langner oesophagus in systemic and hereditary disease ... · sun et al. cancer epidemiol biomarkers...

Cord Langner MDInstitute of PathologyMedical University of Graz / Austriawww.medunigraz.at/ENGIP

The oesophagus in systemic and hereditary disease

Austrian Society of Pathology / Austrian Division of IAP

Graz, April 25, 2015

Outline

� Systemic diseases

� Skin diseases

� Chronic inflammatory bowel diseases

� Mixed connective tissue diseases

� Vasculitis

� Oesophageal cancer predisposition

syndromes

Salaria et al. Am J Surg Pathol 2013

� Atrophic epithelial changes

� Prominent band-like

infiltrate of lymphocytes

involving epithelium and

lamina propia, scattered

degenerated keratinocytes

(Civatte bodies)

� Globular IgM deposits at

the dermo-epidermal

junction

Salaria et al. Am J Surg Pathol 2013

Galloro et al. Dig Liver Dis 2005

Suprabasal acantholysis, IgG autoantibodies directed against the cell

surface of keratinocytes

DD: bullous pemphigoid with IgG autoantibodies at the dermo-epidermal

junction that attack the hemidesmosomes, causing subepidermal blister formation

Galloro et al. Dig Liver Dis 2005

Fukuchi et al. Dis Esophagus 2011

Crohn‘s Disease: Distribution within the GI Tract

Upper GI tract: microscopic lesions in 50-75%

Isolated small bowel CD in 30-35%

Isolated large bowel CD in 15-25%

CD affecting both small and large bowel in 40-50%

Upper GI Tract Involvement in IBD – Part 1

Author Crohn‘s disease Ulcerative colitis

Oberhuber et al. 1997 Focal gastritis (antrum 48%, corpus 14%),

granulomas 15%

Not analysed

Wright & Riddell 1998 Focal gastritis 31%, focal duodenitis 40%,

granulomas 9%.

Not analysed

Oberhuber et al. 1998 Focal duodenitis in 43 cases (12%), 33 with

granulomas

Focal bulbitis in 73 cases (13%), 22 with

granulomas

Focal antrumgastritis in 238 cases (42%), 11

with granulomas

Focal corpusgastritis in 113 cases (37%), 6

with granulomas

Not analysed

Yao et al. 2000 Microaggregates 55%, granulomas 18% No microaggregates and no granulomas in 23

cases

Parente et al. 2000 Focal gastritis in 40/94 (43%) HP-negative

cases, granulomas in 5 cases

Focal gastritis in 5/42 (12%) HP-negative

cases, bust also in 11/57 (19%) HP-negative

non-IBD control cases, no granulomas

Upper GI Tract Involvement in IBD – Part 2

Author Crohn‘s disease Ulcerative colitis

Sharif et al. 2002 Focal gastritis in 28/43 (65%) children;

granulomas in 6 (14%); mild to moderate

chronic non-HP gastritis in 35%

Focal gastritis in 5/24 (21%) children; mild to

moderate chronic non-HP Gastritis in 50%

Kundhal et al. 2003 Focal antrumgastritis in 52% Focal antrumgastritis in 8%

Xin et al. 2004 Focal gastritis in 1/19 (5%) Focal gastritis in 1/8 (12.5%)

Petrolla et al. 2008 Focal gastritis 36% CD ileitis vs. 5% non-CD

ileitis

Not analysed

Lin et al. 2010 Not analysed Focal gastritis in 17/59 (29%) cases, one

case with granulomas

Sonnenberg et al. 2011 Focal gastritis in 11/208 (5%) cases No focal gastritis in 280 cases

Hummel et al. 2012 Focal gastritis in 48/70 (69%) children; focal

duodenitis in 13 (19%) children

Focal gastritis in 6/33 (18%) children; no focal

duodenitis

Mc Hugh et al. 2013 13/25 (52%) children with focal gastritis have

CD; 31/262 (11.8%) cases with focal gastritis

(19 x IBD, of these 9 x CD and 9 x UC)

3/25 (12%) children with focal gastritis have

UC; 31/262 (11.8%) cases with focal gastritis

(19 x IBD, of these 9 x CD and 9 x UC)

Ushiku et al. 2013 Focal gastritis in 34/62 (55%) children;

granulomatous gastritis in 9/62 (15%)

Focal gastritis in 17/57 (30%) children; no

granulomatous gastritis

Levine et al. Inflamm Bowel Dis 2011

De Bie et al. Inflamm Bowel Dis 2013

Mayo Clinic Experience: 20 patients (0.2% of their CD patients)

� Distribution

Distal third alone in 16 (80%)

Middle and lower third 3 (15%)

Whole esophagus 1 (5%)

� Endoscopy

Ulcers in 17 (85 %; superficial aphthous-type ulcers in 15 of these patients)

Erythema and erosions in 8 (40%)

Strictures in 4 (20%)

� Histology

Active chronic inflammation in 75%

Ulceration in 30%

No granulomas

Decker et al. Inflamm Bowel Dis 2001

Differential diagnosis:Superinfection!Rule out Herpes and Cytomegalovirus!

� Extraoesophageal CD precededorwas found at the same time as thediagnosis of oesophageal CD in all cases

Lower gut (ileum / colon) involvementin 19 (95%)

Upper gut (stomach / duodenum) involvement in 14 (70%)

Oral aphthous ulceration in 6 (30%)

� Symptoms in 16 (80%)

Dysphagia in 11 (55%)

Odynophagia in 8 (40%)

Heartburn in 6 (30%)

Chest pain in 2 (10%)

Sakuraba et al. Biomed Res Int 2014

„We defined the aphthae, erosions, or ulcers in the oesophagus as Crohn’s

disease related when they were located far from the gastroesophageal junction

or were present when there was no evidence of reflux oesophagitis or when

histology showed inflammation consistent with Crohn’s disease.”

1st H-ECCO Masterclass 11th Congress of ECCOMarch 16-19, 2016Amsterdam, The Netherlandshttps://www.ecco-ibd.eu/ecco16

Roberts et al. Gut 2006

Uzuki et al. Pathol Res Pract 2011

Ntoumazios et al. Semin Arthritis Rheum 2006

Dysfunction of the lower oesophageal shincter

Motility disorder with absent primary and

secondary peristalsis

Gastroesophageal reflux risease (GERD)

Barrett‘s esophagus

Loss of normal oesophageal

clearance

Low LES pressure (in the presence of a normal (striated muscle) proximal oesophagus

Delayed gastric emptying

Sicca syndrome

Ideguchi et al. Rheumatol Int 2014

Ebert Dig Dis Sci 2009Wu et al. World J gastroenterol 2012

Ideguchi et al. Rheumatol Int 2014

� Oesophageal involvement is accompanied by other GI manifestations in >50% of cases

� Localization

Predominantly middle or lower part

� Endoscopy

Erosions, aphthous, linear or deep penetrating / perforating ulcers

� Histology

Unspecific active chronic inflammation rather than vasculitis

Outline

� Systemic diseases

� Skin diseases

� Chronic inflammatory bowel diseases

� Mixed connective tissue diseases

� Vasculitis

� Oesophageal cancer predisposition

syndromes

Tylosis

� Tylosis esophageal cancer is inherited as an

autosomal-dominant trait, and the cutaneous

phenotype is fully penetrant by the onset of

puberty

� The syndrome is characterized by

� Non-epidermolytic palmoplantar keratoderma

� Oral precursor lesions

� High lifetime risk of oesophageal squamous cell

carcinoma (up to 95% by the age of 65)

Blaydon et al. Am J Human Genet 2012

Blaydon et al. Am J Human Genet 2012

� RHBDF2 missense mutations are the underlying cause of

this highly penetrant form of inherited oesophageal cancer

� Altered RHBDF2 represents a gain-of-function allele that

results in sustained EGFR signaling within the cells; this

sustained EGFR signaling, in turn, leads to a

hyperproliferative phenotype

� The results support the hypothesis that tylosis results from

dysregulated wound repair that leads to precancerous

lesions in the oesophagus (pharynx and oral cavity)

Singhi et al. Mod Pathol 2014

Postoperative histology showed a poorly differentiated exophytic squamous cell carcinoma with a diameter of 0.8 cm infiltrating the superficial layer of

the mucosa without lymph node metastasis (pT1aN0M0R0G3)

56-year-old female with„crackleware oesophagus “

BRCA2� BRCA2 (breast cancer 2) is a tumor suppressor

gene located on chromosome 13q12.3

� BRCA2 mutations were identified in families with

breast cancer who did not have mutations in

BRCA1 and have a high incidence in male breast

cancer

� The gene is important in facilitating repair of

double stranded breaks by binding directly to the

Rad51 protein and recruiting this recombinase

protein to sites of DNA damage

Hu et al. Oncogene 2004

126 patients with oesophageal SCC

78 family history positive

48 family history negative

N = 9 (12%) N = 0 (0%)

direct full sequencing of germline DNA for BRCA2 mutations

Akbari et al. Oncogene 2008

197 patients with oesophageal ESCC

254 controls

N = 9 (4.6%) N = 2 (0.8%)

Screening for germline mutations in the coding region ofthe BRCA2 gene

Nine other BRCA2 variants in single cases only, including two deletions, and seven missense mutations, of which six were judged to be pathogenic

In total, a suspicious deleterious BRCA2 variant wa s identified in 15 of 197 ESCC cases (7.6%)

Familial Barrett Oesophagus

� Definition:

Familial clustering, that is, presence of first or

second degree relatives with Barrett's

oesophagus, oesophageal adenocarcinoma, or

oesophagogastric junctional adenocarcinoma

� Putative cause:

So far undiscovered susceptibility genes that

predispose individuals to develop intestinal

metaplasia in the distal oesophagus

Chak et al. Gut 2002

Chak et al. Cancer Epidemiol Biomarkers Prev 2006

71 out of 411 (17.3%) of individuals with BE, EAC, GEJ-AC reported an affected first- and/or second-degree relative

The diagnosis was confirmed in 30 (7.3%) individuals

17/276 (6.2%) BE

11/116 (9.5%) EAC

2/21 (9.5%) GEJ-AC

Chak et al. Cancer Epidemiol Biomarkers Prev 2011

Median BMI 28.24 27.8 27.26

Sun et al. Cancer Epidemiol Biomarkers Prev 2010

� The authors analyzed data on 881 singly ascertained pedigrees to determine whether FBE is caused by a common environmental or genetic agent and, if genetic, to identify the mode of inheritance of FBE

� The inheritance models were compared by likelihood ratio tests and Akaike's A Information Criterion

� The results indicate that random environmental and/or multifactorial components are insufficient to fully explain the familial nature of FBE, but rather, there is segregation of a major type transmitted from one generation to the next

� The authors conclude “an incompletely dominant autosomal inheritance model together with a polygenic component fits the data best”

Low -Penetrance Polymorphisms Linked to Oesophageal Cancer

� Genetic polymorphisms in metabolic pathway

proteins or in proteins involved in DNA repair, cel l

cycle, and apoptosis have been linked to both

squamous cell and adenocarcinoma

� Aldehyde dehydrogenase 2 (ALDH2)

polymorphisms as risk factor for squamous cell

carcinoma

� O(6)-methyguanine-DNA methytransferase

(MGMT) as risk factor for adenocarcinomaSha & Kurtz. Hematol Oncol Clin North Am 2010

Take Home Message I

� The oesophagus may be affected in skin diseases,

such as lichen ruber and pemphigus vulgaris /

bullous pemphigoid

� Morphological changes resemble skin histology

� Oesophageal involvement in Crohn’s disease is rare

and commonly shows unspecific histological

changes

� In virtually all cases of oesophageal Crohn’s disea se

other parts of the GIT are affected (lower > upper GIT)

� Differential diagnosis includes CMV (super-)infecti on

Take Home Message II

� Scleroderma and mixed connective tissue disease

lead to progredient muscular atrophy and fibrosis,

predominantly of the inner muscular wall (striated

muscle is not affected)

� Complications are GERD and Barrett’s oesophagus

� Both osophageal squamous and adenocarcinoma

may occur in a familial setting

� Tylosis is characterized by non-epidermolytic

palmoplantar keratoderma, oral precursor lesions an d

a high lifetime risk of cancer (autosomal dominant)

Thank you very much foryour attention !

Cord Langner MDInstitute of Pathology

Medical University of Graz / Austria [email protected]

European Network of Gastrointestinal Pathologywww.medunigraz.at/ENGIP

langner oesophagus in systemic and hereditary disease ... · sun et al. cancer epidemiol biomarkers...

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