If they do not need admission, which clinic should they be booked into? -In Chesterfield there is a CUP clinic lead by Palliative Care consultant.Should this be the standard?Should there be a team in each hospital designated to look after patients who have a potential malignancy?Should it be an Oncologist running this clinic?Should clinic be dependent on most prominent sign?
46 CUP peer review measures – newly introduced Hospitals to develop CUP teamNamed oncologistCNSNamed palliative care consultantCUP assessment serviceFast access clinicMDTAim to improve patient experience, outcomes and ?reduce LoS