Cecilia M. Smith and Gordon L. Yung
NEUROFIBROMATOSIS
Neurofibromatosis type 1 (NF1, von Recklinghausen disease) is characterized by cutaneous neuro-fibromas, café-au-lait spots, Lisch nodules of the iris, and various other systemic manifestations. Von Recklinghausen disease, an autosomal dominant dysplasia of ectoderm and mesoderm with a variable clinical expression, appears in all races, with a prevalence of 1 in 3,000 live births. The NF1 gene is located on chromosome 17. In 30% to 50% of patients, there is no family history of the disease. The lungs and thorax are involved by cutaneous and subcutaneous neurofibromas on the chest wall, kyphoscoliosis, ribbon deformity of the ribs, thoracic neoplasms, and interstitial lung disease (ILD).
Interstitial pneumonitis occurs in a subset of patients with NF1. In a review of the literature, there were 64 patients with NF1 who had diffuse lung disease (DLD). Some authors state that 7% to 20% of adults with NF1 have ILD. The mean age of patients with NF1 and DLD was 50 years, with more males than females. Most patients report dyspnea as a complaint. The cause of the pneumonitis remains obscure. Pathologically, it is grossly and microscopically indistinguishable from idiopathic interstitial pneumonitis. The lung surface is often studded with bullae of varying sizes with striking upper-lobe predominance; a honeycombed appearance is common on sectioning. Histologic specimens show diffuse interstitial fibrosis and architectural disruption, with extensive alveolar destruction and cystic changes. Hyperplasia of neurolemma cells of intrapulmonary nerves has been described.
Dyspnea of insidious onset is often the presenting manifestation, although discovery in an asymptomatic individual through an incidental chest roentgenogram may occur. Cough occurs in approximately one-third of patients and chest pain in 5%. Chest radiographs in 63 patients revealed bullous lung disease in 73%, predominantly in the upper lobes. Basilar linear densities were present in 63% and honeycombing in 13%. HRCT scans revealed bullae (50%), reticular abnormalities (50%), ground-glass abnormality (37%), cysts (25%), and emphysema (25%). In one study, HRCT scans in 6 nonsmokers with NF1 demonstrated 2- to 18-mm thin wall cysts, upper-lobe predominant patchy ground-glass densities, and centrilobular micronodules. Lung cysts were located in the central or subpleural regions, or both. There was no radiologic evidence of lung fibrosis, honeycombing, or severe bullous disease. The chest radiograph may initially reveal only accentuated interstitial markings or diffusely mottled, ill-defined infiltrates. The infiltrates usually progress over years to a coarse linear or reticulated pattern and bulla formation. Interstitial fibrosis is usually symmetric with a basal predominance. Bullae form diffuse fibrobullous interstitial disease. Other thoracic manifestations of this disease include paravertebral neurofibroma, lateral meningocele, kyphoscoliotic vertebral deformity, and cutaneous neurofibroma. Physiologic measurements reveal a combination of restrictive and obstructive defects, diminished carbon monoxide diffusing capacity (DLCO), and hypoxemia (initially limited to exercise).
The diagnosis is generally obvious because the neurocutaneous manifestations almost invariably precede the interstitial pneumonitis. Rarely, biopsy is necessary to exclude another infiltrative pulmonary process. The course is variable and often slowly progressive. No specific therapy currently exists for pulmonary fibrosis associated with NF1.
Rarely, patients develop progressive respiratory failure with pulmonary hypertension (PH) leading to death. PH, when it occurs, has a late onset and female predominance and can occur late in the course of pulmonary disease. However, NF1-associated PH also can occur in patients with mild or absent parenchymal lung disease. Precapillary plexiform pulmonary arteriopathy is seen in NF1-associated PH, similar to idiopathic pulmonary arterial hypertension. Dyspnea and symptoms of right-heart failure are major symptoms leading to the diagnosis of PH. Conventional treatment with oxygen, diuretics, and anticoagulation should be considered. Treatment with pulmonary vasodilator medications, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, and prostanoids have each been used in patients with NF1-associated PH, but the role of these medications is not clear. The response to these medications has varied. It has been reported that there has been a limited response with poor outcome. In one small series of seven patients, five patients died within 3 years of presentation.
Emphasis on early referral for lung transplantation assessment in eligible patients should be stressed. Often, referral is appropriate early in the course of the patient’s disease presentation.
Other thoracic manifestations include severe scoliosis and neurofibromas of the posterior or superior mediastinum. Neurofibromas arise from nerve sheaths in the sympathetic chain, vagus, and intercostal and intrapulmonary nerves. These tumors are commonly found adjacent to the spinal column. Neurofibromas can present in the tongue, larynx, trachea, and bronchi and cause airway obstruction. Patients may also have a hoarse voice, difficulty swallowing, or a deviated trachea. Neurogenic tumors involving the lung are rare, although multiple neurofibromas of varying size can occur. Hypoxemia can be caused by right-to-left shunts within these tumors. These tumors are usually benign, but malignant change can occur. The development of carcinoma can be a complication of the diffuse interstitial disease.
LYMPHANGIOLEIOMYOMATOSIS
Lymphangioleiomyomatosis or lymphangiomatosis (LAM) is a rare, progressive cystic pulmonary disorder with female predominance. LAM occurs in approximately 30% of women with the tuberous sclerosis complex (TSC) as well as in women without tuberous sclerosis (sporadic LAM, S-LAM). There is proliferation and infiltration of pulmonary interstitial smooth muscle cells with cystic destruction within the lungs. LAM frequently involves other organs (e.g., the kidneys, retroperitoneal or abdominal lymph nodes, liver, uterus, and pancreas) in addition to the lungs and can also be associated with abdominal and thoracic lymphatic spread with lymphadenopathy and abdominal tumors. Renal angiomyolipomas have been reported in 30% to 50% of patients with LAM. The incidence of meningioma is increased in women with LAM.
LAM occurs almost exclusively in women of childbearing age, in whom the disease can progress either rapidly or slowly to respiratory failure and death. There are rare cases of LAM diagnosed in males with TSC. In one series of 29 men with TSC, a retrospective review of CT scans of the chest was performed to assess the frequency of cystic lung disease. Thirty-eight percent (11/29) of the men had findings of four or more cysts present. The mean age was 46.3 years. None experienced a pneumothorax or chylothorax.
Over the last decade, there have been advances in the basic science of LAM. LAM and TSC are caused by mutations in one or the other of the tuberous sclerosis genes, TSC1 or TSC2. These genes control cell growth, cell survival, and cell motility through the Akt/mammalian target of rapamycin (mTOR) signaling pathway. Encoded proteins, hamartin or tuberin, are either deficient or dysfunctional, which results in loss of regulation of signals. The activation of mTOR kinase and S6 kinase leads to inappropriate cellular proliferation, migration, and invasion. Its incidence in young women, exacerbations during pregnancy, and associated steroid receptors in the lung, coupled with the known effect of estrogen and progesterone on smooth muscle, suggests that hormonal interactions are important in its pathogenesis, though these mechanisms are not well understood.
The hallmarks of pathology in LAM are nodular and tortuous masses of smooth muscle and epithelioid cells around bronchovascular structures that extend into the interstitium, without significant fibrosis. Diffuse cystic dilatation of terminal airspaces is a unique feature, ranging in size from subcentimeter to several centimeters in diameter. Grossly, the pleura is thickened, and large thick-walled cystic airspaces give rise to a honeycombed appearance of the lungs. Hilar, mediastinal, and retroperitoneal lymph nodes are often enlarged and spongy, and the thoracic duct is distended with lymph. Chylothorax can be present because of lymphatic rupture. Microscopically, a striking nodular proliferation of smooth muscle is seen within the pleura and alveolar walls, as well as in and around the walls of bronchioles, venules, and lymphatics. Immunohistochemistry stains assist in confirming the diagnosis with positive melanocytic and muscle markers. These smooth muscle cells exhibit melanoma-related marker, HMB45 immunoreactivity, distinct from other causes of smooth muscle proliferation. HMB45, a monoclonal antibody, also reacts with angiomyolipomas, clear cell tumors of the lung, and melanoma cells.
Bronchiolar obstruction from smooth muscle proliferation leads to air trapping, resulting in destruction of alveolar septa and honeycombed cystic spaces, especially at the lung bases. Ultrastructural studies of lung biopsy specimens demonstrate degradation of elastic fibers in areas of smooth muscle accumulation, which may be a factor leading to the development of emphysematous changes. Venous obstruction results in dilatation and rupture of venules, chronic low-grade hemorrhage, and, ultimately, hemosiderosis. Both estrogen and progesterone cell-surface receptors have been demonstrated in the lung.
Pulmonary manifestations are the most common presenting symptoms in patients with LAM. Of the 230 patients enrolled in the NHLBI Lymphangioleiomyomatosis Registry, spontaneous pneumothorax was the event that led to the diagnosis of LAM in approximately one-third of the patients. The average age at onset of symptoms was 39 years (range 18–76 years) and 41 years for the average age at diagnosis. TSC was present in approximately 15%. Progressive dyspnea and recurrent pneumothorax are the most common presentations. Other symptoms include wheezing, cough, and chylous pleural effusion.
Pneumothorax presents in approximately 70% of patients. Of these, more than 70% recur with an average of 4.4. Pleurodesis is recommended after the first pneumothorax in a patient known to have LAM due to the high recurrence rate. With conservative therapy (chest tube drainage or aspiration), the recurrence rate is approximately 66%; with surgical or chemical pleurodesis, the recurrence rate decreases to 32% and 27%, respectively.
Chylous pleural effusions occur bilaterally or unilaterally in about 33% of patients. Other clinical manifestations include hemoptysis (30%), ascites (11%), pericardial effusion (6%), chyloptysis (7%), and chyluria (3%). With abdominal lymphatic obstruction, chylous ascites can develop. Occasionally, communication between dilated retroperitoneal lymphatics and a kidney or ureter result in chyluria. Patients presenting with angiomyolipoma and pulmonary symptoms should be evaluated for LAM by chest CT scan, because the two are associated. Some patients may be asymptomatic at diagnosis.
The physical examination frequently is not revealing until late in the clinical course, when end-inspiratory rales, diminished lower-lobe breath sounds, scattered rhonchi, hyperinflation, signs of pleural effusion and/or ascites, and intra-abdominal or lymphatic masses are present. Abrupt exacerbation of dyspnea may signal the development of pneumothorax. Clubbing is rare.
LAM can be discovered by abnormal HRCT scan evidence of thin-walled cystic changes. Less commonly, it may be discovered on biopsy of an abdominal or retroperitoneal mass thought to be lymphoma or ovarian cancer. The chest roentgenogram initially may be normal or demonstrate reticulonodular interstitial opacities or severe emphysematous changes with hyperinflation in advanced disease. Occasionally, small cysts coalesce to form large blebs. This occurs predominantly at the lung bases. HRCT scan is more useful than the chest radiograph in assessing the presence and extent of cysts. HRCT typically demonstrates numerous small (2–20 mm) thin-walled cysts throughout both lungs. Greater morphologic and physiologic correlation is seen with the HRCT scan than with the chest radiograph.
Laboratory findings of complete blood count, serum chemistry, and liver enzyme levels are nonspecific except for chyluria. Pulmonary function tests (PFTs) most commonly reveal mild to severe airflow obstruction, followed by reduced diffusion capacity. Bronchodilator response is present in 17% of patients reported in the NHLBI Lymphangioleiomyomatosis Registry. PFTs were normal in approximately 34% of Registry patients. Hypoxemia (worsened by exertion), reduced flows and DLCO, and progressive increase in plethysmographic lung volume also are characteristic. Significant functional impairment usually precedes any radiographic abnormality (other than pneumothorax). Diminished exercise capacity is seen, most likely caused by ventilatory limitation. Serial exercise testing has been suggested as a means to monitor disease progression and screen for exertional hypoxemia.
The diagnosis of LAM is likely in a young female presenting with dyspnea, emphysematous changes on the chest radiograph, recurrent pneumothorax, and/or chylous pleural effusion associated with renal tumors; PFTs may be normal or abnormal. The radiographic distribution and nature of the lesions are highly characteristic. Biopsy is generally necessary to confirm the diagnosis. Of 75 lung specimens obtained by transbronchial and open-lung biopsy, only LAM showed HMB45-positive cells. It has been suggested that if only a transbronchial biopsy is available, this marker can assist in confirming the diagnosis. A study assessing the diagnostic usefulness of the serologic test for vascular endothelial growth factor-D (VEGF-D) demonstrated its potential as a biomarker. This may eventually eliminate the need for biopsy. VEGF-D is a lymphangiogenic growth factor, and serum VEGF-D levels are higher in women with S-LAM than in women with other cystic lung diseases. Serum VEGF-D levels are significantly higher in women with TSC-LAM compared to women with TSC alone. Serum VEGF-D levels greater than 600 pg/mL were highly associated with the diagnosis of LAM; values greater than 800 pg/mL were diagnostically specific in a study of 48 women presenting with cystic lung disease.
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