Just Accepted by The Journal of Maternal-Fetal & Neonatal Medicine Review Article Rare Congenital pulmonary malformation with diagnostic challenging: Congenital Pulmonary Lymphangiectasia, report of four autopsy cases and review of literature. Havva Serap Toru, Cem Yasar Sanhal, Gulden Tasova Yilmaz, Irem Hicran Ozbudak, Inanc Mendilcioglu, Gulay Ozbilim doi: 10.3109/14767058.2014.956719
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
Abstract Congenital pulmonary lymphangiectasia (CPL) is a rare congenital disorder that typically presents with intractable respiratory failure in the first few days of life. There is an association non-immun hydrops and CPL. In this study we reviewed four CPL cases between January2006-January 2014 among 684 fetal-pediatric autopsies. All cases were in the second trimester. In light microscopy there were marked dilatated channels in the subpleural -peribronchial-subseptal region of the lungs. The channels were lined with flattened cells which were expressing CD 31 and D2-40, negative for CD34. Although pulmonary interstitial emphysema (PIE) was considered an important differential diagnosis, a giant cell reaction surrounding the interstitial cystic lesions, a histological hallmark of PIE. CPL is characterized by dilatation of the pulmonary lymphatic vessels and occurs as a congenital anomaly. Noonan classified it into three groups. Primary developmental defect of pulmonary lymphatics is group 3. Group 3 is called also as CPL; normal regression of the connective tissue elements fails to occur after the 16th week of fetal life, associated with an aggressive clinical course, poor prognosis. In fetal autopsy examination CPL should be recognized if there is a fetus with pleural effusion, non-immune hydrops. There is no clinical evidence for CPL.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
Review Article
Rare Congenital pulmonary malformation with diagnostic challenging: Congenital Pulmonary Lymphangiectasia, report of four autopsy cases and review of literature.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
Dr Cem Yasar Sanhal MD1, Dr Gulden Tasova Yilmaz2, Dr Irem Hicran Ozbudak3, Professor Inanc Mendilcioglu4, Professor Gulay Ozbilim5,
1School of Medicine, Gynecology and Obstetrics, Dumlupinar Bulvar?, Konyaalt?, Antalya, 07059 Turkey 2
Akdeniz University, School of Medicine Department of Pathology, Antalya, 07059 Turkey
3
School of Medicine, Department of Pathology, Dumlupinar Bulvar?, Konyaalt?, Antalya, 07059
Turkey 4
School of Medicine, Gynecology and Obstetrics, Dumlupinar Bulvar?, Konyaalt?, Antalya,
07059 Turkey 5
Faculty of Medicine, Department of Pathology, Dumlupinar Bulvar?, Konyaalt?, Antalya, 07059
Turkey running head: Congenital pulmonary Lymphangiectasia a rare entity with diagnostic challenging Dr Havva Serap Toru MD (Corresponding Author) Email: [email protected] Akdeniz University, School of Medicine, Department of Pathology, Akdeniz Universitesi Hastanesi Patoloji A.D., Antalya, Turkey Abstract Congenital pulmonary lymphangiectasia (CPL) is a rare congenital disorder that typically presents with intractable respiratory failure in the first few days of life. There is an association non-immun hydrops and CPL. In this study we reviewed four CPL cases between January2006-January 2014 among 684 fetalpediatric autopsies. All cases were in the second trimester. In light microscopy there were marked dilatated channels in the subpleural -peribronchial-subseptal region of the lungs. The channels were lined with flattened cells which were expressing CD 31 and D2-40, negative for CD34. Although pulmonary interstitial emphysema (PIE) was considered an important differential diagnosis, a giant cell
reaction surrounding the interstitial cystic lesions, a histological hallmark of PIE. CPL is characterized by dilatation of the pulmonary lymphatic vessels and occurs as a congenital anomaly. Noonan classified it into three groups. Primary developmental defect of pulmonary lymphatics is group 3. Group 3 is called also as CPL; normal regression of the connective tissue elements fails to occur after the 16th week of fetal life, associated with an aggressive clinical course, poor prognosis. J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
In fetal autopsy examination CPL should be recognized if there is a fetus with pleural effusion, non-immune hydrops. There is no clinical evidence for CPL. Keywords Congenital pulmonary lymphangiectasia pleural effusion non-immune hydrops pulmonary malformation prenatal death Introduction: Pulmonary lymphangiectasia (PL) is a rare congenital disorder that typically presents with intractable respiratory failure in the first few days of life (1). The incidence of PL is unknown, but autopsy results suggest 0.5-1% of stillborns or infants who die in neonatal period have PL (2). There is an association between non-immune hydrops and PL (3-4). Congenital pulmonary effusion (CPE) is a prenatally idetified entity which can be either chylous (lymphatic) or serous . Chylous CPE is usually associated with chromosomal anomalies, cardiac dysfunction and infections. A primary lymphatic accumulation is secondary to lymphatic anomalies in thoracic duct, lung tissue or pleura (4-6). PL can present in the antenatal period as non-immune hydrops fetalis with pleural effusions, at birth as stillbirth or severe respiratory distress (7). This entity has a very high mortality that may occur suddenly after birth. If a term neonate presents with severe respiratory distress associated with pleural effusion, clinical diagnose of PL should be thougt (8). PL is characterized by dilatation of the pulmonary lymphatic vessels and occurs as a congenital anomaly. Noonan classified it into three groups. Type 1 is a generalized lymphangiectasis with thoracic and extra thoracic involvement. Type 2 is secondary to pulmonary venous obstruction due to congenital heart disease. Type 3 is also primary developmental defect of pulmonary lymphatics. Type 3 is called also as Congenital pulmonary lymphangiectasia (CPL), that is the normal regression of the connective tissue elements which fail to occur after the 16th week of fetal life, associated with an aggressive clinical course and poor prognosis (9). This classification
wasmodified and PL was subdivided into two groups such as primary and secondary PL (Table 1) (7, 10). We aimed to identify the prenatal findings, diagnostic difficulties and prenatal-postnatal treatment of the disease with literature review.
Case Report: J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
In this study we reviewed 4 CPL cases among 684 fetal and pediatric autopsies which were performed between January 2006-January 2014. Case 1 was a 19-week-female fetus of a twentyyear-old woman. The patient was offered to terminate the pregnancy after of the certain diagnosis of anhydroamniosis due to preterm rupture of membranes. Macroscopic pathological examination revealed normal findings except growth retardation. In addition, grade 3 chorioamnionitis was detected during light microscopy of the placenta. Case 2 was a 24-week-female fetus of a thirty-one-year-old woman. In ultrasonographic evaluation severe skin edema and bilateral pleural effusion was detected (Figure 1). Macroscopically hydrops fetalis, short neck, depressed nasal bridge, big drooping ears and micrognathia were observed. In the previous pregnancy at 18th gestational week hidrops was detected and termination was performed. The examination of that fetus disclosed any noticeable pathology, except diffuse subcutaneous edema. Case 3 was a 17-week-male fetus of a forty-year-old women presented with a spontaneous abortion. In karyotype analysis Trisomy 21 was detected. Macroscopically subcutaneous edema and micrognathia was determined. In light microscopy additionally focal cytomegaly was detected in right adrenal gland. Case 4 was a 17-week-male fetus of a thirty five-year-old women presented with anhydoamniosis because of preterm membrane rupture. Macroscopy showed normal findings. In placental light microscopy evaluation grade 3 chorioamnionitis was detected. In light microscopy of all cases there were marked dilatated channels in the subpleural peribronchial-subseptal region of the lungs (Figure 2,3). The channels were lined with flattened cells which were expressing CD 31 and D2-40 (Figure 4), negative for CD34. The channels were line with flattened cells expressing CD31 and D2-40 (figure 3), and which were negative for CD34. These findings were compatible with type 3 (Table 1).
Discussion:
The incidence of PL was not truely defined yet. Autopsy studies suggest that 0.5%-1% of infants who were stillborn or died in the first year after birth had PL (7). studying line with this data 0.58% of our perinatal autopsy cases suffered from PL. The association between congenital chylothorax accompanying hydrops fetalis and CPL was formerly defined (11) and one of our cases presented with hydrops fetalis. CPL might also be associated with abnormalities such as Noonan, Turner, Down (12-14), Frijins (15), Hennekam J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
(11, 16), Urioste syndromes (12-13, 17). Additionally, syndromic lymphedema anomaly was proposed by Northup et al (18). Trisomy 21 was detected in our case 3. The etiology of PL is not known. Between 9-16th gestational weeks, the persistence of large lymphatic vessels are the normal developmental form of lung tissue, and the interruption at the regression of lymphatic channels about 20 weeks of gestation was suggested as one of the potential causes of PL (8). Large lymphatic channels in early gestational weeks should not be considered as an abnormal finding. But we also compared the lymphatic channels of our cases with other normal fetal lung specimens which were at the same gestation. Control group was consisted of ten male fetuses with 17 weeks of gestation and ten 19 weeks of gestation which don’t have any congenital anomaly, infection or growth retardation. Both cases had markedly dilated lymphatics that support diagnoses of PL. According to three layered grading system of inflammation in chorioamnionitis, both of them had grade 3(19). This finding suggests infectious etiology of CPL which is described in literature (10). But we need futher studies for make a decision. Lymphatic vessels were first described by Gaspare Assellini in seventeenth century. In 1902 Florence Sabin proposed the lymphatic system development model, this was the most popular one. In 1910 Huntington and McClure proposed another model which suggests that primary lymph sacs arise in the mesenchyme independetly and then establish venous connection, which is supported with recent studies (8). The most recent genes in lymphangiogenesis are Ang2, D6, FoxC2, Elk (Net), Lyve I, Nrp2, Podoplanin, Prox I, SLC, Vegfr3, VEGFC, Tie2 (8). Another challenging entity in differential diagnosis of CPL is pulmonary interstitial emphysema (PIE). PIE has overlapping clinic and pathological findings, the giant cell reaction surrounding the interstitial cystic lesions is a histological hallmark of PIE (20).
In post-mortem examination while the removal of the lungs during the autopsies cause collapse in lymphatic channels, this makes difficult to diagnose lymphatic pathologies (8). Because of this some CPL cases are missed diagnosed. To diagnose PL should be recognized. In perinatal period if a fetal hydrops is presented PL should be taken in consideration (1, 21). For diagnostic approach family and obstetric history, sonographic examination, magnetic resonans imaging, fetal echo and Doppler blood flow J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
assessment, maternal blood examination including bblood type and Rhesus factor, serology can be used (8). In conclusion during fetal autopsy examination CPL should be recognized if there is a fetus with pleural effusion, non-immune hydrops history. There is no clinical evidence for CPL except pleural effusion in prenatal period. In differential diagnosis of prenatal pleural effusion after ruling out the chromosomal abnormalities, infection and cardiac pathologies; CPL should be considered (22). After ruling out chromosomal anomalies, cardiac dysfunction, congenital cardiac anomalies and infections prenatal pleuroamniotic shunts are life-saving prenatal therapy.
References:
1. Dempsey EM, Sant'Anna GM, Williams RL, Brouillette RT. Congenital pulmonary lymphangiectasia presenting as nonimmune fetal hydrops and severe respiratory distress at birth: not uniformly fatal. Pediatr Pulmonol. 2005;40(3):270-4. 2. Bouchart F, Dubar A, Tabley A, Litzler PY, Haas-Hubscher C, Redonnet M, et al. Coarctation of the aorta in adults: surgical results and long-term follow-up. Ann Thorac Surg. 2000;70(5):1483-8; discussion 8-9. 3. Hunter WS, Becroft DM. Congenital pulmonary lymphangiectasis associated with pleural effusions. Arch Dis Child. 1984;59(3):278-9. PMCID: 1628562. 4. Wilson RH, Duncan A, Hume R, Bain AD. Prenatal pleural effusion associated with congenital pulmonary lymphangiectasia. Prenat Diagn. 1985;5(1):73-6. 5. Defoort P, Thiery M. Antenatal diagnosis of congenital chylothorax by gray scale sonography. J Clin Ultrasound. 1978;6(1):47-8. 6. Reece EA, Lockwood CJ, Rizzo N, Pilu G, Bovicelli L, Hobbins JC. Intrinsic intrathoracic malformations of the fetus: sonographic detection and clinical presentation. Obstet Gynecol. 1987;70(4):627-32. 7. Esther CR, Jr., Barker PM. Pulmonary lymphangiectasia: diagnosis and clinical course. Pediatr Pulmonol. 2004;38(4):308-13. 8. Bellini C, Boccardo F, Campisi C, Bonioli E. Congenital pulmonary lymphangiectasia. Orphanet J Rare Dis. 2006;1:43. PMCID: 1637094.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
9. Noonan JA, Walters LR, Reeves JT. Congenital pulmonary lymphangiectasis. Am J Dis Child. 1970;120(4):314-9. 10. Bellini C, Mazzella M, Campisi C, Taddei G, Mosca F, Toma P, et al. Multimodal imaging in the congenital pulmonary lymphangiectasia-congenital chylothorax-hydrops fetalis continuum. Lymphology. 2004;37(1):22-30. 11. Bellini C, Mazzella M, Arioni C, Campisi C, Taddei G, Toma P, et al. Hennekam syndrome presenting as nonimmune hydrops fetalis, congenital chylothorax, and congenital pulmonary lymphangiectasia. Am J Med Genet A. 2003;120A(1):92-6. 12. Bellini C, Bonioli E, Josso N, Belville C, Mazzella M, Costabel S, et al. Persistence of Mullerian derivatives and intestinal lymphangiectasis in two newborn brothers: confirmation of the Urioste syndrome. Am J Med Genet. 2001;104(1):69-74. 13. Urioste M, Rodriguez JI, Barcia JM, Martin M, Escriba R, Pardo M, et al. Persistence of mullerian derivatives, lymphangiectasis, hepatic failure, postaxial polydactyly, renal and craniofacial anomalies. Am J Med Genet. 1993;47(4):494-503. 14. Moerman P, Vandenberghe K, Devlieger H, Van Hole C, Fryns JP, Lauweryns JM. Congenital pulmonary lymphangiectasis with chylothorax: a heterogeneous lymphatic vessel abnormality. Am J Med Genet. 1993;47(1):54-8. 15. Chung CJ, Fordham LA, Barker P, Cooper LL. Children with congenital pulmonary lymphangiectasia: after infancy. AJR Am J Roentgenol. 1999;173(6):1583-8. 16. Van Balkom ID, Alders M, Allanson J, Bellini C, Frank U, De Jong G, et al. Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review. Am J Med Genet. 2002;112(4):412-21. 17. van Haelst MM, Hoogeboom J, Galjaard RJ, Kleijer WJ, den Hollander NS, de Krijger RR, et al. Lymphangiectasia with persistent Mullerian derivatives: confirmation of autosomal recessive Urioste syndrome. Am J Med Genet. 2001;104(1):65-8. 18. Northup KA, Witte MH, Witte CL. Syndromic classification of hereditary lymphedema. Lymphology. 2003;36(4):162-89. 19. Gilbert-Barness E, Debich-Spicer DE. Handbook of Pediatric Autopsy Pathology. Breaugh MJ, editor. Totowa, New Jersey: Humana Press; 2005. 20. Yamada S. An Autopsy Case of Congenital Pulmonary Lymphangiectasis Masquerading as Pulmonary Interstitial Emphysema Congenital Anomalies - Case Studies and Mechanisms. 2012(February):11. 21. Stevenson DA, Pysher TJ, Ward RM, Carey JC. Familial congenital non-immune hydrops, chylothorax, and pulmonary lymphangiectasia. Am J Med Genet A. 2006;140(4):36872. PMCID: 2568883. 22. Wilson RD, Pawel B, Bebbington M, Johnson MP, Lim FY, Stamilio D, et al. Congenital pulmonary lymphangiectasis sequence: a rare, heterogeneous, and lethal etiology for prenatal pleural effusion. Prenat Diagn. 2006;26(11):1058-61.
Figure 1
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
Figure 2
Figure 3
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Figure 4
Table I- Classification of Pulmonary Lymphangiectasia Primary pulmonary developmental defect Failure of normal regression process of lymphatic channels of the fetal lung (20 weeks’ Primary Pulmonary Lymphangiectasia
gestation)
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Dilated pulmonary lymphatics Hemihypertrophy and lymphedema may be present Sydromic: Autosomal Dominant (AD)*, Autosomal Recessive (AR)**, X-linked*** Hypoplastic left heart syndrome, pulmonary vein atresia, congenital mitral stenosis, cor triatum Secondary Pulmonary Lymphangiectasia Thoracic duct agenesis Obstructive forms Infections * Yellow nail syndrome, Noonan, Intestinal lymphengiectasia, Lymphedema/cerebral arterio venous anomaly ** PEHO syndrome, German syndrome, Hennekam lymphangiectasia, Campomelia (cumming type), Hypotricosis lymphedema telengiectasia, Knobloch syndrome, Urioste syndrome *** Lymphedeme hypoparathyroidism, Mandibulofacial dysostosis
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
Abstract Congenital pulmonary lymphangiectasia (CPL) is a rare congenital disorder that typically presents with intractable respiratory failure in the first few days of life. There is an association non-immun hydrops and CPL. In this study we reviewed four CPL cases between January2006-January 2014 among 684 fetal-pediatric autopsies. All cases were in the second trimester. In light microscopy there were marked dilatated channels in the subpleural -peribronchial-subseptal region of the lungs. The channels were lined with flattened cells which were expressing CD 31 and D2-40, negative for CD34. Although pulmonary interstitial emphysema (PIE) was considered an important differential diagnosis, a giant cell reaction surrounding the interstitial cystic lesions, a histological hallmark of PIE. CPL is characterized by dilatation of the pulmonary lymphatic vessels and occurs as a congenital anomaly. Noonan classified it into three groups. Primary developmental defect of pulmonary lymphatics is group 3. Group 3 is called also as CPL; normal regression of the connective tissue elements fails to occur after the 16th week of fetal life, associated with an aggressive clinical course, poor prognosis. In fetal autopsy examination CPL should be recognized if there is a fetus with pleural effusion, non-immune hydrops. There is no clinical evidence for CPL.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
Review Article
Rare Congenital pulmonary malformation with diagnostic challenging: Congenital Pulmonary Lymphangiectasia, report of four autopsy cases and review of literature.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
Dr Cem Yasar Sanhal MD1, Dr Gulden Tasova Yilmaz2, Dr Irem Hicran Ozbudak3, Professor Inanc Mendilcioglu4, Professor Gulay Ozbilim5,
1School of Medicine, Gynecology and Obstetrics, Dumlupinar Bulvar?, Konyaalt?, Antalya, 07059 Turkey 2
Akdeniz University, School of Medicine Department of Pathology, Antalya, 07059 Turkey
3
School of Medicine, Department of Pathology, Dumlupinar Bulvar?, Konyaalt?, Antalya, 07059
Turkey 4
School of Medicine, Gynecology and Obstetrics, Dumlupinar Bulvar?, Konyaalt?, Antalya,
07059 Turkey 5
Faculty of Medicine, Department of Pathology, Dumlupinar Bulvar?, Konyaalt?, Antalya, 07059
Turkey running head: Congenital pulmonary Lymphangiectasia a rare entity with diagnostic challenging Dr Havva Serap Toru MD (Corresponding Author) Email: [email protected] Akdeniz University, School of Medicine, Department of Pathology, Akdeniz Universitesi Hastanesi Patoloji A.D., Antalya, Turkey Abstract Congenital pulmonary lymphangiectasia (CPL) is a rare congenital disorder that typically presents with intractable respiratory failure in the first few days of life. There is an association non-immun hydrops and CPL. In this study we reviewed four CPL cases between January2006-January 2014 among 684 fetalpediatric autopsies. All cases were in the second trimester. In light microscopy there were marked dilatated channels in the subpleural -peribronchial-subseptal region of the lungs. The channels were lined with flattened cells which were expressing CD 31 and D2-40, negative for CD34. Although pulmonary interstitial emphysema (PIE) was considered an important differential diagnosis, a giant cell
reaction surrounding the interstitial cystic lesions, a histological hallmark of PIE. CPL is characterized by dilatation of the pulmonary lymphatic vessels and occurs as a congenital anomaly. Noonan classified it into three groups. Primary developmental defect of pulmonary lymphatics is group 3. Group 3 is called also as CPL; normal regression of the connective tissue elements fails to occur after the 16th week of fetal life, associated with an aggressive clinical course, poor prognosis. J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
In fetal autopsy examination CPL should be recognized if there is a fetus with pleural effusion, non-immune hydrops. There is no clinical evidence for CPL. Keywords Congenital pulmonary lymphangiectasia pleural effusion non-immune hydrops pulmonary malformation prenatal death Introduction: Pulmonary lymphangiectasia (PL) is a rare congenital disorder that typically presents with intractable respiratory failure in the first few days of life (1). The incidence of PL is unknown, but autopsy results suggest 0.5-1% of stillborns or infants who die in neonatal period have PL (2). There is an association between non-immune hydrops and PL (3-4). Congenital pulmonary effusion (CPE) is a prenatally idetified entity which can be either chylous (lymphatic) or serous . Chylous CPE is usually associated with chromosomal anomalies, cardiac dysfunction and infections. A primary lymphatic accumulation is secondary to lymphatic anomalies in thoracic duct, lung tissue or pleura (4-6). PL can present in the antenatal period as non-immune hydrops fetalis with pleural effusions, at birth as stillbirth or severe respiratory distress (7). This entity has a very high mortality that may occur suddenly after birth. If a term neonate presents with severe respiratory distress associated with pleural effusion, clinical diagnose of PL should be thougt (8). PL is characterized by dilatation of the pulmonary lymphatic vessels and occurs as a congenital anomaly. Noonan classified it into three groups. Type 1 is a generalized lymphangiectasis with thoracic and extra thoracic involvement. Type 2 is secondary to pulmonary venous obstruction due to congenital heart disease. Type 3 is also primary developmental defect of pulmonary lymphatics. Type 3 is called also as Congenital pulmonary lymphangiectasia (CPL), that is the normal regression of the connective tissue elements which fail to occur after the 16th week of fetal life, associated with an aggressive clinical course and poor prognosis (9). This classification
wasmodified and PL was subdivided into two groups such as primary and secondary PL (Table 1) (7, 10). We aimed to identify the prenatal findings, diagnostic difficulties and prenatal-postnatal treatment of the disease with literature review.
Case Report: J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
In this study we reviewed 4 CPL cases among 684 fetal and pediatric autopsies which were performed between January 2006-January 2014. Case 1 was a 19-week-female fetus of a twentyyear-old woman. The patient was offered to terminate the pregnancy after of the certain diagnosis of anhydroamniosis due to preterm rupture of membranes. Macroscopic pathological examination revealed normal findings except growth retardation. In addition, grade 3 chorioamnionitis was detected during light microscopy of the placenta. Case 2 was a 24-week-female fetus of a thirty-one-year-old woman. In ultrasonographic evaluation severe skin edema and bilateral pleural effusion was detected (Figure 1). Macroscopically hydrops fetalis, short neck, depressed nasal bridge, big drooping ears and micrognathia were observed. In the previous pregnancy at 18th gestational week hidrops was detected and termination was performed. The examination of that fetus disclosed any noticeable pathology, except diffuse subcutaneous edema. Case 3 was a 17-week-male fetus of a forty-year-old women presented with a spontaneous abortion. In karyotype analysis Trisomy 21 was detected. Macroscopically subcutaneous edema and micrognathia was determined. In light microscopy additionally focal cytomegaly was detected in right adrenal gland. Case 4 was a 17-week-male fetus of a thirty five-year-old women presented with anhydoamniosis because of preterm membrane rupture. Macroscopy showed normal findings. In placental light microscopy evaluation grade 3 chorioamnionitis was detected. In light microscopy of all cases there were marked dilatated channels in the subpleural peribronchial-subseptal region of the lungs (Figure 2,3). The channels were lined with flattened cells which were expressing CD 31 and D2-40 (Figure 4), negative for CD34. The channels were line with flattened cells expressing CD31 and D2-40 (figure 3), and which were negative for CD34. These findings were compatible with type 3 (Table 1).
Discussion:
The incidence of PL was not truely defined yet. Autopsy studies suggest that 0.5%-1% of infants who were stillborn or died in the first year after birth had PL (7). studying line with this data 0.58% of our perinatal autopsy cases suffered from PL. The association between congenital chylothorax accompanying hydrops fetalis and CPL was formerly defined (11) and one of our cases presented with hydrops fetalis. CPL might also be associated with abnormalities such as Noonan, Turner, Down (12-14), Frijins (15), Hennekam J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
(11, 16), Urioste syndromes (12-13, 17). Additionally, syndromic lymphedema anomaly was proposed by Northup et al (18). Trisomy 21 was detected in our case 3. The etiology of PL is not known. Between 9-16th gestational weeks, the persistence of large lymphatic vessels are the normal developmental form of lung tissue, and the interruption at the regression of lymphatic channels about 20 weeks of gestation was suggested as one of the potential causes of PL (8). Large lymphatic channels in early gestational weeks should not be considered as an abnormal finding. But we also compared the lymphatic channels of our cases with other normal fetal lung specimens which were at the same gestation. Control group was consisted of ten male fetuses with 17 weeks of gestation and ten 19 weeks of gestation which don’t have any congenital anomaly, infection or growth retardation. Both cases had markedly dilated lymphatics that support diagnoses of PL. According to three layered grading system of inflammation in chorioamnionitis, both of them had grade 3(19). This finding suggests infectious etiology of CPL which is described in literature (10). But we need futher studies for make a decision. Lymphatic vessels were first described by Gaspare Assellini in seventeenth century. In 1902 Florence Sabin proposed the lymphatic system development model, this was the most popular one. In 1910 Huntington and McClure proposed another model which suggests that primary lymph sacs arise in the mesenchyme independetly and then establish venous connection, which is supported with recent studies (8). The most recent genes in lymphangiogenesis are Ang2, D6, FoxC2, Elk (Net), Lyve I, Nrp2, Podoplanin, Prox I, SLC, Vegfr3, VEGFC, Tie2 (8). Another challenging entity in differential diagnosis of CPL is pulmonary interstitial emphysema (PIE). PIE has overlapping clinic and pathological findings, the giant cell reaction surrounding the interstitial cystic lesions is a histological hallmark of PIE (20).
In post-mortem examination while the removal of the lungs during the autopsies cause collapse in lymphatic channels, this makes difficult to diagnose lymphatic pathologies (8). Because of this some CPL cases are missed diagnosed. To diagnose PL should be recognized. In perinatal period if a fetal hydrops is presented PL should be taken in consideration (1, 21). For diagnostic approach family and obstetric history, sonographic examination, magnetic resonans imaging, fetal echo and Doppler blood flow J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by The University of Manchester on 10/15/14 For personal use only.
assessment, maternal blood examination including bblood type and Rhesus factor, serology can be used (8). In conclusion during fetal autopsy examination CPL should be recognized if there is a fetus with pleural effusion, non-immune hydrops history. There is no clinical evidence for CPL except pleural effusion in prenatal period. In differential diagnosis of prenatal pleural effusion after ruling out the chromosomal abnormalities, infection and cardiac pathologies; CPL should be considered (22). After ruling out chromosomal anomalies, cardiac dysfunction, congenital cardiac anomalies and infections prenatal pleuroamniotic shunts are life-saving prenatal therapy.
References:
1. Dempsey EM, Sant'Anna GM, Williams RL, Brouillette RT. Congenital pulmonary lymphangiectasia presenting as nonimmune fetal hydrops and severe respiratory distress at birth: not uniformly fatal. Pediatr Pulmonol. 2005;40(3):270-4. 2. Bouchart F, Dubar A, Tabley A, Litzler PY, Haas-Hubscher C, Redonnet M, et al. Coarctation of the aorta in adults: surgical results and long-term follow-up. Ann Thorac Surg. 2000;70(5):1483-8; discussion 8-9. 3. Hunter WS, Becroft DM. Congenital pulmonary lymphangiectasis associated with pleural effusions. Arch Dis Child. 1984;59(3):278-9. PMCID: 1628562. 4. Wilson RH, Duncan A, Hume R, Bain AD. Prenatal pleural effusion associated with congenital pulmonary lymphangiectasia. Prenat Diagn. 1985;5(1):73-6. 5. Defoort P, Thiery M. Antenatal diagnosis of congenital chylothorax by gray scale sonography. J Clin Ultrasound. 1978;6(1):47-8. 6. Reece EA, Lockwood CJ, Rizzo N, Pilu G, Bovicelli L, Hobbins JC. Intrinsic intrathoracic malformations of the fetus: sonographic detection and clinical presentation. Obstet Gynecol. 1987;70(4):627-32. 7. Esther CR, Jr., Barker PM. Pulmonary lymphangiectasia: diagnosis and clinical course. Pediatr Pulmonol. 2004;38(4):308-13. 8. Bellini C, Boccardo F, Campisi C, Bonioli E. Congenital pulmonary lymphangiectasia. Orphanet J Rare Dis. 2006;1:43. PMCID: 1637094.
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9. Noonan JA, Walters LR, Reeves JT. Congenital pulmonary lymphangiectasis. Am J Dis Child. 1970;120(4):314-9. 10. Bellini C, Mazzella M, Campisi C, Taddei G, Mosca F, Toma P, et al. Multimodal imaging in the congenital pulmonary lymphangiectasia-congenital chylothorax-hydrops fetalis continuum. Lymphology. 2004;37(1):22-30. 11. Bellini C, Mazzella M, Arioni C, Campisi C, Taddei G, Toma P, et al. Hennekam syndrome presenting as nonimmune hydrops fetalis, congenital chylothorax, and congenital pulmonary lymphangiectasia. Am J Med Genet A. 2003;120A(1):92-6. 12. Bellini C, Bonioli E, Josso N, Belville C, Mazzella M, Costabel S, et al. Persistence of Mullerian derivatives and intestinal lymphangiectasis in two newborn brothers: confirmation of the Urioste syndrome. Am J Med Genet. 2001;104(1):69-74. 13. Urioste M, Rodriguez JI, Barcia JM, Martin M, Escriba R, Pardo M, et al. Persistence of mullerian derivatives, lymphangiectasis, hepatic failure, postaxial polydactyly, renal and craniofacial anomalies. Am J Med Genet. 1993;47(4):494-503. 14. Moerman P, Vandenberghe K, Devlieger H, Van Hole C, Fryns JP, Lauweryns JM. Congenital pulmonary lymphangiectasis with chylothorax: a heterogeneous lymphatic vessel abnormality. Am J Med Genet. 1993;47(1):54-8. 15. Chung CJ, Fordham LA, Barker P, Cooper LL. Children with congenital pulmonary lymphangiectasia: after infancy. AJR Am J Roentgenol. 1999;173(6):1583-8. 16. Van Balkom ID, Alders M, Allanson J, Bellini C, Frank U, De Jong G, et al. Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review. Am J Med Genet. 2002;112(4):412-21. 17. van Haelst MM, Hoogeboom J, Galjaard RJ, Kleijer WJ, den Hollander NS, de Krijger RR, et al. Lymphangiectasia with persistent Mullerian derivatives: confirmation of autosomal recessive Urioste syndrome. Am J Med Genet. 2001;104(1):65-8. 18. Northup KA, Witte MH, Witte CL. Syndromic classification of hereditary lymphedema. Lymphology. 2003;36(4):162-89. 19. Gilbert-Barness E, Debich-Spicer DE. Handbook of Pediatric Autopsy Pathology. Breaugh MJ, editor. Totowa, New Jersey: Humana Press; 2005. 20. Yamada S. An Autopsy Case of Congenital Pulmonary Lymphangiectasis Masquerading as Pulmonary Interstitial Emphysema Congenital Anomalies - Case Studies and Mechanisms. 2012(February):11. 21. Stevenson DA, Pysher TJ, Ward RM, Carey JC. Familial congenital non-immune hydrops, chylothorax, and pulmonary lymphangiectasia. Am J Med Genet A. 2006;140(4):36872. PMCID: 2568883. 22. Wilson RD, Pawel B, Bebbington M, Johnson MP, Lim FY, Stamilio D, et al. Congenital pulmonary lymphangiectasis sequence: a rare, heterogeneous, and lethal etiology for prenatal pleural effusion. Prenat Diagn. 2006;26(11):1058-61.
Figure 1
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Figure 2
Figure 3
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Figure 4
Table I- Classification of Pulmonary Lymphangiectasia Primary pulmonary developmental defect Failure of normal regression process of lymphatic channels of the fetal lung (20 weeks’ Primary Pulmonary Lymphangiectasia
gestation)
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Dilated pulmonary lymphatics Hemihypertrophy and lymphedema may be present Sydromic: Autosomal Dominant (AD)*, Autosomal Recessive (AR)**, X-linked*** Hypoplastic left heart syndrome, pulmonary vein atresia, congenital mitral stenosis, cor triatum Secondary Pulmonary Lymphangiectasia Thoracic duct agenesis Obstructive forms Infections * Yellow nail syndrome, Noonan, Intestinal lymphengiectasia, Lymphedema/cerebral arterio venous anomaly ** PEHO syndrome, German syndrome, Hennekam lymphangiectasia, Campomelia (cumming type), Hypotricosis lymphedema telengiectasia, Knobloch syndrome, Urioste syndrome *** Lymphedeme hypoparathyroidism, Mandibulofacial dysostosis
