Retinal angioma associated with von Hippel‐Lindau disease

Von Hippel‐Lindau disease is a multi‐system disorder that can produce hamartomas (benign tumour‐like nodules) of the eyes, skin and nervous system. Retinal capillary angioma is a common ocular association of this congenital phakomatosis that may result in blinding sequelae, if not managed appropriately. We present a case of retinal angioma associated with von Hippel‐Lindau disease and discuss the ocular and systemic signs, diagnosis and management. The optometrist is of particular importance in screening for this disorder, as it is often first detected in a routine eye examination.     

Pathology and genetics of phaeochromocytoma and paraganglioma

Phaeochromocytoma and paraganglioma (PHEO/PGL) are rare tumours with an estimated annual incidence of 3 per million. Advances in molecular understanding have led to the recognition that at least 30–40% arise in the setting of hereditary disease. Germline mutations in the succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD and SDHAF2 are the most prevalent of the more than 19 hereditary genetic abnormalities which have been reported. It is therefore recommended that, depending on local resources and availability, at least some degree of genetic testing should be offered to all PHEO/PGL patients, including those with clinically sporadic disease. It is now accepted that that all PHEO/PGL have some metastatic potential; therefore, concepts of benign and malignant PHEO/PGL have no meaning and have been replaced by a risk stratification approach. Although there is broad acceptance that certain features, including high proliferative activity, invasive growth, increased cellularity, large tumour nests and comedonecrosis, are associated with an increased risk of metastasis, it remains difficult to predict the clinical behaviour of individual tumours and no single risk stratification scheme is endorsed or in widespread use. In this review, we provide an update on advances in the pathology and genetics of PHEO/PGL with an emphasis on the changes introduced in the WHO 2017 classification of endocrine neoplasia relevant to practising surgical pathologists.     

Persistent exudative retinal detachment after photodynamic therapy and intravitreal bevacizumab injection for multiple retinal capillary hemangiomas in a patient with von Hippel–Lindau disease

Photodynamic therapy (PDT) has been used in treating peripheral retinal capillary hemangioma (RCH) with satisfactory results. We report a rare case of von Hippel-Lindau (VHL) disease with three large peripheral RCHs, treated with PDT and intravitreal bevacizumab injection (IVB), who developed persistent bullous exudative retinal detachment (RD) despite significant tumor regression. The patient is a sporadic case of VHL disease, with a de novo nonsense mutation in codon 161 with C → T transition at nucleotide position 694 of the VHL gene. Multiple RCHs were noted in both eyes. Four small RCHs were found in the left eye and were treated with laser photocoagulation. Three large RCHs in the peripheral retina of the right eye were complicated with cystoid macular edema and subretinal fluid accumulation. The RCHs were treated with PDT combined with IVB, and bullous exudative RD developed on the second day after treatment. Three months after PDT, the tumors had regressed significantly, but exudative RD persisted, despite multiple IVB and intravitreal triamcinolone acetonide injection (IVTA). External drainage with sclera buckling, IVB, and IVTA were performed, and the retina attached after surgical intervention. The application of PDT in the treatment of RCHs and its possible complications are discussed.     

Subepyndemal hemangioblastomas of the cervicomedullary junction: lessons learned in the management of two cases

Objective This retrospective case series analyzes two cases of hemangioblastomas in the cervicomedullary junction. Methods A survey of the pediatric staff and of the operative reports from medical records with a review of the literature and medical records of patients with the condition was conducted. Results Two patients were successfully treated surgically. Conclusion Surgery is the treatment of choice for hemangioblastomas of the cervicomedullary junction. Careful monitoring for unique complications, treatment of the tumor as a vascular malformation, and screening for von Hippel Lindau must all be employed to safely care for this challenging group of patients.     

Useful immunohistochemical markers in differentiating hemangioblastoma versus metastatic renal cell carcinoma

Hemangioblastomas (HBs) account for nearly a tenth of all posterior fossa neoplasms and can be the presenting finding in patients with von Hippel‐Lindau (VHL) syndrome. HB must be differentiated from renal cell carcinoma (RCC), also seen in VHL, as the distinction between these lesions dictates the management of these patients. Currently inhibin A and RCC marker have been used in the diagnosis of HB and metastatic RCC, both with inconsistent results. Additional immunohistochemical markers including CD10, PAX‐2, D2‐40, and FLi‐1 have been shown to have potential for the distinction of these two entities. Fifteen cerebellar HBs and 17 metastatic clear cell RCCs to the brain were selected for the study. All cases were immunostained with RCC marker, inhibin, CD10, PAX‐2, D2‐40, and Fli‐1. The staining patterns were scored based on intensity and extent of tumor staining. In the differentiation of HB and metastatic RCC, D2‐40 and RCC marker proved to be poor markers with less than 50% of HBs and RCCs, respectively, showing positive staining. PAX‐2 and CD10 were superior to RCC marker in the diagnosis of metastatic RCC, with PAX‐2 having better specificity. Fli‐1 failed to stain tumor cells in both HBs and RCC. Inhibin A, in combination with PAX‐2, showed to be the most useful markers to differentiate HB from metastatic RCC.     

Alu‐Alu recombination underlies the vast majority of large VHL germline deletions: Molecular characterization and genotype–phenotype correlations in VHL patients

Von Hippel‐Lindau disease (VHL) is an autosomal dominant cancer syndrome. Affected individuals are predisposed to multiple tumors, primarily of the central nervous system (CNS), eyes, adrenals, and kidneys. The VHL tumor suppressor gene on chromosome 3p26–25 is partially or completely deleted in 20 to 30% of families with VHL. We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families. In 33 of the index patients, the breakpoints were precisely characterized by DNA sequencing. Of the 66 breakpoints, 90% were located in Alu elements, revealing Alu‐mediated recombination as the major mechanism for large germline deletions of the VHL gene, which lies in a region of high Alu density. Interestingly, an AluYa5 element in VHL intron 2, the evolutionarily youngest Alu element and the only such element in the entire region, was found to be the most recombinogenic, involved in 7 out of the 33 deletions. In comparison to VHL patients in general, the 54 index cases and their affected relatives showed a higher occurrence of renal cell carcinomas (RCC) and of CNS hemangioblastomas. We not only noted the association of RCC with retention of the HSPC300 gene, but also observed a significant correlation between retention of HSPC300 and the development of retinal angiomas (AR). This study reveals that germline VHL deletions provide a particularly rich source for the study of Alu‐mediated unequal crossover events, and provides evidence for a protective role of the loss of the actin‐regulator gene HSPC300 for the development of both RCC and AR. Hum Mutat 30, 1–11, 2009. © 2009 Wiley‐Liss, Inc.     

Hämangioblastome des zentralnervensystems

Zusammenfassung Bei 46 Patienten mit einem Hämagio-blastom des Zentralnervensystems (Neurologische Universitäts-Klinik Hamburg-Eppendorf,1950–1980) fanden sich überwiegend (n = 40) Kleinhirnangioblastome (Lindau-Tumoren), von denen 21 im Jahre 1983 nachuntersucht werden.Kopfschmerz als Initialsymptom fand sich etwa dreimal so häufig wie Schwindel, sensomotorische Ausfälle and cerebelläre Gangstörung (43% zu 10–15%). Hirndrucksymptome waren häufiger diagnostisch wegweisend als Schwindel und Gangstörung. Seit der Einführung des CCT erlaubte die zusammengefaßte Beurteilung von CCT und Vertebralisangiographie immer die zutreffende preoperative Diagnose. Die geringe Gesamtoperationsmortalität von 13,5% konnte im letzten Jahrzehnt auf 0% gesenkt werden. Bei einer Gesamtrezidivhäufigkeit von 8,7% fand sich bei 21 Nachuntersuchungen einschließlich CCT and EOG kein Rezidiv.Nicht so haufig wie bisher allgemein angenommen, kamen in unserem Krankengut vor: Familiäre Häufung (0%), multiple Tumorlokalisationen and gleichzeitiges Vorkommen mit Angiomatosis retinae (0%), Polyglobulie (10,8%). Psychische Veräenderungen (45,6%) ließen sich stets nur bei gleichzeitig bestehender Hirndrucksymptomatik nachweisen.Die Ergebnisse der Nachuntersuchungen zeigen, daß Reststörungen bzw. mögliche Rezidive genauer and früher als durch die klinische Untersuchung allein mit einer zusammengefaßten Beurteilung von CCT and EOG erkannt and verlaufsmäßig objektiviert werden können.