Advances in the diagnosis and treatment of fetal congenital cystic adenoma of the lung
I. Overview
Fetal lung development is one of the decisive factors for survival after birth, and accurate prenatal diagnosis and evaluation of diseases affecting fetal lung development are very important. The most common disorders affecting fetal lung development include CCAM, Bronchopulmonary Sequestration (BPS), congenital diaphragmatic hernia and pleural effusion. The incidence of fetal CCAM accounts for approximately 25% of congenital lung lesions.
II. Etiology
CCAM is due to the overgrowth of the fetal terminal bronchi, forming a clearly defined lesion in the lung parenchyma, often involving part of the lung lobes or the whole lung lobes, and may involve the lung parenchyma unilaterally or bilaterally, and 90% of them may have mediastinal shift.
The exact etiology of CCAM is not fully understood, but the most common view is that CCAM is a malformation-like lesion, i.e., an overgrowth of one or more tissue components, which may be due to local obstruction of lung development and subsequent overgrowth of developed lung tissue due to unknown factors during fetal lung bud development.
Chen HW summarized 16 cases of prenatally diagnosed fetal lung disease, of which 8 (8/16) were CCAM, 5 (5/16) were BPS and 3 (3/16) were mixed lesions of CCAM combined with BPS. The presence of mixed lesions suggests that CCAM and BPS may have the same original germinal base development.
Moerman et al. found from the autopsies of four CCAM cases that each had segmental bronchial agenesis or atresia, providing further evidence for the hypothesis that bronchial atresia is a primary defect in the development of CCAM, and proposed that the primary defect is a developmental restriction, arrest, or defect in the process of bronchopulmonary germination and branching causing bronchial atresia and bronchial agenesis due to atresia. Studies have hypothesized that this defect can occur at 24 days of embryonic development or as late as 19 weeks of gestation.
Cass et al. detected a 2-fold increase in the cell proliferation index and only 1/5 of the apoptotic bodies in CCAM lesions compared to normal fetal lungs at the corresponding gestational weeks, thus hypothesizing that CCAM is the result of an imbalance between cell proliferation and apoptosis during lung development.Fromont-Hankard et al. proposed that abnormal expression of glial cell-derived neurotrophic factor (GDNF) leads to lung stagnation. It has also been shown that enhanced expression of the Hoxb-5 gene is associated with the development of CCAM.
Kulwa reported a case of fetal CCAM in which the mother had a clear history of alcohol abuse during pregnancy, suggesting that alcohol may act as a teratogen to reduce the production of retinoic acid (RA) through the mediation of P450 and the inhibition of ethanol dehydrogenase, leading to the development of CCAM. The above literature reports provide a basis for a more in-depth elucidation of the mechanism of CCAM.
III. Pathology and typing
The pathological pattern of CCAM is very different from other types of pulmonary cysts, and its characteristic pathological changes include: lack of cartilaginous tissue and bronchial glands in the cyst wall; cyst wall covered with monolayer, pseudostratified, compound cuboidal or columnar ciliated epithelium and mucus epithelium; overproduction of terminal fine bronchial structures, and absence of alveolar differentiation.
Stocker et al. analyzed 38 cases of CCAM and classified them into three types according to their gross and histologic morphology: type I accounted for 65% of the lesions, which consisted of a single or complex large cystic lumen, mostly >2 cm in diameter, lined with pseudostratified ciliated columnar epithelium, with some epithelium containing mucus cells and a thick wall containing thin layers of smooth muscle and elastic tissue, with relatively normal alveoli visible between the cavities.
Type II accounts for 25% of the cases and consists of complex small cystic cavities, mostly <1 cm in diameter, lined with ciliated columnar or cuboidal epithelium, without cartilage or mucus glands in the cyst wall, with similar respiratory bronchial and dilated alveolar structures between the cysts, often with other malformations. Type III, which accounts for 10% of cases, is a large, non-cystic, solid lesion with microcysts that are difficult to identify with the naked eye and microscopically appear as fine bronchial-like structures, lined with cuboidal or columnar epithelium, and partially containing cilia.
According to the pathological changes, the prenatal diagnosis of CCAM by ultrasound is also divided into three types: type I is a large cystic type, in which a cystic mass is seen in the thoracic cavity, with a diameter of >2 cm and no separation, and lung tissue echogenicity is visible around the cystic mass. Type II is a microcystic type, in which cystic masses are seen in the thoracic cavity, manifesting as multiple small cysts with a cavity diameter <2 cm. Type III is a mixed type, also known as multicystic lung, which is formed by the fusion of smaller cysts with lung tissue, manifesting as enlarged lobes in the affected thoracic cavity with enhanced and uniform echogenicity and mediastinal shift to the opposite side.
The prognosis of CCAM type I and II alone is good, but type III is often prone to fetal edema and has a poor prognosis. CCAM is supplied by the pulmonary circulatory system, and its pathophysiology is mainly characterized by compression of the mass causing displacement of the mediastinum, which in turn leads to impaired venous return, resulting in fetal edema, and by lung compression due to the occupancy of the mass, resulting in poor lung development.
Davenport M et al. summarized a total of 67 cases of prenatally diagnosed fetal chest masses from 1995 to 2001, with a mean gestational age of 21 weeks (19-28 weeks), of which 43% were right-sided, 54% were left-sided, and 3% were bilateral. The macrocystic type accounted for 40%, microcystic type for 52% and mixed type for 8%. While Adzick NS et al in a review of 22 cases of prenatal diagnosis of fetal CCAM suggested that microscopic lesions (less than 5 mm) combined with fetal edema suggested a poor prognosis; giant lesions (single or multiple, greater than or equal to 5 mm) without combined fetal edema had a good prognosis; 4 cases were giant lesions and completely disappeared in the subsequent ultrasound follow-up (18%).
IV. Diagnosis and evaluation in the fetal period
(I) Prenatal diagnosis
Prenatal ultrasonography, due to its technical maturity, widespread use and ease of monitoring, has become the preferred mode of examination for CCAM. Serial ultrasound studies of fetal thoracic lesions help to clarify the specific type of these lesions, determine their pathophysiological features, predict clinical outcome, and form management opinions based on prognosis. Due to the sensitivity of ultrasound to fetal pulmonary masses, prenatal confirmation of the diagnosis is not difficult, but differentiation from BPS is required, and the application of Doppler to the source of blood supply to the mass can be the main point of differentiation, i.e., the blood supply to the pulmonary circulation in CCAM and the body circulation in BPS.
In 1983, Smith et al. reported the first magnetic resonance imaging (MRI) examination of the fetus. Although ultrasound remains the imaging method of choice for fetal examination, MRI is increasingly becoming an important complement to ultrasound diagnosis with the development of MRI technology and its advantages of no radiological damage, multisection imaging, broad field of view and good soft tissue contrast resolution. Prenatal MRI has been reported to provide more information about normal versus abnormal lung development and to better predict postnatal fetal outcome with the analytical evaluation of lung relaxation time and measurement of lung volume.
MRI is safer for the fetus because of its radiofrequency wavelength of several meters and energy of only 10-7ev, which is 1/1010 of CT. MRI can suggest more details of congenital structural malformations of the fetus, and MRI can compensate for the lack of ultrasound diagnosis in the diagnosis of fetal chest malformations, especially for atypical lesions or the combination of multiple complex malformations. (2) Fetal growth
(ii) Fetal evaluation
CCAM is most commonly found between 18 and 26 weeks, and the size 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 a range of normal values for lung volume measured by fetal 3D ultrasound from 16 weeks to 36 weeks to understand the development of fetal lung at each gestational week, providing a valuable reference standard for the assessment of fetal mass volume and pulmonary dysplasia.
One of the most commonly used methods is ultrasonography to calculate the cephalopulmonary ratio (CVR), which refers to the volume of the pulmonary mass (volume is W*H*L*0.523)/fetal head circumference, and has a very different clinical significance when the CVR is greater or less than 1.6. Mark et al. counted a total of 101 cases of CCAM detected at 17-38 weeks prenatally. Of these, 76 cases did not present with edema and their outcome was good (66 of them had postnatal mass resection and 10 simply required follow-up); 25 cases that presented with edema died, all at 25-36 weeks.
For those with CVR less than or equal to 1.6, 86% did not develop edema; for those greater than 1.6, 75% developed edema. In the cases without edema, the masses showed a gradual decrease in size after about 25-28 weeks. Lllanes S et al. summarized a total of 48 cases of prenatal ultrasound suggestive of fetal chest masses, 90% with CCAM and 10% with BPS, and followed their regression: 22 cases (22/48) showed gradual disappearance of the masses, 17 cases (17/48) showed no change in the masses, and 6 cases (6/48) showed worsening of the condition.
Lerullo AM et al. summarized the regression of 34 cases of prenatally diagnosed fetal CCAM in a 4-year review and found that the pulmonary masses spontaneously disappeared or shrank in 76% of cases, with an overall fetal survival rate of 88%. monni G et al. reported 26 cases of prenatally diagnosed fetal CCAM, with 3 (3/26) cases of complete disappearance of the lesion. 5 (5/26) cases were not treated surgically. This suggests that conservative treatment is still the appropriate choice if the fetus does not present with edema or excessive amniotic fluid.
Grethel et al. summarized 15 years of experience with 294 cases of intrauterine interventions 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. (ii) The fetal edema is related to the volume of the occupying lesion, so regular monitoring of the fetus by ultrasound is essential.
(iii) Recommendations for fetal delivery
Antenatal detection of fetal CCAM is a reasonable option 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 all cases without symptoms; in cases of mediastinal shift, microcystic, and suspected airway obstruction, cesarean section is recommended as an option. Antsaklis agrees that early delivery and postnatal surgery should be performed after 32 weeks of gestation, while fetal intervention at <32 weeks is recommended.
V. Treatment
(i) Hormonal therapy
The possible mechanism of hormonal therapy is to address the immaturity of the lungs in CCAM cases: in the study of CCAM cases, the expression of the Hox b5 gene was found to be similar to early lung tissue; CD34 staining of lung tissue was also similar to early lung tissues; suggesting a congenital deficiency in lung development in CCAM.
Curran PF et al. treated 16 cases of microcystic CCAM with prenatal hormone therapy. Of these, 13 were born alive and 11/13 (84.6%) survived until discharge. During treatment with the drug, the CVR was greater than 1.6 in all cases, and there was also non-immune edema in 9 cases (69.2%). In the hormone treated cases, the CVR decreased in 8 cases (61.5%) and the edema resolved in 7 cases (77.8%), while in 2 cases the edema failed to resolve. The conclusion suggests that hormone therapy is an effective method in high-risk microcystic CCAM cases.
(II) Shunt puncture
The drainage of cysts (shunt puncture) first of all requires a visualization system that can keep track of the mass as well as the specifics of the puncture. The fetoscope is applied to place the drainage tube between the thoracic cyst and the amniotic cavity under the guidance of the visualization system for therapeutic purposes. Evaluation of the shunt: The visualization system is used to understand the postoperative reopening of the lung and the possible detection of previously undiagnosed cases of pulmonary isolation and to stop the continued progression of edema.
The drainage fluid may be subjected to relevant laboratory tests.
1. cytologic examination for the presence of lymphatic fluid exudate;
2. Infection indicators;
The mean gestational age at prenatal diagnosis of CCAM was 20 weeks and the mean gestational age at placement was 23+1 weeks in Wilson et al. The mean volume of the preoperative mass in CCAM was 50.5-25.7 cm3; the mean postoperative volume was reduced by 51%. The mean gestational age at birth after this treatment was 33+3 weeks and the mean time at placement was 10+2 weeks in CCAM cases. The mean gestational age at birth after this treatment was 33+3 weeks, and the mean time to placement was 10+2 weeks. The postnatal survival rate was 70%. Indications for treatment included fetal edema and signs of pulmonary dysplasia.
Successful tube placement resulted in a significant increase in gestational age at birth, and a clinical summary by Schott S et al. suggested a 70% survival rate for thoracic shunts in cases of giant alveolar disease.
(iii) EXIT procedure (extra-uterine fetal surgery at delivery ex-utero intrapartum therapy , EXIT)
The principles of EXIT surgery are: 1) severe mediastinal displacement; 2) persistently high CVR (>1.6) combined with significant compression of normal lung tissue; 3) combined fetal edema.
The EXIT procedure requires careful planning and complete teamwork, including: anesthesia, cardiac circulation, neonatology, nursing, obstetrics, pediatric surgery, and extracorporeal membrane lung (ECMO) support therapy. Possible risks after birth include: recurrence, airway fistula, bleeding, celiac disease, sepsis, and gastroesophageal reflux.
Essential to the success of the EXIT procedure is ensuring gas exchange in the uteroplacenta and hemodynamic stability of the fetus. In addition, the family must be informed of the potential risks, including maternal hemorrhage, the need for further lung tissue removal after birth, prolonged NICU monitoring, and the corresponding increased costs. Risks to the mother include excessive amniotic fluid, preterm delivery, chorioamnionitis, and hemorrhage. the EXIT procedure allows for rapid removal of the pulmonary mass after birth, eliminating acute respiratory failure due to mediastinal displacement, air trapping, and compression of normal lung tissue.
(iv) Open fetal surgery
The principles or goals of fetal surgery are.
1.Restoration of normal anatomy ;
2.Restoration of normal physiology;
3. To allow the lungs to grow and develop before birth. There are no clear indications for performing open fetal surgery in the fetal period. For asymptomatic or non-edematous CCAM with a CVR <1.6, the changes can be observed dynamically. In contrast, a large mass with a CVR >1.6 and significant compression or significant mediastinal shift, a tendency for edema or pre-existing edema, and excessive amniotic fluid mostly require intervention in the fetal period, including open fetal surgery.
Mark counted 13 cases of fetal surgery with a gestational age of 21-29 weeks, of which 8 cases survived (62%); 5 cases died. The summary of outcomes obtained in the surviving cases were: resolution of edema within 1-2 weeks; recovery of mediastinal position within 3 weeks; accelerated lung growth; and delivery at an average of 8 weeks.
(v) Surgical options after birth
The combination of CCAM with other congenital malformations is rare, and most cases can be treated surgically after birth by normal delivery, and early surgical resection has become a generally accepted view. However, there is also a view that no further treatment is needed after birth (18% of total prenatal diagnoses).
Lllanes S et al. summarized that in cases where a CCAM mass was detected prenatally by ultrasound and followed up until its disappearance before delivery, postnatal CT was performed and still found 64% of the abnormalities, and 67% were consistent with the postoperative pathological histological diagnosis; this suggests that relying on ultrasound imaging alone for diagnosis and planning for surgical treatment is clearly not sufficient. Therefore, those with a prenatal fetal diagnosis of CCAM will require a repeat CT examination after birth to clarify the diagnosis. Those with definite symptoms after birth require emergency surgical treatment; there are no clear criteria for when to operate in asymptomatic cases.
Adzick NS noted that surgery should be chosen after at least 1 month of life because the risk of anesthesia begins to decrease gradually at 4 weeks of age. Factors associated with the need for surgical resection are the presence of significant respiratory symptoms, recurrent infections and risk of mass malignancy; other clinical manifestations such as coughing up blood, hemothorax, etc. However, there is an opinion that it is best not to wait until symptoms are present before surgery, as that has an impact on overall lung development. In the absence of comorbidities, there is no significant correlation between the long-term outcome of surgery and the timing of surgery.
VI. Summary
Intervention for congenital lung lesions, most commonly CCAM, in severely affected fetuses (e.g., edema) can significantly alter perinatal survival rates. However, not much more is known about the short- or long-term outcome of lung development and neurological development, and a small number of cases have shown that congenital lung lesions increase neonatal morbidity, mainly preterm birth and respiratory distress at birth.
The prognosis is better in the absence of combined edema in CCAM, while it is worse in the presence of edema. In fact, the need for fetal interventions is still a minority. There are no clear indications for open fetal surgery in the fetal period, and early intervention or even open fetal surgery is needed for CVR >1.6, definite mediastinal shift, and fetal propensity for edema or if edema is already present.