Pleuropulmonary blastoma (PPB) was defined in 1988 by Manivel and colleagues in a series describing 11
intrathoracic-pulmonary neoplasms in young children. The PPB is a unique peripheral pulmonary or
pleural-based tumor of childhood that is characterized in its earliest form as a bland-appearing
multiloculated cyst with small foci of tumor cells and in later forms as mixed and predominantly
primitive, overtly malignant neoplasms. Prior to the introduction of the PPB as a distinct entity, this
tumor had been reported in the earlier literature as pulmonary blastoma, sarcoma arising in mesenchymal
cystic hamartoma, embryonal sarcoma, malignant mesenchymoma, primary pulmonary rhabdomyosarcoma and
rhabdomyosarcoma arising in congenital adenomatoid malformation or bronchogenic cyst. Over the past 15
years, the PPB has come to be recognized in centers around the world and with the establishment of the
Pleuropulmonary Blastoma Registry by Jack Priest, M.D. and colleagues, there has been improved
understanding of this rare pediatric neoplasm. The registry website serves as an important resource for
physicians and families (http://www.ppbregistry.org).
This five month old female presented acutely with fever, tachypnea and labored respirations. She was
diagnosed with Influenza B and admitted to the hospital. Born at term with an uneventful neonatal
course, she had no significant illnesses prior to admission, although her mother stated that her
breathing had not been "normal" for some time. The family history was notable for maternal acute B-cell
leukemia in childhood. A chest X-ray on admission showed hyperaeration of the left lung. A CT scan was
performed and showed a markedly emphysematous left upper lobe with compressive atelectasis of the left
lower lobe and mediastinal shift. There were multiple, fine septations in the hyperinflated lobe with no
visible normal lung tissue. The radiographic differential diagnosis included congenital cystic pulmonary
airway malformation (formerly called congenital cystic adenomatoid malformation) and congenital lobar
emphysema. The patient recovered from her upper respiratory infection and returned approximately 3 weeks
later for resection of the abnormal left upper lobe. At surgery, the left upper lobe showed massive
overinflation with attenuation of the visceral pleura. The upper lobe was dissected off the lower lobe
with ligation of upper lobe branches of the pulmonary vascular structures and the left upper lobe
bronchus. No other cystic abnormalities involving the pleura, mediastinum or left lower lobe were noted.
Gross examination of the 11 x 7 x 1.3 cm left upper lobe showed a 6.5 cm diameter bulla in the apex.
Upon sectioning, multiple incomplete fibrous septae with mural thicknesses of 2 mm or less and collapsed
air-filled cysts ranging from 1.0 to 2.0 cm in diameter were noted. The uninvolved parenchyma showed
atelectasis and consolidation. Microscopic sections showed pleural-based cysts whose walls were variably
cellular and lined by a bland low-cuboidal type epithelium. Focal condensations of primitive stellate,
round and spindle-shaped cells were noted beneath the cyst lining cells imparting a cambium layer-like
appearance. The primitive cells showed nuclear hyperchromatism and high nuclear-to-cytoplasmic ratios
and were mitotically active. Loose fibrovascular tissue containing spindle-shaped cells resembling
fibroblasts predominated in the deeper portions of the septae. Small nodules of primitive cartilage were
also seen focally in the cyst walls. The multicystic lesion did not involve the margins of excision.
Following the pathologic diagnosis, further clinical evaluation included a full body CT scan and head MR
which showed no evidence of metastatic disease. However, a hypodense lesion in the lower pole of the
left kidney was discovered. A subsequent renal ultrasound was performed and the interpretation was a
simple renal cyst.
The patient was then followed with serial chest X-rays and CTs. At 4 months post-surgery a CT scan
identified 3 parenchymal cysts in the remaining left lung ranging from 0.24 to 0.62 cm in diameter, which
in retrospect were there 1 month post-surgery. Two cysts in the left kidney were also noted. At 6
months post-surgery CT scans showed 4 distinct cystic lesions in the left lung ranging from 0.27 to 2.1
cm in diameter, and two distinct cystic lesions in the right lung, each measuring 0.24 and 0.57 cm in
diameter. The left kidney contained three distinct cysts, each measuring 1.9 cm in maximum dimension. A
left partial nephrectomy and wedge resections of the left lower lobe lung cysts were performed.
Gross examination of the kidney showed a subcapsular multiloculated cyst measuring 1 cm in maximum
dimension. Microscopic examination of the kidney showed a multilocular cyst lined by bland, flattened
cuboidal epithelium. The cyst walls contained loosely arranged primitive mesenchymal cells with a
stellate configuration in a myxoid background. No cambium layer was seen. Within the parenchyma
adjacent to the cysts, rare abortive glomeruli and dilated, irregular tubules were seen similar to that
seen in embryologic renal dysplasia. No blastema or cartilage was present. The wedge biopsies of lung
showed subpleural, thin-walled multiloculated cysts, each measuring 1.2 and 1.5 cm in greatest dimension.
Microscopically the cysts had a similar architecture to the previous left upper lobe specimen. There
were subepithelial condensations of spindle cells showing rare mitotic activity. No cartilage was
present. Focally, the subepithelial spindle cells contained abundant pink cytoplasm suggestive of
rhabdomyoblastic differentiation. These cells were desmin positive.
Case 1 - Figure 1 - Lung, Left upper lobe. The resected left upper lobe shows a 6.5 cm diameter thin-walled bulla in the apex. Incomplete fibrous septae traverse the bulla (long arrow). Consolidated lung parenchyma is visible at one aspect (short arrow).
Case 1 - Figure 2 - Lung, Left upper lobe. Sections show the cystic structures are pleural-based (upper panel). The bulla consisted of collapsed cyst walls with variable cellularity (lower panel). (H&E, original magnification x100 (upper panel); x 200 (lower panel)).
Case 1 - Figure 3 - Lung, Left upper lobe. Sections of cyst walls show focal condensations of primitive stellate, round and spindle-shaped cells beneath the benign cyst lining. A small nodule of primitive cartilage is developing out of the mesenchymal cells (arrow). (H&E, original magnification x 400).
Case 1 - Figure 4 - Lung, Left upper lobe. More developed cartilage nodules are shown here. The cartilage appears to arise from the spindled mesenchymal cells beneath the epithelium in a pattern reminiscent of mesenchymal chondrosarcoma. (H&E, original magnification x 400).
Case 1 - Figure 5 - Left kidney. The renal lesion is composed of bland cyst walls lined by flattened cuboidal cells with primitive stellate cells in a loose, myxoid stroma within the cyst wall. No cambium layer, atypical cells, blastema or cartilage is seen. (H&E, original magnification x 200; inset x 400).
Case 1 - Figure 6 - Lung, Left lower lobe. Cysts from the left lower lobe showed similar features to the upper lobe with small nodules of primitive cells within the cyst walls. Mitotic activity was seen focally. (H&E, original magnification x200; inset x 400).
Case 1 - Figure 7 - Lung, Left lower lobe. Focally the primitive cells contained abundant pink cytoplasm consistent with rhabdomyoblasts. A desmin immunohistochemical stain confirms the skeletal muscle differentiation. (H&E upper panel and lower left, original magnification x 200 and x400; Anti-desmin immunostain lower right, original magnification x 200).
The patient was started on Vincristine, Actinomycin D, Cyclophosphamide alternating with Carboplatin,
Etoposide and Ifosfamide following her second surgery. She is currently well with no recurrence 9 months
after her original diagnosis. The right lung cysts are being followed radiographically.
Lung, left upper and lower lobes
- Pleuropulmonary blastoma, Type I, multifocal
Kidney, left, partial nephrectomy
- Cystic nephroma of childhood
One of the important pathologic features of the PPB is that this neoplasm manifests itself as one of
three morphologic subtypes which correlate with the age at diagnosis and outcome. These three subtypes
are characterized in the following manner:
Type I PPB is the least common type (25/156 cases or 16%) and
occurs on average in the youngest age group compared to the other types (median age 9 months; range 0 to
37 months). These patients may present with dyspnea, pneumothorax or compression of intrathoracic
structures, with or without mediastinal shift, by large hyperinflated cyst(s). Type I PPB is a
potentially deceptive lesion as it is composed of benign-appearing, peripherally-located, thin-walled
cyst(s) often submitted to the pathology laboratory as a "congenital lung cyst." There are no grossly
observable solid, nodular or plaque-like thickenings in this collapsed multicystic structure. The
neoplastic component of the Type I PPB is only apparent microscopically with the identification of
primitive tumor cells beneath a benign surface epithelium. This layer of subepithelial tumor cells may
be continuous and several cell layers thick (resembling the cambium layer of botryoid rhabdomyosarcoma).
This subepithelial layer contains cells with small, rounded or spindled hyperchromatic nuclei. Obvious
rhabdomyoblastic differentiation is present in some but not all cases. When it is present, elongated
strap cells with abundant eosinophilic cytoplasm or large rounded cells with similar appearing cytoplasm
are the same features as those in an embryonal rhabdomyosarcoma with differentiation. Skeletal muscle
differentiation can also be demonstrated by immunohistochemical stains for desmin, muscle-specific actin,
myogenin or Myo-D1 both in the cells with cytological attributes of rhabdomyoblasts as well as in
scattered primitive subepithelial cells. Some tumors also have nodules of immature cartilage in the cyst
walls. The present case illustrates one of the challenges in the diagnosing a Type I PPB with the
presence of widely scattered and subtle collections of primitive small cells in a subepithelial location
within an otherwise bland, hypocellular septal stroma. Extensive sampling of the cyst walls in these
cases is essential. These diminutive subepithelial buds of primitive small cells and/or nodules of
immature cartilage may or may not be accompanied by more compelling foci of dense subepithelial or septal
mixed round and spindle cell proliferation. The primitive small and/or spindle cells in these examples
may show immunoperoxidase staining for one or another of the muscle markers, however, the absence of
myogenic immunophenotype does not preclude the diagnosis of Type I PPB in our experience.
Type II PPB occurs in somewhat older children (median 31 months,
range 6 to 64) and represents 40% to 45% of all PPB. Like the Type I PPB, a cystic pattern is identified
either grossly or is represented by microscopic means consisting of remnants of septa in an otherwise
predominantly solid neoplasm. When cystic areas are noted in the gross examination, they are generally
characterized as being thickened or plaque-like areas composed of rhabdomyosarcomatous, spindle cell
sarcoma or blastematous elements. This complex microscopic appearance within septa which are not
obviously thickened or nodular in the gross examination is sufficient to categorize the tumor as a type
II PPB. It remains to be seen whether there is a prognostic difference between the microscopic and
macroscopic type II PPB since there is clearly a distinction in the tumor burden.
Type III PPB accounts for about 40% of cases occurs in children
with a median age of 42 months (range 1 to 147 months). These patients present with fever, cough, chest
and abdominal pain, dyspnea and weight loss. Radiographically, these tumors are homogenous or
heterogeneous solid masses with or without involvement of chest wall or mediastinal structures. The
entire hemi-thorax may be opacified by the mass. 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. Microscopically the Type
III PPB (and solid areas of the Type II PPB) shows one or more of four basic histologic patterns which
may blend into each other:  cohesive aggregates of primitive small cells with hyperchromatic nuclei,
high nuclear-to-cytoplasmic ratio and brisk mitoses resembling the blastema of a Wilms;  spindled,
stellate and small ovoid cells in a variably prominent myxoid stroma resembling rhabdomyosarcoma; 
spindle cell sarcoma with aspects of congenital-infantile fibrosarcoma;  nodules of immature or
overtly malignant cartilage. Individual or groupings of large anaplastic cells with highly atypical
mitotic figures are present in many cases. Eosinophilic hyaline bodies are often seen in association of
anaplastic cells. Within any one tumor, not all patterns are equally represented and one or two patterns
may dominate the overall microscopic appearance. Unlike the classic pulmonary blastoma, the PPB does not
have a malignant or even immature epithelial component.
Relationship between pathologic types
The pathologic categories of PPB appear to be related along a spectrum showing increased biologic
aggressiveness as the neoplasm progressively acquires solid features. It is also interesting to note
that the median ages of the three types show PPB type I occurring in the youngest group and type III
occurring in the oldest group with type II tumors in the intermediate group. The age differences between
the three types are statistically significant. The clinical progression of a type I to a type II or III
PPB has been well documented in those cases whose previously diagnosed "congenital lung cyst" or
"congenital cystic adenomatoid malformation" has been followed a year or two later by a type II or III
PPB. Wright has documented the progression of a type I PPB, originally interpreted as a cystic hamartoma
which recurred as a solid type III PPB. A related issue is the management of an otherwise asymptomatic
cystic lesion in the lung of an infant or young child in terms of the question that it may represent a
Immunohistochemistry and genetic analysis are generally unnecessary to establishing the diagnosis of
PPB in the majority of the cases. PPB commonly shows staining for desmin and myogenin in areas of
obvious rhabdomyosarcomatous differentiation. S100 protein is typically limited to the cartilaginous
nodules. When subepithelial foci of primitive cells are identified in a suspected type I PPB, these
cells are inconsistently immunoreactive for desmin and/or myogenin in the absence of apparent
rhabdomyoblasts. These primitive cells like the other septal stromal cells are positive for vimentin.
Cytokeratin highlights the flattened to cuboidal epithelial cells but is negative in the tumor cells.
Fluorescence in situ hybridization (FISH) can identify trisomy 8, a common
abnormality in PPBs. Trisomy 8 is not specific to the PPB since it has been observed in embryonal
rhabdomyosarcoma, granulocytic sarcoma, Ewing sarcoma and congenital-infantile fibrosarcoma. Trisomy 2,
and p53 mutations/deletions have also been described.
Because there is significant variability in the morphologic appearance of PPB, the differential
diagnosis is broad. For Type I PPBs, the distinction from a multilocular pulmonary cyst in the category
of congenital pulmonary airway malformations (CPAM) type 1 or 4 (formerly called congenital cystic
adenomatoid malformations) is critical to the appropriate management of the patient. Both CPAM and Type
I PPB occur in infants and young children and can either be discovered incidentally or present with
respiratory distress. In fact, we are advocates for the approach that all peripheral lung cysts with the
question of a Type 4 CPAM in infants and children less than 2 years old are type I PPB until proven
otherwise. Proving otherwise is best accomplished by submission of the entire gross specimen for
histologic examination. 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 1 PPB is appropriate. Ancillary studies to differentiate benign cysts
from Type I PPB are only helpful if they are positive, since the absence of muscle differentiation does
not preclude the pathologic diagnosis of Type I PPB. The utility of FISH in detecting the characteristic
trisomy 8 in Type I PPB with few neoplastic cells is uncertain.
Type I tumors should be distinguished from Type II tumors that have a solid component represented by
grossly observable thickened, nodular or plaque-like areas containing overtly 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.
In Type II and Type III PPB, there is no issue whether the pathology is benign or malignant.
Depending on the predominance of one or more sarcomatous or blastemal elements, the differential
diagnosis includes primary and metastatic rhabdomyosarcoma, malignant teratoma, synovial sarcoma and
other spindle cell or undifferentiated sarcomas. In solid tumors with a predominant blastemal pattern,
metastatic Wilms tumor could be considered and a good radiographic study or cytokeratin
immunohistochemistry (PPB is negative for cytokeratin) would be helpful in making this latter
Treatment and Outcome
Type II and Type III PPB can spread through direct extension into adjacent uninvolved lung, pleura,
diaphragm, chest wall and mediastinal structures or by hematogenous dissemination. The most common sites
for distant metastases are the brain (26/172, 15%), bone (10/172, 6%), liver (7/172, 4%) and less
commonly adrenal, eye, spinal cord, ovary and pancreas. Because of the predilection for brain
metastasis, a head MR is recommended as part of the staging evaluation. Cerebrospinal fluid and bone
marrow evaluation do not appear to be necessary.
Treatment for PPB is based on a combined, multimodality approach similar to other pediatric sarcoma
regimens. Additional details and dose regimens is given on the PPB Registry website (http://www.ppbregistry.org). For Type I PPB, complete surgical
excision is recommended, followed by adjuvant chemotherapy with Vincristine, Actinomycin D and
Cyclophosphamide (VAC). For Type II and Type III PPB, the recommendations are neo-adjuvant/adjuvant
chemotherapy with VAC alternating with Cisplatin and Doxorubicin and complete surgical excision. The
decision to give radiation therapy is individualized for each patient and treating institution.
Survival data show marked differences in outcome between Type I tumors and Type II/Type III tumors.
In the most recent analysis of overall survival including 16 Type I patients, 43 Type II patients and 31
Type III patients, approximately 84%, 51% and 44% survive respectively at 75 months following diagnosis
(unpublished data, PPB Registry). For Type I tumors, of 7 patients treated with surgery followed by
chemotherapy, all 7 are alive. Of 12 patients treated with surgery alone, 4 recurred. 3/4 recurrences
were as Type II or III tumors and all 3 of these patients died of disease. The one patient who
experienced recurrence as a Type I tumor was treated with repeat surgery and chemotherapy and has done
well. The high risk of recurrence and poor salvage rate of Type I PPB treated with resection alone has
prompted the recommendation of adjuvant chemotherapy in these patients.
Approximately 23% of patients with PPB have either constitutional or familial associations with other
neoplasms/hyperplasias and dysplasias. Multifocal PPB or cystic nephromas can occur within the same
patient and siblings and close relatives may also have PPB, cystic nephroma, nephroblastomatosis, Wilms
tumor, thyroid hyperplasia and neoplasia, sarcomas, medulloblastoma, germ cell tumor, Hodgkin disease,
leukemia, and Langerhans cell histiocytosis among others. Of these, cystic nephroma (the childhood
variant) may be the most common association being described in 8 families to date.
|PPB is divided into 3 clinicopathologic types that represent a continuum of histologic and biologic progression.|
|Type I PPB is a neoplasm whose diagnostic features can be subtle and may be exquisitely localized; extensive sampling of the cyst walls is critical.|
|Type II PPB can be distinguished from Type I PPB by the presence of grossly identifiable thickened plaque-like, nodular or solid areas containing rhabdomyosarcomatous, blastematous or spindle cell sarcomatous elements|
|Type II and III PPB have a predilection for metastasizing to brain, bone and liver.|
|PPB have a constitutional or familial basis in 23% of cases and can manifest as multifocal PPB or the association with other neoplasms, dysplasia and/or hyperplasias in patients or their close relatives; association with cystic nephroma is common.|
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