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Figure 9 (Adapted from (Schlemper et al. 1997)) Showing percentage of diagnostic up and downgrades between biopsy and later resection specimen
diagnosis.
Figure 10 (Adapted from (Schlemper et al. 2001)) Discrepancies between biopsy diagnosis and resection specimen diagnosis.
expansion maybe a non-necessary criterion. This is true,
indeed but it may help to bridge and overcome the differences
in a constructive rather than an destructive way. The Western
standpoint is that Japanese colleagues “overdo” the carcinoma
diagnoses leading to a good prognosis and high incidences of
“gastric carcinoma,” a proportion of which may not have
become invasive for many years if at all, This standpoint, however, overlooks the subsequent rare differences between a
biopsy diagnosis and the final diagnosis on the resection
specimen in Japan. There is very strong evidence that when
more biopsies, or sections are taken (>5), and when more
expert pathologists (>2) are involved, in the patients diagnosis
the accurary increases to the very best global standards in all
stages of the esophagitis-metaplasia-dysplasia-adenocarcinoma sequence (Bennett et al. 2015).
3. Gastric Differentiation
In general, most columnar neoplasms of the upper gastrointestinal
tract show an intestinal differentiation. This means they share a lot
in common with tubular adenomas of the colon: hyperchromatic,
2 GENOMICS, MOLECULAR PATHOLOGY, AND PATHOLOGY OF ESOPHAGEAL AND GASTRIC CANCER 35
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Figure 11 (Adapted after (Borchard et al. 2000)) Expansion patterns from A retrograde intratubular and horizontal expansion along the surface in
adenomas and later B retrograde vertical expansion by increased proliferation to C disordered vertical lateral expansion of invasive carcinomas.
carcinoma at the first diagnosis (Vieth et al. 2003). Such areas
are sometimes hard to identify and the proliferation index may
be of help in these cases since it is quiet low in pyloric gland
adenoma with no higher grade of neoplasia.
Gastric surface epithelium can give rise to neoplasms as well.
Then these neoplasms show a foveolar differentiation with
small epithelial cells, cuboidal nuclei that are hyperchromatic.
Abrupt transitions to the adjacent non neoplastic epithelium
indicate the borders of the lesion. Characteristically these
lesions show so-called apical mucin caps.
Mixtures between different gastric differentiations can be
seen especially in Barrett’s (Vieth et al. 2016) and in patients
Figure 12 H&E of lateral expansion underneath the surface in as the
earliest sign of invasion into the adjacent lamina propria in tubular well
differentiated gastric adenocarcinoma.
with syndromatic polyposis (Hackeng et al. 2017).
Furthermore, neoplasia can arise from chief cells and lead to
so-called chief cell adenoma (Müller-Höcker and Rellecke
2003) which show typically a very suspicious architecture with
enlarged and palisading nuclei of the epithelium in case of low
grade dysplasia. In high grade dysplasia the nuclei become round
and leave their basal orientation and can build up so called cushions of up to 3–5 nuclei on top of each other within in the epithelium. In case of transition to carcinoma the afore mentioned lateral
expansion can be seen.
This is different in cases where the neoplasms derive from
deep gastric glands (pyloric glands) and lead to so called pyloric
gland adenomas. The cytology is completely different in such
cases. The cytoplasm is pale eosinophilic, nuclei are basal orientated but slightly elevated and show a round shape. The
glands are densely packed and mimic a strange hyperplastic
architecture as Elster (Elster 1976) noted in 1967 without
knowing that he probably described and depicted the first
pyloric gland adenoma in the literature. Besides the blandlooking cytology ca 30% of such lesions harbor transition to a
marked lateral expansion. Fortunately, these lesions almost
never metastasize and invade the submucosal layer infrequently. Unfortunately, there is an ongoing discussion of the
dignity of such lesions. Most Western authors conclude by the
low risk for metastasis that chief cell adenomas are benign
lesions per se whereas Japanese authors per se make a carcinoma diagnosis based on cytology (and architecture). Probably
the Japanese colleagues are correct and at least it is consistent
with general criteria for a carcinoma diagnosis. The fact that
pyloric gland adenoma also share features with chief cell adenomas (Kushima et al. 2013) but don’t harbor parietal cells and
show a different architecture that led to the idea to see pyloric
gland adenomas and chief cell adenomas as two branches of a
common progenitor cell. It is further complicated that chief cell
adenomas are synonymously called oxyntic gland adenomas or
fundic gland adenomas/carcinomas. Theoretically, this
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Figure 13 (Adapted after (Kushima et al. 2013)) Classification of gastric carcinomas over decades. Today including most variants and growth patterns.
It is obvious that Laurén classification is not up to date anymore even it helped surgeons to determine the distance of safety margins for preventing
relapses as marker for the aggressiveness of a tumor.
includes pyloric gland adenomas since they mostly develop in
oxyntic mucosa as well. It is foreseeable that the terminology
for pyloric gland/chief cell/fundic gland/oxyntic gland (Ushiku
et al. 2020) needs to be adapted in the future to a more logical
and uniform approach.
4. Classification of Gastric Carcinomas
For decades most pathologists worldwide stuck to the so-called
Laurén classification with two alternatives how to classify gastric
carcinomas namely into an intestinal type and a diffuse type. The
reason was that this indicated the surgeons how far the resection
margin needed to be. It was known that diffuse type of cancer
has a worse prognosis and needed more aggressive options of
treatment when advanced compared to intestinal type of cancer. Many shortcomings are associated with this classification
namely also that “intestinal” and “diffuse” are not real opposites.
The Japan Gastric cancer society early tried to overcome these
issues by introducing updated versions by various authors taken
the general growth pattern more detailed into account. Finally
the WHO recognized these attempts and also proposed in the
2019 edition of gastrointestinal tumor classification (Digestive
System Tumours WHO Classification of Tumours 2019) the
use of the recent Japanese classification with mild terminology
changes (Figure 13). This was a great step in the worldwide harmonization process since obviously comparison of studies was
not properly possible anymore. It is possible to use the new terminology and old terminology in diagnostic pathology if clinicians want to stick to a certain terminology for their patients.
Such further terminology can be given in brackets, easily.
One issue remaining with the increasing number of Helicobacter
eradication therapies and the decreasing frequency of Helicobacter
infected individuals is that we can see strange effects such as
positive Helicobacter stool tests in individuals after successful
eradication therapy and non-inflamed stomach. It turned out that
there may be other Helicobacter infected areas in the GI-tract that
can harbor a Helicobacter infection such as the bile ducts and especially the gallbladder. The meaning of such findings is still unclear.
One can speculate if Helicobacter bacteria in the gallbladder may
contribute to inflammation or malignant transformation within
the gallbladder (Backert et al. 2018). Another sequel is the findings
of precancerous lesions such as adenomas within non inflamed
Helicobacter negative stomachs (Bertz et al. 2021).
Interestingly the rare foveolar adenomas are nowadays seen
more often than in previous decades with high frequencies of
Helicobacter infections. Even carcinomas are now detected in
Helicobacter negative stomachs that have not been detected in
earlier times. One can hypothesize two scenarios: a point of no
return has been crossed prior to a successful Helicobacter eradication therapy. Cases developing gastric cancer after cure of
2 GENOMICS, MOLECULAR PATHOLOGY, AND PATHOLOGY OF ESOPHAGEAL AND GASTRIC CANCER 37
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MALT Lymphoma by eradication therapy point into this
direction (Rentien et al. 2018). This may explain some but not
all of such cases since there are for sure Helicobacter naiive
stomachs seen with gastric neoplasia (adenoma and carcinoma) and here it may be speculated that other triggers initiated malignant transformation (e.g. other infective agents then
Helicobacter and/or environmental causes). Further research
needs to clarify these issues to develop proper screening and
early detection in those with higher risk for malignant
transformation.
In conclusion there is major progress in the diagnostic, prognostic, and predictive biomarkers in the management of both
esophageal and gastric cancer. The next decade will see the
implementation of increasing holistic tissue molecular
pathology profiles at all stages to act as an adjunct to classical
histopathological diagnosis.
Key Take Home Messages
1 Esophageal squamous cancer is more rapidly invasive than
esophageal and gastric adenocarcinoma.
2
The molecular genotype/phenotypes of esophageal cancers
can predict response to therapy.
3 The more specialist pathologists involved in the diagnosis
the greater the accuracy (>2).
The samples takes by biopsy or sampled in the resection the
4
greater the accurarcy.
Areas for Further Research
1 There is insufficient data on circulating diagnostic bio-
markers for esophageal cancer risk and development.
2
The best prognostic biomarkers are unknown.
Trusted Websites for Further Reading
https://jhu.pure.elsevier.com/en/publications/molecular-
evolution-of-the-metaplasia-dysplasia-adenocarcinoma-se-4
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538857
https://cancersearch.org/condition/barrett-adenocarcinoma~
c/#.details
References
Abnet, C.C., Freedman, N.D., Hu, N. et al. (2010 September). A shared
susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and
esophageal squamous cell carcinoma. Nat Genet 42 (9): 764–767. doi:
10.1038/ng.649. Epub 2010 Aug 22. PMID: 20729852; PMCID:
PMC2947317.
Agrawal, N., Jiao, Y., Bettegowda, C. et al. (2012 October). Comparative
genomic analysis of esophageal adenocarcinoma and squamous cell
carcinoma. Cancer Discov 2 (10): 899–905. doi: 10.1158/2159-8290.
CD-12-0189. Epub 2012 Aug 9. PMID: 22877736; PMCID: PMC3473124.
Backert, S., Tegtmeyer, N., Oyarzabal, O.A. et al. (2018 June 21). Unusual
Manifestation of Live Staphylococcus saprophyticus, Corynebacterium
urinapleomorphum, and Helicobacter pylori in the Gallbladder with
Cholecystitis. Int J Mol Sci 19 (7): 1826. doi: 10.3390/ijms19071826.
PMID: 29933576; PMCID: PMC6073424.
Barber, M., Murrell, A., Ito, Y. et al. (2008 November). Mechanisms and
sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J
Pathol 216 (3): 295–306. doi: 10.1002/path.2426. PMID: 18788075.
Bartley, A.N., Washington, M.K., Ventura, C.B. et al. (2016 December).
HER2 testing and clinical decision making in gastroesophageal
adenocarcinoma: guideline from the college of American pathologists,
American society for clinical pathology, and American society of clinical
oncology. Am J Clin Pathol. 146 (6): 647–669. doi: 10.1093/ajcp/aqw206.
Epub 2016 Nov 14. PMID: 28077399; PMCID: PMC6272805.
Bennett, C., Moayyedi, P., Corley, D.A. et al. (2015 May). BOB CAT
Consortium. BOB CAT: a large-scale review and delphi consensus for
management of Barrett’s Esophagus With No Dysplasia, Indefinite for,
or Low-Grade Dysplasia. Am J Gastroenterol 110 (5): 662–682.
Bertz, S., Angeloni, M., Drgac, J. et al. (2021 January 5). Helicobacter
infection and gastric adenoma. Microorganisms 9 (1): 108. doi: 10.3390/
microorganisms9010108. PMID: 33466325; PMCID: PMC7824786.
Blair, V.R., McLeod, M., Carneiro, F. et al. (2020 August). Hereditary diffuse
gastric cancer: updated clinical practice guidelines. Lancet Oncol 21 (8):
e386–e397. doi: 10.1016/S1470-2045(20)30219-9. PMID: 32758476;
PMCID: PMC7116190.
Borchard F. Formen und Nomenklatur der gastrointestinalen
Epithelexpansion: Was ist Invasion? [Forms and nomenclature of
gastrointestinal epithelial expansion: what is invasion?]. Verh Dtsch Ges
Pathol. 2000;84:50-61. German. PMID: 11217449.
Cancer Genome Atlas Research Network (2014). Comprehensive molecular
characterization of gastric adenocarcinoma. Nature 513: 202–209.
Carneiro, F., Fukayama, M., Grabsch, H.I., and Yasui, W. (2019). Gastric
adenocarcinoma in the book: digestive system tumors: WHO classification
of tumors editorial board in 5th Edition. Chapter 3: 85–95.
Cecchi, F., Rabe, D.C., and Bottaro, D.P. (2012 June). Targeting the HGF/
Met signaling pathway in cancer therapy. Expert Opin Ther Targets 16
(6): 553–572. doi: 10.1517/14728222.2012.680957. Epub 2012 Apr 25.
PMID: 22530990; PMCID: PMC3711667.
Cho, J.Y., Lim, J.Y., Cheong, J.H. et al. (2011 April 1). Gene expression
signature-based prognostic risk score in gastric cancer. Clin Cancer Res
17 (7): 1850–1857. doi: 10.1158/1078-0432.CCR-10-2180. Epub 2011
Mar 29. PMID: 21447720; PMCID: PMC3078023.
Cho, S.Y., Park, J.W., Liu, Y. et al. (2017). Sporadic Early-Onset Di_use
gastric cancers have high frequency of somatic CDH1 alterations, but
low frequency of somatic RHOA mutations compared with late-onset
cancers. Gastroenterology 153: 536–549.
Crabb, D.W., Berk, M.A., Hall, T.R. et al. (1985 July). Familial
gastroesophageal reflux and development of Barrett’s esophagus. Ann
Intern Med 103 (1): 52–54. doi: 10.7326/0003-4819-103-1-52. PMID:
4003988.
Digestive System Tumours WHO Classification of Tumours. (2019).
Volume 1 WHO classification of tumours editorial board, 5e. IARC Press
Lyon.
Dong, J., Maj, C., Tsavachidis, S. et al. (2013). Sex-specific genetic
associations for Barrett’s Esophagus and Esophageal Adenocarcinoma.
Gastroenterology 159 (6): 2065–2076.e1. doi: 10.1053/j.gastro.2020.08.052.
Epub 2020 Sep 9. PMID: 32918910.
38 1 UPPER GASTROINTESTINAL CANCER
https://t.me/medicina_free
Drovdlic, C.M., Goddard, K.A., Chak, A. et al. (2003 September).
Demographic and phenotypic features of 70 families segregating
Barrett’s oesophagus and oesophageal adenocarcinoma. J Med Genet 40
(9): 651–656. DOI: 10.1136/jmg.40.9.651. PMID: 12960209; PMCID:
PMC1735581.
Elster, K. (1976). Histologic classification of gastric polyps. In: Pathology of
the Gastro-intestinal Tract (ed. B.C. Morson), 78–92. Berlin: Springer.
Eng, C., Spechler, S.J., Ruben, R., and Li, F.P. (1993 July-August). Familial
Barrett esophagus and adenocarcinoma of the gastroesophageal
junction. Cancer Epidemiol Biomarkers Prev. 2 (4): 397–399. Erratum in:
(1993 September-October). Cancer Epidemiol Biomarkers Prev 2 (5):
505. PMID: 8348064.
Everhart, C.W., Jr, Holtzapple, P.G., and Humphries, T.J. (1983 August).
Barrett’s esophagus: inherited epithelium or inherited reflux? J Clin
Gastroenterol 5 (4): 357–358. PMID: 6886360.
Fahmy, N. and King, J.F. (1993 August). Barrett’s esophagus: an acquired
condition with genetic predisposition. Am J Gastroenterol 88 (8): 1262–
1265. PMID: 8338095.
Fecteau, R.E., Kong, J., Kresak, A. et al. (2016 October 1). Association
between Germline mutation in VSIG10L and Familial Barrett Neoplasia.
JAMA Oncol. 2(10):1333–1339. doi: 10.1001/jamaoncol.2016.2054.
PMID: 27467440; PMCID: PMC5063702.
Fitzgerald, R.C., Hardwick, R., Huntsman, D. et al. (2010 July). International
gastric cancer linkage consortium. Hereditary diffuse gastric cancer:
updated consensus guidelines for clinical management and directions
for future research. J Med Genet 47 (7): 436–444. doi: 10.1136/
jmg.2009.074237. Erratum in: (2011 March). J Med Genet 48 (3): 216.
Van Krieken, Nicola [corrected to Van Grieken, Nicola C]. PMID:
20591882; PMCID: PMC2991043.
Gaston, D., Hansford, S., Oliveira, C. et al. (2014 October 23). Germline
mutations in MAP3K6 are associated with familial gastric cancer. PLoS
Genet 10 (10): e1004669. doi: 10.1371/journal.pgen.1004669. PMID:
25340522; PMCID: PMC4207611.
Gayther, S.A., Gorringe, K.L., Ramus, S.J. et al. (1998 September 15).
Identification of germ-line E-cadherin mutations in gastric cancer
families of European origin. Cancer Res 58 (18): 4086–4089.
Gharahkhani, P., Fitzgerald, R.C., Vaughan, T.L. et al. (2016 October).
Genome-wide association studies in oesophageal adenocarcinoma and
Barrett’s oesophagus: a large-scale meta-analysis. Lancet Oncol 17 (10):
1363–1373. doi: 10.1016/S1470-2045(16)30240-6. Epub 2016 Aug 12.
PMID: 27527254; PMCID: PMC5052458.
Global Cancer observatory. (2020). https://GECo.iarc.fr/today/data/
factsheets/cancers/7-Stomach-fact-sheet.pdf
Groves, C., Jankowski, J., Barker, F., and Holdstock, G. (2005 September). A
family history of Barrett’s oesophagus: another risk factor? Scand J
Gastroenterol 40 (9): 1127–1128. doi: 10.1080/00365520510023189.
PMID: 16211720.
Guilford, P., Hopkins, J., Harraway, J. et al. (1998 March 26). E-cadherin
germline mutations in familial gastric cancer. Nature 392 (6674): 402–
405. doi: 10.1038/32918. PMID: 9537325.
Hackeng, W.M., Montgomery, E.A., Giardiello, F.M. et al. (2017 March).
Morphology and genetics of pyloric gland adenomas in familial
adenomatous polyposis. Histopathology 70 (4): 549–557. doi: 10.1111/
his.13105. Epub 2016 Dec 13. PMID: 27767239; PMCID: PMC5300963.
Hansford, S., Kaurah, P., Li-Chang, H. et al. (2015 April). Hereditary diffuse
gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol 1
(1): 23–32. doi: 10.1001/jamaoncol.2014.168. Erratum in: (2015 April).
JAMA Oncol 1 (1): 110. PMID: 26182300.
Helgason, H., Rafnar, T., Olafsdottir, H.S. et al. (2015 August). Loss-of-
function variants in ATM confer risk of gastric cancer. Nat Genet 47 (8):
906–910. doi: 10.1038/ng.3342. Epub 2015 Jun 22. PMID: 26098866.
Hu, N., Wang, Z., Song, X. et al. (2016 October). Genome-wide association
study of gastric adenocarcinoma in Asia: a comparison of associations
between cardia and non-cardia tumours. Gut 65 (10):1611–1618.
doi: 10.1136/gutjnl-2015-309340. Epub 2015 Jun 30. PMID: 26129866;
PMCID: PMC5568652.
Huang, K.L., Mashl, R.J., Wu, Y. et al. . (2018 April 5). Pathogenic Germline
variants in 10,389 adult cancers. Cell 173 (2): 355–370.e14. doi: 10.1016/j.
cell.2018.03.039. PMID: 29625052; PMCID: PMC5949147.
Ilson, D.H., Moughan, J., Suntharalingam, M. et al. (2014). RTOG 0436: a
phase III trial evaluating the addition of cetuximab to paclitaxel,
cisplatin, and radiation for patients with esophageal cancer treated
without surgery [ASCO abstract 4007]. J Clin Oncol 32 (15).
doi: 10.1200/jco.2014.32.15_suppl.4007.
Janjigian, Y.Y., Werner, D., Pauligk, C. et al. (2012 October). Prognosis of
metastatic gastric and gastroesophageal junction cancer by HER2 status:
a European and USA International collaborative analysis. Ann Oncol. 23
(10): 2656–2662. doi: 10.1093/annonc/mds104. Epub 2012 Jun 11.
PMID: 22689179.
Jankowski, J.A. and Satsangi, J. (2013 April). Barrett’s esophagus:
evolutionary insights from genomics. Gastroenterology 144 (4): 667–
669. doi: 10.1053/j.gastro.2013.02.014.Epub 2013 Feb 21.
Jankowski, J.A., Wright, N.A., Meltzer, S.J. et al. (1999 April). Molecular
evolution of the metaplasia-dysplasia-adenocarcinoma sequence in the
esophagus. Am J Pathol 154 (4): 965–973. doi: 10.1016/S0002-9440
(10)65346-1.
Jee, C.D., Kim, M.A., Jung, E.J. et al. (2009 May). Identification of genes
epigenetically silenced by CpG methylation in human gastric carcinoma.
Eur J Cancer 45 (7): 1282–1293. doi: 10.1016/j.ejca.2008.12.027. Epub
2009 Feb 3. PMID: 19195878.
Jin, G., Ma, H., Wu, C. et al. (2012 November 2). Genetic variants at 6p21.1
and 7p15.3 are associated with risk of multiple cancers in Han Chinese.
Am J Hum Genet. 91(5):928–934. doi: 10.1016/j.ajhg.2012.09.009. Epub
2012 Oct 25. PMID: 23103227; PMCID: PMC3487121.
Jochem, V.J., Fuerst, P.A., and Fromkes, J.J. (1992 April). Familial Barrett’s
esophagus associated with adenocarcinoma. Gastroenterology 102 (4 Pt
1): 1400–1402. PMID: 1551547.
Jones, E.G. (1964 May). Familial Gastric Cancer. N Z Med J 63: 287–296.
PMID: 14158754.
Kakiuchi, M., Nishizawa, T., Ueda, H. et al. (2014 June). Recurrent gain-of-
function mutations of RHOA in diffuse-type gastric carcinoma. Nat
Genet 46 (6): 583–587. doi: 10.1038/ng.2984. Epub 2014 May 11. PMID:
24816255.
Kang, G.H., Lee, S., Kim, J.S., and Jung, H.Y. (2003 April). Profile of
aberrant CpG island methylation along multistep gastric carcinogenesis.
Lab Invest 83 (4): 519–526. doi: 10.1097/01.lab.0000064704.53132.65.
Erratum in: Lab Invest 2003 Jul;83(7):1093. PMID: 12695555.
Kim, K.M., Kwon, M.S., Hong, S.J. et al. (2003 October). Genetic
classification of intestinal-type and diffuse-type gastric cancers based on
chromosomal loss and microsatellite instability. Virchows Arch 443 (4):
491–500. doi: 10.1007/s00428-003-0840-0. Epub 2003 Aug 15. PMID:
12920592.
2 GENOMICS, MOLECULAR PATHOLOGY, AND PATHOLOGY OF ESOPHAGEAL AND GASTRIC CANCER 39
https://t.me/medicina_free
Kim, T.Y., Jong, H.S., Jung, Y. et al. (2004 July). DNA hypermethylation in
gastric cancer. Aliment Pharmacol Ther 20 (Suppl 1): 131–142.
doi: 10.1111/j.1365-2036.2004.01984.x. PMID: 15298619.
Krompecher, E. (1924). Basalzellen, Metaplasie und Regeneration. Beitr
path Anat 72: 163–183. (2004). Pneumologie 58 (9): 680–685. DOI:
10.1055/ s-2004-818417.
Kushima, R., Sekine, S., Matsubara, A. et al. (2013 June). Gastric
adenocarcinoma of the fundic gland type shares common genetic and
phenotypic features with pyloric gland adenoma. Pathol Int 63 (6): 318–
325. doi: 10.1111/pin.12070. PMID: 23782334.
Kwon, C.H., Kim, Y.K., Lee, S. et al. (2018 March). Gastric poorly cohesive
carcinoma: a correlative study of mutational signatures and prognostic
significance based on histopathological subtypes. Histopathology 72 (4):
556–568. doi: 10.1111/his.13383. Epub 2017 Nov 29. PMID: 28873240.
Le, D.T., Uram, J.N., Wang, H. et al. (2015 June 25). PD-1 blockade in
tumors with mismatch-repair deficiency. N Engl J Med. 372 (26): 2509–
2520. doi: 10.1056/NEJMoa1500596. Epub 2015 May 30. PMID:
26028255; PMCID: PMC4481136.
Lennerz, J.K., Kwak, E.L., Ackerman, A. et al. (2011). MET amplification
identifies a small and aggressive subgroup of esophagogastric
adenocarcinoma with evidence of responsiveness to crizotinib. J Clin
Oncol 29 (36): 4803–4810. doi: 10.1200/JCO.2011.35.4928. Epub 2011
Oct 31. PMID: 22042947; PMCID: PMC3255989.
Lichtenstein, P., Holm, N.V., Verkasalo, P.K. et al. (2000 July 13)
Environmental and heritable factors in the causation of cancer–analyses
of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med
343 (2): 78–85. doi: 10.1056/NEJM200007133430201. PMID: 10891514.
Lott, P.C. and Carvajal-Carmona, L.G. (2018 December). Resolving gastric
cancer aetiology: an update in genetic predisposition. Lancet Gastroenterol
Hepatol 3 (12): 874–883. doi: 10.1016/S2468-1253(18)30237-1. PMID:
30507471; PMCID: PMC6500447.
Majewski, I.J., Kluijt, I., Cats, A. et al. (2013 March). An α-E-catenin
(CTNNA1) mutation in hereditary diffuse gastric cancer. J Pathol. 229
(4): 621–629. doi: 10.1002/path.4152. PMID: 23208944.
Melzer, E., Shtoyerman, R., Appelman, Z., and Kashtan, H. (2006 March).
Familial Barrett’s adenocarcinoma. Am J Gastroenterol 101 (3):677.
doi: 10.1111/j.1572-0241.2006.473_7.x. PMID: 16542304.
Mikhail, S., Ciombor, K., Noonan, A. et al. (2015 September 8). Upfront
molecular testing in patients with advanced gastro-esophageal cancer: is
it time yet? Oncotarget 6 (26): 22206–22213. doi: 10.18632/
oncotarget.4247. PMID: 26082439; PMCID: PMC4673157.
Müller-Höcker, J. and Rellecke, P. (2003 May). Chief cell proliferation of the
gastric mucosa mimicking early gastric cancer: an unusual variant of
fundic gland polyp. Virchows Arch. 442 (5): 496–500. doi: 10.1007/
s00428-003-0780-8. Epub 2003 Apr 16. PMID: 12698365.
Munitiz, V., Parrilla, P., Ortiz, A. et al. (2008 August). High risk of
malignancy in familial Barrett’s esophagus: presentation of one family. J
Clin Gastroenterol. 42 (7): 806–809. doi: 10.1097/MCG.0b013e3180329015.
PMID: 18385604.
Muro, K., Chung, H.C., Shankaran, V. et al.(2016 June) Pembrolizumab for
patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a
multicentre, open-label, phase 1b trial. Lancet Oncol. 2016 Jun;17(6):717–
726. doi: 10.1016/S1470-2045(16)00175-3. PMID: 27157491.
Oliveira, C., Pinheiro, H., Figueiredo, J. et al. (2015 February). Familial
gastric cancer: genetic susceptibility, pathology, and implications for
management. Lancet Oncol 16 (2): e60–70. doi: 10.1016/S1470-
2045(14)71016-2. PMID: 25638682.
Oliveira, C., Seruca, R., Hoogerbrugge, N. et al. (2013 August). Clinical
utility gene card for: hereditary diffuse gastric cancer (HDGC). Eur J
Hum Genet 21 (8). doi: 10.1038/ejhg.2012.247. Epub 2013 Feb 27.
PMID: 23443028; PMCID: PMC3722670.
Park, C., Cho, J., Lee, J. et al. (2017 August 10). Host immune response index
in gastric cancer identified by comprehensive analyses of tumor immunity.
Oncoimmunology 6 (11): e1356150. doi: 10.1080/2162402X.2017.1356150.
PMID: 29147610; PMCID: PMC5674954.
Pharoah, P.D., Guilford, P., and Caldas, C. (2001 December). International
gastric cancer linkage consortium. Incidence of gastric cancer and breast
cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse
gastric cancer families. Gastroenterology 121 (6): 1348–1353.
doi: 10.1053/gast.2001.29611. PMID: 11729114.
Poynton, A.R., Walsh, T.N., O’Sullivan, G., and Hennessy, T.P. (1996
September). Carcinoma arising in familial Barrett’s esophagus. Am J
Gastroenterol 91 (9): 1855–1856. PMID: 8792715.
Ratti, M., Lampis, A., Hahne, J.C. et al. (2018 November). Microsatellite
instability in gastric cancer: molecular bases, clinical perspectives, and
new treatment approaches. Cell Mol Life Sci 75 (22): 4151–4162.
doi: 10.1007/s00018-018-2906-9. Epub 2018 Sep 1. PMID: 30173350;
PMCID: PMC6182336.
Refolo, M.G., Lotesoriere, C., Messa, C. et al. (2020 August). Integrated
immune gene expression signature and molecular classification in
gastric cancer: new insights. J Leukoc Biol 108 (2): 633–646. doi: 10.1002/
JLB.4MR0120-221R. Epub 2020 Mar 14. PMID: 32170872.
Reid, B.J., Li, X., Galipeau, P.C., and Vaughan, T.L. (2010 February).
Barrett’s oesophagus and oesophageal adenocarcinoma: time for a new
synthesis. Nat Rev Cancer 10 (2): 87–101. doi: 10.1038/nrc2773. PMID:
20094044; PMCID: PMC2879265.
Rentien, A.L., Lévy, M., Copie-Bergman, C. et al. (2018 February). Long-
term course of precancerous lesions arising in patients with gastric
MALT lymphoma. Dig Liver Dis 50 (2): 181–188. doi: 10.1016/j.
dld.2017.10.014. Epub 2017 Oct 27. PMID: 29102522.
Rodriquenz, M.G., Roviello, G., D’Angelo, A. et al. (2020 May 11). MSI and
EBV positive gastric cancer’s subgroups and their link with novel
immunotherapy. J Clin Med 9 (5): 1427. doi: 10.3390/jcm9051427.
PMID: 32403403; PMCID: PMC7291039.
Study Group of Millennium Genome Project for Cancer Sakamoto, H.,
Yoshimura, K., Saeki, N. et al. (2008 June). Genetic variation in PSCA is
associated with susceptibility to diffuse-type gastric cancer. Nat Genet
40 (6): 730–740. doi: 10.1038/ng.152. Epub 2008 May 18. PMID:
18488030.
Sakurai, U., Lauwers, G.Y., Vieth, M. et al. (2014 November). Gastric high-
grade dysplasia can be associated with submucosal invasion: evaluation
of its prevalence in a series of 121 endoscopically resected specimens. Am
J Surg Pathol 38 (11): 1545–1550. doi: 10.1097/PAS.0000000000000274.
PMID: 25310837.
Sappati Biyyani, R.S., Chessler, L., McCain, E. et al. (2007). Familial trends
of inheritance in gastro esophageal reflux disease, Barrett’s esophagus
and Barrett’s adenocarcinoma: 20 families. Dis Esophagus 20 (1): 53–57.
doi: 10.1111/j.1442-2050.2007.00651.x. PMID: 17227311.
Schlemper, R.J., Itabashi, M., Kato, Y. et al. (1997 June 14) Differences in
diagnostic criteria for gastric carcinoma between Japanese and western
pathologists. Lancet 349 (9067): 1725–1729. doi: 10.1016/S0140-6736(96)
12249-2. Erratum in: Lancet 1997 Aug 16;350(9076):524. PMID: 9193382.
Schlemper, R.J., Kato, Y., and Stolte, M. (2001 July). Review of histological
classifications of gastrointestinal epithelial neoplasia: differences in
40 1 UPPER GASTROINTESTINAL CANCER
https://t.me/medicina_free
diagnosis of early carcinomas between Japanese and Western pathologists.
J Gastroenterol 36 (7): 445–456. doi: 10.1007/s005350170067. PMID:
11480788.
Shah, M.A., Khanin, R., Tang, L. et al. (2011 May 1). Molecular classification
of gastric cancer: a new paradigm. Clin Cancer Res 17 (9): 2693–2701.
doi: 10.1158/1078-0432.CCR-10-2203. Epub 2011 Mar 23. PMID:
21430069; PMCID: PMC3100216.
Shen, L., Li, J., Xu, J. et al. (2015 January). Bevacizumab plus capecitabine
and cisplatin in Chinese patients with inoperable locally advanced or
metastatic gastric or gastroesophageal junction cancer: randomized,
double-blind, phase III study (AVATAR study). Gastric Cancer 18 (1):
168–176. doi: 10.1007/s10120-014-0351-5. Epub 2014 Feb 21. PMID:
24557418; PMCID: PMC4544634.
Shi, L., Zhao, M., Luo, Q. et al. (2010 June) Overexpression of PIP5KL1
suppresses cell proliferation and migration in human gastric cancer
cells. Mol Biol Rep 37 (5): 2189–2198. doi: 10.1007/s11033-009-9701-5.
Epub 2009 Aug 13. PMID: 19680787.
Shi, Y., Hu, Z., Wu, C. et al. (2011 October 30). A genome-wide association
study identifies new susceptibility loci for non-cardia gastric cancer at
3q13.31 and 5p13.1. Nat Genet 43 (12): 1215–1218. doi: 10.1038/ng.978.
PMID: 22037551.
Shibuya, M. (2011 December). Vascular Endothelial growth factor (VEGF)
and its receptor (VEGFR) signaling in angiogenesis: a crucial target for
anti- and pro-angiogenic therapies. Genes Cancer. 2(12):1097–1105.
doi: 10.1177/1947601911423031. PMID: 22866201; PMCID: PMC3411125.
Shimura, T., Toden, S., Kandimalla, R. et al. (2021 November 1).
Genomewide expression profiling identifies a novel miRNA-based
signature for the detection of peritoneal metastasis in patients with
gastric cancer. Ann Surg 274 (5): e425–e434. doi: 10.1097/
SLA.0000000000003647. PMID: 31663973; PMCID: PMC7577555.
Su, Z., Gay, L.J., Strange, A. et al. (2012 October). Common variants at the
MHC locus and at chromosome 16q24.1 predispose to Barrett’s
esophagus. Nat Genet 44 (10): 1131–1136. doi: 10.1038/ng.2408. Epub
2012 Sep 9.
Syngal, S., Brand, R.E., Church, J.M. et al. (2015 February). American
College of Gastroenterology. ACG clinical guideline: genetic testing and
management of hereditary gastrointestinal cancer syndromes. Am J
Gastroenterol 110 (2): 223–262. quiz 263. doi: 10.1038/ajg.2014.435.
Epub 2015 Feb 3. PMID: 25645574; PMCID: PMC4695986.
Takahashi, T. and Iwama, N. (1985). Three-dimensional microstructure of
gastrointestinal tumors. Gland pattern and its diagnostic significance.
Pathol Annu 20 Pt 1: 419–440. PMID: 3887299.
Tan, I.B., Ivanova, T., Lim, K.H. et al. (2011 August). Intrinsic subtypes of
gastric cancer, based on gene expression pattern, predict survival and
respond differently to chemotherapy. Gastroenterology. 141 (2): 476–85,
485.e1–11. doi: 10.1053/j.gastro.2011.04.042. Epub 2011 Apr 28. PMID:
21684283; PMCID: PMC3152688.
Taylor, P.R., Abnet, C.C., and Dawsey, S.M. (2013 April). Squamous
dysplasia–the precursor lesion for esophageal squamous cell carcinoma.
Cancer Epidemiol Biomarkers Prev 22 (4): 540–552. doi: 10.1158/1055-
9965.EPI-12-1347. PMID: 23549398; PMCID: PMC3681095.
Tew, W.P., Kelsen, D.P., and Ilson, D.H. (2005 September). Targeted
therapies for esophageal cancer. Oncologist 10 (8): 590–601. doi: 10.1634/
theoncologist.10-8-590. PMID: 16177283.
To, H., Clemons, N.J., Duong, C.P. et al. (2016 July). The genetics of Barrett’s
Esophagus: a Familial and Population-Based Perspective. Dig Dis Sci 61
(7): 1826–1834. doi: 10.1007/s10620-016-4109-2. Epub 2016 Mar 12.
PMID: 26971090.
To, K.F., Leung, W.K., Lee, T.L. et al. (2002 December 20). Promoter
hypermethylation of tumor-related genes in gastric intestinal metaplasia of
patients with and without gastric cancer. Int J Cancer. 2002 Dec
20;102(6):623-8. doi: 10.1002/ijc.10783. PMID: 12448005.
Ueda, T., Volinia, S., Okumura, H. et al. (2010 February). Relation between
micro RNA expression and progression and prognosis of gastric cancer:
a microRNA expression analysis. Lancet Oncl 11 (2): 136–146; PMID:
20022810.
Ushiku, T., Kunita, A., Kuroda, R. et al. (2020 February). Oxyntic gland
neoplasm of the stomach: expanding the spectrum and proposal of
terminology. Mod Pathol 33(2):206–216. doi: 10.1038/s41379-019-0338-
1. Epub 2019 Aug 2. PMID: 31375767.
van Nistelrooij, A.M.J., van Marion, R., van Ijcken, W.F.J. et al. (2018 July).
Germline variant in MSX1 identified in a Dutch family with clustering
of Barrett’s esophagus and esophageal adenocarcinoma. Fam Cancer 17
(3): 435–440. doi: 10.1007/s10689-017-0054-2. PMID: 29134539;
PMCID: PMC5999157.
Vieth, M., Kushima, R., Borchard, F., and Stolte, M. (2003 April) Pyloric
gland adenoma: a clinico-pathological analysis of 90 cases. Virchows
Arch 442 (4): 317–321. doi: 10.1007/s00428-002-0750-6. Epub 2003 Mar
26. PMID: 12715167.
Vieth, M., Montgomery, E.A., and Riddell, R.H. (2016). Observations of
different patterns of dysplasia in barretts esophagus - a first step to
harmonize grading. Cesk Patol 52 (3): 154–163. English. PMID:
27526016.
Vieth, M. and Stolte, M. (2005). Distinction of High-Grade Intraepithelial
Neoplasia and Tubular Gastric Adenocarcinoma. In: The Diversity of
Gastric Carcinoma (ed. M. Kaminishi, K. Takubo, and K. Mafune).
Tokyo: Springer. doi: 10.1007/4-431-27713-7_7.
Vieth, M. and Stolte, M. (2005 December). Pathology of early upper GI
cancers. Best Pract Res Clin Gastroenterol. 19 (6): 857–869. doi: 10.1016/j.
bpg.2005.02.008 PMID: 16338646.
Wanebo, H.J., Kennedy, B.J., Chmiel, J. et al. (1993 November). Cancer of
the stomach. A patient care study by the American College of Surgeons.
Ann Surg. 218 (5): 583–592. doi: 10.1097/00000658-199321850-00002.
PMID: 8239772; PMCID: PMC1243028.
Wang, C., Wang, L., Liang, B. et al. (2021 May). Synergistic antitumor effect
of the anti-ErbB2 antibodies trastuzumab and H2-18 on trastuzumabresistant gastric cancer cells. Oncol Lett 21 (5): 400. doi: 10.3892/
ol.2021.12661. Epub 2021 Mar 18. PMID: 33777223; PMCID:
PMC7988693.
Wang, K., Yuen, S.T., Xu, J. et al. (2014 June). Whole-genome sequencing
and comprehensive molecular profiling identify new driver mutations in
gastric cancer. Nat Genet 46 (6): 573–582. doi: 10.1038/ng.2983. Epub
2014 May 11. PMID: 24816253.
Wang, Z., Dai, J., Hu, N. et al. (2017 April). Identification of new
susceptibility loci for gastric non-cardia adenocarcinoma: pooled results
from two Chinese genome-wide association studies. Gut 66 (4): 581–
587. doi: 10.1136/gutjnl-2015-310612. Epub 2015 Dec 23. PMID:
26701879; PMCID: PMC4963301.
Wei, B., Tai, Y., Tong, H. et al. (2017 August 1). Correlations between
VEGF-A expression and prognosis in patients with gastric
adenocarcinoma. Int J Clin Exp Pathol 10 (8): 8461–8469. PMID:
31966698; PMCID: PMC6965380.
2 GENOMICS, MOLECULAR PATHOLOGY, AND PATHOLOGY OF ESOPHAGEAL AND GASTRIC CANCER 41
https://t.me/medicina_free
Westerterp, M., Koppert, L.B., Buskens, C.J. et al. (2005 May). Outcome of
surgical treatment for early adenocarcinoma of the esophagus or gastro-
esophageal junction. Virchows Arch 446 (5): 497–504. doi: 10.1007/
s00428-005-1243-1. Epub 2005 Apr 19. PMID: 15838647.
Wilke, H., Van Cutsem, E., Oh, S.C. et al. (2014). RAINBOW: a global,
phase 3, randomized, double-blind study of ramucirumab plus paclitaxel
versus placebo plus paclitaxel in the treatment of metastatic gastric
adenocarcinoma following disease progression on first-line platinum-
and fluoropyrimidine-containing combination therapy: results of a
multiple Cox regression analysis adjusting for prognostic factors. J Clin
Oncol 32 (15): 10.1200.
Wong, S.S., Kim, K.M., Ting, J.C. et al. (2014 November 19 Genomic
landscape and genetic heterogeneity in gastric adenocarcinoma revealed
by whole-genome sequencing. Nat Commun 5: 5477. doi: 10.1038/
ncomms6477 PMID: 25407104.
Wu, M.S., Chang, M.C., Huang, S.P. et al. (2001 January). Correlation of
histologic subtypes and replication error phenotype with comparative
genomic hybridization in gastric cancer. Genes Chromosom Cancer 30 (1):
80–86. doi: 10.1002/1098-2264(2000)9999:9999<::aid-gcc1062>3.0.co;2-r.
PMID: 11107179.
Yan, C., Zhu, M., Ding, Y. et al. (2020 April). Meta-analysis of genome-wide
association studies and functional assays decipher susceptibility genes
for gastric cancer in Chinese populations. Gut 69 (4): 641–651. doi:
10.1136/gutjnl-2019-318760. Epub 2019 Aug 5. PMID: 31383772.
Yao X, Ajani JA, Song S. Molecular biology and immunology of gastric
cancer peritoneal metastasis. Transl Gastroenterol Hepatol. 2020 Oct
5;5:57. doi: 10.21037/tgh.2020.02.08. PMID: 33073052; PMCID:
PMC7530317.
Yoon, H.H., Bendell, J.C., Braiteh, F.S. et al. (2016 December). Ramucirumab
combined with FOLFOX as front-line therapy for advanced esophageal,
gastroesophageal junction, or gastric adenocarcinoma: a randomized,
double-blind, multicenter Phase II trial. Ann Oncol 27 (12): 2196–2203.
doi: 10.1093/annonc/mdw423. Epub 2016 Oct 20. Erratum in: Ann
Oncol. 2019 Dec 1;30(12):2016. PMID: 27765757; PMCID: PMC7360144.
Zanghieri, G., Di Gregorio, C., Sacchetti, C. et al. (1990 November 1). Familial
occurrence of gastric cancer in the 2-year experience of a population-based
registry. Cancer 66 (9): 2047–2051. doi: 10.1002/1097-0142(19901101)66:
9<2047::aid-cncr2820660934>3.0.co;2-g. PMID: 2224804.Format.
Zhang, T., Zhang, L., Fan, S. et al. (2015 July 28). Patient-derived gastric
carcinoma xenograft mouse models faithfully represent human tumor
molecular diversity. PLoS One 10 (7): e0134493. doi: 10.1371/journal.
pone.0134493. PMID: 26217940; PMCID: PMC4517891).
3 Screening, Surveillance, and Prevention
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of Esophageal and Gastric Cancers
Khairul Najmi Muhammad Nawawi
Raja A.R. Ali
1
Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
2
UNSW Microbiome Research Centre, St. George and Sutherland Clinical Campuses, School of Clinical Medicine, Faculty of Health and Medicine,
University of New South Wales, Sydney, New South Wales, Australia
3
GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
4
School of Medical and Life Sciences, Sunway University, Selangor, Malaysia
[Aspects of relevant colorectal data are covered in Chapter 11].
Introduction
Upper gastrointestinal (GI) cancers remain among the most
important cancers worldwide. In 2020, gastric cancer ranked fifth
(1,089,103 new cases, 5.6%) in terms of incidence and fourth
(768,793 deaths, 7.7%) in terms of mortality globally (Sung et al.
2021). However, in South Central Asian countries such as Iran,
Afghanistan, and Turkmenistan, it is the leading cause of cancerrelated deaths. Esophageal cancer ranks seventh in terms of incidence (604,100 new cases, 3.1%) and sixth in terms of mortality
(544,076 deaths, 5.5%) (Sung et al. 2021). The incidence of esophageal cancer varies according to histologic subtypes and geography. The highest incidence rates of esophageal adenocarcinoma
(EAC) are in the Netherlands (age-standardized rate (ASR): 7.7)
and the United Kingdom (ASR: 7.5), while Malawi (ASR: 21),
Mongolia (ASR: 20.9), Kenya (ASR: 20.3), and China (ASR: 18.8)
are among the countries with the highest incidence of esophageal
squamous cell carcinoma (ESCC) (Huang et al. 2021).
The prognosis of upper GI cancers is generally poor, mainly
due to their late diagnosis. For example, the overall five-year
survival rate for patients with esophageal cancer is below 20%,
although the rate can be improved to nearly 50% with neoadjuvant chemoradiotherapy and surgery (Huang et al. 2021;
Shapiro et al. 2015). Similarly, the survival rate among patients
with gastric cancer is less than 10% when the cancer is diagnosed at an advanced stage but is significantly improved, by up
to 85%, if it is detected early (Wang et al. 2004). Due to the
aggressive nature of these cancers, it is critical to detect the precursor lesions/early cancers. In the long run, the aim is to
reduce the disease burden, reverse the incidence trend, and
eventually improve the patients’ outcomes. In this chapter, the
Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach,
Second Edition. Edited by Janusz A. Z. Jankowski.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
1,3,4
1,3
, Emad M. El-Omar2 &
risk factors, screening, and surveillance strategies, and preventive measures for upper GI cancers – namely, esophageal and
gastric cancers – will be discussed.
Esophageal Cancer
Risk Factors for Esophageal Adenocarcinoma
Non-modifiable Risk Factors
The incidence of EAC increases with age, especially after the age
of 50 years, with a significant male predilection (6- to 8-fold
higher risk than females) (Bhat et al. 2011). Compared to ESCC,
EAC is more prevalent in the West. Data from the cancer registry
in the United States (Surveillance, Epidemiology, and End Results
(SEER)) demonstrated a five-times higher incidence rate of EAC
among whites compared to that among blacks. Compared with
Hispanics, whites had a 200% increased risk of EAC (Cook et al.
2009). Although there is no recognized familial syndrome related
to EAC, some studies that evaluated the role of germline mutation
in EAC development have found a few susceptible genetic loci,
such as TBX1, FOXP1, FOXF1, BARX1, HLA, and CRTC1
(Levine et al. 2013; Su et al. 2012). However, the use of genetics in
clinical practice to predict the risk of EAC is still limited and it
does not offer greater sensitivity when used in combination with
other EAC risk factors (Dong et al. 2018) (see Table 1).
Modifiable Risk Factors
Obesity has become a global pandemic and is associated with a
higher risk of getting major non-communicable diseases,
including type 2 diabetes, coronary heart disease, stroke, and cancers. A recent meta-analysis that included more than 280 population-based studies worldwide has estimated a global prevalence of
central obesity in adults to be 41.5%; it was 31.3% in the 1990s
(Wong et al. 2020). Obesity has been linked to the development of
EAC via, for example, a higher prevalence of gastroesophageal
42
3 SCREENING, SURVEILLANCE, AND PREVENTION OF ESOPHAGEAL AND GASTRIC CANCERS 43
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Table 1 Non-modifiable and modifiable risk factors.
Types of cancers Risk factors
Non-modifiable Modifiable
Esophageal adenocarcinoma Age > 50 years
Male sex
White race
Family history
Germline mutation: TBX1, FOXP1, FOXF1, BARX1, HLA, CRTC1
Esophageal squamous cell
carcinoma
Gastric cancer Age > 50 years
GERD, gastroesophageal reflux disease; HDGC, hereditary diffuse gastric cancer.
Male sex (in low-prevalence area such as the United State male-to-female
ratio = 4:1)
Germline mutation: PLCE1, TP53, HLA II, CDKN2A, cyclin D1, CDK4/6, RB1,
NFE2L2, CHEK1, CHEK2, NOTCH1, NOTCH3
Associated Diseases:
Tylosis
Achalasia
Head and neck squamous cell carcinoma
Male sex (5-fold for cardia, 2-fold for non-cardia)
Family history
East Asian countries
Hereditary syndromes:
HDGC
Peutz-Jeghers syndrome
Juvenile polyposis
Lynch syndrome
Hereditary breast/ovarian cancer syndrome
Familial adenomatous polyposis
Chronic GERD symptoms
Cigarette smoking
Processed meat intake
Cigarette smoking
Alcohol consumption
Pickled vegetables
High-temperature drinks
Helicobacter pylori infection
Cigarette smoking
Obesity (cardia type)
Moderate-high salt intake
Pickled/smoked/dried foods
Western/unhealthy diet
Red/processed meat intake
reflux disease (GERD), higher incidence of Barrett’s esophagus
(BE), the role of systemic inflammation and adipokines, alteration of esophageal microbiota due to high-fat diets, and the
effect of insulin resistance (Schlottmann et al. 2020).
GERD is a well-documented risk factor for EAC. A landmark
Swedish-population-based case-control study in 1999 demonstrated an odds ratio (OR) of 7.7 for EAC in individuals with
recurrent reflux symptoms. The likelihood of EAC was much
higher in those with long-standing and severe reflux symptoms
(OR: 43.5), and this risk was not associated with ESCC (OR: 1.1)
(Lagergren et al. 1999). Obese individuals are more likely to
experience GERD symptoms. In a cross-sectional study
involving 453 volunteers, a dose–response relationship between
the frequency of GERD symptoms and a higher body mass
index (BMI) was found, whereby 35% of symptomatic individuals were overweight (BMI 25–30) and 39% were obese (BMI >
30) (El-Serag et al. 2005). Many studies have also shown a
positive association between obesity, central adiposity, and a
higher waist-to-hip ratio with BE (Baik et al. 2017; Edelstein et
al. 2007; Stein et al. 2005). In addition, the mean BMI was found
to be higher in patients with long-segment BE as compared to
those with short-segment BE (32.7 vs. 30.3, P = 0.001) (Abdallah
et al. 2015). The higher prevalence of BE in obesity is most likely
due to the co-existing GERD, although this association may not
be related to the presence of GERD, as shown by a meta-analysis
of 17 studies (adjusted OR: 1.98) (Singh et al. 2013a).
Apart from the reflux phenomenon, systemic inflammation and adipokines (e.g., adiponectin and leptin) have also
been implicated in EAC in obese individuals. Adiponectin
regulates cell proliferation, induces apoptosis, inhibits
growth factors, and has anti-inflammatory effects (Barb
et al. 2007). The plasma level of adiponectin has been shown
to be inversely associated with other cancers, such as breast,
endometrial, and colorectal cancers (Dal Maso et al. 2004;
Tworoger et al. 2007; Wei et al. 2005). Specific to esophageal
adenocarcinoma, a high level of adiponectin was associated
with a less advanced tumor stage (Howard et al. 2014) and a
lower risk of BE progression to adenocarcinoma (Duggan
et al. 2013). Leptin, however, was shown to be positively associated with BE (adjusted OR: 3.25) (Rubenstein et al. 2013).
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