General information on PPB and the other DICER1-related tumors types is provided in each section. In addition, we wish to highlight a few critical topics which have been learned from children and families participating in the International PPB/DICER1 Registry.
Pleuropulmonary blastoma (PPB) is a distinctive, rare neoplasm of pleuropulmonary mesenchyme occurring in children. It is virtually always arises from the lungs or pleura. A series of 350 cases has been published by the International PPB/DICER1 Registry and is available upon request.
PPB is subdivided into four pathologic subtypes, determined by radiographic and pathologic appearance. Type I PPB is purely cystic with no grossly identifiable nodular disease. Type II PPB presents with grossly apparent cystic and solid disease. Type III PPB is entirely solid with no grossly detectable cystic areas though Type III PPB may have cyst-like spaces due to necrotic/degenerated tumor which under the microscope can be differentiated from the “true” cysts of Type I or II PPB. Type I can regress to Type Ir PPB (see below) but it can also progress to Type II or III. Regression of Types II and III PPB has not been observed.
The original reports of PPB included 3 main types, Type I, Type II and Type III PPB, each of which contain malignant cells. Since 2006, PPB Registry pathologists have recognized a fourth category called Type Ir (regressed or nonprogressed) PPB. This is a cystic lesion similar to Type I PPB. It has a micro-architecture similar to Type I with very delicate septa without malignant cells. There may be small spindle cells which are not primitive and foci of dystrophic calcification. It appears to be a lesion which has “regressed” from an earlier Type I or, alternatively, it is a genetically-determined lung cyst which did not evolve far enough along a dysplastic path as to become malignant. Type Ir may present with pneumothorax. It may exhibit large or small lung cysts and may be an incidental finding in an individual undergoing surveillance imaging for DICER1 variation. Type Ir has been detected at all ages from infancy to adulthood. The cysts of Type Ir are different from other lung cysts such as those in the congenital pulmonary airway malformation (CPAM) or congenital cystic adenomatoid malformation (CCAM) categories. Pathologists encountering unusual lung cysts are encouraged to contact the PPB/DICER1 Registry regarding free central pathology review by Registry pathologists.
Prognosis varies dramatically by subtype with overall 5-year survival rates of 89%, 71%, 53% and 100% for Types I, II, III and Ir PPB respectively. In addition, treatment is based on subtype. Type I PPB is generally treated with complete resection when feasible. Chemotherapy for Type I PPB may be required in specific circumstances. Surgery and intensive chemotherapy are required for all children with Type II or III PPB. Radiation may also be given in specific circumstances. Young children with Type Ir PPB may undergo surgery to determine the diagnosis however in Type Ir PPB, malignant cells are not present therefore chemotherapy is not generally given. In certain instances, individuals with Type Ir PPB may not require surgery or other treatment. Further information regarding treatment of Types I, II, III and Ir PPB is available from the Registry.
Since its inception in 1987, the Registry has collected detailed information on family history and from this learned that some children with PPB or their relatives have developed other kinds of tumors (see Registry Publications). In 2009, a linkage analysis by Dr. Ashley Hill showed germline loss of function in the DICER1 gene in 11 families with PPB. This critical finding brought the Registry one step closer to understanding the events underlying the familial manifestations of PPB and related tumors. Since that time, our understanding of this unique tumor predisposition continued to expand.
We have learned that most individuals with germline DICER1 pathogenic variation lead healthy lives, however thyroid nodules and lung cysts are common. In addition to PPB, DICER1-related tumors include renal tumors (most commonly cystic nephroma but also Wilms tumor and renal sarcoma), ovarian tumors (Sertoli-Leydig cell tumor, gynandroblastoma and sarcoma), certain eye and nasal tumors, rhabdomyosarcoma and other soft tissue neoplasms, thyroid cancer and certain brain tumors including intracranial sarcoma, pineoblastoma pituitary blastoma and others. Individuals with pathogenic DICER1 variation may also have thyroid nodules, macrocephaly or juvenile gastrointestinal polyps.
Importantly, preoperative assessment of the family history may provide clues to the diagnosis of these rare tumors, allowing the most appropriate surgical procedure to be undertaken. For example, a young child with a cystic lung lesion a family history of Sertoli-Leydig cell tumor suggests the preoperative diagnosis of PPB. The cystic lesion may represent PPB and care should be taken to avoid spillage of malignant cells.
PPB and other DICER1-related conditions are rare. International collaboration is the best way to improve outcomes for children and adults with these conditions. Meaningful data on these rare conditions can only be collected if we all work together. We encourage all treating physicians and families to consider participation in the Registry.
The Registry will work with families and physicians regarding Informed Consent, HIPAA consent, IRB processing and related issues as needed. Regardless of enrollment status, the Registry will work with families and physicians on any questions related to PPB and other DICER1-related cancers. Go here for contact information. Together we can find a cure!
Registry research suggest 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 8, 36 and 41 months respectively. Numerous Registry and literature reports 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.
PPB, especially Types II and III PPB, may have vascular involvement and tumor thrombus may be present. Pre-surgical ultrasound and echocardiogram is recommended to evaluate for this possibility in tumors near the mediastinum. (See References or contact the Registry for more information.)
The central nervous system is the second most common site of metastases in Types II and III PPB, occurring in up to 11% of children with Type II PPB and 54% of children with Type III PPB. These metastatic tumors be detected at diagnosis, during treatment or following conclusion of treatment. Most CNS metastases occur within the first 2 years following diagnosis but may occur up to 5 years later and may occur even when intrathoracic disease is under control. Some children with CNS metastases may be cured thus brain MRI imaging is recommended at diagnosis, during treatment and after conclusion of treatment. Please contact the Registry for more information including a proposed imaging schedule. Additionally, research to detect CNS metastases as early as possible is underway.
Radiographic findings of PPB are as follows:
CT scans may show a mass lesion or suggest lobar or larger consolidation. CTs may also show multiloculated cystic or cystic/solid changes. PPB often appears to involve the lung parenchyma and pleura, but the chest wall peripherally or the mediastinum centrally may be involved as well. Because of the underlying genetics of PPB, bilateral manifestations must be assiduously sought in radiographic studies. The rare possibility of vascular invasion and superior vena cava syndrome must also be considered; pulmonary vein invasion with extension into the left atrium has been reported (see above).
As above, preoperative assessment of the family history may provide clues to the diagnosis of these rare tumors, allowing the most appropriate surgical procedure to be undertaken. For example, a young child with a cystic lung lesion a family history of Sertoli-Leydig cell tumor (or thyroid nodules or other DICER1-related conditions) suggests the preoperative diagnosis of PPB. The cystic lesion may represent PPB and care should be taken to avoid spillage of malignant cells.
Pleural effusion is common and a diagnosis of empyema may be considered. Advanced PPB may involve pleura and/or lung parenchyma extensively, crossing lobar boundaries and causing mediastinal shift. The site of origin may be difficult to discern. Involvement of the entire hemithorax is common. PPB tissue is often friable, necrotic and hemorrhagic. In Type III PPB, spillage is common.
In addition to lung and pleura, PPB may invade the chest wall, mediastinum, diaphragm, superior vena cava and right atrium, or pulmonary vein and left atrium.
Tumor that has been removed for clinical reasons is of great utility in PPB research. If circumstances allow, enrollment in the Registry to allow sharing of clinical data and tumor tissue is strongly encouraged. We hope that by working together we can find more effective and less toxic treatments for these rare tumors.
Consultation for pathologists to review/confirm the diagnosis of PPB is provided by Registry pathologists at no charge. This process also fulfills the need for central path review if the child is enrolled in the Registry.
Type I lesions are exclusively cystic, thin-walled structures with no grossly notable solid tumor component. 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 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 eosinophilic 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 or septal 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.
Type I PPB most often arises in the peripheral lung, but examples of cystic changes appearing to originate in parietal pleura have been seen.
Type I tumors should be distinguished from subtle, “early” Type II tumors that have a solid component represented by thickened, nodular or plaque-like areas containing sarcomatous or blastematous elements. The importance of this distinction is based on worse prognosis; more aggressive chemotherapy may be needed.
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 characteristic Trisomy 8 in Type I tumors with few neoplastic cells is uncertain.
Type II PPB is a cystic and solid neoplasm. Like Type I PPB, a cystic pattern is identified grossly or, in an otherwise predominantly solid neoplasm, microscopically by remnants of septa. The cystic regions in Type II have the same characteristics as in Type I; the cysts are lined with ciliated columnar respiratory epithelium and may have a sub-epithelial condensation of tumor cells with a sarcoma botryoid-like appearance. When the specimen is predominantly cystic, Type II PPB is differentiated from Type I PPB by thickened or plaque-like areas composed of an overgrowth of rhabdomyosarcomatous, spindle cell sarcomatous, or blastematous elements. Even within septae that are not obviously thickened or nodular at gross examination, this complex microscopic appearance is sufficient to categorize a tumor as Type II PPB. It remains to be determined whether there is a prognostic difference between microscopic and macroscopic Type II PPB because there is clearly a distinction in the solid tumor burden.
The microscopic characteristics of the manifestly solid portions of Type II PPB are described below in the section on Type III PPB.
The site of origin of Type II PPB may be difficult to determine. Lesions may be clearly pleural (visceral or parietal) or may be clearly intraparenchymal. It is common for them to nearly fill the hemithorax. It is unusual for thoracic lymph nodes to be involved.
Type III PPB tumors are homogeneous or heterogeneous solid masses with or without involvement of chest wall or mediastinal structures. The entire hemithorax may be opacified. Grossly, a well-circumscribed, solid, mucoid, tan-white and friable mass with pleural attachments involving a lobe or entire lung is seen. Hemorrhage and necrosis account in part for the friability of the tumor. If the tumor has extended into the surrounding pleural space, the resection specimen may be submitted in a piecemeal fashion.
The site of origin of Types II and III PPB may be difficult to determine. They may be clearly pleural (visceral or parietal) or may be clearly intraparenchymal.
The solid areas of tumor in Type II and III PPB have mixed blastematous and sarcomatous features. One of the prominent patterns is comprised of cellular islands of small, primitive, blastematous cells with oval nuclei, granular chromatin, and inconspicuous nucleoli; these cells have little discernible cytoplasm and mitotic figures are numerous. The stroma in the blastematous foci often blends into spindle cell sarcomatous areas with the vague fascicular pattern of malignant fibrous histiocytoma or fibrosarcoma or the stroma may be sharply demarcated from the blastematous islands and have a less densely cellular appearance of short, oval-to-fusiform cells in a pale-staining background and have a resemblance to the stroma surrounding the blastema of a Wilms’ tumor.
Foci of skeletal muscle differentiation including polygonal or elongated rhabdomyoblasts, often with cross-striations, either as isolated cells or as groups of cells are found in most cases. This is similar to the rhabdomyoblastic differentiation found in Type I. If such cells are not obvious by routine histology, they are often found by immunohistochemistry. Cartilaginous differentiation, either in the form of chondroid matrix or well-formed islands of hyaline cartilage, is found in most, but not all, cases of Type II and Type III. Although the chondroid component is usually a minor one, it is occasionally prominent enough to suggest the possibility of chondrosarcoma. The nodules of cartilage, when present, have a enough cellularity and atypia to qualify as chondrosarcoma in most cases. In other cases, the cartilage has immature or fetal features.
Focal cellular anaplasia in the form of giant, bizarre-appearing pleomorphic cells with irregular hyperchromatic nuclei is present in most, but not all, cases of Type II and Type III. Anaplastic cells are not found in the blastematous or chondroid foci, but rather in the uncommitted mesenchymal foci or, less often, in the rhabdomyoblastic areas. Anaplasia is not typically seen in Type I.
Necrosis, occasionally producing apparent “cystic” change, is a prominent feature in the solid areas and is consistent with the common surgical finding of highly friable, necrotic or empyematous tissue. These “cystic” areas do not show the epithelial lining that defines the “true” cysts of Type I and Type II. Less frequently observed are areas of myxoid degeneration producing myxoid pools or areas with a pericytomatous or liposarcomatous pattern; these findings also should not be interpreted as “true” cysts.
Individual or groupings of large anaplastic cells with highly atypical mitotic figures are present in many Type II and most Type III cases. Eosinophilic hyaline bodies are often seen in association with anaplastic cells. The Registry is studying the prognostic significance of anaplasia, as judged by Wilms’ tumor criteria and other histologic features of PPB. Within any one tumor, not all patterns are equally represented and one or two patterns may dominate the overall microscopic appearance.
In some cases, needle core biopsies have been used to make a PPB diagnosis. Small biopsies do not always contain the heterogeneity of histologic appearances that is so characteristic of PPB.
Muscle specific actin and desmin are consistently positive in the obvious rhabdomyoblasts and also decorate to a lesser degree the small primitive cells in the cambium layer zones. Blastematous islands occasionally show weak staining for muscle specific actin. Vimentin stains the rhabdomyoblastic cells, cartilage, fibrosarcoma, or fibrous histiocytoma-like foci, and focally decorates blastematous islands. Weak neuron-specific enolase staining of blastematous areas is rarely seen. S-100 protein staining is confined to areas of conspicuous cartilaginous differentiation, and cytokeratin staining is limited to the epithelium of the cystic spaces or entrapped respiratory or mesothelial elements.
Electron microscopic examination supports the rhabdomyoblastic differentiation seen on histologic and immunohistochemical examination, with abortive Z-band formation and thick and thin filaments. Chondrocytic differentiation with a loose granular matrix and abundant rough endoplasmic reticulum can be seen. The majority of cells corresponding to the blastematous elements. Spindle cell areas shows little cytoplasm and few distinguishing features and are best described as primitive mesenchymal cells.
FNAC has been attempted in the diagnosis of PPB in a number of cases, but has not been uniformly successful. The composition of the PPB tumor mass may be extremely heterogeneous and many portions may be virtually necrotic. In addition, as noted above, pleural fluid surrounding a PPB is usually non-diagnostic. Due to these concerns, techniques other than needle biopsy/ cytology are preferred.
Metastatic disease demonstrates solid tumor patterns similar to that observed at the primary site. The histologic hallmark of Type I disease, cystic spaces with ciliated columnar respiratory epithelium with foci of underlying condensations of malignant cells, is not generally found in metastatic lesions. There is a tendency toward simplification of the histologic appearance, compared to the primary disease, with an abundance of either the rhabdomyoblastic or spindle cell elements. In a given patient, the microscopic appearances of different metastatic lesions are generally identical to each other.
Pathologists and treating physicians are asked to consider sending fresh tissue to the PPB/DICER1 Registry so that it can be used to improve our understanding of potential therapeutic targets.