study of tenwek esophageal squamous dysplasia prevalence by michael mwachiro steve burgert

Study of Tenwek Esophageal Squamous Dysplasia Prevalence:

The STEP study

KESHO Conference 29th November 2014∞

Principal Investigator, Michael Mwachiro MBChBPresented by

Co-Investigator, Stephen L. Burgert, MDTenwek Hospital – Bomet, Kenya

TENWEK STEP STUDY TEAM• Michael M Mwachiro MBChB1, Principal Investigator• Stephen L Burgert MD1, • Wairimu Waweru MBChB, MMED2, • Russell E White MD, MPH, FACS1,• Collins Bett1

• Robert Chepkwony, KRCHN1

• Jessie Githanga MBChB, MMED2, • Sanford M Dawsey MD3 • Mark Topazian, MD4

1Tenwek Hospital, Bomet, Kenya; 2Department of Pathology, University of Nairobi School of Medicine, Nairobi, Kenya; 3National Cancer Institute, Bethesda, MD, USA.4Mayo Clinic, Rochester, MN, USA.

Esophageal Cancer - Worldwide

• Esophageal cancer is the eighth most common cancer and the sixth most common cause of cancer-related death in the world, with an estimated 482,000 new cases and 407,000 deaths in 2008 (1)

• High rates of esophageal cancer are found along geographic belts, one following the ancient Silk Road from north central China through the central Asian republics to northern Iran, and one from eastern to southern Africa

1. Jemal A, Bray F, CenterMM,Ferlay J, Ward E, FormanD. Global cancer statistics. CA Cancer J Clin 2011;61:69–90.

Geographic Variation of Esophageal Cancer

Low-Risk High-Risk

Rates <10 50 -100+

M:F 3 - 4:1 1 - 1.5:1

% ESCC 40-50% 90%

Nairobi Cancer Registry Report 2004-2008

MEN: Esophageal Cancer is the second most common cancer (after Prostate Cancer)

WOMEN: Esophageal Cancer is the third most common cancer (after Breast and Cervical Cancer)

A. Korir, N. Okerosi, DM Parkin 14th May 2014

Squamous Cell Esophageal Cancervs.

Adenocarcinoma of the Esophagus

Worldwide in developing countries the vast majority of esophageal cancers are of squamous cell pathology.

Tenwek Hospital Endoscopy Services - 2012

• 2,030 endoscopy cases• 484 patients with esophageal cancer• 145 patients with gastric/duodenal

cancer• 319 esophageal stents placed

White RE, Abnet CC, Mungatana CZ, Dawsey SM. Oesophageal cancer: A common malignancy in young people of Bomet District, Kenya. Lancet 2002; 36(9331): 462-63.

Parker RK, Dawsey SM, Abnet CC, White RE. Frequent occurrence of esophageal cancer in young people in western Kenya. Diseases of the Esophagus 2010 (20): 128-135.

Challenges in a Developing Country

• Inadequate Reporting System• Fatalistic Attitude• Late Presentation• Inconsistent Referral Patterns• Traditional Healers/Treatment• Chemotherapy and Radiation Therapy Usually

Not Available • Financial Constraints

Esophageal Cancer

Esophageal CA – post-dilation

Deploying esophageal Stent

Deployed esophageal stent

After esophageal stent placement – drinking from the “Ceremonial Cup”

Survival Following Treatment at Tenwek Hospital

• Stenting alone– Median Survival 9 months– Dysphagia score 0-2 at time of death

• Surgery alone– Median survival 24 months stage I and II– Median survival 14 months stage III and IV

Esophageal Dysplasia

• Dysplasia has been shown to be an important element along the pathway leading to development of Esophageal Carcinoma- both for Adenocarcinoma and Squamous Cell carcinoma

• Interventions at eradicating the dysplasia would be useful in stopping the progression to carcinoma

Esophageal Squamous dysplasia - Histology

Dysplasia – Histology Criteria

• Squamous dysplasia requires– the presence of nuclear atypia (enlargement,

pleomorphism, and hyperchromasia) – loss of normal cell polarity, – and abnormal tissue maturation without invasion

of epithelial cells through the basement membrane

Grading of Esophageal Squamous Dysplasia

• Mild dysplasia - these abnormalities are confined to the lower third of the epithelium

• Moderate dysplasia - they are present in the lower two thirds of the epithelium

• Severe dysplasia - they also involve the upper third of the epithelium.

• Full thickness involvement of the epithelium, called carcinoma in situ by some, is considered synonymous with severe dysplasia based on their similar histologic appearance

Esophageal Squamous Dysplasia Progression in China

Over a total of 13.5 years for the Linxian cohort Esophageal Squamous Cell Carcinoma developed in:

8% of participants with normal histology (baseline positive cytology sample)

24% with mild dysplasia 50% with moderate dysplasia 74% with severe dysplasia 58% with dysplasia NOS (not otherwise specified) and 75% with carcinoma in situ

Wang et al Gut 2005

ESCC Possible Risk Factors

Low-Risk Populations• Tobacco• Alcohol• Low SES

High-Risk Populations• [Tobacco, alcohol]• Diet (low selenium)• Tobacco carcinogens from

other sources:• PAHs• Nitrosamines• Acetaldehyde

• Poor oral health• Hot drinks• Low SES• Family history

OVERALL OBJECTIVES • Esophageal squamous cell cancer (ESCC) is a

common malignancy in the developing world and is the leading cancer diagnosis at Tenwek Hospital, a referral hospital in western Kenya.

• Our long-term goal is to understand the pathogenesis and risk factors for ESCC in Kenya, and to establish effective screening and prevention programs.

• To provide effective treatment options for patients identified with esophageal squamous dysplasia.

Study of Tenwek Esophageal Squamous Dysplasia Prevalence:

The STEP study

STEP study

• Study of

• Tenwek

• Esophageal Squamous Dysplasia

• Prevalence

OBJECTIVE – STEP Study

• We hypothesized that asymptomatic esophageal squamous dysplasia (ESD), the precursor lesion of ESCC, is common in our region, raising the possibility of screening for ESD to prevent ESCC.

• This study aimed to determine the prevalence of ESD in adult residents in the traditional Tenwek Hospital catchment area and to explore the impact of demographic data and environmental exposures on the prevalence of ESD.

METHODS:

• 305** asymptomatic adult residents of villages within 50 km of Tenwek Hospital completed a detailed survey and underwent trans-oral videoendoscopy of the esophagus with Lugol’s chromoendoscopy, mapping of identified lesions, and biopsy.

• Each subject was classified by their worst biopsy diagnosis, and the overall prevalence of ESD, the age-adjusted prevalence of ESD and the sex- and age-specific prevalence of ESD by decade will be calculated.

• The association between potential risk factors and ESD was analyzed by univariate and multivariate logistic regression.

Inclusion Criteria• Residence within 50 kms of Tenwek Hospital• Age between 20-79 years• Exclusion of the following symptoms and allergies

• Dysphagia• Odynophagia• Haematemsis• Weight loss• Allergy to iodine• Allergy to lidocaine

• Exclusion of significant health problems such as:• Bleeding disorders• Heart arrhythmias• Diabetes• Lung disease or breathing problems• Stroke

• Subject should be fasting/NPO (Nil Per Oral) from previous night

Recruitment Model

Community level

Tenwek Hospital

Administrators

Zone A

Zone C

Zone B

Meeting at the village

Going through the consent form and questionnaire

Endoscopy procedure

Making up of Lugol’s iodine solution

• Lugol’s iodine stain: 12g I2 + 24g KI in 1L H2O

• Make it up yourself: right formula, fresh

• Iodine reversibly stains glycogen (abundant in

normal superficial squamous cells, absent in rapidly

dividing cells); → normal epithelium is brown,

dysplasia is unstained

Endoscopic view

Esophageal dysplasia – before Lugol’s stain

Esophageal dysplasia – after Lugol’s stain

Extracting biopsy from forceps

Orienting biopsy specimens

• So what did we find?

Results and Discussion

RESULTS

• Subject accrual is currently completed. Results are presented for 305 patients. (complete histologic and endoscopic data)

• Enrollment up to this time had been 313 subjects

• Subject drop-out rate was 3.6% and subject compliance was 97.5%

Table 1: Characteristics of participants who were screened in the STEP study (n=305)

Characteristic N (%)

Total 305

Age, years (mean, SD) 46.7 (15.5)

< 50 163 (53)

≥ 50 142 (47)

Male 163 (53)

Location

A 98 (32)

B 61 (20)

C 145 (48)

Kalenjin ethnicity 304 (99.7)

Education, post-primary 105 (34)

Tobacco smokers 60 (20)

Alcohol drinkers 98 (32)

Family history of cancer 34 (11)

Family history of esophageal cancer 19 (6)

Table 2: Histologic Diagnosis

Diagnosis Number N (%)

Normal 115 37

Mild esophagitis 119 39

Moderate- severe esophagitis 27 9

Mild dysplasia 35 11.5

Moderate dysplasia 8 2.6

Severe dysplasia 1 0.3

Table 3: Prevalence of esophageal squamous dysplasia, by participant characteristics, in the STEP study

Worst Biopsy Diagnosis

CharacteristicNormal Dysplasia Dysplasia Prevalence

(%, 95% CI)(n=261) (n=44) p-value

Mean age (mean, SD) 46 (15) 51 (15) 0.04

Sex

Male 137 26 16 (11-22)

Female 124 18 13 (8-19) 0.5Location

A 79 19 19 (12-29)

B 48 13 21 (12-34) C 133 12 8 (4-14) 0.01

Post primary education

No 166 34 17 (12-23)

Yes 95 10 10 (5-17) 0.09

Tobacco smokers

No 214 31 13 (9-17)

Yes 47 13 22 (12-34) 0.1

Alcohol drinkers

No 185 21 10 (6-15)

Yes 75 23 23 (16-33) 0.003

Family history of cancer

No 232 39 14 (10-19)

Yes 29 5 15 (5-31) 1.00

Family history of esophageal cancer

No 243 42 15 (11-19)

Yes 17 2 11 (1-33) 1.00

Table 4: Prevalence of esophageal squamous dysplasia (ESD) by age and sex in the STEP study

Characteristic Worst Biopsy Diagnosis

Normal1 Dysplasia2 Dysplasia Prevalence

(n= 261) (n=44) (%, 95% CI)Age

<30 49 3 6 (1-16)30-39 57 9 14 (6-24)40-49 39 6 13 (5-27)50-59 57 10 15 (7-26)

≥60 59 16 21 (13-32)

Age: Male<30 21 2 9 (1-28)

30-39 31 4 11 (3-27)40-49 21 3 13 (3-32)50-59 29 8 22 (9-38)

≥60 35 9 20 (10-35)

Age: Female<30 28 1 3 (0.1-18)

30-39 26 5 16 (5-34)40-49 18 3 14 (3-36)50-59 28 2 7 (1-22)

≥60 24 7 23 (10-41)1 Includes normal squamous epithelium and esophagitis2 Includes mild, moderate and severe dysplasia

Table 5: Distribution of Unstained Lesions (USLs) and Dysplasia Biopsies in the STEP Study

Location USLs (%) Dysplasia Biopsies (%)

Upper third 11 (3) 2 (4)

Middle third 153 (44) 28 (58)

Lower third 180 (52) 18 (38)

Total 344 (100) 48 (100)

Table 6: Screening Characteristics of Unstained Lesions (USLs) for Identifying Dysplasia in the STEP study

Dysplasia + -

USL+ 27 175 202- 13 200 213

40 375 415

% (95% CI)Sensitivity 27/40 68 (50-81)Specificity 200/375 53 (48-58)PPV 27/202 13 (9-19)NPV 200/213 94 (90-97)

Assuming that the 305 subjects who underwent endoscopy are representative of the Bomet

population:

14 % of asymptomatic adults exhibit squamous cell

dysplasia of the esophagusActual prevalence is probably higher, given 68% sensitivity

of tool

*White RE, et al. Esophageal dysplasia in asymptomatic residents of western Kenya: Interim results of a

cytologic and endoscopic screening program. Gastroenterology 2004; 126: A24.

A previous screening study of 5760 subjects done by Tenwek with cytology balloon sampling had a dysplasia prevalence rate of 2.6%

and a 56% sensitivity*

Table 7: Univariate and multivariable adjusted odds ratios of dysplasia in STEP study

Odds ratios (95% CI)

Characteristic Univariate Multivariate

Age 1.02 (1.00, 1.04) 1.01 (0.99-1.04)

Male 1.31 (0.68-2.50) 0.87 (0.41-1.87)

Location (Compared to C)

A 2.67 (1.23-5.78) 2.55 (1.14-5.72)

B 3.00 (1.28-7.03) 2.84 (1.19-6.78)

Tobacco smokers 1.90 (0.93-3.93) 0.86 (0.34-2.19)

Alcohol drinkers 2.70 (1.41- 5.17) 2.35 (1.11-6.04)

Family history of cancer 1.03 (0.37-2.81) 0.90 (0.32-2.56)

Dysplasia in China and Iran

• in a 2002 endoscopic screening study in Linxian China (where 15% of the people die of esophageal cancer), which was restricted to asymptomatic subjects 50-64 years old, the overall prevalence of squamous dysplasia was 32% (18% high-grade, 14% low-grade)*

• a similar recent endoscopic screening study of 300 adults (aged 40-75) in Iran (total dysplasia 6%, high-grade 1.4%, low-grade 4.6%).

Results of the STEP Study in perspective

Population Total Dysplasia High-Grade Dysplasia

China 30 15

Iran 6 1.4

Kenya 14 3.0

Prevalence of Dysplasia and HGD, by Population

• Even in China, endoscopic screening of all adults in high-risk areas,

although possibly “cost-effective”, cannot screen comprehensively, so it

probably cannot, by itself, significantly reduce ESCC mortality

• In Iran and Kenya, endoscopic screening will be less cost-effective than

in China, and in Kenya, the required infrastructure is rarely available

• For this technique to reduce mortality, it must be preceded by another

primary screen that can significantly and accurately stratify risk

Ongoing analysis - STEP Study

• Detailed subject characteristics and risk factors

• Genetic analysis of specimens

• Polycyclic Aromatic Hydrocarbon (PAH) exposure levels from this subset

CONCLUSIONS –STEP STUDY

1. Endoscopic screening as performed in the STEP study is feasible, patient acceptable, and safe in our population

2. The overall prevalence of squamous dysplasia in this population was 14.4% (2.6% high-grade and 11.5% low-grade)

3. The prevalence of dysplasia was greater in patients >50 years old, was similar in men and women, and varied significantly by location of residence

CONCLUSIONS (continued)4. USLs were 68% sensitive and 53% specific for identifying biopsy sites containing squamous dysplasia

5. Patient risk stratification (by age, residence location, etc.) may improve the yield of dysplasia in future screening efforts and geographic location was a significant predictor of dysplasia (p 0.01).

The next Steps?• DIRECT Study - Ongoing- Study of Dysplasia In

Relatives of patients with Esophageal Cancer at Tenwek

• EXPECT Study - Ongoing- Endoscopic (X) Prevention of Esophageal Cancer at Tenwek Hospital by removal or ablation of esophageal squamous cell dysplasia

• LEADER Study - Low grade EsophAgeal Dysplasia Evaluation Report

• BOOST Study - Study of the Biomarkers Of Oesophageal Squamous Dysplasia at Tenwek Hospital

Multiband MucosectomyMultiband mucosectomy technique

Graphic courtesy of SM Dawsey and Jacques Bergman

Esophageal dysplasia

Esophageal dysplasia – Lugol’s stain

Esophageal Endoscopic Mucosal Resection (EMR)

Three months after EMR

HALO360 Ablation Catheter

Radiofrequency Ablation

SquamousDysplasia Ablation Case

HALO360

Courtesy of:Jacques BergmanAMCAmsterdam

Radio Frequency Ablation

Pouw et al GIE 2008

Thank you for your attention

We look forward to further discussions on effective screening and prevention programs for esophageal squamous cell carcinoma in Africa.