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* From the Departments of Medicine and Geriatrics (Drs. Leung, Chan, and Chu) and Pathology (Dr. Yuen), United Christian Hospital, Hong Kong, SAR, China.
Correspondence to: Chung-Ming Chu, MD, FCCP, Division of Respiratory Medicine, Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong SAR, China; e-mail: chucm{at}ha.org.hk
A 55-year-old man presented in January 2002 with a cough, left lower chest wall pain, and fever for 1 month. His medical history was remarkable for a right neck mass in 1998, when an MRI had shown a right submandibular mass with invasion of the surrounding structures (Fig 1 ). A wide resection of the mass was performed, with histology showing fibrosis and chronic inflammatory infiltrate (Fig 2 ). In 2000, he had presented with right proptosis and right third cranial nerve palsy. His right eye vision was also impaired with a large central scotoma. His eye condition improved with systemic corticosteroid therapy.
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The patient’s temperature was 39°C. Other vital signs were stable. There was a mild reduction in breath sound over the left lung base. The findings of examinations of the other systems were normal.
Laboratory and Radiographic Findings
The liver function test results were deranged with an alkaline phosphatase concentration of 267 IU/L and an alanine transaminase concentration of 112 IU/L. The erythrocyte sedimentation rate was > 130 mm/h, and the C-reactive protein (CRP) concentration was 225.0 mg/L. The findings of ultrasonography studies of the liver were normal. A CT scan of the thorax showed a 5-cm mass in the left lower lobe (Fig 3 ). The histology of the percutaneous lung biopsy specimen showed the replacement of lung parenchyma by chronic inflammation and fibrosis (Fig 4 ).
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Diagnosis: Multifocal fibrosclerosis with pulmonary involvement
Discussion
Multifocal fibrosclerosis is an uncommon fibroproliferative systemic disorder with multiple manifestations. It can involve almost every organ with fibroblastic proliferation. The microscopic pathology of these disorders is similar, showing a fibrotic process infiltrated with blood vessels, lymphocytes, and plasma cells. It has been suggested that these disorders are all interrelated and are probably different manifestations of a common disorder of fibroblastic proliferation. More common presentations include mediastinal fibrosis, retroperitoneal fibrosis, orbital pseudotumor, Riedel thyroiditis, and sclerosing cholangitis. Less common are Dupuytren contracture, Peyronie disease, testicular fibrosis, and pancreatic fibrosis. Newer syndromes have been added to the list, including pseudotumor of the pancreatic head associated with obstructive jaundice, panhypopituitarism, cervical epidural pseudotumor, renal pseudotumor, and sclerosing lobulitis of the breast. Clinical presentations depend on the site of involvement. It may present as infiltrative mass lesions mimicking malignancies and causing local symptoms such as obstruction and compression, or constitutional symptoms. Imaging with a CT scan or an MRI can show the extent of the lesion. A biopsy is usually required to establish the diagnosis and to exclude malignancy.
The etiology of multifocal fibrosclerosis is unknown. A hereditary origin was proposed by Comings et al in 1967 when they described two brothers with multifocal fibrosclerosis. A possible genetic predisposition was suggested by De Luca et al. They studied a series of 13 patients with idiopathic retroperitoneal fibrosis and found the presence of immunophenotype human leukocyte antigen B27 in 44% of the cases. Other authors have suggested that the condition may be immunologically mediated, in view of its response to corticosteroid and immunosuppressive therapy. Although it has been suggested that methysergide can cause retroperitoneal fibrosis, no other multifocal fibrosclerosis variant has been linked to use of the drug.
Pulmonary involvement is not a common presentation of multifocal fibrosclerosis. There has been only one previous report of lung manifestation. Kishimoto et al reported a 53-year-old male patient with a history of orbital pseudotumor and chronic paranasal sinusitis. The patient also had bilateral pulmonary nodules. Neither antibiotics nor antituberculous drugs were effective in changing the size of the lung lesions. A needle biopsy of the lung lesions revealed inflammatory granulation tissue consisting of infiltrated polymorphous cells and proliferated fibroblasts. Later on, he had increased fatigue, and there was worsening of the pulmonary nodules, with elevated CRP. The findings of an extensive search for tuberculosis were negative. Therefore, systemic corticosteroid therapy was administered, and there was dramatic improvement of pulmonary shadows and CRP levels.
There is no consensus on the best treatment of this condition as it is very rare. Treatment experience is based entirely on case reports. Surgical treatment is sometimes necessary to relieve the obstructive and compressive effect of the infiltrating mass. For medical treatment, corticosteroid and other immunosuppressive therapies (eg, azathioprine, cyclophosphamide, cyclosporin, or mycophenolate mofetil) have been used. Although an immune process in the pathogenesis of multifocal fibrosclerosis has been postulated, patients are not uniformly responsive to corticosteroid therapy. On the other hand, withdrawal of or noncompliance with corticosteroid therapy may precipitate a relapse of fibrosclerosis at the same site or in other sites. Tamoxifen, a nonsteroidal antiestrogen agent, has been shown to be effective in treating patients with retroperitoneal fibrosis, and some have advocated for this drug to be the primary treatment for patients with retroperitoneal fibrosis. Tamoxifen probably works by inducing transforming growth factor-ß, which is in turn an inhibitor of fibroblast growth factor.
The survival time for patients with this condition is quite variable, ranging from 5 to > 20 years for most people. It is not known why certain cases are more aggressive. Patients should be followed up regularly to look for a recurrence, either in the same site or in other sites. Monitoring of the clinical features, measurement of inflammatory markers, and performance of regular imaging studies may detect a recurrence. Drieskens et al have performed positron emission tomography scans in a patient with multifocal fibrosclerosis and have demonstrated a high 18F-fluorodeoxyglucose uptake in involved areas, which likely was caused by active inflammation involving lymphocytes, plasmas cells, and fibroblasts. They suggested that positron emission tomography could play a role in establishing the diagnosis and the sites of involvement, and in evaluating the activity and patient response to corticosteroid therapy.
Follow-up
The clinical and histologic features of our patient were compatible with a diagnosis of multifocal fibrosclerosis with submandibular soft-tissue and lung involvements. The patient’s history of right eye proptosis, impaired vision, and right third nerve palsy were suggestive of an orbital pseudotumor compressing the right optic nerve and right third nerves, and both conditions have responded to corticosteroid treatment. We think that the patient also had sclerosing cholangitis, although he declined to undergo a liver biopsy. Therapy with tamoxifen was started, but a fever still persisted. Therefore, therapy with prednisolone, 40 mg daily, was started, and the patient quickly responded with a decline in temperature. A follow-up chest radiograph and liver function test results showed improvements. The dosage of prednisolone was gradually decreased. Two months after the prednisolone dosage was decreased, enlargement of the pulmonary lesion was noted. Therefore, therapy with prednisolone, 20 mg daily, was resumed, and the size of the pulmonary lesion declined. We decided to maintain long-term corticosteroid treatment in view of repeated relapses of the condition.
Clinical Pearls
1. Multifocal fibrosclerosis is a rare proliferative systemic disorder that can involve virtually any organ, causing compressive or obstructive symptoms.
2. Pulmonary manifestations are uncommon and can present as fever with a mass seen on a chest radiograph.
3. A biopsy of the lesion is usually required for diagnosis and to exclude malignancy.
4. Treatment options include corticosteroid therapy, immunosuppressive therapy (eg, azathioprine, cyclophosphamide, cyclosporin, or mycophenolate mofetil), and tamoxifen therapy.
5. After an initial response, the patient should be monitored closely for any recurrence, which can occur at the same or in other sites. Monitoring of the clinical features, inflammatory markers, and imaging may detect a recurrence.
Acknowledgements
We thank G.C. Emerson, editorial consultant, New York, NY, for his editorial advice.
Received for publication July 19, 2005. Accepted for publication September 3, 2005.
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