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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.

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DICER1-Related Disorders

Synonyms: DICER1-Pleuropulmonary Blastoma Familial Tumor Predisposition Syndrome, DICER1 Syndrome

, MD, , MD, , MD, , MD, , BS, , MD, , MS, CGC, , PhD, , MD, , MD, and , MD.

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Summary

Clinical characteristics.

DICER1-related disorders are a familial tumor susceptibility syndrome that confers increased risk most commonly for pleuropulmonary blastoma (PPB); ovarian sex cord-stromal tumors (Sertoli-Leydig cell tumor [SLCT], juvenile granulosa cell tumor [JGCT], and gynandroblastoma); cystic nephroma (CN); and thyroid gland neoplasia (multinodular goiter [MNG], adenomas, or differentiated thyroid cancer). Less commonly observed tumors are ciliary body medulloepithelioma (CBME); botryoid-type embryonal rhabdomyosarcoma (ERMS) of the cervix or other sites; nasal chondromesenchymal hamartoma (NCMH); renal sarcoma; pituitary blastoma; and pineoblastoma. Novel phenotypes continue to be discovered. The majority of tumors in families with a DICER1 germline pathogenic variant occur in individuals younger than age 40 years. PPB, a neoplasm that arises during lung development or shortly after birth, typically presents in infants and children younger than age six years. Age of onset of ovarian sex cord-stromal tumors is not well defined. CN presents in children younger than age four years.

Diagnosis/testing.

A DICER1-related tumor is suspected based on clinical presentation (which varies by age and tumor type) and findings on imaging and pathologic examination of resected or biopsied tissue. The diagnosis of a DICER1-related disorder is confirmed by identification of a heterozygous DICER1 germline pathogenic variant that is known or suspected to cause loss of function.

Management.

Treatment of manifestations: Treatment for DICER1-related malignant tumors relies on identification of the tumor type and stage; most often treatment involves surgical resection with or without chemotherapy. The treatment of PPB may also include use of radiation, primarily to treat recurrence or metastases.

Surveillance: No guidelines regarding initial screening evaluations or surveillance of persons with a germline DICER1 pathogenic variant have been established. Based on data from the International PPB Registry (IPPBR), which includes more than 500 persons with symptomatic or asymptomatic DICER1-related disorders, the authors recommend (1) annual physical examination and targeted review of systems, and (2) imaging study type and frequency based on tumor type, patient age, and presence or absence of clinical findings. Formal surveillance for some of the rarer DICER1-related tumors may not be warranted given the low risk of developing one.

Evaluation of relatives at risk: If the germline DICER1 pathogenic variant has been identified in an affected family member, it is reasonable to offer molecular genetic testing to at-risk relatives of all ages to clarify their genetic status and to provide recommendations for age-appropriate surveillance and early intervention. If first-degree relatives are not able to undergo molecular genetic testing, surveillance should be based on clinical changes that would warrant further investigation.

Pregnancy management: Because large lung cysts can in rare instances cause respiratory distress in newborns, it is recommended that prenatal identification of lung cysts prompt consultation with specialists in high-risk obstetrics and fetal medicine to monitor the pregnancy and manage the delivery.

Genetic counseling.

DICER1-related disorders are inherited in an autosomal dominant manner. In individuals with PPB with a detectable germline DICER1 pathogenic variant, 80% of the germline pathogenic variants were inherited from a parent and 20% were de novo. Each child of an individual with a DICER1 germline pathogenic variant has a 50% chance of inheriting the variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.

GeneReview Scope

DICER1-Related Disorders: Included Phenotypes 1
  • Pleuropulmonary blastoma
  • Ovarian sex-cord stromal tumors
  • Cystic nephroma
  • Nodular hyperplasia of the thyroid gland
  • Ciliary body medulloepithelioma
  • Botryoid-type embryonal rhabdomyosarcoma
  • Nasal chondromesenchymal hamartoma
  • Pituitary blastoma
  • Pineoblastoma

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

Germline mutation of DICER1 defines a familial tumor susceptibility syndrome called DICER1-pleuropulmonary blastoma familial tumor predisposition syndrome (also known as DICER1 syndrome and pleuropulmonary blastoma familial tumor and dysplasia syndrome) that confers increased risk for the following tumors:

  • Pleuropulmonary blastoma (PPB)
  • Ovarian sex cord-stromal tumors (Sertoli-Leydig cell tumor [SLCT], juvenile granulosa cell tumor [JGCT], and gynandroblastoma)
  • Cystic nephroma (CN)
  • Thyroid gland neoplasia including multinodular goiter (MNG), adenomas, or differentiated thyroid cancer
  • Ciliary body medulloepithelioma (CBME)
  • Botryoid-type embryonal rhabdomyosarcoma (ERMS) of the cervix or other sites
  • Nasal chondromesenchymal hamartoma (NCMH)
  • Pituitary blastoma
  • Pineoblastoma

Note: Rarely, Wilms tumor, neuroblastoma, and other more common childhood cancers (which by themselves do not suggest the presence of a germline DICER1 pathogenic variant) have been reported.

Clinical and Radiologic Findings

The clinical presentation, findings on imaging, and pathologic findings of each tumor type are summarized briefly below.

Pleuropulmonary Blastoma (PPB)

Clinical presentation. The clinical presentation of PPB varies by age and tumor type. Children younger than age two years most commonly present with shortness of breath with or without pneumothorax secondary to PPB cyst rupture. Older children with advanced disease often present with shortness of breath, weight loss, and fever.

Imaging. CT is the preferred imaging modality to detect tumors/cysts, determine site(s) of disease, and help classify tumors as purely cystic (type I), cystic and solid (type II), or purely solid (type III) [Priest et al 1997]. Most PPBs appear to arise from lung parenchyma and are commonly situated in the lung periphery adjacent to the pleura. Rarely, PPBs arise in the parietal pleura or diaphragm. Tumors arising primarily in the chest wall or mediastinum should prompt consideration of other diagnoses (see Differential Diagnosis).

Note: (1) Plain x-ray images are insensitive to small cystic changes and cannot reliably distinguish between masses and pneumonia consolidations. (2) In general, MRI has limited value in the evaluation of chest lesions; however, thoracic MRI can be useful in management of types II and III PPB for differentiating PPB from other soft tissues in the thorax, for following response to chemotherapy, and for reducing diagnostic radiation exposure. (3) For evaluation of lesions with extensive air-filled cystic components, chest CT is preferred.

For more information on CT findings click here (pdf).

Diagnosis of PPB is based on pathologic examination of a biopsy or surgically excised cystic and/or solid lung tissue. For more information on pathologic findings click here (pdf).

Note: (1) In asymptomatic newborns and young children with multiple pulmonary cysts and/or pneumothorax as well as family history to support the diagnosis of a DICER1-related disorder, the positive predictive value of a DICER1 pathogenic variant is expected to be high [Priest et al 2009]; thus, detection of a germline DICER1 pathogenic variant prior to surgical intervention can help determine the appropriate surgical management which would include complete surgical resection. (2) Failure to detect a germline DICER1 pathogenic variant does not rule out the diagnosis of PPB.

Ovarian Sex Cord-Stromal Tumors

Germline DICER1 pathogenic variants described in females with ovarian sex cord-stromal tumors include (most commonly) Sertoli-Leydig cell tumor (SLCT), and (rarely) juvenile granulosa cell tumor (JGCT) and gynandroblastoma [Foulkes et al 2011, Rio Frio et al 2011, Schultz et al 2011, Slade et al 2011].

Clinical presentation. Ovarian sex cord-stromal tumors may present as an isolated adnexal mass with or without clinical signs or laboratory findings of hormone production.

As a group, these tumors are typically unilateral but can occur bilaterally, often large (≥10 cm) and predominantly solid.

Signs of hormone production can include precocious puberty, menstrual irregularities, or signs of virilization such as hirsutism, acne, or voice changes.

Laboratory findings may include elevation of hormonal markers such as inhibin A and/or B or estradiol (generally produced by granulosa cell elements) or testosterone (generally produced by Sertoli/Leydig cell elements).

Rarely, sex cord-stromal tumors – particularly SLCT of the retiform subtype - may present with elevations in alpha-fetoprotein (AFP). Tumor marker elevation may occasionally occur in the absence of a prominent mass on imaging, in which case, sampling of the ovarian vein may reveal the diagnosis.

Imaging. Ultrasound examination is the initial diagnostic modality for most suspected adnexal masses or unexplained elevation of hormonal markers. MRI and/or CT may provide additional information.

Diagnosis of ovarian sex cord-stromal tumors is based on pathologic examination. For information on pathologic findings click here (pdf).

Cystic Nephroma (CN)

Germline DICER1 pathogenic variants have been described in CN [Hill et al 2009, Bahubeshi et al 2010, Doros et al 2014].

Clinical presentation. CN most commonly presents in the first four years of life as a painless enlarging abdominal or flank mass. The finding of bilateral tumors is a rare event that is highly suggestive of a germline DICER1 pathogenic variant [Bahubeshi et al 2010].

Imaging. CN appears as one or more cystic masses of the kidney on ultrasound examination, CT, and/or MRI.

Diagnosis of CN is based on pathologic examination. See pathologic findings (pdf).

Thyroid Gland Neoplasia including Multinodular Goiter (MNG), Adenomas, or Differentiated Thyroid Cancer

Clinical presentation. Thyroid gland neoplasia typically presents as a palpable mass in the neck.

Imaging. Ultrasound examination can identify the number and location of a nodule or nodules as well as characteristics that can be used to predict the malignant potential. MNG is by definition multifocal and cystic or mixed solid and cystic; adenomas and differentiated thyroid cancer are most often unifocal and solid.

Diagnosis of the specific type of thyroid gland neoplasia is based on pathologic examination of cells or tissue obtained by fine needle aspirate or surgical resection. See pathologic findings (pdf).

Ciliary Body Medulloepithelioma (CBME)

Clinical presentation. CBME, a primitive neuroepithelial neoplasm, arises in the anterior chamber of the eye. Poor vision and pain are common presenting symptoms. Common signs include decreased visual acuity and leukocoria. Clinical examination of the eye shows a cyst or mass in the iris, anterior chamber, or ciliary body; or glaucoma or cataract [Broughton & Zimmerman 1978].

Imaging. Ultrasound examination, MRI, or CT can identify the specific location of the mass as well as its typical heterogeneous, cystic features. CT and MRI provide better resolution than ultrasound, can determine the extent of a tumor, and may be able to distinguish CBME from other intraocular tumors. CT can detect calcification, which is useful in the differential diagnosis.

Diagnosis of CBME in most cases is based on pathologic examination; however, examination by an ophthalmologist experienced in the diagnosis of ocular tumors may aid in the diagnosis of CBME non-invasively and without enucleation. See pathologic findings (pdf).

Botryoid-Type Embryonal Rhabdomyosarcoma (ERMS)

Germline DICER1 pathogenic variants have been described in patients with ERMS [Dehner et al 2012, Doros et al 2012].

Clinical presentation. Botryoid and solid types of ERMS in individuals with DICER1-related disorders are mainly seen in the pelvic organs, as in sporadically occurring ERMS. Symptoms depend on the tumor location site.

One unique association in individuals with DICER1-related disorders is ERMS of the uterine cervix in older children and young adults, which can present with vaginal spotting or passage of myxoid, hemorrhagic solid tissue.

Imaging. CT and MRI are useful in determining the local and distant extent of disease.

Diagnosis of ERMS is based on pathologic examination. See pathologic findings (pdf).

Nasal Chondromesenchymal Hamartoma (NCMH)

Clinical presentation. NCMH presents in the nasal cavity or sinuses commonly as a unilateral polyp or mass or rarely as bilateral polyps or masses . It typically presents as a mass. Symptoms vary depending on size and location and can include persistent nasal drainage/rhinorrhea, nasal obstruction/swelling, and respiratory or feeding difficulties in an infant. Bony destruction can be seen.

Imaging. Nasal endoscopy, CT, or MRI can visualize the tumor. CT is better than the other two methods for visualizing bony changes.

Diagnosis of NCMH is based on pathologic examination of the nasal or sinus mass after surgical removal. See pathologic findings (pdf).

Pituitary Blastoma

DICER1 pathogenic variants have been described in pituitary blastoma [de Kock et al 2013a].

Clinical presentation. Pituitary blastoma was first reported in 2008 as a rare primitive malignant neoplasm presenting in the first two years of life [Scheithauer et al 2012]. Children can present with ophthalmoplegia, proptosis, visual disturbance, and/or clinical endocrinopathy, typically Cushing disease.

Imaging. MRI is best for visualizing these tumors, which are located in the suprasellar region.

Diagnosis of pituitary blastoma is based on pathologic examination of the pituitary mass after surgical removal. See pathologic findings (pdf).

Pineoblastoma

A DICER1 germline pathogenic variant has been reported in an individual with a pineoblastoma [Sabbaghian et al 2012].

Clinical presentation. Pineoblastoma is a malignant primitive neoplasm of the pineal gland. It typically presents with findings of increased intracranial pressure stemming from obstructive hydrocephalus due to compression of the cerebral aqueduct by the tumor mass. Neuro-ophthalmologic abnormalities including upgaze paralysis and nystagmus may be seen. Focal neurologic deficits are found in 25% of affected individuals.

Imaging. MRI is best for visualizing pineal neoplasms, which are typically located in the posterior wall of the third ventricle in the quadrigeminal cistern.

Diagnosis of pineoblastoma is based on pathologic examination of the mass after biopsy or surgical removal. See pathologic findings (pdf).

Confirming the Diagnosis

To confirm/establish the diagnosis of a DICER-1 related disorder in a proband requires identification of a heterozygous germline DICER1 pathogenic variant that is known or suspected to cause loss of function [Hill et al 2009, Rio Frio et al 2011, Schultz et al 2011, Slade et al 2011].

Sequence analysis should be performed first; if no pathogenic variant is identified, deletion/duplication analysis may be considered.

Table 1.

Summary of Molecular Genetic Testing Used in DICER1-Related Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
DICER1Sequence analysis 2~65% 3
Deletion/duplication analysis 4See footnote 5
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Of the 119 children with PPB who were tested, 77 (65%) had a germline loss-of-function variant in the coding region of DICER1 [Hill et al 2010]. It is not known what type of allelic variant accounts for the remainder.

4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

One family with a deletion involving DICER1 as causative of this disorder has been reported to date [Sabbaghian et al 2014] (see Molecular Genetics).

Clinical Characteristics

Clinical Description

Studies to date have focused on germline DICER1 pathogenic variants occurring in children with pleuropulmonary blastoma (PPB), in girls and women with ovarian sex cord-stromal tumors, children with cystic nephroma, and families with thyroid hyperplasia. The majority of tumors in families with a germline DICER1 pathogenic variant occur in individuals younger than age 40 years. Little is known about the risk for malignancies or other conditions in older adults with a germline DICER1 pathogenic variant.

Pleuropulmonary blastoma (PPB), a neoplasm that arises during lung development or shortly after birth, typically presents clinically in infants and in children younger than age six years; however, rare occurrences have been reported in older children and one adult. The natural history of PPB suggests that many tumors have a precancerous/early cancerous stage in the form of lung cysts. Although not all PPB lung cysts transform into high-grade sarcoma, no clinical or biologic markers can identify which cysts will progress to sarcoma. Progression from cyst to sarcoma can occur quickly (in a matter of months). Treatment is much more effective in the early cystic stage.

Symptoms and radiographic features correlate with three pathologic types that represent different stages in the natural history of the disease. Pathologic type is used to stratify patients into therapeutic groups (see Treatment of Manifestations) and, at this time, is the only known statistically significant predictor of outcome.

Typically, type I PPB becomes evident in infants and young children (median age 8 months) when they come to medical attention for difficulty breathing due to a large space-occupying cyst in the lung or pneumothorax secondary to a rupture of the air-filled cyst. Occasionally affected children are asymptomatic when lung cysts are identified on radiographic studies performed for non-respiratory symptoms.

In cases in which progression occurs, the mesenchymal cells of a type I PPB expand and overgrow the cyst septa and replace the cyst with a cystic and solid (type II) or purely solid (type III) sarcoma. The median ages at diagnosis for types II and III PPB are 35 and 41 months, respectively. A child with type II or III PPB typically presents with weight loss, fever, shortness of breath, and opacity on chest radiograph. Pneumothorax can also occur in type II PPB.

Not all type I PPBs progress to type II or III PPBs. The incidence of sarcomatous transformation in a type I PPB is not known. Type I PPBs that lack tumor cells (referred to as type IR PPB) are thought to have a limited biologic potential.

Type I PPB has no metastatic potential, but type II or III PPB can present with metastasis to the brain, bone, local thoracic lymph nodes, and liver.

Children with PPB type II or III who fail therapy may have tumor recurrence locally in the thorax and/or distant metastatic disease. The brain, followed by bone, is the most common site of distant metastasis in PPB. The outcome of these patients is poor, although some have survived long-term.

Other tumors observed in persons with PPB

Ovarian sex cord-stromal tumors. Age of onset, which is tumor-type specific, varies widely. Most ovarian sex cord-stromal tumors present at an early stage.

Germline heterozygous DICER1 pathogenic variants were seen in:

  • Four of six individuals with ovarian sex cord-stromal tumors and a personal or family history of PPB [Schultz et al 2011];
  • Two of three young women with ovarian sex cord-stromal tumor and a personal or family history consistent with the tumor types seen in DICER1-related disorders but without PPB;
  • Familial multinodular goiter (MNG) and MNG with SLCT, independent of PPB [Rio Frio et al 2011].

Types of ovarian sex cord-stromal tumors:

  • Sertoli-Leydig cell tumor (SLCT) may present with typical signs of an ovarian tumor including abdominal distention, abdominal pain, or mass. Signs of virilization such as hirsutism, voice changes, or acne may also be seen. While the tumor can occur at any age, it occurs most often in young adults.

    Ovarian sex cord-stromal tumors are staged using the International Federation of Gynecology and Obstetrics (FIGO) staging system. Well-differentiated, Stage Ia tumors generally behave in a benign fashion. Poorly differentiated or higher stage tumors are associated with a poorer prognosis.
  • Juvenile granulosa cell tumor (JGCT) presents in two broad clinical patterns:

    (1) In very young girls with signs of precocious puberty. These tumors are generally found as FIGO Stage Ia and are generally associated with an excellent prognosis.

    (2) In children and adolescents older than age ten years with or without signs of hormone production. These may behave in a more aggressive fashion.

    Stage appears to be the most important prognostic feature. Level of differentiation appears less important than in SLCT. However, both mitotic rate and preoperative vs. intraoperative rupture may play a role in prognosis [Schneider et al 2003].
  • Gynandroblastoma. These exceedingly rare tumors typically occur in adults, although there is a (rarer) juvenile form. Girls and young women with this tumor may present with or without signs of excess hormonal production. Two individuals with gynandroblastoma and a germline DICER1 pathogenic variant have been described [Schultz et al 2011].

    The tumors are usually found at an early stage and typically cured with resection alone [Schultz et al 2011]. Only one case of recurrent gynandroblastoma is noted in the literature [Chivukula et al 2007].

Cystic nephroma (CN) is typically considered a benign neoplasm that presents as a cystic parenchymal renal tumor (most commonly as a painless, enlarging abdominal or flank mass) in children less than age four years. Hematuria, hypertension, and urinary tract infection are uncommon presentations.

CN may grow rapidly and cause concern for mass effect on normal functioning kidneys, a particular concern in bilateral tumors.

A small number of children with CN and a germline DICER1 pathogenic variant have later developed high-grade renal sarcomas resembling PPB [Doros et al 2014]. This sarcomatous transformation in the kidney may be similar to the transformation observed in the lung. In both instances, the incidence of sarcomatous transformation is not known.

Multinodular goiter (MNG) and thyroid cancer. Two reports and International PPB Registry (IPPBR) data support an increased risk of developing thyroid cysts and/or multinodular goiter (MNG) in families with a germline DICER1 pathogenic variant [Rio Frio et al 2011, Slade et al 2011].

While a heterozygous germline DICER1 pathogenic variant appears to be associated with an increased risk of developing MNG, current data also suggest a low risk of developing syndrome-associated differentiated thyroid cancer (DTC) (i.e., either papillary [PTC] or follicular thyroid cancer [FTC]) [Hill et al 2009, Rio Frio et al 2011, Slade et al 2011]. Differentiated thyroid cancers have occurred in children with PPB and in family members with a germline DICER1 pathogenic variant. Whether or not additional factors (e.g., chemotherapy and diagnostic or therapeutic radiation) contribute to the development of these tumors is not known. The outcome of thyroid tumors in this group appears favorable.

Ciliary body medulloepithelioma (CBME) typically occurs in young children with only rare examples in adults reported in the literature. Four CBMEs were observed among 550-600 individuals with PPB: three in affected individuals and one in a parent. Fewer than 1% of persons with pleuropulmonary blastoma manifest CBME, and 5% of persons with medulloepithelioma have a history of PPB [Priest et al 2011, Kaliki et al 2013].

Although CBMEs are considered malignant neoplasms based on their histology, distant metastasis and mortality are rare [Broughton & Zimmerman 1978]. Mortality from CBME usually results from intracranial spread rather than systemic metastases.

In four children with CBME and PPB [Priest et al 2011], the mean age of diagnosis was seven years; the duration of symptoms before the diagnosis of CBME was nine months. Two children had decreased visual acuity noted by family members, one failed a school visual acuity test, and one had headaches and discolored pupils. In three of the four, cataract was associated with the tumors. All four were alive and well seven months to 44 years after the diagnosis of CBME.

Botryoid-type embryonal rhabdomyosarcoma (ERMS) of the cervix seen in DICER1 syndrome, which most commonly occurs in pubertal and post-pubertal adolescent girls and young women, presents with vaginal bleeding or spotting or passage of tissue. These polypoid, well-differentiated rhabdomyosarcomas do well following complete surgical excision and chemotherapy (see Management) [Dehner et al 2012, Doros et al 2012].

Nasal chondromesenchymal hamartoma (NCMH) is considered a benign neoplasm. Surgical removal is curative; however, local recurrences can occur (see Management). Of approximately 625 individuals with PPB, four children developed NCMH. These four are among 28 cases reported throughout the literature [Priest et al 2010].

Pituitary blastoma. A new entity discovered in 2008, pituitary blastoma typically presents in children under age two years [Scheithauer et al 2012]. Germline and somatic “second hit” pathogenic variants of DICER1 in multiple cases of pituitary blastoma have been reported in abstract form [de Kock et al 2013b]. Surgery with or without adjuvant therapy can be curative, although of the six reported cases, two were known to have died of the disease.

Pineoblastoma is a type of primitive neuroectodermal tumor of the pineal gland that typically occurs in children. Only one has been reported to date, associated with a germline DICER1 pathogenic variant. Pineoblastomas are generally large and associated with obstructive hydrocephalus at diagnosis [Tate et al 2011]. Classically pineoblastoma has been described to have a short clinical course and poor prognosis. With chemotherapy and radiation therapy, overall survival is improved 60%-75% in some studies [Jakacki et al 1995].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Penetrance

The penetrance of heterozygous germline DICER1 pathogenic variants appears to be reduced; however, the penetrance for any specific DICER1-related disorder is not known. While it is uncommon to have more than one individual in a family diagnosed with PPB, some of the other conditions associated with a germline DICER1 pathogenic variant (e.g., nodular hyperplasia of the thyroid, benign lung cysts) may have higher penetrance.

Nomenclature

Pleuropulmonary blastoma (PPB) has been referred to as “rhabdomyosarcoma arising in congenital cyst.”

Pulmonary blastomas, biphasic epithelial and mesenchymal malignancies of the lung occurring in a broader age group, are not related to PPBs.

Nodular hyperplasia of the thyroid is commonly called goiter.

Ciliary body (or ocular) medulloepithelioma has also been called diktyoma or a teratoneuroma.

Prevalence

The prevalence of DICER1-related disorders is not known. With the exception of thyroid gland neoplasia, all the conditions associated with a germline DICER1 pathogenic variant are rare. For example, about 25-30 cases of PPB from the United States are reported to the International PPB Registry (IPPBR) annually.

Differential Diagnosis

Pleuropulmonary Blastoma (PPB)

Congenital cystic adenomatoid malformation (CCAM). Type I PPB cannot be distinguished radiographically from benign congenital cystic lung malformations; however, pneumothoraces and the presence of multifocal or bilateral cysts are more common in PPB than in other conditions. The difficulties in distinguishing PPB from CCAM have led some pediatric surgeons to advocate excision of all CCAMs [Priest et al 2009, Oliveira et al 2011].

Pulmonary sequestrations and peripheral bronchogenic cysts are more complex lesions that are commonly diagnosed prenatally. Although their radiographic and histologic features should facilitate differentiation from PPB [Shanti & Klein 2008], there is one report of a pulmonary sequestration in a patient with a germline DICER1 pathogenic variant [Foulkes et al 2011].

Lung cysts and pneumothoraces. Multiple inherited and non-inherited disorders can present with lung cysts and/or pneumothorax. However, many of these can be distinguished from PPB on the basis of medical history and physical examination.

Solid lung tumors of childhood. Lung and other thoracic tumors are rare in children under age six years, the age at which PPB most commonly occurs. Rarely, PPB is seen in teenagers. One adult with PPB has been reported [Hill et al 1999].

  • Most tumors presenting in the newborn period are solid lung tumors; they include fetal lung interstitial tumor [Dishop et al 2010], congenital peribronchial myofibroblastic tumor, and solid type 3 CCAM. There are no known genetic associations with these three conditions. To date, solid PPB has not been observed in a newborn.
  • Synovial sarcoma is the main differential diagnosis for PPB in young adults. Synovial sarcomas can be pleural-based and cystic [Cummings et al 2010]. PPBs are typically more heterogeneous than synovial sarcomas, but the spindle cell components of PPB and synovial sarcoma can be remarkably similar. Immunohistochemistry demonstrating epithelial markers or identification of a fusion protein involving the gene SYT is helpful for making a diagnosis of synovial sarcoma.
  • Rhabdomyosarcoma and Ewing sarcoma tend to originate in the chest wall or soft tissue of the diaphragm rather than the lung parenchyma.
  • Pulmonary blastoma is a biphasic tumor with malignant epithelial elements and mesenchyme with a median age range at presentation of 43 years [Van Loo et al 2011].
  • Inflammatory myofibroblastic tumors originate in the lung (typically in children age >3-4 four years) as a well-circumscribed, lobar-based mass. These tumors comprise myofibroblasts that can be demonstrated by immunostain for smooth muscle actin. Forty percent to 50% of inflammatory myofibroblastic tumors have translocations involving ALK (the gene encoding anaplastic lymphoma kinase) and show immunostaining for the ALK protein.

Other Tumors

Ovarian sex cord-stromal tumors

  • Ovarian germ cell tumors are seen more commonly in young children whereas epithelial ovarian tumors are seen more often in older women.
  • Ovarian small cell carcinoma of the hypercalcemic type may mimic an ovarian stromal tumor but the distinction is usually clear when the calcium level is evaluated.
  • Sertoli/Leydig cell tumor (SLCT) and rarely juvenile granulosa cell tumor (JGCT) may also secrete alpha-fetoprotein (AFP), thus leading to consideration of immature teratoma or yolk sac tumor. Typically the elevation in AFP is less than 500 nanograms/milliliter with sex cord-stromal tumors and pathologic examination generally confirms the correct diagnosis.
  • Adult granulosa cell tumors are occasionally seen in children and are also associated with elevation of inhibin A and/or B but are pathologically distinct from the juvenile form.

Renal cysts and cystic tumors

  • Cystic renal tumors include congenital mesoblastic nephroma (solid and cystic), cystic partially differentiated nephroblastoma (CPDN), cystic Wilms tumor, renal cell carcinoma, clear cell sarcoma, cystic variants of mesoblastic nephroma, and multicystic dysplastic kidney.
  • Another cystic neoplasm of the kidney that appears to be more common in CN typically occurring in women over age 50 years is the so-called mixed epithelial and stromal tumor (aka adult CN). The cysts of these tumors resemble those in DICER1-related CN but often contain a cellular stroma resembling ovarian stroma; however, to date this tumor has NOT been associated with a DICER1 germline pathogenic variant.
  • Isolated renal cysts are common in the general population, and the prevalence rises with increasing age. Simple renal cysts (Bosniak category I) and cystic renal dysplasia are most commonly seen in children. Birt-Hogg-Dubé syndrome [Toro et al 2007] is also associated with renal cysts, oncocytoma, and chromophobe renal cell carcinoma. None of these latter lesions are known to be associated with PPB or a DICER1 germline pathogenic variant.

Multinodular goiter (MNG)

  • MNG is common; an increased incidence is associated with iodine deficiency, female gender, and advancing age. Elevated thyroid stimulating hormone (TSH) from iodine deficiency, goitrogens, and inborn errors of thyroid hormone biosynthesis are also considered secondary factors associated with an increased risk of developing disease.
  • The method of detection correlates with disease prevalence: a higher percent of disease is found by ultrasound examination or autopsy compared to physical examination. In general, in iodine-sufficient countries the prevalence of MNG is estimated at 4% of the population [Pinchera et al 1996]. Familial MNG is suggested by early-onset MNG without iodine deficiency most frequently described with an autosomal dominant pattern of inheritance (reviewed in Paschke [2011]).
  • MNG is common in adults, even outside of iodine-deficient regions [Pinchera et al 1996, Paschke 2011, Rio Frio et al 2011, Slade et al 2011, Colamaio et al 2012]. Familial MNG and MNG associated with tumors should prompt consideration of the following:
    • Familial non-medullary thyroid carcinoma [Shin et al 2001, Oue et al 2008, Rome et al 2008], associated with multifocal and bilateral papillary thyroid carcinoma and multinodular goiter
    • Familial multinodular goiter. Two loci have been identified: MNG1 linked to 14q31; MNG2 linked to Xp22. Recent work has identified DICER1 pathogenic variants at MNG1 in persons with MNG with and without ovarian SLCTs [Rio Frio et al 2011]. The identity of MNG2 (OMIM 300273) remains unknown.
    • PTEN hamartoma tumor syndrome (PHTS), which includes Cowden syndrome and is associated with distinct mucocutaneous lesions and breast, thyroid, and endometrial carcinomas. Thyroid adenoma and MNG are minor criteria and epithelial thyroid tumors (non-medullary) are major criteria (both follicular and papillary thyroid cancer).
    • Birt-Hogg-Dubé syndrome [Toro et al 2007], caused by mutation of FLCN. MNG is a reported association in BHD, but it is unclear whether it is truly syndrome related.
    • Pendred syndrome, which includes severe bilateral sensorineural hearing impairment and vestibular dysfunction
    • McCune-Albright syndrome. MNG is a common feature with a low risk of thyroid carcinoma.
  • Other disorders associated with familial MNG include the following thyroid dyshormonogeneses:
    • Thyroglobulin (OMIM 188450), caused by mutation of TG
    • Thyroid peroxidase (OMIM 606765), caused by mutation of TPO
    • Sodium iodide symporter (OMIM 601843), caused by mutation of SLC5A5
    • TSH receptor (OMIM 603372), caused by mutation of TSHR
    • Iodotyrosine deiodinase (OMIM 612025), caused by mutation of IYD
    • Thyroid oxidase 2 (OMIM 606759), cause by mutation of DUOX2

Ciliary body medulloepithelioma (CBME)

  • In children the clinical differential diagnosis of a mass in the ciliary body includes an anteriorly located retinoblastoma, ciliary body cyst, or leiomyoma and xanthogranuloma of the ciliary body. Anteriorly located retinoblastoma occurs in older children and is frequently calcified [Vajaranant et al 2005].
  • In adults, the clinical differential diagnosis of a mass in the ciliary body includes adenoma or adenocarcinoma of the ciliary epithelium (pigmented or non-pigmented), mesoectodermal leiomyoma, neurilemmoma, metastatic carcinoma, and granuloma.

Cervical embryonal rhabdomyosarcoma (ERMS)

  • Because cervical ERMS is a pedunculated polyp presenting at the cervical os, a benign cervical polyp composed in part of endocervical glands and a squamous mucosa is a common clinical impression.
  • Other non-neoplastic polypoid lesions of the cervix are granulation tissue polyp, decidua, and squamous papilloma.
  • Mesodermal stromal polyp is composed of enlarged stellate and spindle cells in a pale staining myxoid stroma without any glandular structures. These stromal cells lack the features of rhabdomyoblasts.
  • Müllerian papilloma is a purely epithelial lesion with a complex papillary pattern; this lesion is seen in children.
  • Müllerian adenosarcoma is a malignant polypoid lesion of the cervix with a pattern of benign endocervical glands and a spindle cell sarcomatous stroma without rhabdomyoblastic differentiation; these tumors, which occur in older women, have been confused with ERMS.

Nasal chondromesenchymal hamartoma (NCMH)

  • The cartilaginous nodules surrounded by a compact, hypercellular zone of immature stromal cells of NCMH can be confused with ERMS. However, the stromal cells of NCMH lack a myogenic phenotype.
  • Other patterns in NCMH may mimic aneurysmal bone cyst or fibrous dysplasia.

Pituitary blastoma

  • Clinically, a pituitary mass in a young child should prompt consideration of adenoma, massive pituitary hyperplasia, and much rarer entities like pituitary carcinoma, hamartoma or teratoma.
  • Non-neoplastic inflammatory entities may also affect this region.

Pineoblastoma

  • Pineoblastomas need to be distinguished from better differentiated pineal parenchymal tumors like pineocytoma and pineal parenchymal tumor of intermediate differentiation. The pineal gland is also a common location for germ cell tumors.
  • Other embryonal tumors like medulloblastoma should be considered if the tumor is not localized to the pineal region but rather extends into the infratentorial region.

Management

Evaluations Following Initial Diagnosis

For an individual diagnosed with a DICER1-related disorder, the two considerations for evaluations following initial diagnosis are:

  • The extent of disease spread (staging) for malignant or potentially malignant DICER1-related disorders;
  • The presence of other synchronous DICER1-related conditions.

Extent of Disease Spread (Staging)

Pleuropulmonary blastoma types I and IR. No metastatic potential is associated with this type; thus, the only additional evaluation is for synchronous DICER1-related disorders (see Surveillance).

Pleuropulmonary blastoma types II and III

  • Brain MRI to evaluate for metastatic disease
  • Radionuclide bone scan to evaluate for metastatic disease, followed by plain radiographs for areas of concern
  • PET scan for diagnosis of solid or cystic and solid tumors, response to therapy, and follow-up. Note, however, that its use has not been validated in PPB.
  • Echocardiography as needed to define intracardiac extension of tumor, tumor thrombi, or pericardial effusion
  • Rarely, spine MRI for a paraspinal or intraspinal extension
  • In the event of systemic embolization and any suggestion of vascular involvement (facial plethora, vena cava syndrome, cardiac murmur): investigation with vascular ultrasound examination
  • CT of the abdomen to assess for liver metastases

Note: Bone marrow evaluation is almost never performed, as bone marrow involvement is extremely rare.

Ovarian sex cord-stromal tumors

  • Intraoperative staging should be performed according to FIGO staging criteria and should include peritoneal cytology and assessment of preoperative or intraoperative rupture. Care should be taken to avoid rupturing the tumor if possible.
  • Spread of ovarian stromal tumors to the chest without extensive abdominopelvic disease is unlikely; however, baseline evaluation with chest CT is reasonable given the concern for synchronous conditions.

Ciliary body medulloepithelioma. Staging includes brain MRI to evaluate for direct intracranial extension and metastatic disease.

Botryoid-type embryonal rhabdomyosarcoma (ERMS) of the cervix or other sites. Staging includes MRI or CT to evaluate extent of primary tumor and for presence of metastatic disease in lymph nodes, liver, and lungs.

Pituitary blastoma. Staging includes brain and spine MRI, and cerebrospinal fluid (CSF) cytology examination.

Pineoblastoma. Staging includes brain and spine MRI, and CSF cytology examination.

Evaluations for Synchronous DICER1-Related Disorders

One or more of the disorders associated with a heterozygous DICER1 germline pathogenic variant may be present at the time of diagnosis or they may develop later in life. Evaluations to be performed for individuals newly diagnosed with a heterozygous DICER1 germline pathogenic variant are included in Surveillance.

Treatment of Manifestations

Pleuropulmonary Blastoma (PPB)

Surgical management. Treatment for all types is complete surgical resection when feasible. Chemotherapy is recommended in all cases of types II and III PPB utilizing aggressive sarcoma-based regimens; for type I less aggressive regimens can be used based on extent of resection and disease.

  • Type I PPB is treated with complete surgical removal with or without adjuvant chemotherapy. The long-term survival for this subgroup is over 94%; the only deaths are following progression to type II or III [Messinger et al 2012].
  • Types II and III PPB are treated with aggressive surgical resection and intensive chemotherapy; survival rates at ten years are 62% for type II and 46% for type III [Williams et al 2012].

Complete resection of PPB is recommended by physicians associated with the International PPB Registry (IPPBR). For cystic and solid or purely solid tumors, primary resection is preferred, but adequate biopsy followed by neoadjuvant chemotherapy and delayed complete resection is acceptable. Surgical removal of every cyst may not be possible when cysts are extensive.

Primary resection of tumors that are cystic and solid or purely solid should be performed with care so as not to disrupt the tumor or induce tumor spill, similar to the care taken with removal of Wilms tumor. Since solid components of PPB are very friable, piecemeal removal and spill are often inevitable.

If it is evident at the time of surgery that the tumor has spread to the chest wall, pericardium, and/ or diaphragm, removal of all grossly visible tumor is recommended. Sites of unresectable residual disease may be titanium clipped for radiographic localization and possible radiotherapy. Involvement of the diaphragm may require excision of a portion of the diaphragm and use of a Gortex patch.

Delayed resection after chemotherapy is performed for tumors deemed unresectable at the time of diagnosis. Individuals receiving neoadjuvant chemotherapy may have marked tumor reduction; however, this response may be transient and tumor can recur rapidly. Chemotherapy alone is insufficient to eradicate solid PPB.

The IPPBR physicians recommend that surgical resection occur no later than after the third cycle of chemotherapy. As with primary surgery, removal of all sites of gross disease should be attempted if possible.

If gross-total resection is not achieved, additional surgery may be required for local control.

Pleural effusions. Drainage of pleural effusions should be approached with caution. Solid tumors often invade the chest wall obliterating the pleural space. Proper placement of needle and catheter can be difficult without radiographic guidance.

Surgery for metastases. Brain parenchyma is the most common metastatic site for PPB. Resection is strongly suggested for intracranial mass lesion(s). Several patients in whom cerebral PPB metastases have been resected have had durable, non-relapse survival [Priest et al 2007].

Therapeutic resection of bone and liver metastases is rarely indicated.

Chemotherapy

  • Type I PPB. Use of chemotherapy is controversial [Priest et al 2006, Messinger et al 2012].
  • Types II and III PPB. Aggressive chemotherapy is necessary. Chemotherapy regimens are typically based on other childhood sarcoma regimens with the inclusion of vincristine, actinomycin-D, cyclophosphamide or ifosfamide, and doxorubicin. Agents that have been used with limited success include etoposide and cisplatin or carboplatin.

The IPPBR is currently conducting the first prospective clinical study of an aggressive multi-agent chemotherapy; specifics are available at the IPPBR Web site (www.ppbregistry.org).

Radiation therapy. Radiation therapy is used primarily to treat PPB recurrence or metastasis, or in the setting of local control of residual unresectable tumor [Priest et al 1997, Kamenova et al 2006, Indolfi et al 2007, Williams et al 2012].

Radiation therapy of brain metastasis can result in long-term survival for some patients.

If radiation therapy is chosen, dosage appropriate for high-grade sarcoma (44 Gy or above) should be used [Indolfi et al 2007].

Treatment failure. Survival after failure of primary therapy for types II and III PPB is poor – 35% at two years and 27.5% at five years, respectively [IPPBR, unpublished data]. Modalities used include surgery, attempted repeat complete resection, and radiation therapy. High-dose chemotherapy and autologous stem cell transplantation have also been used. Intracavitary 32P and cisplatin have also been used on occasion. Because cases are few and chemotherapy regimens used to treat recurrences have varied, data to support specific treatment recommendations in the setting of recurrent disease are limited.

Ovarian Sex Cord-Stromal Tumors

Ovarian sex cord-stromal tumors (including Sertoli-Leydig cell tumor, juvenile granulosa cell tumor, and gynandroblastoma) are rare and few studies have focused on clinical variables, treatment, and prognosis. Treatment regimens are based on those used for ovarian germ cell tumors and data are limited [Schneider et al 2002, Schultz et al 2012].

If imaging or laboratory studies suggest the presence of an ovarian tumor, consultation with specialists in surgery/gynecology and oncology is suggested. Surgical resection with staging procedures is usually the initial treatment. Fertility-sparing surgery is recommended for most girls and young women.

Most patients undergo unilateral salpingo-oophorectomy with sampling of peritoneal fluid and cytologic examination of peritoneal washings. Lymph nodes should be carefully examined intraoperatively and removed if they are clinically concerning. Level of differentiation and stage influence outcome and are critical to determining whether adjuvant therapy is necessary. Effort must be made to avoid rupture of the tumor as this would result in an increased stage for some patients. If rupture occurs, the timing of rupture (preoperative vs. intraoperative rupture) must be carefully documented as this may influence the need for adjuvant therapy.

The decision to use adjuvant treatment such as chemotherapy following surgery for SLCT or JGCT is based on histology and stage:

  • Sertoli-Leydig cell tumor. For SLCT stage greater than Ia (including Ic with perioperative or preoperative rupture or poorly differentiated SLCT), adjuvant chemotherapy is sometimes used. Depending on the stage, pathology, and need for fertility preservation, consideration should also be given to additional surgery.

    When chemotherapy is used, a platinum-based regimen such as cisplatin, etoposide, and bleomycin (PEB) or cisplatin, etoposide, and ifosfamide (PEI) is often used. Additional regimens more often used in adults may include taxanes or anthracyclines. A Phase II randomized trial is currently open through Gynecology Oncology Group comparing cisplatin, etoposide and bleomycin to carboplatin and paclitaxel.

    Follow-up monitoring for ovarian sex cord-stromal tumors should include attention to tumor markers and imaging. Imaging with either MRI or ultrasound may be preferred over CT as neither involves ionizing radiation; however, the use of MRI in very young children is limited by the need for sedation. If MRI is used, the radiologist should be notified of the clinical concern for ovarian tumor so that appropriate imaging protocols are used.
  • Juvenile granulosa cell tumor (JGCT). In young children with FIGO Stage Ia JGCT the prognosis is excellent with resection alone.

    Adjuvant chemotherapy, often given with higher-stage disease, is suggested for stages higher than Ic. The most common regimens in the United States include a platinum analog, generally cisplatin, etoposide, and bleomycin (PEB) and in Europe cisplatin, etoposide, and ifosfamide (PEI).

    An individualized approach is needed in the instance of preoperative vs intraoperative tumor rupture.

    Generally speaking, recurrent JGCT is difficult to treat and the approach is highly individualized. Hyperthermic chemotherapy has been used by some investigators. Although a small number of survivors of advanced or recurrent JGCTs underwent radiation therapy, the use of radiation therapy in the treatment of recurrent ovarian sex cord-stromal tumors is not well defined.
  • Gynandroblastoma. The malignant potential of gynandroblastoma is not yet clear. Most are found in an early stage, and surgical resection has been curative for the majority of the reported cases.

Other Tumors

Cystic nephroma

  • Surgery. Treatment consists of surgical resection via partial or full nephrectomy. Surgical removal of every cyst may not be possible for patients with extensive bilateral cysts.
  • Chemotherapy. Although the use of chemotherapy has been considered in rare cases with extensive bilateral disease and continued rapid growth, its efficacy has not been studied.

Multinodular goiter (MNG) and thyroid cancer

  • Observation with or without biopsy. The approach to preoperative investigation is the same for patients with a sporadic nodule with or without a DICER1 pathogenic variant. See guidelines from the American Thyroid Association (purchase required) or the American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid Association collaborative (available online).
  • Ultrasound examination is used to confirm the nodule and to determine the need for fine needle aspiration biopsy (FNA). In general, FNA is recommended for nodules measuring ≥1 cm. FNAB of smaller nodules should be considered in patients with a history of previous radiation exposure and/or concerning sonographic features, including (but not limited to) microcalcifications and abnormal lymph nodes. FNA results that show benign-appearing follicular cells (including Hürthle cells and/or lymphocytes) indicate (in most cases) nodular hyperplasia, follicular adenoma, or lymphocytic thyroiditis. Continued follow-up care is appropriate in the presence of a stable nodule(s).
  • Surgery is appropriate for symptomatic nodules or nodules with significant growth on serial US examination. If the results of the FNA are positive for papillary thyroid carcinoma, total thyroidectomy is the treatment of choice in patients who are surgical candidates.
  • Radioactive iodine (RAI) is the most effective medical treatment for patients found to have distant (lung) metastasis or persistent disease not amenable to repeat surgery.

Ciliary body medulloepithelioma (CBME). The four management options include:

  • Observation. In one patient age nine years with CBME and PPB, the CBME was monitored in six-month intervals over a two-year period by high-resolution imaging and ocular examination. The histology of the CBME was unknown [Priest et al 2011].
  • Local resection. Small, well-circumscribed (<3 clock hours) tumors may be treated by local resection with preservation of useful vision. However, many of these tumors will progress. In one series of ten individuals with CBME, six were initially treated with local resection, including two who received application of a radioactive plaque. However, in all six, tumor recurred after a mean of 2.5 years. Four required enucleation, one received local cryotherapy, and one needed exenteration and irradiation [Shields et al 1996].
  • Enucleation. Most CBME have advanced features at diagnosis (friable appearance, a neoplastic cyclitic membrane or adjacent free-floating cysts) that should prompt enucleation. Long-term survival is common after this definitive therapy. Four of the five individuals reported with CBME and PPB underwent enucleation with follow-up ranging from seven months to 44 years [Priest et al 2011, Laird et al 2013].
  • Orbital exenteration. Although rarely indicated, exenteration (with consideration of adjunct chemotherapy and radiation) is required for a CBME that extends beyond the globe. Although long-term survival has been observed following exenteration, it is generally associated with a poor prognosis [Broughton & Zimmerman 1978].

Botryoid-type embryonal rhabdomyosarcoma of the cervix may not require hysterectomy since these tumors are usually confined to the cervix and typically do not have deep stromal invasion. Local resection followed by chemotherapy appropriate for ERMS is one management approach. On completion of chemotherapy, biopsies are performed to determine if residual viable tumor is present. The decision for additional treatment is based on the results of the post-chemotherapy biopsies and follow-up imaging studies.

Nasal chondromesenchymal hamartoma (NCMH). The extent of this tumor is best determined by appropriate imaging studies and is usually managed by surgical resection. When access to the tumor is adequate one approach is endonasal endoscopy with resection. If complete resection is difficult, these tumors can be effectively debulked in most cases; however, complete extirpation is preferred.

Pituitary blastoma. All six reported patients with pituitary blastoma had surgical resection of the mass by a variety of approaches [Scheithauer et al 2012]; five had subtotal resection and the sixth had a gross total resection. For adjuvant therapy one patient received “polychemotherapy” and another received temozolomide and 5400 cGy radiation therapy. Normalization of endocrine laboratory values, especially ACTH, is expected post-operatively and is a useful marker of disease activity. Some children have required two surgeries to successfully extirpate the tumor.

Pineoblastoma. Immediate management issues may include interventions for obstructive hydrocephalus. MRI of the entire spinal axis is indicated, as is CSF cytology and serum and CSF sampling of germ cell tumor markers (beta-human chorionic gonadotropin, alpha-fetoprotein). Open resection, rather than biopsy, is the treatment of choice for pineoblastoma. An aggressive surgical approach is associated with prolonged survival. Following maximal surgical resection, standard adjuvant therapy includes fractionated radiotherapy (to brain and spine) and chemotherapy [Tate et al 2011].

Surveillance

No guidelines regarding initial screening evaluations or surveillance of persons with a germline DICER1 pathogenic variant have been established. Based on data from the International PPB Registry (IPPBR) which includes more than 500 persons with symptomatic or asymptomatic DICER1-related disorders, the authors recommend (1) annual physical examination and targeted review of systems, and (2) imaging study type and frequency based on tumor type, patient age, and suspicious clinical findings.

PPB. Baseline chest CT to evaluate for lung cysts or tumors in a patient of any age

Note: The most critical age group for chest CT is children under age three years, the peak risk age for solid PPB. The negative predictive value of a normal chest CT for development of PPB is not known.

CN

  • Baseline kidney CT or ultrasound examination in a patient diagnosed with PPB
  • In a patient of any age, especially those younger than age four years, annual abdominal examination and monitoring for abdominal pain, swelling, or hematuria
    Note: The negative predictive value of a normal kidney CT or ultrasound examination for development of CN is not known.

Thyroid gland neoplasia

  • Thyroid physical examination in a patient of any age
    • If thyroid gland asymmetry and/or a nodule are detected, perform thyroid ultrasound examination to confirm as well as to determine if surveillance or fine needle aspiration biopsy is warranted.
    • If no nodules are detected, continue annual physical examination and consider repeat thyroid US every three to five years.
  • Thyroid ultrasound examination if the patient has previously received chemotherapy or as a baseline if chemotherapy is anticipated
  • Thyroid function testing as indicated based on clinical signs and symptoms of hypo- or hyperthyroidism

Ovarian stromal tumors

  • Examination of all females of any age for signs and symptoms of precocious puberty or virilization, and masses in the abdomen or pelvis. If any are detected, perform appropriate imaging and laboratory evaluations.
  • Imaging: abdominal-pelvic US examination, MRI, or CT
  • Laboratory testing: serum markers AFP, beta-HCG, LDH, inhibin A and B, estradiol, testosterone, CA125, and serum electrolytes including calcium
    Note: There is no current recommendation for laboratory screening in the absence of a mass or clinical findings of sex hormone excess.
  • For women and the parents of young girls with a DICER1 germline pathogenic variant: education regarding the possible presenting signs and symptoms of ovarian sex cord-stromal tumors (abdominal distension, precocious puberty, amenorrhea, and signs of virilization [hirsutism, voice changes, acne])

CBME

  • Evaluation of young children for ciliary body medulloepithelioma including measurement of visual acuity
  • Visual inspection of the eye and orbit

Botryoid ERMS. In infants, children, and young adults: when signs/symptoms of hematuria or abnormal vaginal bleeding are present, endoscopic evaluation of the bladder or direct visualization of the cervix, respectively

NCMH. In infants, children, adolescents, and adults:

  • Review of systems including respiratory and feeding difficulties, rhinorrhea, epistaxis, visual disturbances, and otitis media
  • Nasal endoscopy as warranted by ophthalmologic signs (e.g., ophthalmoplegia, proptosis, ptosis, hypotropia, and enophthalmos) resulting from orbital involvement of the tumor

Pituitary blastoma. Brain MRI for persons with a DICER1 germline pathogenic variant with signs of cortisol excess

Pineoblastoma. Brain MRI for persons with a DICER1 germline pathogenic variant with signs of increased intracranial pressure such as headache, full fontanel, vomiting, and lethargy, or other neurologic defects including upgaze paralysis and nystagmus

Evaluation of Relatives at Risk

If the germline DICER1 pathogenic variant has been identified in an affected family member, it is reasonable to offer molecular genetic testing to at-risk relatives of all ages to clarify their genetic status and to provide recommendations for age-appropriate surveillance and early intervention.

If first-degree relatives are not able to undergo molecular genetic testing, surveillance should be based on clinical changes that would warrant further investigation as detailed above (see Surveillance).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although large lung cysts in the fetus can theoretically impair lung development, such an occurrence appears to be uncommon. According to the IPPBR, prenatal ultrasound examination has detected lung cysts in seven cases at 31-35 weeks’ gestational age.

Because large lung cysts can cause respiratory distress in newborns, it is recommended that prenatal identification of lung cysts prompt consultation with specialists in high-risk obstetrics and fetal medicine to monitor the pregnancy and manage the delivery.

Therapies Under Investigation

The first prospective treatment trial is now open at many institutions in the United States and Europe. For details on study enrollment and institutional approval, see the IPPBR Web site.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Tumor susceptibility in individuals with a DICER1-related disorder is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Of the 65% of individuals with PPB who have a detectable germline DICER1 pathogenic variant, 80% have inherited the germline pathogenic variant from a parent. De novo germline variants account for approximately 20% of cases [Hill et al 2010].
  • The apparent absence of a family history in multiplex and simplex cases (i.e., a single occurrence in the family) could result from reduced penetrance or lack of information about the family.
  • Although multiple PPBs within a family with DICER1-pleuropulmonary blastoma (PPB) familial tumor predisposition syndrome are rare, approximately 35% of index cases of PPB have a close relative with a benign lung cyst or other PPB-related condition.
  • It is appropriate to evaluate the parents of an affected individual with molecular genetic testing of DICER1 for the pathogenic variant identified in the proband.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are de novo mutation in the proband or germline mosaicism in a parent. Although no instances of germline mosaicism have been reported, it remains a possibility.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

Offspring of a proband. Each child of an individual with germline DICER1 pathogenic variant has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has a germline DICER1 pathogenic variant, his or her family members may be at risk for PPB and/or related tumors.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant, the variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future. Consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • American Childhood Cancer Organization (ACCO)
    PO Box 498
    Kensington MD 20895-0498
    Phone: 800-366-2223 (toll-free); 301-962-3520
    Fax: 301-962-3521
    Email: staff@acco.org
  • CancerCare
    275 Seventh Avenue
    Floor 22
    New York NY 10001
    Phone: 800-813-4673 (toll-free); 212-712-8400 (administrative)
    Fax: 212-712-8495
    Email: info@cancercare.org
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-4-CANCER
  • National Coalition for Cancer Survivorship (NCCS)
    A consumer organization that advocates on behalf of all people with cancer
    1010 Wayne Avenue
    Suite 770
    Silver Spring MD 20910
    Phone: 888-650-9127 (toll-free); 301-650-9127
    Fax: 301-565-9670
    Email: info@canceradvocacy.org
  • International Ovarian and Testicular Stromal Tumor Registry
    2545 Chicago Avenue South
    Suite 412
    Minneapolis MN 55404
    Phone: 612-813-5861
    Fax: 612-813-6325
    Email: krisann.schultz@childrensMN.org; otst@childrensmn.org
  • International Pleuropulmonary Blastoma Registry
    2545 Chicago Avenue South
    Suite 412
    Minneapolis MN 55404
    Phone: 612-813-7115
    Fax: 612-813-7108
    Email: info@ppbregistry.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

DICER1-Related Disorders: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
DICER114q32​.13Endoribonuclease DicerDICER1 databaseDICER1

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for DICER1-Related Disorders (View All in OMIM)

138800GOITER, MULTINODULAR 1, WITH OR WITHOUT SERTOLI-LEYDIG CELL TUMORS; MNG1
601200PLEUROPULMONARY BLASTOMA; PPB
606241DICER, DROSOPHILA, HOMOLOG OF, 1; DICER1

Molecular Genetic Pathogenesis

Click here (pdf) for detailed information on the molecular genetic pathogenesis of DICER1-related disorders.

Gene structure. DICER1 produces a 10277-bp transcript (NM_177438.2). For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. Benign variants are seen in the coding region of the gene.

Pathogenic allelic variants. Several families with DICER1-related disorders have been identified as having either single nucleotide changes or small insertion/deletions that result in premature truncation of the protein product. A small number of splice and missense variants have been identified in conserved amino acids and are predicted to be deleterious (Table 2). One large germline deletion affecting DICER1 has been detected by MLPA [Sabbaghian et al 2014].

Table 2.

Examples of DICER1 Variants

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Benignc.1935G>A (rs61751177)SynonymousNM_177438​.2
NP_803187​.1
c.3033G>A (rs8019857)Synonymous
Pathogenic 1c.1376+1G>TSplice
c.4748T>Gp.Leu1583Arg
c.2243_2244insCTAAp.Tyr749Ter
c.4960_4961dupGAp.Asp1654GlufsTer7
c.1966C>Tp.Arg656Ter
c.1694_1695delATp.Thr566ArgfsTer7
c.3270-6_4051-1280delinsG 2p.Tyr1091SerfsTer2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variants associated with DICER1-related disorders

2.

Deletion of exon 21; deletion breakpoints in flanking introns [Sabbaghian et al 2014]

Normal gene product. DICER1 encodes an RNase III enzyme comprising 1922 amino acid residues. The protein functions in the microRNA (miRNA) and siRNA biogenesis pathways cleaving precursor double stranded RNAs into their active forms.

Abnormal gene product. Loss-of-function germline pathogenic variants in DICER1 coupled with somatic missense pathogenic variants in particular amino acids lead to defective production of mature miRNAs from the 5’ (5p) end of the miRNA hairpin [Pugh et al 2014]. Most individuals who are heterozygous for a germline DICER1 loss-of-function pathogenic variant show no visible effects, presumably because DICER1 enzyme expression from the wild-type allele can be upregulated.

Cancers and benign tumors with somatic DICER1 pathogenic variants. Somatic DICER1 pathogenic variants have been described in PPB, CN, Wilms tumor, epithelial and non-epithelial ovarian tumors, ERMS, one prostate carcinoma, and one testicular germ cell tumor [Slade et al 2011, de Boer et al 2012, Heravi-Moussavi et al 2012, de Kock et al 2013a, Wu et al 2013, Doros et al 2014, Pugh et al 2014]. Somatic missense pathogenic variants appear to preferentially affect amino acids in the RNase IIIb domain (1705, 1709, 1809, 1810 or 1813) and are characterized as “missense hotspots.” These somatic pathogenic variants lead to defective production of mature miRNAs from the 5’ (5p) end of the miRNA hairpin but preserve the cleavage of the 3’ (3p) end of the hairpin [Gurtan et al 2012, Anglesio et al 2013, Pugh et al 2014].

Three of 15 PPBs analyzed by exome sequencing showed tumor-specific loss of function and missense pathogenic variants in DICER1 with normal germline [Pugh et al 2014].

Somatic missense DICER1 pathogenic variants were seen in 18 (90%) of 20 cases of CN obtained from the Cooperative Human Tissue Network. Loss-of-function pathogenic variants were seen in 70% (14/20) of these tumors; however, since germline DNA was not examined it was unknown if the mutated allele was present in the germline as well as in the tumor [Doros et al 2014].

In a study of ERMS tumors obtained from the Cooperative Human Tissue Network, loss-of-function pathogenic variants were seen in two (4%) of 52 tumors; however, because germline DNA was not examined, it could not be determined if the mutated allele was in the germline or in the tumor specifically [Doros et al 2012].

One pineoblastoma reported by Sabbaghian et al [2012] and one pineoblastoma from the International PPB Registry (IPPBR) [personal communication] – each from children with a germline DICER1 pathogenic variant – did not have specific somatic missense pathogenic variants in tumor analysis, suggesting an alternate tumorigenesis pathway.

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Chapter Notes

Author Notes

Web sites with additional information about DICER1-related disorders

About the Authors’ research. The authors of this study represent a multidisciplinary collaborative group that seeks to understand the clinical, pathologic, and genetic basis of the rare childhood cancer PPB and its associated conditions. The IPPBR is dedicated to understanding the clinical and pathologic aspects of the disease and treatment outcomes. The IPPBR has opened enrollment in the first prospective treatment trial in this disease. The IPPBR Web site provides a treasure trove of data for families affected by PPB and the physicians caring for them. The authors of this work are focused on improving the care of DICER1 syndrome families and are studying the clinical genetics and genetic pathogenesis of the disease. This cancer appears to arise during lung embryogenesis through a series of genetic events. Young children with the disease present with lung cysts that carry risk for transformation into a high grade sarcoma in the first three to five years of life. Using a linkage study, Dr. Hill’s group with the IPPBR recently identified heterozygous germline mutation of DICER1 as the genetic basis of PPB. Preliminary data from PPB mouse models and study of human tumors suggests that DICER1 protein is diminished in lung epithelium overlying the mesenchymal tumor suggesting that loss of miRNAs in developing lung epithelium may affect regulation of secreted growth factors driving mesenchymal proliferation and setting the stage for cancerous transformation. Further work of the Hill group and others has identified recurrent, somatic missense DICER1 pathogenic variants in tumor cells confirming that DICER1 functions as a two-hit tumor suppressor and loss of DICER1 protein leads to loss of miRNAs important in controlling proliferation and differentiation in development. A better understanding of this syndrome is essential to the development of clinical criteria for identifying these families and for guiding their medical care.

Acknowledgments

The authors thank Dr John R Priest for his contributions to data collection used in this review.

This work was supported in part by National Cancer Institute (NCI), NIH/NCI R01CA143167 (P.I. Hill), the Intramural Research Program of the NIH, Hyundai Hope on Wheels, Pine Tree Apple Tennis Classic, MF Schutt Foundation and Children’s Hospitals and Clinics of Minnesota Foundation, and St. Baldrick’s Foundation.

Revision History

  • 24 April 2014 (me) Review posted live
  • 23 July 2012 (dh/ym) Original submission
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