Section 2 -

Early Esophageal Cancer Manfred Stolte Bayreuth

Introduction In recent years, the incidence of gastric cancer has declined sharply, squamous cell carcinoma of the esophagus has remained relatively constant, but Barrett's adenocarcinoma has increased dramatically. Other, extremely rare, malignant tumours of the oesophagus are not considered here. While in the early nineties our institute diagnosed squamous cell carcinomas and Barrett's adenocarcinomas almost exclusively at an advanced stage, the last 6 years have seen a considerable change for the better. Today, some 25% of our squamous cell carcinomas and about 60% of our Barrett's carcinomas are early lesions. I shall limit my discussion to these two early neoplasms. 1. Early Neoplasms of the Squamous Epithelium 1.1. Biopsy diagnosis and its pitfalls A knowledge of biopsy diagnosis of intraepithelial neoplasia ranging up to high-grade intraepithelial neoplasia (carcinoma in situ) is assumed. Diagnosing intra-epithelial neoplasia is problematical when the superficial cell layer of the (squamous epithelium is normal and an "undermining" (pagetoid) intra-epithelial neoplasia is found at the base. In such a case, the differential diagnosis from regenerative changes in the basal cell layer is sometimes difficult. While regenerative hyperplasia of the basal layer at the edge of a lesion or healed lesion shows compact hyperchromatic nuclei, undermining intraepithelial neoplasia polymorphous nuclei with irregular chromatin, increased nucleoli and pathological mitoses. A gap is often to be seen between the pagetoid undermining neoplasia and the normal epithelium above. Our experience suggests than the undermining neoplasia is almost always an indication that the biopsy was obtained from the margin of a carcinoma in situ or early invasive carcinoma. High-grade intraepithelial neoplasia (carcinoma in situ) is relatively easy to diagnose when all the layers of epithelium are replaced by neoplastic cells. However, an invasive carcinoma cannot reliably be excluded in biopsy material lacking any lamina propria. A presumptive diagnosis of carcinoma in situ or early carcinoma can be rendered more probable by considering the endoscopic findings. Conditions leading to overdiagnosis of a squamous cell carcinoma in biopsy material are: Herpes esophagitis, Pseudoepitheliomatous hyperplasia, and Regenerative changes in the margin of an erosive or ulcerative reflux esophagitis. A further pitfall is the misdiagnosis of a sarcoma in the presence of pleomorphic fibroblasts in granulation tissue in the centre of an esophageal ulcer. As a consultant pathologist. I have corrected squamous cell carcinoma misdiagnoses in reflux esophagitis in 10, and sarcoma misdiagnoses in 6, cases. Every pathologist diagnosing a squamous cell carcinoma in a biopsy should therefore be aware of the following points : Such carcinomas are virtually never a consequence of reflux disease! Before diagnosing a squamous cell carcinoma, the endoscopic finding must be factored in! Another pitfall is pseudoepitheliomatous hyperplasia, in particular on the summit of granular cell tumours. 1.2. Diagnostic work-up of the endoscopic resectate The resectate must be pinned to cork. The resection lines are marked with Indian ink. The material is then lamellated, and all lamellae embedded in paraffin for histology. The major risk factor for lymphogenic metastasization is the depth of infiltration, which, following the Japanese, is classified: m1 = Carcinoma in situ m2 = Infiltration of the lamina propria m3 = Infiltration of the muscularis mucosae sm1 = Infiltration of the upper third of the submucosa sm2 = Infiltration into the middle third of the submucosa sm3 = Infiltration into the lower third of the submucosa In the categories m2 – 3, lymph node metastases are found in some 5%, in sm1 24.1%, in sm2 33.6% and in sm3 48.4%. Additional risk factors for lymphogenic metastasization are poorly differentiated carcinomas and invasion of lymphatic vessels. 2. Early Neoplasms of Barrett's Mucosa 2.1. Biopsy-based differential diagnosis between regenerative changes and low-grade intraepithelial neoplasia Interobserver variability in the histological diagnosis of early neoplasia of Barrett's mucosa is relatively poor, in particular for low-grade intraepithelial neoplasia. This is underscored by the evaluation of cases diagnosed as low-grade intraepithelial neoplasia sent to use by other German pathologists between 2000 and 2005. Of a total of 257 diagnoses, I confirmed only 10.9%, while 64.2% were regenerative changes, 2.7% high-grade intraepithelial neoplasia, and 22.2% well-differentiated Barrett's adenocarcinoma. Most of these cases were overdiagnosis of regenerative changes. Furthermore, the extremely variable prevalence of low-grade dysplasia reported in numerous publications indicates that regenerative changes in Barrett's mucosa are apparently overdiagnosed as low-grade dysplasia the world over. In many cases, back-to-back glands located at the base of Barrett's mucosa, with hyperchromatic nuclei and increased mitotic figures are overdiagnosed as low-grade dysplasia. Back-to-back glands, however, are merely a result of the p-division of the stem cells during the regenerative process. The nuclei in the basal third of the regenerative glands have compact chromatin with no prominent nucleoli, the epithelium shows progressive maturation in the apical direction, and the surface epithelium is normal. In support of the world-wide overdiagnosis of regenerative changes in Barrett's mucosa are the results of follow-up studies of a primary diagnosis of a low-grade intraepithelial neoplasia. In 60 – 70% of these cases, follow-up reported "regression" of the neoplasia, while progression was very rarely reported. In low-grade intraepithelial neoplasia (dysplasia) the architecture of Barrett's mucosa with parallel arrangement of glands is largely normal. The neoplastic epithelial cells with basal, often peg-like, nuclei extend to the surface epithelium of Barrett's mucosa, and there is abrupt transition to the neighbouring Barrett's epithelium. On the basis of our experience, we would suggest that the reliable biopsy-based diagnosis of low-grade intraepithelial neoplasia may merely be the tip of the iceberg, and that the neoplasia may also be an extension of high-grade intraepithelial neoplasia or an adenocarcinoma. 2.2. Differential diagnosis between low-grade and high-grade intraepithelial neoplasia and adenocarcinoma in Barrett's mucosa In high-grade intraepithelial neoplasia, too, the normal architecture of Barrett's mucosa is relatively well preserved, and ass in low-grade intraepithelialneoplasia the epithelium of Barrett's glands has been replaced by neoplastic epithelium. In comparison with the epithelium of the low-gradeform, however, neoplastic epithelium in high-grade dysplasia reveals all the cytological criteria of malignancy. The nuclei are irregularly arranged (loss of polarity, increased polymorphism and hyperchromatism with irregularly structured chromatin, prominent nucleoli and increased pathological mitotic figures)- As with high-grade intraepithelial neoplasia, all the above-mentioned cytological criteria of malignancy are also found in well-differentiated Barrett's adenocarcinoma. In addition, invasive growth of the neoplastic tubuli is seen. This architectural disruption is interpreted by many pathologists as a "partial substrate" of high-grade intraepithelial neoplasia, and not invasive intramucosal carcinoma. These pathologists diagnose carcinoma only when there is disruption of the neoplastic glands with single tumour cells within the lamina propria and solid invasive trabecular tumor pegs. In our own experience, however, these criteria are to be seen only in moderately or poorly differentiated adenocarcinomas, not in well-differentiated adenocarcinoma. We believe that - in analogy to well-differentiated early gastric carcinoma - transversally arranged interconnected neoplastic tubuli must be interpreted as invasive growth through the lamina propria. This interpretation is supported by the fact that these well-differentiated tubular Barrett's adenocarcinomas often fail to show tumour cell dissociation, even in the invasive front in the newly formed muscularis mucosae, the original lamina propria of the esophageal mucosa, the original muscularis mucosae, and the submucosa, but are here characterized by invasive neoplastic tubuli. When confronted by such findings in the endoscopic mucosectomy or surgical specimens, most Western pathologists also diagnose adenocarcinoma – as in the case of well-differentiated tubular adenocarcinoma in the stomach or colorectum. This is also confirmed by comparing the diagnosis of high-grade intraepithelial neoplasia in biopsy material with the definitive diagnosis in the surgical specimen: in 40%-70% of the cases, carcinoma is diagnosed in the surgical specimen, sometimes with signs of advanced carcinoma. This is not at all surprising, since in our experience well-differentiated Barrett's carcinomas often mimics high-grade intraepithelial neoplasia at the surface, while invasive carcinoma is unequivocally diagnosed in the base. Most well- and moderately differentiated early Barrett's carcinomas limited to the mucosa show no tumour cell dissociation, but invasive growth of the neoplastic tubuli. This applies not only to the early carcinomas limited to Barrett's mucosa, but also to those invading the newly formed muscularis mucosae, the original lamina propria of the esophageal mucosa and those with invasion of the original muscularis mucosae of the esophageal mucosa. Invasion of the submucosa is associated with a statistically significant increase in tumour cell dissociation, degree of malignancy and lymph vessel invasion. 2.3. Diagnostic work-up of the endoscopic resectate and risk factors for lymphogenic metastasization The resectate is pinned to cork, and examined under the stereomicroscope. This has shown that more than 80% of early carcinomas of Barrett's mucosa can be identified by the changes to surface structure. Similar changes may often also be found in low- and high-grade intraepithelial neoplasia. However in some 20% of the cases, regenerative changes of non-neoplastic Barrett's mucosa may also lead to suspicious changes in surface structure. The endoscopic resectate is divided up into 2-3 mm wide strips, each of which is embedded separately for histological work-up. In analogy to the classification of early squamous cell carcinoma, we differentiate the depth of infiltration of Barrett's adenocarcinomas as follows: m1 = carcinoma limited to Barrett's mucosa m2 = carcinoma infiltrating the newly formed muscularis mucosae of Barrett's mucosa m3 = carcinoma infiltrating the original lamina propria of the oesophageal mucosa m4 = infiltration of the original muscularis mucosa of the esophageal mucosa sm1 = Infiltration of the superficial third of the submucosa sm2 = infiltration of the middle third of the submucosa sm3 = infiltration of the deep third of the submucosa Whether this depth of infiltration classification is of any practical value, e.g. whether m4 carcinomas more frequently metastasize to the lymph nodes than m1 carcinomas, or whether, in analogy to early gastric carcinoma, sm1 carcinomas relatively rarely metastasize to the lymph nodes, may be answered by the results of our currently ongoing follow-up investigations. In the absence of such data, the risk of metastasis can, as a working hypothesis in analogy to early gastric carcinoma, be differentiated as follows: Low risk Depth of infiltration limited to the mucosa (m1 to m4) Well to moderately well-differentiated adenocarcinoma (G1, G2) No invasion of lymphatic or blood vessels (L0, V0) High risk Depth of infiltration into the submucosa (sm1 to sm3), or Poorly differentiated and undifferentiated carcinoma (G3, G4), or Invasion of lymphatic of blood vessels (L1, V1) Further follow-up investigations must show whether this risk classification is correct. Conclusions Conditions leading to overdiagnosis of squamous cell carcinoma in the esophagus are herpes esophagitis, pseudoepitheliomatous hyperplasia (in particular in subepithelial granular cell tumours) and regenerative changes in the margin of erosive or ulcerous non-neoplastic lesions. Consideration of the endoscopic picture is therefore very important. Risk factors for lymphogenic metastasization of early squamous cell carcinoma are depth of infiltration (m3, sm1 to sm3) and invasion of lymphatic vessels. Regenerative changes in Barrett's mucosa continue to be overdiagnosed as "low-grade intraepithelial neoplasia" in 60 to 70% of the cases world-wide. In view of this, 4 weeks' treatment with high-dose PPI, followed by renewed endoscopy/biopsy is recommended initially. Reliable diagnosis of low-grade intraepithelial neoplasia not infrequently indicates that the lesion is the margin of a high-grade intraepithelial neoplasia or a well-differentiated Barrett's adenocarcinoma. In more than 50% of the cases, the diagnosis high-grade intraepithelial neoplasia of Barrett's mucosa in biopsy material represents underdiagnosis of a well-differentiated Barrett's adenocarcinoma.. This is supported not only by the findings in the surgical specimen and endoscopic resectate with a primary diagnosis of high-grade intra-epithelial neoplasia – most well- and moderately differentiated early Barrett's carcinomas grow within the mucosa with invasive neoplastic tubuli. Tumour cell dissociation in the invasion front usually presents when there is invasion of the submucosa. Risk factors for lymphogenic metastasization of early Barrett's carcinoma are depth of infiltration to the submucosa, poor differentiation of the carcinoma, and lymph vessel invasion. References see in: Stolte M., Vieth M., May A., Gossner L., Dostler I., Ell Ch. Early neoplasia in Barrett's Esophagus. In: Fujita R., Jass JR., Kaminishi M., Schlemper RJ (Eds.). Early Cancer of the Gastrointestinal Tract. Springer, Tokyo 2006.