As perinatal medicine, prenatal diagnosis and fetal ultrasound imaging continue to advance in China, maternal-fetal medicine has gradually attracted attention. Fetal surgery has now been adopted for certain fatal congenital malformations. For common fetal lung malformations, this paper reviews the progress of domestic and foreign literature regarding the diagnosis and treatment of fetal-neonatal bronchopulmonary isolation.
I. Overview
Fetal lung development is one of the determinants of survival after birth, and accurate prenatal diagnosis and evaluation are important for disorders affecting fetal lung development. Common congenital malformations of the lung can be broadly classified into 3 categories.
1, are bronchopulmonary malformations ;
2. Vascular malformations;
3, is the co-existence of both.
The most common disorders affecting fetal lung development are Bronchopulmonary Sequestration (BPS), congenital cystic adenoma of the lung (CCAM), congenital diaphragmatic hernia and pleural effusion. BPS was named by Pryce in 1946 and suggests a lung segment lacking normal lobe tissue and airway pattern and supplied by the body circulation.
Etiology and typology
(A) Etiology
Bronchopulmonary segregation, also known as Bronchopulmonary Sequestration (BPS), is a nonfunctional mass of pulmonary tissue supplied by an abnormal artery of the body circulation without bronchial connection to the natural tracheobronchial tree. the mechanism of BPS is not well understood. Most scholars support Pryce’s theory of traction: that is, in the early stages of embryonic development, there are many visceral capillaries connected to the dorsal aorta in the prointestine and around the lung buds, which gradually absorb and disappear when detachment from the lung tissue occurs.
This period begins probably at 4 weeks of embryonic life. For some reason, the visceral capillaries attached to the dorsal aorta are not completely absorbed and when they remain, they become anomalous branch vessels of the aorta and pull on a part of the embryonic lung tissue, forming pulmonary segregation.
Pulmonary segregation is a rare genetic congenital disorder that results from an imbalance between cell proliferation and apoptosis during lung development. genetic alterations in alpha integrin cytoplasmic signaling are an important cause of lung tissue lesions in CCAM as well as BPS. Abnormal cell adhesion molecules and HOX protein regulation are also responsible. The experiments also confirmed the importance of specific cell adhesion molecules for lung tissue development and airway formation, which are aberrantly expressed in BPS and CCAM cases. This suggests that the pathogenesis of BPS and CCAM cases is associated with altered cytoplasmic integral protein signaling mechanisms.
(ii) Typing
Depending on the period of residual vascular traction, two subtypes of the disease are formed: intralobular and interlobular. Intralobar pulmonary isolation is formed when the embryonic lung tissue is tractioned at the time of detachment from the prointestine, and extralobar pulmonary isolation is formed when the traction is tractioned after detachment. Interlobular bronchopulmonary segregation is completely independent of the normal lung and is wrapped by a separate pleura, whereas intralobar bronchopulmonary segregation mixes with the surrounding normal lung tissue.
Interlobular bronchopulmonary isolation can be located in the chest, inside the diaphragm, or in the lower part of the diaphragm. Intralobar and intralobar bronchopulmonary isolation can occur together. The entire lung can be isolated. Bilateral bronchopulmonary isolation has been reported, but is very rare. The arterial blood supply in pulmonary isolation is derived from the inferior diaphragmatic artery the superior phrenic artery, and venous return can be to the pulmonary veins or veins of the body circulation. The abnormal blood supply may lead to high-volume heart failure due to massive arteriovenous shunts through the parenchyma of bronchopulmonary isolation or massive hemoptysis blood loss or pleural effusion.
The interlobular type is more often diagnosed in the fetal or neonatal period, while the intralobar type is most often diagnosed and detected in childhood. Of the two types, the intralobar type accounts for approximately 75% of cases. In the interlobular type of BPS, the veins return to the pulmonary veins, whereas in the intralobar type, they return to the odd veins. There is also the extrathoracic type, which has a smaller percentage. There is controversy regarding the intralobar pulmonary isolates, where the view is that most intralobar types are found and diagnosed in the context of recurrent chronic inflammation of the lungs. In contrast, long-term recurrent chronic inflammation can lead to secondary hypertrophy of the pulmonary ligament vessels, resulting in secondary pulmonary segregation.
Increasingly, the observation of prenatal diagnosis suggests that the intralobar type of pulmonary isolation may be secondary to a chronic inflammatory response. Interlobular pulmonary bronchopulmonary segregation is more frequent in males (3:1 male to female ratio), is more common on the left side, and can be complicated by a number of conditions such as congenital diaphragmatic hernia, spinal malformations, and congenital heart disease. Interlobular pulmonary segregation may coexist with other systemic malformations, including diaphragmatic hernia, cardiovascular malformations, pulmonary dysplasia, and intestinal duplication malformations. Also its mass may be located under the diaphragm and look like a neuroblastoma or adrenal hemorrhage, which is more likely to be misdiagnosed.
III. Diagnosis and evaluation
(I) Prenatal diagnosis
On prenatal ultrasonography, bronchopulmonary isolation presents as a homogeneous mass with well-defined borders and dense echogenicity. The detection of arteries of the body circulation, either from the aorta to the arteries of the fetal lung lesion, after exploration by color flow Doppler is a diagnostic feature of fetal bronchopulmonary isolation. However, if such Doppler features are not detected, an echogenic dense microcystic congenital cystic adenoma-like malformation and bronchopulmonary isolation may have the same prenatal ultrasonographic changes.
Ultra-fast fetal magnetic resonance imaging can help identify congenital cystic adenomatoid malformations and bronchopulmonary segregation. Furthermore, prenatally derived diagnostic fetal lung masses showing clinicopathologic features of congenital cystic adenomatoid malformation and bronchopulmonary segregation (mixed lesions) are suggestive of a common embryologic basis for some lung masses.
BPS is a homogeneous, hyperechoic mass detected by ultrasound in mid-pregnancy. For the prenatal diagnosis of BPS, the accuracy of examination in the mid-trimester is higher than in the late trimester. In the statistics of the Liu YP study, the mass was seen to be progressively smaller and degenerated before delivery in 7 of 11 cases.
In late pregnancy the mass was seen to shrink and the ultrasound showed heterogeneity as well as hypoechogenicity with lobulated mass margins. In cases where imaging reveals fetal abnormalities, attention must be paid to these possible conditions: fetal edema, abnormal systemic blood supply, the effect of the mass on the mediastinum, and the possible presence of other organ malformations.
Monitoring for abnormal venous return and venous occlusion is an important way to monitor the presence of hydrothorax and fetal edema, and ultrasound Doppler can detect both abnormal blood supply from the body circulation, which sometimes cannot be accurately identified by ultrasound, making it impossible to differentiate from microadenoma CCAM.
With the development of MRI technology and its advantages of no radiological damage, multi-sectional imaging, wide field of view and good soft tissue contrast resolution, MRI is increasingly becoming an important supplement to ultrasound diagnosis. MRI is useful in diagnosing fetal thoracic malformations, especially for atypical lesions or combined with multiple complex malformations, and can compensate for the lack of ultrasound diagnosis.
Prenatal MRI can provide stereoscopic, homogeneous images while clearly showing the blood supply. Prenatal MRI has been reported to provide more information on normal versus abnormal lung development and better predict fetal outcome after birth by analyzing and evaluating lung relaxation time and measuring lung volume. It helps in the comprehensive prenatal assessment of the fetus and the development of a treatment plan after delivery. Therefore, prenatal MRI is more effective than ultrasound.
Some small lesions (less than 60%) disappear completely during the ultrasound prenatal examination. However, CT after birth still suggests the presence of lesions. Therefore, CT must be performed after birth.
It must be noted that in the absence of fetal non-immune edema or other malformations, the survival rate of BPS exceeds 90%. Moreover, the chances of prenatal complications, such as fetal edema and pleural effusion, are lower than those of CCAM, and the prognosis is better.
(II) Postnatal diagnosis
It is difficult to diagnose bronchopulmonary isolation based on history and clinical manifestations alone, and the disease itself may not always have obvious symptoms. With the rapid development of imaging, the abnormal arteries and draining veins of BPS can be clearly shown and their diagnostic value has been significantly improved. Diagnostic modalities include.
(1) X-ray diagnosis: X-ray chest examination is the most basic method to diagnose pulmonary isolation disease, which often shows a mass or infiltrative sign in the lower lobe, mostly located in the inner basal and posterior basal segments, and is characterized by X-rays that can shrink after treatment, but never disappear for a long time, showing dynamic changes.
(2) Ultrasound diagnosis: Ultrasound and color Doppler ultrasound are of great value in the diagnosis of this disease, as they can reveal not only the internal structural features of the lesion in the lung, but also the abnormal arteries, which are reliable evidence for the diagnosis of this disease.The ultrasound features of PS are: round or round-like and irregular solid masses in the lung with clear margins, regular morphology, uneven internal echogenicity, and often liquid dark areas of variable size.
The B ultrasound can detect and diagnose PS in the fetus, and in the case of cystic PS, the B ultrasound is more likely to detect abnormal arteries when there is a co-infection. In the absence of co-infection, B-ultrasound is not as good for diagnosis due to the interference of gas within the sac. This is the limitation of B-ultrasound.
(3) CT diagnosis: CT examination is now the main tool for postnatal diagnosis of pulmonary isolation, but its detection rate of blood vessels is not high. the most diagnostic sign of CT examination: the lesion is connected to the thoracic aorta, spinal column or inferior pulmonary vein in a striated manner. With the continuous development of medical imaging technology, especially the popularization and upgrading of multi-row spiral CT, spiral CT enhanced scanning with vascular imaging can replace angiography to some extent in the diagnosis of pulmonary isolation.
The CT performance varies with the anatomy of the disease. The intralobular lung type mainly shows a uniform density mass, round, ovoid, a few can be triangular or polygonal, with clear borders, and the CT value of uniform density is similar to that of muscle; the intralobular type with bronchial communication shows inhomogeneous density, and cystic changes are seen inside the sac, and the density inside the sac is close to that of water, with clear border rules. If infection is associated with the mass, a fluid level may be seen, which may change within a short period of time.
Signs such as emphysema or bronchiectasis are seen around the mass. The lung lobe appearance shows an increased density shadow adjacent to the posterior mediastinum or diaphragm with clear margins and uniform density, and cystic changes rarely occur.
(MRI is similar to CT in that the lobar endotype and bronchus do not communicate with each other, and TWI shows a low to medium signal and TWI shows a high signal with a uniform signal and clear borders. In the case of intralobular type with bronchial communication, the lesion is a mixture of mass and cystic lesion, in which liquid level can be seen, sometimes low signal air can be seen, and the boundary is clear.
Due to the vascular flow-space effect, gradient echo sequence (GRE) and multiplanar imaging capabilities of MRI such as 2D TOF, 3D TOF and cine MR, especially the development of the new technology of 3D dynamic magnetic resonance angiography (3D DCEMRA) for vascular display in recent years, it has overcome the shortcomings of conventional MRA and significantly improved the quality of vascular imaging, which can display the blood supplying arteries of the isolated lung from multiple angles. This new technique overcomes the shortcomings of conventional MRA and significantly improves the quality of vascular imaging by showing the origin, number and size of the blood supplying arteries and the draining venous return of the isolated lung from multiple angles.
Therefore, MR is superior for the visualization of blood supply arteries. However, MR can produce artifacts in and around the lesion due to the presence of air in the lung; therefore, MR is not as good as CT for the visualization of the lesion and its surrounding area.
(iii) Evaluation of the fetus
An oversized mass may compress the esophagus as well as the veins causing impaired reflux further leading to fetal edema, which can cause fetal interventions necessary or preterm delivery [30]. Therefore, the volume of the mass, the rate of change in mass size and whether it causes fetal edema are important indicators of fetal prognosis.
The literature reports the range of normal values of lung volume measured by fetal 3D ultrasound from 16 weeks to 36 weeks to understand the development of fetal lung at each gestational week, which provides a valuable reference standard for assessing the volume of fetal lung masses and pulmonary dysplasia. In cases where congenital malformations of the lungs are found in the fetus, ultrasound needs to be used to measure and calculate the mass volume as well as the residual lung volume.
Also, monitoring of abnormal venous return and venous occlusion by prenatal ultrasound is an important way to monitor the presence of hydrothorax and fetal edema. In addition, the function of the residual lung is an important factor in determining the prognosis of the fetus. Congenital dysplasia of the lungs is more difficult to diagnose using ultrasound. The cause is presumed to be an abnormal blood supply from the dorsal arch artery in the 4th week of embryonic life. However, it can be evaluated using mediastinal shift.
Grethl summarized 15 years of experience with 294 cases of intrauterine intervention for thoracic occupational lesions and combined fetal edema, with a postoperative survival rate of >95% in those without combined fetal edema, and concluded that although the cause of combined fetal edema is not fully understood, the occurrence of fetal edema is indeed related to the volume of the occupational lesion. It is believed that although the cause of combined fetal edema is not fully understood, the occurrence of fetal edema is indeed related to the volume of the occupying lesion, so regular monitoring of the fetus by ultrasound is essential.
(iv) Recommendations for infant delivery
If the fetal BPS is detected prenatally, it is a reasonable choice to continue the pregnancy if there is no combined fetal edema and the outcome is good. Delivery is usually after 32 weeks. Conventional spontaneous delivery is used in the absence of general symptoms; if mediastinal shift, pleural effusion, or suspected respiratory obstruction are present, early cesarean delivery is recommended. Emergency cesarean section should be performed after 32 weeks of gestation in case of fetal edema or oversized occupying lesions and difficulty in vaginal delivery, and emergency surgical treatment after birth.
IV. Treatment
(I) Fetal surgery
BPS is sometimes combined with pleural effusion or fetal edema. The outcome of combined fetal edema is not ideal and intervention in the fetal period is usually considered. Measures include fetal surgery and interventional ablation. The first ultrasound-mediated blood supply by laser electrocoagulation of the tumor and drainage of the pleural fluid has been successfully performed in the Netherlands. The presence of fetal edema is now a common indication for fetal surgical intervention. Again, the blood supply can be occluded by injection of anhydrous alcohol as well as polyethylene glycol monododecyl ether as a sclerosing agent.
(ii) Elective surgery after birth
In cases of fetal diagnosis of BPS, even if the mass disappears as indicated by ultrasound in the later part of the prenatal period, a reexamination is required after birth to clarify the diagnosis, and a CT examination is required because of false-negative results on X-ray or ultrasound. For those with definite symptoms after birth, emergency surgery is required, and Adzick NS states that surgery should be chosen at least 1 month after birth because the risk of anesthetics begins to decrease at 4 weeks of age.
For those cases not treated surgically immediately after birth, long-term follow-up is needed. If recurrent pulmonary infections, bleeding, gastrointestinal symptoms, or heart failure conditions are present, surgery needs to be considered. It is best not to wait until symptoms are present before surgery, as that can have an impact on overall lung development.
(1) Treatment principles: Once pulmonary isolation is diagnosed, surgical resection is generally required to treat the patient considering the potential risks, such as hemoptysis due to pulmonary hypertension and heart failure due to left-to-right shunt, recurrent pulmonary infections that are difficult to control, hemoptysis due to bronchiectasis or occasional cancer in some patients. Patients with intralobular pulmonary isolation often have co-infections. Patients with extralobar pulmonary isolation are often combined with other congenital malformations, and their prognosis is worse if they are not treated surgically.
(2) Purpose of surgery: To remove the infected lesion, eliminate the left-to-right shunt in the isolated lung, and prevent the lesion from becoming distantly infected and cancerous.
(3) Timing of surgery: It should be done during the infection control period, or as early as possible if there has been no co-infection.
(4) Surgical method: Usually, lobectomy is performed in principle for the intralobar type, and isolated lung tissue is removed for the extralobar type. Pulmonary isolation is often associated with thoracic adhesions due to co-infection, and is more common in the intralobar type, so more attention should be paid during separation to avoid injury to the abnormal arteries.
The inferior pulmonary ligament should be routinely explored during open chest exploration to understand the pulsation of the anomalous artery, as most of the anomalous arteries supplying the isolated lung from the body circulation enter the isolated lung via the inferior pulmonary ligament. At present, we have successfully performed minimally invasive surgery for isolated lung under total thoracoscopy, including: extralobular isolated lung/intra-diaphragmatic isolated lung, etc. The results are obvious, and the surgical complications as well as the postoperative recovery time are much better than those of traditional open thoracotomy.
V. Summary
Congenital isolated lung disease is a rare congenital condition with a genetic component. Intervention in severely affected fetuses (e.g., edema) can significantly alter perinatal survival rates. prognosis is better in the absence of combined edema in CCAM, and worse in the presence of edema. In fact, the majority of fetuses with combined BPS have a good prognosis and those requiring fetal intervention are still in the minority. There is no clear indication for open fetal surgery in the fetal period, and early intervention or even open fetal surgery is needed if the fetus is prone to edema or has edema.