The Malignant Transformation of the Colonic Epithelium: An Anatomic Paradox

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1 The Malignant Transformation of the Colonic Epithelium: An Anatomic Paradox The defining feature of colorectal adenocarcinoma is invasion through the muscularis mucosae into the submucosa. Neoplastic lesions confined to mucosa have virtually no risk of metastasis and should be considered INTRAEPITHELIAL (INTRAMUCOSAL) NEOPLASIA [S.R. Hamilton, 2000]

2 The Malignant Transformation of the Colonic Epithelium: An Anatomic Paradox Histologic Examination Carcinomatous Autoinjection Ultrastructural Observations Immunological Studies Injection Studies Fenoglio et al, Gastroenterology 1973 E-cadherin APC Alpha-catenin Beta-catenin Tamura et al, Cancer Res, 1996

3 The Malignant Transformation of the Colonic Epithelium: Terminology and Classification -- ADENOMA, HIGH GRADE DYSPLASIA -- HIGH GRADE INTRAEPITHELIAL NEOPLASIA -- IN SITU ADENOCARCINOMA -- INTRAMUCOSAL ADENOCARCINOMA CANCERIZED ADENOMA: - With Minimal Risk -With Low Risk - With High Risk [Risio et al, Patologi GIS C or, 2006]

4 European Guidelines for Diagnosis and QA of Pathology in Colorectal Cancer Screening P. Quirke, M. Risio, M. Vieth, R. Lambert NO NEOPLASIA Category 1 of the original Vienna Classification. MUCOSAL LOW GRADE NEOPLASIA Category 3 of the original Vienna Classification; Mild and moderate dysplasia; Low grade dysplasia; Low grade intraepithelial neoplasia WHO MUCOSAL HIGH GRADE NEOPLASIA Category 4 and 5.1 of the original Vienna Classification; Severe dysplasia; High grade dysplasia; High grade intraepithelial neoplasia WHO 2000; Carcinoma in situ; Intramucosal carcinoma. INVASIVE NEOPLASIA Category 5.2 of the original Vienna Classification; Carcinoma invading the submucosa or beyond.

5 Morfogenesi della cancerizzazione colonica: La Barriera Muscolare e la Rete Linfatica Adenoma comprendente aree di carcinoma invasivo che dissocia e supera la muscolaris mucosae e si estende alla sottomucosa

6 Morfogenesi della cancerizzazione colonica: La Distopia Sottomucosa Pseudoinvasione: - Assenza di reazione desmoplastica Dislocazione o erniazione nella sottomucosa di isole di tessuto displastico: Pseudoinvasione - Mantello connettivale attorno alle ghiandole displastiche - Depositi emosiderinici

7 CANCERIZED ADENOMA: Endoscopic Prevalence % FOBT FLEXSIG

8 Incidence/ CANCERIZED ADENOMA: Age Distribution CANCERIZED ADENOMA ADVANCED CARCINOMA Age (ys)

9 Average Size: 2 cm SIZE AND SITE >50% Malignant Polyps < 2 cm Malignant Polyps/Polyps % Malignant Pol yps/ 50 Po lyps RIGHT LEFT RECTUM mm < > 35 Nusko et al., Endoscopy 1997

10 Cancerized Adenomas: The Metastatic Risk (8-16%) Histologic Features Distinguishing LOW (7 %) and HIGH (35 %) Risk of Lymph Node Metastasis GRADE OF DIFFERENTIATION OF INVASIVE CARCINOMA (G1-G2, Low Grade vs G3-G4, High Grade) VASCULAR INVASION RESECTION MARGIN [ Coverlizza, Risio, Fenoglio-Preiser, Cancer 1989 ]

11 Cancerized Adenoma: Grading of Carcinoma LOW GRADE Well Differentiated + Moderately Differentiated HIGH GRADE Poorly Differentiated

12 pt1 Cancer Cancerized Adenoma TUMOR GRADE Poorly differentiated carcinomas are identified by the presence of either irregularly folded, distorted and often small tubules or the lack of any tubular formation and showing marked cytological pleomorphism. In the absence of good evidence we recommend that a grade of poor differentiation should be applied when ANY area of the lesion is considered to show poor differentiataion. Budding of the tumor cells at the front of invasion should not influence grading of the tumour.

13 Cancerized Adenoma: Vascular Invasion

14 pt1 Cancer Cancerized Adenoma LYMPHOVASCULAR INVASION Sometimes retraction artefact around tumour aggregates can make assessment uncertain, in which case this uncertainty should be recorded and the observation interpreted by the MDT in the light of any other adverse histological features. At the moment there are no consistent data available on the additional use of immunohistochemistry.

15 Cancerized Adenoma: Resection Margin 1 mm COOPER, 1998 healthy ROSSINI, mm SUGIHARA, mm CRANLEY, mm WILLIAMS, 19 87

16 Adenoma Cancerizzato: Margine di Exeresi Stato del Margine di Exeresi: Energia Trasmessa? Infiltrazione Sottomucosa?

17 AUTHOR PAESE YR R/PENR PERIOD P/E/S N POL N POL MAL %POL MN POL IN SITUN SITU SU POL T N POL INV X EPID NV SU POL COLACCHIO USA 1981 R S , , , FUCINI POLIP USA 1986 R S NV 69 NV 34 NV 35 NV FUCINI SURGER NV HACKELSBERG GERMANY 1995 R P/E/S 3170 NV NV NV NV 87 2, PINES ISRAELE 1990 R E NV NV NV NV NV 66 NV CONTE USA 1987 R P/S NV 89 NV 59 NV 30 NV VOLK USA 1995 R P NV NV NV NV NV 47 NV MULLER UK 1989 R P/E 367 NV NV NV NV 34 9, COOPER USA 1995 R NV P NV NV NV NV NV 140 NV NIVATVONGS USA 1991 R S NV 158 NV 7 NV 151 NV KYZER USA 1992 R P/E NV NV NV NV NV 44 NV MASAKI JAPAN 2000 R NV S NV NV NV NV NV 75 NV PARK KOREA 2000 R S NV 90 NV 40 NV 50 NV RICHARDS USA 1986 R S NV 126 NV 41 NV 85 NV RUSSELL USA 1990 R S NV 87 NV 21 NV 66 NV SHATNEY USA 1974 R S/P NV 49 NV 31 NV 28 NV CHRISTIE PED USA 1988 R S NV NV NV 0 NV 101 NV CHRISTIE SES MORSON UK 1984 R NV P NV NV NV NV NV 60 NV COVERLIZZA ITALY 1989 R P/E 2334 NV NV NV NV 81 3, GERAGHTY UK 1990 R P/E NV NV NV NV NV 81 NV KAWAMURA JAPAN 1999 R S NV NV NV NV NV 50 NV KITAMURA JAPAN 1997 R S NV 90 NV 24 NV 66 NV KITAMURA END HISTOLOGICAL RISK FACTORS AND CLINICAL OUTCOME IN COLORECTAL MALIGNANT POLYP: A POOLED DATA ANALYSIS Hassan C, Risio M, Dis Colon Rectum 2005 Systematic Review of The Published Studies ( ) 31 Studies Were Selected Adenomas Containing Invasive Carcinoma: Surgery: 54% - Polipectomy: 46% BARTNIK POLAND 1985 R E ,0562 NV NV 9 5, SUGIHARA JAPAN 1989 R S , , LANGER USA 1984 R P/E/S NV 37 NV 14 NV 25 NV POLLARD USA 1992 R S NV NV NV NV NV 82 NV Follow-up Data in 20 Series (Median: 60 Months) ROSSINI ITALY 1982 R E ,8278 NV NV 31 1, DELL'ABATE ITALY 2001 R S ,5046 NV NV 27 2, CHANTEREAU FRANCE 1992 R EPID NV 146 NV 34 NV 112 NV HAGGITT USA 1985 R P NV 129 NV NV NETZER SWISS 1998 R E/P/S NV 70 NV NV NV 70 NV CRANLEY USA 1986 R E ,6264 NV NV 40 2, WHITLOW USA 1997 R S ,7484 NV NV 59 0, NV

18 Cancerized Adenomas: Metastatic Potential LYMPH NODE METASTASES PREVALENCE: 9% (94/1093) MORTALITY: 6.9% (vs 2.1% OR: 3.3) HEMATOGENOUS METASTASES OVERALL PREVALENCE: 2.9% (54/1868) PREVALENCE IN SURGICAL SERIES: 3% PREVALENCE IN ENDOSCOPIC SERIES: 2.7%

19 Cancerized Adenomas: Relationships between Histological Risk Factors and Clinical Outcomes VASCULAR INVASION RESIDUAL DISEASE RECURRENT DISEASE LYMPH NODE METASTASIS HAEMATIC METASTASIS MORTALITY Positive 6 / 34 (17.6%) - 12 / 34 (35.3%) * 13 / 250 (5.2%) 7 / 210 (3.3%) Negative 17 / 111 (15.3%) - 8 / 111 (7.2%) 38 / 1279 (3%) 28 / 1194 (2.3%) Odds Ratio % CI * p < 0.05 [Hassan, Risio, Dis Colon Rectum 2005]

20 Cancerized Adenomas: Relationships between Histological Risk Factors and Clinical Outcomes GRADE OF INVASIVE CARCINOMA RESIDUAL DISEASE RECURRENT DISEASE LYMPH NODE METASTASIS HAEMATIC METASTASIS MORTALITY High Grade (PD) 10 / 56 (18.7%) - 13 / 56 (23.2%) 11 / 114 (9.6%) * 14 / 96 (14.6%) * Low Grade (WD, MD) 29 / 324 (9%) - 23 / 324 (7.1%) 40 / 1520 (2.6%) 27 / 1487 (1.8%) Odds Ratio % CI * p < 0.05 [Hassan, Risio, Dis Colon Rectum 2005]

21 Cancerized Adenomas: Relationships between Histological Risk Factors and Clinical Outcomes MARGIN OF RESECTION RESIDUAL DISEASE RECURRENT DISEASE LYMPH NODE METASTASIS HAEMATIC METASTASIS MORTALITY Positive 55 / 81 (30.4%) * 13 / 77 (16.8%) * 13 / 181 (7.2%) 30 / 325 (9.2%) * 26 / 325 (8%) * Negative 4 / 142 (2.8%) 4 / 357 (1.12%) 13 / 142 (9.2%) 8 / 655 (1.2%) 9 / 655 (1.4%) Odds Ratio % CI * p < 0.05 [Hassan, Risio, Dis Colon Rectum 2005]

22 CANCERIZED ADENOMAS: Low Risk (55%) vs High Risk (45%) % Low Risk SURGERY: 20% High Risk SURGERY: 80% Residual Disease Lymph Node Metastases 0,1 Haematic Metastases 0.04 Mortality [Hassan, Risio, Dis Colon Rectum 2005]

23 Adenoma Cancerizzato: La Variabilità Biologica Nell ambito dei programmi di screening si ritiene raccomandabile prevedere la revisione da parte di un secondo patologo dei casi di adenoma cancerizzato, prima di decidere il tipo di trattamento., anche al fine di ridurre il rischio di sovratrattamento GISCoR, 2006

24 Cancerized Adenoma: Haggitt s Levels Level 1 Level 3 Level 2

25 Cancerized Sessile Adenoma: Kikuchi s Levels

26 Cancerized Adenoma: Carcinoma Microstaging Lymph Node Metastasis Width sm < 4000 µm: 2.5% Width sm > 4000 µm: 18.2% Depth sm < 2000 µm: 3.9% Depth sm > 2000 µm: 17.1% Ueno et al, Gastroenterology 2004

27 Adenomi Cancerizzati: Il Volume di Invasione 10 / / / 60 Rapporto Quantitativo TESSUTO ADENOMATOSO ADENOCARCINOMA

28 CANCERIZED ADENOMA : MICROSTAGING Status of the Resection Margin Depth of Invasion (µm) Width of Invasion (µm) Adenoma / Carcinoma Ratio Risio et al, GISCoR 2006

29 Cancerized Adenoma: Tumor Budding LOW-GRADE BUDDING: 0-9 foci in a field (250x) HIGH-GRADE BUDDING: > 10 foci in a field (250x) Ueno, Jass, Histopathology 2002

30 CATEPSIN + [Guzinska-Ustimowicz et al, 2004] LAMININ-5 (γ2) + upar + [Pyke etal, 1995] LAMININ-5 (γ2, β3) + LAMININ-5 (α3) - [Sordat et al, 2000] E-CADHERIN - [Sordat et al, 2000] Molecular Pathology of Tumor Budding in Early Colorectal Cancer TIMP-1 + (myofibroblasts) [Holten-Andersen et al, 2005] MIN [Wright, Stewart, 2003]

31 CANCERIZED ADENOMA: Tumor Budding INFLAMMATORY-TYPE BUDDING [Shinto et al, 2005] METAPLASTIC-TYPE BUDDING [ Prall, 2007 ]

32 Prall 2005 Kazama IHC:MNF 116 IHC: CAM5.2 and AE1/AE , 785 low/high n.a. n.a. n.a. present/absent Kanazawa 2007 H&E n.a. n.a. n.a. none/mild/ moderate/marked Nakamura 2008 H&E n.a. n.a. n.a. None/mild/ =low moderate/marked=high Choi or more H&E 20x (0-3)/(4-5)/(6-10)/(11-38) Park or more H&E 20x (0-3)/(4-5)/(6-9)/(10-38) Hori 2005 H&E x Yasuda 2007 H&E present/absent Ishikawa 2008 IHC:MNF negative/positive

33 ADENOMI CANCERIZZATI: Tumor Budding SELEZIONE DEL CAMPO PIU INTENSO [ Ueno et al, 2004 ] MEDIA DA PIU CAMPI [ Morodomi et al, 1989 ]

34 ADENOMI CANCERIZZATI: Tumor Budding BUDDING INFIAMMATORIO [Shinto et al, 2005] BUDDING METAPLASTICO [ Prall, 2007 ]

35 CANCERIZED ADENOMA: Tumor Budding and Metastatic Risk No-risk Group: 0.7% Unfavorable Tumor Grade Single-risk Group: 20.7% Multiple-risk Group: 36.4% Definite Vascular Invasion Tumor Budding Ueno et al, Gastroenterology 2004; 127:

36 CANCERIZED ADENOMA : Assessment of the Metastatic Risk Carcinoma Grading Vascular Invasion Tumor Budding + Microstaging MINIMAL RISK (0-0,7%) LOW RISK (8-18%) HIGH RISK (20-40%) Risio et al, GISCoR 2006

37 ADENOMA VILLOSO CON DISPLASIA DI ALTO GRADO DELL EPITELIO, MINIMA (<10%) COMPONENTE SERRATA E FOCOLAIO DI ADENOCARCINOMA INFILTRANTE LA SOTTOMUCOSA (pt1) - Rapporto Tessuto Adenomatoso / Adenocarcinoma: 90 / 10 - Grado Adenocarcinoma: 1 / 4; Basso Grado sec. WHO - Profondità di Invasione Sottomucoa: < 2000 micron - Ampiezza di Invasione Sottomucosa: < 4000 micron - Invasione Vascolare/Embolizzazione Neoplastica: Non Evidente - Budding Tumorale: Basso Grado - Margine di Resezione Endoscopica: focale interessamento (Distanza bordo carcinoma piano di exeresi: 0,9 mm; singola ghiandola neoplastica compresa nel campo di osservazione 10x in corrispondenza del margine superiore della banda di diatermocoagulazione ADENOMA CANCERIZZATO A BASSO POTENZIALE METASTATICO; IL COINVOLGIMENTO DEL MARGINE DI RESEZIONE E PREDITTIVO DI RISCHIO DI RICORRENZA LOCALE DI ADENOCARCINOMA

38 Le Condizioni della Diagnosi: Procedure di Prelievo Endoscopico PER LA DIAGNOSI DI CANCERIZZAZIONE E IRRINUNCIABILE LA POLIPECTOMIA ENDOSCOPICA COMPLETA: PRELIEVI BIOPTICI MULTIPLI O LA FRAMMENTAZIONE DELLA LESIONE NON CONSENTONO LA SICURA ESCLUSIONE DI UNA COMPONENTE NEOPLASTICA INFILTRANTE LA SOTTOMUCOSA IN TALI CASI IL GIUDIZIO DIAGNOSTICO DOVRA FORZATAMENTE ESSERE LIMITATO AD ELEMENTI DESCRITTIVI DEL CAMPIONE IN ESAME GISCoR, 2006

39 Le Condizioni della Diagnosi: Procedure di Prelievo Endoscopico Frammentazione del Materiale Incongruo Orientamento del Piano di Microtomia

40 L Interazione tra Patologo ed Endoscopista Il Livello Tecnico: Trattamento dei Reperti ( Handling ).L Endoscopista seleziona tra i polipi >0,5cm quelli (semipeduncolati, peduncolo < 0,3cm,) in cui è difficile la identificazione del piano di resezione dopo fissazione e provvede alla marcatura dello stesso. [Risio et al, Patologi GISCOr, 2006]

41 Forme Inusuali di Carcinoma Colorettale Iniziale Carcinoma Minimale De Novo Carcinoma Piatto Carcinoma Polipoide Minimale Carcinoma Endocrino Carcinoma a Cellule ad Anello con Castone in Adenoma..potranno essere singolarmente valutate da un panel di patologi in ambito GISCoR GISCoR, 2006

42 Adenomi Cancerizzati: Istotipi Inusuali CARCINOMA DI CELLULE AD ANELLO CON CASTONE

43 Adenomi Cancerizzati: Istotipi Inusuali CARCINOMA ENDOCRINO

44 Adenomi Cancerizzati: Istotipi Inusuali CANCERIZZAZIONE DELL ADENOMA PIATTO

45 La Cancerizzazione del Polipo Serrato

46 Cancerized Adenoma: Polyp Morphology Peduncolated Sessile (66.5%) (34.5%) % RECTUM LEFT RIGHT Peduncolated Sessile

47 Peduncolated vs Sessile % ,0 Peduncolated Sessile Positive Margin High Grade Carcinoma Vascular Invasion HIGH RISK

48 Peduncolated vs Sessile % ,4 Recurrent Disease Lymph Node Metastasis 1 3,6 Hematogenous Metastasis 0,6 4,8 Mortality Peduncolated Sessile

49 Treatment: MINIMAL RISK LOW RISK CANCERIZED ADENOMAS ENDOSCOPY MORTALITY FROM SURGERY 0.7% - 2% CIROCCO CONTE COOPER HAGGITT LANGER LIPPER WILLIAMS WILCOX WAYE RIDDELL POLLARD MORSON

50 Treatment: LOW RISK CANCERIZED ADENOMAS PEDUNCOLATED SESSILE ENDOSCOPY CONTE LANGER LIPPER MORSON RIDDELL ROSSINI SURGERY CIROCCO COOPER HAGGITT POLLARD WILCOX WILLIAMS WAYE

51 Treatment: HIGH RISK CANCERIZED ADENOMAS Low Risk from Surgery High Risk from Surgery SURGERY MORTALITY 5.5% ENDOSCOPY MORTALITY 10.5%