Achalasia

Background

Achalasia is an esophageal motor disorder characterized by failure of relaxation of the lower esophageal sphincter and lack of progressive peristalsis in the esophageal body. It may be primary or secondary to several conditions including Chagas's disease and malignancies.

Outline

Epidemiology
Pathogenesis
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY CHARACTERIZATION

GEOGRAPHY

Five year prospective study of the incidence, clinical features, and diagnosis of achalasia in Edinburgh.

Howard PJ, Maher L, Pryde A, Cameron EW, Heading RC.

Department of Medicine, Royal Infirmary of Edinburgh.

Gut 1992 Aug;33(8):1011-5 Abstract quote

With the increasing availability of manometry, patients with achalasia are often referred at an early stage when they lack the classic features of established disease. A prospective five year study of the presenting features of untreated achalasia referred to our department was undertaken.

Twenty men and 18 women presented throughout adult life, with a mean age at the time of diagnosis of 44 years (range 17 to 76 years). The presenting symptoms were dysphagia: for solids (100%) and for liquids (97%), chest pain (74%), and weight loss (60%). Endoscopy was reported as normal in 15 patients and achalasia was suggested in only 21 of 33 barium examinations. Fourteen had been treated for gastrooesophageal reflux but none had been misdiagnosed as having cardiac or psychiatric disease.

The annual incidence of achalasia in the Lothian region is 0.8/100,000 of population. Persistent dysphagia is the cardinal symptom of achalasia which presents throughout adult life. Nevertheless, recent onset achalasia is often misdiagnosed as gastrooesophageal reflux disease. Because endoscopy is frequently normal and the diagnosis is often not made by radiology, manometric investigation is necessary if the condition is to be recognised and treated at an early stage.

A prospective study of the clinical features, manometric findings, incidence and prevalence of achalasia in Singapore.

Ho KY, Tay HH, Kang JY.

Department of Medicine, National University of Singapore.

J Gastroenterol Hepatol 1999 Aug;14(8):791-5 Abstract quote

BACKGROUND: This study aimed to describe the clinical features, manometric findings, prevalence and incidence of achalasia in Singapore.

METHODS: A total of 615 new patients referred for oesophageal manometry between 1989 and 1996 were examined prospectively. Twenty-four men and 25 women fulfilled the manometric and clinical criteria for achalasia.

RESULTS: Their median age of onset of symptoms was 37 years (range 15-71) and 37% first developed symptoms after the age of 50 years. The presenting symptoms were dysphagia (100%), regurgitation (80%), weight loss (67%) and chest discomfort (33%). Five patients (10%) had a history of benign (mostly autoimmune) thyroid disorders. Endoscopy was reported as normal in 10/43 patients (23%) and achalasia was suggested in only 31 (72%) of 43 barium examinations. Lower oesophageal sphincter (LOS) dysfunction was present in 82% of cases. Using data from medical records and from a survey of gastroenterologists and surgeons in Singapore, the prevalence (in 1996) and incidence of achalasia in Singapore were estimated to be 1.8 per 100000, and 0.3 per 100000 per year, respectively. The incidence was significantly lower in Malays than Chinese or Indians. The age-specific incidence of achalasia for both genders followed a bimodal distribution with the larger peak in the sixth decade. No cases of oesophageal carcinoma were identified among these patients.

CONCLUSION: Achalasia is an uncommon condition in Singapore. The clinical and manometric features were similar to those described in Western countries.

DISEASE ASSOCIATIONS CHARACTERIZATION

Achalasia secondary to nongastrointestinal malignancies.

Feczko PJ, Halpert RD.

Gastrointest Radiol 1985;10(3):273-6 Abstract quote

Secondary or "pseudo" achalasia of the esophagus can mimic idiopathic achalasia radiographically and can be difficult to diagnose. Typically, it is due to invasive carcinoma involving the gastroesophageal junction, usually gastric adenocarcinoma. Occasionally, an achalasialike condition can be produced by tumors not involving the gastroesophageal junction.

We report 2 cases, 1 of lung carcinoma and the other of hepatoma, in which the patients had radiographic and endoscopic changes compatible with achalasia. However, the onset of symptoms was abrupt and the patients were elderly; these are unusual features for primary achalasia. There have been several other reports of nongastrointestinal neoplasms producing a clinical and radiographic picture similar to achalasia.

Although there are several theories as to the cause, our cases would support the concept that direct tumor involvement of the gastroesophageal junction is not necessary to produce significant esophageal dysmotility.

Achalasia of the esophagus in childhood. Surgical treatment in 35 cases, with special reference to familial cases and glucocorticoid deficiency association.

Nihoul-Fekete C, Bawab F, Lortat-Jacob S, Arhan P.

Department of Pediatric Surgery, Hopital des Enfants Malades, Paris.

Hepatogastroenterology 1991 Dec;38(6):510-3 Abstract quote

Achalasia of the esophagus is a relatively rare problem in children, but it may be the cause of severe lung disease, growth retardation and respiratory death in young infants. Surgical esophago-cardio-myotomy remains the treatment of choice, and this article details 25 years of experience with 35 children with achalasia of the esophagus and their late post-operative follow-up.

The occurrence of achalasia in the first six months of life, the existence of a familial factor, the prevalent possible association with genetic diseases (familial dysautonomia, glucocorticoid insufficiency, Rozycki syndrome) suggest that achalasia in childhood may in certain cases represent a congenital problem, somewhat different from the adult form, which is considered to be an acquired disease.

PATHOGENESIS CHARACTERIZATION

GENERAL Depletion or complete absence of myenteric ganglion cells associated with a myenteric inflammatory infiltrate composed predominantly of T cells

Autoantibodies to Auerbach's plexus in achalasia.

Storch WB, Eckardt VF, Wienbeck M, Eberl T, Auer PG, Hecker A, Junginger T, Bosseckert H.

Institute for Laboratory Medicine, Monchengladbach, Germany.

Cell Mol Biol (Noisy-le-grand) 1995 Dec;41(8):1033-8 Abstract quote

Achalasia is a motor disorder of the oesopagus characterized by decrease in ganglion cell density in Auerbach's plexus. The cause of the lesion is unknown. This is to repeat on the occurrence of autoimmune phenomena in patients with achalasia, in particular circulating antibodies against Auerbach's plexus and its possible meaning. IgG-antibodies against

Auerbach's plexus were determined by standard indirect immunofluorescence. Antibodies to the cytoplasm of Auerbach's plexus were found in 37 of 58 patients with achalasia at variable stages of the disease (I-IV) with a disease duration ranging from 1 to 20 years but only in 4 out of 54 healthy controls (specificity 93%, sensitivity 64%, p < 0.0001), and in none of 12 patients with Hirschsprung's disease as well as 12 patients with cancer of oesophagus and only in one of 11 patients with peptic oesophagitis as well as in one of 13 patients with myasthenia gravis.

The present observations suggest that autoimmunity to Auerbach's plexus plays a role in the pathogenesis of achalasia, the mechanism of action is unknown.

Anti-myenteric neuronal antibodies in patients with achalasia. A prospective study.

Verne GN, Sallustio JE, Eaker EY.

Division of Gastroenterology, University of Florida, Gainesville, USA.

Dig Dis Sci 1997 Feb;42(2):307-13 Abstract quote

Achalasia is a motility disorder of the esophagus characterized by the loss of inhibitory neurons in the distal esophagus. Although idiopathic in nature, autoimmune mechanisms have been proposed, and we set out to determine the presence of myenteric neuronal antibodies.

We prospectively studied 18 patients with well-characterized achalasia (by clinical, x-ray, and manometric evidence), nine with gastroesophageal reflux disease, and analyzed the sera from 22 disease-free controls. Using double-label, indirect immunofluorescence techniques, rat esophageal and intestinal sections were double-labeled with sera (dilutions of 1:50 to 1:400) from the three groups and with neurofilament antibody to localize neurons. Seven of 18 achalasia patients had sera that stained the majority of neurons within plexi in the esophageal and intestinal sections, including both NADPH diaphorase (nitric oxide synthase) -positive and -negative neurons. None of the gastroesophageal reflux patients or the controls showed staining.

Neuronal antibodies in achalasia provide an attractive hypothesis to explain this diffuse, possibly immune-based disorder.

LABORATORY/RADIOLOGIC/OTHER CHARACTERIZATION

Manometric and radiologic correlations in achalasia.

Meshkinpour H, Kaye L, Elias A, Glick ME.

University of California, Irvine Medical Center, Orange.

Am J Gastroenterol 1992 Nov;87(11):1567-70 Abstract quote

Achalasia is an esophageal motor disorder distinguished by clinical, radiologic, and manometric features.

To evaluate the correlation among these features, we studied 109 achalasia patients. The four most common clinical complaints, the four most commonly encountered radiologic findings, and two manometric parameters were analyzed with a correlation matrix test and a multiple regression analysis. Significant correlation existed among symptoms of dysphagia, regurgitation, and weight loss. In contrast, chest pain inversely correlated with these symptoms. Dysphagia and weight loss significantly correlated with a bird-beak deformity but not with esophageal dilatation or a sigmoid esophagus. Moreover, no significant relationship between lower esophageal sphincter pressure and esophageal dilatation or sphincter pressure and sigmoid esophagus was found. However, in those patients with a resting lower esophageal sphincter pressure greater than 45 mm Hg, a reasonable correlation among clinical, radiologic, and manometric parameters did exist.

In conclusion, although in a subset of patients with markedly increased lower esophageal sphincter pressure, a good correlation between clinical, radiologic, and manometric findings exists, such a correlation cannot be established in all of the achalasia patients; esophageal dilatation or a sigmoid esophagus may not be due to a hypertensive sphincter, and their presence must not necessarily be interpreted as an indication of severity of the disease; there is an inverse correlation between chest pain and symptoms of dysphagia, regurgitation, and weight loss; and finally, achalasia and hiatal hernia may coexist in 6% of the patients.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

Achalasia. A morphologic study of 42 resected specimens.

Goldblum JR, Whyte RI, Orringer MB, Appelman HD.

Department of Pathology, University of Michigan Hospitals, Ann Arbor

Am J Surg Pathol 1994 Apr;18(4):327-37 Abstract quote

Achalasia is characterized by failure of relaxation of the lower esophageal sphincter and absence of progressive peristalsis in the esophageal body. Few data are available regarding the morphologic features of achalasia, in particular its histologic progression.

The esophagi of 42 patients with achalasia treated with total thoracic esophagectomy were examined histologically in order to systematically identify morphologic features of clinically unresponsive achalasia and to determine what could be learned about the disease's evolution. In all cases, 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- and distal portions of the esophagus. Inflammation within myenteric nerves, present in all cases, generally consisted of a mixture of lymphocytes and eosinophils, occasionally with plasma and mast cells. Focal replacement of myenteric nerves by collagen occurred in all cases, and there was almost complete replacement in several cases. Actual destruction of the residual ganglion cells was not seen. The resected esophagi also shared extramyenteric morphologic features. Some features probably stemmed from physiologic obstruction, such as muscular hypertrophy, mainly of the muscularis propria (all cases), with secondary degeneration and fibrosis (29 cases), and eosinophilia of the muscularis propria (22 cases). Other changes, probably resulting from chronic stasis of ingested materials in the lumen, included diffuse squamous hyperplasia (all cases), lymphocytic mucosal esophagitis (28 cases), lymphocytic inflammation of the lamina propria and submucosa with prominent germinal centers (all cases), and submucosal periductal or glandular inflammation with complete loss of submucosal glands in half of the cases. One patient had high-grade squamous dysplasia, and another had superficially invasive squamous cell carcinoma. A third group of changes was probably due to previous esophagomyotomy, including abnormal gastroesophageal reflux, as shown by pH reflux testing (13 cases) and Barrett's mucosa (four cases). In one case of Barrett's there was low-grade dysplasia.

Clinically unresponsive, surgically resected achalasia has almost total loss of ganglion cells, and widespread destruction of myenteric nerves has already occurred. The only active component is myenteric inflammation. However, it cannot be determined whether this inflammation is a manifestation of ongoing nerve destruction or whether it is a secondary phenomenon.

Histopathologic features in esophagomyotomy specimens from patients with achalasia.

Goldblum JR, Rice TW, Richter JE.

Department of Anatomic Pathology, Cleveland Clinic Foundation, Ohio, USA.

Gastroenterology 1996 Sep;111(3):648-54 Abstract quote

BACKGROUND & AIMS: A previous study evaluating the morphological features of esophagi resected for endstage achalasia showed marked depletion of myenteric ganglion cells, widespread destruction of nerves, and variable chronic inflammation. The aim of this study was to evaluate the histological features in esophagomyotomy specimens from 11 patients with early achalasia, defined as minimal to moderate esophageal dilation without sigmoid deformity.

METHODS: The histological features of esophagomyotomy specimens from 11 patients with achalasia were analyzed and compared with the findings of control specimens obtained from 8 patients who underwent esophagectomy for intramucosal adenocarcinoma.

RESULTS: Control specimens had normal numbers of ganglion cells (0.70-0.91 ganglion cells per high-power field) and minimal inflammation. Three patients with vigorous achalasia had normal ganglion cell numbers (0.79-0.91 ganglion cells per high-power field) and at least mild myenteric inflammation without neural fibrosis. The remaining 8 patients had few or no ganglion cells (0-0.30 ganglion cells per high-power field) and at least mild myenteric inflammation and neural fibrosis. Ganglionitis was found in 2 cases. Ganglion cell number was inversely correlated with degree of myenteric neural fibrosis (P < 0.001).

CONCLUSIONS: Vigorous achalasia has pathological features that are distinct from classic achalasia. The earliest pathological changes consist of myenteric inflammation with injury to and subsequent loss of ganglion cells and injury to and fibrosis of myenteric nerves.

VARIANTS

Squamous Mucosal Alterations in Esophagectomy Specimens From Patients With End-Stage Achalasia

Michael B. Lehman, M.D. ; Sarah B. Clark, M.D. ; Adrian H. Ormsby, M.D. ; Thomas W. Rice, M.D. ; Joel E. Richter, M.D. ; John R. Goldblum, M.D.

From the Center for Swallowing and Esophageal Disorders and the Departments of Anatomic Pathology (M.B.L., S.B.C., A.H.O., J.R.G.), Cardiothoracic Surgery (T.W.R.), and Gastroenterology (J.E.R.), Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.

Am J Surg Pathol 2001;25:1413-1418 Abstract quote

Achalasia is an esophageal motor disorder in which the primary morphologic changes are found in the myenteric plexus. However, a number of secondary alterations are characteristically found in esophagectomy specimens, including the mucosa. In addition, these patients are at increased risk of developing esophageal squamous cell carcinoma.

We studied the squamous mucosal alterations in 35 esophagectomy specimens from patients with end-stage achalasia and compared them with those found in the squamous mucosa near the esophagogastric junction from pediatric autopsies (18 years) from patients with no known esophageal disease. A representative block was immunostained for p53 (DO7), CD3, and CD20. p53 immunoreactivity was graded as follows: 0 = no staining; 1+ = rare basal cell staining; 2+ = extensive basal cell staining; 3+ = suprabasilar staining. Intraepithelial lymphocyte counts were performed by counting five high power fields (HPF) and calculating an average/HPF. Ages of achalasia patients at esophagectomy ranged from 21 to 78 years (mean 56 years), including 20 men and 15 women. Disease duration ranged from 1 to 44 years (mean 17 years). In all cases the squamous mucosa from achalasia patients was markedly hyperplastic with papillomatosis and basal cell hyperplasia. p53 staining in the squamous mucosa from achalasia patients was significantly more common than in controls (32 of 35 [91%] vs 1 of 17 [6%]; p <0.05). In all achalasia cases CD3+ cells far outnumbered CD20+ cells. There was a significantly greater number of CD3+ cells in achalasia cases (range 32�239/HPF; mean 107/HPF) compared with controls (range 0.8�12/HPF; mean 6/HPF) (p <0.05).

In conclusion, the squamous mucosa in esophagectomy specimens from patients with end-stage achalasia shows significant alterations including marked squamous hyperplasia, an increased frequency of p53 immunoreactivity, and increased numbers of CD3+ cells when compared with controls. These changes may be related to the increased risk of squamous cell carcinoma in these patients.

SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHER CHARACTERIZATION

SPECIAL STAINS

IMMUNOPEROXIDASE

The nature of the myenteric infiltrate in achalasia: an immunohistochemical analysis.

Clark SB, Rice TW, Tubbs RR, Richter JE, Goldblum JR.

Center for Swallowing and Esophageal Disease and the Department of Anatomic Pathology, The Cleveland Clinic Foundation, Ohio, USA.

Am J Surg Pathol 2000 Aug;24(8):1153-8 Abstract quote

Achalasia is an esophageal motor disorder characterized by abnormal relaxation of the lower esophageal sphincter and absence of progressive peristalsis in the esophageal body. Previous studies evaluating esophagomyotomy and esophageal resection specimens have shown the presence of myenteric inflammation to be a consistent and early pathologic change in patients with achalasia.

Thus, the goal of this study was to determine the immunohistochemical characteristics of the inflammatory infiltrate within the myenteric plexus in patients with clinically early and end-stage achalasia. Using formalin-fixed tissue, we analyzed the immunohistochemical features of the myenteric lymphocytes using antibodies that recognize B cells (CD20), T cells (CD3), T cell subsets (CD8), and the activation state of T cell subpopulations (TIA-1 and granzyme B) in nine patients with clinically early achalasia who underwent esophagomyotomy and 13 patients with clinically endstage achalasia who underwent esophageal resection. The myenteric infiltrate in all nine esophagomyotomy specimens was composed predominantly of T cells (CD3-positive), the majority of which also stained for CD8. In five of nine specimens, the majority of CD8-positive cells stained for TIA-1. In the esophageal resection specimens, the myenteric infiltrate was composed predominantly of CD3-positive T cells in seven of 13 cases. In three cases, there was a predominance of CD20-positive B cells, and in the remaining three cases there were relatively equal numbers of T and B cells. In eight of 13 cases, the majority of T cells stained for CD8. TIA-1 immunoreactivity was found in the majority of CD8-positive cells in nine of 13 cases. In all esophagomyotomy and esophageal resection specimens studied, rare granzyme B-positive cells were detected.

In conclusion, the majority of myenteric inflammatory cells in patients with achalasia are CD3-positive T cells, most of which are also CD8-positive, although the relative percentage of such cells appears to decrease with disease progression. Furthermore, many of the CD3-positive/CD8-positive myenteric lymphocytes also express TIA-1, suggesting they are resting or activated cytotoxic T cells. The immunohistochemical demonstration of granzyme B in a subpopulation of these cells supports the contention that achalasia is an immune-mediated disease, although the inciting antigen remains an enigma.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

PSEUDO-ACHALASIA

Pseudo-achalasia following laparoscopically placed adjustable gastric banding.

Wiesner W, Hauser M, Schob O, Weber M, Hauser RS.

Institute for Diagnostic Radiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.

Obes Surg 2001 Aug;11(4):513-8 Abstract quote

BACKGROUND: The complication of pseudo-achalasia may occur after laparoscopic adjustable gastric banding (LAGB) in patients with normal band position and normal stomal width. We hypothesized that this complication occurs especially in patients with preexisting insufficiency of the lower esophageal sphincter (LES), who show poor compliance secondary to lacking the sensation of satiety and who therefore also have insufficient weight loss at follow-up.

METHODS: Early and late postoperative barium meal studies of 120 LAGB patients were retrospectively analyzed to identify patients who developed esophageal widening and dysmotility despite normal band position and normal stomal width. Results were compared with preoperative endoscopies, clinical findings, each patient's compliance with dietary instructions and postoperative weight loss.

RESULTS: 9/120 patients developed pouch dilatation, esophageal widening and esophageal dysmotility as a late complication, despite normal band position and normal stomal width. All these patients had shown preexisting insufficiency of their LES endoscopically. They all showed bad compliance with dietary instruction, and they all abused their distal esophagus as an additional pouch. 7 of these patients presented with insufficient weight loss at follow-up, whereas of 3 other patients with pre-existing LES insufficiency who had shown good compliance, only 1 showed insufficient weight loss. Insufficient weight loss after 1 year was significantly more common in patients with pre-existing LES insufficiency (8/12 patients, 67%) than in patients with a competent LES (26/108 patients, 24%).

CONCLUSION: Patients with pre-existing LES insufficiency appear to be at risk for pouch dilatation and esophageal decompensation despite normal band position and normal stomal width. These patients are prone to show lack of satiety and poor compliance with dietary instruction, use of their lower esophagus as additional space for food, and tend to have insufficient weight loss. Preoperative manometry should be used to identify such patients, where the indication for gastric banding should be discussed very critically.

The pathogenesis of pseudoachalasia: a clinicopathologic study of 13 cases of a rare entity.

Liu W, Fackler W, Rice TW, Richter JE, Achkar E, Goldblum JR.

Department of Anatomic Pathology, Cleveland Clinic Foundation, Ohio 44195, USA.

Am J Surg Pathol 2002 Jun;26(6):784-8 Abstract quote
Pseudoachalasia is an esophageal motor disorder usually associated with malignancy that has clinical, radiographic, and manometric findings that are often indistinguishable from primary achalasia. There are few reports examining the histologic features of the associated neoplasms and their relationship with the esophageal myenteric plexus.

We studied the clinical and pathologic features of 13 cases of pseudoachalasia seen at our institution between 1979 and 1999. Detailed clinical and radiographic data were obtained from medical records. In all cases available histologic material was reviewed to confirm the presence and type of associated neoplasm. When possible, the relationship of the neoplasm to the esophageal myenteric plexus was examined. In selected cases immunohistochemical stains were performed to further evaluate this relationship.

All patients had clinical, radiographic, and manometric features similar to primary achalasia. The cohort included seven men and six women, age range 24-79 years (median 61 years). Associated neoplasms included esophageal adenocarcinoma arising in Barrett's esophagus (n = 1), adenocarcinoma of the esophagogastric junction (n = 7), metastatic renal cell carcinoma to the esophagogastric junction (n = 1), breast adenocarcinoma (n = 1), pulmonary small cell carcinoma (n = 1), pleural malignant mesothelioma (n = 1), and mediastinal fibrosis (n = 1). The mechanism of pseudoachalasia was consistent with neoplastic infiltration of the esophageal myenteric plexus in 11 cases. Neoplastic cells surrounded myenteric ganglion cells, which appeared normal in number and morphology. In the patient with pulmonary small cell carcinoma, there was no evidence of neoplastic infiltration of the esophagogastric junction, and anti-ANNA-1 antibody was detected, suggesting a paraneoplastic syndrome. Tissue obtained at the time of esophagomyotomy revealed lymphocytic myenteric inflammation and marked depletion of ganglion cells identical to that seen in primary achalasia.

The mechanism pseudoachalasia in the patient with breast adenocarcinoma is uncertain, as there was no evidence of direct involvement of the esophagogastric junction. In summary, we describe 13 cases of pseudoachalasia resulting in a clinical syndrome indistinguishable from primary achalasia. The most common mechanism is direct involvement of the esophageal myenteric plexus by neoplastic cells. Rarely, a distant neoplasm may cause this syndrome as a paraneoplastic process.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

Esophageal carcinoma and achalasia: prevalence, incidence and results of treatment.

Peracchia A, Segalin A, Bardini R, Ruol A, Bonavina L, Baessato M.

Clinica Chirurgica I, Padova, Italy

Hepatogastroenterology 1991 Dec;38(6):514-6 Abstract quote

Between 1980 and 1988, we treated 1,521 patients with squamous cell carcinoma of the esophagus and 336 patients with adenocarcinoma of the gastric cardia. Between 1967 and 1988, 244 patients with esophageal achalasia were also observed. Among 1,857 patients with cancer, achalasia was present in 21 cases (1.1%). In 18 patients the mean and median interval between the diagnosis of achalasia and cancer was 11.5 and 8 years, respectively. In 3 cases achalasia was detected during the work-up for esophageal cancer. The previous treatment for achalasia administered elsewhere was as follows: balloon dilatation in 6 cases, myotomy and Nissen repair in 2, and distal esophageal resection in 1. Thirteen patients (61.9%) underwent resection, resulting in 1 postoperative death, and a mean and median survival of 23.3 and 13 months, respectively. Push intubation was performed in 4 cases, chemotherapy in 2, a by-pass procedure in 1, endoscopic Nd:YAG laser in 1, while 1 further patient did not receive any treatment for the carcinoma, but only balloon dilatation of the LES. The mean follow-up of the 244 patients with primary esophageal achalasia was 44.6 months (range 1-108), and only 1 patient developed an esophageal cancer, giving an incidence of 18.6 cases per 100,000 per year.

Conclusions: in our experience, achalasia is present in a minority of patients with esophageal cancer, and larger prospective controlled trials are needed to assess the true incidence of malignant degeneration in the achalasic patient.

Achalasia complicated by oesophageal squamous cell carcinoma: a prospective study in 195 patients.

Meijssen MA, Tilanus HW, van Blankenstein M, Hop WC, Ong GL.

Department of Internal Medicine II, Erasmus University Hospital Dijkzigt, Rotterdam, The Netherlands.

Gut 1992 Feb;33(2):155-8 Abstract quote

To determine the incidence of oesophageal carcinoma in patients with achalasia and to establish the efficacy of endoscopic surveillance, 195 consecutive patients with achalasia (90 men and 105 women, mean age 52 years), who were treated by pneumatic dilatation in our institution between 1973 and 1988 were prospectively studied.

None of the patients had undergone cardiomyotomy. Follow up totalled 874 person years after pneumatic dilatation. In this period three patients developed an oesophageal squamous cell carcinoma. The mean age at diagnosis of the oesophageal carcinoma was 68 years (37, 77, and 89 years). The mean period between the onset of dysphagia and the diagnosis of the tumour was 17 years (19, 28, and 5 years); the mean interval between the diagnosis of achalasia and carcinoma was 5.7 years (5, 8, and 4 years). The incidence of oesophageal squamous cell carcinoma in this series (3.4/1000 patients per year) is significantly higher than the statistically expected incidence (0.104/1000 patients per year) using age and sex specific incidence data from the population of the Netherlands (Poisson statistics: p less than 0.001).

The risk of developing oesophageal squamous cell carcinoma in patients with achalasia is therefore increased 33 fold. Periodic endoscopy showed the potential for detecting early stage oesophageal carcinoma in two cases but a larger study with a longer follow up is required to determine the efficacy of endoscopic screening in improving the prognosis for patients with achalasia who develop oesophageal squamous cell carcinoma.

Achalasia and squamous cell carcinoma of the esophagus: analysis of 241 patients.

Streitz JM Jr, Ellis FH Jr, Gibb SP, Heatley GM.

Duluth Clinic, University of Minnesota School of Medicine, USA.

Ann Thorac Surg 1995 Jun;59(6):1604-9 Abstract quote

Achalasia of the esophagus is presumed by many to be a premalignant lesion leading to an increased risk of squamous cell carcinoma. There is disagreement, however, as to the precise risk of malignant degeneration and there is no consensus as to either the need for close surveillance of achalasia patients or the surveillance technique that should be employed.

A review of the available literature on the subject has disclosed a wide range of reported cancer risks in achalasia patients, from zero to 33 times that of the normal population. Cancers, when discovered, are often unresectable and the median survival when they are resectable is low. A personal experience with 241 achalasia patients treated during the past quarter of a century disclosed that 9 had carcinoma, for a prevalence of 3.7%. Carcinoma developed in 3 of these 9 while they were under our observation. This translates into one cancer per 1,138 patient-years of follow-up, an incidence of 88 per 100,000 population, and a risk 14.5 times that of the age-adjusted and sex-adjusted general population. Because of the low postresection survival rate if treatment is delayed until carcinoma of the esophagus becomes symptomatic, closer surveillance of achalasia patients is recommended than has been the case.

Because it seems unlikely that close endoscopic surveillance will prove to be cost-effective, periodic (every 2 to 3 years) blind brush biopsy warrants further study as a means of surveillance.

Achalasia and esophageal cancer: incidence, prevalence, and prognosis.

Brucher BL, Stein HJ, Bartels H, Feussner H, Siewert JR.

Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universitat, Ismaninger Strasse 22, 81675 Munchen, Germany.

World J Surg 2001 Jun;25(6):745-9 Abstract quote

Reported incidence rates of carcinoma in patients with achalasia and the prevalence of achalasia in patients with esophageal cancer vary widely in the literature. The prognosis of an "achalasia-carcinoma" is generally considered poor, although systematic studies assessing the incidence, prevalence, and prognosis of patients with "achalasia-carcinoma" are scant.

We investigated the incidence of esophageal cancer in a large series of patients with known achalasia, assessed the prevalence of achalasia in patients presenting with esophageal cancer, and evaluated the prognosis of these patients compared to that of patients with esophageal cancer without achalasia. Between 1982 and 1998 a total of 124 patients with primary achalasia were treated and followed at our department. During the same time period 1366 patients presented with esophageal cancer (879 esophageal squamous cell carcinomas, 487 adenocarcinomas). Of the 124 patients with primary achalasia, 4 developed a carcinoma during a mean follow-up of 5.6 years (i.e., an incidence of one 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 (50%) had early-stage disease (stage I, IIA, or IIB). There was no difference in the prognosis of patients with resected achalasia-carcinoma versus those with esophageal carcinoma but no achalasia.

Thus in our 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. With liberal use of surveillance, carcinoma could often be detected at an early stage in these patients, with a prognosis that was not worse than that of patients with squamous cell esophageal cancer but no achalasia.

TREATMENT

Controlled trial of botulinum toxin injection versus placebo and pneumatic dilation in achalasia.

Annese V, Basciani M, Perri F, Lombardi G, Frusciante V, Simone P, Andriulli A, Vantrappen G.

Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy.

Gastroenterology 1996 Dec;111(6):1418-24 Abstract quote

BACKGROUND & AIMS: Intrasphincteric injection of botulinum toxin has been suggested as an alternative treatment modality in esophageal achalasia. A controlled trial comparing botulinum toxin, placebo, and pneumatic dilation is reported.

METHODS: Sixteen patients received random intrasphincteric injections of either botulinum toxin or saline. The efficacy of treatment was assessed by symptom score, esophageal manometry, and scintigraphy. In case of failure, pneumatic dilation was performed.

RESULTS: One month after injection, symptoms had improved in all patients treated with botulinum toxin (symptom score, 0.9 +/- 0.6 vs. 5.5 +/- 1.4; P < 0.02). In the placebo group, symptoms were unchanged in all patients, who were all dilated. Lower esophageal sphincter pressure decreased by 49% after treatment with botulinum toxin (P < 0.03) and by 72% after dilation (P < 0.01). Similarly, esophageal retention decreased by 47% after treatment with botulinum toxin (P < 0.02) and by 59% after dilation (P < 0.02). No significant difference in symptom score and esophageal function test results was found between patients treated with botulinum toxin injections and those undergoing dilation. However, 7 of the 8 patients in the botulinum toxin group required a second injection because of recurrent dysphagia.

CONCLUSIONS: Treatment of achalasia with botulinum toxin was as effective as pneumatic dilation in relieving symptoms and improving esophageal function. The effect of the first injection was temporary, but the effect of the second injection lasted longer.

Evaluation of the use of botulinum toxin in children with achalasia.

Hurwitz M, Bahar RJ, Ament ME, Tolia V, Molleston J, Reinstein LJ, Walton JM, Erhart N, Wasserman D, Justinich C, Vargas J.

Department of Pediatrics, University of California Los Angeles School of Medicine, 90095-1752, USA.

J Pediatr Gastroenterol Nutr 2000 May;30(5):509-14 Abstract quote

BACKGROUND: Achalasia is rare in children. Recently, injection of botulinum toxin into the lower esophageal sphincter has been studied as an alternative to esophageal pneumatic dilatation or surgical myotomy as treatment for achalasia. In the current study, the effects of botulinum toxin were investigated in the largest known series of children with achalasia.

METHODS: Treatment for achalasia was assessed in 23 pediatric patients who received botulinum toxin from June 1995 through November 1998. Those who continued to receive botulinum toxin and did not subsequently undergo pneumatic dilatation or surgery were considered repeat responders. Results were compared with those of published studies evaluating the use of botulinum toxin in adults with achalasia.

RESULTS: Nineteen patients initially responded to botulinum toxin. Mean duration of effect was 4.2 months +/- 4.0 (SD). At the end of the study period, three were repeat responders, three experienced dysphagia but did not receive pneumatic dilatation or surgery, three underwent pneumatic dilatation, eight underwent surgery, three underwent pneumatic dilatation with subsequent surgery, and three awaited surgery. Meta-analysis shows that, in the current study group, the data point expressing time of follow-up evaluation versus percentage of patients needing one injection session without additional procedures (botulinum toxin injection, pneumatic dilatation, or surgery) falls within the curve for those in studies on adult patients receiving botulinum toxin for achalasia.

CONCLUSIONS: Botulinum toxin effectively initiates the resolution of symptoms associated with achalasia in children. However, one half of patients are expected to need an additional procedure approximately 7 months after one injection session. The authors recommend that botulinum toxin be used only for children with achalasia who are poor candidates for either pneumatic dilatation or surgery.

Laparoscopic and Thoracoscopic Esophagomyotomy for Children With Achalasia.

Mehra M, Bahar RJ, Ament ME, Waldhausen J, Gershman G, Georgeson K, Fox V, Fishman S, Werlin S, Sato T, Hill I, Tolia V, Atkinson J.

Department of Pediatrics, Division of Gastroenterology and Nutrition, and Department of Pediatric Surgery, University of California Los Angeles School of Medicine, Los Angeles, California; Department of Surgery, Children's Hospital and Regional Medical Center, Seattle, Washington; Department of Surgery, Children's Hospital, Birmingham, Alabama; Department of Pediatrics, Division of Gastroenterology and Department of Surgery, Children's Hospital, Boston, Massachusetts; Department of Pediatrics, Division of Gastroenterology and Department of Pediatric Surgery, Children's Hospital of Wisconsin and Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pediatrics, Division of Gastroenterology, Wake Forest University School of Medicine, Winston-Salem, North Carolina; #Department of Pediatrics, Division of Gastroenterology, Children's Hospital of Michigan, Detroit, Michigan, U.S.A.

J Pediatr Gastroenterol Nutr 2001 Oct;33(4):466-471 ABSTRACT QUOTE

BACKGROUND: Minimally invasive esophagomyotomy, consisting of a laparoscopic or thoracoscopic approach, has become a preferred surgical treatment for adults with achalasia. This multicenter study reports on the clinical status of children who have undergone minimally invasive esophagomyotomy for achalasia.

METHODS: Symptomatology for achalasia was assessed in 22 pediatric patients who underwent minimally invasive esophagomyotomy for achalasia between 1995 and 2000. All patients were evaluated for duration of hospitalization, postoperative resumption of feeds, postoperative complications, and symptomatic relief. Participants were assigned pre-and postoperative symptom severity scores ranging from 0 (no symptoms) to 3 (severe).

RESULTS: The median age of the 10 females and 12 males at time of surgery was 11.3 years +/- 3.4 (standard deviation). Transabdominal laparoscopic esophagomyotomy with fundoplication was performed in 18 patients, and thoracoscopic esophagomyotomy without fundoplication was performed in 4. Two patients required conversion from transabdominal laparoscopic esophagomyotomy to open esophagomyotomy because of intraoperative esophageal perforation. The mean duration of postsurgical follow-up was 17 +/- 16 (standard deviation) months (range, 1-54 months). Mean duration of hospitalization (days +/- standard error or mean) was less for transabdominal laparoscopic esophagomyotomy than for converted open esophagomyotomy (2.7 +/- 0.3 vs. 9.0 +/- 3.0 days; P < 0.05) or for thoracoscopic esophagomyotomy (4.8 +/- 1.7 days; P = not significant). Mean time to resumption of soft feedings (days +/- standard error or mean) occurred sooner after transabdominal laparoscopic esophagomyotomy than after converted open esophagomyotomy (2.0 +/- 0.2 vs. 5.5 +/- 0.5 days; P < 0.001) or after thoracoscopic esophagomyotomy (4.0 +/- 1.3 days; P = not significant). Patients experienced significant pre-to postoperative improvement in mean severity score with regard to dysphagia (2.6 vs. 0.4; P < 0.001) and regurgitation (1.7 vs. 0.2; P < 0.001).

CONCLUSIONS: Minimally invasive esophagomyotomy can provide excellent symptomatic relief from dysphagia and regurgitation for children with achalasia.

Pneumatic dilatation for childhood achalasia.

Babu R, Grier D, Cusick E, Spicer RD.

Department of Paediatric Surgery, Royal Hospital for Sick Children, Bristol, UK.

Pediatr Surg Int 2001 Sep;17(7):505-7 Abstract quote

Treatment of achalasia by pneumatic balloon dilatation (PBD) is well established in adults. Due to limited experience and the rarity of the condition in children, there are relatively few reports in the paediatric literature. Although PBD has been reported as a primary method of treatment, there are no reports of secondary PBD for childhood achalasia.

Between 1995 and 1999, five patients underwent treatment for achalasia (age: 9-14 years, M:F = 4:1). The presenting symptoms were dysphagia (5). vomiting episodes (2), aspiration (1), food-bolus obstruction (1), and failure to thrive (1). In all patients a barium swallow and manometry were used to confirm the diagnosis. Three underwent primary PBD. Two who had previously undergone surgical myotomy underwent secondary PBD for recurrence of symptoms. Dilatation was performed using a 35-mm balloon with the child under general anaesthesia. Technical success was defined as demonstration of a waist under screening at lower pressures followed by abolition of the waist at higher pressures. In addition to reviewing our results, a systematic review of the literature was performed (Medline, Cochrane Library, Pubmed, Embase). Three patients (primary dilatation) showed excellent improvement after a single dilatation. In two cases (secondary dilatation) three and five attempts were required. No complications were encountered. The mean follow-up period was 2 years (1-3.5 years) and four patients remained asymptomatic, an overall success rate of 80%. The literature review revealed similar good results in most of the recent reports.

Thus, PBD as a primary treatment for childhood achalasia has a success rate of 70%-90% with minimal side effects, short hospital stay, and good patient acceptability over an operation. We have also established the usefulness of this method as a secondary treatment when symptoms recur after surgery.

Thoracoscopic esophagomyotomy for achalasia: Preoperative patterns of acid reflux and long-term follow-up.

Maher JW, Conklin J, Heitshusen DS.

Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa, and the Department of Gastroenterology, Mayo Clinic, Rochester, Minn.

Surgery 2001 Oct;130(4):570-7 Abstract quote

Background. The best technique for surgical esophagomyotomy to treat achalasia remains contentious. The controversies include the best approach (thoracoscopic or laparoscopic) and the need for an antireflux procedure. Postoperative pH studies have suggested pathologic gastroesophageal reflux (GER) in many cases; however, control studies of reflux patterns are scarce. This study presents pH studies before esophagomyotomy as well as long-term follow-up of patients undergoing esophagomyotomy.

Methods. Forty-nine patients underwent esophagomyotomy (45 thoracoscopically, 4 laparoscopically) for achalasia. Before treatment, 24-hour pH studies were conducted for 38 patients with achalasia. The patients were evaluated postoperatively for dysphagia and reflux. Results were classified as excellent, good, fair, or poor.

Results. The findings of the pretreatment pH studies were abnormal in 15 patients (39%). Twelve patients (32%) had GER either with esophageal fermentation (6 patients [16%]) or without fermentation (6 patients [16%]). Eight percent had esophageal fermentation alone. There was no correlation between GER and previous pneumatic dilatation. Twenty-three patients (60%) had normal pH scores; of these, 24% had esophageal fermentation, whereas 29% had neither reflux nor fermentation. Operative results were excellent in 70% of patients, good in 10%, and fair in 20%. All patients considered their conditions improved. Four patients required a subsequent operation because of dysphagia (n = 3) or reflux (n = 1), and their original procedures were classified as failures. Their current status is fair (n = 2), good (n = 1), and excellent (n = 1). GER was documented before the original operation in 3 of the 4 patients in whom the procedure failed. Fifteen patients were eligible for 5-year follow-up. Their results are excellent or good (n = 11) (73%) and fair (n = 4) (27%).

Conclusions. A high percentage of patients with achalasia exhibit pathologic GER before surgical therapy and seem to be at higher risk for failed surgical treatment. Thoracoscopic esophagomyotomy resulted in improvement in 92% of patients, and long-term follow-up indicates that these results are durable.

Esophagectomy for achalasia: patient selection and clinical experience.

Devaney EJ, Lannettoni MD, Orringer MB, Marshall B.

Department of Surgery, University of Michigan Medical Center, Ann Arbor 48109, USA

Ann Thorac Surg 2001 Sep;72(3):854-8 Abstract quote

BACKGROUND: In 1989, we predicted an increasing number of esophagectomies for megaesophagus and for recurrent symptoms after prior esophagomyotomy or balloon dilatation for achalasia. Patient selection in this group is challenging, as the potential operative morbidity of an esophagectomy must be weighed against the expected clinical outcome after a redo esophagomyotomy or alternative procedures designed to salvage the native esophagus.

METHODS: The hospital records of 93 patients undergoing esophagectomy for achalasia during the past 20 years were reviewed retrospectively and the results of operation assessed using our prospectively established Esophageal Resection Database and follow-up information obtained through personal contact with the patients.

RESULTS: Patient age averaged 51 years. Indications for esophagectomy included tortuous megaesophagus (64%), failure of prior myotomy (63%), and associated reflux stricture (7%). Ninety-four percent of the patients underwent a transhiatal esophagectomy. Stomach was used as the esophageal substitute in 91% cases. Intraoperative blood loss averaged 672 mL. Postoperative length of stay averaged 12.5 days. Major complications included anastomotic leak (10%), recurrent laryngeal nerve injury (5%), delayed mediastinal bleeding requiring thoracotomy (2%), and chylothorax (2%). There were 2 hospital deaths (2%) from respiratory insufficiency and sepsis. Follow-up has averaged 38 months. In all, 95% of patients eat well; nearly 50% have required an anastomotic dilatation; troublesome regurgitation has been rare; and 4% have refractory postvagotomy dumping.

CONCLUSIONS: Esophagectomy, preferably through a transhiatal approach, is generally safe and effective therapy in selected patients with achalasia. Unique technical considerations include difficulty encircling the dilated cervical esophagus, deviation of the esophagus into the right chest, large aortic esophageal arteries, and adherence of the exposed esophageal submucosa to the adjacent aorta after prior myotomy.

Laparoscopic Heller myotomy and Dor fundoplication for achalasia: analysis of successes and failures.

Patti MG, Molena D, Fisichella PM, Whang K, Yamada H, Perretta S, Way LW.

Department of Surgery, University of California, 533 Parnassus Ave, Room U-122, San Francisco, CA 94143-0788, USA.

Arch Surg 2001 Aug;136(8):870-7 Abstract quote

BACKGROUND: In the treatment of achalasia, surgery has been traditionally reserved for patients with residual dysphagia after pneumatic dilatation. The results of laparoscopic Heller myotomy have proven to be so good, however, that most experts now consider surgery the primary treatment.

HYPOTHESIS: The outcome of laparoscopic myotomy and fundoplication for achalasia is dictated by technical factors.

SETTING: University hospital tertiary care center.

DESIGN: Retrospective study.

PATIENTS AND METHODS: One hundred two patients with esophageal achalasia underwent laparoscopic Heller myotomy and Dor fundoplication. Fifty-seven patients had been previously treated by pneumatic dilatation or botulinum toxin. The design of the operation involved a 7-cm myotomy, which extended 1.5 cm onto the gastric wall, and a Dor fundoplication. Esophagrams, esophageal manometric findings, and video records of the procedure were analyzed to determine the technical factors that contributed to the clinical success or failure of the operation.

MAIN OUTCOME MEASURE: Swallowing status.

RESULTS: In 91 (89%) of the 102 patients, good or excellent results were obtained after the first operation. A second operation was performed in 5 patients to either lengthen the myotomy (3 patients) or take down the fundoplication (2 patients). Dysphagia resolved in 4 of these patients. The remaining 6 patients were treated by pneumatic dilatation, but dysphagia improved in only 1. At the conclusion of treatment, excellent or good results had been obtained in 96 (94%) of the 102 patients.

CONCLUSIONS: These data show that a Heller myotomy was unsuccessful in patients with an esophageal stricture; a short myotomy and a constricting Dor fundoplication were the avoidable causes of residual dysphagia; a second operation, but not pneumatic dilatation, was able to correct most failures; and that the identified technical flaws were eliminated from the last half of the patients in the series.

Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.

Commonly Used Terms

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Esophagus

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EPIDEMIOLOGY	CHARACTERIZATION
GEOGRAPHY
Five year prospective study of the incidence, clinical features, and diagnosis of achalasia in Edinburgh. Howard PJ, Maher L, Pryde A, Cameron EW, Heading RC. Department of Medicine, Royal Infirmary of Edinburgh.	Gut 1992 Aug;33(8):1011-5 Abstract quote With the increasing availability of manometry, patients with achalasia are often referred at an early stage when they lack the classic features of established disease. A prospective five year study of the presenting features of untreated achalasia referred to our department was undertaken. Twenty men and 18 women presented throughout adult life, with a mean age at the time of diagnosis of 44 years (range 17 to 76 years). The presenting symptoms were dysphagia: for solids (100%) and for liquids (97%), chest pain (74%), and weight loss (60%). Endoscopy was reported as normal in 15 patients and achalasia was suggested in only 21 of 33 barium examinations. Fourteen had been treated for gastrooesophageal reflux but none had been misdiagnosed as having cardiac or psychiatric disease. The annual incidence of achalasia in the Lothian region is 0.8/100,000 of population. Persistent dysphagia is the cardinal symptom of achalasia which presents throughout adult life. Nevertheless, recent onset achalasia is often misdiagnosed as gastrooesophageal reflux disease. Because endoscopy is frequently normal and the diagnosis is often not made by radiology, manometric investigation is necessary if the condition is to be recognised and treated at an early stage.
A prospective study of the clinical features, manometric findings, incidence and prevalence of achalasia in Singapore. Ho KY, Tay HH, Kang JY. Department of Medicine, National University of Singapore.	J Gastroenterol Hepatol 1999 Aug;14(8):791-5 Abstract quote BACKGROUND: This study aimed to describe the clinical features, manometric findings, prevalence and incidence of achalasia in Singapore. METHODS: A total of 615 new patients referred for oesophageal manometry between 1989 and 1996 were examined prospectively. Twenty-four men and 25 women fulfilled the manometric and clinical criteria for achalasia. RESULTS: Their median age of onset of symptoms was 37 years (range 15-71) and 37% first developed symptoms after the age of 50 years. The presenting symptoms were dysphagia (100%), regurgitation (80%), weight loss (67%) and chest discomfort (33%). Five patients (10%) had a history of benign (mostly autoimmune) thyroid disorders. Endoscopy was reported as normal in 10/43 patients (23%) and achalasia was suggested in only 31 (72%) of 43 barium examinations. Lower oesophageal sphincter (LOS) dysfunction was present in 82% of cases. Using data from medical records and from a survey of gastroenterologists and surgeons in Singapore, the prevalence (in 1996) and incidence of achalasia in Singapore were estimated to be 1.8 per 100000, and 0.3 per 100000 per year, respectively. The incidence was significantly lower in Malays than Chinese or Indians. The age-specific incidence of achalasia for both genders followed a bimodal distribution with the larger peak in the sixth decade. No cases of oesophageal carcinoma were identified among these patients. CONCLUSION: Achalasia is an uncommon condition in Singapore. The clinical and manometric features were similar to those described in Western countries.

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
Achalasia. A morphologic study of 42 resected specimens. Goldblum JR, Whyte RI, Orringer MB, Appelman HD. Department of Pathology, University of Michigan Hospitals, Ann Arbor	Am J Surg Pathol 1994 Apr;18(4):327-37 Abstract quote Achalasia is characterized by failure of relaxation of the lower esophageal sphincter and absence of progressive peristalsis in the esophageal body. Few data are available regarding the morphologic features of achalasia, in particular its histologic progression. The esophagi of 42 patients with achalasia treated with total thoracic esophagectomy were examined histologically in order to systematically identify morphologic features of clinically unresponsive achalasia and to determine what could be learned about the disease's evolution. In all cases, 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- and distal portions of the esophagus. Inflammation within myenteric nerves, present in all cases, generally consisted of a mixture of lymphocytes and eosinophils, occasionally with plasma and mast cells. Focal replacement of myenteric nerves by collagen occurred in all cases, and there was almost complete replacement in several cases. Actual destruction of the residual ganglion cells was not seen. The resected esophagi also shared extramyenteric morphologic features. Some features probably stemmed from physiologic obstruction, such as muscular hypertrophy, mainly of the muscularis propria (all cases), with secondary degeneration and fibrosis (29 cases), and eosinophilia of the muscularis propria (22 cases). Other changes, probably resulting from chronic stasis of ingested materials in the lumen, included diffuse squamous hyperplasia (all cases), lymphocytic mucosal esophagitis (28 cases), lymphocytic inflammation of the lamina propria and submucosa with prominent germinal centers (all cases), and submucosal periductal or glandular inflammation with complete loss of submucosal glands in half of the cases. One patient had high-grade squamous dysplasia, and another had superficially invasive squamous cell carcinoma. A third group of changes was probably due to previous esophagomyotomy, including abnormal gastroesophageal reflux, as shown by pH reflux testing (13 cases) and Barrett's mucosa (four cases). In one case of Barrett's there was low-grade dysplasia. Clinically unresponsive, surgically resected achalasia has almost total loss of ganglion cells, and widespread destruction of myenteric nerves has already occurred. The only active component is myenteric inflammation. However, it cannot be determined whether this inflammation is a manifestation of ongoing nerve destruction or whether it is a secondary phenomenon.
Histopathologic features in esophagomyotomy specimens from patients with achalasia. Goldblum JR, Rice TW, Richter JE. Department of Anatomic Pathology, Cleveland Clinic Foundation, Ohio, USA.	Gastroenterology 1996 Sep;111(3):648-54 Abstract quote BACKGROUND & AIMS: A previous study evaluating the morphological features of esophagi resected for endstage achalasia showed marked depletion of myenteric ganglion cells, widespread destruction of nerves, and variable chronic inflammation. The aim of this study was to evaluate the histological features in esophagomyotomy specimens from 11 patients with early achalasia, defined as minimal to moderate esophageal dilation without sigmoid deformity. METHODS: The histological features of esophagomyotomy specimens from 11 patients with achalasia were analyzed and compared with the findings of control specimens obtained from 8 patients who underwent esophagectomy for intramucosal adenocarcinoma. RESULTS: Control specimens had normal numbers of ganglion cells (0.70-0.91 ganglion cells per high-power field) and minimal inflammation. Three patients with vigorous achalasia had normal ganglion cell numbers (0.79-0.91 ganglion cells per high-power field) and at least mild myenteric inflammation without neural fibrosis. The remaining 8 patients had few or no ganglion cells (0-0.30 ganglion cells per high-power field) and at least mild myenteric inflammation and neural fibrosis. Ganglionitis was found in 2 cases. Ganglion cell number was inversely correlated with degree of myenteric neural fibrosis (P < 0.001). CONCLUSIONS: Vigorous achalasia has pathological features that are distinct from classic achalasia. The earliest pathological changes consist of myenteric inflammation with injury to and subsequent loss of ganglion cells and injury to and fibrosis of myenteric nerves.
VARIANTS
Squamous Mucosal Alterations in Esophagectomy Specimens From Patients With End-Stage Achalasia Michael B. Lehman, M.D. ; Sarah B. Clark, M.D. ; Adrian H. Ormsby, M.D. ; Thomas W. Rice, M.D. ; Joel E. Richter, M.D. ; John R. Goldblum, M.D. From the Center for Swallowing and Esophageal Disorders and the Departments of Anatomic Pathology (M.B.L., S.B.C., A.H.O., J.R.G.), Cardiothoracic Surgery (T.W.R.), and Gastroenterology (J.E.R.), Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.	Am J Surg Pathol 2001;25:1413-1418 Abstract quote Achalasia is an esophageal motor disorder in which the primary morphologic changes are found in the myenteric plexus. However, a number of secondary alterations are characteristically found in esophagectomy specimens, including the mucosa. In addition, these patients are at increased risk of developing esophageal squamous cell carcinoma. We studied the squamous mucosal alterations in 35 esophagectomy specimens from patients with end-stage achalasia and compared them with those found in the squamous mucosa near the esophagogastric junction from pediatric autopsies (18 years) from patients with no known esophageal disease. A representative block was immunostained for p53 (DO7), CD3, and CD20. p53 immunoreactivity was graded as follows: 0 = no staining; 1+ = rare basal cell staining; 2+ = extensive basal cell staining; 3+ = suprabasilar staining. Intraepithelial lymphocyte counts were performed by counting five high power fields (HPF) and calculating an average/HPF. Ages of achalasia patients at esophagectomy ranged from 21 to 78 years (mean 56 years), including 20 men and 15 women. Disease duration ranged from 1 to 44 years (mean 17 years). In all cases the squamous mucosa from achalasia patients was markedly hyperplastic with papillomatosis and basal cell hyperplasia. p53 staining in the squamous mucosa from achalasia patients was significantly more common than in controls (32 of 35 [91%] vs 1 of 17 [6%]; p <0.05). In all achalasia cases CD3+ cells far outnumbered CD20+ cells. There was a significantly greater number of CD3+ cells in achalasia cases (range 32�239/HPF; mean 107/HPF) compared with controls (range 0.8�12/HPF; mean 6/HPF) (p <0.05). In conclusion, the squamous mucosa in esophagectomy specimens from patients with end-stage achalasia shows significant alterations including marked squamous hyperplasia, an increased frequency of p53 immunoreactivity, and increased numbers of CD3+ cells when compared with controls. These changes may be related to the increased risk of squamous cell carcinoma in these patients.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
PSEUDO-ACHALASIA
Pseudo-achalasia following laparoscopically placed adjustable gastric banding. Wiesner W, Hauser M, Schob O, Weber M, Hauser RS. Institute for Diagnostic Radiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.	Obes Surg 2001 Aug;11(4):513-8 Abstract quote BACKGROUND: The complication of pseudo-achalasia may occur after laparoscopic adjustable gastric banding (LAGB) in patients with normal band position and normal stomal width. We hypothesized that this complication occurs especially in patients with preexisting insufficiency of the lower esophageal sphincter (LES), who show poor compliance secondary to lacking the sensation of satiety and who therefore also have insufficient weight loss at follow-up. METHODS: Early and late postoperative barium meal studies of 120 LAGB patients were retrospectively analyzed to identify patients who developed esophageal widening and dysmotility despite normal band position and normal stomal width. Results were compared with preoperative endoscopies, clinical findings, each patient's compliance with dietary instructions and postoperative weight loss. RESULTS: 9/120 patients developed pouch dilatation, esophageal widening and esophageal dysmotility as a late complication, despite normal band position and normal stomal width. All these patients had shown preexisting insufficiency of their LES endoscopically. They all showed bad compliance with dietary instruction, and they all abused their distal esophagus as an additional pouch. 7 of these patients presented with insufficient weight loss at follow-up, whereas of 3 other patients with pre-existing LES insufficiency who had shown good compliance, only 1 showed insufficient weight loss. Insufficient weight loss after 1 year was significantly more common in patients with pre-existing LES insufficiency (8/12 patients, 67%) than in patients with a competent LES (26/108 patients, 24%). CONCLUSION: Patients with pre-existing LES insufficiency appear to be at risk for pouch dilatation and esophageal decompensation despite normal band position and normal stomal width. These patients are prone to show lack of satiety and poor compliance with dietary instruction, use of their lower esophagus as additional space for food, and tend to have insufficient weight loss. Preoperative manometry should be used to identify such patients, where the indication for gastric banding should be discussed very critically.
The pathogenesis of pseudoachalasia: a clinicopathologic study of 13 cases of a rare entity. Liu W, Fackler W, Rice TW, Richter JE, Achkar E, Goldblum JR. Department of Anatomic Pathology, Cleveland Clinic Foundation, Ohio 44195, USA.	Am J Surg Pathol 2002 Jun;26(6):784-8 Abstract quote Pseudoachalasia is an esophageal motor disorder usually associated with malignancy that has clinical, radiographic, and manometric findings that are often indistinguishable from primary achalasia. There are few reports examining the histologic features of the associated neoplasms and their relationship with the esophageal myenteric plexus. We studied the clinical and pathologic features of 13 cases of pseudoachalasia seen at our institution between 1979 and 1999. Detailed clinical and radiographic data were obtained from medical records. In all cases available histologic material was reviewed to confirm the presence and type of associated neoplasm. When possible, the relationship of the neoplasm to the esophageal myenteric plexus was examined. In selected cases immunohistochemical stains were performed to further evaluate this relationship. All patients had clinical, radiographic, and manometric features similar to primary achalasia. The cohort included seven men and six women, age range 24-79 years (median 61 years). Associated neoplasms included esophageal adenocarcinoma arising in Barrett's esophagus (n = 1), adenocarcinoma of the esophagogastric junction (n = 7), metastatic renal cell carcinoma to the esophagogastric junction (n = 1), breast adenocarcinoma (n = 1), pulmonary small cell carcinoma (n = 1), pleural malignant mesothelioma (n = 1), and mediastinal fibrosis (n = 1). The mechanism of pseudoachalasia was consistent with neoplastic infiltration of the esophageal myenteric plexus in 11 cases. Neoplastic cells surrounded myenteric ganglion cells, which appeared normal in number and morphology. In the patient with pulmonary small cell carcinoma, there was no evidence of neoplastic infiltration of the esophagogastric junction, and anti-ANNA-1 antibody was detected, suggesting a paraneoplastic syndrome. Tissue obtained at the time of esophagomyotomy revealed lymphocytic myenteric inflammation and marked depletion of ganglion cells identical to that seen in primary achalasia. The mechanism pseudoachalasia in the patient with breast adenocarcinoma is uncertain, as there was no evidence of direct involvement of the esophagogastric junction. In summary, we describe 13 cases of pseudoachalasia resulting in a clinical syndrome indistinguishable from primary achalasia. The most common mechanism is direct involvement of the esophageal myenteric plexus by neoplastic cells. Rarely, a distant neoplasm may cause this syndrome as a paraneoplastic process.

PATHOGENESIS	CHARACTERIZATION
GENERAL	Depletion or complete absence of myenteric ganglion cells associated with a myenteric inflammatory infiltrate composed predominantly of T cells
Autoantibodies to Auerbach's plexus in achalasia. Storch WB, Eckardt VF, Wienbeck M, Eberl T, Auer PG, Hecker A, Junginger T, Bosseckert H. Institute for Laboratory Medicine, Monchengladbach, Germany.	Cell Mol Biol (Noisy-le-grand) 1995 Dec;41(8):1033-8 Abstract quote Achalasia is a motor disorder of the oesopagus characterized by decrease in ganglion cell density in Auerbach's plexus. The cause of the lesion is unknown. This is to repeat on the occurrence of autoimmune phenomena in patients with achalasia, in particular circulating antibodies against Auerbach's plexus and its possible meaning. IgG-antibodies against Auerbach's plexus were determined by standard indirect immunofluorescence. Antibodies to the cytoplasm of Auerbach's plexus were found in 37 of 58 patients with achalasia at variable stages of the disease (I-IV) with a disease duration ranging from 1 to 20 years but only in 4 out of 54 healthy controls (specificity 93%, sensitivity 64%, p < 0.0001), and in none of 12 patients with Hirschsprung's disease as well as 12 patients with cancer of oesophagus and only in one of 11 patients with peptic oesophagitis as well as in one of 13 patients with myasthenia gravis. The present observations suggest that autoimmunity to Auerbach's plexus plays a role in the pathogenesis of achalasia, the mechanism of action is unknown.
Anti-myenteric neuronal antibodies in patients with achalasia. A prospective study. Verne GN, Sallustio JE, Eaker EY. Division of Gastroenterology, University of Florida, Gainesville, USA.	Dig Dis Sci 1997 Feb;42(2):307-13 Abstract quote Achalasia is a motility disorder of the esophagus characterized by the loss of inhibitory neurons in the distal esophagus. Although idiopathic in nature, autoimmune mechanisms have been proposed, and we set out to determine the presence of myenteric neuronal antibodies. We prospectively studied 18 patients with well-characterized achalasia (by clinical, x-ray, and manometric evidence), nine with gastroesophageal reflux disease, and analyzed the sera from 22 disease-free controls. Using double-label, indirect immunofluorescence techniques, rat esophageal and intestinal sections were double-labeled with sera (dilutions of 1:50 to 1:400) from the three groups and with neurofilament antibody to localize neurons. Seven of 18 achalasia patients had sera that stained the majority of neurons within plexi in the esophageal and intestinal sections, including both NADPH diaphorase (nitric oxide synthase) -positive and -negative neurons. None of the gastroesophageal reflux patients or the controls showed staining. Neuronal antibodies in achalasia provide an attractive hypothesis to explain this diffuse, possibly immune-based disorder.

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE
The nature of the myenteric infiltrate in achalasia: an immunohistochemical analysis. Clark SB, Rice TW, Tubbs RR, Richter JE, Goldblum JR. Center for Swallowing and Esophageal Disease and the Department of Anatomic Pathology, The Cleveland Clinic Foundation, Ohio, USA.	Am J Surg Pathol 2000 Aug;24(8):1153-8 Abstract quote Achalasia is an esophageal motor disorder characterized by abnormal relaxation of the lower esophageal sphincter and absence of progressive peristalsis in the esophageal body. Previous studies evaluating esophagomyotomy and esophageal resection specimens have shown the presence of myenteric inflammation to be a consistent and early pathologic change in patients with achalasia. Thus, the goal of this study was to determine the immunohistochemical characteristics of the inflammatory infiltrate within the myenteric plexus in patients with clinically early and end-stage achalasia. Using formalin-fixed tissue, we analyzed the immunohistochemical features of the myenteric lymphocytes using antibodies that recognize B cells (CD20), T cells (CD3), T cell subsets (CD8), and the activation state of T cell subpopulations (TIA-1 and granzyme B) in nine patients with clinically early achalasia who underwent esophagomyotomy and 13 patients with clinically endstage achalasia who underwent esophageal resection. The myenteric infiltrate in all nine esophagomyotomy specimens was composed predominantly of T cells (CD3-positive), the majority of which also stained for CD8. In five of nine specimens, the majority of CD8-positive cells stained for TIA-1. In the esophageal resection specimens, the myenteric infiltrate was composed predominantly of CD3-positive T cells in seven of 13 cases. In three cases, there was a predominance of CD20-positive B cells, and in the remaining three cases there were relatively equal numbers of T and B cells. In eight of 13 cases, the majority of T cells stained for CD8. TIA-1 immunoreactivity was found in the majority of CD8-positive cells in nine of 13 cases. In all esophagomyotomy and esophageal resection specimens studied, rare granzyme B-positive cells were detected. In conclusion, the majority of myenteric inflammatory cells in patients with achalasia are CD3-positive T cells, most of which are also CD8-positive, although the relative percentage of such cells appears to decrease with disease progression. Furthermore, many of the CD3-positive/CD8-positive myenteric lymphocytes also express TIA-1, suggesting they are resting or activated cytotoxic T cells. The immunohistochemical demonstration of granzyme B in a subpopulation of these cells supports the contention that achalasia is an immune-mediated disease, although the inciting antigen remains an enigma.