The STEP study aimed to determine the prevalence of esophageal squamous dysplasia (ESD) in the Tenwek Hospital catchment area in Kenya. 305 asymptomatic adults underwent endoscopy with biopsy. The prevalence of ESD was 14%, higher than a previous study. Risk factors for ESD included living in certain locations, alcohol consumption, and older age. Unstained lesions on endoscopy had low sensitivity (68%) for detecting dysplasia, though high specificity (53%) and negative predictive value (94%). The results suggest screening for ESD may help prevent esophageal squamous cell carcinoma in this high-risk region.

1. Study of Tenwek Esophageal Squamous
Dysplasia Prevalence:
The STEP study
KESHO Conference 29th November 2014
∞
Principal Investigator, Michael Mwachiro MBChB
Presented by
Co-Investigator, Stephen L. Burgert, MD
Tenwek Hospital – Bomet, Kenya

2. 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.

4. 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.

5. 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%

6. 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

7. Squamous Cell Esophageal Cancer
vs.
Adenocarcinoma of the Esophagus
Worldwide in developing countries the vast
majority of esophageal cancers are of squamous
cell pathology.

10. Tenwek Hospital
Endoscopy Services - 2012
• 2,030 endoscopy cases
• 484 patients with esophageal cancer
• 145 patients with gastric/duodenal
cancer
• 319 esophageal stents placed

11. 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.

12. 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.

14. 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

15. Esophageal Cancer

18. Esophageal CA – post-dilation

19. Deploying esophageal Stent

20. Deployed esophageal stent

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

22. 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

23. 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

24. Esophageal Squamous dysplasia - Histology

25. 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

26. 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

27. 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

28. 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

29. 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.

30. Study of Tenwek Esophageal Squamous
Dysplasia Prevalence:
The STEP study

31. STEP study
• Study of
• Tenwek
• Esophageal Squamous Dysplasia
• Prevalence

32. 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.

33. 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.

34. 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

35. Recruitment Model
Administrators
Community
level
Tenwek
Hospital

36. Zone
A
Zone C
Zone B

38. Meeting at the village

39. Going through the
consent form and questionnaire

40. Endoscopy procedure

41. 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

42. Endoscopic view

43. Esophageal dysplasia – before Lugol’s stain

44. Esophageal dysplasia – after Lugol’s stain

45. Extracting biopsy from forceps

46. Orienting biopsy specimens

47. • So what did we find?
Results and Discussion

48. 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%

49. 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)

50. 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

51. Table 3: Prevalence of esophageal squamous dysplasia, by participant
characteristics, in the STEP study
Worst Biopsy Diagnosis
Characteristic
Normal Dysplasia Dysplasia Prevalence
(n=261) (n=44) (%, 95% CI) 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) 0.5
Location
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

52. 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 esophagitis
2 Includes mild, moderate and severe dysplasia

53. 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)

54. 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)

55. Assuming that the 305 subjects who underwent
endoscopy are representative of the Bomet
population:
14 % of asymptomatic adults
exhibit squamous cell
dysplasia of the esophagus
Actual prevalence is probably higher, given 68% sensitivity
of tool
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*
*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.

56. 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)

57. 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%).

58. Results of the STEP Study
in perspective
Prevalence of Dysplasia and HGD, by Population
Population Total Dysplasia High-Grade Dysplasia
China 30 15
Iran 6 1.4
Kenya 14 3.0
• 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

59. Ongoing analysis -
STEP Study
• Detailed subject characteristics and risk
factors
• Genetic analysis of specimens
• Polycyclic Aromatic Hydrocarbon (PAH)
exposure levels from this subset

60. 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

61. 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).

62. 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

63. MultiMbaunldti bmauncdo Mseucctoomseyc ttoemchynique
Graphic courtesy of SM Dawsey and Jacques Bergman

64. Esophageal dysplasia

65. Esophageal dysplasia – Lugol’s stain

66. Esophageal Endoscopic Mucosal
Resection (EMR)

67. Three months after EMR

68. HALO360 Ablation Catheter

69. Radiofrequency Ablation

70. Squamous
Dysplasia
Ablation Case
HALO360
Courtesy of:
Jacques Bergman
AMC
Amsterdam
Radio Frequency Ablation
Pouw et al GIE 2008

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