🔗

Mappings

MONDO

MONDO:0011014 pleuropulmonary blastoma

MONDO is the primary disease anchor for the PPB disease-level entry.

NCIT

NCIT:C5669 Pleuropulmonary Blastoma

NCIT provides standard oncology disease grounding for PPB.

NCIT

NCIT:C5669 Pleuropulmonary Blastoma

NCIT provides standard oncology disease grounding for PPB.

◆

Subtypes

4

Type I pleuropulmonary blastoma MONDO:0020555 NCIT:C45626

NCIT NCIT:C45626

Purely cystic PPB with primitive small cells beneath a benign epithelial lining. Type I PPB presents in infancy, may mimic congenital cystic lung lesions, and carries the lowest mortality provided progression to type II/III is prevented.

NCIT: Type I Pleuropulmonary Blastoma (skos:exactMatch) NCIT:C45626

Show evidence (2 references)

PMID:36541021 SUPPORT Human Clinical

"Type I PPB is a purely cystic lesion that has a microscopic population of primitive small cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells."

Defines the type I histologic subtype and contrasts it with type Ir.

PMID:25209242 SUPPORT Human Clinical

"The median ages at diagnosis for type I, type II, and type III patients were 8, 35, and 41 months, respectively."

Supports infant-onset disease for type I PPB.

Type Ir pleuropulmonary blastoma NCIT:C211861

NCIT NCIT:C211861

Regressed or nonprogressed purely cystic PPB lacking primitive small cells. Type Ir remains part of the same PPB mechanism continuum and is modeled here as a histologic facet rather than a separate disease page.

NCIT: Type Ir Pleuropulmonary Blastoma (skos:exactMatch) NCIT:C211861

Show evidence (1 reference)

PMID:36541021 SUPPORT Human Clinical

"Type I PPB is a purely cystic lesion that has a microscopic population of primitive small cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells."

Defines the type Ir subtype as the primitive-cell-negative cystic lesion.

Type II pleuropulmonary blastoma MONDO:0020556 NCIT:C45627

NCIT NCIT:C45627

Mixed cystic and solid PPB with aggressive primitive sarcomatous overgrowth. Type II disease usually presents after infancy and has intermediate outcomes between type I/Ir and type III PPB.

NCIT: Type II Pleuropulmonary Blastoma (skos:exactMatch) NCIT:C45627

Show evidence (2 references)

PMID:25209242 SUPPORT Human Clinical

"Pleuropulmonary blastoma (PPB) has 3 subtypes on a tumor progression pathway ranging from type I (cystic) to type II (cystic/solid) and type III (completely solid)."

Defines type II as the cystic/solid histologic subtype within the PPB continuum.

PMID:25209242 SUPPORT Human Clinical

"The median ages at diagnosis for type I, type II, and type III patients were 8, 35, and 41 months, respectively."

Supports typical preschool-age presentation for type II PPB.

Type III pleuropulmonary blastoma MONDO:0020557 NCIT:C45628

NCIT NCIT:C45628

Completely solid PPB composed of high-grade primitive sarcoma. Type III has the latest median age at diagnosis and the worst survival among the canonical PPB histologic subtypes.

NCIT: Type III Pleuropulmonary Blastoma (skos:exactMatch) NCIT:C45628

Show evidence (2 references)

PMID:25209242 SUPPORT Human Clinical

"Pleuropulmonary blastoma (PPB) has 3 subtypes on a tumor progression pathway ranging from type I (cystic) to type II (cystic/solid) and type III (completely solid)."

Defines type III as the completely solid endpoint of the PPB continuum.

PMID:25209242 SUPPORT Human Clinical

"The median ages at diagnosis for type I, type II, and type III patients were 8, 35, and 41 months, respectively."

Supports the later age at diagnosis typical of type III PPB.

⚙

Pathophysiology

9

Germline DICER1 Predisposition

Heterozygous germline DICER1 loss-of-function variants create the inherited predisposition context for many PPB cases and place the disease within the DICER1 tumor predisposition syndrome spectrum.

DICER1 link

miRNA processing link ⚠ ABNORMAL

Downstream

Compound DICER1 Disruption Additional somatic DICER1 alteration creates lesion-level dysfunction.

Show evidence (2 references)

PMID:19556464 SUPPORT Human Clinical

"Here, we show that 11 multiplex PPB families harbor heterozygous germline mutations in DICER1, a gene encoding an endoribonuclease critical to the generation of small noncoding regulatory RNAs."

Establishes germline DICER1 mutation as the familial predisposition driver.

PMID:25209242 SUPPORT Human Clinical

"A germline mutation in DICER1 is the genetic cause in the majority of PPB cases."

Extends the DICER1 predisposition mechanism to the larger registry cohort.

Compound DICER1 Disruption

Progressive PPB typically combines a germline or somatic DICER1 loss-of-function allele with a somatic RNase IIIb hotspot mutation, fitting a specialized two-hit tumor suppressor model.

DICER1 link

miRNA processing link ⚠ ABNORMAL

Downstream

Aberrant 5p miRNA Processing RNase IIIb dysfunction impairs normal 5p miRNA maturation.

Show evidence (1 reference)

PMID:24909177 SUPPORT Human Clinical

"In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain."

Supports the characteristic two-hit DICER1 architecture in PPB.

Aberrant 5p miRNA Processing

DICER1-disrupted PPB retains abnormal 5p miRNA hairpin-loop sequence and reduces normal miRNA-mediated post-transcriptional repression.

miRNA processing link ⚠ ABNORMAL miRNA-mediated post-transcriptional gene silencing link ↓ DECREASED

Downstream

Epithelial FGF9 Overexpression Loss of epithelial miRNA control permits excess FGF9 signaling in early PPB.

Show evidence (1 reference)

PMID:24909177 SUPPORT Human Clinical

"5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1."

Provides direct molecular evidence that DICER1 disruption alters 5p miRNA processing.

Epithelial FGF9 Overexpression

Type I PPB shows excess epithelial FGF9 expression, linking epithelial DICER1-associated miRNA dysregulation to paracrine growth signaling.

epithelial cell of lung link

FGF9 link

fibroblast growth factor receptor signaling pathway link ↑ INCREASED

lung epithelium link

Downstream

Pulmonary Mesenchymal Hyperplasia Excess epithelial FGF9 stimulates neighboring mesenchymal expansion.

Show evidence (1 reference)

PMID:25978641 SUPPORT Human Clinical

"FGF9 is overexpressed in lung epithelium in the initial multicystic stage of Type I PPB"

Supports epithelial FGF9 overexpression in human type I PPB tissue.

Pulmonary Mesenchymal Hyperplasia

Increased epithelial FGF9 drives non-cell-autonomous expansion of pulmonary mesenchyme and builds the multicystic type I PPB architecture.

mesenchymal cell link

mesenchymal cell proliferation link ↑ INCREASED lung development link ⚠ ABNORMAL

lung mesenchyme link

Downstream

Multicystic Type I Lesion Mesenchymal hyperplasia remodels the developing lung into cystic PPB.

Show evidence (1 reference)

PMID:25978641 SUPPORT Model Organism

"increased Fgf9 expression results in pulmonary mesenchymal hyperplasia and a multicystic architecture that is histologically and molecularly indistinguishable from Type I PPB."

Provides causal model-organism evidence linking excess FGF9 to the type I PPB phenotype.

Multicystic Type I Lesion

The earliest PPB lesion is a delicate multilocular cyst with subepithelial primitive mesenchymal cells; some lesions regress to type Ir, whereas others progress toward solid sarcoma.

epithelial cell of lung link mesenchymal cell link

lung development link ⚠ ABNORMAL

lung link

Downstream

Sarcomatous Progression A subset of cystic lesions progresses to type II or III PPB.

Show evidence (1 reference)

PMID:18223332 SUPPORT Human Clinical

"Type I PPB is a delicate multilocular cyst with variable numbers of primitive mesenchymal cells beneath a benign epithelial surface."

Defines the characteristic microscopic architecture of the early cystic lesion.

TP53 Loss

Frequent biallelic TP53 loss is a recurrent cooperating event in progressive PPB and supports evolution toward high-grade solid sarcoma.

TP53 link

Downstream

Sarcomatous Progression TP53 loss accompanies the transition to aggressive type II/III disease.

Show evidence (1 reference)

PMID:24909177 SUPPORT Human Clinical

"In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain."

Supports TP53 loss as a frequent recurrent lesion in PPB.

RAS Pathway Activation

Somatic NRAS or BRAF mutations occur in a subset of PPB and add oncogenic signaling support to the progressive sarcoma phenotype.

NRAS link BRAF link

cell population proliferation link ↑ INCREASED

Downstream

Sarcomatous Progression RAS pathway mutations are additional contributors to progression from cysts to tumors.

Show evidence (1 reference)

PMID:24909177 SUPPORT Human Clinical

"In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain."

Supports occasional oncogenic NRAS/BRAF lesions as additional progression-associated hits.

Sarcomatous Progression

PPB can remain cystic or evolve into type II/III high-grade sarcoma with markedly worse outcomes and metastatic risk.

mesenchymal cell link

cell population proliferation link ↑ INCREASED

Show evidence (2 references)

PMID:24909177 SUPPORT Human Clinical

"Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma."

Defines the core cyst-to-sarcoma transition that drives PPB natural history.

PMID:25209242 SUPPORT Human Clinical

"The 5-year overall survival (OS) rate for type I/Ir patients was 91%; all deaths in this group were due to progression to type II or III."

Links progression from cystic PPB to the lethal high-grade phenotype.

✶

Histopathology

3

Type I Cystic Primitive Mesenchymal Lesion VERY_FREQUENT

Type I PPB is a multilocular cyst with primitive mesenchymal cells beneath a benign epithelial lining.

Show evidence (1 reference)

PMID:18223332 SUPPORT Human Clinical

"Type I PPB is a delicate multilocular cyst with variable numbers of primitive mesenchymal cells beneath a benign epithelial surface."

Defines the core microscopic lesion in type I PPB.

Rhabdomyoblastic and Cartilaginous Differentiation FREQUENT

Type I PPB commonly contains rhabdomyoblastic differentiation and cartilage nodules within the primitive mesenchymal component.

Show evidence (1 reference)

PMID:18223332 SUPPORT Human Clinical

"Rhabdomyoblasts and cartilage nodules are seen in 49% and 40% of cases, respectively."

Supports recurrent rhabdomyoblastic and cartilaginous differentiation in PPB.

Primitive Blastomatous-Sarcomatous Tissue VERY_FREQUENT

Progressive PPB contains primitive blastomatous and sarcomatous tissue that underlies the type II and type III solid components.

Show evidence (1 reference)

PMID:34345335 SUPPORT Human Clinical

"It is characterized histologically by a primitive, variably mixed blastomatous and sarcomatous tissue."

Supports the mixed primitive sarcomatous histology of progressive PPB.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

5

Respiratory 4

Cough Cough (HP:0012735)

Show evidence (1 reference)

PMID:37119756 SUPPORT Human Clinical

"Clinical expression of PPB is nonspecific and variable. It ranges from a dry cough to respiratory distress."

Supports cough as part of the PPB presenting phenotype spectrum.

Dyspnea Dyspnea (HP:0002094)

Show evidence (1 reference)

PMID:34345335 SUPPORT Human Clinical

"We report a case of 3 years old female admitted at our hospital with fever, non productive cough and dyspnea, who was diagnosed with type II PPB."

Provides direct clinical evidence for dyspnea at presentation.

Respiratory distress Respiratory distress (HP:0002098)

Show evidence (1 reference)

PMID:11002236 SUPPORT Human Clinical

"Respiratory distress was the most common clinical symptom."

Supports respiratory distress as the most common clinical symptom in this cohort.

Pneumothorax Pneumothorax (HP:0002107)

Show evidence (1 reference)

PMID:32175165 SUPPORT Human Clinical

"Herein, we present two cases of pleuropulmonary blastoma type 3 presenting with pneumothorax, a rare clinical presentation of pleuropulmonary blastoma, which was successfully treated with surgery."

Supports pneumothorax as a documented PPB presentation.

Other 1

Pulmonary cyst Pulmonary cyst (HP:0032445)

Show evidence (1 reference)

PMID:16410110 SUPPORT Human Clinical

"PPB must be included in the differential diagnosis of a fetus, neonate, or child with a cystic lung mass."

Supports cystic lung presentation as an important diagnostic phenotype.

🧬

Genetic Associations

4

DICER1 (Germline Loss-of-Function with Somatic RNase IIIb Second Hit)

Show evidence (2 references)

PMID:19556464 SUPPORT Human Clinical

"Here, we show that 11 multiplex PPB families harbor heterozygous germline mutations in DICER1, a gene encoding an endoribonuclease critical to the generation of small noncoding regulatory RNAs."

Supports germline DICER1 predisposition in familial PPB.

PMID:24909177 SUPPORT Human Clinical

"In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain."

Supports the characteristic somatic second-hit pattern in PPB.

TP53 (Frequent Somatic Biallelic Loss)

Show evidence (1 reference)

PMID:24909177 SUPPORT Human Clinical

"In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain."

Supports TP53 loss as a frequent recurrent genomic lesion in PPB.

NRAS (Occasional Somatic Activating Mutation)

Show evidence (1 reference)

PMID:24909177 SUPPORT Human Clinical

"In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain."

Supports recurrent but subset-restricted NRAS involvement in PPB.

BRAF (Occasional Somatic Activating Mutation)

Show evidence (1 reference)

PMID:24909177 SUPPORT Human Clinical

"In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain."

Supports occasional BRAF involvement in progressive PPB.

💊

Treatments

3

Complete Tumor Resection

Action: complete tumor resection Ontology label: Complete Resection NCIT:C175027

Complete surgical excision is a central therapeutic goal across PPB and is especially important for cystic type I disease to prevent progression.

Show evidence (2 references)

PMID:33826235 SUPPORT Human Clinical

"Complete tumor resection is a main prognostic factor and can be performed at diagnosis or after neoadjuvant treatment that includes chemotherapy and in some cases radiotherapy."

Supports complete resection as a major prognostic and therapeutic objective.

PMID:36541021 SUPPORT Human Clinical

"For young children with type I PPB, outcomes are favorable, but complete resection is indicated because of the risk for progression."

Supports complete excision even for favorable cystic disease.

Multi-Agent Chemotherapy

Action: chemotherapy MAXO:0000647

Agent: ifosfamide ↗ vincristine ↗ actinomycin D ↗ doxorubicin ↗

Multi-agent chemotherapy is a major component of PPB treatment, with IVADo favored for type II and type III disease in the registry era.

Show evidence (2 references)

PMID:36137255 SUPPORT Human Clinical

"Beginning in 2007, the IVADo regimen (ifosfamide, vincristine, actinomycin-D, and doxorubicin) was recommended as a potential treatment regimen for children with type II and type III PPB."

Supports IVADo as the registry-endorsed regimen for advanced PPB.

PMID:36137255 SUPPORT Human Clinical

"Adjusted analyses suggest improved overall survival for children treated with IVADo in comparison with historical controls with an estimated hazard ratio of 0.65 (95% CI, 0.39 to 1.08)."

Supports the clinical benefit of IVADo-based chemotherapy in type II/III PPB.

Radiation Therapy

Action: radiation therapy MAXO:0000014

Radiotherapy is used selectively as part of multimodality therapy for residual, unresectable, or advanced disease rather than as routine treatment for all PPB.

Show evidence (1 reference)

PMID:33826235 SUPPORT Human Clinical

"Complete tumor resection is a main prognostic factor and can be performed at diagnosis or after neoadjuvant treatment that includes chemotherapy and in some cases radiotherapy."

Supports selective use of radiotherapy within multimodality treatment.

{ }

Source YAML

click to show

name: Pleuropulmonary Blastoma
creation_date: '2026-04-12T00:00:00Z'
updated_date: '2026-04-12T00:00:00Z'
description: >-
  Pleuropulmonary blastoma (PPB) is a rare pediatric intrathoracic malignancy of
  lung or pleural mesenchyme that arises along a cystic-to-solid developmental
  continuum. The core disease program is DICER1-associated and is organized here
  as a single disease-level mechanism graph with histologic subtype facets rather
  than separate dismech pages for type I, type Ir, type II, and type III PPB.
categories:
- Pediatric Cancer
- Thoracic Cancer
- Sarcoma
- DICER1-Associated Neoplasm
parents:
- lung neoplasm
- sarcoma
disease_term:
  preferred_term: pleuropulmonary blastoma
  term:
    id: MONDO:0011014
    label: pleuropulmonary blastoma
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011014
      label: pleuropulmonary blastoma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: MONDO is the primary disease anchor for the PPB disease-level entry.
  ncit_mappings:
  - term:
      id: NCIT:C5669
      label: Pleuropulmonary Blastoma
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: NCIT provides standard oncology disease grounding for PPB.
has_subtypes:
- name: Type I
  display_name: Type I pleuropulmonary blastoma
  classification: histological
  subtype_term:
    preferred_term: Type I pleuropulmonary blastoma
    term:
      id: MONDO:0020555
      label: pleuropulmonary blastoma type 1
  mappings:
    ncit_mappings:
    - term:
        id: NCIT:C45626
        label: Type I Pleuropulmonary Blastoma
      mapping_predicate: skos:exactMatch
      mapping_source: NCIT
      mapping_justification: NCIT provides oncology-specific grounding for the cystic type I subtype.
  description: >-
    Purely cystic PPB with primitive small cells beneath a benign epithelial
    lining. Type I PPB presents in infancy, may mimic congenital cystic lung
    lesions, and carries the lowest mortality provided progression to type II/III
    is prevented.
  evidence:
  - reference: PMID:36541021
    reference_title: "Type I and Ir pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Type I PPB is a purely cystic lesion that has a microscopic population of
      primitive small cells with or without rhabdomyoblastic features and may
      progress to type II or III PPB, whereas type Ir lacks primitive small cells.
    explanation: >-
      Defines the type I histologic subtype and contrasts it with type Ir.
  - reference: PMID:25209242
    reference_title: "Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median ages at diagnosis for type I, type II, and type III patients
      were 8, 35, and 41 months, respectively.
    explanation: >-
      Supports infant-onset disease for type I PPB.
- name: Type Ir
  display_name: Type Ir pleuropulmonary blastoma
  classification: histological
  mappings:
    ncit_mappings:
    - term:
        id: NCIT:C211861
        label: Type Ir Pleuropulmonary Blastoma
      mapping_predicate: skos:exactMatch
      mapping_source: NCIT
      mapping_justification: NCIT provides the specific regressed subtype term not currently available in MONDO.
  description: >-
    Regressed or nonprogressed purely cystic PPB lacking primitive small cells.
    Type Ir remains part of the same PPB mechanism continuum and is modeled here
    as a histologic facet rather than a separate disease page.
  review_notes: >-
    Type Ir was kept within the parent PPB entry per cancer curation guidance;
    MONDO does not currently provide a distinct type Ir subclass, so NCIT carries
    the subtype grounding.
  evidence:
  - reference: PMID:36541021
    reference_title: "Type I and Ir pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Type I PPB is a purely cystic lesion that has a microscopic population of
      primitive small cells with or without rhabdomyoblastic features and may
      progress to type II or III PPB, whereas type Ir lacks primitive small cells.
    explanation: >-
      Defines the type Ir subtype as the primitive-cell-negative cystic lesion.
- name: Type II
  display_name: Type II pleuropulmonary blastoma
  classification: histological
  subtype_term:
    preferred_term: Type II pleuropulmonary blastoma
    term:
      id: MONDO:0020556
      label: pleuropulmonary blastoma type 2
  mappings:
    ncit_mappings:
    - term:
        id: NCIT:C45627
        label: Type II Pleuropulmonary Blastoma
      mapping_predicate: skos:exactMatch
      mapping_source: NCIT
      mapping_justification: NCIT provides oncology-specific grounding for type II PPB.
  description: >-
    Mixed cystic and solid PPB with aggressive primitive sarcomatous overgrowth.
    Type II disease usually presents after infancy and has intermediate outcomes
    between type I/Ir and type III PPB.
  evidence:
  - reference: PMID:25209242
    reference_title: "Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pleuropulmonary blastoma (PPB) has 3 subtypes on a tumor progression pathway
      ranging from type I (cystic) to type II (cystic/solid) and type III
      (completely solid).
    explanation: >-
      Defines type II as the cystic/solid histologic subtype within the PPB continuum.
  - reference: PMID:25209242
    reference_title: "Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median ages at diagnosis for type I, type II, and type III patients
      were 8, 35, and 41 months, respectively.
    explanation: >-
      Supports typical preschool-age presentation for type II PPB.
- name: Type III
  display_name: Type III pleuropulmonary blastoma
  classification: histological
  subtype_term:
    preferred_term: Type III pleuropulmonary blastoma
    term:
      id: MONDO:0020557
      label: pleuropulmonary blastoma type 3
  mappings:
    ncit_mappings:
    - term:
        id: NCIT:C45628
        label: Type III Pleuropulmonary Blastoma
      mapping_predicate: skos:exactMatch
      mapping_source: NCIT
      mapping_justification: NCIT provides oncology-specific grounding for type III PPB.
  description: >-
    Completely solid PPB composed of high-grade primitive sarcoma. Type III has
    the latest median age at diagnosis and the worst survival among the canonical
    PPB histologic subtypes.
  evidence:
  - reference: PMID:25209242
    reference_title: "Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pleuropulmonary blastoma (PPB) has 3 subtypes on a tumor progression pathway
      ranging from type I (cystic) to type II (cystic/solid) and type III
      (completely solid).
    explanation: >-
      Defines type III as the completely solid endpoint of the PPB continuum.
  - reference: PMID:25209242
    reference_title: "Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median ages at diagnosis for type I, type II, and type III patients
      were 8, 35, and 41 months, respectively.
    explanation: >-
      Supports the later age at diagnosis typical of type III PPB.
prevalence:
- population: Pediatric cancers
  percentage: 0.3
  notes: PPB is rare, representing approximately 0.3% of pediatric cancers.
  evidence:
  - reference: PMID:37119756
    reference_title: "Type II pleuropulmonary blastoma mistaken for rhabdomyosarcoma: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pleuropulmonary blastoma (PPB) is rare, representing 0.3 % of all pediatric cancers.
    explanation: >-
      Provides a disease-level rarity estimate for PPB among pediatric cancers.
progression:
- phase: Histologic continuum
  notes: >-
    PPB is modeled as a single disease program with histologic subtype facets that
    track its cystic-to-solid progression continuum.
  evidence:
  - reference: PMID:25209242
    reference_title: "Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pleuropulmonary blastoma (PPB) has 3 subtypes on a tumor progression pathway
      ranging from type I (cystic) to type II (cystic/solid) and type III
      (completely solid).
    explanation: >-
      Supports representing PPB as a developmental continuum rather than separate diseases.
- phase: Type I diagnosis
  subtype: Type I
  age_range: median 8 months
  evidence:
  - reference: PMID:25209242
    reference_title: "Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median ages at diagnosis for type I, type II, and type III patients
      were 8, 35, and 41 months, respectively.
    explanation: >-
      Documents the age distribution for type I PPB.
- phase: Type II diagnosis
  subtype: Type II
  age_range: median 35 months
  evidence:
  - reference: PMID:25209242
    reference_title: "Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median ages at diagnosis for type I, type II, and type III patients
      were 8, 35, and 41 months, respectively.
    explanation: >-
      Documents the age distribution for type II PPB.
- phase: Type III diagnosis
  subtype: Type III
  age_range: median 41 months
  evidence:
  - reference: PMID:25209242
    reference_title: "Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median ages at diagnosis for type I, type II, and type III patients
      were 8, 35, and 41 months, respectively.
    explanation: >-
      Documents the age distribution for type III PPB.
- phase: Type I/Ir progression risk
  subtype: Type I
  notes: >-
    Even cystic PPB requires complete excision and surveillance because a subset
    progresses to type II or III disease.
  evidence:
  - reference: PMID:36541021
    reference_title: "Type I and Ir pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For young children with type I PPB, outcomes are favorable, but complete
      resection is indicated because of the risk for progression.
    explanation: >-
      Supports persistent progression risk in cystic PPB despite generally favorable outcomes.
pathophysiology:
- name: Germline DICER1 Predisposition
  description: >-
    Heterozygous germline DICER1 loss-of-function variants create the inherited
    predisposition context for many PPB cases and place the disease within the
    DICER1 tumor predisposition syndrome spectrum.
  genes:
  - preferred_term: DICER1
    term:
      id: hgnc:17098
      label: DICER1
  biological_processes:
  - preferred_term: miRNA processing
    modifier: ABNORMAL
    term:
      id: GO:0035196
      label: miRNA processing
  evidence:
  - reference: PMID:19556464
    reference_title: DICER1 mutations in familial pleuropulmonary blastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we show that 11 multiplex PPB families harbor heterozygous germline
      mutations in DICER1, a gene encoding an endoribonuclease critical to the
      generation of small noncoding regulatory RNAs.
    explanation: >-
      Establishes germline DICER1 mutation as the familial predisposition driver.
  - reference: PMID:25209242
    reference_title: "Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A germline mutation in DICER1 is the genetic cause in the majority of PPB cases.
    explanation: >-
      Extends the DICER1 predisposition mechanism to the larger registry cohort.
  downstream:
  - target: Compound DICER1 Disruption
    description: Additional somatic DICER1 alteration creates lesion-level dysfunction.
- name: Compound DICER1 Disruption
  description: >-
    Progressive PPB typically combines a germline or somatic DICER1 loss-of-function
    allele with a somatic RNase IIIb hotspot mutation, fitting a specialized
    two-hit tumor suppressor model.
  genes:
  - preferred_term: DICER1
    term:
      id: hgnc:17098
      label: DICER1
  biological_processes:
  - preferred_term: miRNA processing
    modifier: ABNORMAL
    term:
      id: GO:0035196
      label: miRNA processing
  evidence:
  - reference: PMID:24909177
    reference_title: Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF
      in some cases, each case had compound disruption of DICER1: a germline (12
      cases) or somatic (3 cases) loss-of-function variant plus a somatic missense
      mutation in the RNase IIIb domain.
    explanation: >-
      Supports the characteristic two-hit DICER1 architecture in PPB.
  downstream:
  - target: Aberrant 5p miRNA Processing
    description: RNase IIIb dysfunction impairs normal 5p miRNA maturation.
- name: Aberrant 5p miRNA Processing
  description: >-
    DICER1-disrupted PPB retains abnormal 5p miRNA hairpin-loop sequence and
    reduces normal miRNA-mediated post-transcriptional repression.
  biological_processes:
  - preferred_term: miRNA processing
    modifier: ABNORMAL
    term:
      id: GO:0035196
      label: miRNA processing
  - preferred_term: miRNA-mediated post-transcriptional gene silencing
    modifier: DECREASED
    term:
      id: GO:0035195
      label: miRNA-mediated post-transcriptional gene silencing
  evidence:
  - reference: PMID:24909177
    reference_title: Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA
      loop sequences normally removed by DICER1.
    explanation: >-
      Provides direct molecular evidence that DICER1 disruption alters 5p miRNA processing.
  downstream:
  - target: Epithelial FGF9 Overexpression
    description: Loss of epithelial miRNA control permits excess FGF9 signaling in early PPB.
- name: Epithelial FGF9 Overexpression
  description: >-
    Type I PPB shows excess epithelial FGF9 expression, linking epithelial DICER1-associated
    miRNA dysregulation to paracrine growth signaling.
  genes:
  - preferred_term: FGF9
    term:
      id: hgnc:3687
      label: FGF9
  cell_types:
  - preferred_term: epithelial cell of lung
    term:
      id: CL:0000082
      label: epithelial cell of lung
  locations:
  - preferred_term: lung epithelium
    term:
      id: UBERON:0000115
      label: lung epithelium
  biological_processes:
  - preferred_term: fibroblast growth factor receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0008543
      label: fibroblast growth factor receptor signaling pathway
  evidence:
  - reference: PMID:25978641
    reference_title: Fibroblast Growth Factor 9 Regulation by MicroRNAs Controls Lung Development and Links DICER1 Loss to the Pathogenesis of Pleuropulmonary Blastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FGF9 is overexpressed in lung epithelium in the initial multicystic stage
      of Type I PPB
    explanation: >-
      Supports epithelial FGF9 overexpression in human type I PPB tissue.
  downstream:
  - target: Pulmonary Mesenchymal Hyperplasia
    description: Excess epithelial FGF9 stimulates neighboring mesenchymal expansion.
- name: Pulmonary Mesenchymal Hyperplasia
  description: >-
    Increased epithelial FGF9 drives non-cell-autonomous expansion of pulmonary
    mesenchyme and builds the multicystic type I PPB architecture.
  cell_types:
  - preferred_term: mesenchymal cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  locations:
  - preferred_term: lung mesenchyme
    term:
      id: UBERON:0004883
      label: lung mesenchyme
  biological_processes:
  - preferred_term: mesenchymal cell proliferation
    modifier: INCREASED
    term:
      id: GO:0010463
      label: mesenchymal cell proliferation
  - preferred_term: lung development
    modifier: ABNORMAL
    term:
      id: GO:0030324
      label: lung development
  evidence:
  - reference: PMID:25978641
    reference_title: Fibroblast Growth Factor 9 Regulation by MicroRNAs Controls Lung Development and Links DICER1 Loss to the Pathogenesis of Pleuropulmonary Blastoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      increased Fgf9 expression results in pulmonary mesenchymal hyperplasia and
      a multicystic architecture that is histologically and molecularly
      indistinguishable from Type I PPB.
    explanation: >-
      Provides causal model-organism evidence linking excess FGF9 to the type I PPB phenotype.
  downstream:
  - target: Multicystic Type I Lesion
    description: Mesenchymal hyperplasia remodels the developing lung into cystic PPB.
- name: Multicystic Type I Lesion
  description: >-
    The earliest PPB lesion is a delicate multilocular cyst with subepithelial
    primitive mesenchymal cells; some lesions regress to type Ir, whereas others
    progress toward solid sarcoma.
  cell_types:
  - preferred_term: epithelial cell of lung
    term:
      id: CL:0000082
      label: epithelial cell of lung
  - preferred_term: mesenchymal cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: lung development
    modifier: ABNORMAL
    term:
      id: GO:0030324
      label: lung development
  evidence:
  - reference: PMID:18223332
    reference_title: "Type I pleuropulmonary blastoma: pathology and biology study of 51 cases from the international pleuropulmonary blastoma registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Type I PPB is a delicate multilocular cyst with variable numbers of primitive
      mesenchymal cells beneath a benign epithelial surface.
    explanation: >-
      Defines the characteristic microscopic architecture of the early cystic lesion.
  downstream:
  - target: Sarcomatous Progression
    description: A subset of cystic lesions progresses to type II or III PPB.
- name: TP53 Loss
  description: >-
    Frequent biallelic TP53 loss is a recurrent cooperating event in progressive
    PPB and supports evolution toward high-grade solid sarcoma.
  genes:
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  evidence:
  - reference: PMID:24909177
    reference_title: Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF
      in some cases, each case had compound disruption of DICER1: a germline (12
      cases) or somatic (3 cases) loss-of-function variant plus a somatic missense
      mutation in the RNase IIIb domain.
    explanation: >-
      Supports TP53 loss as a frequent recurrent lesion in PPB.
  downstream:
  - target: Sarcomatous Progression
    description: TP53 loss accompanies the transition to aggressive type II/III disease.
- name: RAS Pathway Activation
  description: >-
    Somatic NRAS or BRAF mutations occur in a subset of PPB and add oncogenic
    signaling support to the progressive sarcoma phenotype.
  genes:
  - preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  - preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:24909177
    reference_title: Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF
      in some cases, each case had compound disruption of DICER1: a germline (12
      cases) or somatic (3 cases) loss-of-function variant plus a somatic missense
      mutation in the RNase IIIb domain.
    explanation: >-
      Supports occasional oncogenic NRAS/BRAF lesions as additional progression-associated hits.
  downstream:
  - target: Sarcomatous Progression
    description: RAS pathway mutations are additional contributors to progression from cysts to tumors.
- name: Sarcomatous Progression
  description: >-
    PPB can remain cystic or evolve into type II/III high-grade sarcoma with
    markedly worse outcomes and metastatic risk.
  cell_types:
  - preferred_term: mesenchymal cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:24909177
    reference_title: Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal
      cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma.
    explanation: >-
      Defines the core cyst-to-sarcoma transition that drives PPB natural history.
  - reference: PMID:25209242
    reference_title: "Pleuropulmonary blastoma: a report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 5-year overall survival (OS) rate for type I/Ir patients was 91%; all
      deaths in this group were due to progression to type II or III.
    explanation: >-
      Links progression from cystic PPB to the lethal high-grade phenotype.
histopathology:
- name: Type I Cystic Primitive Mesenchymal Lesion
  finding_term:
    preferred_term: Primitive Mesenchymal Stroma Formation
    term:
      id: NCIT:C155651
      label: Primitive Mesenchymal Stroma Formation
  frequency: VERY_FREQUENT
  description: >-
    Type I PPB is a multilocular cyst with primitive mesenchymal cells beneath a
    benign epithelial lining.
  evidence:
  - reference: PMID:18223332
    reference_title: "Type I pleuropulmonary blastoma: pathology and biology study of 51 cases from the international pleuropulmonary blastoma registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Type I PPB is a delicate multilocular cyst with variable numbers of primitive
      mesenchymal cells beneath a benign epithelial surface.
    explanation: >-
      Defines the core microscopic lesion in type I PPB.
- name: Rhabdomyoblastic and Cartilaginous Differentiation
  finding_term:
    preferred_term: Rhabdomyosarcomatous Differentiation
    term:
      id: NCIT:C35937
      label: Rhabdomyosarcomatous Differentiation
  frequency: FREQUENT
  description: >-
    Type I PPB commonly contains rhabdomyoblastic differentiation and cartilage
    nodules within the primitive mesenchymal component.
  evidence:
  - reference: PMID:18223332
    reference_title: "Type I pleuropulmonary blastoma: pathology and biology study of 51 cases from the international pleuropulmonary blastoma registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rhabdomyoblasts and cartilage nodules are seen in 49% and 40% of cases, respectively.
    explanation: >-
      Supports recurrent rhabdomyoblastic and cartilaginous differentiation in PPB.
- name: Primitive Blastomatous-Sarcomatous Tissue
  finding_term:
    preferred_term: Sarcoma
    term:
      id: NCIT:C9118
      label: Sarcoma
  frequency: VERY_FREQUENT
  description: >-
    Progressive PPB contains primitive blastomatous and sarcomatous tissue that
    underlies the type II and type III solid components.
  evidence:
  - reference: PMID:34345335
    reference_title: "Type II pleuropulmonary blastoma in a 3-years-old female with dyspnea: a case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized histologically by a primitive, variably mixed
      blastomatous and sarcomatous tissue.
    explanation: >-
      Supports the mixed primitive sarcomatous histology of progressive PPB.
phenotypes:
- category: Respiratory
  name: Pulmonary cyst
  subtype: Type I
  diagnostic: true
  description: >-
    Type I PPB often presents as a cystic lung mass that overlaps clinically with
    congenital cystic lung lesions.
  phenotype_term:
    preferred_term: cystic lung lesion
    term:
      id: HP:0032445
      label: Pulmonary cyst
  evidence:
  - reference: PMID:16410110
    reference_title: Prenatal presentation and outcome of children with pleuropulmonary blastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PPB must be included in the differential diagnosis of a fetus, neonate, or
      child with a cystic lung mass.
    explanation: >-
      Supports cystic lung presentation as an important diagnostic phenotype.
- category: Respiratory
  name: Cough
  subtype: Type II
  description: >-
    PPB can present with dry or nonproductive cough as part of a nonspecific
    respiratory symptom complex.
  phenotype_term:
    preferred_term: cough
    term:
      id: HP:0012735
      label: Cough
  evidence:
  - reference: PMID:37119756
    reference_title: "Type II pleuropulmonary blastoma mistaken for rhabdomyosarcoma: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical expression of PPB is nonspecific and variable. It ranges from a
      dry cough to respiratory distress.
    explanation: >-
      Supports cough as part of the PPB presenting phenotype spectrum.
- category: Respiratory
  name: Dyspnea
  subtype: Type II
  description: >-
    Dyspnea reflects intrathoracic mass effect from mixed cystic-solid PPB.
  phenotype_term:
    preferred_term: dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:34345335
    reference_title: "Type II pleuropulmonary blastoma in a 3-years-old female with dyspnea: a case report and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a case of 3 years old female admitted at our hospital with fever,
      non productive cough and dyspnea, who was diagnosed with type II PPB.
    explanation: >-
      Provides direct clinical evidence for dyspnea at presentation.
- category: Respiratory
  name: Respiratory distress
  subtype: Type II
  description: >-
    Respiratory distress is a common presenting manifestation, especially with
    larger type II/III intrathoracic tumors.
  phenotype_term:
    preferred_term: respiratory distress
    term:
      id: HP:0002098
      label: Respiratory distress
  evidence:
  - reference: PMID:11002236
    reference_title: "Pleuropulmonary blastoma: management and prognosis of 11 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Respiratory distress was the most common clinical symptom.
    explanation: >-
      Supports respiratory distress as the most common clinical symptom in this cohort.
- category: Respiratory
  name: Pneumothorax
  subtype: Type III
  description: >-
    Pneumothorax is an uncommon but characteristic presentation of advanced PPB,
    especially when cystic or necrotic tumor ruptures into the pleural space.
  phenotype_term:
    preferred_term: pneumothorax
    term:
      id: HP:0002107
      label: Pneumothorax
  evidence:
  - reference: PMID:32175165
    reference_title: "Pleuropulmonary blastoma: A report of two cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we present two cases of pleuropulmonary blastoma type 3 presenting
      with pneumothorax, a rare clinical presentation of pleuropulmonary blastoma,
      which was successfully treated with surgery.
    explanation: >-
      Supports pneumothorax as a documented PPB presentation.
genetic:
- name: DICER1
  gene_term:
    preferred_term: DICER1
    term:
      id: hgnc:17098
      label: DICER1
  association: Germline Loss-of-Function with Somatic RNase IIIb Second Hit
  notes: >-
    DICER1 is the central predisposition and tumorigenic gene in PPB. Many cases
    arise in the setting of germline loss-of-function variation, whereas progressive
    tumors acquire a lesion-specific RNase IIIb missense mutation.
  evidence:
  - reference: PMID:19556464
    reference_title: DICER1 mutations in familial pleuropulmonary blastoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we show that 11 multiplex PPB families harbor heterozygous germline
      mutations in DICER1, a gene encoding an endoribonuclease critical to the
      generation of small noncoding regulatory RNAs.
    explanation: >-
      Supports germline DICER1 predisposition in familial PPB.
  - reference: PMID:24909177
    reference_title: Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF
      in some cases, each case had compound disruption of DICER1: a germline (12
      cases) or somatic (3 cases) loss-of-function variant plus a somatic missense
      mutation in the RNase IIIb domain.
    explanation: >-
      Supports the characteristic somatic second-hit pattern in PPB.
- name: TP53
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  association: Frequent Somatic Biallelic Loss
  notes: >-
    TP53 loss is a common cooperating lesion in progressive PPB and is linked to
    the aggressive type II/III sarcoma phenotype.
  evidence:
  - reference: PMID:24909177
    reference_title: Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF
      in some cases, each case had compound disruption of DICER1: a germline (12
      cases) or somatic (3 cases) loss-of-function variant plus a somatic missense
      mutation in the RNase IIIb domain.
    explanation: >-
      Supports TP53 loss as a frequent recurrent genomic lesion in PPB.
- name: NRAS
  gene_term:
    preferred_term: NRAS
    term:
      id: hgnc:7989
      label: NRAS
  association: Occasional Somatic Activating Mutation
  notes: >-
    NRAS mutation is an uncommon progression-associated lesion that implicates
    added Ras pathway activation in a subset of PPB.
  evidence:
  - reference: PMID:24909177
    reference_title: Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF
      in some cases, each case had compound disruption of DICER1: a germline (12
      cases) or somatic (3 cases) loss-of-function variant plus a somatic missense
      mutation in the RNase IIIb domain.
    explanation: >-
      Supports recurrent but subset-restricted NRAS involvement in PPB.
- name: BRAF
  gene_term:
    preferred_term: BRAF
    term:
      id: hgnc:1097
      label: BRAF
  association: Occasional Somatic Activating Mutation
  notes: >-
    BRAF mutation is an uncommon additional Ras pathway lesion in PPB and should
    be interpreted as a progression-associated cooperating event rather than the
    primary disease-defining driver.
  evidence:
  - reference: PMID:24909177
    reference_title: Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF
      in some cases, each case had compound disruption of DICER1: a germline (12
      cases) or somatic (3 cases) loss-of-function variant plus a somatic missense
      mutation in the RNase IIIb domain.
    explanation: >-
      Supports occasional BRAF involvement in progressive PPB.
treatments:
- name: Complete Tumor Resection
  description: >-
    Complete surgical excision is a central therapeutic goal across PPB and is
    especially important for cystic type I disease to prevent progression.
  treatment_term:
    preferred_term: complete tumor resection
    term:
      id: NCIT:C175027
      label: Complete Resection
  evidence:
  - reference: PMID:33826235
    reference_title: "Pleuropulmonary blastoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete tumor resection is a main prognostic factor and can be performed at
      diagnosis or after neoadjuvant treatment that includes chemotherapy and in
      some cases radiotherapy.
    explanation: >-
      Supports complete resection as a major prognostic and therapeutic objective.
  - reference: PMID:36541021
    reference_title: "Type I and Ir pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For young children with type I PPB, outcomes are favorable, but complete
      resection is indicated because of the risk for progression.
    explanation: >-
      Supports complete excision even for favorable cystic disease.
- name: Multi-Agent Chemotherapy
  description: >-
    Multi-agent chemotherapy is a major component of PPB treatment, with IVADo
    favored for type II and type III disease in the registry era.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
    therapeutic_agent:
    - preferred_term: ifosfamide
      term:
        id: CHEBI:5864
        label: ifosfamide
    - preferred_term: vincristine
      term:
        id: CHEBI:28445
        label: vincristine
    - preferred_term: actinomycin D
      term:
        id: CHEBI:27666
        label: actinomycin D
    - preferred_term: doxorubicin
      term:
        id: CHEBI:28748
        label: doxorubicin
  evidence:
  - reference: PMID:36137255
    reference_title: "Outcomes for Children With Type II and Type III Pleuropulmonary Blastoma Following Chemotherapy: A Report From the International PPB/DICER1 Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Beginning in 2007, the IVADo regimen (ifosfamide, vincristine, actinomycin-D,
      and doxorubicin) was recommended as a potential treatment regimen for children
      with type II and type III PPB.
    explanation: >-
      Supports IVADo as the registry-endorsed regimen for advanced PPB.
  - reference: PMID:36137255
    reference_title: "Outcomes for Children With Type II and Type III Pleuropulmonary Blastoma Following Chemotherapy: A Report From the International PPB/DICER1 Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adjusted analyses suggest improved overall survival for children treated with
      IVADo in comparison with historical controls with an estimated hazard ratio
      of 0.65 (95% CI, 0.39 to 1.08).
    explanation: >-
      Supports the clinical benefit of IVADo-based chemotherapy in type II/III PPB.
- name: Radiation Therapy
  description: >-
    Radiotherapy is used selectively as part of multimodality therapy for residual,
    unresectable, or advanced disease rather than as routine treatment for all PPB.
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: MAXO:0000014
      label: radiation therapy
  evidence:
  - reference: PMID:33826235
    reference_title: "Pleuropulmonary blastoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete tumor resection is a main prognostic factor and can be performed at
      diagnosis or after neoadjuvant treatment that includes chemotherapy and in
      some cases radiotherapy.
    explanation: >-
      Supports selective use of radiotherapy within multimodality treatment.

📚

References & Deep Research

Deep Research

1

Pleuropulmonary Blastoma Deep Research Notes ▸

Pleuropulmonary Blastoma Deep Research Notes

Date: 2026-04-12 Curator: Codex manual synthesis

Scope

Disease: Pleuropulmonary blastoma (PPB)

Primary disease anchor: - MONDO:0011014 pleuropulmonary blastoma

Cancer-modeling choices applied from dismech issue #1198: - The dismech page is the disease-level mechanism graph for PPB, not a page per ontology child. - disease_term stays MONDO-first. - NCIT is added at disease mapping level and subtype mapping level for oncology grounding. - Type I, Type Ir, Type II, and Type III are modeled as flat histological subtype facets inside one PPB entry. - Type Ir is not split into its own disease file; it shares the same causal program and is represented as a subtype facet with NCIT grounding. - No subtype is intended to imply a separate local page or "Not Yet Curated" debt. - NCIT was preferred over MAXO only where it provided materially better oncology specificity, such as disease/subtype mapping and complete resection. - MAXO remained appropriate for generic chemotherapy and radiation actions because NCIT did not provide an exact IVADo regimen term.

Core Disease Summary

PPB is a rare pediatric intrathoracic mesenchymal malignancy that progresses along a cystic-to-solid continuum.

Key disease-defining points: - Registry-scale natural history: PMID:25209242 - "Pleuropulmonary blastoma (PPB) has 3 subtypes on a tumor progression pathway ranging from type I (cystic) to type II (cystic/solid) and type III (completely solid)." - "A germline mutation in DICER1 is the genetic cause in the majority of PPB cases." - Familial predisposition discovery: PMID:19556464 - "Here, we show that 11 multiplex PPB families harbor heterozygous germline mutations in DICER1..." - Progressive tumor genomics: PMID:24909177 - PPB cysts can "progress to high-grade sarcoma." - Tumors show compound DICER1 disruption plus frequent TP53 loss and occasional NRAS/BRAF mutation.

Subtype Axis

Histologic subtype facet retained inside the single PPB entry: - Type I - Purely cystic lesion with primitive small cells. - MONDO:0020555 - NCIT:C45626 - Type Ir - Purely cystic lesion lacking primitive small cells. - No MONDO subtype located during curation. - NCIT:C211861 - Type II - Mixed cystic and solid PPB. - MONDO:0020556 - NCIT:C45627 - Type III - Purely solid PPB. - MONDO:0020557 - NCIT:C45628

Supporting subtype evidence: - PMID:36541021 - "Type I PPB is a purely cystic lesion that has a microscopic population of primitive small cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells." - PMID:25209242 - "Thirty-three percent of the 350 PPB cases were type I or type I regressed (type Ir), 35% were type II, and 32% were type III or type II/III." - "The median ages at diagnosis for type I, type II, and type III patients were 8, 35, and 41 months, respectively."

Pathology and Natural History

Type I pathology: - PMID:18223332 - "Type I PPB is a delicate multilocular cyst with variable numbers of primitive mesenchymal cells beneath a benign epithelial surface." - "Rhabdomyoblasts and cartilage nodules are seen in 49% and 40% of cases, respectively." - "recognition of this lesion as a neoplasm with malignant potential rather than a developmental cystic malformation is vital..."

Progression and prognosis: - PMID:25209242 - "The 5-year overall survival (OS) rate for type I/Ir patients was 91%; all deaths in this group were due to progression to type II or III." - "Metastatic disease at the diagnosis of types II and III was also an independent unfavorable prognostic factor." - PMID:36541021 - "For young children with type I PPB, outcomes are favorable, but complete resection is indicated because of the risk for progression."

Mechanism Synthesis

Atomic mechanism chain used in the YAML:

Germline DICER1 predisposition
PMID:19556464
Heterozygous germline DICER1 mutations define familial PPB predisposition.
Compound DICER1 disruption
PMID:24909177
Loss-of-function DICER1 allele plus somatic RNase IIIb missense mutation.
Aberrant 5p miRNA processing
PMID:24909177
"5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1."
Epithelial FGF9 overexpression
PMID:25978641
"FGF9 is overexpressed in lung epithelium in the initial multicystic stage of Type I PPB..."
Pulmonary mesenchymal hyperplasia
PMID:25978641
Increased epithelial Fgf9 in mice "results in pulmonary mesenchymal hyperplasia and a multicystic architecture..."
TP53 loss
PMID:24909177
Frequent biallelic TP53 loss is a recurrent cooperating lesion in progressive PPB.
RAS pathway activation
PMID:24909177
NRAS or BRAF mutation occurs in some cases.
Sarcomatous progression
PMID:24909177
PPB cysts can progress to high-grade sarcoma.
PMID:25209242
Clinical registry data ties progression to worse survival.

Mechanistic interpretation: - The key upstream distinction is between predisposition and lesion-level transformation. - DICER1 is not modeled as a single bundled node; predisposition, second-hit disruption, miRNA processing failure, epithelial FGF9 dysregulation, and mesenchymal hyperplasia are split into separate causal steps. - TP53 loss and RAS-pathway mutation are treated as additional cooperating progression lesions rather than as alternative root causes.

Clinical Presentation

Useful phenotype-supporting references: - PMID:16410110 - "PPB must be included in the differential diagnosis of a fetus, neonate, or child with a cystic lung mass." - PMID:37119756 - "Clinical expression of PPB is nonspecific and variable. It ranges from a dry cough to respiratory distress." - PMID:34345335 - Type II case abstract includes fever, nonproductive cough, and dyspnea. - PMID:32175165 - Type III cases "presenting with pneumothorax" support that phenotype as a real but uncommon presentation. - PMID:11002236 - "Respiratory distress was the most common clinical symptom."

Phenotype terms selected for YAML: - HP:0032445 Pulmonary cyst - HP:0012735 Cough - HP:0002094 Dyspnea - HP:0002098 Respiratory distress - HP:0002107 Pneumothorax

Treatment Evidence

Surgery: - PMID:33826235 - "Complete tumor resection is a main prognostic factor..." - PMID:36541021 - Complete resection is indicated even in type I disease because of progression risk.

Chemotherapy: - PMID:36137255 - "Beginning in 2007, the IVADo regimen (ifosfamide, vincristine, actinomycin-D, and doxorubicin) was recommended..." - "Adjusted analyses suggest improved overall survival for children treated with IVADo..."

Radiotherapy: - PMID:33826235 - Chemotherapy and "in some cases radiotherapy" are included in multimodal treatment.

Modeling note: - Exact NCIT regimen grounding for full IVADo was not available from the queried ontology results. - The treatment entry therefore uses MAXO chemotherapy plus CHEBI agents rather than an inexact NCIT regimen approximation.

Ontology Grounding Used

Disease and subtype grounding: - MONDO:0011014 pleuropulmonary blastoma - NCIT:C5669 Pleuropulmonary Blastoma - MONDO:0020555 pleuropulmonary blastoma type 1 - MONDO:0020556 pleuropulmonary blastoma type 2 - MONDO:0020557 pleuropulmonary blastoma type 3 - NCIT:C45626 Type I Pleuropulmonary Blastoma - NCIT:C211861 Type Ir Pleuropulmonary Blastoma - NCIT:C45627 Type II Pleuropulmonary Blastoma - NCIT:C45628 Type III Pleuropulmonary Blastoma

Representative histopathology terms: - NCIT:C155651 Primitive Mesenchymal Stroma Formation - NCIT:C35937 Rhabdomyosarcomatous Differentiation - NCIT:C9118 Sarcoma

Representative biological process terms: - GO:0035196 miRNA processing - GO:0035195 miRNA-mediated post-transcriptional gene silencing - GO:0008543 fibroblast growth factor receptor signaling pathway - GO:0010463 mesenchymal cell proliferation - GO:0030324 lung development

Representative anatomy and cell terms: - CL:0000082 epithelial cell of lung - CL:0008019 mesenchymal cell - UBERON:0000115 lung epithelium - UBERON:0004883 lung mesenchyme - UBERON:0002048 lung

Representative gene terms: - hgnc:17098 DICER1 - hgnc:3687 FGF9 - hgnc:11998 TP53 - hgnc:7989 NRAS - hgnc:1097 BRAF

References Used Directly in Curation

PMID:11002236
PMID:16410110
PMID:18223332
PMID:19556464
PMID:24909177
PMID:25209242
PMID:25978641
PMID:32175165
PMID:33826235
PMID:34345335
PMID:36137255
PMID:36541021
PMID:37119756
PMID:38671641

Pleuropulmonary Blastoma

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Pleuropulmonary Blastoma Deep Research Notes

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Treatment Evidence

Ontology Grounding Used

References Used Directly in Curation