Tuberous sclerosis complex presenting as a pulmonary solitary nodule

Sir: Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease characterized by hamartomatous lesions in several organs. TSC-related pulmonary manifestations comprise several pathological conditions, such as lymphangioleiomyomatosis (LAM), multifocal micronodular pneumocyte hyperplasia (MMPH), clear cell sugar tumour, angiomyolipoma and micronodular ⁄ interstitial clear cell LAM-like proliferations: they may involve the lung singly or in different combinations, but none of them per se is diagnostic of TSC. LAM and MMPH, although rare, are the most common features of TSC in the lung. They generally present on imaging as thin-walled cystic changes randomly distributed throughout the lungs in LAM and as diffuse or predominantly lower zone micronodules in MMPH. We report a unique case of TSC incidentally diagnosed during the medical work-up for a pulmonary solitary ‘coin’ lesion morphologically consistent with a hitherto unreported ‘macronodular form’ of MMPH. A 49-year-old previously healthy and asymptomatic, non-smoking female working as a caretaker at an old people’s home was incidentally found to have a 25-mm nodule in the right lower lobe of the lung at chest X-ray performed for a doubtful intradermal tuberculin reaction during a routine medical check-up. Chest computer tomographic (CT) scan confirmed the presence of a non-calcified, well-demarcated pulmonary nodule with soft tissue density initially suggesting a pulmonary hamartoma (Figure 1A) without other parenchymal abnormalities or lymphadenopathy. Routine laboratory tests and pulmonary function studies were unremarkable. The patient underwent a thoracotomy with wedge resection of the right lower lobe. The intraoperative finding of small, firm nodules on the surface of the visceral pleura led to a segmentectomy of the right upper and middle lobes. Grossly, the right pulmonary lower lobe specimen contained a grey-whitish, rounded nodule, 25 mm across, while small, irregularly shaped spots were observed in the lung parenchyma adjacent to the nodule and in the other lobes. At histology, the nodule consisted of a sharply outlined proliferation of mediumto-large, hyperplastic, polygonal type II pneumocytes lining the alveoli, sometimes displaying nuclear inclusions but lacking cytological atypia (Figure 1B) and positively immunostaining for cytokeratin AE1 ⁄ AE3 and TTF-1. Several microscopic foci (ranging from 1 to 4 mm in diameter) characterized by the same proliferation of hyperplastic pneumocytes were randomly distributed in the remaining lung parenchyma in all lung specimens. In addition, a few small cystic nodules consisting of a subpleural and perilymphatic proliferation of spindle-shaped, oval-to-rounded cells with a myoid appearance (eosinophilic cytoplasm and blunt fusiform nuclei) were noted (Figure 1C). These cells were immunoreactive for smooth muscle actin, desmin, HMB45 (Figure 1D), oestrogen and progesterone receptors. A diagnosis of nodular and MMPH associated with pulmonary LAM was made. The patient was further investigated for the possibility of other TSCrelated lesions. Cranial magnetic resonance imaging and abdominal ultrasonography showed no evidence of brain lesions or renal abnormalities, respectively. However, dermatological examination revealed several facial angiofibromas in the perinasal area (Figure 1E). Based on the new TSC Consensus Conference clinical criteria, the presence of two major features (pulmonary LAM and facial angiofibromas) in our patient was considered diagnostic of TSC. The patient, with no history of TSC in her family, had a healthy 25-year-old son. Finally, a pulmonary high-resolution (HR) CT scan showed the presence of a few thin-walled cysts mainly involving the left upper lobe (Figure 1F). Since the patient has remained asymptomatic, no treatment has been instituted and she is alive and well 14 months after surgery. TSC is an autosomal dominant disorder characterized by hamartomatous and neoplastic lesions involving multiple organs. In the lung, the most frequent features of TSC are LAM and MMPH, while clear cell sugar tumour, angiomyolipoma and clear cell LAMlike interstitial proliferation occur less frequently. Pulmonary LAM consists of HMB45-immunoreactive myoid cells growing around lymphatics and radiologically appearing as thin-walled air-filled cysts diffusely arranged throughout both lungs, while MMPH is a multifocal proliferation of type II pneumocytes appearing as a diffuse micronodular picture on HRCT scan of the chest. Both LAM and MMPH may occur singly or together, as sporadic disease or in patients with TSC. Patients with LAM and ⁄ or MMPH are commonly symptomatic at diagnosis suffering progressive dyspnoea on exertion, but Franz et al. prospectively found Correspondence 769