BACKGROUND: Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have been misdiagnosed and we may have missed DICER1-associated PPBs, a diagnosis with important clinical implications for patients and their families. To gain insight in potential misdiagnoses, we systematically assessed somatic DICER1 gene mutation status in an unselected, retrospective cohort of patients with a CPAM diagnosis.
METHODS: In the Amsterdam University Medical Center (the Netherlands), it has been standard policy to resect CPAM lesions. We included all consecutive cases of children (age 0-18 years) with a diagnosis of CPAM between 2007 and 2017 at this center. Clinical and radiographic features were reviewed, and DICER1 gene sequencing was performed on DNA retrieved from CPAM tissue samples.
RESULTS: Twenty-eight patients with a surgically removed CPAM were included. CPAM type 1 and type 2 were the most common subtypes (n = 12 and n = 13). For 21 patients a chest CT scan was available for reassessment by two pediatric radiologists. In 9 patients (9/21, 43%) the CPAM subtype scored by the radiologists did not correspond with the subtype given at pathology assessment. No pathogenic mutations and no copy number variations of the DICER1 gene were found in the DNA extracted from CPAM tissue (0/28).
CONCLUSIONS: Our findings suggest that the initial CPAM diagnoses were correct. These findings should be validated through larger studies to draw conclusions regarding whether systematic DICER1 genetic testing is required in children with a pathological confirmed diagnosis of CPAM or not.
METHODS: Level IV.

Here we intend to document a rare case of PPB type III in a 2-year male presenting with an extensive tumor occupying the right hemithorax with immunohistochemical (IHC) study. Pleuropulmonary blastoma (PPB) is a rare variably aggressive, dysodontogenetic, childhood primary intrathoracic malignancy which in up to 25% of cases can be extrapulmonary with attachment to the parietal pleura. It is found in pediatric population under 5 years of age. It was initially proposed as a distinct entity by Manivel et al. in 1988. PPB is a proliferation of primitive mesenchymal cells that initially form air-filled cysts lined by benign-appearing epithelium (type I, cystic). Later on, the mesenchymal cells outgrow the cysts with formation of focal solid areas (type II, solid and cystic) and finally, mainly solid mass (type III, solid PPB).

BACKGROUND: Pleuropulmonary blastoma (PPB) is a rare sarcomatous malignancy involving the lung and pleura which occurs in early childhood. Cystic PPB in the early stage can be misdiagnosed as other cystic diseases. Early detection of this entity is important for appropriate treatment and prevention of disease progression. Hotspot mutations in the ribonuclease IIIb (RNase IIIb) domain of DICER1 have been reported to have a crucial role as genetic factors of PPB and DICER1 familial syndrome. We reviewed the clinicopathologic findings of PPB and the status of DICER1 hotspot mutation and patients\' clinical course.
METHODS: We retrospectively reviewed all patients with histologically confirmed PPB at Asan Medical Center between 2000 and 2017. Ten cases were identified in the database, and their clinicopathologic parameters were evaluated. PPB was classified into the following 3 pathologic subtypes: type I (purely cystic), type II (mixed cystic and solid), and type III (entirely solid). The status of DICER1 mutation in 2 hotspot regions of the RNase IIIb domain was evaluated by Sanger sequencing.
RESULTS: The most frequent PPB type was II (6 cases), followed by I and III (2 cases each). The age at diagnosis ranged from 16 months to 15 years. All patients underwent surgery, and all patients received adjuvant or neoadjuvant chemotherapy. Four of 7 patients had missense mutations in the RNase IIIb hotspot; the base and predicted corresponding amino acid changes were c.5113 G>A (p.E1705K), c.5407 G>A (p.E1803K), c.5425 G>A (p.G1809R), and c.5428 G>T (p.D1810Y). There was no particular association between the presence of the hotspot mutation and histologic type. Nine patients survived with no evidence of disease for a median interval of 93 (range, 13-199) months. Only 1 patient diagnosed with type III PPB at the age of 18 years had recurrence after 20.8 months and eventually died 66 months after the initial diagnosis.
CONCLUSIONS: Late detection of solid PPB is associated with poor prognosis. Considering the rarity of PPB disease and the importance of DICER1 hotspot mutation in pathogenesis, DICER1 hotspot mutation testing and identification in the early cystic stage can improve patient outcomes.

Lorvotuzumab mertansine (IMGN901) is an antibody-drug conjugate linking an antimitotic agent (DM1) to an anti-CD56 antibody (lorvotuzumab). Preclinical efficacy has been noted in Wilms tumor, rhabdomyosarcoma, and neuroblastoma. Synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST), and pleuropulmonary blastoma also express CD56. A phase 2 trial of lorvotuzumab mertansine was conducted to assess its efficacy, recommended phase 2 dose, and toxicities.
Eligible patients had relapsed after or progressed on standard therapy for their tumor type. Lorvotuzumab mertansine (110 mg/m2 per dose) was administered at the adult recommended phase 2 dose intravenously on days 1 and 8 of 21-day cycles. Dexamethasone premedication was used. Pharmacokinetic samples, peripheral blood CD56-positive cell counts, and tumor CD56 expression were assessed.
Sixty-two patients enrolled. The median age was 14.3 years (range, 2.8-29.9 years); 35 were male. Diagnoses included Wilms tumor (n = 17), rhabdomyosarcoma (n = 17), neuroblastoma (n = 12), synovial sarcoma (n = 10), MPNST (n = 5), and pleuropulmonary blastoma (n = 1). Five patients experienced 9 dose-limiting toxicities: hyperglycemia (n = 1), colonic fistula (n = 1) with perforation (n = 1), nausea (n = 1) with vomiting (n = 1), increased alanine aminotransferase in cycle 1 (n = 2), and increased alanine aminotransferase in cycle 2 (n = 1) with increased aspartate aminotransferase (n = 1). Non-dose-limiting toxicities (grade 3 or higher) attributed to lorvotuzumab mertansine were rare. The median values of the maximum concentration, half-life, and area under the curve from zero to infinity for DM1 were 0.87 µg/mL, 35 hours, and 27.9 µg/mL h, respectively. Peripheral blood CD56+ leukocytes decreased by 71.9% on day 8. One patient with rhabdomyosarcoma had a partial response, and 1 patient with synovial sarcoma achieved a delayed complete response.
Lorvotuzumab mertansine (110 mg/m2 ) is tolerated in children at the adult recommended phase 2 dose; clinical activity is limited.

To describe utilization and long-term outcomes of pneumonectomy in children and adolescents with cancer.
Pneumonectomy in adults is associated with significant morbidity and mortality. Little is known about the indications and outcomes of pneumonectomy for pediatric tumors.
The Pediatric Surgical Oncology Research Collaborative (PSORC) identified pediatric patients <21 years of age who underwent pneumonectomy from 1990 to 2017 for primary or metastatic tumors at 12 institutions. Clinical information was collected; outcomes included operative complications, long-term function, recurrence, and survival. Univariate log rank, and multivariable Cox analyses determined factors associated with survival.
Thirty-eight patients (mean 12 ± 6 yrs) were identified; median (IQR) follow-up was 19 (5-38) months. Twenty-six patients (68%) underwent pneumonectomy for primary tumors and 12 (32%) for metastases. The most frequent histologies were osteosarcoma (n = 6), inflammatory myofibroblastic tumors (IMT; n = 6), and pleuropulmonary blastoma (n = 5). Median postoperative ventilator days were 0 (0-1), intensive care 2 (1-3), and hospital 8 (5-16). Early postoperative complications occurred in 10 patients including 1 death. Of 25 (66%) patients alive at 1 year, 15 reported return to preoperative pulmonary status. All IMT patients survived while all osteosarcoma patients died during follow-up. On multivariable analysis, metastatic indications were associated with nonsurvival (HR = 3.37, P = 0.045).
This is the largest review of children who underwent pneumonectomy for cancer. There is decreased procedure-related morbidity and mortality than reported for adults. Survival is worse with preoperative metastatic disease, especially osteosarcoma.

Very rare tumors (VRTs) account for up to 11% of childhood cancers. Dedicated national groups and registries only exist in some European countries. Pleuropulmonary blastoma (PPB) is a very rare intrathoracic pediatric tumor with a potentially severe prognosis. Due to its rarity, it sometimes goes unrecognized. We investigated PPB diagnostic capability and possible correlations between diagnostic performance and VRT-dedicated activities. The number of cases of PPB registered between 2000 and 2014 at pediatric oncology centers in Europe was compared with the number of expected cases. Data sources included VRT registries, population-based cancer registries, and hospital registries. Data were obtained for 25 countries, grouped into 4 geographical regions. The expected cases were 111, and the observed cases were 129. The observed-to-expected ratio was 1.86 for Northern Europe, 1.33 for Southern Europe, 1.22 for Central Europe, and 0.65 for Eastern Europe. More cases than expected were registered in all countries with an official VRT registry.Conclusion: The number of cases observed is consistent with expectations, but disparities exist across Europe. Difficulties in diagnosing PPB emerged in most Eastern countries. The incidence rate of PPB may be underestimated. The creation of VRT-dedicated groups and a European Registry for VRTs could help to reduce inequalities.What is Known:• Very rare pediatric tumors are often not recognized, despite representing almost 11% of childhood cancers .• Pleuropulmonary blastoma is a rare pediatric tumor with a poor prognosis.What is New:• The ability to diagnose and register pleuropulmonary blastoma varies in Europe.Registries dedicated to very rare pediatric tumors improve the diagnostic rates.• The incidence rate of pleuropulmonary blastoma may currently be underestimated.

BACKGROUND: The prognosis of solid pediatric tumors strongly correlates with accurate staging and complete local control. Currently, surgeons rely on macroscopic cues and intraoperative cryosection to determine resection borders. Multiphoton Microscopy (MPM) is a real time technique that allows imaging of tissue without time-consuming tissue processing.
OBJECTIVE: This pilot study evaluates the diagnostic potential of MPM in pediatric solid tumors compared to routine histopathology.
METHODS: Slides of pediatric tumor samples (nephroblastoma and neuroblastoma [n = 2]; ganglioneuroma, pleuropulmonary blastoma, hepatocellular carcinoma [n = 1]) were prepared to allow direct comparison of MPM with conventional light microscopy. Additionally, we applied MPM to native tumor tissue blocks to evaluate direct visualization of malignant cells through the tumor capsule. Images were interpreted by an attending surgical pathologist. Detectability of tumor-specific features was compared between MPM and conventional histology.
RESULTS: A total of 7 tumors from 7 recruited patients were analyzed. All MPM images were accurate in diagnosing typical criteria of each particular neoplasm. In addition, MPM clearly visualized tumors through the capsule without sectioning or labeling procedures. The quality of MPM was sufficient to make the diagnosis and visualize typical entity-specific architectural changes.
CONCLUSIONS: MPM is comparable to conventional histopathology in the diagnosis of pediatric solid tumors without the need for fixation or staining. It therefore has tremendous potential for future real-time intraoperative diagnostics and as an alternative to conventional frozen section histopathology.
METHODS: III.

OBJECTIVE: To investigate clinical and pathological features of lung lesions in children.
METHODS: Clinical manifestations, radiologic imaging, histopathological features and immunohistochemical results were analyzed in 215 cases of lung lesions in children.
RESULTS: A total of 215 cases of lung lesions in children aged 0 day to 13 years (average age of 27.2 months and the median age of 18.0 months) were selected, including 137 male and 78 female patients with a male to female ratio of 1.76:1.00. The incidence of congenital lung disease was higher in patients of less than 1 year old than those of over 1 year old age, and the difference of the two groups was statistically significant (P = 0.004). 142 cases had acquired lung diseases, and 73 cases had congenital bronchopulmonary dysplasia. Lung abscess was the most common lesion seen in 86 cases (40.0%), including 1 case of fungal abscess. Congenital pulmonary airway malformation (CPAM) was the second most common, seen in 44 patients (20.5%), including 20 cases of type 1, 18 cases of type 2 and 6 cases of type 4 CPAM. Pulmonary sequestration was found in 25 cases (11.6%) including 14 cases of intralobar type and 11 cases of extralobar type. Two cases of extralobar pulmonary sequestration showed simultaneous CPAM2 type 2 lesion. Other lesions included tuberculosis (13 cases, 6.0%), emphysema (12 cases, 5.6%), interstitial pneumonia (7 cases, 3.2%), pulmonary hemorrhage (6 cases, 2.8%), bronchogenic cyst (4 cases, 1.9%), bronchiolitis obliterans (2 cases, 0.9%), idiopathic pulmonary hemosiderin deposition disease (2 cases, 0.9%) and 1 cases of lung non-specific changes. 13 cases of neoplastic lesions (6.0%) were found, of which 11 cases were primary tumors (5.1%), including inflammatory myofibroblastic tumor in 5 patients (2.3%), pleuropulmonary blastoma in 5 cases (1 case of type I, 2 type II and 2 type III) and 1 case of mucoepidermoid carcinoma (0.5%) and 2 cases of metastatic tumors (hepatoblastoma and Wilm\'s tumor, 0.9%).
CONCLUSIONS: Infectious diseases are the most common lung diseases in children. Congenital bronchopulmonary dysplasia is the most common in children of less than 1 year old. Malignant lesions are rare.

OBJECTIVE: To study the clinicopathological and immunohistochemical features, histogenesis and prognosis of pleuropulmonary blastoma (PPB) in children.
METHODS: PPB specimens from 16 pediatric cases with an age ranging from 1 year and 7 months to 5 years and 3 months (mean age of 3 years) were retrieved and analyzed by routine histological, immunohistochemical and electron methods.
RESULTS: Among 16 patients, there were 2 type I, 7 type II and 7 type III PPB cases. Type I PPB as multilocular cystic structure, consisted of thin fibrous wall lining the respiratory epithelium, subepithelial primitive blastema or immature mesenchymal cells, with or without rhabdomyoblastic differentiation or cartilage; Type II PPB as cystic-solid tumor, comparing with type I, consisted of intracystic components with appearance of anaplastic tumor cells. Type III PPB consisted of completely solid mass, the same as the solid region of type II, had mixed pattern including blastema, undifferentiated spindle-cell proliferations and sarcomas. In addition, anaplastic tumor cells and intra-and extra- cytoplasmic eosinophilic globules were also commonly present. Epithelial components in PPB were benign. Immunohistochemical study showed primitive mesenchymal differentiation of tumors. All cases were positive for vimentin, desmin, myogenin and SMA in tumors with skeletal muscle differentiation, S-100 was positive in tumors with cartilage differentiation. All tumors were negative for synaptophysin, CD99, and CD117. Benign epithelial components were positive for AE1/AE3 and EMA. In 12 cases, electron microscopy revealed few organelles in the primitive mesenchymal cells and rich heterochromatin in mesenchymal cells, the latter also demonstrating cytoplasmic myofilament dysplasia. Nine cases had clinical follow-up ranging from 5 to 48 months, of which 4 patients died.
CONCLUSIONS: PPB is a rare lung neoplasm of children under the age of 6 years, with distinct pathological morphology. PPB may arise from lung or pleura mesenchymal cells and has a poor clinical outcome.

Pleuropulmonary blastoma (PPB) is a rare malignant dysontogenetic neoplasm primarily affecting younger children, even in newborns with an unfavorable outcome. PPB is histologically composed of a primitive, variably mixed blastematous and sarcomatous components, and exclusively subclassified as type I (purely cystic), type II (both cystic and solid elements) and type III (completely solid) by increasing histological evidence of malignancy. At present, well-documented cases or cases of truly precise presentation of either pathological or immunohistochemical findings in PPB are rare. The authors report one case of PPB in a 44-month-old child presenting as a solid and cystic mass with special emphasis on its radiological, histopathological and immunohistochemical aspects. The histological diagnosis was PPB, which would belong to the type II category.