World J. Surg. 25, 745–749, 2001 DOI: 10.1007/s00268-001-0026-3
WORLD Journal of
SURGERY © 2001 by the Socie´te´ Internationale de Chirurgie
Achalasia and Esophageal Cancer: Incidence, Prevalence, and Prognosis Bjo ¨rn Lucas Dietrich Maria Bru ¨cher, M.D., Hubert Jakob Stein, M.D., Holger Bartels, M.D., Hubert Feussner, M.D., Jo ¨rg Ru ¨diger Siewert, M.D. Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universita¨t, Ismaninger Strasse 22, 81675 Mu ¨nchen, Germany Abstract. 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.
A coincidence of achalasia and esophageal cancer was first noted by Fagge in 1872 [1]. Since then, achalasia has frequently been described as a predisposing factor for esophageal squamous cell carcinoma [2, 3]. Several cases of esophageal adenocarcinoma arising in patients with achalasia have also been reported [4, 5]. The reported incidence of carcinoma in patients with achalasia and the prevalence of achalasia in patients with esophageal cancer varies widely in the literature [3]. The problem of detecting esophageal cancer in patients with Parts of this study have been presented at the 115th Annual Meeting of the German Society of Surgery 1998 [published as an abstract in Langenbecks Archiv fu ¨r Chirurgie Suppl II (Kongressbericht 1998)] and at the 38th World Congress of Surgery of the ISS 1999 [published as an abstract in the Abstract Book of the ISS]. Correspondence to: B.L.D.M. Bru ¨cher, M.D., e-mail:
[email protected].
achalasia is that the dilated esophagus compensates readily for partial obstruction of the lumen by a tumor. Furthermore, patients with achalasia have usually adapted to a certain degree of dysphagia. Consequently, esophageal cancer in patients with achalasia is often diagnosed at an advanced tumor stage when no surveillance endoscopy is performed, and the prognosis of an “achalasia-carcinoma” is considered poor [6]. Systematic studies assessing the prognosis of patients with “achalasia-carcinoma” are rare. We investigated the incidence of esophageal cancer in a large series of patients with achalasia enrolled in a follow-up program, assessed the prevalence of achalasia in patients presenting with esophageal cancer, and evaluated the stage distribution and prognosis of these patients compared to that of patients with esophageal cancer but without achalasia. Patients and Methods Patients with Known Achalasia Between 1982 and 1998 a total of 124 patients with primary achalasia were treated and followed at our department. There were 73 males (58.9%) and 51 females (41.1%) with a mean age of 49 years (range 9 –91 years). Achalasia was based on classic manometric criteria (i.e., hypertensive lower esophageal sphincter with incomplete relaxation on swallowing, elevated esophageal baseline pressure, and complete absence of esophageal peristalsis). In 66 of 124 patients the diagnosis of primary achalasia had been established a median of 5.4 years (range 0.5–31.6 years) before presentation at our department. In the remainder the diagnosis was first established on presentation at our department. In all 124 patients the presence of primary achalasia was established or confirmed by esophageal manometry, and esophageal cancer was excluded by endoscopy with extensive biopsies of all suspicious lesions. The median duration between the onset of symptoms of achalasia (dysphagia, regurgitation) and the eventual diagnosis of the disorder was 8.6 years (range 0.5–32.3 years). Thirty-six patients (29.0%) were treated with Heller cardiomyotomy and Thal (Dor) fundoplasty; the remainder were managed by pneumatic dilatation (n ⫽ 101), medical therapy (n ⫽ 39), or Botulinum toxin injection (n ⫽ 8). Frequently multiple treatment modalities were employed in individual patients. Irrespective of the treatment modality, sur-
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Fig. 1. Patients with primary achalasia and an esophageal carcinoma that developed during follow-up: durations between achalasia treatment and development of the carcinoma.
veillance endoscopy was recommended at 1- to 2-year intervals in all patients. The median follow-up was 5.6 years (range 0.5–15.0 years) since initial presentation at our department. Two patients had a follow-up at 5 years and two at less than 5 years. Because of the short mean follow-up of only 5.6 years, the incidence of patients developing esophageal cancer may be higher even when the follow-up is completed. Patients Presenting with Esophageal Cancer During the same time period a total of 1366 patients with esophageal carcinoma were seen: 879 patients with squamous cell esophageal cancer and 487 with adenocarcinoma. Of the 879 patients with squamous cell esophageal cancer, 557 underwent esophagectomy. The TNM categories and the presence of residual tumor after resection were classified according to the UICC 1992 criteria [7]. Evidence for preexisting achalasia in these patients was sought by a detailed review of their history. The distribution of tumor stages and the survival time in patients with achalasiacarcinoma were compared to that of patients with esophageal cancer and no history of achalasia. Results In 4 of 124 (3.2%) patients with primary achalasia, esophageal squamous cell carcinomas were diagnosed 14.5, 12.0, 7.7, and 5.1 years, respectively, after initial presentation at our department. This translates into an incidence of one carcinoma for 173.6 patient-years of follow-up. The intervals between the first symptoms of achalasia and the diagnosis of esophageal cancer in these patients were 17.8, 27.5, 38.6, and 42.5 years, respectively (mean
31.6 years). The durations between the various treatments of achalasia and the development of esophageal cancer are summarized in Figure 1. In three patients the tumor was diagnosed by surveillance endoscopy (two stage I, one stage IIA). In one patient recurrent dysphagia with subsequent endoscopy led to the diagnosis (tumor stage IIB). In three patients the tumor length was 5 cm and in one it was 4 cm. In three patients the tumor was located in the distal esophagus, and in one it was in the middle esophagus. Two patients had a poorly differentiated (G3) tumor and two patients a well differentiated (G2) tumor. Of the 879 patients presenting with esophageal squamous cell carcinoma, 13 had a history of primary achalasia (i.e., a prevalence of 1.5%). This includes patients who developed esophageal cancer and had a history of achalasia. The mean duration between the first symptom of achalasia and the diagnosis of esophageal cancer in this patient group was 32.0 years (range 16.8 – 44.7 years). Nine of the thirteen patients (69.3%) had had a previous myotomy, and the remainder had been managed by pneumatic dilatation. Of 487 patients presenting with adenocarcinoma of the esophagus, 1 had a history of achalasia (0.2%). In this patient the adenocarcinoma developed 22.3 years after myotomy and subsequent induction of excessive gastroesophageal reflux and intestinal metaplasia in the esophagus (i.e., Barrett’s esophagus). Two of fourteen patients with “achalasia-carcinoma” underwent palliative treatment because of metastatic disease at the time of diagnosis. Twelve patients underwent an esophagectomy; in two of these patients the resection was performed after neoadjuvant radiochemotherapy. There were no hospital deaths. Complete tumor resection (R0 resection) could be achieved in 91.7% (11 of 12 patients); one patient (8.3%) had microscopic residual tumor (R1) in the tumor bed (Table 1). According to the UICC
Bru ¨cher et al.: Achalasia and Esophageal Cancer
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Table 1. Postoperative UICC, pTNM, and R classifications for 12 patients with achalasia-carcinoma who underwent esophagectomy. Patient no. 1 2 3 4 5 6 7 8 9 10 11 12
TNM system T
N
N⫹/Nall
M
UICC system
Resection (R)
Survival (months)
Status
pT1m pT2 pT4 pT1 pT3 pT3 ypT2 pT2 pT4 pT2 ypT4 pT2
pN0 pN1 pN0 pN0 pN0 pN1 ypN1 pN1 pN1 pN0 ypN1 pN0
0/14 6/26 0/29 0/45 0/7 1/29 3/17 1/18 2/57 0/45 5/24 0/17
pM0 pM1 pM0 pM0 pM0 pM0 ypM0 pM0 pM0 pM0 ypM0 pM0
I IV III I IIA III IIB IIB III IIA III IIA
R0 R0 R0 R0 R0 R0 R0 R0 R0 R0 R1 R0
15.3 15.6 71.3 75.3 3.8 24.2 145.5 42.4 12.1 23.9 10.9 1.7
† † † † † † Alive Alive † Alive † Alive
†: dead. Table 2. Reported incidence of “achalasia-carcinoma” in the recent literature.
Study
Year
Length of investigation (years)
Wychulis [15] Chuong [17] Peracchia [19] Aggestrup [20] Meijssen [18] Sandler [21] Streitz [22] Badaloni [23] Present study
1971 1984 1991 1992 1992 1995 1995 1996 1998
32 17 21 35 15 — 25 5 16
No. of patients with achalasia
No. of patients who developed esophageal cancer at follow-up
1318 91 244 66 195 1062 241 281 124
7 0 1 10 3 24 9 8 4
Mean follow-up (years)
Cancer incidence/ patient-years of follow-up
Estimated increase in esophageal cancer risk
Average duration between first achalasia symptoms and esophageal cancer (years)
13.0 6.5 3.7 23.2 4.5 — — — 5.6
1/2443 0/953 1/1200 1.375 1/293 1/9864 1/1138 — 1/173
⫻7 ⫻0 ⫻16.6 ⫻26.9 ⫻32.9 ⫻16 ⫻14.5 — ⫻140
28.4 — 9 — 17 — — 17.7 32
—: not mentioned in the publication.
criteria [7], 7 of 14 patients with “achalasia-carcinoma” had earlystage disease (stage I, IIA, or IIB), 3 patients stage III disease, and 1 patient stage IV disease (due to metastatic involvement of resected celiac axis lymph nodes); 2 patients (14.3%) had unresectable lesions due to distant metastasis. Compared to the 866 patients with esophageal squamous cell carcinoma but no history of achalasia, the prevalence of early tumor stages (stage I, IIA, IIB) was higher in the patients with “achalasia-carcinomas” (50% vs. 32%). The median overall survival was 15.6 months for the patients with resected squamous cell “achalasia-carcinoma” and 18.7 months for patients with resected esophageal squamous cell carcinoma without achalasia. The median survival time for patients with squamous cell achalasia carcinoma who had an R0 resection was 24.6 months compared to 25.2 months for patients with R0 resections who had squamous cell esophageal cancer but no achalasia (p ⬍ 0.81). Discussion Guisez in 1919 was the first to identify stasis of food as a major predisposing factor for esophageal cancer [8]. In 1931 Rake emphasized stasis as a pathophysiologic concept and described in detail the associated histologic changes [9]. Today the development of squamous cell esophageal carcinoma in patients with
achalasia is considered to be the consequence of stasis esophagitis due to chronic retention and stasis of ingested food and other potentially noxious compounds [6, 10 –15]. Although most esophageal carcinomas developing in patients with achalasia are squamous cell carcinoma, adenocarcinoma associated with Barrett’s esophagus has been reported [16]. Our data confirm these observations; 1 of 14 patients with “achalasiacarcinoma” in the present series had an adenocarcinoma, which developed after myotomy and subsequent induction of excessive gastroesophageal reflux and Barrett’s esophagus. The pathogenesis of the carcinoma in this patient therefore must be differentiated from the more common stasis-associated squamous cell carcinoma in patients with achalasia. Compared to the incidence rates in the literature (ranging from 0 per 953 patient-years of follow-up to 1 per 293 patient-years [17, 18] (Table 2), the incidence of cancer in patients with achalasia is rather high in the present study. Our data translate into a risk for developing esophageal cancer in patients with achalasia that is 140 times higher than that of the general population, which carries an annual risk for developing esophageal cancer of 4 per 100,000 in Germany [24]. Based on this calculation the magnitude of the cancer risk for patients with achalasia in our population is as high as the risk for developing esophageal adenocarcinoma in patients with known Barrett’s esophagus [25]. Because surveillance endos-
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copy is generally recommended in patients with Barrett’s esophagus [25], it appears also to be justified in patients with achalasia. Whether surveillance endoscopy should be generally recommended in all patients with esophageal achalasia is controversial. This is because most authors note durations of at least 15 years between the first symptom of achalasia and the development of esophageal cancer in these patients [2, 10, 11, 15, 18, 20, 26, 27]. This was also the case in the present study, with an average duration of 32 years between the onset of achalasia symptoms and the diagnosis of cancer. A selective approach toward surveillance endoscopy in patients with long-standing achalasia only may therefore be reasonable. However, esophageal achalasia is frequently misdiagnosed [28]. It is therefore not uncommon that achalasia is diagnosed 10 years and more after the onset of symptoms and numerous unsuccessful physician consultations [28, 29]. Consequently, the patient may already be at risk for esophageal cancer when the diagnosis of achalasia is established. The long duration between the onset of symptoms and the diagnosis of achalasia in the present study (8.6 years) supports this contention and may explain the rather high rate of esophageal cancer that developed during follow-up in our patient population. Based on these observations we support the implementation of surveillance endoscopy based on the duration of symptoms of achalasia rather than the date of the diagnosis. Initiation of surveillance endoscopy in patients with a history of 10 to 15 years of achalasia symptoms appears prudent. In many patients this coincides with the diagnosis of achalasia. This concept is in accordance with the recommendations of the American Society of Gastrointestinal Endoscopy [30] and a recent Consensus Conference of the International Society for Diseases of the Esophagus (ISDE) [31]. The benefits of surveillance endoscopy in patients with longstanding achalasia are shown by the surprisingly high prevalence of early tumor stages in patients with “achalasia-carcinoma” in the present study. This is in contrast to the literature [15, 26] and appears to be the result of liberal use of endoscopy during the past few years and the already implemented surveillance endoscopy program for patients with long-standing achalasia at our and many other institutions in Germany. As a consequence, the R0 (complete) resection rate in our series was markedly higher than that reported in the literature [18]. Consequently, and contrary to the general perception, the prognosis of these patients was not worse than that of patients with esophageal cancer but no achalasia. Whether the treatment modality of esophageal achalasia affects the subsequent risk of cancer is unclear at the present time. Brossard et al. reported that esophageal squamous cell carcinoma occurs 8.0 times more frequently in untreated patients with achalasia and 4.5 times more often in patients treated by pneumatic dilatation than in those who had had a surgical myotomy [32]. Our data do not confirm these findings, as 9 of our 13 patients with achalasia-associated squamous cell cancer had had a previous myotomy. More studies are certainly necessary to clarify this issue. Conclusions Our data show a surprisingly high incidence of esophageal cancer in patients with long-standing achalasia. The cancer was frequently detected at an early stage. In contrast to reports in the literature, the prognosis of these patients did not differ from that
World J. Surg. Vol. 25, No. 6, June 2001
of patients with esophageal squamous cell carcinoma but no achalasia. These data thus support the concept of surveillance endoscopy in patients with long-standing achalasia as suggested by the consensus conference of the International Society for Diseases of the Esophagus [31]. Re´sume´ Fond du proble`me: L’incidence de cancer chez le patient porteur d’achalasie et la pre´valence d’achalasie chez le patient porteur d’un cancer de l’œsophage varient beaucoup dans la litte´rature. Le pronostic de l’association “achalasie-cancer” est ge´ne´ralement conside´re´ mauvais. Cependant, les ´etudes syste´matiques ´evaluant l’incidence, la pre´valence et le pronostic des patients ayant l’association «achalasie-cancer» sont rares. Objectif: Nous avons examine´ l’incidence du cancer de l’œsophage dans une grande se´rie de patients connus pour ˆetre porteurs d’achalasie. Nous avons ´egalement ´evalue´ la pre´valence d’achalasie chez les patients pre´sentant un cancer de l’œsophage ainsi que le pronostic de ces patients en comparaison avec des patients porteurs d’un cancer de l’œsophage sans achalasie. Patients et me´thodes. Entre 1982 et 1998, 124 patients porteurs d’une achalasie primitive ont ´ete´ traite´s et suivis dans notre de´partement. Pendant la meˆme pe´riode, nous avons vu 1366 patients pour cancer de l’œsophage (879 cancers ´epidermoı¨des, 487 ade´nocarcinomes). Re´sultats: Quatre des 124 patients porteurs d’achalasie primitive ont de´veloppe´ un cancer pendant le suivi moyen de 5.6 ans, c’est-a`dire une incidence d’un cancer pour 173.6 patients/anne´es de suivi. Treize des 879 patients (1.5%) pre´sentant un cancer ´epidermoı¨de de l’œsophage et un des 487 patients (0.2%) pre´sentant un ade´nocarcinome de l’œsophage avaient une histoire ante´rieure d’achalasie primitive. Sept patients porteurs de l’association achalasie-cancer (50%) avaient un cancer du de´but (stade I, IIA et IIB). Il n’y avait aucune diffe´rence de pronostic entre les patients re´se´que´s pour l’association achalasie-cancer compare´ `a ceux porteurs de cancer de l’œsophage sans achalasie. Conclusions: dans notre population de patients porteurs d’achalasie de longue date, le risque de de´velopper un cancer de l’œsophage est augmente´ d’environ 140 fois par rapport `a la population en ge´ne´rale. Avec une bonne surveillance, on pourrait de´tecter le cancer `a un stade du de´but chez ces patients dont le pronostic ne serait pas pire que celui des patients porteurs de cancer ´epidermoı¨de de l’œsophage sans achalasie. Resumen Antecedentes: la incidencia de carcinoma en pacientes con acalasia y la prevalencia de acalasia en el ca´ncer esofa´gico varı´a en forma muy amplia en los informes de la literatura. El prono ´stico de un “carcinoma de acalasia” es generalmente considerado como pobre. Sin embargo, son escasos los estudios sistema´ticos que evalu ´en la incidencia, prevalencia y prono ´stico de pacientes con “carcinoma de acalasia”. Propo ´sitos: se investigo ´ la incidencia del ca´ncer de eso ´fago en una amplia serie de pacientes con acalasia conocida, se determino ´ la prevalencia de acalasia en pacientes que se presentaron con ca´ncer esofa´gico y se evaluo ´ el prono ´stico en estos pacientes en comparacio ´n con aquellos con ca´ncer esofa´gico y sin acalasia. Pacientes y me´todos: en el periodo 1982 a 1998 se trataron 124 pacientes con acalasia primaria en nuestro departamento. En el mismo periodo se presentaron 1366
Bru ¨cher et al.: Achalasia and Esophageal Cancer
pacientes con ca´ncer esofa´gico (879 carcinomas escamocelulares, 487 adenocarcinoma). Resultados: cuatro de los 124 pacientes con acalasia primaria desarrollaron carcinoma en un seguimiento promedio de 5.6 an ˜os, o sea que la incidencia fue de 1 carcinoma por cada 173.6 pacientes-an ˜os de seguimiento. Trece de 879 pacientes (1.5%) que se presentaron con adenocarcinoma esofa´gico y 1 de 487 (0.2%) tenı´an historia previa de acalasia primaria. Siete pacientes con carcinoma de acalasia (50%) exhibı´an enfermedad poco avanzada (estado I, IIA y IIIB). No se observo ´ diferencia en el prono ´stico de los pacientes con carcinoma de acalasia resecados versus los pacientes con carcinoma esofa´gicos y libres de acalasia. Conclusiones: en nuestra poblacio ´n de pacientes con acalasia de larga duracio ´n se incrementa 140 veces el riesgo de desarrollar carcinoma en comparacio ´n con la poblacio ´n normal. Mediante un programa liberal de deteccio ´n, se logra identificar el carcinoma en sus fases tempranas, con un prono ´stico que no es peor que el de los pacientes con carcinoma escamocelular que no tienen acalasia. Acknowledgments We thank Mrs. Diplmath R. Busch, Institut fu ¨r Medizinische Statistik und Epidemiologie, Technische Universita¨t Mu ¨nchen, for her valuable help with the statistical analysis of the data. References 1. Fagge, C.H.: A case of simple stenosis of the esophagus followed by epithelium. Guys Hosp. Rep. 17:413, 1872 2. Just-Viera, J.O., Morris, J.D., Haight, C.: Achalasia and esophageal carcinoma. Ann. Thorac. Surg. 3:526, 1967 3. Kornblum, K., Fischer, L.C.: Carcinoma as a complication of achalasia of the cardia. A.J.R. 43:364, 1940 4. Ellis, F.H., Jr., Gibb, S.P., Balogh, K., Schwaber, J.R.: Esophageal achalasia and adenocarcinoma in Barret’s esophagus: a report of two cases and a review of the literature. Dis. Esophagus 10(1):55, 1997 5. Goodman, P., Scott, L., Verani, R., Berggreen, C.: Esophageal adenocarcinoma in a patient with surgically treated achalasia. Dig. Dis. Sci. 35:1549, 1990 6. Ribeiro, U., Jr., Posner, M.C., Safatle-Ribeiro, A.V., Reynolds, J.C.: Risk factors for squamous cell carcinoma of the oesophagus. Br. J. Surg. 83:1174, 1996 7. Sobin, L.H., Wittekind, C.: TNM Classification of Malignant Tumours, 5th edition. New York, Wiley-Liss, 1997, pp. 52–55 8. Guisez, J.: De la fre´quence des ste´noses spasmodiques graves et de la pre´cocite´ du cancer de l’oesophage. Gaz. Hop. Paris 92:479, 1919 9. Rake, G.: Epithelioma of the oesophagus in association with achalasia of the cardia. Lancet 2:682, 1931 10. Camara-Lopes, L.H.: Carcinoma of the esophagus as a complication of mega-esophagus: an analysis of seven cases. Am. J. Dig. Dis. 6:742, 1961 11. Carter, R., Brewer, L.A.: Achalasia and esophageal carcinoma: studies in early diagnosis for improved surgical management. Am. J. Surg. 130:114, 1975 12. Just-Viera, J.O., Haight, C.: Achalasia and carcinoma of the esophagus. Surg. Gynecol. Obstet. 128:1081, 1969
749 13. Kurooka, M., Hongyo, T., Nakajima, H., Baskar, R., Li, L.Y., Fukuda, K., Sutoh, K., Miyata, M., Matsuda, H., Nomura, T.: High incidence of esophageal cancer in esophageal achalasia by the oral administration of N-amyl-N-methylnitrosamine and its prevention by nicardipine hydrochloride in mice. Cancer Lett. 127(1–2):55, 1998 14. Pierce, W.S., MacVaugh, H., III, Johnson, J.: Carcinoma of the esophagus arising in patients with achalasia of the cardia. J. Thorac. Cardiovasc. Surg. 59:335, 1970 15. Wychulis, A.R., Woolam, G.L., Anderson, H.A., Ellis, F.H.: Achalasia and carcinoma of the esophagus. J.A.M.A. 215:1638, 1971 16. Barrett, N.R.: Achalasia of the cardia: reflections upon a clinical study of over 100 cases. B.M.J. 1:1135, 1964 17. Chuong, J.J.H., DuBovik, S., McCallum, R.W.: Achalasia as a risk factor for esophageal carcinoma: a reappraisal. Dig. Dis. Sci. 29:1105, 1984 18. Meijssen, M.A.C., Tilanus, H.W., van Blankenstein, M., Hop, W.C.J., Ong, G.L.: Achalasia complicated by oesophageal squamous cell carcinoma: a prospective study in 195 patients. Gut. 33:155, 1992 19. Peracchia, A., Segalin, A., Bardini, R., Ruol, A., Bonavina, L., Baessato, M.: Esophageal carcinoma and achalasia: prevalence, incidence and results of treatment. Hepatogastroenterology 38:514, 1991 20. Aggestrup, S., Holm, J.C., Sorensen, H.R.: Does achalasia predispose to cancer of the esophagus? Chest 102:1013, 1992 21. Sandler, R.S., Nyren, O., Ekbom, A., Eisen, G.M., Yuen, J., Joseffsson, S.: The risk of esophageal cancer in patients with achalasia. J.A.M.A. 274:1359, 1995 22. Streitz, J.M., Ellis, H., Gibb, S.P., Heatley, G.M.: Achalasia and squamous cell carcinoma of the esophagus: analysis of 241 patients. Ann. Thorac. Surg. 59:1604, 1995 23. Badaloni, A.E., Boerr, L.A., Cenoz, M.C., Corti, R.E., Chiocca, J.C., Kognan, Z., Loviscek, L., Salis, G.B., Sivori, E., Soifer, L.: Prevalence of esophageal carcinoma in achalasia in argentina. In Recent Advances in Diseases of the Esophagus, Peracchia, A., Rosati, R., Bonavina, L., Fumagalli, U., Bona, S., Chella, B., editors, Milan, Monduzzi Editore, 1996, pp. 41– 44 24. Becker, N., Wahrendorf, J.: Atlas of Cancer Mortality in the Federal Republic of Germany 1981–1990, 3rd edition, Berlin, Springer-Verlag, 1997, pp. 100 –129 25. Stein, H.J., Siewert, J.R.: Barrett’s esophagus: pathogenesis, epidemiology, functional abnormalities, malignant degeneration and surgical management. Dysphagia 8:276, 1993 26. Hankins, J.R., McLaughlin, S.: The association of carcinoma of the esophagus with achalasia. J. Thorac. Cardiovasc. Surg. 69:355, 1975 27. Lortat-Jacob, J.L., Richard, C.A., Fekete, F., Testart, J.: Cardiospasm and esophageal carcinoma: report of 24 cases. Surgery 66:969, 1969 28. Eckardt, V.F., Kohne, U., Junginger, T., Westermeier, T.: Risk factors for diagnostic delay in achalasia. Dig. Dis. Sci. 42:580, 1997 29. Howard, P.J., Maher, L., Pryde, A., Cameron, E.W., Heading, R.C.: Five year prospective study of the incidence, clinical features, and diagnosis of achalasia in Edinburgh. Gut. 33:1011, 1992 30. American Society of Gastrointestinal Endoscopy: The role of endoscopy in the surveillance of premalignant conditions of the upper gastrointestinal tract (ASGE publication no. 1002). Gastrointest. Endosc. 34:18S, 1988 31. Stein, H.J., Panel of Experts: Esophageal cancer: screening and surveillance: results of a consensus conference held at the Vith world congress of the International Society for Diseases of the Esophagus. Dis. Esophagus 9:3, 1996 32. Brossard, E., Ollyo, J.B., Fontolliet, C.H., Savary, M., Monnier, P.: Achalasia and squamous cell carcinoma of the esophagus: is an endoscopic surveillance justified [abstract]? Gastroenterology 102(Suppl):A4, 1992
