Adenoma cancerizzato con infiltrazione sottomucosa: chirurgia o follow up?

1. Adenoma cancerizzato con infiltrazione sottomucosa: chirurgia o follow up? Dottor Claudio Avellini Triveneta di Chirurgia marzo 2009

2. Polipectomia endoscopica • The choice between surveillance and major surgery when an endoscopically removed polyp is found to be an ACIC will depend on its metastatic potential, ranging from 8 to 16%, and roughly equivalent to the range that occurs in colorectal carcinoma stage pT1 (10–17%). • At present, histopathologic parameters alone determine whether a high (35%) or low (7%) risk of nodal metastases exists Risio, Tech. Coloproctol. 2004 • The state of the resection margins, the grade of the invasive carcinoma, the presence or absence of vascular invasion. (Coverlizza, Cancer ‘89)

3. Esame macroscopico e prelievo per esame istologico • Valutazione dimensioni (> diam testa, peduncolo a parte), tipo (peduncolato, sessile, rilevato, piano, escavato etc), distanza dai margini laterali, evidenza e dimensione di lesione invasiva. • Supporto per evitare deformazioni e indicare la base (specie se peduncolo < 0.3 cm). Marcatura margine( china e bouin)profondo (en bloc), ricostruzione frammenti e marcatura (piecemeal). • Fissazione. • Riduzione per sezioni parallele di 2-3 mm di spessore (sagittale mediana e paramediane) • Seriazione shaving sui margini/prelievi ppd ai margini(Burroughs. JCP 2000)

4. Valutazione istologica di adenoma cancerizzato • Asportazione completa • Grading (G1-2: low; G3: high; G4 anaplastico) • Emboli (ven., linf.): assente, focale, discreta, massiva • Budding tumorale: cellule isolate (<5) in stroma margine di infiltrazione (low: 0-9 foci; high 10 foci o + a 25X) • Microstadiazione : rapporto % tessuto adenomatoso /carcinomatoso (> rapporto < rischio). Livello infiltraz. peduncolo (livelli di Haggitt--> 0:im; 1: testa lesione(sm1) 2: collo lesione e 3: tutto peduncolo(sm2); 4: sm base polipo (sm3--> superf. int. muscolare propria). Risio. Pathologica 2006

5. Invasione sottomucosa • Diagnosi di invasione: sez. sagittale mediana e paramediane di polipo peduncolato o su forceps biopsy di lesione sessile o più grande(artefatti che occultano il carcinoma o lesione invasiva retratta, non visibile su prelievo superficiale da ad. villoso) • Profondità e ampiezza invasione per rilevanza clinica e rischio di metastasi linfonodali: gruppo 1 (m, sm1): EMR possibile; gruppo 2 (sm2): preferita chirurgia. Cut off sm1/2 = 1000 micron(misura ecoendo o istologica,. • Invasione submucosa profonda: non attendibile valutazione dei margini profondi ed elevato rischio di metastasi. Biopsie su fondo asportazione /margine profondo piecemeal. Bergmann. Surg Endosc 2003

6. Margini (2006) • La completa escissione prevede assenza di neoplasia su sezioni seriate dei margini, sia verticali che laterali in EMR(entro 0.5 mm , Bergmann.Surg Endosc 2003; 2-3 mm. Greff. Endoscopy 2001). Individuare il peduncolo. • Valutare la profondità di invasione in micron, su sezione istologica, dal bordo profondo della muscolaris mucosae e la distanza tra punto di massima infiltrazione e margine di resezione. • Ca su o vicino al margine= outcome negativo anche senza parametri istologici sfavorevoli. Invasione del peduncolo a margini liberi: non outcome necessariamente negativo

7. Parametri istologici • Grade III cancers comprise 5–10% of cases and are associated with a higher incidence of adverse outcomes than grades I and II. • Tumours with prevalence of signet ring cells (greater than 50%) should be considered signet ring cell carcinoma and regarded as high-grade cancers (grade III). An anaplastic component in ACIC (even in the form of small, single or scattered foci) should be identified, as its occurrence strongly correlates with the risk of lymph node metastases. • Histological detection of lymphatic invasion requires the presence of cancer cells within endothelial-lined channels or spaces distinguishing such features from retraction artefacts. • Venous invasion  tumour emboli within endothelial-lined channels surrounded by a smooth muscle wall. Risio, Tech. Coloproctol. 2004

11. Margini • The ACIC resection margin obtained by endoscopic • polypectomy is histologically indicated by a strip of coagulative • necrosis (i.e., diathermy change) covering the • entire width of the stalk and with an average thickness of • about 1 mm. • The presence of cancer cells at or near the • resection margin is a reliable histological marker of • adverse outcome. • A negative margin is reported when • there is an absence of cancer within the diathermy and one • high-power field from diathermy, or more than 1 mm from • the actual margin of resection Risio, Tech. Coloproctol. 2004

12. Tumor budding • Tumor budding (Figure 4) is defined as the presence of tiny detached clusters and cords of tumors cells embedded in desmoplastic stroma at the leading edge of the invasive front of the tumor and is assessed on high magnification. • The tumor cells in tumor budding often assume a spindled configuration, and that phenotypic change is often designated as an epithelial-mesenchymal transition. • Underlying the light morphologic changes are loss of junctional complexes, incomplete desmosomes, and extension of podia into the adjacent stroma. • The number of tumor cells per bud is arbitrarily defined as 5 or fewer in most publications. (Washington, CAP, Arch Pathol Lab Med 2008)

14. Tumor budding • Because of incomplete validation and lack of standardized criteria for evaluation, reporting of tumor border configuration and tumor budding is optional.(Washington, CAP, Arch Pathol Lab Med 08)

15. Profili di rischio • A positive resection margin is clearly predictive of local disease, the presence of poorly differentiated carcinoma is associated • with a higher mortality, and that of vascular invasion with • a higher risk of lymph node metastasis. • These observations clearly suggest that, following endoscopic polypectomy, all the histological risk factors need to be carefully evaluated by the pathologist and that the classification of patients in low- and high-risk groups is clinically meaningful Risio, Tech. Coloproctol. 2004

16. Rischio metastasi • Lymph node metastases were found in 19 patients (12.3 percent). Univariate analysis showed that lymphatic invasion, focal dedifferentiation at the submucosal invasive front, status of the remaining muscularis mucosa, and depth of submucosal invasion all had a significant influence on lymph node metastasis. • Multivariate analysis showed lymphatic invasion (P = 0.014) and high-grade focal dedifferentiation at the submucosal invasive front (P = 0.049) to be independent factors predicting lymph node metastasis. No lymph node metastasis was found in tumors with a depth of submucosal invasion of <1.3 mm. • (Tominaga, Dis colon rectum 2005)

17. Molecular changes • In the early stages, acquisition of the metastatic phenotype could be solely dependent on alterations of the molecular mechanisms in cell-cell and cell-matrix interactions integrated with cell motility multiple genomic alterations ( DCC and Met genes are involved whereas the expression of matrix metalloproteinase 7 (MMP-7) is crucial) • Recent cytogenetic evidence supports the possibility of a stochastic model for colorectal carcinoma, in which the transition from early to advanced stages is probabilistically regulated by loss of chromosome 17 versus 17p subtelomeric deletions. ACIC with loss of chromosome 17 in cancer sectors actually represents the emergence from high-grade dysplasia adenomatous tissue of a cell clone with genotypically determined low evolution rates • Conversely, ACIC with 1p13.3 deletions in early cancer are likely to represent a fast transition toward the progressive invasion through the intestinal wall Risio, Tech. Coloproctol. 2004

18. Field cancerization • Field cancerization may have an etiologic role in • a substantial number of recurrences. For example, a surgical • resection margin that includes a genetically altered • field can explain the occurrence of scar recurrence. • Since multiple independent patches of cancer fields may be present in • the same organ exposed to the same insult, clean molecular • margins may not necessarily prevent recurrences in the • residual organ. • In this study, 53% of patients with positive molecular margins had unfavorable overall survival outcome • (Dakubo , Cancer cell International 2007)