What are the characteristic differences between adenocarcinoma arising in CLE and squamous cell carcinoma of the esophagus?
A.H. Holscher, E. Bollschweiler, J.R. Siewert (Munich)
In a series of 505 patients with resected esophageal carcinomas, we saw 302 squamous cell carcinomas (SC) (59.8%) and 203 adenocarcinomas (AC) (40.2%). The ratio of male to female was quite similar with 7:1 for squamous cell carcinomas and 8:1 for adenocarcinomas. The patients with squamous cell carcinomas, however, were in the median about 7 years younger than those with adenocarcinomas (SC: 52.9 (32-80) years; AC: 60.1 (29-82) years).
The localization of the esophageal cancers showed the usual distribution with all adenocarcinomas located in the infrabifurcal part of the esophagus whereas the squamous cell carcinomas showed 7% in the cervical part, 24% suprabifurcal, 21% ad bifurcationem and 51% infrabifurcal.
The histologic grading of the esophageal carcinomas was quite similar for squamous cell or adenocarcinomas (GI: 9.6 vs. 7.2%, G2: 45.4 vs. 47.8%, G3: 34.9 vs. 39.9%, G4: 10.1 vs. 5.1%). The postoperative T-category demonstrated more advanced T-stages for resected adenocarcinomas. The stage pTl was found in 17% for SC and 13.5% for AC whereas stage pT2 amounted to 18.5% in SC and AC in 30.7%. The most striking difference was concerning the pT3-stage with 51% for SC and 30.1% for AC. In pT4-stages there were 13.5% for SC and 25.7% for AC. The comparison of the postoperative N-category between SC and AC is difficult because it is questionable if the UICC-classification of 1987 for squamous cell carcinoma of the esophagus should also be applied for adenocarcinoma of the distal esophagus. If one uses the pN-classification of gastric cancer for the adenocarcinoma of the distal esophagus, as we do for the adenocarcinoma of the gastroesophageal junction, the results are as follows: SC had 39% NO and AC 27.3%, whereas pNl-stage was found in 45.5% for SC and 34.1% for AC. 15.5% of the SC were classified as pMl LYMPH, that means distal lymph node metastases and 38.6% of the AC-patients had a pN2-status. Concerning distant organ metastases (Ml), like liver etc., the distribution was 6.3% for SC vs. 14.2% for AC.
If the alcohol consumption is compared between patients with squamous cell carcinoma and those with adenocarcinoma, there were more patients with high alcohol intake in the group of squamous cell carcinoma patients than in the group of adenocarcinoma patients (normal alcohol intake SC 21%, AC 34%; medium intake SC 55%, AC 56%; high intake SC 24%, AC 10%).
The long-term prognosis after resection of squamous cell carcinoma (transthoracic enbloc-resection) or adenocarcinoma (transmediastinal esophagectomy), was not significantly different. The 5-year survival rate for the series of 302 patients with resected squamous cell carcinomas was 22% vs. 28% for the patients with resected adenocarcinoma (n = 203). This slight, but not significant difference in survival
between the two whole series, is due to a significant difference in the prognosis concerning the T 1-stage. Patients with Tl-adenocarcinoma (n = 27) had a significantly (p < 0.05) better prognosis than those patients with a Tl-squamous cell carcinoma (n = 51) of the esophagus (78 vs. 53% 5-year survival rate) .
1. Holscher AH, Bollschweiler E, Schiller M, Tachibana M, Nakamura T, Siewert JR. Early esophageal cancer: prognostic advantage of a adeno- compared lo squamous cell carcinomas. Proceedings of the 5th International Congress of the International Society for Diseases of the Esophagus, Kyoto 1992;95.
S.N. Click (Philadelphia)
Malignant epithelial neoplasms of the hollow gastrointestinal viscera have a limited number of morphologic manifestations. Any combination of intraluminal polypoid growth, ulceration or narrowing of the lumen involving a length of approximately 3-6 cm and with abrupt transition to the adjacent uninvolved segments, is the rule. These tumors are predominantly adenocarcinomas with the exception of the esophagus, where the mucosa is lined by squamous cells. However, exposure to gastroesophageal reflux (GER) predisposes the latter to columnar metaplasia (Barrett's esophagus) in some patients and these individuals are at risk for the development of adenocarcinoma in the transformed tissue [1-5]. Indeed, almost all cases (with rare exceptions) of adenocarcinoma of the esophagus result from this pathogenetic pathway . Furthermore, recent data suggests that adenocarcinoma represents over 1/3 of cancers of the esophagus and that the importance of this entity has been under-emphasized [2,4].
The diagnosis of adenocarcinoma arising in CLE is based upon the recovery of tissue through endoscopic biopsy. Thus a prospective specific histologic diagnosis based upon epidemiologic and radiologic information has little impact on patient management in most cases. However, they provide an improved understanding with regard to the significance of this process and in some cases contribute to the overall outcome. There are several diagnostic dilemmas that can be clarified. A high probability of adenocarcinoma of the esophagus can be suggested, with a distinction made between both squamous carcinoma of the esophagus and gastric carcinoma extending into the esophagus. Of greater importance is the ability to recognize radiologic features which suggest malignant neoplasm as opposed to, or superimposed upon, a benign peptic stricture. On occasion, endoscopy, even with biopsy and brushing, can be misleading.
From an epidemiologic perspective, Barrett's adenocarcinoma occurs predomi-
nantly in white males . This relationship is not well understood. Conversely, squamous cell carcinoma is common in black males and has a high association with a history of alcohol ingestion and smoking. While there has been no evidence to link drinking with adenocarcinoma there have been conflicting reports concerning the influence of smoking . Although a number of patients with adenocarcinoma in CLE will have a history of reflux symptoms, in as many as 50% such complaints cannot be elicited.
On barium esophagram, the most consistent feature of adenocarcinoma is the location of the lesion (Fig. 1 A,B). A personal review of 23 cases of adenocarcinoma of the esophagus revealed 20 of the lesions having the epicenter (midpoint) within the lower 6-8 cm of the esophagus. Furthermore, during this same period there were
Figure 1. .A) Typical squamous cell carcinoma (arrows) appearing as tabulated plaque in the midesophagus. B) Adenocarcinoma in CLE with its superior component located in the distal 6 cm of the esophagus (black arrow) and its distal limit at the gastroesophageal junction (open arrow).
Fig. 2. A) Adenocarcinoma in CLE. Annular infiltrative lesion in the distal esophagus. B) Extension into the gastric cardia (arrows). Involvement of the stomach is minimal.
only two instances of squamous cell carcinoma arising in this segment. This is consistent with the proposed pathogenesis, as adenocarcinoma in CLE tends to arise within 2 cm of the histologic squamocolumnar junction and the transition is seldom higher than 8 cm from the anatomic gastroesophageal junction. In distinction from esophageal involvement from gastric adenocarcinoma, a minority of the tumors in CLE will infiltrate the gastric cardia, but as a rule the abnormalities identified in the stomach are minimal and the epicenter of the lesion will suggest an esophageal origin (Fig. 2A,B). From a clinical standpoint, this differential is probably of little relevance, although it is always beneficial to know the extent of a primary gastric tumor. At times this information can only be assessed by radiology, as the endoscope cannot
Figure 3. .Adenocarcinoma in CLE. Plaque-like appearance confined to one wall in distal esophagus (arrows). The lower esophagus is patulous and the adjacent mucosa demonstrates a reticular pattern.
Figure 4. .A) Peptic stricture with malignant degeneration. Asymmetric narrowing with rounded mass effect and spiculatal contour (arrows). B) Peptic stricture with malignant degeneration. Long benign appearing stenosis (large arrow) with subtle nodular scalloping (small arrows) along mucosal surface.
transverse a high-grade stenosis, or the invasion is predominantly submucosal.
As stated previously, there usually is nothing specific with regard to the morphologic appearance of these epithelial neoplasms . However, there are a few trends that should be recognized. Squamous cell carcinoma has a tendency to be circumferential while adenocarcinoma in CLE is, in the vast majority, confined to one wall (Fig. 3). The major exception is when adenocarcinoma is superimposed within a peptic stricture. The features that suggest neoplasm in this setting are: discrete mucosal nodules within the stenosis; numerous irregular barium spiculations within the stenosis (representing superficial ulceration and/or barium collecting between smaller nodules); submucosal defects within the stricture; and asymmetric transition with the normal lumen (proximally and/or distally) (Fig. 4A,B). Not only is the mass
Figure 5. .A) Adenocarcinoma in CLE. Large mass in distal esophagus with deep central ulceration (arrow). B) Adenocarcinoma in CLE. Ulcerated mass (arrow) within benign peptic stricture just superior to a hiatal hernia.
in adenocarcinoma usually on one wall, but in the majority, a deep central ulcer crater surrounded by tumor can be demonstrated (Fig. 5A,B). This may be related to its columnar origin with behavioral characteristics more consistent with gastric adenocarcinoma. Such an appearance is uncommon in squamous cell carcinoma, so that when a lesion with these features is identified closer to the midesophagus, the possibility of adenocarcinoma increases. It has been suggested  that the involvement of a longer length segment of the esophagus with an infiltrative or varicoid appearance may be more typical of adenocarcinoma (Fig. 6A,B). While this does occur (and possibly in some, reflects the presence of a long peptic stricture), in my experience, it also may be seen in squamous cell carcinoma and neither the frequency nor the specificity is sufficient for reliable differentiation.
Fig. 6. A) Extensive varicoid adenocarcinoma. Proximal margin (arrow) is at the level of the tracheal bifurcation. B) The lesion extends to the distal esophagus. It has been postulated that this appearance is suggestive of adenocarcinoma.
On occasion, ancillary observations on barium study may predict a malignant appearing lesion to be adenocarcinoma. A large hiatal hernia, massive repeated GER, a wide patulous lower esophageal sphincter (LES) (>4 cm) and specific findings that suggest Barrett's esophagus (e.g., reticular mucosal pattern and midesophageal stricture) are included in this group .
One specific scenario should be mentioned. The previous discussion has focused upon cases of advanced adenocarcinoma. However, as patients with reflux symptoms undergo radiologic evaluation more frequently than those with squamous carcinoma (symptoms are usually late) the likelihood of detecting earlier lesions is increased .
Figure 7. .Early adenocarcinoma. Small mass (open arrows) with central ulcer (arrow) in the distal esophagus. This was detected during work-up of reflux symptoms. The lesion was confined to the submucosa and the lymph nodes were normal.
The presence of any slight asymmetric narrowing or contour defect (i.e., flattening or mural elevation) or nodular or polypoidal mucosal excrescences should heighten the index of suspicion (Fig. 7). Any discrete ulcer should also be approached cautiously. Even when initial endoscopy and biopsy are not confirmatory, such alterations should be aggressively pursued.
In summary, in most cases the radiologic distinction between adenocarcinoma in CLE and squamous cell carcinoma can be readily made on the basis of a distal location, particularly in a white male. The presence of a history of reflux symptoms provides further support. With more proximal tumors, a deep discrete ulcer may also help differentiate. However, the major value of barium radiology involves those instances of malignant degeneration within a peptic stricture, determining the presence and extent of gastric involvement and, most importantly, subtle alterations which may predict an early and more curable lesion.