The ophthalmic manifestation of PPBFTDS is CBM, which is a rare embryonal ocular tumor arising from primitive medullary epithelium, occurring most commonly in children in the first decade of life, with a mean age at diagnosis of 5 years [165, 170, 178]. CBM occurs rarely in adults. The tumor arises from the nonpigmented ciliary epithelium of the pars plicata and rarely from the iris, retina or optic nerve head [179–182]. CBM is histopathologically classified as nonteratoid (50–63 % of cases with 10–31 % benign and 19–40 % malignant) or teratoid (37–50 % of cases with 0–31 % benign and 19–50 % malignant). Overall, 20–34 % are benign and 66–80 % are malignant [170, 178]. Heteroplastic tissue including cartilage, striated muscle and/or neuroglia is present in teratoid CBM [170]. Associated clinical features of CBM include secondary glaucoma (44–50 % of cases), iris neovascularization (51 %), cataract (26–50 %), lens subluxation (27 %), lens coloboma (20 %), retrolental neoplastic cyclitic membrane (51 %), intratumoral cysts (61 %) and extraocular extension (10 %) [170, 178, 183]. A neoplastic epiretinal membrane has been observed in some enucleated eyes with CBM. In one larger case series by Kaliki and colleagues [170] of 41 patients with CBM, 2 cases (5 %) were associated with PPB. Less than 1 % of patients with PPB develop CBM, and 5 % of CBM patients have a history of PPB [170]. CBM has not been reported as a chemotherapy-related secondary tumor in childhood cancer patients [184]. Metastasis is uncommon, but in cases with extrascleral extension of tumor at presentation due to a delay in diagnosis, systemic metastasis to cervical lymph nodes and the parotid gland can occur [170, 183]. Intraocular tumor recurrence may also occur after primary treatment, frequently after local resection by partial lamellar sclerouvectomy. Tumor-related death occurs in cases with orbital involvement and/or intracranial extension [178, 183].

There has been one report of choroidal metastasis of PPB in a 3.5-year-old girl with a large PPB tumor of unknown type who developed a choroidal relapse 15 months after diagnosis and five months after treatment with surgical resection and chemotherapy [185]. Chemotherapy was given, and she received radiation therapy to the eye and was disease-free at 35 months.

No guidelines regarding surveillance of those with a known germline DICER1 mutation have been established, but annual physical examination, targeted review of systems and imaging based on patient age, presence or absence of clinical findings and suspected tumor type are recommended [164]. Due to the rarity of PPB and its nonspecific symptoms, it may not be considered in the differential diagnosis of children with respiratory distress, persistent pneumonitis, cough, chest pain, fever and/or atelectasis, resulting in a delayed diagnosis [166, 186]. Some present with pleural effusion (type II or III) or pneumothorax (type I or II) [164, 171]. There may no history of familial disease [166]. Computed tomography (CT) of the chest and investigation for associated diseases is recommended in the workup of possible PPB [166, 171]. Magnetic resonance imaging (MRI) of the brain and bone scan are recommend in new diagnoses of type II or III to evaluate for metastasis. In infants, type I PPB may be mistaken for a congenital cystic lesion of the lungs such as congenital pulmonary airway malformation. In these patients, PPB is more likely if there is a family history of PPB or associated tumors but pathological examination is required [171]. In all cases, diagnosis is confirmed on pathologic examination. Interestingly, in a report of 350 pathology-confirmed cases by the International Pleuropulmonary Blastoma Registry , 435 cases were initially included but 85 (20 %) were another entity [171], demonstrating the importance of central pathology review for rare tumors.

The diagnosis of CBM is often delayed due to difficulty in visualizing the ciliary body mass until gradual enlargement leads to secondary effects [170]. The most common presenting signs and symptoms are decreased visual acuity, red and painful eye and leukocoria . On slit lamp exam, CBM is irregularly shaped with a smooth surface and gray to fleshy pink color. Vessels may be visible on or near the surface. In about half of cases, cysts or tumor are present in the anterior chamber [174]. Definitive diagnosis is by histopathologic examination or by the presence of the clinical findings of a ciliary body mass with intratumoral cysts on ultrasound biomicroscopy and/or anterior segment optical coherence tomography, with associated iris neovascularization, corectopia, ectropion uveae, lenticular changes or retrolental neoplastic cyclitic membrane [170]. MRI and CT have also been used to determine the extent of the tumor and distinguish CBM from other intraocular tumors [164]. The intratumoral cysts can occasionally dislodge from the tumor and float in the aqueous or vitreous. Fluorescein angiogram of the retrolental neoplastic cyclitic membrane that often develops in CBM reveals rapid filling of large disorganized vessels emanating from the ciliary body across the hyaloid face [170]. This can help differentiate CBM with a retrolental cyclitic membrane from a retinoblastoma or Coats disease with a total retinal detachment.

While repeated formal ophthalmologic screening of PPB patients may not be warranted by the low risk of CBM development, standard vision screening is recommended, along with the awareness of the relationship of CBM to PPB and the possibility of a familial tumor susceptibility syndrome [165].

Treatment of PPB is multi-modal and includes surgical resection, adjuvant chemotherapy and radiation therapy [171, 186]. Type I PPB may be treated with primary surgical resection only or with adjuvant chemotherapy in some cases [171]. The use of chemotherapy to prevent progression to type II or III is unclear. Gross total surgical resection of the tumor is associated with improved prognosis, though this may be difficult in type II and III tumors [164, 166, 175, 176, 186]. Type II and III PPB are aggressive sarcomas that require chemotherapy after the first surgery. Chemotherapeutic agents may include vincristine , cyclophosphamide , dactinomycin , doxorubicin and irinotecan [186]. Radiation therapy may be used in type II or III PPB, especially in cases of recurrence or metastasis, or in tumors that cannot be removed [164, 171]. Myeloablative chemotherapy followed by rescue treatment with transplantation of autologous stem cells has been reported but is controversial and reserved for cases of relapse or poor response to standard therapy [166, 171].

Primary tumor treatment options for CBM include enucleation, local resection by partial lamellar sclerouvectomy, plaque radiotherapy, external beam radiotherapy, cryotherapy and observation [165, 170]. The role of systemic chemotherapy is not well-established. Treatment selection primarily depends on size of the tumor. Small tumors may be controlled by plaque radiotherapy or local resection. Enucleation is recommended for larger tumors and for smaller tumors that failed to respond to more conservative treatment. Exenteration is required in cases with extensive orbital invasion. Observation of a clinically diagnosed non-progressing CBM monitored every 6 months, without secondary glaucoma and with good visual acuity has been reported [165].