In a substantial proportion of patients with thymoma, many different types of paraneoplastic syndromes are observed. The association between thymoma and autoimmune liver diseases, however, has been found in very few cases.
We report the case of a 31-year-old man affected by autoimmune hepatitis associated with myasthenia gravis and thymoma, successfully treated with extended thymectomy.
The patient is free from neoplastic and hepatic disease 4 years after surgery. Eighteen months after thymectomy, an exacerbation of hepatitis was successfully treated with steroids.
To the authors’ knowledge, only 7 cases of myasthenia gravis associated with thymoma and autoimmune hepatitis have been reported in the English-language literature. The exact role of thymoma in immune-mediated hepatitis is unclear. It seems likely that thymoma-associated T-cell abnormalities, due to the presence of thymoma, may have a role in the development of this rare clinical triad of autoimmune hepatitis, thymoma and myasthenia gravis.
Tumori 2016; 102(Suppl. 2): e40 - e42
Article Type: CASE REPORT
AuthorsPaolo Mendogni, Lorenzo Rosso, Davide Tosi, Alessandro Palleschi, Ilaria Righi, Francesca Minonzio, Nicola Fusco, Mario Nosotti
- • Accepted on 23/01/2016
- • Available online on 12/04/2016
- • Published online on 11/11/2016
This article is available as full text PDF.
Thymoma is a tumor which originates from thymic epithelial cells that maintain the capacity to support T-lymphocyte differentiation and export. In a substantial proportion of patients with thymomas, different types of autoimmune diseases are observed. Often these paraneoplastic manifestations are neurological or organ specific, although multisystem disorders have also been documented. The association between thymoma and autoimmune liver disease, however, has been found in very few cases. There have been numerous reports in the literature of primary biliary cirrhosis (1), primary sclerosing cholangitis (2) and autoimmune cholangitis, while to the best of our knowledge only 7 cases of myasthenia gravis (MG) associated with thymoma and autoimmune hepatitis have been reported in the English-language literature (3-4-5).
In May 2011, a previously healthy 31-year-old man was admitted to our institution with a 2-week history of worsening jaundice, pruritus, decreased appetite, and fatigue. The patient had no history of previous liver disease or jaundice, receipt of blood products, intravenous drug abuse, or exposure to alcohol or hepatotoxic drugs. Physical examination showed icterus with painless hepatomegaly, while no stigmata of chronic liver disease were present. There were no other significant physical findings and his neurological examination was normal. The main initial laboratory findings revealed severe liver dysfunction (aspartate aminotransferase 2,305 IU/L, alanine aminotransferase 4,002 IU/L; total bilirubin 24 mg/dL) and elevated levels of serum lactate dehydrogenase. Further evaluation regarding the etiology of possible underlying liver disease was undertaken and common viral etiologies were excluded (serology for acute and chronic viral hepatitis was negative), and screening tests for Wilson’s disease showed values within the normal range. Immunological tests demonstrated a positive result for antinuclear antibodies at a titer of 1:80, with a speckled and nucleolar pattern of staining, and a test for anti-smooth muscle antibodies was also positive. These results were strongly suggestive of autoimmune hepatitis.
Ultrasound of the abdomen revealed mild hepatomegaly with an increased echostructure of the liver and moderate dilatation of the intrahepatic bile duct (5.3 mm). Percutaneous liver biopsy was performed under ultrasound guidance to confirm the presence of liver disease. Biopsy showed severe acute hepatitis with a distorted lobular architecture and irregular widening of the portal tracts due to diffuse acute inflammatory cell infiltration. These histological features were consistent with acute autoimmune hepatitis.
Computed tomography scan of the chest revealed a solid anterior mediastinal mass of 7 × 4 cm that occupied the aortopulmonary window and compressed the main bronchus (
Preoperative chest CT scan showing a large solid anterior mediastinal mass.
Even though the patient did not at the time manifest any neurological symptoms that could lead to a suspicion of MG, in light of the possibility of a thymoma, serum muscle-specific-kinase antibodies were tested and found to be negative, while the acetylcholine receptor (AChR) antibody titer was elevated at 43 pmol/mL (normal ≤0.5 pmol/mL). Electromyography (EMG) was normal, while single-fiber EMG revealed a neuromuscular transmission delay. The elevated AChR antibodies and the single-fiber EMG results were consistent with a diagnosis of MG.
Oral corticosteroid treatment with 20 mg prednisone per day was commenced and resulted in immediate improvement of aminotransferase activity. In October 2011 the patient underwent an extended thymectomy via a median sternotomy, in which the tumor and adjacent thymus were completely resected. The mediastinal mass was successfully resected, and macroscopically it was clearly demarcated from the surrounding tissue. On microscopic examination it was well encapsulated; however, histology confirmed the lesion to be a B1 thymoma with focal capsular invasion. The postoperative course was uneventful. Oral prednisone was tapered down over the following months. At 3 months’ follow-up, repeat laboratory studies revealed complete normalization of the patient’s liver chemistries.
Eighteen months after the thymectomy there was an exacerbation of the hepatitis, which was treated with steroids. Four years after surgery there were no signs of recurrence of the thymoma.
The thymus plays an important role in the growth and differentiation of T lymphocytes. Consequently, disorders of the thymus, such as thymoma, can be reflected clinically in disturbances of the immune system. Therefore, it is understandable that 40% of patients with thymomas manifest a wide array of immunologically mediated disorders, which may be considered paraneoplastic phenomena. Because of the elevated frequency of these unique clinical combinations, it has been suggested that they be considered part of a global autoimmune syndrome rather than a spectrum of isolated coincidental diseases.
Thymoma is, in fact, often able to induce a wide array of paraneoplastic syndromes, most of which appear to be autoimmune or endocrine related. Approximately one-third of patients with thymomas present with MG, while 5%-10% are afflicted with other disorders such as pure red cell aplasia, hypogammaglobulinemia, autoimmune colitis, aplastic anemia, rheumatoid arthritis, systemic lupus erythematosus, anti-Hu neurological disorders (6), and precursor B-cell acute lymphoblastic leukemia (7). The coexistence of thymoma and autoimmune liver disease has been very rarely observed.
Autoimmune hepatitis is a rare, chronic and progressive disease of the liver; the prognosis is generally good with immunosuppressive treatment, but some patients may ultimately develop hepatocellular carcinoma or liver failure. Our patient showed coexistence of autoimmune hepatitis and MG associated with thymoma. He presented symptoms of acute hepatitis, and although there were no apparent neurological symptoms, the electrophysiological findings were consistent with the diagnosis and the AChR antibody assay was also positive at a titer of 43 pmol/mL.
The association between MG and thymic disease including thymoma is well known. The thymus plays an immunological stimulator role in that it can synthesize anti-AChR antibodies. Approximately 10%-15% of patients with MG present with thymoma and patients with MG often have circulating antibodies to a variety of tissue constituents. Several studies have in fact shown that in MG patients there is an increased occurrence of other autoimmune diseases. However, MG has been very rarely linked to autoimmune chronic active hepatitis.
The association of thymoma with other autoimmune diseases is well known, while the combination of autoimmune hepatitis, MG and thymoma in the same patient is a rare event. To our knowledge, since the first report of thymoma, MG and autoimmune hepatitis in 1995 (8), only 7 patients with this unique combination of paraneoplastic manifestations have been described. The exact role of thymoma in immune-mediated hepatitis is unclear.
Surgical excision is the primary treatment for a thymoma; moreover, about 75% of patients with MG appear to benefit from this procedure. Most centers choose a transsternal approach for thymectomy, while others prefer an “extended thymectomy”, which involves combined transsternal-transcervical exposure with en bloc removal of the gland to ensure radical resection. In our patient, a standard transsternal thymectomy was performed.
In conclusion, our case indicated that 3 different disorders originating from dysregulation of the immune system occurred in our patient and caused severe, potentially life-threatening liver dysfunction. It also showed that autoimmune hepatitis is part of the large spectrum of autoimmune paraneoplastic diseases associated with thymoma. Although the pathogenesis of autoimmune hepatitis in MG and thymoma is unclear, it seems likely that thymoma-associated T-cell abnormalities, due to the presence of thymoma, may play a role in the development of this rare clinical triad of autoimmune hepatitis, thymoma and MG. However, to elucidate the exact mechanism of immunopathogenesis, further studies are required.
- Mendogni, Paolo [PubMed] [Google Scholar] 1, * Corresponding Author (firstname.lastname@example.org)
- Rosso, Lorenzo [PubMed] [Google Scholar] 1
- Tosi, Davide [PubMed] [Google Scholar] 1
- Palleschi, Alessandro [PubMed] [Google Scholar] 1
- Righi, Ilaria [PubMed] [Google Scholar] 1
- Minonzio, Francesca [PubMed] [Google Scholar] 2
- Fusco, Nicola [PubMed] [Google Scholar] 3
- Nosotti, Mario [PubMed] [Google Scholar] 1
Thoracic Surgery and Lung Transplant Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan - Italy
Department of Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan - Italy
Pathology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan - Italy