Cytology and the Investigation of Carcinoma of Unknown Primary (CUP) Dr Anna Green ST5, St Thomas Hospital London, UK

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1 Cytology and the Investigation of Carcinoma of Unknown Primary (CUP) Dr Anna Green ST5, St Thomas Hospital London, UK

2 Objectives Introduction to CUP Our experience of cytology and CUP Role of Cytology in CUP The future of CUP investigation and management

3 Cancer of Unknown Origin: MUO, pcupand ccup Malignancy of undefined primary origin (MUO): Metastatic malignancy identified on the basis of a limited number of tests, without an obvious primary site, before comprehensive investigation. Provisional carcinoma of unknown primary (provisional CUP/pCUP): Metastatic epithelial or neuroendocrinemalignancy identified on the basis of histology/ cytology, with no primary site detected despite a selected initial screen of investigations, before specialist review and possible further specialised investigations. Confirmed carcinoma of unknown primary (confirmed CUP/cCUP): Metastatic epithelial or neuroendocrinemalignancy identified on the basis of final histology, with no primary site detected despite a selected initial screen of investigations, specialist review, and further specialisedinvestigations as appropriate.

4 MUO Initial Ix Metastatic epithelial or neuroendocrinemalignancy, primary revealed during screening investigations Lymphoma and other haematologicmalignancies Metastatic germ cell tumour Metastatic melanoma Sarcoma Metastatic epithelial or neuroendocrinemalignancy, no primary revealed pcup Further Ix Metastatic epithelial or neuroendocrinemalignancy, primary revealed Metastatic epithelial or neuroendocrinemalignancy, no primary revealed ccup

5 Epidemiology 2% of total cancers registered in 2012 (ONS) M47% F53% 22% of patients presenting with metastases (JF Bishop et al. Prognosisof sub-types of cancer of unknownprimary(cup) comparedto metastaticcancer. Journal of Clinical Oncology, 2007; 25(18S))

6 CUP as % of all cancers registered (England) %

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8 N. Pavlidis. Cancer of unknown primary: biological and clinical characteristics. Annals of Oncology 2003; 14(S3): iii11 iii18. >50% of patients with CUP present with multiple sites of involvement.

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10 Prognosis of CUP 4th mostcommoncause of cancer deathin Englandand Wales. 1 year survival: 16% 5 year survival: 8% Mediansurvival: ~6-9 months

11 Prognosis of CUP Those with metastatic adenocarcinoma with unknown primary were80% more likelyto die thanthosewithmetastatic adenocarcinoma witha knownprimary(hr 1.8, 95%CI ). JF Bishop et al. Prognosisof sub-types of cancer of unknownprimary(cup) comparedto metastaticcancer. Journal of Clinical Oncology 2007; 25(18S).

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13 CUP and Cellular Pathology Management of metastatic malignancy is determined by primary site MUO Pan-CK; CD45; PLAP; S100 ±other sarcoma IHC pcup CK7, CK20, TTF-1, PLAP, ER/PSA P63, CK5 CDX2, WT1, PAX5, RCC, HepPar1 ccup

14 CUP and Cellular Pathology Adenocarcinoma of unknown origin: CK7, CK20, TTF-1, PLAP, ER (women only) and PSA (men only) Use additional immunohistochemistryto refine the differential diagnosis, guided by the results of the panel of antibodies in the previous recommendation and the clinical picture. No recommendation regarding poorly diff carcinoma, use of panel to differentiate adenocarcinoma from SCC

15 GSTT CUP MDM April 2013 November 2013 No. new patients referred: 47 Not CUP: 28 ccup: 19 Investigation Histology: 13 Histology + Cytology: 4 Cytology: 2 Adenocarcinoma 9 Squamous cell carcinoma 3 Poorly differentiated carcinoma 4 Adenosquamous carcinoma 2 Carcinoma, NOS 1

16 CUP Dxon Cytology 68 yr old Male Presented with cervical lymphadenopathy FNA of right level 4 lymph node

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18 CK20 ( ) CK5 ( ) P63 ( ) TTF1 ( ) CK7 BerEP4 CK7 CK20 ( ) CK5 ( ) P63 ( ) TTF1 ( ) PSA ( ) PRAP ( )

19 Cytology and CUP The most common single sites are: lymph nodes, lung, liver and bone. A pleural effusion may be the only or most accessible site of malignant involvement. 7% of cases of carcinomatous pleural effusions are CUP. N. Pavlidis. Cancer of unknown primary: biological and clinical characteristics. Annals of Oncology 2003; 14(S3): iii11 iii18.

20 Cytology & CUP Advantages -Less invasive -On-site assessment -Accurate -IHC on cell block or fixed preparations -Material for molecular Disadvantages -Insufficient material -Loss of architecture

21 Investigation of Specific Presentations 1. Intrapulmonary nodules without evidence of endobronchialdisease Flexible bronchosopywith biopsy, brushings and washings 2. Investigation of malignant peritoneal disease Obtain a tissue sample for histological examination in patients with MUO who present with ascites, if technically possible.

22 Management of Specific Presentations of CUP Squamous carcinoma involving upper-or mid-neck nodes Squamous carcinoma involving the inguinal nodes

23 Management of Specific Presentations of CUP Adenocarcinoma involving the axillarynodes

24 The Future: Gene expression profiling &/or clinically actionable mutations? A need for new methods of detection of the primary site? Is the primary site the most important factor?

25 Gene Expression Profiling Largely developed using metastatic tumours with known primary sites Use RT-PCR or Micro-array technology

26 Raji Pillai et al. Validation and Reproducibility of a Microarray-Based Gene Expression Test for Tumor Identification in Formalin-Fixed, Paraffin-Embedded Specimens. J Mol Diagn. 2011; 13(1):

27 The Future: Gene expression profiling Is GEP applicable to CUP? NICE guidance 2010: Currently there is limited evidence that gene-expression based profiling changes the management of patients with CUP and no evidence of improvement in outcome. The contribution of gene-expression based profiling to improving conventional diagnostic strategies should be investigated.

28 GEP vsihc: Overall accuracy: GEP in agreement with reference diagnosis in 89.2% of specimens IHC in agreement with reference diagnosis in 83.3% (difference statistically significant, P = 0.013; OR % CI ) Accuracy varied by known primary site

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30 Results

31 Clinically Actionable Mutations Is the site of tumour origin the most important factor in determining treatment? Screening for molecular abnormalities is already standard clinical practice eg. EGFR mutations in NSCLC, BRAF mutation in metastatic melanoma, Her2 overexpressionin breast/gastric cancer

32 12/16 patients with CUP had actionable mutations or copynumber aberrations

33 Conclusions CUP is a diagnosis of exclusion, which relies on significant pathology input CUP is the 4 th most common cause of cancer death Cytology may be the only source of tissuefor diagnosis and to guide management The literature on the role of cytology in CUP is scanty The future of management and diagnosis is likely to incorporate/ depend on molecular pathology

34 Acknowledgements Dr Ash Chandra Dr Giuseppe Culoraand Dr Mike Green Dr Sarah Ngan

35 References Cancer Statistics Registrations, England (Series MB1), No. 43, 2012 NICE Clinical Guideline 104: Diagnosis and management of metastatic malignant disease of unknown primary origin N. Pavlidis, G. Pentheroudakis. Cancer of unknown primary site. The Lancet 2012; 379(9824): PomjanskiN et al. ImmunocytochemicalIdentification of Carcinomas of Unknown Primary in Serous Effusions. Diagnostic Cytopathology2005; 33(5): N. Pavlidiset al. Diagnostic and therapeutic management of cancer of an unknown primary. European Journal of Cancer 2003;39: N. Pavlidis. Cancer of unknown primary: biological and clinical characteristics. Annals of Oncology 2003; 14 (S3): iii11 iii18 JD. Hainsworth, FA.Greco. Gene expression profiling in patients with carcinoma of unknown primary site: from translational research to standard of care. VirchowsArchiv2014; 464(4): HFP. Hillen. Unknown primary tumours. PostgradMed J 2000;76: FF. Holmes, TL. Fouts. Metastatic cancer of unknown primary site. Cancer 1970, 26(4): Stella et al. Cancers of unknown primary origin: current perspectives and future therapeutic strategies. Journal of Translational Medicine 2012, 10:12. G. Pentheroudakis, V. Golfinopoulos, N. Pavlidis. Switching benchmarks in cancer of unknown primary: from autopsy to microarray. EurJ Cancer Sep;43(14): RW. Tothillet al. Massively-parallel sequencing assists the diagnosis and guided treatment of cancers of unknown primary. J Pathol 2013; 231: M. Riihimäkiet al. Comparison of survival of patients with metastases from known versus unknown primaries: survival in metastatic cancer.bmc Cancer 2013;13:36. Raji Pillai et al. Validation and Reproducibility of a Microarray-Based Gene Expression Test for Tumor Identification in Formalin-Fixed, Paraffin-Embedded Specimens. J Mol Diagn. 2011; 13(1): 48 56