= VHL = RETINOCEREBELLAR ANGIOMATOSIS

[Eugen von Hippel (1867–1939)], professor of ophthalmology in Heidelberg, Halle and Göttingen, Germany

Arvid Vilhelm Lindau (1892–1958), chair of general pathology, bacteriology and general health science in Lund, Sweden

= autosomal dominant inherited neurocutaneous dysplasia complex grouped under hereditary phakomatosis (although the skin is not affected)

Prevalence: 1÷31,000 – 1÷53,000 births

Genetics: mutation of VHL tumor suppressor gene located on chromosome 3p25-p26 with 80–100% high penetrance + variable delayed expressivity (ie, different subset of 40 types of lesions in 14 different organs); in 20% familial

Effect: propensity to develop multiple clear cell neoplasms like retinal and CNS hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma, pancreatic serous cystadenoma, pancreatic endocrine tumor (PET)

Age at onset: 2^nd–3^rd decade; M÷F = 1÷1

Diagnostic criteria:

• Hemangioblastoma = almost always disease-defining tumor

1. >1 hemangioblastoma of CNS
2. 1 hemangioblastoma + visceral manifestation
3. 1 manifestation + known family history

Subclassification (NIH):

• Type I = renal + pancreatic cysts, high risk for renal cell carcinoma, NO pheochromocytoma
• Type IIA = pheochromocytoma, pancreatic islet cell tumor (typically without cysts)
• Type IIB = pheochromocytoma + renal + pancreatic disease

• CNS MANIFESTATION
  Age at presentation: 25–35 years
  • signs of increased intracranial pressure: headache, vomiting
  • vision changes: reactive retinal inflammation with exudate + hemorrhage, retinal detachment, glaucoma, cataract, uveitis, decreasing visual acuity, eye pain
  • cerebellar symptoms: vertigo, dysdiadochokinesia, dysmetria, Romberg sign
  • spinal cord symptoms (uncommon): loss of sensation, impaired proprioception
  1. Retinal angiomatosis = von Hippel tumor (>50%) earliest manifestation of disease; multiple in up to 66%, bilateral in up to 50%
     Histo: hemangioblastoma of retina
     Dx: indirect ophthalmoscopy + fluorescein angiography
     • small tumors rarely detected by imaging studies
     • globe distortion
     • thick calcified retinal density (calcified angioma-induced hematoma)
     
     US:
     • small hyperechoic biconvex homogeneous solid noncalcified masses, usually in temporal retina
     • NO choroidal excavation
     
     Cx:
     1. repeated vitreous hemorrhage (frequent)
     2. exudative retinal detachment posteriorly
  2. Hemangioblastoma of CNS = Lindau tumor (40%)
     = benign nonglial neoplasm as the most commonly recognized manifestation of vHL disease
     Age: 15–40 years
     Site: cerebellum (65%), brainstem (20%), spinal cord (15%); multiple lesions in 10–15% (may be metachronous)
     ◊4–20% of single hemangioblastomas occur in von Hippel-Lindau disease!
     CT:
     • large cystic lesion with 3–15-mm mural nodule (75%)
     • solid enhancing lesion (10%)
     • enhancing lesion with multiple cystic areas (15%)
     • intense tumor blush / blushing mural nodule
     • NO calcifications (DDx: cystic astrocytoma calcifies in 25%)
     
     MR (modality of choice):
     • hypointense cystic component on T1WI (slightly hyperintense to CSF ← protein content); hyperintense on T2WI
     • small tubular areas of flow void within mural nodule (= enlarged feeding + draining vessels); intense contrast enhancement of mural nodule
     • slightly hypointense solid lesion on T1WI; hyperintense on T2WI; intense contrast enhancement
     
     Angio:
     • intense staining of mural nodule (“mother-in-law phenomenon” = tumor blush “comes early and stays late”, very dense)
     • presence of feeding vessels
     
     Prognosis: most frequent cause of morbidity and mortality; frequent recurrence after incomplete resection
• LABYRINTH
  1. Endolymphatic sac neoplasm
     = aggressive adenomatous tumor with mixed histologic features
     • sensorineural hearing loss
     
     Location: retrolabyrinthine temporal bone
     Site: endolymphatic sac
     • aggressive lytic lesion containing intratumoral osseous spicules + areas of hemorrhage
     • heterogeneous enhancement with hyperintense areas on T1WI + T2WI (due to hemorrhage)
• HEART
  1. Rhabdomyoma
• KIDNEYS
  • polycythemia ← elevated erythropoietin level (in 15% with hemangioblastoma, in 10% with renal cell ca.)
  1. Cortical renal cysts (59–63%)
     multiple + bilateral (may be confused with adult polycystic kidney disease); simple appearing cysts often contain small foci of renal cell carcinoma
  2. Renal cell carcinoma (24–45%)
     Age: 20–50 years
     • multicentric in 87%, bilateral in 10–75%; many arise from cyst wall
     • sensitivity: 35% for angiography, 37% for US, 45% for CT ← inability to reliably distinguish between cystic RCC, cancer within cyst, atypical cyst
     • 50% metastatic at time of discovery
     
     Prognosis: slower growing with higher 10-year survival rate than RCC without vHL; RCC is cause of death in 30–50% as the 2^nd most frequent cause of mortality!
     Screening and management strategy:
     • follow solid lesion every 6–12 month until the largest lesion is 3 cm → nephron-sparing surgery
  3. Renal adenoma
  4. Renal hemangioma
• ADRENAL pheochromocytoma (0–60%)
  bilateral in up to 40%; confined to certain families
• EPIDIDYMIS
  1. Cystadenoma of epididymis
• PANCREAS
  1. Microcystic serous pancreatic adenoma (12–56%)
  2. Microcystic serous pancreatic carcinoma (rare)
  3. Pancreatic endocrine tumor (PET in 5–17%)
     Mean age: 38 years (slightly younger than sporadic PET)
     • multiple mostly nonfunctioning PETs (30%) with clear cell change (60%)
     
     Prognosis: metastases in 1.4% with >3 cm tumor
  4. Pancreatic hemangioblastoma
  5. Pancreatic cysts (in 50–91%)
     Incidence: in up to 72% (autopsies)
     Location: pancreatic body + tail
     • usually multiple multilocular cysts (spectrum from single cyst to cystic replacement of gland)
     • ± peripheral calcifications
     • Pancreatic cysts may be only manifestation for years
     • Pancreatic cysts in a patient with a family history of von Hippel-Lindau disease are DIAGNOSTIC!
• LIVER
  1. Liver hemangioma
  2. Adenoma
• OTHERS
  1. Paraganglioma
  2. Cysts in virtually any organ: liver, spleen, adrenal, epididymis, omentum, mesentery, lung, bone

MULTIPLE ORGAN NEOPLASMS

• Kidney: renal cell carcinoma (up to 40%), renal angioma (up to 45%)
• Liver: adenoma, angioma
• Pancreas: cystadenoma / adenocarcinoma
• Epididymis: adenoma
• Adrenal gland: pheochromocytoma

MULTIPLE ORGAN CYSTS

1. Kidney (usually multiple cortical cysts in 75–100% at early age, most common abdominal manifestation)
2. Pancreas (in 9–72% often numerous cysts; second most common affected abdominal organ)
3. Others: liver, spleen, omentum, mesentery, epididymis, adrenals, lung, bone