Venous malformations

INTRODUCTION — Venous malformations (VMs) are the most frequent slow-flow vascular malformations seen in specialized multidisciplinary centers for vascular anomalies [1]. They result from inborn errors in the development of the venous network, leading to dilated and dysfunctional veins that are deficient in smooth muscle cells. Although inherited forms exist, more than 90 percent of VMs occur sporadically. VMs are present at birth and grow proportionally with the child but may become clinically evident later in life. Depending on their location and extension, symptoms are highly variable and include pain, bleeding, disfigurement, and functional impairment, resulting in significant impairment of quality of life, morbidity, and mortality [2].

This topic will review the pathogenesis, clinical manifestations, diagnosis, and treatment of VMs. Other congenital vascular anomalies and vascular tumors are discussed separately.

●(See "Vascular lesions in the newborn".)

●(See "Klippel-Trenaunay syndrome: Clinical manifestations, diagnosis, and management".)

●(See "Capillary malformations (port wine birthmarks) and associated syndromes".)

●(See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications".)

●(See "PHACE syndrome".)

●(See "Tufted angioma, kaposiform hemangioendothelioma (KHE), and Kasabach-Merritt phenomenon (KMP)".)

●(See "Congenital hemangiomas: Rapidly involuting congenital hemangioma (RICH), noninvoluting congenital hemangioma (NICH), and partially involuting congenital hemangioma (PICH)".)

EPIDEMIOLOGY — VMs are a rare disorder, but they are the most common vascular malformation seen in specialized centers. Although epidemiologic data are lacking, their incidence has been estimated at 1 in 2000 to 5000 births. There is no sex predilection [1].

PATHOGENESIS

Genetics and inheritance — More than 90 percent of VMs occur sporadically and consist of unifocal lesions. Multifocal lesions are seen in patients with the rare, inherited forms that exhibit autosomal dominant transmission, such as cutaneomucosal venous malformation (VMCM; 1 percent of all VMs) and glomuvenous malformation (GVM; 5 percent of all VMs), and also in two exceedingly rare, sporadic forms: multifocal venous malformation (MVM) and blue rubber bleb nevus (BRBN) syndrome (Bean syndrome) [3,4].

●TEK – TEK gene on chromosome 9p encodes the endothelial receptor tyrosine kinase TIE2. Differing gain-of-function variants in TEK can cause all four subtypes of VMs [5-11]:

•Cutaneomucosal venous malformation (VMCM) – In VMCM, R849W is the most common germline TEK variant. It causes only weak TIE2 hyperphosphorylation and needs a somatic second hit for lesion formation [6,7,9,10].

•Sporadic venous malformation – In sporadic VMs, the somatic L914F variant is identified in 60 percent of TEK mutation-positive lesions [7,8]. The L914F variant has not been identified in the germline, suggesting that it may be incompatible with life when present in all cells.

•Multifocal venous malformation (MVM) and blue rubber bleb nevus (BRBN) syndrome – In MVM and BRBN syndrome, lesions most often contain double somatic variants in TEK [5]. In MVM, the most common combination is Y897C-R915C, whereas in BRBN syndrome, it is T1105N-T1106P. In MVM, the patient is mosaic for the R915C change, on top of which the Y897C change can be seen in the lesion. In BRBN syndrome, the two variants seem to have occurred at the same time in a "niche," as both are found with equal frequency in various lesions [5].

●PIK3CA – Pathogenic variants in the PIK3CA gene, encoding the p110a catalytic subunit of PI3K, cause approximately 20 percent of common VMs and, similar to TEK variants, result in excessive activation of AKT, low levels of PDGF-beta, and disrupted pericyte coverage surrounding endothelial cells [12]. Three "hotspot" variants, E542K and E545K in the helical domain (exon 9) and H1047R in the kinase domain (exon 20), are frequently identified. The exact same variants are frequently seen in human cancers [13]. In contrast with TIE2-mutated VMs, PIK3CA-mutated VMs do not tend to extend to the skin surface [12].

●GLMN – Glomuvenous malformations (GVMs; MIM #138000) are inherited in an autosomal dominant fashion and caused by loss-of-function variants in the glomulin gene GLMN on chromosome 1p21-22. These variants lead to disruption of pericyte differentiation and accumulation of rounded "glomus" cells in lesions [14,15]. Several somatic second hits have been identified in GVMs, the most common of which is acquired uniparental isodisomy, which leads to duplication of the inherited mutant allele and loss of the wild-type allele in affected tissues [16].

●KRIT1 – Nodular VMs presenting as a group of small, bell-shaped VMs, especially on the face, may be associated with cerebral cavernous malformations of the brain, caused by germline variants in the cerebral cavernous malformation 1 (CCM1) gene, also called KRIT1 [17-20]. (See "Brain arteriovenous malformations" and "Vascular malformations of the central nervous system", section on 'Cavernous malformations'.)

●IDH1 and IDH2 – Maffucci syndrome, which is characterized by multiple enchondromas and multiple subcutaneous vascular lesions (spindle cell hemangiomas) that may clinically mimic venous anomalies, is caused by somatic variants in the isocitrate dehydrogenase genes IDH1 and IDH2 [21]. Maffucci syndrome is also associated with a high risk of chondrosarcoma and other cancers [21-23].

Signaling pathways — The mutated TIE2 proteins result in a sustained and ligand-independent activation of the TIE2 receptor and subsequent sustained hyperphosphorylation of AKT, even in confluent cells [24]. The AKT-mediated inhibition of FOXO1 leads to inappropriately low platelet-derived growth factor-beta (PDGF-beta) levels and defective and sparse pericyte coverage [24].

The tyrosine kinase receptor TIE2, located on endothelial cells, and its ligand angiopoietin-1 (ANG-1), secreted by vascular smooth muscle cells (or pericytes), play a major role in the maturation and stability of veins [25-27]. Knockout of TIE2 or ANG-1 in mice results in impaired blood vessel branching and deficient pericyte coverage [28]. The other ligand, angiopoietin-2 (ANG-2), which is produced by the endothelial cells, seems to be a context-dependent inhibitor of ANG-1 effects, demonstrating tight control of this signaling pathway in endothelial-smooth muscle cell cross-talk.

Binding of ANG-1 to TIE2 activates the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) signaling pathway, an important pathway implicated in multiple cellular processes, such as protein synthesis, metabolism, and survival [29]. mTOR exists as two complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Activated PI3K phosphorylates AKT on threonine 308, leading to partial activation of AKT. Full activation of AKT requires a second phosphorylation that is induced by mTORC2 [30]. AKT is thereby able to regulate positively the transcription factor STAT-1 and negatively the transcription factor forkhead box protein O1 (FOXO1). The latter results in decreased levels of pericyte attractant platelet-derived growth factor-beta (PDGF-beta). Cell confluence influences PDGF-beta production, in that AKT activity is elevated in sparse endothelial cells and diminishes with confluence, inversely correlating with PDGF-beta production. This implies that normal endothelial cells, when in cell-cell contact upon tube formation, secrete PDGF-beta in order to recruit pericytes [24,31,32].

Animal models — The identification of mutation in the TIE2-PI3K-AKT-mTOR pathway led to the development of the first murine model of VMs; mice injected with TIE2-L914F-mutated human umbilical vein endothelial cells developed VMs histologically similar to those of patients with VMs [33]. In these mice, sirolimus decreased the proliferation of endothelial cells and inhibited the excessive activation of AKT, which is responsible for smooth muscle deficiency [33]. Sirolimus was also shown to facilitate the nuclear localization of FOXO1 and the expression of platelet-derived growth factor-beta (PDGF-beta) in mutant endothelial cells, improving paracrine interactions between endothelial cells and smooth muscle cells [34].

Vascular changes — VMs are slow-flow vascular malformations composed of a network of veins with continuous endothelial lining surrounded by sparse, irregularly distributed vascular smooth muscle cells (pericytes); these vessels are thin-walled, dilated, ectatic, and dysfunctional [6]. Glomuvenous malformations (GVMs) are characterized by the presence of undifferentiated pericytes (glomus cells) surrounding convoluted venous channels [15].

Coagulation abnormalities — The slow flow of blood through the dilated and ectatic vessels results in blood stagnation, activation of the coagulation cascade, thrombus formation, and thrombolysis. This coagulation disorder, called localized intravascular coagulopathy, occurs in approximately 42 percent of patients with VMs [35-39].

CLINICAL PRESENTATION

Common features — VMs develop primarily in cutaneous, subcutaneous, or mucosal tissues, but they can affect any tissue or organ, including muscles, joints, viscera, and the central nervous system. (See "Vascular malformations of the central nervous system".)

●Age at presentation – VMs are usually present at birth, grow with the child, and slowly expand over time. Hormonal changes and puberty can exacerbate the growth. Some VMs, particularly those with predominant intramuscular localization, may become evident only later in life.

●Site of involvement – Approximately 40 percent of VMs occur on the extremities, 20 percent on the trunk, and 40 percent on the cervicofacial area [40]. The vast majority are unifocal; only 1 percent are multifocal, with multiple cutaneous and visceral lesions.

●Lesion appearance – VMs typically manifest as a light to dark blue skin discoloration overlying a soft, compressible, subcutaneous mass (picture 1). However, the clinical presentation may be highly variable, depending upon the size, location, and mass effect of the lesion on the adjacent organs. Cervicofacial VMs may lead to physical distortion, facial asymmetry, exophthalmos, or dental disorganization.

●Associated symptoms – Symptoms are usually absent at birth but appear during childhood, become more severe as the child grows (depending upon the size and location of the malformation), and may be disabling:

•Pain – Pain is a frequent complaint and is attributed to joint, tendon, or muscle involvement. Pain may worsen at puberty and during intense physical efforts or menstrual periods. It can be more severe in the morning at awakening, presumably due to stasis and swelling [41].

•Migraine – Migraine is frequently associated with VMs located in the temporal muscle. Involvement of the oral cavity, including the tongue, causes difficulty in speech and mastication. VMs located in the extremities often cause muscle weakness, limb length discrepancy, and hypoplasia of the affected side.

•Thrombosis – Thrombosis due to stagnant blood flow is common in VMs. It presents with rapid distension, firmness, and pain in the affected areas. However, VMs are unlikely to cause pulmonary embolism because the thrombosed channels are sequestered from the main conducting channels. Persistent thrombi can calcify, resulting in the formation of rounded, hyaline, organized thrombi (phleboliths) that may be palpable or visible on imaging.

Complications

Localized intravascular coagulopathy — Localized intravascular coagulopathy, also called chronic consumptive coagulopathy, occurs in approximately 42 percent of patients with large VMs [35-39]. Its severity depends upon the size and extension of VMs and is reflected by elevated D-dimer levels (>0.5 mcg/mL). D-dimer levels are markedly elevated (>1 mcg/mL) in 25 percent of patients with VMs, in the absence of other conditions associated with D-dimer increase, such as cancer, inflammatory diseases, or thrombophilia. (See 'Coagulation abnormalities' above.)

Localized intravascular coagulopathy is considered severe when high D-dimer levels (>1.8 mcg/mL) are associated with low fibrinogen levels (<150 mg/dL). Severe localized intravascular coagulopathy may progress to disseminated intravascular coagulation, with marked consumption of platelets, coagulation factors, and fibrinogen, and risk of severe bleeding during surgical procedures [37,38,42]. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Disseminated intravascular coagulation in infants and children".)

Involvement of vital structures/organs — Some VMs can be associated with life-threatening complications, due to extension to vital structures [43]. Deep oropharyngeal VMs compress and deviate the upper airways, causing snoring and sleep apnea. VMs invading the gastrointestinal or urogenital tract frequently cause bleeding and chronic anemia. Lesions involving bones predispose to pathologic fractures.

Clinical variants

Cutaneomucosal venous malformations — Cutaneomucosal venous malformations (VMCMs; MIM #600195) are an uncommon type of VM inherited in an autosomal dominant fashion. VMCMs present as multiple small, superficial lesions of various hues of blue that are easily compressible. Lesions involve skin and oral mucosa (picture 2) and seldom invade the muscle. There are no reports of VMCMs extending to joint or bone. VMCMs involve the cervicofacial area in approximately 50 percent of cases and the extremities in 40 percent [15]. Due to their small size, they are usually asymptomatic and are not painful at compression.

Multifocal venous malformations — Multifocal venous malformations (MVMs) are similar to VMCM lesions but occur sporadically. They usually present as multiple small (<5 cm in diameter), raised lesions of various hues of blue involving the skin, oral mucosa, and occasionally, the subcutaneous tissues (picture 3) and skeletal muscle.

MVMs are most frequently located in the cervicofacial area and extremities, typically have a hemispherical shape, are soft to the touch, and rarely emptied by external pressure. Due to their small size, these lesions are usually asymptomatic.

Glomuvenous malformations — Glomuvenous malformations (GVMs) (formerly known as "capillary-lymphatic-venous malformations" glomangioma or glomangiomatosis) are a clinicopathologic variant of VMs characterized histologically by the presence of undifferentiated smooth muscle cells (glomus cells) surrounding convoluted venous channels. They may occur sporadically (de novo mutation) or, most commonly, be inherited in an autosomal dominant fashion (MIM #138000) [14,15].

GVMs present at birth as cobblestone or plaque-like, slightly hyperkeratotic, dark blue or purple, multifocal lesions of various sizes (picture 4). Lesions are more superficial than VMs, as they involve the skin and rarely the mucosae, but never extend deeply into muscles. In contrast with MVMs and VMCMs, GVMs are mainly located on the extremities, are often painful on palpation, and cannot be emptied by compression. Some patients with GVMs recall the appearance of new vascular lesions after trauma [15].

Mixed and syndromic venous malformations — Venous anomalies can occur in combination with other vascular malformations, such as capillary-venous malformations and capillary-lymphatic-venous malformations. They usually involve cutaneous and subcutaneous tissues but rarely the muscle. Syndromes with a venous anomaly include the blue rubber bleb nevus (BRBN) syndrome, Maffucci syndrome, and Klippel-Trenaunay syndrome.

Blue rubber bleb nevus syndrome — Blue rubber bleb nevus (BRBN) syndrome (Bean syndrome) is a rare congenital disorder characterized by numerous, diffuse, cutaneous, and internal VMs. Patients with BRBN syndrome are often born with a so-called "dominant" lesion and with time develop multiple VMs that affect the skin, soft tissue, and gastrointestinal tract (picture 5) [5]. Skin lesions are often multiple, small, round, rubbery, and located on the palms and soles. Gastrointestinal sessile lesions cause chronic bleeding and anemia. Rarely, lesions may be found in other organs, such as the liver, spleen, bladder, kidney, lung, and brain [5,44,45].

Maffucci syndrome — Maffucci syndrome is a rare, sporadic genetic syndrome characterized by multiple enchondromas, multiple superficial and subcutaneous spindle cell hemangiomas of the distal extremities (image 1), and increased cancer risk [43]. The disease manifests during childhood with the development of multiple painful enchondromas in the bones of the hands and feet, as well as in the long bones. (See "Nonmalignant bone lesions in children and adolescents", section on 'Enchondroma'.)

Spindle cell hemangiomas become apparent around puberty as subcutaneous red/brown or bluish vascular nodules located on the extremities and may progress to multifocal painful lesions over time. Histologically, spindle cell hemangiomas are benign vascular tumors composed of thin-walled, venous-like channels that may contain phleboliths, separated by areas of nodular proliferations of spindled fibroblastic cells.

With time, there is often severe disfiguration of the affected body parts (picture 6). Patients with Maffucci syndrome also have a high risk of malignancy, including chondrosarcoma, glioma, fibrosarcoma, and angiosarcoma [46,47].

Klippel-Trenaunay syndrome — Klippel-Trenaunay syndrome is a rare congenital disorder characterized by the presence of capillary-lymphatic-venous malformation or varicosities and limb overgrowth. The pathogenesis, clinical presentation, diagnosis, and management of Klippel-Trenaunay syndrome are discussed in detail elsewhere. (See "Klippel-Trenaunay syndrome: Clinical manifestations, diagnosis, and management".)

DIAGNOSIS

Clinical suspicion — The diagnosis of VM should be suspected in patients presenting with a solitary, light to dark blue skin discoloration and an underlying soft, subcutaneous mass present since birth or early childhood. A history of slow growth over time or growth triggered by puberty, trauma, physical effort, or menstrual periods is an additional clue to the clinical diagnosis. A family history of similar lesions may suggest an inherited form.

Physical examination — The clinical diagnosis is based upon the lesion appearance and characteristic findings on physical examination.

Common VMs range from small varicosities to extensive lesions of the face, extremities, or trunk. They can be emptied by compression and appear less prominent in the upright position. In contrast, they increase in volume with increasing venous pressure (eg, during Valsalva maneuver, crying, or straining), in a dependent position, or with exercise. Due to slow flow, there is no thrill or bruit, and the affected area is not warmer than the surrounding areas. Palpation is not painful unless thrombosis occurs.

Imaging — Superficial and localized lesions may not require imaging studies. In case of extensive lesions, Doppler ultrasonography and magnetic resonance imaging (MRI) represent the preferred methods for initial grading of VMs and post-treatment follow-up [40].

●Doppler ultrasonography – Doppler ultrasound can confirm a slow flow or the absence of flow within the malformation. Sometimes, flow may be observed when performing the Valsalva maneuver or compression. Generally, VMs appear as hypoechoic or heterogeneous and compressible. The detection of phleboliths further supports the diagnosis [43,48].

●MRI – MRI with contrast enhancement is the gold standard for assessing the VM extension and infiltration into adjacent organs and structures (image 2 and picture 7). Gadolinium contrast allows a diffuse enhancement of venous channels (not observed in lymphatic malformations). Recommended sequences are T1- (pre- and post-contrast) and T2-weighted images with fat saturation. Typically, images may have intermediate signal intensity on T1 and hyperintense signal on T2 in relation to the content or the presence of hemorrhage or thrombosis. With T2-weighted images, phleboliths appear as focal areas of hypointense signal [49,50].

Lesions can be graded using MRI based upon the size and margins [51,52]:

●Grade 1 – Well defined, ≤5 cm in diameter

●Grade 2A – Well defined, >5 cm in diameter

●Grade 2B – Ill defined, ≤5 cm in diameter

●Grade 3 – Ill defined, >5 cm in diameter

This grading system has a prognostic significance and may predict the response to sclerotherapy. Small and well-defined lesions (grade 1) have a better therapeutic response to sclerotherapy than grade 3 lesions [51].

Other imaging techniques that may be helpful include plain radiographs to detect pathognomonic phleboliths and computed tomography (CT) scans to evaluate bone infiltration. Phlebography (direct percutaneous contrast injection under fluoroscopy) is infrequently performed in the diagnostic setting. However, phlebography is usually performed prior to percutaneous sclerotherapy. (See 'Sclerotherapy' below.)

Laboratory tests — Coagulation evaluation with measurement of blood levels of D-dimer and fibrinogen is indicated in patients with suspected large or multifocal VMs, with or without a history of thrombotic events. The finding of elevated D-dimer blood levels (>0.5 mcg/mL) suggesting localized intravascular coagulopathy is pathognomonic of VMs. (See 'Coagulation abnormalities' above.)

D-dimer level is a helpful biomarker for the diagnosis of VMs, with high specificity but low sensitivity, as approximately 40 percent of patients with VMs have D-dimer levels >0.5 mcg/mL and up to 25 percent have levels >1 mcg/mL. When D-dimer levels are elevated in a patient with a VM without any concurrent disease that may induce a D-dimer increase, the likelihood that a venous component is present is approximately 96 percent [37,38]. This is true for pure, isolated VMs (unifocal or multifocal), as well as for mixed and syndromic lesions (capillary-venous malformation and Klippel-Trenaunay syndrome). However, normal D-dimer levels cannot rule out a VM because small VMs may have limited intravascular clotting that does not result in elevated D-dimer levels.

D-dimer levels are also helpful in differentiating among variants of VMs as well as in distinguishing VMs from other vascular anomalies. As an example, D-dimer levels are normal in glomuvenous malformations (GVMs), lymphatic malformations, Maffucci syndrome, and in fast-flow lesions (eg, arteriovenous malformations). D-dimer levels are elevated in the majority of patients with Klippel-Trenaunay syndrome but not in those with Parkes Weber syndrome, which is commonly misdiagnosed as Klippel-Trenaunay syndrome [38]. (See "Klippel-Trenaunay syndrome: Clinical manifestations, diagnosis, and management" and "Klippel-Trenaunay syndrome: Clinical manifestations, diagnosis, and management", section on 'Parkes Weber syndrome'.)

Biopsy — As diagnosis of VMs is usually based on clinical and imaging findings, biopsy is not usually required. Furthermore, biopsy is not always feasible due to the VM location and the increased risk of bleeding, which may result in inadequate sampling. However, if the diagnosis is in doubt, histopathologic and genetic analyses of a biopsy may be helpful for accurate diagnosis.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of VMs includes several conditions presenting as "blue lesions":

●Cutaneous angiosarcoma – Cutaneous angiosarcoma is a rare, aggressive, malignant tumor arising in either blood or lymphatic vessels and characterized by uncontrolled proliferation of vascular endothelial cells. It occurs more frequently in the head and neck areas of older adult males [53]. These tumors present as diffuse and ecchymotic macular, nodular, or plaque-like lesions with rapid expansive growth and tendency to ulcerate. Histopathologic examination clarifies the diagnosis. (See "Head and neck sarcomas", section on 'Angiosarcoma'.)

●Collateral venous network – Collateral venous network can result from a severe stenosis or agenesia of a deep venous trunk and may be misdiagnosed as a VM. Such collateral venous networks are asymptomatic, and veins are histologically normal.

●Lymphatic malformations – Lymphatic malformations are often difficult to distinguish from VMs, particularly in case of hemorrhage into the lymphatic cysts, resulting in a blue coloration of the overlying skin. Compared with VMs, lymphatic malformations are not compressible. Ultrasonography shows hypo- or anechoic cysts with thick septa and fluid levels, although these pathognomonic signs are not always present. D-dimers are usually normal in lymphatic malformations, unless there is a large associated venous component, such as in Klippel-Trenaunay syndrome. Histopathologic examination of lymphatic malformations show positive D2-40 staining (podoplanin), a specific marker for lymphatic endothelial cells [45]. (See "Vascular lesions in the newborn", section on 'Lymphatic malformations' and "Klippel-Trenaunay syndrome: Clinical manifestations, diagnosis, and management".)

●Subcutaneous (deep) infantile hemangiomas – Subcutaneous infantile hemangiomas can mimic VMs (picture 8). In contrast to VMs, this vascular tumor usually grows postnatally, between two weeks and two months of life, and regresses spontaneously from 10 to 12 months onwards during several years. Doppler ultrasound is the best examination to differentiate the fast-flow infantile hemangioma from the slow-flow VM. D-dimer levels are normal in infantile hemangiomas [54]. (See "Infantile hemangiomas: Evaluation and diagnosis".)

●Congenital hemangiomas – Congenital hemangiomas are, like VMs, present and fully developed at birth. Depending on their evolution, they are classified in three types:

•Rapidly involuting congenital hemangioma (RICH), which regress spontaneously within the first year of life

•Noninvoluting congenital hemangioma (NICH), which remain stable and grow as the child grows

•Partially involuting congenital hemangioma (PICH), which regresses incompletely before stabilizing

Congenital hemangiomas usually present as a single, well-limited, red-purple lesion with overlying telangiectasias surrounded by a pale, peripheral halo. NICHs are flat, while RICHs and PICHs exhibit exophytic presentations (picture 9A-C). Most congenital hemangiomas are localized on the limbs, followed by the head and neck region and the trunk. The size is usually >2 cm in diameter [55,56].

In contrast with VM, doppler examination of congenital hemangiomas reveals a high-flow vascular lesion. (See "Congenital hemangiomas: Rapidly involuting congenital hemangioma (RICH), noninvoluting congenital hemangioma (NICH), and partially involuting congenital hemangioma (PICH)".)

●Dermal melanocytoses – Dermal melanocytoses, including the Mongolian spot, nevus of Ota, and blue nevi, arise from dermal melanocytes that never reached their normal site at the basal layer of the skin. The Mongolian spot is a congenital, large, macular, blue-gray pigmentation present in infants of East Asian ancestry (but not limited to them) that typically disappears with puberty. It is commonly located in the lumbosacral region (picture 10). Nevi of Ota and Ito are dermal melanocytoses that differ from the Mongolian spot by having a speckled, rather than uniform, appearance. The nevus of Ota manifests as a unilateral discoloration of the face involving the periorbital region, sclera, conjunctiva, temple, forehead, malar area, and nose (picture 11). The nevus of Ito is localized in the supraclavicular, scapular, and deltoid region (picture 12). The common blue nevus is a well-circumscribed blue nodule or macular plaque seen on any site of the body. (See "Skin lesions in the newborn and infant", section on 'Dermal melanocytosis' and "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Congenital dermal melanocytosis (Mongolian spots)'.)

MANAGEMENT

General considerations — The management of patients with VMs involves an interdisciplinary team including a dermatologist, an interventional radiologist, a hematologist, a plastic and/or vascular surgeon, and an orthopedic surgeon as needed. Patients with small VMs and mild symptoms may not need treatment. Indications for treatment include esthetic disfigurement, functional impairment, and pain [57,58].

The approach to management should be tailored for the individual patient, based upon location and extent of the malformation, clinical symptoms, and patient's preference [58]. The main therapeutic modalities include surgical resection and sclerotherapy. Supportive therapies include elastic compression and pain control. However, there are no randomized trials comparing the efficacy of these treatment modalities [59]. The choice of one modality over another or a combination of modalities is based upon limited evidence from observational studies, most of which have methodologic limitations, and clinical experience.

Supportive therapies

Compression — Tailored compression garments are indicated for symptomatic and extensive VMs of the extremities to reduce pain and the risk of thrombosis. Compression is contraindicated in glomuvenous malformations (GVMs), as it increases pain, and is not effective in Maffucci syndrome.

Pain control — In patients in whom pain persists despite compression and in those with lesions in anatomic sites that are not amenable to compression, low-dose aspirin and/or anti-inflammatory drugs are a therapeutic option. When pain is associated with localized intravascular coagulopathy, low molecular weight heparin at a dose of 100 anti-factor Xa units/kg/day is introduced for 20 days, or longer if pain relapses [37,43]. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Low molecular weight heparin'.)

Coagulopathy control — Localized intravascular coagulopathy is usually well tolerated in usual everyday life, but systemic activation may occur during surgery or other invasive procedures. Thus, coagulation evaluation with measurement of blood levels of D-dimer and fibrinogen is mandatory before starting any surgical treatment. Patients with evidence of localized intravascular coagulopathy (D-dimer >0.5 mcg/mL) may develop disseminated intravascular coagulation with increased risk of bleeding during surgery. Preventive treatment with low molecular weight heparin at a prophylactic dose of 100 anti-Xa/kg/day should be started 24 hours prior to any surgical procedure for a total of five to seven days [37,38]. Consultation with hematology is indicated if high levels of D-dimer are associated with low fibrinogen.

Surgery — Surgery may be a therapeutic option for small VMs amenable to complete excision or for larger VMs with well-defined margins. Surgery alone is often performed for the treatment of GVMs due to their small size and low degree of invasion through adjacent tissues.

For large VMs, surgery is rarely performed without prior sclerotherapy, due to difficulty obtaining surgical free margins, elevated risk of relapse, and high surgical morbidity. Surgical techniques may include simple excision and repair, skin graft, local skin expanders, or free fasciocutaneous or muscle flaps, depending upon the size and location of the malformation.

Coagulation evaluation with measurement of blood levels of D-dimer and fibrinogen is mandatory before starting any surgical treatment. Patients with high D-dimers and normal or low fibrinogen should receive prophylactic low molecular weight heparin 24 hours prior to surgery and for five to seven days postoperatively to avoid intraoperative and/or postoperative bleeding [37,60].

Sclerotherapy — Sclerotherapy is an alternative invasive treatment option. The use of sclerotherapy and surgery varies in different centers, depending on the specialties involved and their expertise in managing vascular anomalies. In many multidisciplinary centers both are used sequentially.

Sclerotherapy is in most cases performed before surgical treatment to diminish the volume of the malformation. However, sclerotherapy may be the sole treatment in patients in whom surgery is technically not feasible. Several sessions may be necessary.

In each session, the injection of a sclerosant agent is preceded by a direct percutaneous phlebography that allows evaluation of the VM architecture, flow rate, rate of venous drainage, and volume of contrast distribution [40]. In children with extensive head and neck malformations that involve the airways, it is necessary to consider performing a tracheostomy prior to sclerotherapy or having the child on mechanical ventilation for 48 to 72 hours after the procedure.

A variety of sclerosing agents can be used to obliterate vascular channels. They are irritant chemicals that cause damage to the vascular endothelium with subsequent inflammation and fibrosis. (See "Injection sclerotherapy techniques for the treatment of telangiectasias, reticular veins, and small varicose veins".)

Due to the lack of large randomized trials, it remains unclear which sclerosing agent is superior in terms of efficacy and safety [52,59,61]:

●Ethanol – Absolute ethanol has been considered to be the most effective sclerosant, but it can cause potentially severe side effects [62,63]. Therefore, it should only be used by experienced interventional radiologists in a hospital setting [52]. A systematic review found that ethanol provides an average response rate, defined as improvement in symptoms or reduction in VM size, of approximately 74 percent (range, 27 to 100 percent) [59]. Ethanol is, however, a highly toxic agent with a rate of serious local and systemic complications between 8 and 28 percent [59,61,64]. Local complications, such as skin necrosis, pain, and blistering, are the most common side effects, occurring in approximately 8 percent of patients. Other possible complications include peripheral nerve injury (2 to 10 percent), transient pain, muscle contracture, deep vein thrombosis, pulmonary embolus, and cardiopulmonary collapse [52,62,65].

The quantity of ethanol can be reduced by the addition of ethylcellulose (gelified ethanol), as ethanol is trapped in the malformation by ethylcellulose, resulting in a prolonged contact time of ethanol with the vasculature. Efficacy on pain and functional and esthetic impairment seems to be similar to that reported with ethanol, but in contrast with absolute ethanol, which is administered under general anesthesia, gelified ethanol can be used under local anesthesia for the treatment of superficial lesions [66].

●Bleomycin – Another sclerosing agent that has been shown to be effective for slow-flow vascular malformations, including VMs, is bleomycin, a cytotoxic antitumoral agent [67-69]. In contrast to ethanol, bleomycin causes minimal swelling and is not neurotoxic, allowing its use in complicated areas, such as those in close contact with nerves, the airway, or the orbit. Bleomycin is especially indicated in areas with high risk for complications when using alcohol.

A concern that still needs to be addressed is the long-term risk of pulmonary fibrosis, the major complication of intravenous administration of bleomycin [70]. This complication has been seen in cancer patients and depends on lifetime accumulated dose. A lifetime dose of 5 mg/kg should not be exceeded. There are no reports of pulmonary fibrosis associated with bleomycin treatment of vascular anomalies.

●Other agents – Other sclerosing agents that have been used for the treatment of VMs include detergents, such as polidocanol, sodium tetradecyl sulfate (STS), and microfoams [71-77]. Their superiority in terms of effectiveness compared with absolute ethanol has yet to be demonstrated [52]. Moreover, even if the overall rate of complications seems lower compared with ethanol sclerotherapy, severe adverse events have been reported with foam sclerotherapy [78-81].

Sirolimus — The mammalian target of rapamycin (mTOR) inhibitor sirolimus (rapamycin) has emerged as a promising targeted therapy for VMs.

In murine models of VM (see 'Animal models' above), sirolimus was shown to decrease the proliferation of endothelial cells and inhibit the excessive activation of AKT, which is responsible for smooth muscle deficiency [33]. Sirolimus was also shown to facilitate the nuclear localization of FOXO1 and the expression of platelet-derived growth factor-beta (PDGF-beta) in mutant endothelial cells, improving paracrine interactions between endothelial cells and smooth muscle cells [34].

●Indications – Sirolimus has shown efficacy in patients with VMs refractory to surgery and/or sclerotherapy and in patients in whom these treatments are not feasible. Sirolimus is not yet approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for venous malformations, yet it is used off-label worldwide. There are no guidelines regarding the management of VMs with sirolimus.

●Administration – In adults, sirolimus is given at the dose of 2 mg once daily. In children younger than 18 years, the recommended dose is 0.8 mg/m²/day in two divided doses.

●Efficacy – The results of preliminary studies indicate that sirolimus is a useful addition to the available treatments for VMs [82]. Similar encouraging results have been reported with sirolimus treatment in several case studies of blue rubber bleb nevus (BRBN) syndrome, lymphatic malformations, and mixed malformations [83-86]. However, the optimal length of sirolimus treatment, timing of administration (before and/or after surgery or sclerotherapy), and its long-term safety remain to be determined.

•In a pilot study of six patients with VMs refractory to standard treatments, sirolimus induced pain relief, functional improvement of the affected body part, and improved self-perceived quality of life in all patients [33]. Sirolimus had an on/off effect on bleeding and oozing in patients with lymphatic malformations. Biologic markers (D-dimers and fibrinogen) improved, and MRIs showed significant decrease in volume after 12 months of treatment. Sirolimus was well tolerated in all these patients. Minor adverse effects included mucositis (50 percent), fatigue (33 percent), headache (33 percent), cutaneous rash (17 percent), and diarrhea (17 percent), all easily managed with symptomatic treatment. One patient presented a grade 3 stomatitis necessitating cessation of sirolimus, and one patient with prior history of cutaneous basocellular carcinoma presented with a basocellular carcinoma after one year on treatment.

•A phase 2 trial evaluated sirolimus in 19 patients with slow-flow malformations, including seven patients with VMs, six patients with lymphatic malformations, two patients with generalized lymphatic anomaly, one patient with capillary-venous malformations, two patients with Klippel-Trenaunay syndrome, and one patient with phosphatase and tensin homolog (PTEN) hamartoma syndrome. After one year of treatment, all patients experienced improved mobility or organ function; reduction of pain, bleeding, or oozing; or reduction or cessation of infections. These improvements appeared within three months from the start of sirolimus and were maintained. Although no clinical disappearance of the lesions was observed, the volume reduction induced by sirolimus allowed for the subsequent conventional treatment of two patients (sclerotherapy and surgery). Sirolimus was well tolerated; headache, skin rash, mucositis, fatigue, and diarrhea were the most frequent grade 1 to 2 adverse events. All were easily manageable with symptomatic treatment or temporary arrest. Mucositis was the most common grade 3 adverse event and led to definitive discontinuation of sirolimus in two patients (10.6 percent) despite dose adjustment [87].

The impact of sirolimus on the VM volume remains unclear:

•In a prospective, multicentric, phase 2 trial, sirolimus was evaluated in 126 children (0 to 14 years) with uncontrollable, complicated vascular anomalies, including 25 patients (20 percent) with kaposiform hemangioendothelioma, 19 patients (15 percent) with VMs, and 20 patients (16 percent) with lymphatic malformations [88]. Sirolimus was given for 12 months. The primary endpoint was the radiologic response. Twenty-one percent of patients with VMs presented a radiologic decrease of ≥75 percent compared with 10 percent of patients with lymphatic malformations.

•In another multicenter trial, 59 children (6 to 18 years) with slow-flow vascular malformations (22 patients with a VM, 18 with a lymphatic malformation, and 19 with a combined malformation) received oral sirolimus after an observation period [89]. The primary outcome was change in radiologic volume. Sirolimus improved symptoms (ie, pain, oozing, bleeding) and quality of life. However, there was no clinically significant decrease in volume compared with the observation phase.

•A prospective, multicentric, phase 3 single arm trial (VASE, NCT02638389; European Union Drug Regulation Authorities Clinical Trials [EudraCT] Number: 2015-001703-32) is underway in Europe to evaluate the efficacy of sirolimus in pediatric and adult patients with VMs that are refractory to standard treatment. In this trial, sirolimus is given for a planned treatment duration of two years. Genomic analysis will be correlated with sirolimus efficacy and symptomatology evolution after stopping sirolimus therapy.

FOLLOW-UP — Regular clinical, imaging, and laboratory follow-up is indicated in all patients with VMs. Lesions often expand around puberty or during pregnancy, due to hormonal changes, and can become symptomatic. Coagulation evaluation is mandatory in all patients with VMs and before any therapeutic intervention or surgical procedure. Patients with evidence of localized intravascular coagulopathy are at risk of developing disseminated intravascular coagulopathy with increased risk of bleeding during and after surgery. (See 'Coagulopathy control' above and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

Most patients with Klippel-Trenaunay syndrome have chronic localized intravascular coagulopathy and need careful follow-up to detect venous thrombosis and/or pulmonary embolism. In these patients, however, elevated D-dimer levels cannot be used to screen for recent thrombosis. (See "Klippel-Trenaunay syndrome: Clinical manifestations, diagnosis, and management", section on 'Clotting disorders and thromboembolism'.)

Patients with Maffucci syndrome need close follow-up due to the high risk of developing malignancies, such as chondrosarcoma, glioma, fibrosarcoma, and angiosarcoma [21,90].

PROGNOSIS — Curative treatment of VMs is rarely possible and recurrence is common. Some patients may return 5 to 10 years later with symptoms and evidence of recurrent disease at a previously treated site. Patients with extensive disease may require repeated treatments over time and multimodal therapeutic strategies to control the disease.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vascular anomalies".)

SUMMARY AND RECOMMENDATIONS

●Definition – Venous malformations (VMs) are rare, slow-flow vascular malformations resulting from inborn errors in the development of the venous network. In most cases, VMs occur sporadically, but they can rarely be inherited in an autosomal dominant fashion. (See 'Introduction' above and 'Epidemiology' above.)

●Pathophysiology – VMs consist of dilated and dysfunctional veins that are deficient in smooth muscle cells. The slow flow through the dilated and ectatic vessels results in blood stagnation and localized intravascular coagulation, reflected by elevated blood levels of D-dimer (>0.5 mcg/mL) and normal or low fibrinogen. (See 'Vascular changes' above.)

●Clinical presentation – VMs typically manifest as a light to dark blue skin discoloration overlying a soft, compressible, subcutaneous mass (picture 1). They are present at birth, grow with the child, and slowly expand over time. However, the clinical presentation may be highly variable, depending upon the size, location, and mass effect of the lesion on the adjacent organs. (See 'Clinical presentation' above.)

●Diagnosis – The diagnosis of VM is based upon the clinical finding of a solitary blue lesion present since birth that is soft and compressible and not painful on palpation. Typically, there is no thrill or bruit, and the affected area is not warmer than the surrounding areas. Doppler ultrasound and MRI can confirm the diagnosis and assess the VM extension and infiltration into adjacent organs and structures. (See 'Diagnosis' above.)

●Management – The management of patients with VMs involves an interdisciplinary team including a dermatologist, an interventional radiologist, a hematologist, a plastic and/or vascular surgeon, and an orthopedic surgeon as needed, ideally in a specialized center for vascular anomalies. Treatment should be individualized and may include supportive therapies, surgery, sclerotherapy, and sirolimus, alone or in combination.

•Supportive measures – Supportive therapies include compression, nonsteroidal anti-inflammatory drugs (NSAIDs) for pain control, and management of localized intravascular coagulation. For patients with evidence of localized intravascular coagulopathy and elevated D-dimer (>0.5 mcg/mL), we suggest anticoagulation using low molecular weight heparin rather than no anticoagulation or other anticoagulants (Grade 2C).

•Additional management – Patients with mild symptoms may not need further treatment. For lesions causing esthetic disfigurement, functional impairment, or pain, we suggest surgery, if feasible, with or without sclerotherapy (Grade 2C). Sclerotherapy may be used for larger lesions prior to surgery to diminish volume and improve surgical outcomes. However, for lesions not amenable to surgical resection, sclerotherapy may be the sole treatment. For lesions that are not amenable to or are refractory to surgery and sclerotherapy, we suggest sirolimus (Grade 2C).