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Malignant transformation of retinocytoma treated with intra-arterial chemotherapy

      Clara Knieper was most likely the first to make the closest description of what is currently known as retinocytoma, in a child named Peter Neuburger, born on May 12, 1899, and who underwent bilateral enucleations 11 years apart.
      • Knieper C.
      Ein Fall von Doppelseitigem Glioma retinae mit Enucleation des einen und nunmehr fast 11 jahriger Atrophie des andern Auges.
      Since then, the clinical features of this rare tumour have become well established and include a translucent greyish retinal mass sometimes associated with a staphyloma, calcific foci, retinal pigment epithelial alterations, cystic areas, and chorioretinal atrophy without exudation and prominent feeder vessels.
      • Singh A.D.
      • Santos S.M.
      • Shields C.L.
      • Shields J.A.
      • Eagle Jr, R.C.
      Observations on 17 patients with retinocytoma.
      • Abouzeid H.
      • Balmer A.
      • Moulin A.P.
      • Mataftsi A.
      • Zografos L.
      • Munier F.L.
      Phenotypic variability of retinocytomas: preregression and postregression growth patterns.
      Retinocytoma is traditionally considered a benign tumour and therefore requiring no treatment. However, malignant transformation was documented in several individual case reports, and a recent study on 36 patients with retinocytoma showed that 12% of these tumours progressed into retinoblastoma.
      • Abouzeid H.
      • Balmer A.
      • Moulin A.P.
      • Mataftsi A.
      • Zografos L.
      • Munier F.L.
      Phenotypic variability of retinocytomas: preregression and postregression growth patterns.
      • Uysal Y.
      • Shields C.L.
      • Shields J.A.
      • Eagle Jr, R.C.
      Malignant transformation of retinocytoma into retinoblastoma.
      • Eagle Jr., R.C.
      • Shields J.A.
      • Donoso L.A.
      • Milner R.S.
      Malignant transformation of spontaneously regressed retinoblastoma, retinoma/retinocytoma variant.
      Little or no response to systemic chemotherapy is another characteristic of retinocytoma.
      • Chung J.
      • Turaka K.
      • Shields C.L.
      Retinocytoma shows lack of response to chemoreduction.
      We describe 2 patients with unilateral and unifocal retinocytomas that were partially transformed into retinoblastoma and treated with intra-arterial chemotherapy. Although the retinoblastoma portions rapidly regressed, the retinocytomas remained unaltered, confirming that these tumours are also resistant to intra-arterial melphalan treatment.

      Case Reports

      Case 1

      An 18-month-old, otherwise healthy male infant was consulted for right-sided esotropia that was present since birth. Ophthalmological examination showed that he could fix and follow. Leukocoria could be elicited upon abduction of the right eye. Fundoscopy revealed a white-grey, elevated, translucent temporal juxtapapillary mass measuring approximately 8 mm × 6 mm. Calcified and cystic areas with overlying dilated retinal vessels were present. The mass was surrounded by an annulus of chorioretinal atrophy. The left eye was normal. Our diagnosis was retinocytoma, and the tumour was observed without any change for 42 months. At the age of 5 years, a new tumour developed from the inferior margin of the retinocytoma and continued to grow despite a session of transpupillary thermotherapy (Fig. 1A). The patient then received intra-arterial chemotherapy consisting of 7.5 mg melphalan. The newly developed tumour rapidly regressed within 2 months, whereas the retinocytoma portion did not show any change (Fig. 1B). At 11-month follow-up, the tumours were stable.
      Fig. 1
      Fig. 1Right fundus view of patient 1 showing (A) a juxtapapillary, white, translucent, partially calcified retinocytoma surrounded by a narrow band of chorioretinal atrophy. The tumour marked by arrows developed 42 months later. (B) After intra-arterial chemotherapy, the retinocytoma remained stable, whereas the retinoblastoma regressed into small calcific flecks.

      Case 2

      A 12-year-old male patient was discovered to have blurred vision in his right eye during a school screening. His medical and family history was noncontributory. His visual acuity was 20/30 OD and 20/20 OS. Fundus examination revealed a white mass measuring 7.5 mm × 6 mm in basal diameter and located in the inferonasal quadrant. The tumour was classified as retinocytoma because of the presence of a surrounding narrow band of chorioretinal atrophy, lack of dilated feeder vessels, and the relatively older age at presentation. The left eye was normal and observation was adopted as management. Four months later, a small dome-shaped growth over the proximal part of the tumour was noted (Fig. 2A). The patient was treated with intra-arterial 7.5 mg melphalan chemotherapy. The outgrowth rapidly disappeared, but the main tumour did not show any change (Fig. 2B). The tumour and his right visual acuity then remained stable for the following 12 months.
      Fig. 2
      Fig. 2Right fundus views of patient 2 demonstrate (A) an inferonasally located retinocytoma that developed a small indiscrete nodular outgrowth (arrows). (B) Two months after intra-arterial melphalan treatment, the small newly emerging active part regressed and the main bulk of the tumour remained unchanged.
      The long-term benign nature of retinocytoma is increasingly challenged by growing clinicopathological evidence that retinoblastoma may actually arise from a retinocytoma.
      • Dimaras H.
      • Khetan V.
      • Halliday W.
      • et al.
      Loss of RB1 induces non-proliferating retinoma: increasing genomic instability correlates with progression to retinoblastoma.
      Clinical observations showed that 3%–12% of patients with retinoblastoma had retinocytoma.
      • Singh A.D.
      • Santos S.M.
      • Shields C.L.
      • Shields J.A.
      • Eagle Jr, R.C.
      Observations on 17 patients with retinocytoma.
      • Abouzeid H.
      • Balmer A.
      • Moulin A.P.
      • Mataftsi A.
      • Zografos L.
      • Munier F.L.
      Phenotypic variability of retinocytomas: preregression and postregression growth patterns.
      A recent histopathological study found that 15.6% of eyes enucleated for retinoblastoma harboured retinocytoma adjacent or contiguous to retinoblastoma and that these were not separate tumours.
      • Dimaras H.
      • Khetan V.
      • Halliday W.
      • et al.
      Loss of RB1 induces non-proliferating retinoma: increasing genomic instability correlates with progression to retinoblastoma.
      In our patients, retinoblastoma arose adjacent to the retinocytoma in 1 case and over the retinocytoma in the other.
      Compared to retinoblastoma, retinocytoma is usually diagnosed at an older age and documented by 2 large series, which found that the median age at diagnosis was 15 and 28 years, respectively.
      • Singh A.D.
      • Santos S.M.
      • Shields C.L.
      • Shields J.A.
      • Eagle Jr, R.C.
      Observations on 17 patients with retinocytoma.
      • Abouzeid H.
      • Balmer A.
      • Moulin A.P.
      • Mataftsi A.
      • Zografos L.
      • Munier F.L.
      Phenotypic variability of retinocytomas: preregression and postregression growth patterns.
      Similar to retinoblastoma, retinocytomas are also RB1−/− but increased expression of p16INK4a keeps the retinocytoma cell in G1 growth arrest, a process called oncogene-induced senescence.
      • Dimaras H.
      • Khetan V.
      • Halliday W.
      • et al.
      Loss of RB1 induces non-proliferating retinoma: increasing genomic instability correlates with progression to retinoblastoma.
      However, when a critical level of genomic instability attains key oncogenes, including KIF14/MDM4, MYCN, or DEK/E2F3, an uncontrolled cellular proliferation and malignant transformation may occur.
      • Dimaras H.
      • Khetan V.
      • Halliday W.
      • et al.
      Loss of RB1 induces non-proliferating retinoma: increasing genomic instability correlates with progression to retinoblastoma.
      In our patients, this critical threshold leading to emergence of retinoblastoma was reached at the age of 5.5 and 12 years, respectively, demonstrating that malignant transformation may occur unexpectedly at any age.
      Retinocytomas are composed of nondividing and well-differentiated cells that confer radioresistance to these tumours.
      • Tso M.O.
      • Zimmerman L.E.
      • Fine B.S.
      • Ellsworth R.M.
      A cause of radioresistance in retinoblastoma: photoreceptor differentiation.
      As systemic chemotherapy became the most widely used modality within the past 2 decades, it was observed that retinocytomas also were unresponsive to a multitude of chemotherapeutic agents.
      • Chung J.
      • Turaka K.
      • Shields C.L.
      Retinocytoma shows lack of response to chemoreduction.
      In 1 patient, a retinocytoma was clinically discovered only after systemic vincristin, etoposide, carboplatin, and cyclosporine had destroyed the overlying retinoblastoma.
      • Dimaras H.
      • Khetan V.
      • Halliday W.
      • Heon E.
      • Chan H.S.L.
      • Gallie B.L.
      Retinoma underlying retinoblastoma revealed after tumor response to 1 cycle of chemotherapy.
      In a 4-year-old patient similar to ours, systemic and intra-arterial chemotherapy combined with photocoagulation was effective in eradicating the bilateral retinoblastomas but failed to cause any change in the retinocytoma components.
      • De Francesco S.
      • De Luca M.
      • Galimberti D.
      • Caini M.
      • Hadjistilianou T.
      Synchronous malignant transformation of bilateral symmetrical retinocytoma.
      Our experience with the 2 patients emphasizes the need for close follow-up of retinocytomas to detect subtle malignant transformations. Although these newly formed retinoblastomas successfully regressed after intra-arterial melphalan administration, retinocytomas did not show any response to this treatment.

      Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this article.

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