Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Esophagogastric  Junction

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Volume: Barrett's Esophagus
Chapter: Adenocarcinomas

Following resection, can DNA ploidy be considered as a prognostic factor?

B.P.L. Wijnhoven, H.W. Tilanus (Rotterdam)

Transformation from a normal to a malignant cell may be associated with changes in total DNA content or ploidy. A normal cell has a chromosome number of 2N, for which the term diploid is applied. A cell with numerical aberrations is designated as aneuploid. Barrett's dysplasia and esophageal adenocarcinomas are characterized by chromosomal instability leading to aneuploidy. It is suggested that chromosome instability, tetraploidization, and asymmetrical chromosome segregation during cell division are the result of dysfunctioning human mitotic checkpoint genes. But also genes with multiple functions that normally exert active checks on the cell cycle processes including apoptosis and chromosome stability, e.g. p53 and k-ras genes, can be deregulated.

Table I.

By using flow cytometry, it is possible to provide objective information about the ploidy status of the tumor with reference to cells with a normal diploid amount of DNA. It has been shown that the evolution from normal esophagus to premalignant Barrett's metaplasia is frequently associated with abnormal DNA content and increased G2/M fraction (4N) of the metaplastic cells. Moreover, abnormal DNA content shows a correlation with the histologic diagnosis of dysplasia and carcinoma. Flow cytometry also detects a subset of patients whose biopsies are histologically indefinite or negative for dysplasia and carcinoma, but who have DNA content abnormalities similar to those otherwise seen only in dysplasia and carcinoma. Therefore, this technique (in combination with histology) may be of use in screening patients with Barrett's esophagus for early signs of malignant change. As their precursor lesion, Barrett's adenocarcinomas often demonstrate aneuploidy. Several studies have consistently documented high levels of DNA aneuploidy, typically ranging from 50-85% [1-6].

What is the relationship between DNA ploidy and pathological characteristics of the tumor?

Most studies report that aneuploid tumors are significantly associated with infiltration of the wall of the esophagus (pT-stage), increased lymph node metastases (pN) and/or advanced stage of disease [2, 3, 5, 6]. Only two studies could not establish a significant relationship between DNA ploidy and pathology.

What is the relationship between DNA ploidy and survival in patients after resection for esophageal adenocarcinoma?

DNA ploidy can predict overall survival or disease free survival after resection, but only two studies identified DNA ploidy as an independent predictor of survival: in patients with Barrett's adenocarcinoma after curative resection (R0) [3], and in lymph node-negative (N0), R0-resected patients [6]. Bittinger et al. found that DNA ploidy is the strongest predictor of survival (and not pTNM stage): patients with diploid or tetraploid tumors had a significantly better prognosis with a 3-year survival rate of 35% in contrast to 8% for aneuploid tumors. Furthermore, within the pT2 and pT3 tumors, DNA ploidy allowed additional prognostic information [3].

In conclusion, current data from the literature demonstrate that aneuploidy in esophageal adenocarcinomas reflects the numerous chromosomal aberrations and this correlates well with the aggressiveness of the tumor. Aneuploid tumors are generally more likely to have positive lymph nodes, which is usually one of the most important prognostic variable in predicting disease free and overall survival. Considering the information obtained from pathological examination of the esophagogastric specimen, the addition of tumor ploidy can alert the clinician to high-risk groups, namely those with increased incidence of lymph node metastases, recurrence, and poorer survival. However, further studies on a larger series of patients with adenocarcinomas of the esophagus will be necessary for verification of these results. One of the great advantages of flow cytometric analysis of DNA ploidy is that it can be reliable on routine, paraffin-embedded tissues and pre-operative mucosal biopsies, thereby enabling assessment of prognosis at the time of cancer diagnosis. However, their clinical relevance for therapeutic decision making (e.g. extent of surgical resection, indication for neo-adjuvant radiotherapy or chemotherapy) remains to be demonstrated.


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Publication date: August 2003 OESO©2015