Coexistence of Lymphangioleiomyomatosis and Angiomyolipomas in a Patient of Tuberous Sclerosis Complex: a case report

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1 Chin J Radiol 2003; 28: Coexistence of Lymphangioleiomyomatosis and Angiomyolipomas in a Patient of Tuberous Sclerosis Complex: a case report FENG-CHI HSIEH 1 KAO-LANG LIU 1 YIH-LEONG CHANG 2 WEN-JENG LEE 1 YUK-MING TSANG 1 Departments of Medical Imaging 1, Pathology 2, National Taiwan University Hospital Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease. The symptoms, radiological features and histopathological evidences are identical to that of pulmonary involvement of tuberous sclerosis complex (TSC). Coexistence of renal angiomyolipomas (AMLs), especially multiple and bilateral sides is often observed. Some investigators have proposed that LAM may be a forme fruste of TSC. We present a case that was firstly diagnosed as LAM and then bilateral multiple renal AMLs were found during pre-transplant evaluation. The case also met the diagnostic criteria of TSC. We discuss the relationship between LAM and TSC. Key words: angiomyolipoma; lymphangioleiomyomatosis; tuberous sclerosis complex Reprint requests to: Dr. Yuk-Ming Tsang Department of Medical Imaging, National Taiwan University Hospital. No. 7, Chung Shan S. Road, Taipei 100, Taiwan, R.O.C. Lymphangioleiomyomatosis (LAM) is a rare, idiopathic disorder that predominantly affects the lung parenchyma of women of childbearing age. It is characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. Coexistence of bilateral renal angiomyolipomas(amls) has been found in some patients of LAM. We report a case of LAM with bilateral large renal AMLs in a young female. She also met the diagnostic criteria of tuberous sclerosis complex (TSC), which is an autosomally inherited disorder characterized by widespread hamartomatous lesions and neurologic manifestations including mental retardation and seizures. CASE REPORT A 30-year-old female suffered from progressive dyspnea and cough since two years ago. She went to a local hospital for help. Chest X-ray was performed in the local hospital and LAM was suspected. She was then transferred to our hospital for further evaluation. No remarkable finding was noted during physical examination. There were neither abnormal breathing sounds like crackers or rhonchi nor any history of cigarette smoking. Increased reticular interstitial opacities and diffuse thin-walled cystic lesions at both lungs were identified on chest roentgenography (Fig. 1). On chest CT scan, diffuse cysts with thin and regular wall were noted (Fig. 2). They appeared symmetrically scattered in distribution and did not spare the costophrenic angles. For achieving a definitive diagnosis, video-assisted thoracic surgery (VATS) was performed for tissue proof. Microscopically, disorderly proliferation of smooth muscle cells along the alveolar septa, small airways and pulmonary lymphatics were observed (Fig. 3). These cells were immunoreactive to smooth muscle actin, HMB-45, and focally positive to estrogen and progesterone receptors. Pathological diagnosis of pulmonary LAM was established.

2 330 Coexistence of LAM and tuberous sclerosis Table 1. Primary Features 1. Facial angiofibromas1 2. Multiple ungual fibromas1 3. Cortical tuber (histologically confirmed) 4. Subependymal nodule or giant cell astrocytoma (histologically confirmed) 5. Multiple calcified subependymal nodules protruding into the ventricle (radiographic evidence) 6. Hypomelanotic macules (more than three) 7. Shagreen patch (connective tissue nevus) 8. Multiple retinal astrocytomas1 Figure 1. Chest plain film reveals reticular interstitial opacities and diffuse thin-walled cystic lesions at both lungs, especially the lower. A chest tube is inserted on the right side. Figure 2. Chest computed tomography demonstrates diffuse cysts with thin and regular wall in bilateral lungs. They appear roughly symmetrically. Secondary Features 1. Affected first-degree relative 2. Cardiac rhabdomyoma (histologically or radiographic 3. Other retinal hamartoma or achromic patch1 4. Cerebral tubers (radiographic 5. Noncalcified subependymal nodules (radiographic 6. Shagreen patch1 7. Forehead plaque1 8. Pulmonary lymphangiomyomatosis (histologically 9. Renal angiomyolipoma (histologically or radiographic 10. Renal cysts (histologically Tertiary Features 1. Hypomelanotic macules1 2. Confetti skin lesions1 3. Renal cysts (radiographic evidence) 4. Randomly distributed enamel pits in deciduous or permanent teeth 5. Hamartomatous rectal polyps (histologically 6. Bone cysts (radiographic evidence) 7. Pulmonary lymphangiomyomatosis (radiographic evidence) 8. Cerebral white matter migration tracts or heterotopias (radiographic evidence) 9. Gingival fibromas1 10. Hamartoma of other organs (histologically 11. Infantile spasms Definite TSC 1 primary feature, 2 secondary features, or 1 secondary plus 2 tertiary features Probable TSC 1 secondary plus 1 tertiary feature or 3 tertiary features Suspect TSC 1 secondary feature or 2 tertiary features 1: Histologic confirmation is not required if the lesion is clinically obvious. In antiestrogen therapy, progressively loss of pulmonary function was still noted. Several episodes of pneumothorax occurred. Lung transplantation was then considered. A pre-transplant evaluation including abdominal CT was done and multiple fat-containing renal tumors were demonstrated, which are pathognomic for AMLs (Fig. 4). The following abdominal MRI also confirmed the diagnosis of AMLs. Pathologically confirmed pulmonary LAM and radiologically dignosed renal AMLs fit the diagnostic criteria (two secondary features) of TSC (Table 1), and therefore the diagnosis was established. DISCUSSION First significant collection of patients, known as LAM today, was reported by Cornog and Enterline in 1966 [1]. LAM affects almost exclusively young women. Proliferation of abnormal smooth muscle cells in the lung parenchyma is the most characteristic histopathological finding. It commonly manifests as

3 Coexistence of LAM and tuberous sclerosis 331 exertional dyspnea and recurrent pneumothorax. Chylothorax and chylous ascites may occur following lymphatic obstruction. Sometimes, pneumothorax may combine with chylothorax. Obstruction of pulmonary venules may lead to vascular congestion and hemoptysis. Progressive respiratory failure and death seem inevitable. The chest roentgenography usually reveals reticular interstitial pattern resulted from summation of numerous cysts. The high resolution CT of chest shows diffuse thin-walled cysts of variable size throughout bilateral lungs. Ill-defined areas of increased attenuation, which may result from hemorrhage or edema, may also be Figure 3. A characteristic cystic alveolar space lined by a thick layer of disorderly proliferative smooth muscle (left) and prominent hemosiderin-laden macrophages within alveolar spaces (right) in LAM. (H & E, 66* original magnification) found. Occasionally, there is ground-glass attenuation, which is due to proliferation of smooth muscle cells in the alveolar walls [2]. The parenchyma between the cysts appears to be normal. Some other diffuse infiltrative lung diseases also cause the formation of pulmonary cysts, including Langerhan cell histiocytosis, cystic pneumocystis carinii pneumonia (PCP), pulmonary cystic metastasis, cystic bronchiectasis, desquamative interstitial pneumonia (DIP), and usual interstitial pneumonia (UIP). Langerhan cell histiocystosis usually occurs in patients with a history of heavy cigarette smoking. The cysts are usually predominantly in the upper lobes and relatively sparing of cardiophrenic angles. Cystic PCP occurs predominantly in patients with acquired immunodeficiency syndrome (AIDS). Areas of ground-glass opacity with thick-walled, irregular cavities or thin-walled cysts are noted. Pulmonary cystic metastasis has a relatively thick wall and there may be numerous small nodules. Cystic bronchiectasis represents cysts lie adjacent to vessels with some show branching appearance. DIP usually represents combination of cysts and ground-glass opacity. The honeycomb cysts in UIP may mimic pulmonary manifestation of LAM, but the honeycomb cysts are relatively thick and irregular in the subpleural regions. Abdominal findings may be present in more than 70% of patients with LAM, and the most common abdominal finding is renal AMLs which are found in 20%-54% of patients with LAM [3, 4]. These AMLs are often small (<1 cm), multiple, bilateral, and asymptomatic in these patients. Other abdominal manifestations including lymphangioleiomyoma, lymphadenopathy and chylous ascites have been reported 4a 4b Figure 4. a. Post-enhanced computed tomogram reveals two fat-containing tumors in left kidney. b. More caudal section, multiple fat-containing tumors are noted in both kidneys. The right kidney is displaced anteriomedially.

4 332 Coexistence of LAM and tuberous sclerosis [5]. AMLs occur as isolated, sporadic entities in 80% of cases, most commonly manifesting in the middleaged women. The other 20% of angiomyolipomas develop in association with TSC. Fat-containing tumors in kidneys are pathognomic to be AMLs. TSC, also known as Bourneville disease, is a phacomatosis, which represents cutaneous and neurological involvement. The classical triad of adenoma sebaceum, seizures, and mental retardation is the most well known. The inheritance is autosomal dominant; however, spontaneous mutation or incomplete penetrance occurs in 50%-75% [6]. Pulmonary involvement in TSC is nearly exclusive in women. Recent study revealed that the prevalence of LAM in women with TSC was 34% [7]. The pathologic findings in the lung and lymph nodes are identical to those found in LAM [8]. In fact, the symptoms, radiographic features, and histopathologic features of patients with pulmonary involvement of TSC are identical to those in LAM. Therefore, many investigators have suggested that LAM may be closely related to, or in fact be, a forme fruste of TSC. The two diseases also have high possibility of coexistence with bilateral renal AMLs. It may be another clue of association between LAM and TSC. At gene level, TSC is related to at least two loci on chromosomes 9 and 16, which referred to as TSC1 and TSC2. Thomas Carsillo and his colleague have found TSC2 mutations in five of seven AMLs from LAM patients. In four patients whose lung tissues were available in the study, all had the same mutation in the abnormal pulmonary smooth muscle cells [9]. Other prospective study for asymptomatic patient of TSC revealed that all patients with pulmomary parenchymal change identical to LAM have large renal AMLs. TSC2 mutations were also identified in all of them. [10] Mutation in the TSC2 seems to play an important role in developing LAM. In our case, the manifestations in the chest roentgenography and CT scan are compatible with LAM. The histopathological findings proved this case indeed a case of LAM. Bilateral renal tumors with components of negative Hounsfield unit (HU) in CT scan, indicating fat-containing tumors, are pathognomic to be renal AMLs. Coexistence of pulmonary LAM, with histologic confirmation, and renal AMLs, with radiological confirmation, meets the diagnostic criteria of TSC set forth in 1992 (Table 1) [11]. Therefore, this patient is also diagnosed as TSC. In cases of LAM, we seldom notice the coexistent abdominal findings. After presenting the case, we may keep in mind that abdominal imaging modalities like sonography or even CT scan may be needed in these patients. According to some recent studies [7,10], the asymptomatic female patient of TSC also need chest CT for the risk of developing LAM. The distinction between LAM and TSC, at least in some cases, is blurred. Some has proposed LAM as a forme fruste of TSC, but the nature of possible relationship still need further exploration. REFERENCES 1. Cornog JL, Enterline HT. Lymphangiomyoma, a benign lesion of chyliferous lymphatics synonymous with lymphangiopericytoma. Cancer 1966; 19: Esther Pallisa, Pilar Sanz, Antonio Roman, Joaquim Majo, Jordi Andreu, Jose Caceres. Lymphangioleiomyomatosis: pulmonary and abdominal findings with pathologic correlation. Radiographics 2002; 22: S185- S Avila NA, Kelly JA, Chu SC, Dwyer AJ, Moss J. Lymphangioleiomyomatosis: abdominopelvic CT and US findings. Radiology 2000; 216: Bernstein SM, Newell JD, Adamczyk D, Mortenson RL, King TE, Lynch DA. How common are renal angiomyolipomas in patients with pulmonary lymphangiomyomatosis? Am J Respir Crit Care Med 1995; 152: Pallisa E, Sanz P, Roman A, Majo J, Andreu J, Caceres J. Lymphangioleiomyomatosis: pulmonary and abdominal findings with pathologic correlation. Radiographics. 2002; 22: S185-S Sullivan EJ. Lymphangioleiomyomatosis: a review. Chest 1998; 114: Moss J, Avila NA, Barnes PM, et al. Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med 2001; 163: Hauck RW, Konig G, Permanetter W, et al. Tuberous sclerosis with pulmonary involvement. Respiration 1990; 57: Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000; 97: McCormack F, Brody A, Meyer C, et al. Pulmonary cysts consistent with lymphangioleiomyomatosis are common in women with tuberous sclerosis: genetic and radiographic analysis. Chest. 2002; 121: Roach ES, Smith M, Huttenlocher P, et at. Report of the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association. J Child Neurol 1992; 7:

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