—  SPECIALTY CONFERENCE  —

Pediatric Pathology

Case 3b - Venous Malformation

Harry Kozakewich
Children's Hospital Boston
Boston, MA





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Clinical History:
This seven year old girl noticed an intermittent bump and pain above her left hip for two months. Examination revealed no cutaneous change but there was a 4cm soft, slightly tender mass in the soft tissues just behind her anterior superior iliac spine. An ultrasound showed a hypoechoic inhomogeneous mass with no evidence of flow and was non-specific. CT scan showed a muscle mass with calcifications, extending into the subcutis. A venous malformation was on the differential list but a tumor could not be excluded. An open biopsy was performed and, following a frozen section diagnosis of "probable vascular malformation", the subcutaneous mass was excised. A diagnosis of vascular malformation, venous and/or lymphatic was provided (year 2000). There was a recurrence in 2007 which was excised in 2009.


Case 3b - Figure 1
Case 3b - Figure 2
Case 3b - Figure 3
Case 3b - Figure 4


Differential Diagnosis:
1. Lymphatic malformation

2. Venous malformation

Pathologic Findings:
The submitted images show large, abnormal vascular structures with irregularly contoured lumens and walls of varying thickness and composition. The walls in some places are devoid of muscle and consist of fibrous tissue only. In other areas, the walls have irregular strands or nodules of smooth muscle, frequently merging with fibromyxoid tissue which is probably the consequence of organized thrombi. Mural elastic tissue is not seen on H&E. The endothelium is thin and flat and the lumens are empty or contain blood or organizing thrombi. The histopathology is very consistent with a venous malformation (VM). Lymphatic malformation (LM), however, is a consideration and it would be reasonable to perform immunohistochemistry to exclude an LM, particularly if the imaging features are not characteristic for VM.

Final diagnosis:
Venous Malformation

Discussion:
VMs, formerly called by terms such as "venous hemangioma" or "cavernous hemangioma", are present at birth but are not always readily evident. Their sizes vary from tiny to large and most often involve the skin and subcutis and frequently the underlying skeletal muscle. Muscle alone may be involved and VMs may occur in viscera, particularly liver, as well as brain. [1]

VMs by histopathology are composed of irregular venous-type channels, lined by flat, inactive endothelium and surrounded by smooth muscle which is often focally absent or scant relative to luminal diameter. The channels also vary in size. They may be back-to back, in clusters, or randomly distributed and usually contain a variable amount of blood, although some may be empty or contain only sedimented protein or red cells. Luminal thrombi are often present, sometimes demonstrating papillary endothelial hyperplasia, and can become organized, sclerotic and calcified phleboliths or can be incorporated into the wall to form fibromyxoid nodules. [2]

Intramuscular VMs have considerable histological similarity to VMs in other tissues and organ systems. [3] Intraosseous VMs, often called "hemangioma" of bone, most often affect vertebral bodies or the cranial vault. The lesion consists mostly of thin-walled vessels of small venular size, but the walls often lack pericytes or smooth muscle. The endothelium is flat and the proliferative index is negligible. Organizing thrombi may be present. [4] Glomuvenous malformation (GVM) is also a form of VM. These were previously called "glomangioma" or familial "glomangiomatosis". [5] These single or multiple lesions almost always occur in the skin and subcutis but can also be intramuscular. Light microscopy shows small, medium or large thin-walled abnormal venous channels with one or more layers of uniform, cuboidal eosinophilic glomus cells substituted for the smooth muscle in many vessels.GVMs are caused by loss of function of the glomulin gene. [6]GVM is to be distinguished from glomus tumor which occurs in adults as a small subungual proliferation of clusters and sheets of glomus cells without the abnormal venous component. Atypical and malignant glomus tumors also occur. [5]

Numerous other venous anomalies are also included under the VM umbrella. Some have characteristic histopathologic features but many require clinical features for diagnosis. Cerebral-cavernous malformations (often called "cavernomas") are VMs in the central nervous system. [7] They are typically small and composed a fairly compact mass of large thin-walled blood vessels with collagenous walls lacking smooth muscle, often in a back-to-back arrangement. Organizing thrombi are common and a rim of brain parenchyma with gliosis and hemosiderin surrounds the lesion. [8, 9] Mutations in three separate genes have been identified. [10] Familial cutaneomucosal venous malformations are caused by a loss of function in the endothelial receptor TIE2. [11, 12] Some lesions have remarkably thin walls but others are less characteristic. The channels are of small and medium size, and the inconspicuous endothelial layer with flat or round nuclei is devoid of a surrounding pericytic or smooth muscle coat except very focally. [13] Blue rubber bleb nevus syndrome is a usually sporadic disorder with cutaneous and gastrointestinal manifestations. The lesions are soft, blue and nodular with a predilection of the skin of the palms, soles and trunk and are present throughout the bowel, particularly the small bowel. [1, 14] The cutaneous lesions often have large channels with thin walls having remarkably little or no smooth muscle while the deeper ones have a layer of smooth muscle although it may be discontinuous. Some fibrous tissue separates the channels. The intestinal lesions involve primarily submucosa with minimal involvement of the mucosa and a typical merging of the muscular layer of the channels with the muscularis mucosa. The muscular layer of the bowel may be involved including the mesentery. [15]

It is probably appropriate to briefly address so-called capillary malformations (CM). The term, CM, is used in a generic sense by clinical colleagues to indicate a vascular stain of the skin rather than a specific type of lesion and it therefore includes stains produced by various vascular malformations such as "port-wine" stains (veno-capillary malformation) and venous and arterial malformations. [16]

References:
  1. Mulliken JB, Fishman SJ, Burrows PE. Vascular anomalies. Curr Probl Surg 37:517,2000.

  2. North PE, Mihm MC. Histopathological diagnosis of infantile hemangiomas and vascular malformations. Facial Plastic Surg Clin North Am 9:505,2001.

  3. Hein KD, Mulliken JB, Kozakewich HPW, et al. Venous malformations of skeletal muscle. Plast Reconstr Surg 110:162,2002.

  4. Brudeur E, Perez-Atayde AR, Jundt G, et al. Vascular lesions of bone in children, adolescents, and young adults. Virchows Archiv 454:161,2009.

  5. Folpe AL, Fanburg-Smith JC, Miettinen M, Weiss SW. Atypical and malignant glomus tumors: analysis of 52 cases, with a proposal for the reclassification of glomus tumors. Am J Surg Pathol 25:1,2001.

  6. Brouillard P, Boon LM, Mulliken JB, et al. Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations ("glomangiomas"). Am J Hum Genet 70:866,2002.

  7. Del Curling O, Kelly DL, Elster AD, et al. An analysis of the natural history of cavernous angiomas. J Neurosurg 75:702,1991.

  8. Tomlinson FH, Houser OW, Scheithauer BW, et al. Angiographically occult vascular malformations: a correlative study of features on magnetic resonance imaging and histological examination. Neurosurgery 34:799,1994.

  9. Burger PC, Scheithauer BW, Vogel FS. In Surgical pathology of the nervous system and its coverings. Churchill Livingstone. Philadelphia: Chapter 7, Pgs. 403-5.

  10. Denier C, Labauge P, Bergametti F, et al. Genotype-phenotype correlations in cerebral cavernous malformations. Ann Neurol 60:550,2006.

  11. Boon LM, Mulliken JB, Enjolras O, et al. Arch Dermatol 140:971,2004.

  12. Wouters V, Limaye N, Uebelhoer A, et al. Herediatary cutaeomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects. Euro J Hum Genet 193:1,2009.

  13. Vikkula M, Boon LM, Carraway KL, et al. Vascular dysmorphogenesis casued by an activating mutation in the receptor tyrosine kinase TIE2. Cell 27:1181,1996.

  14. Bean WB. Anomylous vascular spiders and related conditions of the skin. Springfield, IL. Charles C Thomas, 1958.

  15. Enjolras O, Wassef M, Chapot R. In Color atlas of vascular tumors and malformations. New York: Cambridge University Press, 2007. Chapter 1ll.B, Pgs.209-13.

  16. Happle R. What is a capillary malformation? J Am Acad Dermatol 59:1077,2000