DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma

AbstractDICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4–5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation in DICER1 provided the opportunity to identify and continue to recognize a number seemingly unrelated extrapulmonary neoplasms: Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations. Each of these neoplasms is characterized by a second somatic mutation in DICER1. In this review, we have summarized the salient clinicopathologic aspects of these tumors whose histopathologic features have several overlapping morphologic attributes particularly the primitive mesenchyme often with rhabdomyoblastic and chondroid differentiation and an uncommitted spindle cell pattern. Several of these tumors have an initial cystic stage from which there is progression to a high grade, complex patterned neoplasm. These pathologic findings in the appropriate clinical setting should serve to alert the pathologist to the possibility of a DICER1-associated neoplasm and initiate appropriate testing on the neoplasm and to alert the clinician about the concern for a DICER1 mutation.

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Outcome of 116 cases of pleuropulmonary blastoma type I and type Ir (regressed): A report from the International PPB Registry (IPPBR).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.9522 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 9522-9522 ◽

Cited By ~ 3

Author(s):

Yoav H. Messinger ◽

Gretchen M Williams ◽

John R. Priest ◽

Anne Harris ◽

Leslie Ann Doros ◽

...

Keyword(s):

Lung Neoplasm ◽

Pleuropulmonary Blastoma ◽

Type I ◽

High Grade ◽

Type Ii ◽

Exact Test ◽

Risk Of Progression ◽

High Grade Sarcoma

9522 Background: Pleuropulmonary blastoma (PPB) is a rare dysembryonic lung neoplasm of early childhood with progression from a purely cystic Type I (T-I) lesion to cystic solid and solid high grade sarcoma (Type II and Type III). A regressed form of PPB (T-Ir) has been recognized pathologically. The outcome of both T-I and T-Ir has been only partially described. Methods: Retrospective analysis of 345 IPPBR cases showed 116 T-I or T-Ir. In all cases the PPB diagnosis was made on surgically removed cysts. The treating physician decided whether to use chemotherapy after surgery. Results: The pathologic diagnosis of the 91 PPB T-I and 25 T-Ir is now confirmed by central review (LPD and DAH). Patients with T-I were younger than T-Ir (median: 8 months vs. 48 months).Diagnosis after age 6 years included only one T-I compared to 10 T-Ir patients. Therapy is not known for 28 T-I and 2 T-Ir. Surgery was followed by chemotherapy in 31 T-I and 2 T-Ir. Six (5%) recurred with the same type, all were alive at last follow-up: 5 (5.5%) T-I, 1 (4%) T-Ir. Progression to high-grade Type II or III occurred in 9/91 (10%) T-I and 2/25 (8%) T-Ir. The addition of chemotherapy did not significantly reduce progressions (Fisher’s exact test). All of the tumor progressions were seen by 75 months of age; this finding is similar to broader IPPBR data: > 95% of patients are diagnosed with Type II/III by 72 months of age. Of the 9 patients with T-I who progressed, 5 ultimately died, whereas the 2 T-Ir who progressed were alive. At last follow-up 111/116 (95.6%) were alive. Conclusions: A cyst in an older individual most likely will be Type Ir. Type I and Type Ir are clinically similar with a small risk of progression to the advanced Type II/III up to 6 years of age. Outcome for those whose cystic PPBs progressed is poor. The role of chemotherapy remains uncertain for the prevention of progression in the pure cystic PPB Type I or Ir. [Table: see text]

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It's Rare So Be Aware: Pleuropulmonary Blastoma Mimicking Congenital Pulmonary Airway Malformation

The Thoracic and Cardiovascular Surgeon Reports ◽

10.1055/s-0037-1598625 ◽

2017 ◽

Vol 06 (01) ◽

pp. e10-e14 ◽

Cited By ~ 3

Author(s):

Fayza Haider ◽

Khulood Al Saad ◽

Fatima Al-Hashimi ◽

Hakima Al-Hashimi

Keyword(s):

Early Childhood ◽

Poor Prognosis ◽

Lung Neoplasm ◽

Good Prognosis ◽

Pleuropulmonary Blastoma ◽

Type I ◽

Congenital Pulmonary Airway Malformation ◽

Cystic Lung ◽

Malignant Changes ◽

Infancy And Early Childhood

Pleuropulmonary blastoma (PPB) is a rare aggressive malignant tumor of infancy and early childhood. The tumor arises in the lung and pleura and is regarded as a pulmonary dysontogenetic or embryonic neoplasm. Four types are defined in literature. Type I PPB is a rare, cystic lung neoplasm in infants characterized by subtle malignant changes and a good prognosis. Recurrences after type I PPB are usually advanced with a poor prognosis.We report this case to increase awareness about this entity so that the pediatricians, pediatric surgeons, radiologist, and pathologist recognize it early.

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Effect of radiation on outcome of types II and III PPB: A report from the International Pleuropulmonary Blastoma Registry.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.9521 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 9521-9521 ◽

Cited By ~ 3

Author(s):

Gretchen M Williams ◽

John R. Priest ◽

Marsha J Finkelstein ◽

Anne Harris ◽

Leslie Ann Doros ◽

...

Keyword(s):

Overall Survival ◽

Radiation Therapy ◽

Prognostic Significance ◽

Tumor Resection ◽

Lung Neoplasm ◽

Pleuropulmonary Blastoma ◽

Type I ◽

Tumor Type ◽

Type Ii ◽

Type Iii

9521 Background: Pleuropulmonary blastoma (PPB) is a rare dysembryonic lung neoplasm of early childhood with progression from a purely cystic (Type I) lesion to a solid high-grade sarcoma Type III (T-III), or a mixed solid/cystic stage Type II (T-II). Surgery and chemotherapy are required for T-II and T-III PPB, but the benefit of radiation therapy for T-II and T-III PPB is debated and is being evaluated in this study. Methods: This is a retrospective analysis of central pathology-reviewed Types II and III PPB from the IPPBR. Treatments were chosen by physician, were not randomized, and included surgery and chemotherapy. The outcome of patients treated with upfront radiation (before progression or relapse) was compared to patients who did not receive radiation. Event-free survival (EFS) and overall survival (OS) were determined to last follow-up, using the Kaplan-Meier analysis, with log-rank test. Results: Outcome for 212 patients (117 Type-II and 95 Type III) was significantly better for T-II than T-III: EFS for T-II was 68.1% vs. T-III 45.7% (P=0.002), and OS for T-II was 75.2% vs. T-III 57.9% (p=0.01). Excluding patients with incomplete therapy information, 174 were treated with surgery and chemotherapy. Of these 44 (25%) also received radiation therapy; 130 patients did not. The table below shows comparison of radiated vs. non-radiated. Radiation provided no additional survival benefit, overall or by tumor Type. Multivariate analysis showed that gender and extent of primary tumor resection (biopsy vs. gross total resection) had no effect on outcome, however T-II vs. T-III retained prognostic significance. Conclusions: For this collection of advanced-type PPB, outcome is significantly better for T-II than T-III. For patients treated initially with surgery and chemotherapy, adding radiation therapy offered no improvement in event-free or overall survival. Limitations of this study include its retrospective nature and non-uniform treatment regimens. [Table: see text]

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Type I Pleuropulmonary Blastoma: A Report From the International Pleuropulmonary Blastoma Registry

Journal of Clinical Oncology ◽

10.1200/jco.2005.05.3595 ◽

2006 ◽

Vol 24 (27) ◽

pp. 4492-4498 ◽

Cited By ~ 71

Author(s):

John R. Priest ◽

D. Ashley Hill ◽

Gretchen M. Williams ◽

Christopher L. Moertel ◽

Yoav Messinger ◽

...

Keyword(s):

Adjuvant Chemotherapy ◽

Lung Neoplasm ◽

Early Recurrence ◽

Good Prognosis ◽

Pleuropulmonary Blastoma ◽

Type I ◽

Recurrence Free Survival ◽

Type Ii ◽

Free Survival ◽

Lung Cysts

Purpose Type I pleuropulmonary blastoma (PPB) is a rare, cystic lung neoplasm in infants characterized by subtle malignant changes and a good prognosis. Recurrences after type I PPB are usually advanced type II or type III neoplasms with a poor prognosis. This article describes the first collection of type I PPB cases, analyzes outcome based on treatments of surgery or surgery plus chemotherapy, and presents type I PPB management recommendations. Patients and Methods Type I PPB cases from the International PPB Registry and literature were evaluated using standard statistical methods for outcomes based on age at diagnosis, sex, thoracic side, surgical extent, length of follow-up, constitutional/familial disease, pre-existing lung cysts, intrathoracic findings, and treatments (surgery or surgery and chemotherapy). Results Thirty-eight type I PPB cases were identified: Registry (n = 30) and literature (n = 8). Twenty children had surgery alone; eight (40%) experienced recurrence; and four died. Eighteen children had surgery and adjuvant chemotherapy; one experienced recurrence and died. All recurrences were type II or III PPB. Recurrence-free survival was higher in the surgery + chemotherapy group (P = .01); overall survival did not differ (P = .18). The improved recurrence-free survival was found only in males. Four of nine children with recurrence survived. Conclusion Adjuvant chemotherapy appears to benefit type I PPB patients. Benefit limited to males requires broader substantiation. Salvage after types II and III recurrence is poor (four of nine; 44%). A rigorous surveillance schedule after type I PPB diagnosis might detect early recurrence and be an acceptable alternative to adjuvant chemotherapy.

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DICER1-Mutated Botryoid Fibroepithelial Polyp of the Parotid Duct: Report of the First Case

Head and Neck Pathology ◽

10.1007/s12105-021-01364-y ◽

2021 ◽

Author(s):

Ramona Erber ◽

Raimund Preidl ◽

Robert Stoehr ◽

Florian Haller ◽

Arndt Hartmann ◽

...

Keyword(s):

Gene Expression Regulation ◽

Differentiated Thyroid Carcinoma ◽

Pleuropulmonary Blastoma ◽

Malignant Neoplasms ◽

Cystic Nephroma ◽

Fibroepithelial Polyp ◽

Ribonuclease Iii ◽

First Case ◽

Parotid Duct ◽

Dicer1 Syndrome

AbstractDICER1, a member of the ribonuclease III family, is involved in the biogenesis of microRNAs and, hence, it influences gene expression regulation. DICER1 germline (associated with the inherited DICER1 syndrome) or somatic mutations have been linked to tumorigenesis in histogenetically diverse benign and malignant neoplasms in different organs including pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, nasal chondromesenchymal hamartoma, poorly differentiated thyroid carcinoma, thyroblastoma, intracranial sarcoma and gonadal Sertoli-Leydig cell tumors in addition to others. Moreover, rare botryoid (giant) fibroepithelial polyps may harbor this mutation. Herein, we describe the first reported case of a DICER1-mutated botryoid fibroepithelial polyp occurring within the parotid duct of a 65-year-old female who has no other features or family history of the DICER1 syndrome. Based on its distinctive morphology, we tested this lesion specifically for DICER1 mutations and confirmed the presence of a pathogenic DICER1 variant with a low allele frequency, consistent with a somatic mutation.

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DICER1 Syndrome and Cancer Predisposition: From a Rare Pediatric Tumor to Lifetime Risk

Frontiers in Oncology ◽

10.3389/fonc.2020.614541 ◽

2021 ◽

Vol 10 ◽

Author(s):

Anna Maria Caroleo ◽

Maria Antonietta De Ioris ◽

Luigi Boccuto ◽

Iside Alessi ◽

Giada Del Baldo ◽

...

Keyword(s):

Thyroid Neoplasms ◽

Pleuropulmonary Blastoma ◽

Type I ◽

Cystic Nephroma ◽

Genetic Condition ◽

Pediatric Tumor ◽

Common Life ◽

Life Threatening ◽

Dicer1 Syndrome

DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the DICER1 gene. The risk to present a neoplasm before the age of 10 years is 5.3 and 31.5% before the age of 60. DICER1 variants have been associated with a syndrome involving familial pleuropulmonary blastoma (PPB), a rare malignant tumor of the lung, which occurs primarily in children under the age of 6 years and represents the most common life-threatening manifestation of DICER1 syndrome. Type I, II, III, and Ir (type I regressed) PPB are reported with a 5-year overall survival ranging from 53 to 100% (for type Ir). DICER1 gene should be screened in all patients with PPB and considered in other tumors mainly in thyroid neoplasms (multinodular goiter, thyroid cancer, adenomas), ovarian tumors (Sertoli-Leydig cell tumor, sarcoma, and gynandroblastoma), and cystic nephroma. A prompt identification of this syndrome is necessary to plan a correct follow-up and screening during lifetime.

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Cystic Nephroma with Pleuropulmonary Blastoma: A Rare Dual Pathology

APSP Journal of Case Reports ◽

10.21699/ajcr.v9i1.657 ◽

2018 ◽

Vol 9 (1) ◽

pp. 3

Author(s):

Kiran Hilal ◽

Anam Khan ◽

Nida Sajjad ◽

Kumail Khandwala

Keyword(s):

Pediatric Patients ◽

Abdominal Mass ◽

Lung Neoplasm ◽

Pleuropulmonary Blastoma ◽

Cystic Nephroma ◽

Rare Entity ◽

Dual Pathology ◽

Cystic Tumors ◽

Synchronous Development ◽

Thoracic Lesion

Cystic nephroma (CN) belongs to a heterogeneous group of renal cystic tumors while pleuropulmonary blastoma is an uncommon pediatric lung neoplasm, believed to be originating either from lung tissue itself or from the pleura. Synchronous development of pleuropulmonary blastoma following cystic nephroma is a rare entity in pediatric patients. The etiology and pathogenesis of this dual pathology is still unknown. We report a case of a child who presented with an abdominal mass diagnosed as cystic nephroma on surgical resection, who later developed a thoracic lesion which was subsequently diagnosed as pleuropulmonary blastoma.

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