Eradication of high-grade dysplasia in columnar-lined (Barrett's) oesophagus by photodynamic therapy with endogenously generated protoporphyrin IX

Summary

Background

High-grade dysplasia in columnar-lined (Barrett's) oesophagus presents a difficult therapeutic dilemma. Choices for management are endoscopic surveillance to detect a cancer or oesophagectomy. One carries the risk of missing invasive cancer, the other carries worrying morbidity and mortality. We have used endoscopic photodynamic therapy to eradicate high-grade dysplasia.

Methods

After the oral administration of 5-aminolaevulinic acid, the accumulation of the endogenously generated photosensitiser protoporphyrin IX was measured with quantitative fluorescence microscopy. Five patients with histologically confirmed high-grade dysplasia were treated with endoscopic photodynamic therapy with 630 nm laser light to activate the photosensitiser.

Findings

Protoporphyrin IX accumulated in the dysplastic epithelium rather than the adjacent stroma. Selective necrosis of the dysplastic epithelium in columnar-lined oesophagus occurred after light activation. High-grade dysplasia was eradicated in all patients and squamous regeneration occurred after acid suppression with a proton-pump inhibitor. There were no complications or recurrence of dysplasia after 26-44 months' endoscopic and histological follow-up. In two cases we saw non-dysplastic Barrett's epithelium underneath regenerative squamous mucosa.

Interpretation

High-grade dysplasia in columnar-lined oesophagus can be eradicated by endoscopic photodynamic therapy with endogenously generated PpIX. Remaining non-dysplastic Barrett's epithelium will require surveillance, but overall the technique has interrupted or delayed the worsening of the dysplasia through to carcinoma. This technique may prevent the need for surgical excision in these patients.

Introduction

Dysplasia in columnar-lined (Barrett's) oesophagus is premalignant, culminating in high-grade dysplasia and oesophageal adenocarcinoma.¹ The incidence of this carcinoma has risen dramatically in Europe and the USA.2, 3 In high-grade dysplasia in Barrett's oesophagus, some advocate oesophageal resection, since carcinoma may be found in the resected specimen in 45% of patients.⁴ Others, concerned that half the patients are receiving a prophylactic operation with substantial morbidity and mortality, advocate intense endoscopic surveillance of dysplasia,⁵ with surgery for those in whom carcinoma is seen. Medical therapy with long-term acid suppression by omeprazole has only produced partial regression of non-dysplastic Barrett's epithelium,⁶ and there is no evidence that dysplasia, particularly high-grade dysplasia, can regress.

Photodynamic therapy involves light-induced activation of an administered photosensitiser in tissue to produce local necrosis. The technique has been used to destroy dysplasia and superficial oesophageal adenocarcinoma with the photosensitiser porfirmer sodium or haemato-porphyrin derivative.7, 8 The difficulties encountered are systemic photosensitisation and stricture formation due to deep oesophageal wall damage. The problems of targeting the photosensitiser directly to the dysplastic mucosa and limiting systemic photosensitisation may be overcome by using endogenous photosensitisation with orally administered 5-aminolaevulinic acid (5-ALA). The synthesis of 5-ALA from glycine and succinyl-CoA is the first step in haemobiosynthesis. This pathway is tightly regulated by end-point inhibition. If excess endogenous 5-ALA is administered, this regulation is bypassed and the photosensitiser protoporphyrin IX (PpIX), the immediate precursor of heme, accumulates intracellularly, due to the slow incorporation of iron into the molecule and the low activity of the responsible enzyme, ferrochelatase.⁹ Accumulation occurs mostly in mucosal cells of the gastrointestinal tract, by contrast with haematoporphyrin derivative, which accumulates in the submucosal vascular stroma.¹⁰ Experimental studies have demonstrated that selective mucosal ablation with little risk of perforation is possible.¹¹ Photosensitisation is limited to 24-48 h, since PpIX is rapidly metabolised and eliminated. We report use of this technique to treat patients with high-grade dysplasia in Barrett's oesophagus.