Sarcoidosis is a chronic disorder that can virtually affect any organ system in the body. Histologically, it is characterized by the presence of T lymphocytes, mononuclear phagocytes, and noncaseating granulomas. Most commonly affected are the intrathoracic structures, with 90% of the reported cases involving the lungs. Esophageal involvement in sarcoidosis is extremely rare. Dysphagia is the most common presentation in these patients and can be attributed to various mechanisms such as direct esophageal wall infiltration, extrinsic compression, cranial neuropathy, and brainstem involvement. A thorough online literature review revealed only 23 reported cases of esophageal involvement in sarcoidosis. This paper reviews these reported cases in detail along with newer diagnostic and treatment options, including direction of future therapy.
Sarcoidosis is an inflammatory, granulomatous, multisystem disorder of unclear etiology [
Sarcoidosis is a global disease with variable incidences, presentation, and prognosis. It has the highest incidence in the United States and Sweden [
Gastrointestinal tract involvement in sarcoidosis is very rare. Elaborate postmortem studies of patients with sarcoidosis, published between 1949 and 1963, did not find any evidence of GI tract involvement [
Esophageal involvement is an extremely rare occurrence in sarcoidosis. A review of the literature revealed only 23 published cases of esophageal involvement in sarcoidosis to date [
The exact causes of sarcoidosis remain unknown. However, various infectious and environmental antigens have been suggested as triggers, causing sarcoid to develop in a genetically susceptible individual. The immune response in sarcoid is similar to those present in other granulomatous diseases caused by a known antigen, such as tuberculosis and berylliosis. There have been various reports of community outbreaks and clustering of cases in time and space which has led to speculation and suggestions of a possible environmental antigen or even a person to person transmission of sarcoid. There have been reports of increased disease incidence and clustering in certain occupations such as nurses and firefighters [
The increased occurrence of sarcoidosis among families and an increased incidence specifically among monozygotic twins had led to initial suggestions that genetic susceptibility plays an important role in sarcoidosis. Compared to Caucasians families where only 5% had more than one affected individual, the rates in African American families were as high as 19% [
The characteristic finding of sarcoidosis is the presence of noncaseating granulomas. The granuloma is comprised of mainly lymphocytes, epitheloid cells, macrophages, and fibroblasts in varying proportions. Some of the macrophages undergo differentiation to form epitheloid cells, mature, lose some of its phagocytic activity, and fuse to form multinucleated giant cells. During the early, acute phase, the core of the granuloma consists of mononuclear phagocytes in different stages of maturation and differentiation. This is surrounded by mainly CD4+ T cells and a few CD8+ T cells and B cells. CD8+ cells and fibroblasts become increased in number during the latter stages, as the granulomas become less active. Granulomas can also be identified in a number of other infectious and noninfectious states. Granulomas found in sarcoidosis are classically nonnecrotizing, tense and usually track along the lymphatics. Granulomas found in hypersensitivity pneumonitis or extrinsic allergic alveolitis are generally nonnecrotizing too, but are loosely formed and track along the airways. Granulomas seen in tuberculosis and histoplasmosis, however, are classically necrotizing tense and are distributed in no particular pattern. The lesions in berylliosis are very similar to those found in sarcoidosis, and therefore effort must be made to inquire about occupational exposure to beryllium and its various compounds [
Macrophages and dendritic cells present the antigens through the framework of the major histocompatibility complex (MHC) class II alleles to the T cells. They also secrete cytokines interleukin-12 (IL-12) which stimulates the maturation of CD4+ T lymphocytes to Th1 cells and interleukin-15 (IL-15) which promotes T lymphocyte propagation. CD4+ T lymphocytes which are the one of the primary cells involved in immunopathogenesis of sarcoidosis releases interleukin-2 (IL-2) and interferon-
A systematic review of the literature using the keywords “gastrointestinal sarcoidosis,” “esophageal sarcoidosis,” and “GI sarcoidosis” was done on Medline/Pubmed, Google Scholar, and the directory of Open access journals and by reviewing references of earlier published case reports. Our search yielded twenty-three documented cases of esophageal involvement in sarcoidosis. A summary of these reported cases can be found in Table
Summary of case reports of esophageal sarcoidosis.
Cases | Sex of patient | Age at onset of symptoms | Involvement and cause | Symptoms | Treatment | Presence of systemic involvement |
---|---|---|---|---|---|---|
Kerley [ |
F | Not known | Direct infiltration of lower esophagus | Dysphagia | Not known | Yes |
Siegel et al. [ |
F | 59 | Direct infiltration of pharyngoesophageal junction | Dysphagia and weight loss | Surgical myotomy | Yes |
Polachek and Marte [ |
M | 65 | Direct infiltration of lower esophagus | Weight loss and abdominal pain | Steroid therapy | Yes |
Hardy et al. [ |
F | 31 | Direct infiltration of lower esophagus | Dysphagia, weight loss, and dysphonia | Steroid therapy | Yes |
Cook et al. [ |
F | 29 | Extrinsic compression of mid esophagus | Dysphagia | Steroid therapy | Yes |
Wiesner et al. [ |
F | 33 | Direct infiltration of lower esophagus | Dysphagia | Surgical resection | Yes |
Davies [ |
M | 49 | Direct infiltration of upper esophagus | Dysphagia | Not known | Yes |
Panosetti and Lehmann [ |
F | 71 | Direct infiltration of pharyngoesophageal junction | Dysphagia | Surgical myotomy | No |
Dufresne et al. [ |
F | 46 | Neural invasion of the lower esophagus | Dysphagia | Surgical myotomy | Yes |
Aronson et al. [ |
M | 82 | Neural invasion of lower esophagus | Dysphagia and hoarseness | Steroid therapy | Yes |
Nidiry et al. [ |
F | 44 | Neural invasion of lower esophagus | Dysphagia | Steroid therapy | Yes |
Cappell [ |
M | 42 | Extrinsic compression of middle esophagus | Dysphagia | Not known | Yes |
Boruchowicz et al. [ |
F | 30 | Neural invasion of lower esophagus | Dysphagia | Surgical myotomy | Yes |
Geissinger et al. [ |
F | 40 | Possible neural involvement of lower esophagus | Dysphagia and weight loss | Steroids and proton pump inhibitors | Yes |
Lukens et al. [ |
F | 48 | Direct infiltration of lower esophagus | Dysphagia | Botulinum toxin injection possibly followed by steroid therapy | Yes |
Murdock and Jacob [ |
F | 54 | Direct infiltration of lower esophagus | Anemia and Barrett’s esophagus | Proton pump inhibitor therapy | Yes |
Wasfi and Margolis [ |
M | 45 | Neural invasion and extrinsic compression of upper esophagus | Dysphagia | Steroid therapy | Yes |
Ohshimo et al. [ |
M | 64 | Direct infiltration of pharyngoesophageal junction | Dysphagia | Surgical myotomy | Yes |
Bredenoord et al. [ |
M | 29 | Neural invasion of the lower esophagus | Dysphagia and weight loss | Steroid therapy | Yes |
Nishikubo et al. [ |
F | 73 | Direct infiltration of cricopharyngeal muscle | Dysphagia | Surgical myotomy | Yes |
Samarasena et al. [ |
M | 46 | Direct infiltration of mid esophagus causing stricture | Dysphagia | Not known | Yes |
Rustagi and Majumder [ |
M | 45 | Extrinsic compression of mid esophagus | Dysphagia, chest pain, and esophageal rupture | Ivor Lewis's esophagectomy | Yes |
Ruiz et al. [ |
M | 37 | Direct infiltration and neural invasion of lower esophagus | Dysphagia and odynophagia | Laparoscopic Heller's myotomy with fundoplication | Yes |
Dysphagia has been reported to be the most common symptom in patients with esophageal sarcoidosis [
Most frequently documented symptoms at presentation.
Dysphagia | 91.3% |
Odynophagia | 4.3% |
Weight loss | 21.7% |
Anemia | 4.3% |
Abdominal and/or chest pain | 8.7% |
Hoarseness of voice | 8.7% |
The esophageal involvement in sarcoidosis can be classified based upon two criteria: the level of involvement and the layer of involvement [ Superficial involvement of the mucosa may manifest macroscopically as mucosal hyperemia, discrete plaque-like or nodular lesions. Murdock and Jacob [ Myopathic involvement in esophageal sarcoidosis occurs due to infiltration of the skeletal muscles of the esophagus and posterior pharynx. Siegel et al. [ Direct involvement of the enteric nervous plexus can cause dysphagia, and the clinical picture can mimic that of achalasia. Dufresne et al. [ Dysphagia as a consequence of extrinsic compression from enlarged mediastinal lymph nodes due to sarcoidosis has also been described. Cook et al. [
Diagnosis of sarcoidosis hinges upon establishing a compatible clinical and histopathologic picture whilst ruling out other granulomatous diseases. A detailed history including particulars about environmental and occupational exposure is key to identifying other granulomatous diseases. A detailed physical exam aids in assessing the extent of involvement of other organ systems. A baseline slit lamp examination to diagnose subclinical uveitis and measurement of 24 hour urine calcium to detect subclinical hypercalciura, are also recommended in all patients. Cardiac involvement, though rare, can cause life-threatening arrhythmias and therefore electrocardiograms are recommended at baseline and at frequent intervals [
There have been no clinical trials comparing the efficacy of the different treatment modalities for the treatment of esophageal sarcoidosis given the rarity of the disease. Dietary modifications, proton pump inhibitors, and surgical and corticosteroid therapy have been used to treat esophageal sarcoidosis.
The role of corticosteroids in the treatment of gastrointestinal sarcoidosis is not clear. However, considering the presence of systemic involvement in almost all cases of esophageal sarcoidosis and the observation that esophageal inflammation secondary to granulomatous inflammation seems to respond to corticosteroids, oral steroids remain the first-line therapy [
Besides inhibiting the production of inflammatory cytokines such as IL-1, IL-2, IFN-
The aim of surgical treatment is to provide symptomatic relief, eradicate outflow tract obstruction, and possibly prevent acid reflux. Cricopharyngeal myotomy can be used for the treatment of both oropharyngeal dysphagia and hypopharyngeal (Zenker’s) diverticulum. Cricopharyngeal myotomy was first performed by Kaplan et al. in 1951 for the treatment of post-poliomyelitis dysphagia and it has since then been increasingly used for dysphagia due to various causes [
Esophageal myotomy to relieve achalasia was first reported by Ernest Heller in 1913 wherein both the anterior and posterior esophageal sphincters were cut. A modification of this technique involves only the dissection of the anterior muscle fibers and this has become the standard surgical procedure [
Botulinum toxin is an irreversible inhibitor of acetylcholine release from presynaptic cholinergic terminals and this helps lower the lower esophageal sphincter tone. However, since new axon growth and regeneration counteracts this effect over time, treatment needs to be repeated at regular intervals. Multiple injections into the lower esophageal sphincter as a result of repeat treatment can cause local inflammation and fibrosis, further limiting the usefulness of this therapy. This option is thus reserved for older patients or those who are not ideal candidates for either surgical or corticosteroid therapy.
Due to the rarity of esophageal involvement in sarcoidosis, the role of immunosuppressive therapy has not been defined. However, their use must be reserved for those patients who experience side effects due to systemic steroid therapy or in those with worsening of symptoms despite corticosteroids. Methotrexate is the most commonly used immunosuppressive agent in systemic sarcoidosis. Methotrexate is believed to decrease the antigen stimulated proliferation of lymphocytes and exerts its anti-inflammatory through adenosine accumulation [
As mentioned earlier, TNF production is a fundamental part of the immunologic process of sarcoidosis. A recent study found TNF to be secreted at higher levels in a subset of patients with refractory sarcoidosis. These observations have led to the logical idea that anti-TNF-
Gastrointestinal sarcoidosis is an extremely infrequent disease with clinically significant involvement seen in less than 1% of patients with sarcoidosis. The diagnosis of esophageal sarcoidosis can be challenging, not only because of the rarity of the disease but also because of the need for histopathologic evidence and the necessity to exclude other granulomatous diseases. It is likely that esophageal sarcoidosis is under-diagnosed due to the slow progression of the disease and difficulties in diagnosing the same. Upper endoscopy, esophageal manometry and endoscopic ultrasound are some valuable tools that can aid in timely diagnosis and therapeutic intervention. Corticosteroid therapy and various surgical techniques are most commonly used to relive symptoms of dysphagia secondary to esophageal involvement. The routine use of disease modifying agents including anti-TNF-