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5/26/2017 1

Early Neoplasms of the Upper GI Tract:

Classification, Clinical Significance and Management

Gregory Y. Lauwers, MD Senior Member

• H. Lee Moffitt Cancer Center & Research Institute

Tampa, FL Gregory.Lauwers@Moffitt.org

“I have no relevant relationships requiring disclosure”

[Inflammation] Dysplasia Advanced CA Early CA

Riddell R. 1983; WHO, 2010

Dysplasia (IEN) is defined as an unequivocal neoplastic lesion showing structural and cytological abnormalities confined to the basement membrane. It results from genetic clonal alterations and is predisposed to progression. Early carcinomas are limited to the mucosa, or at least, invade minimally the submucosa, lesions without potential (or limited) risk of developing lymph node metastases.

Inter-observer agreement in assessing dysplasia

• Overall: fair (ĸ ~ 0.3)
• Indefinite & LGD: poor to fair (ĸ ~0.0-0.3)
• Negative & HGD: good (ĸ~ 0.3-0.5)
• Similar agreement for GI specialists & generalists

Weaknesses in study design Lack of “real life” histological context Assessment of precision, not accuracy (outcomes)

• Technical (fixation, processing, sampling)
• Overlapping features of dysplastic and reactive changes

(active inflammation, post-inflammatory regeneration)

• Synthesis of several histologic parameters which may

have conflicting significance

• Histological diversity of dysplastic changes

Impediments to accurate grading of dysplasia

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Early Neoplasms of the Upper GI Tract

• Squamous intraepithelial neoplasia
• BE: classic and phenotypic variants of

dysplasia

• Gastric dysplasia and early gastric cancer

Esophageal carcinoma

Age-standardized death rates from esophagus cancer by country (per 100,000 inhabitants),

WHO, 2010

5 4 3 2 1

ADENOCARCINOMA OF THE DISTAL ESOPHAGUS [US]

lamina propria lamina propria lamina propria lamina propria lamina propria

Normal Esoph. Regenerative epith with atypia LG- IEN HG IEN /CIS Invasive Carcinoma

• Progression: 25% & 75% of pts with LGIEN and HGIEN

develop inv. CA within10 yrs (5% for patients w/ esophagitis)

LGIEN HGIEN Invasive ca normal CIS

Esophageal intraepithelial neoplasia

Structural features Cytological features Increased cellular density Nuclear enlargement and pleomorphism Intercellular edema Nuclear overlaping Loss of differentiation/ surface maturation Dyskeratosis Loss of cellular polarity Hyperchromasia Regular and irregular neoplastic buds Conspicuous nucleoli Sharp demarcation /Oblique line Increased and atypical mitoses

Kobayashi M, et al. Oncology 2006; 71: 237-245

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Diagnostic clue : oblique line

Neoplastic Non-neoplastic

Oblique line, increased cellular density, loss of polarity

Loss of polarity & nuclear atypia

lamina propria

LGIEN

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lamina propria

HGIEN

lamina propria

CIS Carcinoma in situ Basal layer type

Ki-67 p53

Histology IHC+ Mutation+ Mutation+/I HC+ Mutation- /IHC+ HGD/CIS 86% 71% 83% 17% LGD 81% 67% 82% 18% RAE 0% 0% 0% 0% NE 0% 0% 0% 0%

Proportions of (+) p53 IHC and p53 mutation show no differences between HGD/CIS & LGD

p53 IHC & p53 mutation of esophageal lesions

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lamina propria

Invasive CA.

Superficially invasive Superficially invasive

Makutuchi H, et al. Rinsho Shoukakinaika12: 1749-1756, 1997.

Lymphatic invasion & LN metastasis in esophageal carcinoma

M1 M2 M3 SM1 SM2 SM3

Lymphatic permeation

0% 5% 35% 54% 72% 91%

Lymph node metastasis

0% 0% 8% 17% 28% 49%

EP LPM MM SM MP

T1a-EP (M1) T1a-LPM (M2) T1a-MM (M3) SM1 (SM1) SM2 (SM2) SM3 (SM3)

MM LPM EP SM

T1a-LMP (M2)

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MM

T1a-MM (M3)

Other indication for surgery: Lymphatic permeation Positive deep [vertical] margin

Low grade IEN or reactive atypia?

• Enlarged nuclei
• Little nuclear variety in

shape

• Intraepithelial lymphocytes
• Limited within the lower

half

• No oblique line

Re-biopsy after 4 w of PPI

Basal cell Hyperplasia: proliferation > 15 % of the total thickness of epith.

• High cell density, but N

polarity is maintained and atypia is absent.

• Reactive change

reflecting disturbances in maturation of squamous epithelium.

Pseudoepitheliomatous hyperplasia

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Management of early squamous neoplasms

Size & endoscopic findings Histology Management < 5 mm

• r regular unstained area

Non-neoplastic LG-IEN Follow up 5 - 10 mm, regular unstained area Mostly LG-IEN Endoscopic resection F-up q. 6 months Biopsy, at least in number 5 – 10 mm, irregular unstained area LG-IEN

• r HG-IEN/CIS

Endoscopic resection Follow up > 10 mm, suspicious of carcinoma HG-IEN/CIS Endoscopic resection Any size or shape Invasive SCC Surgical resection Chemo / radiation

• Resemble sporadic

adenomas

• Lack of maturation

& top-down pattern

• Limited glandular

distortion

• Pencil-shape

hyperchromatic nuclei

• Limited nuclear

stratification

• Reduced

differentiation

• Increased

proliferation

• Clonal character
• Range of

epithelia from truly normal, normalized, reactive and regenerative

• Diagnosis of

dysplasia is based on recognition of what is perceived as not dysplasia

• Marked architectural

distortion

• Lack of maturation
• Marked nuclear

stratification

• Marked nuclear

enlargement

• Marked nuclear

hyperchromasia

• Mitoses onsurface
• Reduced differentiation
• Increased proliferation
• p53 overexpression or

loss HIGH-GRADE DYSPLASIA LOW-GRADE DYSPLASIA NEGATIVE

Unequivocally neoplastic lesions

indefinite low grade no high grade

Normal

Barrett Esoph. LGD HGD Intramucosal CA

SQUAMOUS EPITHELIUM

INTESTINALIZED EPITHELIUM

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Corley DA . Gastroenterology ‘02

Age at dx of BE: 61.4yrs Age at cancer dx:66.4yrs Age at dx of BE:72.6yrs Age at cancer dx:78.9yrs

Importance of early detection Interobserver variation

4 LGD 18 HGD 2 Intramucosal CA

My diagnosis: High grade dysplasia

Montgomery E. Hum Pathol 2001

Interobserver variation

3 TINED 3 Indefinite 8 LGD 9 HGD 1 Intramucosal CA

My diagnosis: intramucosal CA

Montgomery E. Hum Pathol 2001

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High-grade dysplasia

Why is this high-grade dysplasia?

Histologic feature CA in resection

Cribiform/solid growth 73% (33/45) Dilated tubules/necrotic debris 79% (23/29) Ulcerated HGD 83% (19/23) Neutrophils in dysplasia 80% (16/20) Invasion of sq. epith 100% (5/5) None of the above 0 (0/16) 1 of the above 39% (7/18) 2 of the above 83% (10/12) 3 of the above 87% (13/15) 4 of the above 88% (7/8)

Zhu W. Am J Clin Pathol 2009;132 Retrospective 127 esophago-gastrectomies performed for HGD, or HGD suspicious for CA [CA present in17% of HGD and 74% of HGD/S cases]

Low-grade dysplasia

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Reactive changes or dysplasia?

Reactive changes mimicking dysplasia

Stromal inflammation / maturing granulation tissue Scattered intra-epithelial inflammation Nuclear and cellular uniformity Surface maturation HGD in the bed of ulcerated BE

Various types of dysplasia

non-Adenomatous Type 2 [foveolar] Serrated

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Prevalence:6.7% (goblet cells in 62%) 94% assoc. typical dyspl. [HGD:+] High rate DNA abnormalities

Non-adenomatous type dysplasia

Maximum dx upon Follow-up Dysplastic Variant N Low-grade High-grade Carcinoma Nonadenomatous

18 0% 78% 17%

Adenomatous

24 25% 54% 21%

Low-grade

13 46% 31% 23%

High-grade

11 82% 18%

Rucker-Schmidt et al. Am J Surg Pathol 2009;33(6):886-93

10 Year Follow-up

Non-adenomatous type dysplasia in BE

Modern Pathology; 2010-23:834-843

Prevalence:46%.(HGD:58%) (adjacent IM: 53%)

Adenomatous & Hybrid Dysplasia: Prevalence:27%.(HGD:91%;100%) (adjacent IM: 100%/82%%)

HGD LGD

(41 resections w/ dysplasia w or w/o associated inv. ACA)

Progression to cancer of various types

• f dysplasia

Dysplasia Association with Progression to cancer Conventional LGD Conventional HGD Conventional LGD (N=22) 1 (5%) Conventional HGD (N=16) 12 (75%) Foveolar Dysplasia (N=17) 4(24%) 13(76%) 8 (47%) Serrated Dysplasia (N=6) 3(50%) 3(50%) 3 (50%)

Srivastava et al, USCAP 2010

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Basal Crypt Dysplasia Basal Crypt Dysplasia

• Prevalence:7.3%
• 87% have prior or concurrent dysplasia or CA
• Association particularly significant w/ regard to the assoc. w/ HGD (P=0.004).

Can we-reliably-recognize BCD?

• 40 bx: 10 BE,9 BCD,10 LGD,9

HGD,2 IMCa [selected by the index

pathologist]

– 5 (blinded) GI pathologists. – K for IOV for entire cohort :0.44 (moderate)

• [IMC (K=0.65)-LGD (K=0.31)]

Metaplastic atypia Metaplastic atypia

• No differences in reproducibility of

Basal Crypt Dysplasia (K=0.44)- LGD (K=0.31) or HGD (K=0.46)

• When disagreement w/ index

diagnosis regarding assessment of BCD (n=17/45 readings), most diagnosed either LGD or HGD rather than BE w/o dysplasia.

Coco et al, 2011 Am J Surg Pathol DNA abnormalities in basal crypt cells

Compared w/ BE, BCD shows: ↑ prevalence rate of p53 positivity

(60% vs.13%, P<0.02)

↑ total & basal crypt Ki-67 proliferation rate (P<0.001) (similar to

LGD or HGD)

Clonal identity (CDKN2A mutations)

Zhang X Am J Surg Pathol ’08; Lomo LC Am J Surg Pathol ’06; Khan S. J. Pathol 2013;231; Srivastava A. USCAP 2011

Molecular anomalies & natural history of basal crypt dysplasia Recurring issue w/ basal crypt dysplasia

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Level 1 Level 2 Level 2

Barrett Esophagus Surveillance

• NO dysplasia

– Endoscopic surveillance at intervals of 3 to 5 years.

– (Repeat at 1 year after 1st first diagnosis not required)

• Indefinite for dysplasia

– Repeat endoscopy after optimization of acid suppressive medications for 3– 6 months – If the indefinite for dysplasia reading is confirmed on repeat examination, a surveillance interval of 12 months is recommended

• Confirmed LGD (& no life-limiting comorbidity)

– Endoscopic therapy is considered as the preferred treatment modality – Endoscopic surveillance every 12 months is an acceptable alternative

• Confirmed HGD

– Endoscopic therapy unless they have life-limiting comorbidities

ACG Clinical Guideline: Diagnosis and Management of Barrett’s Esophagus 2015

• May arise in:

– Atrophic gastritis w/ metaplasia (H. pylori, autoimmune) – Normal mucosa – Fundic gland polyps (up to 50% in AFP pts) – Hyperplastic polyps (2-16%) – Peutz-Jeghers polyps (2-3%)

Gastric Epithelial Dysplasia

Low grade dysplasia High grade dysplasia

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Low Grade Dysplasia High Grade Dysplasia

Atrophic gastritis Intestinal metaplasia Low-grade dysplasia High-grade dysplasia De Vries, Gastroenterology 2008;134

~29% ~3%

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Prevalence of Submucosal and LVI in HGD

LGD (n=4) HGD (n=78) HGD+ACA (n= 4) ACA (n=35) Submucosal Invasion 3 (3.8%) 3 (75%) 4 (11.4%) Vascular Invasion 1 (1.3%) 3 (75%) 1 (2.9%) Lymphatic Invasion 2 (2.6%) 3 (50%) 1 (2.9%)

Sakurai U et al. AJSP 2015

• The low rate of progression indicates that the current

grading system does not significantly under-evaluate the malignant potential of gastric dysplasia, but does not fully exclude the risk of submucosal and lymphovascular invasion

Intramucosal CA

breach of basement membrane invasion into the lamina propria

IMC without desmoplasia

“lacy” pattern “cribiform” pattern “disunion” pattern

Intramucosal Cancer Without Desmoplasia

• 69-year-old male with dyspepsia

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61 62

Your Opinion?

Is this…. 1.Intestinal Metaplasia? 2.I do not know, but I am not worried? 3.I do not know, but I am worried? 4.Well differentiated adenocarcinoma? Is this…. 1.Intestinal Metaplasia? 2.I do not know, but I am not worried? 3.I do not know, but I am worried? 4.Well differentiated adenocarcinoma?

Mod Pathol 2013

64 anastomosing glands. branching glands tortuous glands budding glands

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Preoperative bx diagnoses of very well differentiated adenocarcinoma (n=18 patients)

– Adenocarcinoma (36%), – Suspicious for adenocarcinoma (14%) – Indeterminate for neoplasia (21%) – Reactive IM (29%)

Delay in diagnosis :

• <1 month in13 (72%);1.5 month (x1);3 mos (x1)(6%).
• 3 cases : 23, 50, 84 mos delay w/ minimal changes in size.
• Resections revealed that all 3 cases remained IMCs

No endoscopically defined lesion w/ endoscopically defined lesion LGD Follow- up within 1 year Endoscopic resection to be considered + annual surveillance & bx of any lesion [+/- stop at 2 yrs] If confirmed: continued surveillance

EMR is important in obtaining accurate diagnosis which is upgraded to HGD or CA in up to 19% of cases diagnosed on pinch biopsies

If negative, surveillance (? how long ?) [2 set of

negative bx usually conclude but close surveillance]

HGD Immediate endoscopic reassessment with extensive sampling and surveillance at 6-month to 1-year intervals (when to stop?) Endoscopic resection to confirm Dx & get negative margins + surveillance at 6 mo to 1yr intervals w/ bx of any lesion (when to stop?)

Virchows Arch 2012: 460:19–46; Gastroenterology 2008;134

Gastric Dysplasia Surveillance

Thank You!