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 [email protected]“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: “I have no relevant ...€¦ · Early Neoplasms of the Upper GI Tract • Squamous intraepithelial neoplasia • BE: classic and phenotypic
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5/26/2017
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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
“I have no relevant relationships requiring disclosure”
[Inflammation] Dysplasia Advanced CAEarly 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
0
ADENOCARCINOMA OF THE DISTAL ESOPHAGUS
[US]
lamina propria lamina propria lamina propria lamina proprialamina propria
NormalEsoph.
Regenerative epithwith atypia
LG- IEN HG IEN/CIS
InvasiveCarcinoma
• Progression: 25% & 75% of pts with LGIEN and HGIEN develop inv. CA within10 yrs (5% for patients w/ esophagitis)
LGIEN HGIEN Invasive canormal 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
(41 resections w/ dysplasia w or w/o associated inv. ACA)
Progression to cancer of various types of dysplasia
Dysplasia
Association with
Progression to cancer
ConventionalLGD
ConventionalHGD
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 DysplasiaBasal 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 atypiaMetaplastic 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 SurgPathol
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 2Level
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%)
� The low rate of progression indicates that the curr ent grading system does not significantly under-evaluat e the malignant potential of gastric dysplasia, but d oes not fully exclude the risk of submucosal and lymphovascular invasion
Intramucosal CA
breach of basement membraneinvasion into the lamina propria IMC without desmoplasia
Intramucosal Cancer Without Desmoplasia• 69-year-old male with dyspepsia
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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
64anastomosing glands.
branching glandstortuous 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 moto 1yr intervals w/ bx of any lesion (when to stop?)