Sporadic Lymphangioleiomyomatosis: Pathogenesis, Treatment, and Prognosis

Introduction:

Lymphangioleiomyomatosis is a genetic disorder that affects young female individuals. The incidence of such a disorder is extremely rare. One out of every 400000 individuals is affected by this condition. Though it is a multisystem disorder, respiratory symptoms are one of the most pronounced symptoms of this condition. Young women are most commonly affected by this condition. This is an autosomal dominant fatal disorder. But recent progress in the medical field has ensured better prognoses and treatment outcomes for this disorder.

What Is the Pathophysiology of Sporadic Lymphangioleiomyomatosis?

The disruption of the signaling pathways causes lymphangioleiomyomatosis cell proliferation. Rapamycin (mTOR) signaling pathway, which is responsible for cellular growth and metabolism, is disrupted in this process. This disruption is caused by the mutation of the TSC2 gene. This gene is responsible for the synthesis of proteins named hamartin and tuberin. These two proteins regulate the functioning of the signaling pathway. Also, tuberin is essential for the regulation of the cell cycle, cell growth, and proliferation, and hamartin is associated with actin cytoskeleton formation. As a result, the mutation is associated with the improper activity of the singling pathway and the reason behind abnormal cell division.

The production of abnormal cells and improper functioning is associated with estrogen. Estrogen-signaling pathways and metalloproteinases influence the migration and invasiveness of the lymphangioleiomyomatosis cells. Also, the function of the lymphangioleiomyomatosis activation of extracellular signal-regulated kinase 2 by estrogen hormone.

The main source of lymphangioleiomyomatosis cells is renal angiomyolipomas (a tumor of the kidney). But in other cases, such cells originated from uterine leiomyomas (smooth muscle tumors of the uterus) and perivascular epithelioid cell tumors (tumors of the soft tissue of the stomach). Sometimes these cells may also originate from the lymphatic system. Specifically, conditions associated with lymphangioleiomyoma (benign tumor of lymph vessels) and lymphadenopathy (swelling of the lymph nodes) are linked to the lymphatic origin of cells. In such cases, lymphangioleiomyomatosis nodules in such cases contain cleft-like spaces lined by endothelial lymphatic cells. These cells express vascular endothelial growth factor, which is responsible for cellular proliferation and the spread of proliferated cells via the venous system. From there, they can reach lung capillaries.

The mechanism of the formation of cysts in such cases is poorly understood. Compression and distension of airway space in such cases by proliferating lymphangioleiomyomatosis cells may be the cause of cyst formation. Also, the degradation of lung fibers by proteinases may be associated with cyst formation.

What Are the Clinical Features of Sporadic Lymphangioleiomyomatosis?

People suffering from Sporadic Lymphangioleiomyomatosis complain of the following things:

• Dyspnea: Breathing Difficulty.

• Hemoptysis: Presence of blood during cough. The blood originates from below the level of the larynx.

• Chyloptysis: Presence of chyle in sputum. Sputum appears milky white.

• Chest pain is sharp and stabbing in nature.

• Fatigue.

• Presence of sounds like crackles and wheezes during respiration.

Dyspnea is caused by obstruction of the airway tract due to the destruction of the lung tissue and the presence of cystic lesions. Hemoptysis and Chyloptysis occur due to the obstruction of lung circulation by lymphangioleiomyomatosis cells.

On examination following findings are noted:

• The presence of chyle in the pleural space (space between two layers of the lung) can be detected. This is caused by thoracic duct obstruction (duct for lymphatic drainage). Chyle can also be detected in the abdominal cavity. It is known as chylous Ascites. This is also caused by lymphatic obstruction.

• Swelling of the lymph nodes in the various parts of the body.

• Presence of air in between the lung and the chest wall. This causes shrinkage of the lungs. This condition is known as pneumothorax.

• Presence of large cystic masses in the abdomen and in the pelvic region. These cystic masses cause abdominal pain, bloating, and distension of the abdomen.

What Is the Prognosis For this Condition?

In such cases, complaints of the patient start with difficulty in respiration. But the gradual decline in lung functions. Patients who have a history of pneumothorax as the first lung sign have a better prognosis and better pulmonary function.

Patients with cellular infiltrates and multiple cystic lesions have a worse prognosis.

Lung function tests and measurement of the flow rates are useful in determining the prognosis and severity of the condition.

What Are the Diagnostic Methods?

Diagnosis of lymphangioleiomyomatosis is done through the following tests:

1. Chest radiographs and computed tomography images will show the presence of multiple thin-walled cysts throughout the lungs. The presence of pneumothorax and lung infiltrates can also be detected in computed tomography images.

2. Ultrasonography imaging can be done to detect the presence of lymphadenopathy, lymphangioleiomyomas, and angiomyolipomas (benign tumors of the fat muscle tissue of the kidney).

3. A transbronchial, thoracoscopic, or open lung biopsy can be done to collect the tissue samples. The histological feature will show lymphangioleiomyomatosis, including immunoreactivity with monoclonal antibodies.

4. A high serum level of Vascular endothelial growth factor D is also a diagnostic marker for this condition.

What Are the Treatment Methods?

Previously this was identified as a fatal disorder. A few decades ago, the only possible treatment for this condition was lung transplantation. But pharmaceutical management of this disease is possible with the identification of the causative factors.

1. The main causative factor of this disorder is a genetic mutation of the TSC2 and TSC1 genes which causes disruption of the mTOR pathway. Sirolimus and Everolimus are two drugs that can act as mTOR inhibitors. These drugs can be helpful in increasing lung functions and reducing the size of chylous effusions, lymphangioleiomyomas.

2. But these drugs are predominantly mTor1 inhibitors. That is why, Simvastatin, a Rho GTPases inhibitor, is used alongside to block the mTOR2 pathway.

3. Estrogen receptor blockers and aromatase inhibitors are used to prevent its pathogenesis.

4. Surgical treatment for lung perfusion and pneumothorax can also be done.

5. Accumulation of chyle in the chest can be removed by aspiration method. Other than this, procedures like pleurodesis (adhesion between the layers of the pleura done using drugs and chemicals), and pleurectomy (surgical removal of pleura) can also be done in such cases.

6. Selective embolization or nephron-sparing surgery can be done in cases of large-sized angiomyolipomas.

7. Fat-containing diet and traveling in airplanes in such cases are strictly prohibited.

Conclusion:

Sporadic lymphangioleiomyomatosis is an extremely rare pathological condition. Young women are mostly affected by this condition. Not only the lungs but other systems of the body, like, the lymphatic system, abdomen, and kidneys, are also affected. Early direction of the condition and pharmaceutical intervention can be useful to prevent any fatal outcome.