Enterprise Interest Nothing to declare

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1 Enterprise Interest Nothing to declare

2 Update of mixed tumours of the GI tract, the pancreas and the liver Introduction to the concept of mixed tumours and clinical implication Jean-Yves SCOAZEC Surgical and Molecular Pathology, BIOpath AMMICa, CNRS UMS3655/INSERM US23 Gustave Roussy Cancer Campus, Villejuif, France

3 Overview The concept of mixed tumour Morphological issues Molecular issues Pathogenesis Clinical implications

4 The concept of mixed tumour Not an entity, but a heterogeneous group of tumours A tumour made of, at least, two distinct components Most cases are made of a combination of different carcinoma subtypes However The two components are not necessarily malignant Adenoma + neuroendocrine tumour The two components are not necessarily high grade Adenocarcinoma + well differentiated neuroendocrine tumour The two components are not necessarily of epithelial origin

5 Adenoma + neuroendocrine carcinoma

6 Adenoma + well-differentiated neuroendocrine tumour

7 Epithelial + mesenchymal Hybrid Hyperplastic Polyp/Mucosal Perineurioma

8 Differential diagnosis Tumours containing non neoplastic elements Adenocarcinoma associated with reactive, non neoplastic neuroendocrine cells colon, pancreas, lung primary and metastatic sites Neuroendocrine tumours entrapping preexisting structures Ductulo-insular tumours of the pancreas CgA

9 Differential diagnosis Inappropriate expression of «differentiation» markers NCAM expression by aggressive adenocarcinomas and hepatocellular carcinomas Pro-invasive NCAM polysialylated variants Recommendations: the expression of NCAM alone is not sufficient for a diagnosis of neuroendocrine carcinoma (component)

10 The concept of mixed tumour In some organs, the term «mixed tumour» is, by definition (WHO), restricted to tumours in which the minor component represents at least 30% of the tumor volume Digestive tract Pancreas In other organs, there is no percentage requirement for the diagnosis of «mixed tumour» Liver («combined tumour», WHO) Gallbladder and extra-hepatic bile ducts Lung («combined tumour», WHO)

11 The concept of mixed tumour Conventionnally, three main types Collision tumours Coincidental growth of two distinct tumours in the same site Entrapment of one tumour by another Metastasis of one tumour into another Composite tumours Several components deriving from the same precursor through a process of common descent Amphicrine tumours Coexistence of several lines of differentiation within the same neoplastic cell

12 The various possible components GI tract Adenoma/adenocarcinoma Squamous Neuroendocrine neoplasm Poorly differentiated Well differentiated Pancreas Ductal adenocarcinoma Acinar adenocarcinoma Neuroendocrine neoplasm Squamous Liver Hepatocellular carcinoma Cholangiocarcinoma Specific tumor subtypes (WHO)

13 The various possible components Eutopic Similar to a lineage normally present in the site of the tumour Ectopic Similar to a lineage not normally present in the site of the tumour Often known to occur in metaplastic lesions of the corresponding organ

14 Mixed tumours: morphology Situation 1: the two (or more) components are segregated («collision tumors») Chromogranin A

15 Mixed tumours: morphology Situation 2: the two (or more) components are intermingled («composite tumors»)

16 Mixed tumours: morphology Situation 2: the two (or more) components are intermingled («composite tumors») Alcian blue CgA + PAS

17 Mixed tumours: morphology GOBLET CELL CARCINOIDS Mucin laden cells PAS+, Alcian blue + expression of MUC2 and various exocrine markers Neuroendocrine cells no minimal percentage required (up to 50%) Amphicrine cells Other cell components Paneth-like cells MUC2 CgA

18 Mixed tumours: morphology Situation 3: biphenotypic differentiation of the same cells (amphicrine carcinoma) CgA + Alcian blue

19 Mixed tumours: morphology Situation 4: tumours made of cells with «intermediate features» CK7 AFP

20 Mixed acinar-endocrine carcinoma CgA Trypsin

21 Mixed tumours: morphology In summary, The two (or more) components must be morphologically identifiable The coexistence of several lines of differentiation must be evidenced and confirmed by special stains and immunohistochemical techniques

22 Mixed tumours: molecular pathology Questions Are mixed tumours poly- or monoclonal? How are the molecular signatures associated with the various components? How do they compare with their «pure» counterparts in the same organ or in other organs?

23 Mixed tumours: molecular pathology N=5 (2 gastric, 3 colorectal) 4 monoclonal 1 polyclonal

24 Mixed tumours: molecular pathology N=6 (all GI) 5 monoclonal 1 polyclonal

25 Mixed tumours: molecular pathology

26 Mixed tumours: molecular pathology The molecular signature of the neuroendocrine component of gastro-intestinal MiNENs is often reminiscent of that of the corresponding adenocarcinomas Colorectal MiNENs: K-ras mutations Pancreatic MiNENs: K-ras mutations but with some differences Colorectal MiNENs: high frequency of b-raf mutations and MSI (10-15%), different methylation profile Pancreatic MiNENs: rare SMAD4 mutations

27 Implications for pathogenesis

28 POLYCLONAL MIXED TUMORS MONOCLONAL MIXED TUMORS Multilineage differentiation Genetic drift Cell plasticity

29 POLYCLONAL MIXED TUMORS Two distinct oncogenic events in the same target population? One oncogenic event with different consequences?

30 MONOCLONAL MIXED TUMORS Mixed adenocarcinomaneuroendocrine tumour ADC ADC NEC A multistep process First step Adenocarcinoma-like tumour Second step Emergence of a neuroendocrine clone within the adenocarcinoma pool Genetic drivers: TP53+RB1 Third step Independent evolution of the two clones Genetic drift

31 MONOCLONAL MIXED TUMORS Mixed tumours of the pancreas Cell plasticity

32 MONOCLONAL MIXED TUMORS Mixed tumours of the pancreas Reprogramming («trans-determination») of local tissue stem cells Role of intrinsic and extrinsic (mesenchymal/stromal) factors «Transdifferentiation» of one mature cell type into another Direct Indirect Cell plasticity Rooman I, Real FX. Gut 2012;61:449-58

33 MONOCLONAL MIXED TUMORS Failsafe mechanisms Acquisition by adenocarcinoma cells of a neuroendocrine phenotype in response to hypoxia, environmental stress or under treatment pressure Cell plasticity

34 MONOCLONAL MIXED TUMORS Mixed tumours with stem cell features Multilineage differentiation

35 MONOCLONAL MIXED TUMORS Mixed tumours with stem cell features Multilineage differentiation variable terminology Liver Hepatocellular carcinoma with stem/progenitor cell features Cholangiolocellular carcinoma Digestive tract Basal cell carcinoma Crypt cell carcinoma Stem cell carcinoma

36 Mixed tumours: clinical implications Prognostic relevance Colorectal MiNENs Gastric MiNENs Pancreatic MiNENs Influence of molecular alterations Endocrine-related Cancer, 2015;22:35-45

37 Mixed tumours: clinical implications Treatment «based on the most aggressive component» no definitive criteria of diagnosis : only retrospective identification in some cases (metastasis) influence independent from volume possible coexistence of two (or more) high grade components based on a grading system based on molecular alterations (personnalized or precision medicine)

38 Mixed tumours: clinical implications By definition (WHO), the term of MiNEN (ex- MANEC) is restricted to tumors in which the minor component represents at least 30% of the tumor volume It might be recommended, however, to indicate in the pathological report the presence of a high grade component (such as poorly differentiated neuroendocrine carcinoma) even if it represents less than 30% of the tumor volume

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40 Mixed tumours: clinical implications Endocrine-related Cancer, 2015;22:35-45 Diagnosis Prognosis Treatment Immunotherapy

41 Conclusion Mixed tumours: one of the most stimulating example of tumor heterogeneity Diagnosis Strong objective morphological criteria Interest of molecular investigations Unmet needs Uniform terminology Uniform diagnostic criteria Open questions Biological mechanisms Clinical implications