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Adenocarcinoma involving the esophagus
Adenocarcinoma involving the esophagus The clinical and pathological features of 20 patients with adenocarcinoma of the esophagus and esophagogastric junction treated between 1958 and 1971 were analyzed and compared with those of 255 cases of epidermoid carcinoma of the esophagus observed during the same period. The survival rate for patients with adenocarcinoma, as a group, was at least as poor, if not poorer, than that for patients with epidermoid carcinomas. The 20 patients with adenocarcinoma fell conveniently into three anatomic-pathological subgroups which differed in average age and survival: primary adenocarcinoma of the esophagus (lowest average age and poorest survival); adenocarcinoma associated with hiatus hernia (oldest average age and best survival); and adenocarcinoma of the esophagogastric junction (intermediate average age and survival). Evidence is accumulating that the columnar-lined esophagus is a premalignant lesion. A plea is made for separate reporting of epidermoid carcinomas and adenocarcinomas of the esophagus as well as for the use of the presented or some similar categorization of adenocarcinomas.
John R. Hankins, M.D., Fred N. Cole, M.D., Safuh Attar, M.D., James L. Frost, M.D., * and Joseph S. McLaughlin, M.D., Baltimore, Md.
During the past five years several large series of patients with carcinoma of the esophagus have been reported. Some series have included both patients with epidermoid carcinoma and those with adenocarcinoma. 2 2 , 25, 2" 3, Others have been limited to epidermoid carcinoma.v- 21, 28, 34 We have analyzed our experience with epidermoid carcinomas and adenocarcinomas separately, for two reasons: First, it is very possible that there are differences in the biologic behavior and response to management of tumors of these two cell types. Second, we believe that presenting the data separately allows a more meaningful comparison with other series. In a former report, we2 3 considered 255 patients with epidermoid carcinoma who were treated between 1958 and 1971. The present report deals with From the Division of Thoracic and Cardiovascular Surgery, University of Maryland School of Medicine, Baltimore, Md. 21201. Received for publication March 13, 1974. • Department of Pathology.
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the 20 patients with adenocarcinoma involving the esophagus or esophagogastric junction who were observed during the same period. The purpose of this study is twofold: (1) to compare the clinical behavior of adenocarcinoma of the esophagus with that of epidermoid carcinoma and (2) to determine what clinicopathological subgroups, if any, made up the adenocarcinoma group. Clinical material
Between January, 1958, and December, 1971, 20 patients with histologically proved adenocarcinoma of the esophagus or the esophagogastric junction were treated at the University of Maryland Hospital. These patients fell naturally into three groups: Group I, primary adenocarcinoma of the esophagus; Group II, adenocarcinoma associated with hiatus hernia; and Group III, adenocarcinoma of the esophagogastric junction without hiatus hernia. Group I: Primary adenocarcinoma. The
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Table I. Group I: Primary adenocarcinoma Case No. 1 (age, sex) Location
I
Type of operation
I
Pathology Gross: Lesion size Microscopic
I
I Middle third Esophagogastrectorn y, Ulcerative : 1.5 by Adenocarcino(38, M ) esophagogastros0.8 em . rna tom y; tumor left Scirrhous Adenocarcino2 Middle and None (biopsy and (46, M) lower thirds autopsy ) ; treated ma (arising in by radiation therapy a columnarlined lower esophagus) Middle and Esophagogastrectomy, Ulcerative: 4.5 em. Adenocarcino3 (55,M) lower thirds esophagogastroslong rna torny: tumor left
Yes
Yes
Yes
Died 11 days postop.; anastomotic leak Died 7 mo. after radiotherapy ; widespread metastases Died 3 1/ 2 mo. postop.; recurrence
criteria for classifying a patient as having primary adenocarcinoma were those used by Raphael, " Lortat-Jacob," and their associates: that is, an unquestioned diagnosis of glandular carcinoma and the absence of tumor in the stomach. Thus, the tumor was shown to arise from the esophagus, without involvement of the cardia or proximal stomach. Only 3 cases satisfied these criteria (Table I). The 3 patients in this subgroup had a lower average age (46 years) and a poorer average length of survival than the other two subgroups . Two survived 3 V2 months after resection and 7 months after radiation therapy, respectively; the latter had widespread metastases to many organs, including osteoblastic metastasis to bone. One patient, who died postoperatively, had undergone a palliative resection of an invasive widespread malignancy and probably would have lived only a few months had he survived the postoperative period. The following case history is representative.
Fig. 1. Case 1. Esophagogram demonstrates virtually complete obstruction of the mid-esophagus.
CASE 1. A 38-year-old black man was transferred from a state mental hospital because of vomiting of 4 weeks' duration and complete dys phagia of recent onset. Weight loss, though not measured, had been marked. An esophagogram revealed complete obstruction of the middle third of the esophagus (F ig. 1). Esophagoscopy demonstrated an ob structing lesion 36 em . from the incisors. On biopsy, it proved to be adenocarcinoma. Esophagogastrectomy was performed through
a left thoracotomy. Metastases were present in the lymph nodes of the periesophagus and lesser curvature of the stomach. After a stormy course produced by an an astomotic leak , the pat ient died 12 days postoperatively. Examination of the resected specimen revealed a superficial mucosal ulceration near the proximal end of the specimen ( in the middle third of the esophagus). Microscopically, this was a "type
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Fig. 2. Case 1. Adenocarcinoma "type ordinaire" undermining normal squamous epithelium. (Hematoxylin and eosin; original magnification xl 03. ) ordinaire" adenocarcinoma with extensive vascul ar and lymphatic permeation (Fig. 2). Tumor was present in the serosal lymphatics at the gastric margin of resection. Sections of the esophagus distal to the tumor showed normal squamo us epithelium.
Group II: Adenocarcinoma associated with hiatus hernia. There were 5 cases in this category (Table II) . The neoplasm was located at the esophagogastric junction in 3. In 2, this was the location of the squamocolumnar junction, whereas in the third the lower esophagus up to the level of transection was lined by columnar epithelium. In the fourth case the tumor involved only the esophagus, with squamous epithelium intervening between the lower edge of the neoplasm and the esophagogastric junction. In the fifth case, the diagnosis was made by esophagoscopy with biopsy 25 em. from the incisors. The relationship of the tumor to the esophagogastric junction could not be ascertained. The average age for those patients with hiatus hernia and cancer was the greatest of the three subgroups-68.6 years . The duration of symptoms , predominantly dysphagia, varied from 2 lh weeks to 20 years but in 3 of the 5 cases was 3 months or
less. Patient 4 had peptic ulcer symptoms for 20 years, but massive hematemesis precipitated admission. The following is a characteristic case: CASE 7. A 70-year-old man complained of dysphagia of 2 months' duration, accompanied by occasional vomiting and eructation. An esophagogram demonstrated a hiatus hernia with shortening of the esophagus and formation of stricture 8 em. above the diaphragm (Fig. 3) . At esophagoscopy, a polypoid tumor mass was seen 30 em. from the alveolar ridge. Cytologic study of the washings revealed malignant cells. At left thoracotomy, a large tumor was found in the lower third of the esophagus, partly within the hiatus hernia. Metastatically involved lymph nodes were present. A palliative esophagogastrectomy with esophagogastrostomy was performed . Examination of the specimen disclosed a firm, fungating mass at the esophagogastric junction. The lesion measured 3 em. in width and encircled the entire lumen . Microscopically, this was a well-differentiated adenocarcinoma which appeared to originate in the fundus of the stomach. Tumor was present in two of five regional lymph nodes as well as in the esophageal resection margin. The patient died of widespread metastasis I year later.
Group OJ: Adenocarcinoma of the esophagogastric junction without hiatus hernia. The 12 patients in this group were men (Table III). Their average age was 59 years
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Table II. Group II: Adenocarcinoma associated with hiatus hernia Case No.1 (age, sex) Location
I
I Type of operation
Pathology Gross: Lesion size Microscopic
I
4 Middle third (56, M) of esophagus 5 Middle third (84, M) (25 cm.)
Esophagogastrectomy, Ulcerative, fungat- Adenocarcinoesophagogastrosing: 2.5 by 1.7 rna ern. tomy; tumor left None (biopsy only) Ulcerative Papillary adenocacinorna Esophago- Esophagogastrectomy; Ulcerative Adenocarcino6 (64, F) no gross tumor left; gastric rna (squamocolon bypass 2 mo. columnar) later junction Esophago- Esophagogastrectomy, Fungating, poly- Adenocarcino7 (70, M) gastric esophagogastrospoid: 5 by 1.5 to ma (squamo3 cm. tomy; tumor left columnar) junction AdenocarcinoEsophago- Esophagogastrectomy, Ulcerative, scir8 (69, F) gastric ma (columesophagogastrosrhous nar-lined tomy; tumor left* junction lower esophagus)
Yes
?
Died 6.9 mo. postop.; recurrence Died 4 mo. after diagnosis
Yes
Died 11 days after colon bypass; anastomotic leak
Yes
Died 1 yr. postop.; recurrence
No
Died 8th mo. postop.; recurrence
'This patient had had transabdominal repair of hiatus hernia 2 years previously.
(range 46 to 82), and the median age 56 years-intermediate between those of Groups I and II. In every case the tumor produced esophageal obstruction, and thus dysphagia was the predominant symptom in all but 2 patients: Patient 19 presented with upper gastrointestinal hemorrhage, and Patient 13 complained only of weight loss and substernal pain. The duration of survival in this group was intermediate between that of Groups I and II. The tumor was located at the esophagogastric junction in 5 and in the cardial end of the stomach with extension into the esophagus in the remaining 7. Whereas all seven cardial tumors were pure adenocarcinomas, two of the junctional neoplasms (Cases 10 and 11) were of mixed histologic type"- 32; that is, they contained a mixture of squamous and glandular elements. CASE 10. A 57-year-old man complained of bloating (6 months' duration) and dysphagia accompanied by regurgitation of undigested food (2 weeks' duration). Esophagoscopy revealed a lesion 50 em. from the incisors. On biopsy it proved to be adenocarcinoma. Left thoracotomy
disclosed a small intraluminal tumor in the terminal esophagus with spread to the cardia of the stomach and metastases to the aortic arch and retroperitoneal lymph nodes. The lesion was resected and an esophagogastric anastomosis was carried out. Microscopic examination of the tumor at the cardioesophageal junction revealed mucoepidermoid carcinoma (Fig. 4). Two months after the operation, esophagoscopy and dilatation were necessary because of recurrent dysphagia from stenosis of the esophagogastric anastomosis. The patient did poorly and died 3112 months postoperatively.
Discussion
Our experience suggests that the prognosis for adenocarcinoma of the esophagus is as poor as, and probably worse than, that for epidermoid carcinoma. Our findings contrast with the experience of Puestow and co-workers, ;<9 who found that patients with adenocarcinoma had a better prognosis, and with that of Turnbull and Goodner," who found no significant difference in survival rate between the two cell types. Among 234 patients with epidermoid carcinoma whom we reviewed, 6 (2.6 per cent) survived 5 years." However, survival for 2 or 3 years
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Fig. 3. Case 7. Esophagogram shows a hiatus hernia with a polypoid, partly obstructing lesion in the esophagus just above the herniated portion of the stomach.
was not unusual, especially in patients with lesions of the lower third of the thoracic esophagus. Of the 56 patients with epidermoid carcinoma of the lower third, 15 were treated for cure with radiation therapy and survived an average of 11 months; 14 were treated by esophagogastrectomy and lived an average of 26 months. Two patients developed anastomotic leaks. Of the 20 patients with adenocarcinoma, only 2 survived more than 1 year: one who died at 14 months and another who is alive at 15 months. The incidence of fatal anastomotic leaks was high-5 out of 17 patients who had surgery. Survival in the 19 determinate cases averaged 4.3 months if the 5 patients dying from anastomotic leaks are included; if these 5 are excluded, the average survival period was 5.6 months. If the 20 patients with adenocarcinoma
had been included in our 14 year survey of epidermoid carcinoma of the esophagus," the survival figures would have been reduced. Thus this review reinforces the concept that adenocarcinoma responds to therapy differently than epidermoid carcinoma and should be considered separately in discussions of results of therapy. Primary adenocarcinoma. Primary adenocarcinoma of the esophagus is so uncommon that until the last decade some authorities doubted that it existed. J. . " The incidence of primary adenocarcinoma in reported series of malignant tumors of the esophagus has varied. Puestow" in 1955 found that adenocarcinomas composed 10 per cent of 603 esophageal malignancies, and Smithers" in 1956 reported 8 per cent of a total of 314. More recently, authors have used more stringent criteria for the diagnosis of primary adenocarcinoma. Raphael and associates" reviewed the literature in 1966 and found only 19 satisfactorily documented cases. They further analyzed 1,312 cases of cancer of the esophagus at the Mayo Clinic and found 44 (3.3 per cent) registered as primary adenocarcinoma. Of this group, 34 were discarded because of the inclusion of squamous and gastric carcinomas or inadequate histologic proof, leaving only 10 acceptable cases (a total of 0.76 per cent of all cancers of the esophagus). Lortat-J acob and colleagues," in reviewing 558 cases of resected esophageal carcinomas, found sixteen primary adenocarcinomas (2.9 per cent) . Turnbull and Goodner:" found 45 cases of primary adenocarcinoma among 1,859 patients with esophageal cancer, an incidence of 2.4 per cent. Lortat-Jacob's group:" subdivided primary adenocarcinoma into three histopathological groups: The first group included adenocarcinomas that arise in a squamous epithelium-lined esophagus and have a structure similar to those generally occurring in the stomach ("type ordinaire") . The second group consisted of lesions that combine both epitheliomatous glandular and epidermoid elements. Adenoid cystic tumors whose structure resembles that of cylindromas of salivary gland or bronchial origin are in-
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Table Ill. Group Ill: Adenocarcinoma of the esophagogastric junction
No.1
Case (age, sex) 9 (51, M) 10 (57,M)
II (56, M)
12 (56, M)
13 (62, M)
14 (68, M)
IS (51, M)
16 (53, M)
17 (66, M)
18 (55, M)
19 (46, M)
20 (82, M)
Pathology
Location
I Type of operation IGross: Lesion size I Microscopic
Ulcerated, annular, Adenocarciconstricting: 8.5 noma em. long Infiltrative, scirMucoepiderrhous: 2.5 em. moid carlong cinoma Ulcerative, nearly Adenoacanthoesophagogastroscircumferential: rna tomy; tumor left 5.5 em. long Esophagogastrectomy, Ulcerative: 7 em. Adenocarciesophagogastroslong noma tomy; tumor left Esophagogastrectomy, Ulcerative, infilAdenocarciesophagogastrostrating noma tomy, splenectomy; no gross tumor left Cardial end Esophagogastrostomy Scirrhous, involv- Adenocarciof stomach, (bypass without re- ing entire distal noma extending section) esophagus as well into esophas stomach agus Cardial end Esophagogastrectomy, Polypoid with Papillary adenoof stomach, esophagogastrosnecrotic center carcinoma extending tomy; tumor left 5 em. long into esophagus Fundus and None (biopsy and AdenocarciPolypoid, ulcercardial end autopsy) noma ative, circumof stomach, ferential (involvextending ing distal third into esophof esophagus, agus proximal 6 em. of stomach Cardial end Esophagogastrectomy, Fungating, circum- Adenocarciof stomach, esophagogastrosferential: 5 by 6 noma extending tomy; no gross tumor em. into esoph- left agus Cardial end Esophagogastrectomy, Infiltrating cirAdenocarcinoof stomach, esophagogastroscumferential (in- ma with papilextending tomy; tumor left volving distal 2.5 lary areas into esophem. of esophagus agus, proximal 4 em. of stomach) Cardial end Esophagogastrectomy, Fungating, ulcer- Adenocarciof stomach, esophagogastrosative: 7.7 by 6.5 noma extending tomy; tumor left em. into esophagus Cardial end Esophagogastrectomy, Fungating, cirAdenocarciof stomach, esophagogastroscumferential noma extending tomy; tumor left into esophagus Esophago-
gastric junction Esophagogastric junction Esophagogastric junction Esophagogastric junction Esophagogastric junction
Esophagogastrectomy, esophagogastrostomy; tumor left Esophagogastrectomy, esophagogastrostomy; tumor left Esophagogastrectomy,
• Supraclavicular metastases later.
Involved I
I nodes No
Yes
Yes No
No*
Outcome
Died 6 mo. postop., recurrence Died 3 mo. postop., recurrence Died 21 days postop., anastomotic leak Died 2 mo. postop., recurrence Died 14 mo. postop., recurrence
Yes
Died 10 mo. postop., of tumor
Yes
Died 2 mo. postop., recurrence
Yes
Died of peritonitis (spontaneous perforation of sigmoid colon) during initial workup Alive 15 mo. postop. without evidence of disease
No
Yes
Died 2.5 mo. postop.; recurrence
Yes
Died 23 days postop.; anastomotic leak
No
Died 8 days postop.; anastomotic leak
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Fig. 4. Case 10. Mucoepidermoid carcinoma with one sheet of malignant epidermoid cells and multiple areas of malignant gland formation. (Hematoxylin and eosin; original magnification x90.)
eluded in this group. The third group was composed of gastric-type adenocarcinomas that arise in an esophagus lined by columnar epithelium. Raphael's group:" subdivided their lO cases of primary esophageal adenocarcinoma in a similar fashion. Four had adenocarcinoma "type ordinaire," for which Raphael postulated an origin from the cardia-like superficial glands of the esophagus. Three had adenoacanthomas, which would correspond to the mixed glandular and epidermoid group of tumors in LortatJacob's series, and another had an adenoid cystic carcinoma (cylindroma) . Raphael deduced an origin from the deep submucosal glands for both the adenoacanthomas and the adenoid cystic carcinoma. One patient had an adenocarcinoma in a columnar-lined esophagus, and Raphael designated the columnar lining as the probable source of origin of this tumor. The tenth patient had a well-differentiated neoplasm which did not fit into any of the above categories. It was eventually classified as a Grade I adenocarcinoma of the mucus glands. Raphael surmised that the prognosis for
"type ordinaire" carcinomas and adenocarcinomas arising in a columnar epithelium-lined esophagus is better than that for adenoid cystic carcinomas and adenoacanthomas. The former group lacked both longitudinal extension in the submucosa and lymphatic spread, whereas the latter two types were highly malignant and tended to disseminate early. Lortat-Jacob further differentiated between the cylindromatous (adenoid cystic) tumors and the combined squamous and glandular neoplasms. They observed that the former seemed more highly malignant and showed a greater tendency toward hematogenous dissemination than the latter. However, it is probably unjustified to make generalizations about the degree of malignancy when dealing with such small series. Our 3 cases of primary adenocarcinoma all appeared to be of the "type ordinaire," and all showed early spread and extensive metastasis. Adenocarcinoma associated with hiatus hernia. The coexistence of cancer with hiatus hernia, while unusual, is probably more common than is generally, realized. Radi-
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ologically, it is difficult to demonstrate that both lesions are present, since a hiatus hernia may obscure a carcinoma and an obstructing carcinoma may prevent sufficient barium from entering the stomach to demonstrate a hiatus hernia. Further, the stricture in peptic esophagitis may be irregular enough to resemble carcinoma on an esophagogram." On the other hand, the narrowing of the lower esophagus produced by a coexisting malignancy may be innocent in appearance, that is, smooth and without intraluminal filling defects or "shouldering." While it has been thought by some- 10, 17 that the combination of hiatus hernia and carcinoma is purely coincidental, Grimes and Zboralske> pointed out that the cardia is an unusual site for the tumor in patients who have carcinoma of the stomach without hiatus hernia, whereas the cardia is a frequent locus for the neoplasm when hiatus hernia is present. In Smither's? series of 70 patients with combined carcinoma and hiatus hernia, twenty-eight malignancies occurred in the cardia and only nine in the rest of the stomach. Grimes and Zboralske> theorized that hiatus hernia may be a predisposing factor in the genesis of carcinoma. The reflux allowed by the hernia produces peptic ulceration which may later heal by a columnar type of re-epithelialization. This type of epithelium may respond quite differently to repeated peptic irritation than does squamous epithelium. Judging by our own experience and that of others.v 20 the overwhelming preponderance of gastroesophageal malignancies occurring in conjunction with hiatus hernias are adenocarcinomas. Only one hiatus hernia was found in association with any of the 255 epidermoid carcinomas seen at this institution during the period covered by this study. Many of the hiatus hernias in Grimes and Zboralske's-" series had existed for long periods before the malignancy supervened. In some of these, a subtle alteration in symptomatology signaled the onset of the neoplasm. Nevertheless, the neoplasm in most cases was in an advanced stage when first diagnosed.
Although the figures are not statistically significant, our patients with adenocarcinoma and hiatus hernia on the average survived longer than those in the other two subgroups. The 3 who underwent esophagogastrectomy survived 12, 8 V2. and 7 months, respectively. Another patient survived 2 months after esophagogastrectomy without restoration of continuity but died of complications of a colon bypass. No residual carcinoma was found at autopsy. The fifth patient survived 4 months without treatment. Four of Groves' and Effler's" patients had regurgitation-like symptoms and heartburn in addition to dysphagia, and each had noticed a recent increase in degree of dysphagia. Three were able to undergo resection. One was alive 8 years and another 1 year after resection. The remaining 8 patients had all been symptomatic less than 1 year and complained of dysphagia without significant peptic-type symptoms. Only 1 of these was alive more than 2 years following resection. Two others had relief of symptoms for more than 2 years before dying of their disease. The authors concluded that survival after resection for carcinoma of the cardia associated with hiatus hernia seemed comparable to that of carcinoma of the cardia not associated with hiatus hernia. Twelve of 13 patients treated by Grimes and Zboralske'" were successfully operated upon, but only 2 survived more than 18 months. The relationship of the columnar epithelium-lined (Barrett's) esophagus and cancer merits comment, because 2 of our patients (Case 2 from the primary adenocarcinoma group and Case 8 from the group with hiatus hernia) had adenocarcinoma in association with a columnar-lined lower esophagus. In his original description of this syndrome, Barrett" believed that the intrathoracic viscus lined by columnar epithelium was actually stomach situated below a congenitally short esophagus. Allison and Johnstone" challenged this concept. While generally presuming a congenital etiology for the anomaly, they considered the columnarlined structure to be esophagus rather than
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stomach. They cited as evidence the lack of a peritoneal covering, the existence of islands of squamous epithelium within the columnar mucosa, the lack of oxyntic cells in the mucosa, and the resemblance of the mucus glands and musculature to those of normal esophagus. Hayward> and AdIer,« a, 4, 14 however, favored an acquired origin from reflux esophagitis. Hayward believed the columnar lining migrated upward from junctional epithelium, whereas Adler suggested it might originate from the superficial cardiac glands. Recent developments have added support to the hypothesis that the anomaly is acquired and that it represents creeping substitution of columnar epithelium, of junctional or gastric origin, for squamous mucosa destroyed by reflux. Goldman and Beckman> and Mossberg" have demonstrated progressive "ascent" of columnar lining over areas previously lined by squamous mucosa on serial esophagoscopic biopsies in patients with esophagitis. Bremner and associates-' excised the distal esophageal mucosa in three groups of dogs. In animals in which the gastroesophageal sphincter remained competent, the denuded mucosa was replaced mostly by squamous epithelium. In dogs in which reflux was encouraged by the creation of a hiatal hernia and the performance of a cardioplasty, re-epithelialization was partly by squamous and partly by columnar epithelium. However, in a third group of animals in which histamine stimulation of gastric acid was added to the reflux-inducing procedures, replacement was almost entirely by columnar epithelium, Naef and Savary" found 62 patients with Barrett's esophagus during 4,950 esophagoscopies. Reflux was present in all, a hiatus hernia was demonstrated in 59, and adenocarcinoma was detected in 9 patients. Other authors 7 , 12, 13, 26, 29, 31, 33, 38, 40, 42, 44 have reported cases of adenocarcinoma occurring in a columnar-lined esophagus. Many of these authors have indicated their suspicion that Barrett's esophagus increases the potentiality for malignancy in the esophagus. To quote Adler": "There appears to be more
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than a chance aSSOCiatIOn between the columnar-lined esophagus with hiatal hernia and carcinoma." Adenocarcinoma of the esophagogastric junction. MacDonald"" compared the clinical and pathological features of 51 patients with adenocarcinoma of the cardial end of the stomach with those of 169 patients with carcinoma elsewhere in the stomach. In the group with cancer of the cardia, the male:female ratio was 7: 1, as compared to a ratio of 2.3: I for the group with cancer elsewhere in the stomach, The group with cardia cancer showed a higher incidence of hiatus hernia, of heartburn, and of past or present duodenal ulcer. When the surgical specimens of those who underwent gastrectomy were compared, twenty-four of twenty-five cardial tumors had spread through the muscularis, whereas ten of sixty-seven distal cancers had not infiltrated beyond the mucosa or submucosa. Twenty-one of the 25 patients with cardial cancer had normal fundal gland mucosa, compared with only 15 of the 67 with cancers elsewhere. In 7 of the cardia cases, multiple patches of columnar epithelium were situated proximal to the neoplasm; in 6 others, the lower esophagus was lined with columnar epithelium. MacDonald'" concluded that carcinoma of the cardia may be a different disease from carcinoma of the remainder of the stomach. Block and Lancaster" reported on 40 patients with adenocarcinoma of the esophagogastric junction. Thirty-one were men. Thirty-nine had exploratory surgery. In 10 the lesion was nonresectable, principally because of hepatic involvement. Four of them underwent esophagogastrostomy without excision of the tumor. In 25 patients (64 per cent) resection with attempt at cure was performed. Of the twenty-five operative specimens, twenty-two contained lymph node metastases, nineteen showed extension of the tumor through all of the wall, and eight showed tumor in the resected end of the esophagus. The operative mortality rate was 20 per cent. The average survival period was 16 months for the entire group and 18 months in those treated by
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resection. Three patients (7 per cent) survived 5 years or more. Humphrey and Cliffton'" compared 284 adenocarcinomas and 308 epidermoid carcinomas of the distal esophagus and cardia. Considering all patients admitted, the disease was limited to the wall of the esophagus or cardia in 42 per cent of the patients with epidermoid carcinoma as compared to only 19.3 per cent of those with adenocarcinoma. Gunnlaugsson and associates, ~~ in a study of 1,657 patients with carcinoma of the esophagus and cardia, compared the results of curative resection in patients with squamous cell carcinoma of the cardia with the results in patients with adenocarcinoma of the cardia. In the group with squamous cell carcinoma, 6 of 11 patients with negative lymph nodes (54.5 per cent) and 2 of 13 with positive nodes (15.4 per cent) survived 5 years. In the group with adenocarcinoma, only 18 of 67 with negative nodes (26,9 per cent) and 13 of 171 with positive nodes (7.6 per cent) were 5 year survivors. In the entire series, survival rates were best for squamous cell carcinoma of the lower esophagus and the esophagogastric junction. Survival rates were poorest for patients with carcinomas of the cervical and upper thoracic esophagus and for those with adenocarcinoma of the cardia.
2
3
4
5
6
REFERENCES Ackerman, L. V., and del Regato, 1. A.: Cancer: Diagnosis, Treatment, and Prognosis, ed. 2, St. Louis, 1954, The C. V. Mosby Company, p. 521. Adler, R. H., and Rodriques, J.: The Association of Hiatus Hernia and Gastroesophageal Malignancy, J. THORAC. SURG. 37: 553, 1959. Adler, R. H.: The Lower Esophagus Lined by Columnar Epithelium: Its Association With Hiatal Hernia, Ulcer, Stricture, and Tumor, J. THORAC. CARDIOVASC. SURG. 45: 13, 1963. Adler, R. H.: The Esophagus With Columnar Epithelium: Its Clinical Significance, Geriatrics 20: 109, 1965. Allison, P. R., and Johnstone, A. S.: The Oesophagus Lined With Gastric Mucous Membrane, Thorax 8: 87, 1953. Allison, P. R.: The Diaphragm, in Gibbon, J. H., Sabiston, D. c., Jr., and Spencer, F. c.,
editors: Surgery of the Chest, Philadelphia, 1969, W. B. Saunders Company, chap. 15. 7 Armstrong, R. A., Blalock, J. B., and Carrera, G. M.: Adenocarcinoma of the Middle Third of the Esophagus Arising From Ectopic Gastric Mucosa, J. THORAC. SURG. 37: 398, 1959. 8 Barrett, N. R.: Chronic Peptic Ulcer of the Oesophagus and "Oesophagitis," Br. J. Surg. 38: 175,1950. 9 Block, G. E., and Lancaster, 1. R.: Adenocarcinoma of the Cardioesophageal Junction, Arch. Surg. 88: 852, 1964. 10 Bockus, H. L.: Gastroenterology, ed. 2, Philadelphia, 1963, W. B. Saunders Company, vol. 1, chap. 1 I. 11 Bremner, C. G., Lynch, V. P., and Ellis, F. H., Jr.: Barrett's Esophagus: Congenital or Acquired? An Experimental Study of Esophageal Mucosal Regeneration in the Dog, Surgery 68: 209, 1970. 12 Burns, W. A., Flores, P. A., Moshyedi, A., and Albacete, R. A.: Clinical Conditions Associated With Columnar Lined Esophagus, Am. J. Dig. Dis. 15: 607, 1970. 13 Dawson, 1. L.: Adenocarcinoma of the Middle Oesophagus Arising in an Oesophagus Lined by Gastric (Parietal) Epithelium, Br. 1. Surg. 51: 940, 1964. 14 De la Pava, S., Pickren, J. W., and Adler, R. H.: Ectopic Gastric Mucosa of the Esophagus: A Study on Histiogenesis, N. Y. J. Med. 64: 1831, 1964. 15 Dodge, O. G.: Gastro-esophageal Carcinoma of Mixed Histologic Type, J. Pathol. 81: 459, 1961. 16 EI-Domeiri, A., Martini, N., and Beattie, E. J., Jr.: Esophageal Reconstruction by Colon Interposition, Arch. Surg. 100: 358, 1970. 17 Feldman, M., and Meyers, P.: Coexistence of Carcinoma of the Stomach and Esophageal Hiatus Gastric Hernia, Am. J. Med. Sci. 224: 519, 1952. 18 Goldman, M. c., and Beckman, R. C.: Barrett Syndrome: Case Report With Discussion About Concepts of Pathogenesis, Gastroenterology 39: 104, 1960. 19 Grimes, O. F., and Zboralske, F. F.: Carcinoma in Association With Hiatal Hernia, J. THORAC. CARDIOVASC. SURG. 55: 30, 1968. 20 Groves, L. K., and Effler, D. B.: Cancer of the Gastric Cardia Associated With Esophagael Hiatus Hernia, Surg. Gynecol. Obstet. 116: 463, 19'63. 21 Guinn, G. A., Jordan, P. H., and Stewart, C. V.: Appraisal of Therapy for Carcinoma of the Esophagus, Am. J. Surg. 122: 703, 1971. 22 Gunnlaugsson, G. H., Wychulis, A. R., Roland, C., and Ellis, F. H., Jr.: Analysis of the Records of 1,657 Patients With Carcinoma
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24 25
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32
33
of the Esophagus and Cardia of the Stomach, Surg. Gynecol. Obstet. 130: 997, 1970. Hankins, J. R., Cole, F. N., Ward, A., Carter, E. A, Weiner, S., and McLaughlin, J. S.: Carcinoma of the Esophagus: The Philosophy for Palliation, Ann. Thorac. Surg. 14: 189, 1972. Hayward, 1.: The Lower End of the Esophagus, Thorax 16: 36, 1961. Humphrey, C. R., and Cliffton, E. E.: Carcinoma of the Distal Part of the Esophagus and Cardia of the Stomach, Surg. Gyneco!. Obstet. 127: 737, 1968. Jernstrom, P., and Brewer, L. A., III: Primary Adenocarcinoma of the Midesophagus Arising in Ectopic Gastric Mucosa With Associated Hiatal Hernia and Reflux Esophagitis (Dawson's Syndrome), Cancer 26: 1343, 1970. Lawler, M. R., Jr., Gobbel, W. G., Jr., Killen, D. A., and Daniel, R. A, Jr.: Carcinoma of the Esophagus, J. THORAC. CARDIOVASC. SURG. 58: 609, 1969. Leon, W., Strug, L. H., and Brickman, I. D.: Carcinoma of the Esophagus: A Disaster, Ann. Thorac. Surg. 11: 583, 1971. Lortat-Jacob, J. L., Maillard, 1. N., Richard, C. A, Fekete, F., Huguier, M., and ConteMarti, J.: Primary Esophageal Adenocarcinoma: Report of 16 Cases, Surgery 64: 535, 1968. MacDonald, W. C.: Clinical and Pathologic Features of Adenocarcinoma of the Gastric Cardia, Cancer 29: 724, 1972. McCorkle, R. G., and Blades, B.: Adenocarcinoma of the Esophagus Arising in Aberrant Gastric Mucosa, Am. Surg. 21: 781, 1955. McPeak, E., and Warren, S.: Histologic Features of Carcinoma of the Cardioesophageal Junction and Cardia, Am. J. Patho!. 24: 971, 1948. Morson, B. C., and Belcher, J, R.: Adenocar-
34
35
36
37 38
39
40
41
42 43
44
45
cinoma of the Oesophagus and Ectopic Gastric Mucosa, Br. J. Cancer 6: 127, 1952. Moseley, R. Y.: Squamous Carcinoma of the Esophagus, Surg. Gyneco!. Obstet. 126: 1242, 1968. Mossberg, S. M.: The Columnar-Lined Esophagus (Barrett Syndrome): An Acquired Condition? Gastroenterology 50: 671, 1966. Naef, A. P., and Savary, M.: Conservative Operations for Peptic Esophagitis With Stenosis in Columnar-Lined Lower Esophagus, Ann. Thorac. Surg. 13: 543, 1972. Parker, E. F., Gregorie, H. B., Jr., Arrants, J. E., and Ravenel, J. M.: Carcinoma of the Esophagus, Ann. Surg. 171: 746, 1970. Pattinson, 1. N., Osborne, G., and Morson, B. c.: Hiatus Hernia With Adenocarcinoma Arising in the Region of the Cardia, J. Fac. Radiol. 7: 90, 1955. Puestow, C. B., Gillesby, W. J., and Guznon, Y. L.: Carcinoma of the Esophagus, Arch. Surg. 70: 662, 1955. Raphael, H. A., Ellis, F. H., Jr., and Dockerty, M. B.: Primary Adenocarcinoma of the Esophagus, Ann. Surg. 162: 785, 1966. Smithers, D. W.: The Association of Cancer of the Stomach and Oesophagus With Herniation at the Oesophageal Hiatus of the Diaphragm, Br. J. Radiol. 28: 554, 1955. Smithers, D. W.: Adenocarcinoma of the Esophagus, Thorax 11: 257, 1956. Stout, A P., and Lattes, R.: Tumors of the Esophagus, (Fascicle 20), in Atlas of Tumor Pathology, Washington, D. C., 1957, Armed Forces Institute of Pathology. Thomas, 1. Y., and Hay, L. J.: Adenocarcinoma of the Esophagus, Surgery 35: 635, 1954. Turnbull, A D. M., and Goodner, J. T.: Primary Adenocarcinoma of the Esophagus, Cancer 22: 915, 1968.
John R. Hankins, M.D., Fred N. Cole, M.D., Safuh Attar, M.D., James L. Frost, M.D., * and Joseph S. McLaughlin, M.D., Baltimore, Md.
During the past five years several large series of patients with carcinoma of the esophagus have been reported. Some series have included both patients with epidermoid carcinoma and those with adenocarcinoma. 2 2 , 25, 2" 3, Others have been limited to epidermoid carcinoma.v- 21, 28, 34 We have analyzed our experience with epidermoid carcinomas and adenocarcinomas separately, for two reasons: First, it is very possible that there are differences in the biologic behavior and response to management of tumors of these two cell types. Second, we believe that presenting the data separately allows a more meaningful comparison with other series. In a former report, we2 3 considered 255 patients with epidermoid carcinoma who were treated between 1958 and 1971. The present report deals with From the Division of Thoracic and Cardiovascular Surgery, University of Maryland School of Medicine, Baltimore, Md. 21201. Received for publication March 13, 1974. • Department of Pathology.
148
the 20 patients with adenocarcinoma involving the esophagus or esophagogastric junction who were observed during the same period. The purpose of this study is twofold: (1) to compare the clinical behavior of adenocarcinoma of the esophagus with that of epidermoid carcinoma and (2) to determine what clinicopathological subgroups, if any, made up the adenocarcinoma group. Clinical material
Between January, 1958, and December, 1971, 20 patients with histologically proved adenocarcinoma of the esophagus or the esophagogastric junction were treated at the University of Maryland Hospital. These patients fell naturally into three groups: Group I, primary adenocarcinoma of the esophagus; Group II, adenocarcinoma associated with hiatus hernia; and Group III, adenocarcinoma of the esophagogastric junction without hiatus hernia. Group I: Primary adenocarcinoma. The
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Table I. Group I: Primary adenocarcinoma Case No. 1 (age, sex) Location
I
Type of operation
I
Pathology Gross: Lesion size Microscopic
I
I Middle third Esophagogastrectorn y, Ulcerative : 1.5 by Adenocarcino(38, M ) esophagogastros0.8 em . rna tom y; tumor left Scirrhous Adenocarcino2 Middle and None (biopsy and (46, M) lower thirds autopsy ) ; treated ma (arising in by radiation therapy a columnarlined lower esophagus) Middle and Esophagogastrectomy, Ulcerative: 4.5 em. Adenocarcino3 (55,M) lower thirds esophagogastroslong rna torny: tumor left
Yes
Yes
Yes
Died 11 days postop.; anastomotic leak Died 7 mo. after radiotherapy ; widespread metastases Died 3 1/ 2 mo. postop.; recurrence
criteria for classifying a patient as having primary adenocarcinoma were those used by Raphael, " Lortat-Jacob," and their associates: that is, an unquestioned diagnosis of glandular carcinoma and the absence of tumor in the stomach. Thus, the tumor was shown to arise from the esophagus, without involvement of the cardia or proximal stomach. Only 3 cases satisfied these criteria (Table I). The 3 patients in this subgroup had a lower average age (46 years) and a poorer average length of survival than the other two subgroups . Two survived 3 V2 months after resection and 7 months after radiation therapy, respectively; the latter had widespread metastases to many organs, including osteoblastic metastasis to bone. One patient, who died postoperatively, had undergone a palliative resection of an invasive widespread malignancy and probably would have lived only a few months had he survived the postoperative period. The following case history is representative.
Fig. 1. Case 1. Esophagogram demonstrates virtually complete obstruction of the mid-esophagus.
CASE 1. A 38-year-old black man was transferred from a state mental hospital because of vomiting of 4 weeks' duration and complete dys phagia of recent onset. Weight loss, though not measured, had been marked. An esophagogram revealed complete obstruction of the middle third of the esophagus (F ig. 1). Esophagoscopy demonstrated an ob structing lesion 36 em . from the incisors. On biopsy, it proved to be adenocarcinoma. Esophagogastrectomy was performed through
a left thoracotomy. Metastases were present in the lymph nodes of the periesophagus and lesser curvature of the stomach. After a stormy course produced by an an astomotic leak , the pat ient died 12 days postoperatively. Examination of the resected specimen revealed a superficial mucosal ulceration near the proximal end of the specimen ( in the middle third of the esophagus). Microscopically, this was a "type
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Fig. 2. Case 1. Adenocarcinoma "type ordinaire" undermining normal squamous epithelium. (Hematoxylin and eosin; original magnification xl 03. ) ordinaire" adenocarcinoma with extensive vascul ar and lymphatic permeation (Fig. 2). Tumor was present in the serosal lymphatics at the gastric margin of resection. Sections of the esophagus distal to the tumor showed normal squamo us epithelium.
Group II: Adenocarcinoma associated with hiatus hernia. There were 5 cases in this category (Table II) . The neoplasm was located at the esophagogastric junction in 3. In 2, this was the location of the squamocolumnar junction, whereas in the third the lower esophagus up to the level of transection was lined by columnar epithelium. In the fourth case the tumor involved only the esophagus, with squamous epithelium intervening between the lower edge of the neoplasm and the esophagogastric junction. In the fifth case, the diagnosis was made by esophagoscopy with biopsy 25 em. from the incisors. The relationship of the tumor to the esophagogastric junction could not be ascertained. The average age for those patients with hiatus hernia and cancer was the greatest of the three subgroups-68.6 years . The duration of symptoms , predominantly dysphagia, varied from 2 lh weeks to 20 years but in 3 of the 5 cases was 3 months or
less. Patient 4 had peptic ulcer symptoms for 20 years, but massive hematemesis precipitated admission. The following is a characteristic case: CASE 7. A 70-year-old man complained of dysphagia of 2 months' duration, accompanied by occasional vomiting and eructation. An esophagogram demonstrated a hiatus hernia with shortening of the esophagus and formation of stricture 8 em. above the diaphragm (Fig. 3) . At esophagoscopy, a polypoid tumor mass was seen 30 em. from the alveolar ridge. Cytologic study of the washings revealed malignant cells. At left thoracotomy, a large tumor was found in the lower third of the esophagus, partly within the hiatus hernia. Metastatically involved lymph nodes were present. A palliative esophagogastrectomy with esophagogastrostomy was performed . Examination of the specimen disclosed a firm, fungating mass at the esophagogastric junction. The lesion measured 3 em. in width and encircled the entire lumen . Microscopically, this was a well-differentiated adenocarcinoma which appeared to originate in the fundus of the stomach. Tumor was present in two of five regional lymph nodes as well as in the esophageal resection margin. The patient died of widespread metastasis I year later.
Group OJ: Adenocarcinoma of the esophagogastric junction without hiatus hernia. The 12 patients in this group were men (Table III). Their average age was 59 years
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Table II. Group II: Adenocarcinoma associated with hiatus hernia Case No.1 (age, sex) Location
I
I Type of operation
Pathology Gross: Lesion size Microscopic
I
4 Middle third (56, M) of esophagus 5 Middle third (84, M) (25 cm.)
Esophagogastrectomy, Ulcerative, fungat- Adenocarcinoesophagogastrosing: 2.5 by 1.7 rna ern. tomy; tumor left None (biopsy only) Ulcerative Papillary adenocacinorna Esophago- Esophagogastrectomy; Ulcerative Adenocarcino6 (64, F) no gross tumor left; gastric rna (squamocolon bypass 2 mo. columnar) later junction Esophago- Esophagogastrectomy, Fungating, poly- Adenocarcino7 (70, M) gastric esophagogastrospoid: 5 by 1.5 to ma (squamo3 cm. tomy; tumor left columnar) junction AdenocarcinoEsophago- Esophagogastrectomy, Ulcerative, scir8 (69, F) gastric ma (columesophagogastrosrhous nar-lined tomy; tumor left* junction lower esophagus)
Yes
?
Died 6.9 mo. postop.; recurrence Died 4 mo. after diagnosis
Yes
Died 11 days after colon bypass; anastomotic leak
Yes
Died 1 yr. postop.; recurrence
No
Died 8th mo. postop.; recurrence
'This patient had had transabdominal repair of hiatus hernia 2 years previously.
(range 46 to 82), and the median age 56 years-intermediate between those of Groups I and II. In every case the tumor produced esophageal obstruction, and thus dysphagia was the predominant symptom in all but 2 patients: Patient 19 presented with upper gastrointestinal hemorrhage, and Patient 13 complained only of weight loss and substernal pain. The duration of survival in this group was intermediate between that of Groups I and II. The tumor was located at the esophagogastric junction in 5 and in the cardial end of the stomach with extension into the esophagus in the remaining 7. Whereas all seven cardial tumors were pure adenocarcinomas, two of the junctional neoplasms (Cases 10 and 11) were of mixed histologic type"- 32; that is, they contained a mixture of squamous and glandular elements. CASE 10. A 57-year-old man complained of bloating (6 months' duration) and dysphagia accompanied by regurgitation of undigested food (2 weeks' duration). Esophagoscopy revealed a lesion 50 em. from the incisors. On biopsy it proved to be adenocarcinoma. Left thoracotomy
disclosed a small intraluminal tumor in the terminal esophagus with spread to the cardia of the stomach and metastases to the aortic arch and retroperitoneal lymph nodes. The lesion was resected and an esophagogastric anastomosis was carried out. Microscopic examination of the tumor at the cardioesophageal junction revealed mucoepidermoid carcinoma (Fig. 4). Two months after the operation, esophagoscopy and dilatation were necessary because of recurrent dysphagia from stenosis of the esophagogastric anastomosis. The patient did poorly and died 3112 months postoperatively.
Discussion
Our experience suggests that the prognosis for adenocarcinoma of the esophagus is as poor as, and probably worse than, that for epidermoid carcinoma. Our findings contrast with the experience of Puestow and co-workers, ;<9 who found that patients with adenocarcinoma had a better prognosis, and with that of Turnbull and Goodner," who found no significant difference in survival rate between the two cell types. Among 234 patients with epidermoid carcinoma whom we reviewed, 6 (2.6 per cent) survived 5 years." However, survival for 2 or 3 years
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Fig. 3. Case 7. Esophagogram shows a hiatus hernia with a polypoid, partly obstructing lesion in the esophagus just above the herniated portion of the stomach.
was not unusual, especially in patients with lesions of the lower third of the thoracic esophagus. Of the 56 patients with epidermoid carcinoma of the lower third, 15 were treated for cure with radiation therapy and survived an average of 11 months; 14 were treated by esophagogastrectomy and lived an average of 26 months. Two patients developed anastomotic leaks. Of the 20 patients with adenocarcinoma, only 2 survived more than 1 year: one who died at 14 months and another who is alive at 15 months. The incidence of fatal anastomotic leaks was high-5 out of 17 patients who had surgery. Survival in the 19 determinate cases averaged 4.3 months if the 5 patients dying from anastomotic leaks are included; if these 5 are excluded, the average survival period was 5.6 months. If the 20 patients with adenocarcinoma
had been included in our 14 year survey of epidermoid carcinoma of the esophagus," the survival figures would have been reduced. Thus this review reinforces the concept that adenocarcinoma responds to therapy differently than epidermoid carcinoma and should be considered separately in discussions of results of therapy. Primary adenocarcinoma. Primary adenocarcinoma of the esophagus is so uncommon that until the last decade some authorities doubted that it existed. J. . " The incidence of primary adenocarcinoma in reported series of malignant tumors of the esophagus has varied. Puestow" in 1955 found that adenocarcinomas composed 10 per cent of 603 esophageal malignancies, and Smithers" in 1956 reported 8 per cent of a total of 314. More recently, authors have used more stringent criteria for the diagnosis of primary adenocarcinoma. Raphael and associates" reviewed the literature in 1966 and found only 19 satisfactorily documented cases. They further analyzed 1,312 cases of cancer of the esophagus at the Mayo Clinic and found 44 (3.3 per cent) registered as primary adenocarcinoma. Of this group, 34 were discarded because of the inclusion of squamous and gastric carcinomas or inadequate histologic proof, leaving only 10 acceptable cases (a total of 0.76 per cent of all cancers of the esophagus). Lortat-J acob and colleagues," in reviewing 558 cases of resected esophageal carcinomas, found sixteen primary adenocarcinomas (2.9 per cent) . Turnbull and Goodner:" found 45 cases of primary adenocarcinoma among 1,859 patients with esophageal cancer, an incidence of 2.4 per cent. Lortat-Jacob's group:" subdivided primary adenocarcinoma into three histopathological groups: The first group included adenocarcinomas that arise in a squamous epithelium-lined esophagus and have a structure similar to those generally occurring in the stomach ("type ordinaire") . The second group consisted of lesions that combine both epitheliomatous glandular and epidermoid elements. Adenoid cystic tumors whose structure resembles that of cylindromas of salivary gland or bronchial origin are in-
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Table Ill. Group Ill: Adenocarcinoma of the esophagogastric junction
No.1
Case (age, sex) 9 (51, M) 10 (57,M)
II (56, M)
12 (56, M)
13 (62, M)
14 (68, M)
IS (51, M)
16 (53, M)
17 (66, M)
18 (55, M)
19 (46, M)
20 (82, M)
Pathology
Location
I Type of operation IGross: Lesion size I Microscopic
Ulcerated, annular, Adenocarciconstricting: 8.5 noma em. long Infiltrative, scirMucoepiderrhous: 2.5 em. moid carlong cinoma Ulcerative, nearly Adenoacanthoesophagogastroscircumferential: rna tomy; tumor left 5.5 em. long Esophagogastrectomy, Ulcerative: 7 em. Adenocarciesophagogastroslong noma tomy; tumor left Esophagogastrectomy, Ulcerative, infilAdenocarciesophagogastrostrating noma tomy, splenectomy; no gross tumor left Cardial end Esophagogastrostomy Scirrhous, involv- Adenocarciof stomach, (bypass without re- ing entire distal noma extending section) esophagus as well into esophas stomach agus Cardial end Esophagogastrectomy, Polypoid with Papillary adenoof stomach, esophagogastrosnecrotic center carcinoma extending tomy; tumor left 5 em. long into esophagus Fundus and None (biopsy and AdenocarciPolypoid, ulcercardial end autopsy) noma ative, circumof stomach, ferential (involvextending ing distal third into esophof esophagus, agus proximal 6 em. of stomach Cardial end Esophagogastrectomy, Fungating, circum- Adenocarciof stomach, esophagogastrosferential: 5 by 6 noma extending tomy; no gross tumor em. into esoph- left agus Cardial end Esophagogastrectomy, Infiltrating cirAdenocarcinoof stomach, esophagogastroscumferential (in- ma with papilextending tomy; tumor left volving distal 2.5 lary areas into esophem. of esophagus agus, proximal 4 em. of stomach) Cardial end Esophagogastrectomy, Fungating, ulcer- Adenocarciof stomach, esophagogastrosative: 7.7 by 6.5 noma extending tomy; tumor left em. into esophagus Cardial end Esophagogastrectomy, Fungating, cirAdenocarciof stomach, esophagogastroscumferential noma extending tomy; tumor left into esophagus Esophago-
gastric junction Esophagogastric junction Esophagogastric junction Esophagogastric junction Esophagogastric junction
Esophagogastrectomy, esophagogastrostomy; tumor left Esophagogastrectomy, esophagogastrostomy; tumor left Esophagogastrectomy,
• Supraclavicular metastases later.
Involved I
I nodes No
Yes
Yes No
No*
Outcome
Died 6 mo. postop., recurrence Died 3 mo. postop., recurrence Died 21 days postop., anastomotic leak Died 2 mo. postop., recurrence Died 14 mo. postop., recurrence
Yes
Died 10 mo. postop., of tumor
Yes
Died 2 mo. postop., recurrence
Yes
Died of peritonitis (spontaneous perforation of sigmoid colon) during initial workup Alive 15 mo. postop. without evidence of disease
No
Yes
Died 2.5 mo. postop.; recurrence
Yes
Died 23 days postop.; anastomotic leak
No
Died 8 days postop.; anastomotic leak
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Fig. 4. Case 10. Mucoepidermoid carcinoma with one sheet of malignant epidermoid cells and multiple areas of malignant gland formation. (Hematoxylin and eosin; original magnification x90.)
eluded in this group. The third group was composed of gastric-type adenocarcinomas that arise in an esophagus lined by columnar epithelium. Raphael's group:" subdivided their lO cases of primary esophageal adenocarcinoma in a similar fashion. Four had adenocarcinoma "type ordinaire," for which Raphael postulated an origin from the cardia-like superficial glands of the esophagus. Three had adenoacanthomas, which would correspond to the mixed glandular and epidermoid group of tumors in LortatJacob's series, and another had an adenoid cystic carcinoma (cylindroma) . Raphael deduced an origin from the deep submucosal glands for both the adenoacanthomas and the adenoid cystic carcinoma. One patient had an adenocarcinoma in a columnar-lined esophagus, and Raphael designated the columnar lining as the probable source of origin of this tumor. The tenth patient had a well-differentiated neoplasm which did not fit into any of the above categories. It was eventually classified as a Grade I adenocarcinoma of the mucus glands. Raphael surmised that the prognosis for
"type ordinaire" carcinomas and adenocarcinomas arising in a columnar epithelium-lined esophagus is better than that for adenoid cystic carcinomas and adenoacanthomas. The former group lacked both longitudinal extension in the submucosa and lymphatic spread, whereas the latter two types were highly malignant and tended to disseminate early. Lortat-Jacob further differentiated between the cylindromatous (adenoid cystic) tumors and the combined squamous and glandular neoplasms. They observed that the former seemed more highly malignant and showed a greater tendency toward hematogenous dissemination than the latter. However, it is probably unjustified to make generalizations about the degree of malignancy when dealing with such small series. Our 3 cases of primary adenocarcinoma all appeared to be of the "type ordinaire," and all showed early spread and extensive metastasis. Adenocarcinoma associated with hiatus hernia. The coexistence of cancer with hiatus hernia, while unusual, is probably more common than is generally, realized. Radi-
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ologically, it is difficult to demonstrate that both lesions are present, since a hiatus hernia may obscure a carcinoma and an obstructing carcinoma may prevent sufficient barium from entering the stomach to demonstrate a hiatus hernia. Further, the stricture in peptic esophagitis may be irregular enough to resemble carcinoma on an esophagogram." On the other hand, the narrowing of the lower esophagus produced by a coexisting malignancy may be innocent in appearance, that is, smooth and without intraluminal filling defects or "shouldering." While it has been thought by some- 10, 17 that the combination of hiatus hernia and carcinoma is purely coincidental, Grimes and Zboralske> pointed out that the cardia is an unusual site for the tumor in patients who have carcinoma of the stomach without hiatus hernia, whereas the cardia is a frequent locus for the neoplasm when hiatus hernia is present. In Smither's? series of 70 patients with combined carcinoma and hiatus hernia, twenty-eight malignancies occurred in the cardia and only nine in the rest of the stomach. Grimes and Zboralske> theorized that hiatus hernia may be a predisposing factor in the genesis of carcinoma. The reflux allowed by the hernia produces peptic ulceration which may later heal by a columnar type of re-epithelialization. This type of epithelium may respond quite differently to repeated peptic irritation than does squamous epithelium. Judging by our own experience and that of others.v 20 the overwhelming preponderance of gastroesophageal malignancies occurring in conjunction with hiatus hernias are adenocarcinomas. Only one hiatus hernia was found in association with any of the 255 epidermoid carcinomas seen at this institution during the period covered by this study. Many of the hiatus hernias in Grimes and Zboralske's-" series had existed for long periods before the malignancy supervened. In some of these, a subtle alteration in symptomatology signaled the onset of the neoplasm. Nevertheless, the neoplasm in most cases was in an advanced stage when first diagnosed.
Although the figures are not statistically significant, our patients with adenocarcinoma and hiatus hernia on the average survived longer than those in the other two subgroups. The 3 who underwent esophagogastrectomy survived 12, 8 V2. and 7 months, respectively. Another patient survived 2 months after esophagogastrectomy without restoration of continuity but died of complications of a colon bypass. No residual carcinoma was found at autopsy. The fifth patient survived 4 months without treatment. Four of Groves' and Effler's" patients had regurgitation-like symptoms and heartburn in addition to dysphagia, and each had noticed a recent increase in degree of dysphagia. Three were able to undergo resection. One was alive 8 years and another 1 year after resection. The remaining 8 patients had all been symptomatic less than 1 year and complained of dysphagia without significant peptic-type symptoms. Only 1 of these was alive more than 2 years following resection. Two others had relief of symptoms for more than 2 years before dying of their disease. The authors concluded that survival after resection for carcinoma of the cardia associated with hiatus hernia seemed comparable to that of carcinoma of the cardia not associated with hiatus hernia. Twelve of 13 patients treated by Grimes and Zboralske'" were successfully operated upon, but only 2 survived more than 18 months. The relationship of the columnar epithelium-lined (Barrett's) esophagus and cancer merits comment, because 2 of our patients (Case 2 from the primary adenocarcinoma group and Case 8 from the group with hiatus hernia) had adenocarcinoma in association with a columnar-lined lower esophagus. In his original description of this syndrome, Barrett" believed that the intrathoracic viscus lined by columnar epithelium was actually stomach situated below a congenitally short esophagus. Allison and Johnstone" challenged this concept. While generally presuming a congenital etiology for the anomaly, they considered the columnarlined structure to be esophagus rather than
I56
Hankins et al.
stomach. They cited as evidence the lack of a peritoneal covering, the existence of islands of squamous epithelium within the columnar mucosa, the lack of oxyntic cells in the mucosa, and the resemblance of the mucus glands and musculature to those of normal esophagus. Hayward> and AdIer,« a, 4, 14 however, favored an acquired origin from reflux esophagitis. Hayward believed the columnar lining migrated upward from junctional epithelium, whereas Adler suggested it might originate from the superficial cardiac glands. Recent developments have added support to the hypothesis that the anomaly is acquired and that it represents creeping substitution of columnar epithelium, of junctional or gastric origin, for squamous mucosa destroyed by reflux. Goldman and Beckman> and Mossberg" have demonstrated progressive "ascent" of columnar lining over areas previously lined by squamous mucosa on serial esophagoscopic biopsies in patients with esophagitis. Bremner and associates-' excised the distal esophageal mucosa in three groups of dogs. In animals in which the gastroesophageal sphincter remained competent, the denuded mucosa was replaced mostly by squamous epithelium. In dogs in which reflux was encouraged by the creation of a hiatal hernia and the performance of a cardioplasty, re-epithelialization was partly by squamous and partly by columnar epithelium. However, in a third group of animals in which histamine stimulation of gastric acid was added to the reflux-inducing procedures, replacement was almost entirely by columnar epithelium, Naef and Savary" found 62 patients with Barrett's esophagus during 4,950 esophagoscopies. Reflux was present in all, a hiatus hernia was demonstrated in 59, and adenocarcinoma was detected in 9 patients. Other authors 7 , 12, 13, 26, 29, 31, 33, 38, 40, 42, 44 have reported cases of adenocarcinoma occurring in a columnar-lined esophagus. Many of these authors have indicated their suspicion that Barrett's esophagus increases the potentiality for malignancy in the esophagus. To quote Adler": "There appears to be more
The Journal 01 Thoracic and Cardiovascular Surgery
than a chance aSSOCiatIOn between the columnar-lined esophagus with hiatal hernia and carcinoma." Adenocarcinoma of the esophagogastric junction. MacDonald"" compared the clinical and pathological features of 51 patients with adenocarcinoma of the cardial end of the stomach with those of 169 patients with carcinoma elsewhere in the stomach. In the group with cancer of the cardia, the male:female ratio was 7: 1, as compared to a ratio of 2.3: I for the group with cancer elsewhere in the stomach, The group with cardia cancer showed a higher incidence of hiatus hernia, of heartburn, and of past or present duodenal ulcer. When the surgical specimens of those who underwent gastrectomy were compared, twenty-four of twenty-five cardial tumors had spread through the muscularis, whereas ten of sixty-seven distal cancers had not infiltrated beyond the mucosa or submucosa. Twenty-one of the 25 patients with cardial cancer had normal fundal gland mucosa, compared with only 15 of the 67 with cancers elsewhere. In 7 of the cardia cases, multiple patches of columnar epithelium were situated proximal to the neoplasm; in 6 others, the lower esophagus was lined with columnar epithelium. MacDonald'" concluded that carcinoma of the cardia may be a different disease from carcinoma of the remainder of the stomach. Block and Lancaster" reported on 40 patients with adenocarcinoma of the esophagogastric junction. Thirty-one were men. Thirty-nine had exploratory surgery. In 10 the lesion was nonresectable, principally because of hepatic involvement. Four of them underwent esophagogastrostomy without excision of the tumor. In 25 patients (64 per cent) resection with attempt at cure was performed. Of the twenty-five operative specimens, twenty-two contained lymph node metastases, nineteen showed extension of the tumor through all of the wall, and eight showed tumor in the resected end of the esophagus. The operative mortality rate was 20 per cent. The average survival period was 16 months for the entire group and 18 months in those treated by
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resection. Three patients (7 per cent) survived 5 years or more. Humphrey and Cliffton'" compared 284 adenocarcinomas and 308 epidermoid carcinomas of the distal esophagus and cardia. Considering all patients admitted, the disease was limited to the wall of the esophagus or cardia in 42 per cent of the patients with epidermoid carcinoma as compared to only 19.3 per cent of those with adenocarcinoma. Gunnlaugsson and associates, ~~ in a study of 1,657 patients with carcinoma of the esophagus and cardia, compared the results of curative resection in patients with squamous cell carcinoma of the cardia with the results in patients with adenocarcinoma of the cardia. In the group with squamous cell carcinoma, 6 of 11 patients with negative lymph nodes (54.5 per cent) and 2 of 13 with positive nodes (15.4 per cent) survived 5 years. In the group with adenocarcinoma, only 18 of 67 with negative nodes (26,9 per cent) and 13 of 171 with positive nodes (7.6 per cent) were 5 year survivors. In the entire series, survival rates were best for squamous cell carcinoma of the lower esophagus and the esophagogastric junction. Survival rates were poorest for patients with carcinomas of the cervical and upper thoracic esophagus and for those with adenocarcinoma of the cardia.
2
3
4
5
6
REFERENCES Ackerman, L. V., and del Regato, 1. A.: Cancer: Diagnosis, Treatment, and Prognosis, ed. 2, St. Louis, 1954, The C. V. Mosby Company, p. 521. Adler, R. H., and Rodriques, J.: The Association of Hiatus Hernia and Gastroesophageal Malignancy, J. THORAC. SURG. 37: 553, 1959. Adler, R. H.: The Lower Esophagus Lined by Columnar Epithelium: Its Association With Hiatal Hernia, Ulcer, Stricture, and Tumor, J. THORAC. CARDIOVASC. SURG. 45: 13, 1963. Adler, R. H.: The Esophagus With Columnar Epithelium: Its Clinical Significance, Geriatrics 20: 109, 1965. Allison, P. R., and Johnstone, A. S.: The Oesophagus Lined With Gastric Mucous Membrane, Thorax 8: 87, 1953. Allison, P. R.: The Diaphragm, in Gibbon, J. H., Sabiston, D. c., Jr., and Spencer, F. c.,
editors: Surgery of the Chest, Philadelphia, 1969, W. B. Saunders Company, chap. 15. 7 Armstrong, R. A., Blalock, J. B., and Carrera, G. M.: Adenocarcinoma of the Middle Third of the Esophagus Arising From Ectopic Gastric Mucosa, J. THORAC. SURG. 37: 398, 1959. 8 Barrett, N. R.: Chronic Peptic Ulcer of the Oesophagus and "Oesophagitis," Br. J. Surg. 38: 175,1950. 9 Block, G. E., and Lancaster, 1. R.: Adenocarcinoma of the Cardioesophageal Junction, Arch. Surg. 88: 852, 1964. 10 Bockus, H. L.: Gastroenterology, ed. 2, Philadelphia, 1963, W. B. Saunders Company, vol. 1, chap. 1 I. 11 Bremner, C. G., Lynch, V. P., and Ellis, F. H., Jr.: Barrett's Esophagus: Congenital or Acquired? An Experimental Study of Esophageal Mucosal Regeneration in the Dog, Surgery 68: 209, 1970. 12 Burns, W. A., Flores, P. A., Moshyedi, A., and Albacete, R. A.: Clinical Conditions Associated With Columnar Lined Esophagus, Am. J. Dig. Dis. 15: 607, 1970. 13 Dawson, 1. L.: Adenocarcinoma of the Middle Oesophagus Arising in an Oesophagus Lined by Gastric (Parietal) Epithelium, Br. 1. Surg. 51: 940, 1964. 14 De la Pava, S., Pickren, J. W., and Adler, R. H.: Ectopic Gastric Mucosa of the Esophagus: A Study on Histiogenesis, N. Y. J. Med. 64: 1831, 1964. 15 Dodge, O. G.: Gastro-esophageal Carcinoma of Mixed Histologic Type, J. Pathol. 81: 459, 1961. 16 EI-Domeiri, A., Martini, N., and Beattie, E. J., Jr.: Esophageal Reconstruction by Colon Interposition, Arch. Surg. 100: 358, 1970. 17 Feldman, M., and Meyers, P.: Coexistence of Carcinoma of the Stomach and Esophageal Hiatus Gastric Hernia, Am. J. Med. Sci. 224: 519, 1952. 18 Goldman, M. c., and Beckman, R. C.: Barrett Syndrome: Case Report With Discussion About Concepts of Pathogenesis, Gastroenterology 39: 104, 1960. 19 Grimes, O. F., and Zboralske, F. F.: Carcinoma in Association With Hiatal Hernia, J. THORAC. CARDIOVASC. SURG. 55: 30, 1968. 20 Groves, L. K., and Effler, D. B.: Cancer of the Gastric Cardia Associated With Esophagael Hiatus Hernia, Surg. Gynecol. Obstet. 116: 463, 19'63. 21 Guinn, G. A., Jordan, P. H., and Stewart, C. V.: Appraisal of Therapy for Carcinoma of the Esophagus, Am. J. Surg. 122: 703, 1971. 22 Gunnlaugsson, G. H., Wychulis, A. R., Roland, C., and Ellis, F. H., Jr.: Analysis of the Records of 1,657 Patients With Carcinoma
The Journal al
15 8
Hankins et al.
Thoracic and Cardiovascular Surgery
23
24 25
26
27
28
29
30 31
32
33
of the Esophagus and Cardia of the Stomach, Surg. Gynecol. Obstet. 130: 997, 1970. Hankins, J. R., Cole, F. N., Ward, A., Carter, E. A, Weiner, S., and McLaughlin, J. S.: Carcinoma of the Esophagus: The Philosophy for Palliation, Ann. Thorac. Surg. 14: 189, 1972. Hayward, 1.: The Lower End of the Esophagus, Thorax 16: 36, 1961. Humphrey, C. R., and Cliffton, E. E.: Carcinoma of the Distal Part of the Esophagus and Cardia of the Stomach, Surg. Gyneco!. Obstet. 127: 737, 1968. Jernstrom, P., and Brewer, L. A., III: Primary Adenocarcinoma of the Midesophagus Arising in Ectopic Gastric Mucosa With Associated Hiatal Hernia and Reflux Esophagitis (Dawson's Syndrome), Cancer 26: 1343, 1970. Lawler, M. R., Jr., Gobbel, W. G., Jr., Killen, D. A., and Daniel, R. A, Jr.: Carcinoma of the Esophagus, J. THORAC. CARDIOVASC. SURG. 58: 609, 1969. Leon, W., Strug, L. H., and Brickman, I. D.: Carcinoma of the Esophagus: A Disaster, Ann. Thorac. Surg. 11: 583, 1971. Lortat-Jacob, J. L., Maillard, 1. N., Richard, C. A, Fekete, F., Huguier, M., and ConteMarti, J.: Primary Esophageal Adenocarcinoma: Report of 16 Cases, Surgery 64: 535, 1968. MacDonald, W. C.: Clinical and Pathologic Features of Adenocarcinoma of the Gastric Cardia, Cancer 29: 724, 1972. McCorkle, R. G., and Blades, B.: Adenocarcinoma of the Esophagus Arising in Aberrant Gastric Mucosa, Am. Surg. 21: 781, 1955. McPeak, E., and Warren, S.: Histologic Features of Carcinoma of the Cardioesophageal Junction and Cardia, Am. J. Patho!. 24: 971, 1948. Morson, B. C., and Belcher, J, R.: Adenocar-
34
35
36
37 38
39
40
41
42 43
44
45
cinoma of the Oesophagus and Ectopic Gastric Mucosa, Br. J. Cancer 6: 127, 1952. Moseley, R. Y.: Squamous Carcinoma of the Esophagus, Surg. Gyneco!. Obstet. 126: 1242, 1968. Mossberg, S. M.: The Columnar-Lined Esophagus (Barrett Syndrome): An Acquired Condition? Gastroenterology 50: 671, 1966. Naef, A. P., and Savary, M.: Conservative Operations for Peptic Esophagitis With Stenosis in Columnar-Lined Lower Esophagus, Ann. Thorac. Surg. 13: 543, 1972. Parker, E. F., Gregorie, H. B., Jr., Arrants, J. E., and Ravenel, J. M.: Carcinoma of the Esophagus, Ann. Surg. 171: 746, 1970. Pattinson, 1. N., Osborne, G., and Morson, B. c.: Hiatus Hernia With Adenocarcinoma Arising in the Region of the Cardia, J. Fac. Radiol. 7: 90, 1955. Puestow, C. B., Gillesby, W. J., and Guznon, Y. L.: Carcinoma of the Esophagus, Arch. Surg. 70: 662, 1955. Raphael, H. A., Ellis, F. H., Jr., and Dockerty, M. B.: Primary Adenocarcinoma of the Esophagus, Ann. Surg. 162: 785, 1966. Smithers, D. W.: The Association of Cancer of the Stomach and Oesophagus With Herniation at the Oesophageal Hiatus of the Diaphragm, Br. J. Radiol. 28: 554, 1955. Smithers, D. W.: Adenocarcinoma of the Esophagus, Thorax 11: 257, 1956. Stout, A P., and Lattes, R.: Tumors of the Esophagus, (Fascicle 20), in Atlas of Tumor Pathology, Washington, D. C., 1957, Armed Forces Institute of Pathology. Thomas, 1. Y., and Hay, L. J.: Adenocarcinoma of the Esophagus, Surgery 35: 635, 1954. Turnbull, A D. M., and Goodner, J. T.: Primary Adenocarcinoma of the Esophagus, Cancer 22: 915, 1968.