CLINICAL REVIEW
Etiology and Pathogenesis of Idiopathic Achalasia
Amanda Pressman, MD and Jose Behar, MD
Abstract: This review examines the etiology and pathogenesis of
idiopathic achalasia. This disease is clinically characterized by
dysphagia of solids and liquids due to the presence of simultaneous
or absent esophageal contractions and impaired or absent relaxa-
tion of the lower esophageal sphincter. It includes a review of (a)
etiology and pathogenesis of this inflammatory process that dam-
age the ganglion cells of the Auerbach plexus that is limited to the
esophagus; (b) genetic abnormalities and polymorphisms asso-
ciated with this disease that may help explain its heterogeneity
expressed by the different motility abnormalities of its phenotypes
as well as differences in its clinical progression. These different
genetic abnormalities may be responsible for the slow progression
of types I or II phenotypes; (c) indirect evidence of viruses present
in these patients that may initiate its development; (d) the abnor-
malities of the muscle layer that may be responsible for the dilation
of the body of the esophagus that ultimately causes the sigmoid-like
esophagus in the very last phase of this disease. This progression to
the end-stage phase tends to occur in about 5% of patients. And,
(e) the chronic inflammatory abnormalities in the squamous
mucosa that may be the cause of the dysplastic and neoplastic
changes that may lead to squamous cell carcinoma whose incidence
in this disease is increased. These mucosal abnormalities are usually
present in patients with markedly dilated body of the esophagus
and severe food stasis.
Key Words: achalasia, esophagus, motility, etiology, pathogenesis,
Auerbach plexus, autoimmune mechanisms, polymorphisms,
viruses, squamous carcinoma
(J Clin Gastroenterol 2017;51:195–202)
I diopathic achalasia is a motility disorder clinically char-
acterized by dysphagia for solids and liquids, recurrent
episodes of spontaneous chest pain early in the disease and
in its late stages food regurgitation leading to weight loss
and pulmonary aspiration. The objective diagnosis is made
by a motility test that shows the presence of normal to high
resting lower esophageal sphincter (LES) pressures that do
not fully relax upon swallowing (achalasia). Depending on
the type of esophageal contractions there are 3 types of
motility patterns: swallows that induce simultaneous pre-
mature contractions (type I) that failed to elicit con-
tractions at all or a pressurization pattern (type II) or that
induce normal to high amplitude simultaneous contractions
(type III or vigorous.1 These abnormalities may progress to
a different pattern and therefore the type of motor abnor-
malities detected may depend on the timing of the diag-
nosis. These motor changes depend on whether the
From the Department of Medicine, Rhode Island Hospital and Alpert
Medical of Brown University, Providence, RI.
The authors declare that they have nothing to disclose.
Address correspondence to: Jose Behar MD, Department of Medicine,
Rhode Island Hospital and Alpert Medical of Brown University,
593 Eddy St., Providence, RI 02903
(e-mail: jose_behar@brown.edu).
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/MCG.0000000000000780
J Clin Gastroenterol  Volume 51, Number 3, March 2017
Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved.
excitatory cholinergic neurons are affected. Pathologically
there is a chronic inflammatory process in the Auerbach
plexus of the esophagus that initially involves the inhibitory
neurons and subsequently impairs the excitatory chol-
inergic neurons. Long-term studies show that, in some
patients, there may be progression of this disease resulting
in dilation of the body of the esophagus. In these enlarged
esophageal bodies there are frequently mucosal abnormal-
ities caused by food stasis that can lead to lymphocytic
esophagitis and dysplastic mucosal changes. Furthermore,
in some cases of type III (spastic or vigorous) the esoph-
ageal contractions may change into type II or I probably as
result of progression of the inflammatory process affecting
the cholinergic neurons of the plexus. Thus in patients with
type II or I, there may be a gradual progression of the
disease, and, in few of them, the body of the esophagus may
markedly dilate (sigmoid esophagus). Histologic examina-
tion of their surgical specimens reveals involvement of all
esophageal layers.
This review of achalasia describes (I) its etiology and
the pathogenesis of the inflammatory process that damage
ganglion cells of the Auerbach plexus that is limited to the
esophagus; (II) a description and timing of the chest pain
that is frequently present in the initial stages of the disease;
(III) the slow progression in types I or II phenotypes
leading to abnormalities of the muscle layer that may be
responsible for the dilation of the body of the esophagus
that is seen in a few patients ultimately resulting in a
sigmoid-like esophagus in the very last phase of this disease.
Progression of this disease to the end-stage phase tends to
occur in about 5% of patients and, (IV) inflammatory
abnormalities of the squamous mucosa that is associated
with dysplastic and neoplastic changes leading to the
development of squamous cell carcinoma whose incidence
in this disease is likely to be increased. These mucosal
abnormalities are usually present in patients with markedly
dilated body of the esophagus and severe food stasis. The
only chance to improve swallowing and nutritional symp-
toms in this small group of patients is by performing an
esophageal resection.2
ETIOLOGY OF ACHALASIA
The current state of research only allows for spec-
ulation into the etiology of achalasia. With the exception of
secondary achalasia due to Chagas disease, the etiology of
the idiopathic type has not been conclusively determined. It
is unclear whether idiopathic achalasia is a single disease or
a syndrome caused by various etiological factors.3
Autoimmune Etiology
Autoimmunity as the cause of achalasia is supported
by 3 lines of evidence:
(1) The frequent association of achalasia with well-
established autoimmune disorders that often occurs in
association with one another, either within a single
individual or family. Compared with the general
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Pressman and Behar
population, patients with achalasia are 5.4 times more
likely to have type I diabetes mellitus, 8.5 times as likely
to have hypothyroidism, 37 times as likely to have
Sjögren syndrome, 43 times as likely to have systemic
lupus erythematosus and 259 times as likely to have
uveitis. Overall, patients with achalasia were 3.6 times
more likely to suffer from an autoimmune condition
compared with the general population.4
(2) The inflammatory infiltrate consists of T cells and
eosinophils present in the myenteric plexus.5,6 It also
includes an increased percentage of 2 CD4 + T-cell
subpopulations frequently present in autoimmune
diseases, Th17 and Th22.
(3) Specific autoantibodies associated with neuronal dam-
age. It is unclear whether they initiate it or whether they
are reacting to the inflammatory process. Circulating
specific antimyenteric autoantibodies directed against
the paraneoplastic Ma-2 (PNMA2) (Ma-2/Ta) antigen
have been detected in their sera. They suggested that
they were probably induced by a viral infection because
herpes simplex virus (HSV)1 DNA (viral infection),
RNA (active replication) were also detected in their
LES biopsies. The prevalence of antimyenteric anti-
bodies and HSV-1 infection in these achalasia patients
was 100% versus 0% in control subjects.7
Antibodies to the cytoplasm of Auerbach’s neurons
were found in 37 of 58 patients with achalasia at variable
stages of the disease with a disease duration ranging from 1
to 20 years but only in 4 of 54 healthy controls. These
studies had a specificity of 93% and sensitivity of 64%
(P < 0.0001) and were not found in 12 patients with
Hirschsprung disease or in 12 patients with cancer of
esophagus, in 1 of 11 patients with peptic esophagitis and in
1 of 13 patients with myasthenia gravis. One study raised
questions regarding the specificity of these autoantibodies
against these neurons8 as similar antibodies were found in
esophagitis suggesting likelihood of being a nonspecific
epiphenomenon in response to the inflammatory process.
The finding that autoantibodies are induced in paraneo-
plastic syndromes causing motility disorders similar to
achalasia suggest that further studies are needed in this line
of research.9
Genetic Etiology
Genetic abnormalities may predispose the develop-
ment of achalasia because of its occasional incidence in
members of the same family and its association with vari-
ous gene deletions and polymorphisms. The genetic etiol-
ogy is also supported by the incidence of achalasia in
patients with Down syndrome, an association of 2 relative
rare diseases. Zárate et al10 reported 5 cases of achalasia
associated with Down syndrome in their Institution
Moreover, there is a strong association of achalasia
with major histocompatibility complex signal molecules
that have been recognized as receptors in the signaling of
the immune response. Its association with the human leu-
kocyte antigen (HLA) haplotypes containing amino acid
polymorphisms also suggests a genetic basis of achalasia.
This genetic association was examined in a study that
included 1068 achalasia patients and 4242 normal con-
trols.11 It found that the 8-residue insertion at position 227
to 234 in the cytoplasmic tail of HLA-DQb1 (encoded by
HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the
strongest risk for achalasia. In addition, 2 amino acid
substitutions in the extracellular domain of HLA-DQa1 at
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J Clin Gastroenterol  Volume 51, Number 3, March 2017
position 41 (lysine encoded by HLA-DQA1*01:03) and of
HLA-DQb1 at position 45 (glutamic acid encoded by
HLA-DQB1*03:01) and (HLA-DQB1*03:0) independently
confer higher achalasia risk. These results also implied that
immune-mediated processes are involved in the
pathophysiology of achalasia.
This relationship was further supported by another
study that compared the HLA class II association in white
patients with achalasia (n = 40) and healthy controls
(n = 275). It reported a high incidence of HLA-DQ1*0101
and 2 HLA-DQ a-b heterodimers having their a-chain
encoded by this allele. Moreover, this relative risk was
significantly higher of DQA1* allele in homozygotes com-
pared with heterozygotes. The results of these studies also
suggested that the presence of the TNFa11 allele when
present in the B7-DRB1*1501 may have a protective role
against acquiring this disease.12
Additional studies have examined whether there is an
association between polymorphisms of genes involved in
the regulation of immune responses and the development of
achalasia. They have tried to explain the factors involved in
the complexity of its pathogenesis and progression. Poly-
morphisms involving the genes of nitric oxide (NO) and
vasoactive intestinal polypeptide (VIP) have been reported
in this disease. There are 3 different types of NOS (nitric
oxide synthase): neuronal (nNOS), inducible (iNOS), and
endothelial (eNOS). Their responsible genes are located on
chromosomes: 12q24.2, 17q11.2-q12, and 7q36. Some
studies have reported that this disease is associated with
polymorphism of all 3 genes. Of these, the polymorphisms
that were most frequently detected were iNOS22 A/Ab
and eNOS 4a4a.13 However, other studies found con-
flicting results. Vigo et al14 studied 258 patients with idio-
pathic achalasia and 547 controls to examine whether NOS
polyphormism is associated with the etiology of this dis-
ease. They found no evidence that the presence of this
polyphormism increases the susceptibility to develop
achalasia at least in the Spanish population.
Besides nitrogen oxide, VIP is the second neuro-
transmitter of the esophageal inhibitory neurons.15 One of
its receptors the VIP receptor 1 gene (VIPR1) belongs to the
secretin family and is expressed in immune cells such as T-
lymphocytes, macrophages and dendritic cells.16 Poly-
morphism of this gene VIPR1 has been suggested to play an
important role in the development of a number of auto-
immune entities including idiopathic achalasia.17 The
VIPR1 gene is localized on chromosome 3p22 and has been
reported to have 5 simple nucleotide polymorphisms such
as (rs421558) intron-1, (rs437876) intron-4, (rs417387)
intron-6, (rs896 and rs9677) (30 UTR).17 Patients with idi-
opathic achalasia show a significant difference in allele,
genotype and phenotype distribution of single-nucleotide
polymorphism rs437876 mapping in intron-4. This associ-
ation, however, was almost entirely due to the group of
patients with late disease onset (P = 0.0005). These results
therefore strongly suggest that idiopathic achalasia is a
heterogenous disease with a different genetic etiology in
cases of early or late disease onset.
Another study focused on the possible contribution of
the protein tyrosine phosphatase N22 (PTPN22) gene
encoded in a lymphoid-specific phosphatase (LYP) is a
down regulator of T-cell activation. This phosphatase is an
intracellular tyrosine phosphatase. This PTPN22 poly-
morphism C1858T has been found to be associated with
different autoimmune diseases. The C18 58T polymorphism
J Clin Gastroenterol  Volume 51, Number 3, March 2017
of PTPN22 gene occurs when the codon 620-arginine is
replaced by tryptophan resulting in the production of Lyp-
W620 instead of Lyp-R620. This defect leads to an increase
in T-lymphocyte activity that is known to be an important
risk factor for the development of autoimmune and other
diseases.17,18 Because of this background it examined
whether it was a risk factor in its etiology in 104 consecutive
patients with achalasia and 300 random controls from the
same geographic area. They found that there was a sig-
nificant sex difference with the PTPN22 1858T allele as a
susceptibility factor that was positive but only for Spanish
women with achalasia.19
Additional polymorphisms of genes known to be
involved in inflammatory conditions were also examined to
determine their role in the etiology of achalasia. The IL23R
polymorphism was examined because this gene is involved
in several inflammatory and autoimmune conditions. These
studies found that a minor allele of the Arg381Gln poly-
morphism was significantly increased in patients with
achalasia compared with healthy controls. This association
seems to be specific to male patients 40 years and older.20
The polymorphism of interleukin (IL)10 cytokine was
also examined to determine whether it contributes to the
etiology of this disease. This study was performed as a case-
control study examining the 1082, 819, and  592 IL10
promoter polymorphisms in 282 achalasia patients and 529
controls that included an independent replication set of 75
patients and 575 controls. The results of these studies found
evidence for an association between polymorphisms of IL10
promoter and idiopathic achalasia, suggesting that the IL10
cytokine may contribute to the pathogenesis of this
disease.21
Therefore all these studies suggest that genetically
achalasia is a highly heterogenous disease that may explain
differences in the age of onset, the severity, and progression
of the disease as well as its various phenotypes.
This genetic hypothesis is also supported by the high
incidence of an achalasia-like motility disorder in Rassf1a-
null mice.22 This mouse has a 20% incidence of mega-
esophagus compared with only 2% in the wild type liter
mates. The motility disorder model in this mouse consists of
a dilated esophagus and a reduction in the numbers of
nerve cells (both ganglia and nerve fibers) in the myenteric
plexus of the dilated mid and lower esophagus. The reduced
or absence of neurons was studied by determining the S100
proteins by immunohistochemistry as markers of neurons.
Like in human achalasia there is also a presence of a
chronic inflammatory infiltrate and subsequent fibrosis of
the myenteric plexus and the muscle layers. These patho-
logic abnormalities closely mimic the gross and histo-
pathologic findings of human patients with achalasia. Thus,
this genetically based mouse model appears to be a repre-
sentative animal model of the human disease with sim-
ilarities to all the pathologic and functional features that
are found in human achalasia.
In support of this hypothesis it has also been suggested
that the Allgrove syndrome due to a mutation of the Aladin
12q13 gene leads to symptoms and motility disorders sim-
ilar to achalasia. It is the most common cause of an
achalasia-like syndrome in young children.23 The mutation
of ALADIN 12q13 gene is an autosomal-recessive disease
that is characterized by the development of achalasia,
alacrimia, and Addison disease.24 However, in contrast to
idiopathic human achalasia where the abnormalities lie in
the neurons of the Auerbach plexus of the esophagus, the
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Etiology and Pathogenesis of Idiopathic Achalasia
esophageal functional abnormalities in this disease origi-
nate in lesions affecting the central nervous system.25
Viral Etiology
The role of viruses in the etiology of achalasia is
controversial. These studies selected specific viruses because
they are neurotropic or they are known to infect the
esophageal mucosa. Viral etiology is being considered
because of reports that viruses are able to cause similar
motor abnormalities in the esophagus of other animal
species. An infection with a newly described bornavirus has
been strongly linked in exotic birds to a disease that dis-
plays many striking similarities to achalasia.26 Some of the
human studies also have suggested that viruses may trigger
a delayed autoimmune response because cytotoxic T cells
isolated from the LES of achalasia patients respond to the
human HSV-1 in the presence of g-interferon and to a lesser
extent to IL2 production. In addition, the HSV-1 DNA
virus has been demonstrated in the vast majority of acha-
lasia patients where this etiology was examined. However,
those results are considered controversial as other studies
also found similar evidence in control subjects. Other
reports have suggested that although achalasia is an
immune-mediated inflammatory disease it may develop in
individuals with a latent infection with HSV-1 causing a
persistent immune activation and self-destruction of
esophageal neurons, most likely only in genetically
susceptible subjects.27 This hypothesis is also supported
with the presence of positivity for the varicella-zoster virus
in the serum that was significantly higher in 58 patients with
achalasia compared with 40 age-matched and sex-matched
controls (P < 0.02). These results suggest that achalasia
could have developed in these patients because the DNA
virus may have persisted in their Auerbach plexus.28 The
viral etiology is also supported by the findings of Furuzawa
and colleagues that showed that 100% of patients with
achalasia had evidence of HSV-1 viral infection but in none
of the controls. They suggested that this infection might
have triggered an autoimmune response because of the
presence of antimyenteric antibodies.7
The significance of the circulating anti-HSV-1 and
HSV-2 antibodies in patients with achalasia has been
questioned because the results of these studies have not
been consistent. In contrast, achalasia and control groups
had similar antibodies levels against HSV-1 virus and its
DNA was not detected by polymerase chain reaction in the
esophageal muscle samples. However, the same study
showed a 3.4-fold increase in the proliferative index of
mononuclear cells from achalasia patients when stimulated
with HSV-1 virus compared with control subjects
(P < 0.01). Despite these conflicting results this study
concluded that the presence of HSV-1-reactive lymphocytes
in the LES of achalasia patients might have damaged the
neurons in the myenteric plexus leading to the motor dys-
function.29 Their conclusions, however, are limited by the
absence of a positive control group (eg, erosive esophagitis
patients) as they could suggest that this reaction could be
due to a nonspecific inflammatory response that is present
in patients with achalasia.
Another virus that was considered in the etiology of
this disease is the measles virus. Preliminary studies using
the complement fixation test against a variety of bacterial
and viral agents reported a significant increase in the anti-
body titer against the measles virus in the sera of 21 patients
with achalasia compared with 12 age-matched and
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Pressman and Behar
sex-matched controls.30 These findings were confirmed by
the hemagglutination inhibition test. However, a similar
study by Niwamoto et al31 using in situ DNA hybridization
challenged this etiology as it failed to demonstrate the
presence of those viruses in esophageal tissues from patients
with achalasia compared with 20 patients undergoing
esophageal resection for diseases other than achalasia. This
study found absence of the HSV-1, cytomegalovirus, or
varicella-zoster virus using polymerase chain reaction
(PCR) amplification with a pair of primers specific for the
HSV 1 and 2. It failed to demonstrate significant differences
between achalasia patients and normal controls with
respect to the 92-bp fragment that is identical to a single
HSV sequence performed by automated DNA sequence
analysis. These 92-bp fragments were identified in nearly all
specimens, including from normal controls. The above-
mentioned negative results were further supported by a
similar PCR amplification using a pair of primers specific
for HSV 1 and 2.
The presence of the measles virus was also not dem-
onstrated by Birginsson et al.32 These studies failed to show
the presence of herpes virus, measles or human papilloma
virus in myotomy specimens using PCR technique from 13
patients with achalasia that were compared with specimens
from esophageal cancer patients and autopsy specimens
from 6 fetuses. They used the PCR DNA amplification
method but did not find any paired oligonucleotide primers
of HV (HSV-1 and 2, cytomegalovirus, Epstein-Barr virus,
varicella-zoster virus, and Herpesviridae virus-6), Marburg
virus, and human paillovirus sequences and exon 3 of the
HPRT gene.
In summary, although the etiology of achalasia has
not been conclusively determined there is increasing evi-
dence that indicate that it is likely caused by autoimmune
mechanisms based on its high association with other
autoimmune disorders and with HLA abnormalities.
However, it is still possible that this esophageal disease
although mediated by autoimmune mechanisms that are
triggered by a delayed response to viral infections in
genetically susceptible individuals.
PATHOGENESIS
Neural Abnormalities
Histologic abnormalities in the Auerbach plexus
appear to be confined to the esophagus. An analysis of the
plexuses of the esophagus, stomach, jejunum, and colon in
34 patients with achalasia of the esophagus showed that
ganglia cells of the distal esophagus were absent in 91% of
cases, whereas the Auerbach plexuses were normal in the
stomach, jejunum, and colon.33 Most of the pathologic
studies of this disease are based on specimens obtained in
patients with moderate to advanced achalasia who had
required surgical treatment of the LES or on resected seg-
ments of the distal esophagus from patients with markedly
dilated body. They showed mostly heavy infiltration of T
lymphocytes, mast cells, plasma cells, and few eosinophils.
Few specimens showed evidence of heavy eosinophilic
infiltration of the muscularis propia. However, this is in
contrast to eosinophilic esophagitis where eosinophils are
predominantly present in the mucosa. It is unclear, how-
ever, whether these inflammatory cells are primarily
responsible for the destruction of the intramural neurons or
are responding to the damage of these cells caused by
autoantibodies, genetic abnormalities or viruses.
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J Clin Gastroenterol  Volume 51, Number 3, March 2017
Goldblum et al34 examined the esophageal histology of
42 patients with achalasia treated with total thoracic
esophagectomy. These specimens were systematically
examined to identify morphologic features of these clin-
ically unresponsive patients with achalasia and to determine
what could be learned about the disease’s evolution. In all
cases, the myenteric ganglion cells within the esophageal
body were markedly diminished, with 20 specimens having
none. Twenty specimens had residual ganglion cells in the
proximal esophagus, and 15 specimens had a few randomly
distributed ganglion cells in the mid-portion and distal
portions of the esophagus. Inflammation within myenteric
nerves, present in all cases, generally consisted of a mixture
of lymphocytes and eosinophils, and occasionally few
plasma and mast cells. Focal replacement of myenteric
nerves by collagen occurred in all cases, and there was
almost complete replacement in several cases. More
recently the histopathologic abnormalities have been cor-
related with the different manometric patterns defined by
new classification of achalasia types based on the Chicago
classification of motility disorders.35 These studies included
patients with type I (n = 20), type II (n = 20), type III
(n = 3); and, esophagogastric junction outflow obstruction
(n = 3). The histopathology revealed complete ganglion cell
loss in 74% of specimens, inflammation in 17%, fibrosis in
11%, and muscle atrophy in 2%. Comparing type I and
type II specimens, there was a statistically significant
greater proportion of type I specimens with aganglionosis
(19/20 vs. 13/20, P = 0.044) and a statistically significant
greater degree of ganglion cell loss in type I specimens
(Wilcoxon rank-sum, P = 0.016). CD3 + and CD8 +
cytotoxic T cells represented the predominant inflammatory
infiltrate determined by immunohistochemistry. Three
patients had completely normal appearing tissue (1 each in
type II, type III, esophagogastric junction outflow
obstruction).
A greater degree, but with a similar pattern, of gan-
glion cell loss observed in type I compared with type II
achalasia specimens suggests that type I may represent a
progression from type II.35 The spectrum of histopatho-
logic findings from complete neuronal loss to lymphocytic
inflammation to apparently normal histopathology—
indicates that achalasia represents a pathogenically heter-
ogeneous disease with the commonality being obstruction
of esophagogastric outflow. Thus this histologic hetero-
geneity is consistent with the variety of genetic abnormal-
ities associated with this disease.
Pathogenesis of Muscle Abnormalities and
Dilation of the Body of the Esophagus
The dilation of the body of the esophagus terminating
into a massive sigmoid-like dilation (stage 3) is a gradual
and a slow process that tends to be seen in patients with
long-standing achalasia with phenotypes I or II (Chicago
classification) and usually in the elderly. In this stage
patients have significant nutritional and pulmonary com-
plications due to severe food stasis and regurgitation.
Although the pathogenesis of this dilation is not known it is
conceivable that it may be due to the gradual development
of muscle abnormalities that may complicate this disease. It
is possible that the inflammatory changes seen in the muscle
layers may be an extension from the adjacent inflammatory
process in the Auerbach plexus.
Initially there is muscle hypertrophy that may be due
to increased effort of the esophageal body to overcome the
J Clin Gastroenterol  Volume 51, Number 3, March 2017
relative functional sphincter obstruction due to its inability
to fully relax upon swallowing. This is particularly the case
in the region of the LES associated with normal or high
pressures.36 This muscular hypertrophy is mainly observed
in the muscularis propria associated with secondary muscle
degeneration, fibrosis, and eosinophilia. Ultra-structural
studies show that alterations in the smooth muscle of all
patients are neither pronounced nor consistent. These
include nonspecific changes such as filament disarray,
mottling of the fiber density in myocytes, thick and long
cytoplasmic dense bodies, long dense plaques, and few
nexus junctions. In addition, the smooth muscle cells may
exhibit nuclear and cytoplasmic inclusions. These muscle
abnormalities are particularly frequent and more severe in
older patients.
A 5-year follow-up radiologic study in patients with
achalasia without any treatment reveal a gradual and sig-
nificant increase in the diameter of the thoracic esophagus,
with a rate of “dilatation” of 6.1 mm/y. In addition, there
was a significant decrease of the internal diameter of the
esophagogastric junction, with a rate of “stenosis” of 1 mm/
y. The LES was hypertensive with an incomplete relaxation
in all patients. This study did not include a “control treated
group” examining whether surgical myotomy or balloon
dilation of the gastroesophageal junction prevents or delays
this progressive esophageal dilation.37
Statistical analysis of the number of muscle cells per
unit area suggested that the gross thickening of the mus-
cular wall of the esophagus in cases of achalasia and diffuse
esophageal spasm is due to hyperplasia and not hyper-
trophy of muscle cells.38 Ellis carried-out a long-term fol-
low-up study in these patients observing that there was a
progressive dilation of the body of the esophagus even as
early as 10 years after the initial diagnosis.38 The incidence
of megaesophagus can vary from 6.2% to 21%.39 It is not
known, however, whether treatment (medical or surgical) of
this obstruction can prevent the progression of some of
these muscle abnormalities particularly the gradual dilation
of the body of the esophagus.
Squamous Cell Carcinoma Complicating
Achalasia
Several studies have reported an increased incidence of
squamous cell carcinoma in patients with achalasia com-
pared with the general population of the United States and
Europe.40 However, there is no consensus as to the precise
risk of malignant degeneration of the squamous mucosa or
the need for a close surveillance of achalasia patients to
detect this complication in its early stages. There is also no
agreement on the frequency of the surveillance or the
diagnostic method that should be used. A review of the
available literature on the subject has disclosed a wide
range of cancer risks in these patients, from 0 to 33 times
higher than that of the control population. The incidence of
this complication also appears to be higher in males than in
females.41 Cancers, when discovered, are often unresectable
and even if they are resectable the median survival is rela-
tively low.42
Most studies have reported that the increased inci-
dence of squamous cell carcinoma is well established par-
ticularly when they include patients with longstanding
achalasia. These observations are supported by the
increased presence of preneoplastic abnormalities in the
esophageal squamous mucosa of these patients. These
preneoplastic abnormalities are probably caused by chronic
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Etiology and Pathogenesis of Idiopathic Achalasia
stasis of ingested foodstuffs that remain in the peristaltic
body of the esophagus for prolonged periods of time due to
the gastroesophageal obstruction. They include diffuse
squamous cellular hyperplasia, lymphocytic infiltration of
the mucosa, the lamina propria, and the submucosa with
prominent germinal centers and submucosal periductal or
glandular inflammation with complete loss of submucosal
glands. In most cases of longstanding achalasia, partic-
ularly in the presence of a markedly dilated esophageal
body, the mucosa appears hyperplastic with papillomatosis
and basal cell hyperplasia. Occasionally, high-grade squ-
amous dysplasia or superficially invasive squamous cell
carcinoma is found incidentally in these patients. In addi-
tion, P53 staining of the squamous mucosa is significantly
more common than in controls. It was detected in 32 of 35
achalasia patients (91%) compare with only in 1 of 17
controls (6%, P < 0.05). They not only include its over-
expression but also mutational changes of this tumor sup-
pressor. Their mucosa also shows the presence of the Ki-67,
a marker of cell proliferation. In addition, in all achalasia
cases CD3 + cells far outnumbered CD20 + cells and were
in greater number (ranging from 32 to 239/HPF with a
mean of 107/HPF) compared with controls (ranging from
0.8 to 12/HPF with a mean of 6/HPF, P < 0.05).43–46 These
abnormalities, frequently seen in these patients, appear to
be associated with signs of chronic inflammation and
especially in areas showing increased cell proliferation.
Nevertheless, the prevalence of squamous cell carci-
noma in this disease varies a great deal in the literature
probably because its incidence is relatively low and tends to
develop in patients with longstanding disease. Some of the
discrepancies in the incidence of this complication appear
to be related to the length of the disease in the population
included in a study.47 With the exception of an occasional
study48 most of the reports have concluded that the risk for
developing esophageal squamous cell carcinoma in patients
with long-standing achalasia is increased by about 140-fold
over that of the general population. This risk is even greater
in males than in females. It is therefore conceivable that
with a liberal use of surveillance, it could be detected more
often at an early stage and perhaps improved the prognosis
that currently appears to be similar to that of patients in the
general population with squamous cell esophageal cancer
without achalasia.49
Moreover, it is somewhat surprising that a successful
treatment does not seem to change the incidence of carci-
noma as reported in a large Danish study.50 This study
contacted 146 patients out of 147 patients with achalasia of
the esophagus treated with a Heller myotomy, 58 females
and 88 males aged 4 to 83 years (median age 46 y). The
mean follow-up time after the operation was 23.2 years
(range of 6 to 41 y). The cause of death was established in
71 patients. There were 3 postoperative deaths and 2 fol-
lowing its recurrence. The remaining 66 patients were found
to have a higher cancer mortality of 33.8 percent compared
with that reported in the Danish population. More
important 10 of 23 patients with achalasia who died of
cancer had a malignant tumor in the esophagus compared
with the expected incidence of <1 patient in the general
population. The mortality rate in patients with achalasia
after 30 years was 66.1% with 11.9% of the deaths caused
by esophageal cancer.50
This association was also examined prospectively to
determine the incidence of esophageal squamous carcinoma
and to establish the efficacy of endoscopic surveillance.51,52
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Pressman and Behar
Meijssen and colleagues enrolled 195 consecutive patients
with achalasia (90 men and 105 women with a mean age of
52 y) treated with a pneumatic dilatation between 1973 and
1988. The follow-up period included 874 person years. In
this period 3 patients developed esophageal squamous cell
carcinoma. The mean age at diagnosis of this carcinoma was
68 years. The mean period between the onset of dysphagia
and the diagnosis of the tumor was 17 years. Thus the
incidence of esophageal squamous cell carcinoma in this
series was 3.4 of 1000 patients per year that is significantly
higher than the statistically expected incidence of this type of
cancer of 0.104 of 1000 patients per year using age-specific
and sex-specific data from the population of the Netherlands
(P < 0.001). Thus there is a 33-fold increased risk of devel-
oping esophageal squamous cell carcinoma in achalasia
patients. Periodic endoscopies showed the potential for
detecting an early stage of esophageal carcinoma only in 2
cases. However, larger studies with longer follow-ups are
required to determine the efficacy of endoscopic screening
and whether it improves the prognosis for these patients who
may develop early esophageal squamous cell carcinoma.53
An additional study performed between 1982 and 1998
enrolled a total of 124 patients with primary achalasia that
were successfully treated and carefully followed.54 Of the
124 patients with primary achalasia, 4 developed a carci-
noma within a mean follow-up period of 5.6 years (an
incidence of 1 carcinoma per 173.6 patient-years of follow-
up). Altogether, 13 of 879 patients (1.5%) presenting with
esophageal squamous cell carcinoma and 1 of 487 patients
(0.2%) presenting with esophageal adenocarcinoma had a
history of primary achalasia. Seven patients with achalasia-
carcinoma had early-stage disease (stage I, IIA, or IIB).
During the same time-period the incidence of esophageal
cancer reported in the general population included 1, 366
patients with esophageal cancer (879 esophageal squamous
cell carcinomas, 487 adenocarcinomas). There was no dif-
ference in the prognosis of patients with resected achalasia-
carcinoma versus those with esophageal carcinoma without
achalasia. Thus in the population of patients with long-
standing achalasia the risk for developing an esophageal
cancer was increased about 140-fold over that of the general
population.
Another study was performed in a cohort of 2896
patients with a discharge diagnosis of achalasia in the
Swedish Inpatient Register between 1965 and 2003. The
cohort was followed through 2003 via record linkages with
essentially complete registers of cancer, causes of death, and
migration. Standardized incidence ratios (SIRs) were used
to estimate the relative risk of esophageal cancer in acha-
lasia patients compared with the age-matched, sex-matched
and calendar period-matched Swedish population. It fur-
ther examined SIRs for esophageal cancer among patients
treated with esophago-myotomy. After excluding the first
year of follow-up, the risks were observed for both squ-
amous cell carcinoma (SIR, 11.0; 95% confidence interval,
6.0-18.4) and adenocarcinoma (SIR, 10.4; 95% confidence
interval, 3.8-22.6) of the esophagus. Notwithstanding that
were similar numbers of men and women in our achalasia
cohort, 20 of 22 esophageal cancers developed in men (SIRs
for adenocarcinoma and squamous cell carcinoma were 8.4
and 13.1, respectively). Increased SIRs among operated
patients pertained mainly to esophageal squamous cell
carcinoma. In contrast to the studies listed below, they
found no evidence that surgical esophago-myotomy
increases the risk of esophageal adenocarcinoma.42
200 | www.jcge.com Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol  Volume 51, Number 3, March 2017
Although the esophageal cancer risk in patients with
longstanding achalasia is much higher than that of the
general population, the absolute risk is rather low. Despite
of patients subjected to a structured endoscopic surveil-
lance, most of their neoplastic lesions remain undetected
until they are in an advanced stage.53 Efforts need to be
made to identify high-risk groups and develop adequate
surveillance strategies with new endoscopic technologies.
Moreover, as suggested before, the incidence of squamous
cell carcinoma is not reduced after treatment with either
Heller myotomy or balloon dilation.
There is also increasing evidence that these surgical
procedures may predispose some patients to the develop-
ment of adenocarcinoma of the esophagus. This compli-
cation appears to be due to the occurrence of gastro-
esophageal acid reflux that may develop in the absence of a
high-pressure zone in the postmyotomy LES. This com-
plication occurs despite of efforts to create a high pressure
of zone by adding a partial fundoplication,54 The addition
of a partial fundoplication and surgical creation of high
pressure zone reduces the incidence but does not completely
eliminates the occurrence of acid reflux in all patients
treated with this procedure.55 Katada et al56 reported that
the Heller-Dor procedure might be more effective in pre-
venting acid reflux than the more frequently performed
Heller-Toupet procedure. Unfortunately these surgical
repairs tend to deteriorate with time although satisfactory
results were still achieved in most patients after15 years57
Although the incidence of gastro-esophageal reflux
disease in these patients is relatively low, this complication
should be entertained because these patients usually do not
complain of heartburn (personal observation). Therefore it
may remained undetected and without acid reflux treatment
it may lead to erosive esophagitis and even Barrett mucosa,
a risk factor for the development of adenocarcinoma of the
esophagus.58,59 The frequency of this complication is sup-
ported by a study that included 463 patients from the 806
treated with laparoscopic Heller myotomy that agreed to
undergo a follow-up 24-hour pH study. Normal pH find-
ings were seen in 423 patients (or 91.4%), while 40 (or
8.6%) had a pathologic acid exposure. Surprisingly, how-
ever, the median symptom scores and the percentage of
esophagitis at endoscopy were similar in both groups (11%
in the group of patients with a normal pH test and 19% in
the group with positive pH test; P = 0.28).60 Prevention of
erosive esophagitis and Barrett esophagus requires early
endoscopic evaluation shortly after surgery since the
esophageal pH test is not an adequate predictor of whether
there is clinical evidence of erosive esophagitis in the post-
operative period. Treatment of this complication if present
should be instituted to prevent the development of Barrett
metaplasia.
Thus the epidemiological, histologic and long-term
follow-up studies strongly suggest that the incidence of
cancer of the esophagus in patients with achalasia is
increased significantly even after they receive appropriate
treatment. These data therefore ought to be considered in
the treatment and long-term evaluation of these patients.
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