Type I PPB occurs in young patients with PPB: median age at diagnosis is 10 months, range 0 - 28 months [Registry Publications]. A literature patient with Type I diagnosed at age 48 months is reported. Type I lesions are exclusively cystic, thin-walled structures with no grossly notable tumor. The cysts may be single or multiloculated with thin fibrous septa. The cysts are lined with ciliated columnar respiratory epithelium. Beneath the epithelium, there is found a continuous or discontinuous zone of condensed small, round-to-spindle-shaped immature or primitive tumor cells with the “cambium layer”-like appearance of sarcoma botryoides. The small primitive mesenchymal cells are often accompanied by a variable number of larger, polygonal or elongated strap-like cells with prominent eosinophyllic cytoplasm, with the features of rhabdomyoblasts. This sub-epithelial condensation of malignant cells is present only focally in some cases and numerous microscopic sections may be required. This common histologic finding of rhabdomyoblastic differentiation explains why early reports of “rhabdomyosarcoma occurring in lung cysts” probably represent cases of PPB.
Most Type I PPBs do not have extensive subepithelial cambium-like zones of embryonal rhabdomyosarcoma or primitive small cell sarcoma, but rather small epithelial buds of primitive cells and/or nodules of immature cartilage. Many examples of Type I PPB have bland histologic features; however, if one notes the presence of dense subepithelial orseptal spindle cells with or without nodules of immature cartilage, a diagnosis of Type I PPB is appropriate. A lung specimen containing peripherally located cysts with thin-walled septae must be considered a PPB until proven otherwise. Proving otherwise is best accomplished by submission of the entire gross specimen for histologic examination. Some Type I PPBs have several layers of mesenchymal cells in a subepithelial or cambium-layer distribution resembling embryonal rhabdomyosarcoma. Others have only small subepithelial buds of primitive small cells, spindle cells and/or nodules of immature cartilage. Anaplasia is rarely observed in Type I disease. The diagnostic elements of Type I PPB are often focal; extensive sampling is necessary. Please review the photomicrographs below.
Type I PPB most often arises in the peripheral lung, but examples of cystic changes appearing to originate in parietal pleura have been seen.
In 2005-2007, several observations by Registry pathologists suggest that lung cysts which show similarities to Type I PPB and which occur in circumstances in which Type I PPB is highly suspect – may regress and not develop into frank malignancy. The special clinical circumstances in which these cases have been observed include siblings of PPB children or children with cystic nephroma and multiple lung cysts. The lung cysts are not typical of CCAM and show some features of Type I PPB, but do not show malignant cells or cambium layers. The Registry is eager to review cases in such situations [see Registry Publications Priest 2009, Hill abstract 2007 Type I PPB].
Type I tumors should be distinguished from subtle, “early” Type II tumors that have a solid component represented only by thickened, nodular or plaque-like areas containing sarcomatous or blastematous elements. The importance of this distinction is based on the worse prognosis and more aggressive chemotherapy regimen applied to the Type II variant.
Ancillary studies to differentiate benign cysts from Type I PPB are only helpful if they are positive. The absence of muscle differentiation does not preclude the diagnosis of Type I PPB. The utility of FISH in detecting the characteristic Trisomy 8 in Type I tumors with few neoplastic cells is uncertain.
Type I PPB Differential Diagnosis
PPB and Early Childhood Lung Cysts: The relationship of PPB to various types of cystic congenital or early childhood airway malformations, such as CCAM types I to III, or to entities within newer rubrics such as congenital pulmonary airway malformations (CPAM) has yet to be defined. It may be that CPAM type 4 represents an entity particularly close to PPB Type I. The problem is that PPB Type I is a neoplasm whose diagnostic features can be subtle and may be exquisitely localized in a collapsed multilocular cyst which has been removed from the periphery of the lung in an infant or young child. Most Type I PPBs do not have extensive subepithelial cambium-like zones of embryonal rhabdomyosarcoma or primitive small cell sarcoma, but rather small sub-epithelial buds of primitive cells and/or nodules of immature cartilage. Extensive sampling of the cyst wall is imperative. Foci of dense subepitelial or spindle cell proliferation with or without thickening of the septum are sufficient in the Registry's experience for the diagnosis of PPB Type I. These primitive and/or spindle cells may not show immunoperoxidase staining for one or another muscle marker and the absence of muscle differentiation does not preclude the diagnosis of PPB Type I in the Registry's experience. For a more complete discussion of diagnosis of Type I PPB and the differentiation of Type I from CPAM. [See Registry Publications and search PubMed or Google Scholar for additional articles: MacSweeney F et al. An assessment of the expanded classification of congenital cystic adenomatoid malformations and their relationship to malignant transformation. Am J Surg Pathol 2003;27(8):1139-46; Hill DA, Dehner LP. A cautionary note about congenital cystic adenomatoid malformation (CCAM) type 4 [Letter]. Am J Surg Pathol 2004;28(4):554-5; MacSweeney F et al. A cautionary note about congenital cystic adenomatoid malformation (CCAM) type 4 [Reply]. Am J Surg Pathol 2004;28(4):555; Stocker JT. Congenital pulmonary airway malformation - a new name for and an expanded classification of congenital cystic adenomatoid malformation of the lung. Histopathology 2002;41(S2):424-31.
Mesenchymal cystic hamartoma of the lung [see Mark E. Mesenchymal cystic hamartoma of the lung. N Engl J Med 1986;315:1255-9] and “rhabdomyosarcoma in a congenital lung cyst” when the malignant cells are only minimally present. [see Pai S et al. Correction: Pleuropulmonary blastoma, not rhabdomyosarcoma in a congenital lung cyst [Letter to the Editor]. Pediatr Blood Cancer 2007;48(3):370-1] are other literature descriptions we believe are Type I PPB, including an early Registry-author description before PPB was recognized [Registry Publications, Allen].
Fetal Lung Institital Tumor (Immature Interstitial mesenchymal tumor): This is a radiographically solid-appearing tumor particularly in very young infants (most often newborns), which has microscopic similarities to Type I PPB. Cases referred to the Registry have been referred as Type I PPB. Nine have been seen by Registry pathologists. It is believed to be a non-malignant proliferation. (See Registry Publications Hill 2007 SPP IIMT abstract.)
Relationship of Type I PPB to Types II and III PPB: The PPB Registry believes that Type I, Type II, and Type III PPB are on a biologic continuum. The median ages at diagnosis of Types I, II, and III are 10, 34, and 44 months, respectively. First, most Type I PPB cases which recur do so as Type II or III disease. Second, numerous Registry and literature cases reveal that Type II and III PPB develop in children known to have pre-existing, unoperated lung cysts. The cysts have been discovered incidentally or following pneumothorax. The cysts have typically been discovered by 30 months of age. Type II or III PPB emerged between 24 and 60 months of age, although one Registry-reviewed case was observed in the cyst stage for 8 years before emergence of Type II PPB [search PubMed or Google Scholar for literature articles:Hasioutou M. et al. Acta Radiologica 2004;3:289-92; Dosios T et al. Periatr Surg Int 2004;20:863-5 (same cases)]. Based on the ultimate development of PPB in these children, we believe that the cysts observed earlier may have been undiagnosed Type I PPB. Type I PPB is the early cystic form of the disease and is not a benign cyst which undergoes “degeneration”. [Registry Publications Dehner 2005].
Type I PPB Radiology: