NEUROENDOCRINE DIFFERENTIATION IN EPITHELIAL TUMORS Marco Volante

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1 NEUROENDOCRINE DIFFERENTIATION IN EPITHELIAL TUMORS Marco Volante University of Turin, San Luigi Hospital, Orbassano, Turin, Italy

2 pure NE tum..a grey zone pure non-ne ca. 0% NE 100% non-ne 100% 0%

3 non-ne NE Courtesy of prof. P. Komminoth Combined/Mixed NE and non-ne carcinomas

4 PRIMARY LOCATION Lung GEP tract Bladder Prostate Uterus Skin Thymus Unknown prevalence, but they are rare

5 Mixed adenocarcinoma/scc of the gallbladder Chromogranin A

6 cytokeratin 34βE12 Mixed urothelial/scc of the bladder

7 Combined SCLC & SQCA of the lung CgA HMW CK

8 Some other examples *Bressenot. Composite RCC with clear cell and carcinoid tumoral elements: a first case report. JCP2010 *Chênevert. Mixed ovarian LCNEC, mucinous ADC and teratoma: two cases and literature review. PRP 2009 * Posligua. Combined LCNEC and papillary serous carcinoma of the endometrium with pagetoid spread. Arch Pathol 2008 * Veras. Ovarian nonsmall cell NE carcinoma: a clinicopathologic and immunohistochemical study of 11 cases. AJSP 2007 Hwang. Merkel cell carcinoma with squamous and sarcomatous differentiation. J Cutan Pathol 2008 Christine. Endocrine mucin producing sweat gland carcinoma: 12 new cases suggest that it is a precursor of some invasive mucinous cas.ajsp2005

9 ANY POSSIBLE COMBINATION? Villous adenoma + NEC NET (G1-G2) NEC ADENOMA CARCINOMA A. Ubiali, A. Benetti, M. Papotti, V. Villanacci, G. Rindi. Virchows Arch 2001

10 A SPECIFIC TYPE: GOBLET CELL CARCINOID CgA

11 RULES FOR CLASSIFICATION No specific definitional criteria except for GEP tumors (WHO 2000 & 2010) with the 30% rule In general terms: suggestive morphology + appropriate immunophenotype

12 CLINICAL SIGNIFICANCE - Tumor type-specific prognosis: unknown Same prognosis for colorectal NEC and MANEC

13 CLINICAL SIGNIFICANCE - Tumor type-specific prognosis: unknown - Biological behavior of individual tumor component: unpredictable Gastric MANEC (20% ADCA, Single LN mts: ADCA

14 CLINICAL SIGNIFICANCE - Tumor type-specific prognosis: unknown -Biological behavior of individual tumor component: unpredictable - Response to therapy pf each individual tumor component: undetermined To treat the worst or the most prevalent?

15 PATHOGENETIC THEORIES Divergent differentiation Courtesy of prof. P. Komminoth Field effect

16 FEW CASES GENETICALLY HETEROGENEOUS

17 ..BUT MOST CASES SIMILAR 5/6 5/6 Am J Clin Pathol 131, 376, 2009 Yasuoka et al. Monoclonality of composite LCNEC and mucinous epithelial tumor of the ovary. Int J Gynecol Pathol 2009 [X-Chromos]

18 Combined/Mixed NE and non-ne carcinomas MANEC/combined carcinomas are rare but their prevalence is possibly underestimated Classification relies on morphology and IHC Biological and clinical behavior including response to treatment is still unclear Pathogenesis is unknown but in most cases probably related to tumor de-differentiation

19 NE non-ne Conventional carcinomas with NE differentiation

20 PRIMARY LOCATION Lung GEP tract Prostate Breast Uterus Skin Prevalence: up to 20% of lung and GI cancers,. up to 100% of prostate cancers

21 However, the identification of a NE component is largely depending on the method & marker employed 12.5% + by CgA IHC 37.5% + by CgA RTPCR

22 colon lung prostate

23 RULES FOR CLASSIFICATION No specific definitional criteria (except for GEP and breast tumors with the <30% and <50% rules, respectively) i.e. lung WHO 2004: Some lung carcinomas, which do not show neuroendocrine morphology by light microscopy, demonstrate immunohistochemical and/or ultrastructural evidence of neuroendocrine differentiation In general terms: Immunophenotype only

24 CLINICAL SIGNIFICANCE - Tumor type-specific prognosis: cotroversial NO Y/N? YES BREAST & COLO-RECTAL CANCERS NSCLC STOMACH & PROSTATE CANCERS Am J Surg Pathol 2006

25 NE PROSTATE CANCER & PROGNOSIS Is NE phenotype linked to poor prognosis? YES Yes di Sant'Agnese PA Hum Pathol 1992 Abrahamsson PA Prostate 1999 van der Kwast TH J Urol 1997 Berruti A Ann Oncol 2001 NO No Allen FJ Br J Urol 1995 Bubendorf L J Pathol 1996 Bostwick DG J Urol 2002 Ahlgren Prostate 2000 Abrahamsson P Urology 2000 Prostate cancer NE cells lack AR and do not respond to Androgen Deprivation Tx.

26 Berruti et al. The prognostic role of IHC CgA expression in prostate cancer patients is significantly modified by androgen-deprivation therapy (ADT). Prostate ,0 0,9 0,8 0,7 PSA-PFS p< ,0 0,9 0,8 0,7 PSA-PFS p=0.46 0,6 0,6 0,5 0,5 Surviving 0,4 0,3 0,2 IHC CgA negative tumors IHC CgA positive tumors Surviving 0,4 0,3 0,2 IHC CgA negative tumors IHC CgA positive tumors Cumulative Proportion PSA Progressing Free Cumulative Propor 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0,1 0, ADT pts IHC CgA negative tumors IHC CgA positive tumors Months p< Months OS Cumulative Proportion PSA Progressing Free Cumulative Proportio 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,1 0, No ADT IHC CgA negative tumors IHC CgA positive tumors Months p=0.31 0, Months OS

27 CLINICAL SIGNIFICANCE -Tumor type-specific prognosis: cotroversial - Response to therapy pf each individual tumor component: undetermined It might be supposed a potential role of molecules selectively active against NE tumor cells (i.e. SS analogs) SSTR2A

28 PATHOGENETIC THEORIES Divergent differentiation Field effect

29 PATHOGENETIC THEORIES: evidence of a dynamic process NE differentiation induced by Chemo- or Radio-therapy?

30 PATHOGENETIC THEORIES: evidence of a dynamic process Primary mets Primary mets NE cells in metastatic tissue at progression after 5FU and/or platinum-based adjuvant CT Double Ki67 & CGA in a primary and metastatic CRC

31 PATHOGENETIC THEORIES: evidence of a dynamic process LNCaP cells

32 PATHOGENETIC THEORIES: evidence of a dynamic process

33 PATHOGENETIC THEORIES: evidence of a dynamic process NON METASTATIC METASTATIC p<0.0001

34 PATHOGENETIC THEORIES: evidence of a stem cell phenotype in NE cancer cells

35 WHO DRIVES NE DIFFERENTIATION? Role of hash-1? - Family of basic helix-loop-helix (bhlh) transcription factors (Johnson, Nature 1990). - Role in peripheral nerve (Lo&Anberson, Neuron 1995) & endo dermal NE cells (Guillemot, Cell 1993) development. - Modulates tumor initiation of SCLC, directly regulating the stem cell marker genes CD133 & ALDH1A1. (Jiang, Cancer Res 2009) Human homologue-1 of achaete-scute gene from Drosophila

36 hash-1 in human NE tumors Nature 1997 SCLC NSCLC SCLC (Hirotaka, Cancer Res 2005) Medullary thyroid carcinoma (Ball, PNAS 1993) Neuroblastoma (Rostomlily, Cancer Res 1997) Gastrointestinal NE ca (Takashi, Cancer Res 2005) Lung NETs Carcinoid SCLC LCNEC

37 hash-1 in NE differentiated prostate cancer hash1 mostly expressed in the NE components CgA Mod Pathol 2008 hash-1

38 hash-1 transfection induces NE phenotype de novo hash1 & NE marker expression. LNCAP cells hash-1 inhibition represses NE phenotype Rapa I et al (manuscript in preparation)

39 Androgen withdrawal induces NE phenotype hash-1 is upmodulated in androgen deprivation wt LNCAP cells Days of ADT LNCaP androgen sensitive PC-3 androgen insensitive Rapa I et al (manuscript in preparation)

40 hash-1 modulation during androgen deprivation in androgen sensitive immortalized primary prostate cancer cells hash-1 CgA Rapa I et al (manuscript in preparation)

41 hash-1 in NE differentiated NSCLC hash-1 CgA

42 hash-1 transfected lung cancer cells (H522 - adenocarcinoma) acquire NE phenotype hash-1 CgA

43 hash-1 transfection increases cell proliferation and reduces cell invasion in lung cancer cells MTT assay Matrigel assay Rapa I et al (manuscript Rapa I et in al preparation) (submitted)

44 hash-1 transfection induces resistance to chemotherapeutic agents in lung cancer cells Rapa I et al (submitted)

45 Conventional carcinomas with NE differentiation NE differentiation in epithelial tumors is common It represents a dynamic process, possibly modulated by treatent modalities (radio/chemo or hormonal manipulation) The cinical significance is still controversial but in vitro data shows that NE differentiated cancer cells have specific biological properties

46 May strawberries become pumpkins??

47 hash-1 transcription factor: focal positivity in adenocarcinoma component, with intense and diffuse positivity in LCNEC

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