Our study is the first case–control investigation of smooth‐muscle pathology and associated lesions of the oesophagus in scleroderma. Our review showed that oesophageal smooth‐muscle atrophy, especially in the circular layer, is common in scleroderma, but is not associated with vascular disease, tissue fibrosis or an inflammatory process in the myenteric plexus or with any neural abnormality visible by histological examination. In this first investigation of ICC in scleroderma, we found that the numbers of ICC were fewer in areas of atrophic circular smooth muscle than in areas of normal‐appearing circular smooth muscle.
Evidence of ischaemic disease in the oesophagus is suggested by functional studies that show impaired oesophageal blood flow as measured by oesophageal rewarming.9
Non‐inflammatory intimal cell proliferation in arterioles of scleroderma cases has been described in an autopsy record review.10
In addition, ultrastructural studies found endothelial damage in dermal microvasculature,11
and capillary endothelial cell swelling, basement membrane thickening and lamination in vessels of the muscularis propria of the oesophagus.12
In our study, normal‐appearing skeletal muscle interdigitated with atrophic smooth muscle, a distribution of atrophic lesions that seem inconsistent with a vascular aetiology. Also, there was no evidence of ischaemic necrosis in any of the 74 cases reviewed. Although vascular intimal proliferation was seen, it was not associated with areas of smooth‐muscle atrophy. The findings in our study are not consistent with a lesion primarily caused by abnormal microcirculation.
Inflammatory infiltrates were not present in the smooth muscle of the scleroderma cases unless there was severe, transmural oesophagitis. This suggests that inflammatory infiltration of the tissue is not a cardinal feature of the pathogenesis of oesophageal smooth‐muscle lesions of scleroderma. Tissue fibrosis is often evoked as the cause of the oesophageal disease in scleroderma. However, we did not find that fibrosis was a major contributor to the smooth‐muscle lesions in our series. The thickened tissue that we would expect to find in fibrotic smooth muscle was not present—in fact, the severely atrophic smooth‐muscle layers in the oesophagus in scleroderma were thinner than normal smooth‐muscle layers, appearing to have collapsed without fibrosis. This observation coincides with those of other authors of case reports and uncontrolled series who have noted that atrophy is more prominent than fibrosis.3,10,13
Scleroderma oesophagus is characterised by a dilated rather than stenotic oesophagus, supporting our histological finding.
Studies of gastrointestinal motility involving patients with scleroderma suggest that neurological dysfunction is common, and that it may precede myopathic dysfunction and histological changes of smooth muscle.14
Manometric evaluation of four cases showed oesophageal hypomotility in areas that later proved to have histologically normal smooth muscle.13
Pharmacological studies of oesophageal motility in patients with scleroderma using manometry showed a response to direct stimulation of oesophageal smooth muscle early in the disease that was not present in patients with more advanced disease.15
Another manometric study showed that patients with scleroderma and recent‐onset dysphagia had uncoordinated myoelectric hyperactivity, whereas patients with disease of longer duration showed diminished myoelectric activity.16
Manometric studies of other portions of the gastrointestinal tract have shown similar findings.17,18,19
The aetiology of these findings is unknown but is presumed to be due to neural dysfunction that precedes muscle disease.
Our review found no histological abnormalities of the myenteric plexus, similar to case reports and series that noted histologically normal myenteric plexus in the oesophagus and other regions of the gastrointestinal tract of patients with scleroderma.13,20,21
Other investigators describe degranulating mast cells and eosinophils associated with myenteric plexus of the intestine in scleroderma.22,23
Our review found lymphocytes, not mast cells, to be the predominant inflammatory cell associated with the myenteric plexus in the oesophagus, consistent with the reported observation of round‐cell infiltrates in the oesophageal myenteric plexus of scleroderma.13
In our study, inflammatory infiltrates were found with comparable frequency in cases and controls, suggesting that the presence of inflammatory cells in the myenteric plexus is not specific to scleroderma.
Although our study found that the myenteric plexus appears normal by light microscopy and an ultrastructural examination of the nerve endings in the oesophagus in scleroderma by other groups showed no abnormalities,12
this does not exclude the possibility that abnormal neural function is involved in the selective loss of smooth muscle. Neural lesions proximal to the tissue studied could cause downstream dysfunction without altering the histological appearance of the myenteric plexus. Antimyenteric neuronal antibodies are found in the serum from patients with scleroderma,24
and passive transfer of human scleroderma sera containing antimyenteric neuronal antibody produces disruption of the migrating motor complex activity in the small intestine of the rat.25
Functional abnormalities caused by or associated with antimyenteric neuronal antibodies could affect oesophageal motility and smooth muscle integrity without altering the histological appearance of the myenteric plexus.
ICC are thought to have a key role in normal oesophageal motility, and therefore injury or dysfunction of ICC may be involved in the oesophageal dysfunction of scleroderma. In this first investigation of ICC in scleroderma, in a limited number of specimens, ICC were fewer in number in atrophic smooth muscle compared with areas of non‐atrophic smooth muscle in the scleroderma cases. Oesophageal ICC are associated with smooth, not skeletal, muscle, and are found in both the longitudinal and the circular layers of smooth muscle.26
The role of ICC in scleroderma pathology is a topic that needs further study.
One important limitation of our case–control autopsy review is that we could not distinguish between actively evolving disease and static lesions. However, cases with longer duration between diagnosis and death were not more likely to have greater degrees of atrophy than cases with shorter duration of disease. This finding may reflect that the insult is a one‐time event, which takes place early in disease. To maximise the number of scleroderma cases, we used tissue from autopsies spanning many decades, introducing variability in tissue preparation. The number of slides available for review was greater for cases than for controls, potentially introducing a bias towards finding more histological abnormalities in the cases. However, the degree of abnormality (eg, muscle atrophy) in cases was so striking, we do not believe that detection bias played a significant role in our evaluation. The lack of difference in the presence of neural inflammatory infiltrate in cases and controls supports this criteria.
This review of a large number of scleroderma cases with contemporaneous controls shows that smooth muscle atrophy, especially of the circular layer, of the oesophagus is characteristic of scleroderma and appears unrelated to vascular lesions, fibrosis, inflammation or to myenteric plexus abnormalities. We also report that the ICC are found in reduced numbers in regions of smooth muscle atrophy. The pattern of preferential, severe atrophy of the circular smooth muscle in the absence of another definable lesion suggests that the dysfunction of the oesophagus in scleroderma is related to the innervation of this layer at a level not observable by light microscopy, or that the lesion is due to a primary smooth‐muscle disease process.