Elevated Platelet-Derived Growth Factor-B in Congenital Cystic Adenomatoid Malformations Requiring Fetal Resection By Kenneth W. Liechty, Timothy M. Crombleholme, Theresa M. Quinn, Darrell L. Cass, Alan W. Flake, and N. Scott Adzick Philadelphia, Pennsylvania Background: During lung development, platelet-derived growth factor-BB (PDGF-BB) is maximal during the canalicu- lar stage and decreases by the saccular stage. PDGF-BB stimulates lung growth by increasing cell proliferation. Fetal CCAMs have been shown to have an elevated proliferative index, but it is not known why some CCAMs rapidly enlarge in utero and cause fetal hydrops, The authors hypothesized that the high proliferative index and rapid enlargement of some fetal CCAMs may be caused by persistently elevated PDGF-BB production compared with normal fetal lung. Methods: To test this hypothesis, tissue was obtained at the time of resection from two fetal CCAMs (22 weeks), three full-term CCAMs, and three normal fetal lungs (21 to 22 weeks). PDGF-BB production by fetal CCAMs was compared with normal age-matched fetal lung using immunohistochem- istry, reverse transcriptionase-polymerase chain reaction (RT- PCR), and Western blot analysis. Results: CCAMs resulting in fetal hydrops and requiring fetal resection had strong mesenchymal immunostaining for PDGF-BB next to epithelial lined cysts, increased PDGF-B gene expression by RT-PCR, and elevated PDGF-BB protein by Western blot, compared with normal age-matched fetal lung. Term CCAMs had minimal PDGF-BB staining, PDGF-B gene expression, and PDGF-BB protein production. Conclusions: CCAMs that grew rapidly and progressed to hydrops, requiring in utero resection, demonstrated in- creased mesenchymal PDGF-B gene expression and PDGF-BB protein production compared with age-matched normal fetal lung, which may, in part, be responsible for the autonomous growth and proliferation seen in hydropic fetal CCAMs. J Pediatr Surg 34:805-810. Copyright © 1999 by W.B. Saun- ders Company. INDEX WORDS: Congenital cystic adenomatoid malforma- tion, platelet-derived growth factor-B, cell proliferation, fetal surgery. C ONGENITAL CYSTIC ADENOMATOID malfor- mations (CCAMs) are characterized by a cystic mass of lung parenchyma with a proliferation of bron- chial structures and a lack of normal alveoli. 1,2 Most CCAMs can be managed after birth, but the prenatal natural history of CCAMs is quite variable and depends on the size and growth properties of the tumor. 3,4In utero, some CCAMs can grow quite rapidly resulting in medias- tinal shift and fetal hydrops, which, if left untreated, is associated with an extremely high mortality rate. 5,6 In particular, the predominantly solid, mesenchymal pre- dominant, type III CCAMs have a poor prognosis, often presenting with nonimmune hydrops in utero. 5 The embryological origin and pathogenesis of CCAMs remains unknown. We have demonstrated previously that CCAMs that progress to fetal hydrops and require in utero resection have an elevated proliferative index and a lower apoptotic index compared with normal age- matched fetal lung. 7 Because normal organogenesis relies on a delicate balance between cell proliferation and cell death, 8 polypeptide growth factors are believed to play a vital role in the regulation of these processes. Platelet- derived growth factor-BB (PDGF-BB) is a mesenchymal growth factor that is maximally expressed during the canalicular stage and decreases by the saccular stage of lung development. 9 PDGF-BB has been shown to stimu- late lung growth by increasing cell proliferation. 1° We hypothesized that dysregulation of PDGF-B gene expres- sion in the developing lung mesenchyme results in rapid CCAM proliferation. To examine the role of PDGF-BB in the pathogenesis of CCAM, we examined both PDGF-BB protein production using immunohistochemis- try and Western blot analysis, as well as PDGF-BB gene expression using semiquantitative reverse transcription- ase-polymerase chain reaction (RT-PCR) analysis, from CCAMs resected in utero and postnatally compared with normal age-matched lung. From The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, PA. Presented at the 1998 Annual Meeting of the Section on Surgery of the American Academy of Pediatrics, San Francisco, California, October 16-19, 1998. Supported by the C. Everett Koop Chair in Pediatric Surgery. Address reprint requests to N. Scott Adzick, MD, The Children's' Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104. Copyright © 1999 by W..B. Saunders Company 0022 -3468/99/3405-0028503.00/0 Journal of Pediatric Surgery, Vo134,No 5 (May), 1999:pp 805-810 805