Dipartimento di Medicina Sperimentale e Clinica Sezione di Chirurgie Specialistiche

e di Diagnostica Istopatologica e Molecolare Università degli Studi di Firenze

Luca Messerini

Il polipo cancerizzato del colon-retto

Adenoma

Adenoma is defined as a lesion of the colon or rectum containing unequivocal epithelial neoplasia (European Guidelines 2010).

Adenomas are defined by the presence of dysplastic epithelium (WHO 2010).

Peduncolated

Sessile

Slightly elevated

Slightly depressed

Completely flat

< 2.5mm

> 2.5mm

Polypoid Non-Polypoid

SIZE MEASUREMENT OF

POLYPS Endoscopy

Fresh Specimens

Formalin-fixed Specimens

Histology Slides

GRADING OF

NEOPLASIA/DYSPLASIA It is divided into low and high grade to improve interobserver agreement, with high grade equating “severe dysplasia” in older systems. Mucosal high grade neoplasia is diagnosed on architecture, supplemented by an appropriate cytology. Changes of mucosal high grade neoplasia should usually involve one or two glands, sufficient to be identified at low power examination.

GRADING OF VILLOUSNESS

Classical Villi Palmate Villi

Foreshortened Villi

Authors Phil Quirke

Mauro Risio

Renè Lambert

Michael Vieth

[Quirke, Risio , Lambet, Vieth 2010]

Mucosal neoplasia

Category 3 Category 4.1 4.2 4.3 4.4

Category 5: submucosal invasion by carcinoma

Low-grade High-grade

«Neoplastic lesions

confined to mucosa

have virtually

no risk of metastasis»

«The defining feature

of colorectal cancer

is invasion through

the muscularis mucosae»«

[S.R. Hamilton, 2000] Fenoglio et al, Gastroenterology 1973

• Adequacy of the excision

• Grading of the carcinoma

7.5.3.4. MARGIN INVOLVEMENT There has been considerable discussion and controversy in the literature over what degree of clearance might be regarded as acceptable in tumours that extend close to the deep submucosal margin. It is important that clearance is measured and recorded in the report. Currently we would recommend that clearance of 1 mm or less indicates margin involvement.

1 field Morson, 1984

≤ 1 mm Cooper, 1995

< 2 mm Volk, 1995

< 3 mm Williams, 1987

[Quirke, Risio,Lambert, Vieth, 2010]

Margin involvement

pT1 Cancer

Cancerized Adenoma

Margin involvement

2,1 mm.

2,1 mm.

Margine negativo Margine positivo (2,1-1,7= 0,4 mm.)

pT1 Cancer

Cancerized Adenoma

[Quirke, Risio , Lambet, Vieth 2010]

8.5.3.2 TUMOR GRADE 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 differentiation. Budding of the tumor cells at the front of invasion should not influence grading of the tumour.

Low-grade/G1-G2 High-grade/G3-G4

Tumour grade in pT1 lesions: 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. Poor differentiation should equate to the WHO categories of poor and undifferentiated tumours. The frequency should not exceed 20%.

pT1 Cancer

Cancerized Adenoma

7.5.3.3 LYMPHOVASCULAR INVASION Definite invasion of endothelium-lined vascular spaces in the submucosa is generally regarded as a significant risk for lymph node or distant metastasis. Sometimes retraction artefact around tumour aggregates can make assessment uncertain, in which case this uncertainty should be recorded and the observation interpreted in a multidiscipliary conference in the light of any other adverse histological features. At the moment there are no consistent data available on the additional use of immunohistochemistry.

[Quirke, Risio , Lambet, Vieth 2010]

Parametri istologici Favorevoli Sfavorevoli

Grading G1,G2 G3,G4

Emboli vascolari assenti presenti

Margine di resezione negativo positivo

L Messerini et al.

Head

Neck

Stalk

Bowell Wall

We conclude that the level of invasion should be the major factor in determining prognosis for the management of carcinoma arising in an adenoma.

Kikuchi 1995

Kudo S 2003

pT1 Cancer

Cancerized Adenoma

7A.4.2 SUBSTAGING Neither the Kikuchi (for sessile lesions) nor Haggitt (for polypoid tumors) are easy to use in practice. The depth and the width of invasion provides a more objective measure. Each classification has advantages and disadvantages. All three approaches need to be evaluated on large series from screening programmes to derive evidence-based recommendations.

[Quirke, Risio , Lambet, Vieth 2010]

7.5.3.5 Tumor Budding Tumour cell budding, i.e., the presence of small islands or single infiltrating tumour cells at the front of tumour invasion. Its ability to predict metastases compared to the previously discussed factors has been proven. However, the diagnostic criteria vary, and studies are in progress to assess its reproducibility. Its evaluation and reporting in accordance with Ueno criteria are advisable, though not mandatory, at this time.

Authors Phil Quirke

Mauro Risio

Renè Lambert

Michael Vieth

[Quirke, Risio , Lambet, Vieth 2010]

Cancerized adenoma : assessment of the metastatic risk

• Margin status • Carcinoma Grading • Vascular Invasion • Tumor Budding

+ • Microstaging

Risio et al, GISCoR 2006

MINIMAL RISK (0-0,7%)

LOW RISK (8-18%)

HIGH RISK (20-40%)

Degree of submucosal invasion Level of the polyp yes Submucosal invasion depth (µm) yes Submucosal invasion width (µm) no

Cancer morphology Budding yes Poorly differentiated clusters yes Infiltrating growth no

Host response Inflammatory cell infitration no Proliferation of myofibroblast no Microvessell density no

Others Adenoma component no

Parameters Validation

Head invasion = Haggitt’s level 1: the depth of submucosal invasion was considered to be 0 µm. Stalk invasion = Haggitt’s level ≥2: the vertical distance from the line between the head and the stalk («Haggitt’s line») to the invasive front was measured as the depth of submucosal invasion.

The risk for lymph-nodes metastasis can be classified into three groups:

• High risk: depth of submucosal invasion ≥1000 µm and high grade budding/sprouting

• Intermediate risk: depth of submucosal invasion ≥1000 µm and low grade budding/sprouting

• Low risk: depth of submucosal invasion <1000 µm

VALUTAZIONE PARAMETRI DI RISCHIO 1) limite di escissione (distanza dal punto di maggiore infiltrazione della sottomucosa) □ margine positivo (distanza ≤ 1mm.) □ margine negativo (distanza >2mm.) □ margine non valutabile □ margine dubbio ( distanza >1 ≤ 2 mm.) per questa categoria i dati riportati in letteratura sono contrastanti e non indicano in maniera univoca se considerare con sicurezza il margine come positivo o negativo. Tali casi dovrebbe essere discussi con i clinici per scegliere il percorso più opportuno. 2) grado di differenziazione (linee guida europee 2010) □ elevato (G1) □ moderato (G2) □ basso (G3) □ indifferenziato (G4) 3) invasione vascolare □ presente □ venosa □ linfatica □ assente □ non valutabile

4) microstadiazione □ livelli di Haggitt: □ 1 □ 2 □ 3 □ 4 (polipi peduncolati) □ classificazione di Kikuchi: □ sm1 □ sm2 □ sm3 (polipi sessili) □ misurazione invasione della sottomucosa (Ueno 2004) profondità __________µm ampiezza ___________µm

5) altre caratteristiche microscopiche budding tumorale □ assente □presente (<5 foci vs. ≥ 5 foci Ueno 2004) cluster poco differenziati □ assente □ presente

(opzionali?)

?

?

follow-up

follow-up o

resezione chirurgica

resezione chirurgica

1) a bassissimo rischio grado di differenziazione G1 o G2 emboli neoplastici assenti distanza dal margine ≥2 mm budding assente invasione sottomucosa <1000 µm

2) a basso rischio grado di differenziazione G1 o G2 emboli neoplastici assenti distanza dal margine <1 mm. < 2mm. budding assente invasione sottomucosa <1000 µm

3) ad alto rischio grado di differenziazione G3 o G4 emboli neoplastici presenti distanza dal margine ≤1 mm. budding presente invasione sottomucosa ≥1000 µm

Categorie Evoluzione Trattamento di rischio sfavorevole

0-1%

0-4%

0-35%

Prelievi bioptici multipli o la frammentazione della

lesione non consentono di valutare:

- l’infiltrazione della sottomucosa

- il margine di resezione

Immunoistochimica: desmina.

Take home message

• Fissazione e campionamento secondo protocollo

• Valutazione di: margine di escissione grading emboli neoplastici

• Valutazione budding

• Microstaging (profondità invasione sottomucosa)

• Categorie di rischio

Le Condizioni della Diagnosi:

Trattamento (“Handling”) del Polipo

Polipi Diminutivi (< 0,5 cm) appoggiati

su supporto rigido col piano di exeresi

(Staff di Endoscopia)

Marcatura della base per polipi semi-

peduncolati o con peduncolo < 0,3 cm

(Staff di Endoscopia)

Prelievo paracentrale

(Piano medio-sagittale)

+

Sezioni parallele ogni 2 mm

+

Calotte laterali residue GISCoR, 2006