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Ciliary body medulloepithelioma: four cases associated with pleuropulmonary blastoma—a report from the International Pleuropulmonary Blastoma Registry
  1. John R Priest1,
  2. Gretchen M Williams2,
  3. Ricarchito Manera3,
  4. Helen Jenkinson4,
  5. Marie-Anne Bründler4,
  6. Samuel Davis5,
  7. Timothy G Murray6,
  8. Carlos A Galliani5,
  9. Louis P Dehner7
  1. 1International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA
  2. 2Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA
  3. 3Loyola University Medical Center, Maywood, Illinois, USA
  4. 4Birmingham Children's Hospital, Birmingham, UK
  5. 5Cook Children's Medical Center, Fort Worth, Texas, USA
  6. 6Bascom Palmer Eye Institute, Miami, Florida, USA
  7. 7Lauren V. Ackerman Lab of Surgical Pathology, Barnes-Jewish & St Louis Children's Hosp, Washington University Medical Center, St. Louis, Missouri, USA
  1. Correspondence to John R Priest, International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, 2545 Chicago Ave. S., Suite 412, Minneapolis, MN 55404, USA; jprst{at}prodigy.net

Abstract

Background and aims Ciliary body medulloepithelioma (CBME) is a rare embryonal ocular tumour of children under age 10 years. Pleuropulmonary blastoma (PPB) is a rare embryonal lung tumour in young children and the sentinel disease of the PPB Family Tumour and Dysplasia Syndrome, a distinctive predisposition leading to unusual dysontogenetic-dysplastic and neoplastic conditions in PPB patients and their relatives. Germline mutations of DICER1 gene, a key regulator of gene silencing, underlie this syndrome. CBME occurs with PPB. The authors' aim was to identify CBME cases associated with PPB.

Methods The authors evaluated International PPB Registry and literature PPB cases for CBME, including review of pathologic specimens.

Results Four CBME were observed among 550–600 PPB cases; three in patients and one in a parent. One CBME was clinically diagnosed; three were confirmed pathologically (one benign teratoid CBME; one benign non-teratoid CBME; one case, details not available).

Conclusions These observations suggest that CBME is a manifestation of the tumour predisposition associated with PPB. Paediatric oncologists and ophthalmologists should be aware that CBME can occur in PPB patients or their relatives and that CBME may indicate a hereditable tumour predisposition for a child or family.

  • Ciliary body medulloepithelioma
  • diktyoma
  • pleuropulmonary blastoma
  • DICER1
  • ppb
  • ciliary body
  • child health (paediatrics)

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Introduction

Cancer susceptibility syndromes are heredofamilial disorders often with inherited mutations; phenotypic manifestations usually include more than one neoplastic disease and/or other dysplasias or somatic abnormalities.1 Hereditary retinoblastoma (Rb) is the archetype of such syndromes in the contemporary period of cytogenetics and molecular genetics with investigators identifying loss of function mutations in both alleles of the Rb gene on chromosome 13q14.1 2 Ocular and orbital tumours are unusual in most inherited syndromes, except in Rb, von Hippel-Lindau syndrome and neurofibromatosis type 1.

Ciliary body medulloepithelioma (CBME) is a rare embryonal ocular tumour arising from primitive medullary epithelium, the inner layer of the optic cup.3 4 Ocular medulloepithelioma is usually situated anteriorly in the ciliary body but also reported in the retina, optic disc, and optic nerve.3 CBME is characterised histopathologically as non-teratoid or teratoid, the latter when heteroplastic tissue is present: primitive cartilage, striated muscle, and/or neuroglia; either form may be benign or malignant.5 6 CBME typically occurs in the first decade of life with mean diagnosis age 5 years.6–9 Enucleation is often required,5 6 9 although children with good visual acuity, stable disease, normal intraocular pressures and rigorous follow-up including high resolution imaging may not be enucleated. Although CBME is generally not considered part of familial tumour predisposition syndromes, a child with bilateral hereditary Rb developed CBME in an irradiated eye10 and another child had both CBME and pineoblastoma, which occurs rarely with Rb.11–13

Pleuropulmonary blastoma (PPB) is another rare dysembryonic tumour of early childhood, occurring in lung and pleura and believed to arise from primitive pleuropulmonary mesenchyme.14 15 PPB is typically diagnosed in infants and children up to age 2 years as an innocuous-appearing lung cyst or from age 2–6 years as an aggressive sarcoma requiring multimodal therapy.16 17 PPB is the pulmonary analogue of more common early childhood embryonal tumours such as Rb, neuroblastoma, Wilms tumour, medulloblastoma and others.14 Among these, PPB is unique because approximately 35% of families affected by PPB manifest a distinctive array of dysontogenetic-dysplastic and/or neoplastic conditions comprising the PPB Family Tumour and Dysplasia Syndrome (PPB–FTDS)17–19 (OMIM #601200).20 Heterozygous germline loss-of-function DICER1 mutations (14q31) reported in the PPB–FTDS are considered the major genetic determinant of this disease complex.18 21–23

The International PPB Registry (www.ppbregistry.org) was organised in 1987 to collect and analyse the clinical, pathologic and epidemiologic features of PPB. This report documents our experience with four cases of CBME associated with PPB. We propose that CBME is an additional neoplasm in the PPB–FTDS.

Methods and materials

The International PPB Registry is a collaboration of the Department of Paediatric Haematology and Oncology at Children's Hospitals and Clinics of Minnesota (St. Paul and Minneapolis, MN) and of the Department of Surgical Pathology at Children's National Medical Center (Washington, DC) and the Lauren V. Ackerman Laboratory of Surgical Pathology, Department of Pathology and Immunology, Washington University Medical Center (St Louis, MO). Registry activities are approved by the Institutional Review Boards at each institution.

PPB cases are accessioned to the Registry following physician or family referral. Confirmation of diagnostic PPB pathology by Registry pathologists is mandatory for case enrolment. The Registry also tabulates literature cases of PPB if clinicopathologic descriptions are typical.24 Literature searches for PPB and CBME using PubMed.gov were conducted, and are continually conducted, with search words: pleuropulmonary blastoma and its equivalent in several languages, PPB, diktyoma, and ocular and ciliary body medulloepithelioma. CBME literature reports were evaluated for mention of PPB or related diseases.

For enrolled PPB cases, the Registry collects comprehensive data on clinical presentation, surgery, pathology, family medical history, radiology, chemotherapy, radiotherapy, clinical course, additional diagnoses in the patient and family, and follow-up, solicited annually. Confirmation of additional diagnoses is determined by pathologic review when possible, by review of pathology reports and/or by family history reporting deemed reliable.

A search for CBME diagnoses in Registry-enrolled and literature PPB cases and in relatives of PPB patients forms the basis for this report.

Results

Among 299 Registry-enrolled PPB cases, CBME was identified in three PPB patients and in the father of a PPB patient. The clinicopathologic findings are summarised in table 1. Five somewhat related cases in PPB kindreds were excluded from further analysis: a PPB patient with congenital phthisis bulbi; a PPB patient with an iris lesion presumed to be PPB metastasis (not biopsied)25;a PPB patient's great aunt who survived after enucleation at age 4 years for globe ‘melanosarcoma’ (diagnosis in 1934; further information not available); a PPB patient's mother with malignant melanoma of the iris at age 24 years; and a PPB patient's aunt with cerebral medulloepithelioma at age 7 months. To our knowledge, no case of CBME is reported in 250–300 literature cases of PPB; no details suggestive of PPB or related diseases were noted in CBME literature cases.

Table 1

Clinical presentation, ophthalmologic features and management of CBME cases associated with PPB

Clinical presentations and diagnosis

Case 1: Parents noted reduced vision 12 months before enucleation. Ophthalmologic evaluation revealed decreased acuity, a vascularised capsular opacity, some elevation of the optic nerve with abnormal vessels (confirmed by ultrasound), and no mass lesion on ultrasound or MRI. Optic nerve and intracranial contents were normal by MRI. Over the following months the cataract progressed; serial ophthalmologic and radiologic evaluations demonstrated an intraocular lesion (figure 1A–B). Lensectomy did not allow adequate visualisation of the intraocular lesion, and enucleation was performed. A thyroid nodule was removed at the same time.

Figure 1

Case 1: (A) External photograph of the right eye revealing an irregular internal margin to the pupil and a mass lesion immediately behind lens. (B) Coronal computerised tomographic image at the level of the anterior orbit revealing a mass at the temporal side of the right globe. (C) H&E stained section of the entire tumour. (D) Microphotograph demonstrating benign teratoid CBME with prominent neuroglial elements (H&E, 10×).

Case 2: The child failed school acuity screening 12 months prior to diagnosis but was functioning well; in ensuing months, several ophthalmologists examined the child, including experienced ocular tumour specialists at two centers; the clinical diagnosis is CBME (figure 2). The child has been followed over a 2-year period at 6-month intervals without progression of the lesion clinically or on high resolution imaging.26 Visual function is excellent and the intraocular pressure is normal.

Figure 2

Case 2: (A) 18-month follow-up imaging of ciliary body medulloepithelioma with slit lamp biomicroscopic photograph documenting amelanotic vascularised ciliary body mass. Note fine lenticular changes and fimbrioid margins of the tumour. (B) High resolution contact B-scan echography documenting the ciliary body medulloepithelioma with intrinsic intra-tumoral cystic spaces. The lesion was moderately vascular on quantitative A-scan analysis (not shown).

Case 3: The child experienced headaches 5 months before enucleation; the parents noted a discoloured pupil 3 months before enucleation (figure 3A). CT and ultrasound evaluation revealed a likely tumour (figure 3B–D); ophthalmologic consultation suggested CBME and enucleation ensued.

Figure 3

Case 3: (A) Slit-lamp biomicroscopic photograph of the right eye with a dilated pupil showing a richly vascularised retrolental mass. (B) Coronal computerised tomographic image at the level of the anterior orbit revealing an enhancing superomedial mass within the right globe near the lens. (C) Echographic B-scan examination demonstrating an echo-reflecting noncalcified retrolental mass (arrow). Exterior surface of the eye to the right. (D) Ultrasound amplitude scan trace of the right eye detecting a mass. (E) Above: Enucleated right eye sectioned in the horizontal plane containing a well circumscribed 10.6×7.8×0.4 mm almond-shaped, grey-white-tan mass (arrows) in the anterior vitreous chamber, arising from the ciliary region, and lying immediately behind the iris. Below: H&E stained section of the upper calotte revealing a non-teratoid CBME. (F) Left: The right eye tumour lying just behind the iris is made up of well differentiated, focally pigmented cords of neuroepithelial cells arranged in a filigree pattern.4 No heterologous elements are discerned. Right: Medullary epithelium forming cords, tubules, occasional rosettes, and primary vitreous. (G) A lower section of the globe reveals an attached retina and filiform synechia running between a semi-translucent grey-white membrane on the posterior surface of the lens and the papilla of the optic nerve.

Case 4: During his childhood, the father of a child with PPB had decreased visual acuity for 6 months and a cataract was noted. An ophthalmologic tumour specialist diagnosed a likely tumour and the globe was enucleated. There was no further treatment. A “diktyoma” diagnosis was made in 1966 at the Harkness Eye Institute, Columbia University Hospital, New York, NY; repeated searching revealed that records and specimens are no longer available. Diktyoma is the designation used at the time for what is now termed CBME. The father had had a lung cyst removed at the age of 1 year; specimens and pathology report were unavailable. The case is included here because of the clinical history, the father's and his mother's explicit memories of ‘diktyoma with cataract’ as the diagnosis, and the prominence as an ocular tumour center of the institution where the diagnosis was made.

Pathologic findings

In the two CBME cases for which pathologic specimens were available, material was reviewed by the authors (M-AB, CAG, LPD). In Case 1, the tumour was determined to be benign, teratoid CBME with abundant neuroglial elements (figure 1C–D). In Case 3, the tumour was a benign, non-teratoid CBME (figure 3E–F). The lens substance was normal but from an opalescent membrane on the posterior lens surface, a thread-like adhesion traversed the vitreous chamber to the retina and created slight tenting at the papilla (figure 3G). Cataract was associated with Cases 1, 2 and 4.

Discussion

Among 299 Registry and 250–300 non-Registry literature PPB cases, CBME was identified in three PPB patients and in the father of a PPB patient. Enucleation was performed in three patients and the CBME pathologically confirmed. One CBME was clinically diagnosed (figure 2) and has been closely followed by one of the authors (TGM). Enucleation has been avoided because of parental preference, good acuity, binocular vision, stable focal disease and the prospect of continued stability. The CBME were diagnosed at ages 4, 6, 8 and 9 years, consistent with the 5-year median diagnosis age for sporadic CBME.3 7 8 CBME was diagnosed 5, 6 and 6 years after the respective PPB diagnoses in the PPB patients; in the PPB father, CBME was diagnosed 3 years after a lung cyst was removed. Pathologically, one CBME was teratoid and benign and one was non-teratoid and benign; classification of the other two is not known.

The diagnosis of CBME in children can be delayed because the disease tends to develop slowly and young patients may not report early visual changes.5 With knowledge that CBME occurs in association with PPB, a CBME diagnosis in Cases 1 and 2 may have been suspected earlier during the year of evaluation.

Both common and rare childhood dysplastic/neoplastic diseases are biologically associated with PPB in the PPB–FTDS.17–19 27–30 Examples are multiple familial PPBs, lung cysts, brain tumours, neuroblastoma, cystic nephroma27 and Wilms tumour, stromal-cell ovarian tumours,29 rhabdomyosarcoma,12 nodular thyroid hyperplasia17 (Rio Frio T, submitted) and nasal chondromesenchymal hamartoma.30 Like CBME, nasal chondromesenchymal hamartoma is an extremely rare tumour yet four cases have occurred with PPB.30–32 Four PPB-related CBME reported here strongly suggest that CBME is a manifestation of the PPB–FTDS. We recognise this assertion lacks a population-based statistical analysis, but it seems highly unlikely that PPB and CBME would occur together purely by chance.

Reports of CBME in the irradiated eye of a child with bilateral hereditary Rb10 and in a child with pineoblastoma11 suggest that CBME rarely also accompanies the Rb spectrum of diseases. Whether any genetically determined molecular mechanism is shared between CBME with PPB and CBME with Rb remains to be investigated.

PPB–FTDS and hereditary Rb bear another similarity ophthalmologists will recognise. Retinoma is a benign eye tumour observed in some members of hereditary Rb kindreds; retinoma may remain benign or progress to Rb.33–35 In PPB, lung cysts in young children may progress to advanced PPB or persist into adulthood without malignant change.17 36 Molecular investigations clarifying the evolution of retinoma into Rb have not yet been extended to the biology of PPB-related cysts.33

Could CBME in PPB patients be related to prior cytotoxic therapy? As noted above, CBME occurred in the irradiated eye of a child with hereditary Rb.10 Prior to developing CBME, three PPB patients reported here had received chemotherapy: three received vincristine and cyclophosphamide; in addition two received ifosfamide, actinomycin and etoposide, one received doxorubicin, and one received carboplatinum. None had radiation therapy. The father with CBME had received no prior cytotoxic therapy. CBME has not been reported as a chemotherapy-related second tumour in childhood cancer patients.37 Perhaps in children with a tumour predisposition syndrome cytotoxic therapy can lead to an unusual second tumour like CBME, but we believe PPB-associated CBME is more likely a direct expression of genetic predisposition.

In one case presented here, PPB and CBME were the only manifestations of the PPB–FTDS in the child or family. In the other three cases, additional PPB–FTDS diagnoses are summarised in the table 1. These and other PPB–FTDS manifestations are described elsewhere in more detail.17 22 29 30 38 39

Inherited germline loss-of-function DICER1 mutations have been described in 11 of 11 studied PPB kindreds18; the mutations occur in 50–70% of PPB patients.21 23 DICER1 directs production of critical small RNA molecules which control gene expression particularly in the embryologic and early developmental stages of all organisms.40 It is not understood how loss of one DICER1 allele may lead to dysplasia or neoplasia. In a mouse model, targeted biallelic Dicer1 loss in retinal anlage early in embryogenesis leads to both structural and functional changes.41 42 Also, Rb formation in mouse retina is more associated with haploinsufficient Dicer1 than with complete Dicer1 loss.43 Reduced “dosage” of Dicer1 protein in retinal cells with a single Dicer1 allele has been implicated in functional impairment of retinal activity.41 DICER1 sequencing in Case 1 and in her unaffected father here revealed an inherited germline mutation, further supporting CBME as a manifestation of the PPB–FTDS phenotype.23 Identifying a DICER1 mutation in a presumed sporadic case of CBME would also add to the significance of this mutation in CBME and certainly in PPB-associated CBME.

Repeated, formal ophthalmologic surveillance of PPB patients might not be warranted by the low possibility that these children will develop CBME. However, standard visual screening is certainly reasonable and, in one child here, initiated investigations leading to the CBME diagnosis. Most importantly, ophthalmologists and paediatric oncologists must be aware of the relationship of CBME to PPB and the possibility of familial neoplastic disease.

Acknowledgments

The authors thank physicians and data managers who supply information, and thank the many families who allow their children to be studied by the International PPB Registry. Special appreciation goes to Nazneen Rahman, MD, PhD, Ingrid Slade, MD, Carol Shields, MD, Steven Rakes, MD, Nancy Battaglia, and Kris Doyle. The Pine Tree Apple Tennis Classic and the Theodora H. Lang Charitable Trust support the International PPB Registry and its staff.

References

Footnotes

  • Competing interests JRP is named in a patent registration involving genetic sequencing methodology of DICER1 gene.

  • Ethics approval This study was conducted with the approval of The International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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