Is the natural history of high-grade dysplasia known?
K. Geboes, P. De Paepe (Leuven)
Cancer develops by a multistep process during which a normal cell progresses subsequently to premalignant, in situ cancer (high grade dysplasia), invasive cancer, metastasis and eventually recurrence. This multistep process is associated with and most probably depends upon defects in genes controlling the normal process of cell proliferation and cell death. Genomic instability leads to the generation of single and later multiple aneuploid populations of cells. One of these, by further genetic changes eventually acquires the capacity for invasion [1-3]. Molecular cytogenetic techniques, in particular comparative genomic hybridization (CGH), are very informative in tracing the clonal evolution and expansion of cancer. With CGH genetic changes that systematically appear at the transition from non-invasive to invasive cancer or from primary tumor to metastasis can be detected. It has been shown that in the same cancer, areas of the in situ component, the invasive component and metastasis have a number of common genetic abnormalities but also different genetic characteristics. The former indicates a common clonal origin while the latter point towards an evolution during tumor progression. This phenomenon has been shown to occur in breast cancer but a similar approach might help to unravel the natural history of high-grade dysplasia and cancer in Barrett's esophagus. This history is at present not precisely known, mainly because of the lack of appropriate techniques, difficulties in follow-up of patients and the limited number of patients of whom data are available. Persistent clonal cytogenetic abnormalities have however been shown in biopsy specimens from four patients with Barrett's esophagus. These abnormal clones can persist for years and can progress to high-grade dysplasia and carcinoma . Several other techniques have been used thusfar for the study of Barrett's esophagus and neoplastic progression. These include a.o. cell proliferation activity and DNA content and nuclear aneuploidy. They may help in identifying patients at risk but are not really helpful in determining the transition from high-grade dysplasia to invasion [5, 6].
At present morphology remains the most reliable and available method for the assessment of neoplastic progression.
Yet, although metaplasia, low-grade dysplasia and high-grade dysplasia as well as invasive cancer are theoretically well defined, there are still some problems in the diagnosis of dysplasia. There is a significant intraobserver and interobserver variation (especially for low-grade dysplasia) and there is also a significant incidence of sampling error since dysplasia can be confined to very small areas. To overcome the latter problem it has been recommended to take four quadrant biopsies at intervals of 2 cm or less throughout the length of the Barrett's segment [7-9]. The diagnostic problems make it however difficult to study adequately the natural history of dysplasia. The temporal course of the progression of dysplasia and the development of carcinoma is therefore not well known.
From the data available it seems to be variable. Low-grade dysplasia may persist for long periods. A direct progression towards carcinoma has been noted although more often an increase in the severity of the dysplasia, before the development of carcinoma, was seen during the observation period [2, 10, 11].
High-grade dysplasia can also persist for many months, sometimes even years without obvious evolution but it can also progress rapidly to carcinoma. In a Dutch study high-grade dysplasia persisted for 36 and 44 months respectively in two patients, without evidence of further neoplastic progression while in 5 patients the time lag between the finding of low-grade dysplasia and cancer varied from 1.5 to 4 years . In a study by Reid et al., four patients with high-grade dysplasia remained histologically stable after a mean follow-up time of 14 months (range: 11-20 months). Progression to adenocarcinoma occurred in an average period of 14 months (range: 5-21 months) . In a prospective study of 81 patients, three patients developed adenocarcinoma. In two of these, high-grade dypslasia persisted for a period of 2.6 - 4.5 years before the discovery of adenocarcinoma on biopsy. The third patient had documented low-grade dysplasia during 4.3 years before the development of the adenocarcinoma . High-grade dysplasia, persistent over a period as long as 5 years was noted in one patient in a series of 34. In the same series another patient developed invasive cancer in a four year period . In some studies a transition from high-grade dysplasia towards invasive cancer is noted to occur in less than one year . In these patients it is however difficult to rule out the possibility that the cancer existed already at the initial endoscopy because of the low number of biopsies taken. In a study of 70 patients undergoing regular endoscopic biopsy procedures as part of their prospective surveillance, 12 were found to have early esophageal carcinoma on prompt follow-up endoscopy (mean, 2 months). Fifteen patients progressed to carcinoma over a period of 27 months (range 12-72) while 43 patients (74%) remained stable or regressed to less severe histologic diagnoses during a mean follow-up of 30 months .
Several studies report regression of dysplasia, even high-grade dysplasia in Barrett's esophagus, either spontaneously or after surgical or medical therapy but this remains highly controversial. Since neoplastic progression is associated with genetic abnormalities, spontaneous regression of dysplasia (defined as unequivocally neoplastic) is highly unlikely. A regression towards a less severe stage has been observed but an absence of dysplasia on follow-up biopsies is more likely explained either by sampling error or by inter- or intraobserver error [1, 3, 14, 15].
In summary, we conclude that the natural history of high-grade dysplasia in Barrett's esophagus is unknown. Progression towards cancer may take several months to years (11-60 months) but the time lag can at present not be determined, certainly not for the individual patient. Application of molecular cytogenetic techniques (CGH) may help to unravel the natural history of high-grade dysplasia and offer new markers by studying the occurrence of genetic abnormalities. Additional research to identify reliable markers is necessary
2. Reid BJ, Blount PL, Rubin CE, Levine DS, Haggitt RC, Rabinovitch PS. Flow-cytometric and histological progression to malignancy in Barrett's esophagus: prospective endoscopic surveillance of a cohort. Gastroenterology 1992;102:1212-1219.
3. Krishnadath KK, Tilanus HW, Van Blankenstein M, Hop WC, Teijgeman R, Mulder AH, Bosman FT, Van Dekken H. Accumulation of genetic abnormalities during neoplastic progression in Barrett's esophagus. Cancer Res 1995;55:1971-1976.
12. Lerut T, Coosemans W, Van Raemdonck D, Dillemans B, DeLeyn P, Marnette JM, Geboes K. Surgical treatment of Barrett's carcinoma. Correlations between morphologic findings and prognosis. J Thorac Cardiovasc Surg 1994;107:1059-1065.