May brain cavernomas be classified following ISSVA/SISAV?

Similarities exist between brain cavernoma (cerebral cavernous malformations, CCM) and peripheral venous angioma. The main features of both will be discussed; in particular, I'll try to answer to the question if CCM may be classified as venous malformation following ISSVA/SISAV classification.

Pathology and clinics

Cerebral cavernous malformations (CCM) are slow flow vascular malformation found in brain.

From a pathological point of view, they are formed by closely packed, dilated sinusoids filled with blood and lined with endothelium with no interposition of brain parenchyma. They probably grow by a process of vessel proliferation in the setting of repetitive intralesional hemorrhages. The CCM exhibit brittle vascular morphology devoid of mature vessel wall elements. Due to repeated haemorrhages and reactive gliosis, CCM are surrounded by hemosiderin, gliosis and calcifications. Some Authors found, in the surrounding brain, enlarged sinusoids with interposing brain parenchima, a malformation traditionally classified as capillary telangiectases, and transitional forms between the two. Based on this, they concluded that capillary telangiectasia and cavernous malformations could represent two pathological extremes within the same vascular malformation category called cerebral capillary malformations (Rigamonti, 1991, Mulliken 00). Moreover, local variant of venous anatomy (the so called "venous angioma" or "developmental venous anomalies" are frequently found in the adiacent brain, in particular in sporadic malformations (Abdulrauf 99) CCM may cause cerebral haemorrhages, seizures, or remain asymtomatic (Awad 93). They rarely increase in size, but "de novo" malformations have been described (Massa-Micon 00). CCM are detected by MR, sice thay are angiographically occult (Hoang 94).

Molecular biology and genetics

Both sporadic and familiar form exist. Familiar forms are autosomic dominant, due to mutation in three differet and unrelated loci, called CCM 1,2 and 3. CCM1 gene encodes for KRIT1 protein; KRIT1 is involved in building gap junctions among endotelial cells. It is now thought that CCM proteins form a ternary complex near the plasma membrane of endothelial cells and link the junctional proteins, integrins and vascular endothelial -cadherin, with intracellular cytoskeleton scaffold. A "two hits" hypothesis have been invoked to explain phenotypical variations in affected individuals, genetic mutation representing the first "predisposing" hit, and local conditions, from reactive oxygen species hypoxia, stress proteins, representing the second "coupe de grace" hit. No genetic studies exist in sporadic CCM.

ISSVA/SISAV classification of vascular malformations (latest release in press)

Low-flow vessels are the landark of venous malformations. So, the key pont is: may CCM be classified as extra-troncular venous malformations occurring in brain?

From a pathologycal point of view, the description from Gupta (Gupta, 2011) of capillary malformations -"...irregular venous-type channels, lined by flat endothelium and surrounded by smooth muscle that is often focally absent or scant relative to channel size..." and venous malformations - "...ectatic vessels, with small venular morphology..." is similar to that of Rigamonti for brain capillary malformations, apart for the surrounding tissue. (Rigamonti, 91).

From a clinical point of view, it is obvious that location causes peculiar clinical pictures. From a radiological point of view, some differences start appearing: in particular, calcifications in body venous malformations usually take the form of flebolytis, while in the brain they are more peripheral and irregular; moreover, haemorrhages are more rare in body vascular malformations than in brain; but , on the other hand, a strict analogy may be don within CCM intra-lesional haemorrhage - that means clots into the CCM - and intralesional thrombosis of body venous malformations; the particular environnement of brain may possibly justify the increased rate af true extralesional, brain haemorrhages. But wath about molecular biology? Are body venous malformations and CCM sustained by similar processes? Are there CCM gene mutations in hereditary body venous malformations? Some data from literature may help: 5% of patients with CCM1 malformation carries retinal angiomas (Labauge 06): this is not surprising, since retina is part of central nervous system. In 9% of patients with familar CCM, cutaneous vascular malformations were found; they were classified following ISSVA criteria as capillary, venous and hypercheratotic capillary-venous malformations.(Sirvente 09). Mutated KRIt1 was found in cutaneous hypercheratotic capillary-venous malformation (Eerola 00). Interestingly, no metameric associations were decibed, as in facial neuro-cutaneous syndromes, excluding any kind of metameric developmental anomaly. Similarly to CCM, no significant data exist for sporadic venpus malformations.

Concluding, CCM and peripheral venous malformations share pathological and genetic similarities, and may be, in my personal opinion, classified in the same group. CCM has peculiar clinical presentation; this make the practical value of this classification limited, because patients are managed in separate clinical settings. On the other hand, this common classification may help to unify body and vasclar malformations in a single scientific and resarch setting.


  1. Abdulrauf SI, Kaynar MY, Awad IA: A comparison of the clinical profile of cavernous malformations with and without associated venous malformations. Neurosurgery 44:41?47, 1999
  2. Awad IA, Barrow DL (eds): Cavernous Malformations. Park Ridge, IL: American Association of Neurological Surgeons, 1993
  3. Dasgupta R, Fishman SJ. ISSVA classification. Semin Pediatr Surg. 2014 Aug;23(4):158-61. *
  4. Eerola I, Plate KH, Spiegel R et al. KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation.Hum Mol Genet 2000;9:1351-1355.
  5. Gupta A, Kozakewich H. Histopathology of vascular anomalies. Clin Plast Surg 2011; 38(1):31-44.
  6. Hoang TA, Hasso AN: Intracranial vascular malformations. Neuroimaging Clin N Am 4:823?847, 1994
  7. Labauge P, Krivosic V,Denier C et al. Frequency of retinal cavernomas in 60 patients with familial cerebral cavernomas: a clinical and genetic study. Arch Ophthalmol 2006;124:885-886.
  8. Massa-Micon B, Luparello V, Bergui M, Pagni CA. De novo cavernoma case report and review of literature. Surg Neurol 2000;53:(5):484-487.
  9. J.B. Mulliken, S.J. Fishman, P.E. Burrows. Vascular anomalies. Curr Probl Surg, 37 (2000),517-584
  10. Rigamonti D, Johnson PC, Spetzler RF, Hadley MN, Drayer BP. Cavernous malformations and capillary telangiectasia: a spectrum within a single pathological entity. Neurosurgery. 1991 Jan;28(1):60-4.
  11. Sirvente J, Enjolras O, Wassef M, Tournier-Lasserve E, Labauge P. Frequency and phenotypes of cutaneous vascular malformations in a consecutive series of 417 patients with familial cerebral cavernous malformations. J Eur Acad Dermatol Venereol. 2009 Sep;23(9):1066-72.

* SISAV classification of venous malformation is in press

Scritto da Mauro Bergui

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