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Case Report |
1 Department of Radiology, University Hospital, ML 0761, 234 Goodman St.,
Cincinnati, OH 45267-0761.
2 Department Of Pathology, University Hospital, Cincinnati, Oh 45267-0761.
3 Department of Pulmonary Medicine, University Hospital, Cincinnati, OH
45267-0761.
Received February 20, 2004;
accepted after revision May 13, 2004.
Address correspondence to C. A. Meyer.
Introduction
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TSC is inherited in an autosomal dominant pattern with nearly 100% penetrance and is caused by a mutation in the TSC1 or TSC2 gene. The TSC1 gene encodes hamartin and the TSC2 gene encodes tuberin. Hamartin and tuberin are believed to be early regulatory steps in cellular protein synthesis and growth. TSC genes are hypothesized to function as tumor suppressor genes that require a "second hit" at the cellular level, leading to loss of functional hamartin or tuberin with subsequent development of hamartomas [1].
Hamartomas in TSC patients are frequently present in the skin, kidneys, brain, and heart. Less frequently, hamartomas involve the retina, gingiva, bones, gastrointestinal tract, and lungs [1]. Although most patients have renal angiomyolipomas, hamartomas in the lung are rare [2]. The association of pulmonary angiomyolipomas to TSC has not been established [3]. Until recently, lymphangioleiomyomatosis (LAM), a hamartomatous cystic lung disease, was the only reported pulmonary radiologic manifestation of TSC and was estimated to occur in 1-2.3% of TSC patients [4]. However, two recent studies found 27-39% of TSC patients without previous pulmonary disease to have LAM when screened with high-resolution CT [5, 6]. Multifocal micronodular pneumocyte hyperplasia (MMPH), another hamartomatous pulmonary lesion, has also been recently described in TSC patients [2, 7-13]. We review the imaging findings in a case of MMPH and provide pathologic correlation.
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TSC was diagnosed when the patient was 21 years old on the basis of renal angiomyolipomas and a family history of TSC (a grandmother, father, three daughters, one son, and two grandsons).
Physical examination showed bibasilar crackles on lung auscultation and cutaneous adenoma sebaceum. Pulmonary function testing revealed mild air trapping, a normal diffusing capacity, and moderate hypoxemia.
Chest radiograph revealed bilateral diffuse fine nodular opacities (Figs. 1A and 1B). High-resolution CT confirmed 1- to 3-mm nodules throughout both lungs randomly distributed in the secondary lobule (Figs. 1C and 1D) and associated mild intralobular interstitial thickening. No air cysts or pleural effusions were present. Expiratory high-resolution CT failed to show air trapping.
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Bronchoscopy with bronchoalveolar lavage revealed 15% eosinophils. Video-assisted thoracoscopic evaluation of the lung revealed multiple nodules. No distinct mass lesions were identifiable grossly in the surgical specimen. Microscopic examination showed scattered foci of interstitial expansion, forming irregular nodules that measured 1- to 3-mm in greatest dimension (Fig. 1E). The airspaces within and surrounding nodular areas contained abundant macrophages. The thickened septa were covered by type 2 pneumocytes showing some degree of cytologic atypia and increased fibrous tissue (Fig. 1F). No smooth muscle proliferation was identified. Immunohistochemical staining for HMB-45 of the nodules and surrounding lung tissue was negative.
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As of 2001, 28 cases of MMPH had been reported in the English language and Japanese language literature [4], usually in pathology-related journals. The notion that MMPH is rare in TSC patients has been challenged recently by a study in which 23 TSC patients without a diagnosis of LAM or pulmonary symptoms were screened with high-resolution CT [6]. Forty-three percent had either a pattern of scattered nodules from 3-10 mm in size or numerous miliary nodules from 1-3 mm. Pulmonary nodules were more common in patients with pulmonary cysts (LAM) than in those without cysts. None of these high-resolution CT-screened patients underwent lung biopsy; however, the likelihood was strong that in the majority of patients, multiple tiny pulmonary nodules were caused by MMPH [6]. In another study of TSC patients (with and without LAM) screened with high-resolution CT, 28% had multiple pulmonary nodules (1-5 mm) suggestive of MMPH [5]. These data suggest that MMPH is not rare in TSC patients and, in fact, is more common than previously recognized.
The presence of multiple tiny pulmonary nodules in a random distribution in a TSC patient should suggest the presence of MMPH. The differential diagnosis should also include a miliary granulomatous infection, Langerhans' cell histiocytosis (LCH), or hematogenous metastases. Simply the presence of nodules with cysts is not useful for discriminating LAM and LCH. In addition to clinical history, the distribution of these findings is the key to differentiating these entities. Characteristically, LCH manifests in its early stage as centrilobular nodules and progresses to cystic lung disease from apex toward the bases, with sparing of the costophrenic angles. The nodules are generally identified on the inferior margin of the affected lung. In MMPH, the nodules are randomly distributed in the secondary lobule and have a slight predilection for the lung periphery and the upper lobes [6]. In general, the cystic lung disease in LAM is more randomly distributed and does not spare the bases.
MMPH occurs more frequently in patients with TSC than with LAM and rarely presents in patients without TSC or LAM [10, 13]. The clinical presentation of MMPH is frequently dominated by pneumothorax from concomitant LAM [10]. The clinical manifestations resulting from isolated MMPH are dyspnea, cough, and mild to moderate hypoxemia [10, 11, 14]. The clinical course of MMPH is usually not progressive and treatment is unnecessary [9-11, 14]. However, one patient without underlying TSC or LAM died of respiratory failure due to MMPH [13]. Thus far, MMPH has not shown a malignant potential despite the hypothetical loss of tumor suppressor function in TSC gene mutations [4, 10].
MMPH was first described in the pathology literature by Popper et al. [7]. The minute pulmonary nodules represent clusters of cuboidal epithelial cells with mild cellular atypia lining thickened alveolar septa [8]. The cell of origin is the type II pneumocyte [8]. HMB-45, which stains for smooth muscle in LAM, is negative, as are stains for estrogen and progesterone receptors in patients with MMPH alone [2, 8]. The microscopic pathology most closely resembles atypical adenomatous hyperplasia [4]. The pathologic differential diagnosis also includes papillary adenoma of type II cells, bronchioloalveolar carcinoma, healing miliary inflammatory processes, and minute pulmonary meningothelial-like nodules [4, 10].
In summary, we report the radiologic manifestations of MMPH, a recently recognized entity in TSC. These lesions are benign hamartomatous proliferations of type II pneumocytes usually with limited clinical significance and no known malignant potential. This lesion should be considered in chest radiographs or high-resolution CT with multiple tiny pulmonary nodules in patients with known TSC or LAM.
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  A M Nagar, H S. Teh, R N. Khoo, A C Morani, K Vrishni, and J Raghuram Multifocal pneumocyte hyperplasia in tuberous sclerosis Thorax, February 1, 2008; 63(2): 186 - 186. [Full Text] [PDF]
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