Chapter 172. Vascular Malformations

Vascular malformations are believed to be due to errors of development of vessels that occur during the fourth and tenth weeks of intrauterine life. Most vascular malformations are sporadic, although several families with inherited forms have been identified. They are very heterogeneous and affect about 0.3% of the population. Vascular malformations are mostly congenital, even if they may be diagnosed only later in life.

Although several genes have been identified as the cause of inherited forms of vascular malformations, the etiology of the most common sporadic lesions is unknown.1–3 Histologically, vascular malformations consist of enlarged, tortuous vessels with quiescent endothelium. In contrast to hemangioma, there is neither parenchymal mass nor cellular proliferation.

For many years, vascular anomalies were grouped under the term angioma, hampering precise classification and leading to incorrect diagnosis and improper management. For example, the term hemangioma has been used both for vascular malformations, often of venous type (cavernous hemangioma) as well as for vascular tumors (strawberry hemangioma). This nomenclature changed in 1982 with the development of a biologic classification by Mulliken and Glowacki. It divided vascular anomalies into two major categories: (1) vascular tumors (with cellular proliferation; hemangioma being the most common) (see Chapter 126), and (2) vascular malformations (structural anomalies of blood vessels) that are subsequently subdivided, depending on the affected vessel type, into arterial, capillary, lymphatic, or venous malformations.4,5 In 1996, this classification was adopted and further developed by the International Society for the Study of Vascular Anomalies (ISSVA) (Table 172-1).6 Vascular malformations mostly affect only one vessel type, yet combined malformations also exist. They are named according to the affected vessel types, (e.g., capillary-venous or venolymphatic malformation). In addition to isolated forms, vascular malformations occur in syndromes such as Klippel–Trenaunay (KT) (capillary-lymphaticovenous malformation with limb hypertrophy), Maffucci syndrome (multiple enchondromas associated with multiple venous anomalies and high incidence of malignancy)7, Cloves syndrome (congenital lipomatous overgrowth with vascular malformations, epidermal nevi, and scoliosis)8,9, or Parkes Weber syndrome (high-flow vascular malformation of the extremity with soft tissue hypertrophy).10

Vascular malformations grow proportionately with the patient. Usually they do not regress. Most frequently, they are well demarcated and localized (Fig. 172-1). In rare instances, they can be the stigmata of deep lesions. Vascular malformations are rheologically divided into slow-flow (capillary, lymphatic, venous, and combined) and fast-flow (arterial, arteriovenous, and combined). Doppler ultrasound is the best noninvasive radiologic examination that provides clues into the differentiation of the various types. Magnetic resonance imaging (MRI) details the extension and precise location of the lesion (Table 172-2).11

Treatment of vascular malformations depends on the affected vessel type, the location of the lesion, and the symptoms. As many lesions are extensive, patients should be aware that a complete cure is often not possible. Treatment is difficult and can have severe complications. Extensive and/or complex lesions should always be managed by a multidisciplinary team.

Epidemiology

Capillary malformation (CM), commonly called port-wine stain, is a slow-flow vascular malformation with an incidence of 0.3% (Fig. 172-2).12 Other blanchable pinkish patches, known as stork bite, angel's kiss, salmon patch, or nevus flammeus neonatorum, are often confused with CM. They are located on the nape of the neck (81%), the eyelids (45%), or the glabella (33%).13 When located on the occiput, it is called Unna nevus (see eFig. 172-2.1). These patches have a much higher incidence (42%) in white infants than in black infants (31%).14 They are also present in various syndromes such as Beckwith–Wiedemann and Rubinstein–Taybi. These lesions disappear spontaneously around the ages of 1–4 years.

CM are mainly sporadic, although there are well-documented pedigrees showing autosomal dominant inheritance.15 When inherited, they are usually multiple and part of the CM-AVM phenotype, that associates atypical CM with arteriovenous malformation (AVM) (see Section “Arteriovenous Malformations”).16–19 No sex preponderance is noted.

Etiology and Pathogenesis

Etiology of CM is currently unknown. Facial CM is thought to be due to clonal expansion of abnormal cells originating from the neural crest.20 The identification of the affected gene (RASA1) in CM-AVM (see Section “Arteriovenous Malformations”) might help unravel the cause of the more common sporadic CM. Histologically, CM is characterized by dilatation of normal numbers of capillaries of the papillary and upper reticular dermis combined with areas of increased number of normal-looking capillaries (see Fig. 172-2). Endothelial cells are flat. Factor VIII, fibronectin, and basement membrane protein are normal but S100 staining shows abnormal innervation.21,22

Clinical Findings

Cutaneous Lesions

(see Figs. 172-2 and 172-3). CM is a red homogenous congenital lesion that is often unilateral, sometimes bilateral, but usually not median. CMs involve skin and subcutis, and sometimes mucosa. Their color varies from pinkish red to deep purple with a geographic contour or a dermatomal distribution. Lesions are flat and painless, do not bleed spontaneously, and are never warm on palpation. They can extend throughout the entire body. Fifty percent of CMs are located on the face where they follow the distribution of the trigeminal nerve: ophthalmic branch V1 (front and upper eyelid), maxillary branch V2 (lower eyelid, cheek, and upper lip) (see Fig. 172-3B), or mandibular V3 (lower lip, chin, and mandibule). In combination with another vascular malformation, CM can be part of a syndrome, such as Sturge–Weber, phakomatosis pigmentovascularis (PPV), Klippel–Trenaunay (KT), Servelle–Martorell, etc. None of these syndromes is inherited. In rare instance, CM can be the cutaneous hallmark of occult spinal dysraphism, especially if located in the lumbosacral area.23

Sturge–Weber Syndrome

Sturge–Weber Syndrome (SWS) is a neuro-oculocutaneous syndrome consisting of a CM located on the opthalmic branch of the trigeminal nerve, a homolateral leptomeningeal capillary-venous malformation, often on the parieto-occipital area, and choroid “angioma” causing glaucoma and sometimes buphthalmos and retinal detachment (Fig. 172-4). Calcifications are frequently seen on the choroid plexus, and anomalies of the venous drainage of the encephalon can occur.24 This malformation can cause epilepsy, leading to neural death, cerebral atrophy, and mental retardation.

Phakomatosis Pigmentovascularis

Phakomatosis pigmentovascularis (PPV) is thought to be an embryogenic anomaly affecting the vasomotor nerves and the melanocytes, both derived from neural crest. Clinically, PPV manifests as a large capillary malformation, which is metameric in distribution and mainly located on the trunk or the extremities, in association with pigmented cutaneous lesions, such as a pigmented nevus, a nevus spilus, a café au lait patch, or an atypical Mongolian spot (see Chapter 75) that is not located on the sacrum (eFig. 172-4.1).25 Nevus anemicus can also be seen in the vicinity as a twin spot.26 These cutaneous lesions can be associated with systemic, visceral (e.g., larynx hypoplasia, intestinal polyposis), muscular (scoliosis), neurologic (mental retardation, epilepsy, intracranial calcification, cerebral atrophy), or ocular involvement (anomaly of the iris).

Klippel–Trenaunay Syndrome

Klippel–Trenaunay syndrome (KTS) is an eponym used for the presence of a capillary-lymphaticovenous malformation located on the extremity with hypertrophy of the affected limb (Fig. 172-5). Venous varicosities on the lateral side of the leg, first described by Servelle, are very common and is specific for this syndrome in 80% of cases.27 It is thought to be due to the persistence of embryologic veins. Valvular incompetence of deep venous system is common. Lower extremities are most commonly affected (95%), although upper limb, thorax, abdomen, and genitalia can also be involved. Lymphatic dermal vesicles cause frequent oozing. Lymphedema can be seen and tends to progress with time. Infection is common after trauma or secondary to small ulceration. VM is often seen in the underlying muscles. Hypertrophy of the limb is another sign of this disorder. It is already present at birth and occasionally evolves after puberty. Evolution toward ulceration, infection, bleeding, and thrombosis is common. Protein-loosing enteropathy can be seen with abdominal involvement. Pulmonary embolism can sometimes lead to death.

Imaging Studies

No imaging studies are mandatory except in some rare situations. If a so-called CM is painful, warm, or spontaneously bleeds, Doppler ultrasound is indicated to exclude the diagnosis of a fast-flow malformation, such as an AVM, a Parkes Weber syndrome, or a proliferating hemangioma. CM located in the frontopalpebral area, especially if the inner part of the upper eyelid is involved, can be part of SWS. Therefore, a brain MRI and an ophthalmic examination have to be performed during the first months of life and repeated once a year until puberty, even if normal at younger age.28 MRI of the spinal cord is needed in presence of a lumbosacral CM. In patients with PPV, ophthalmologic, neurologic, and orthopedic follow-up is mandatory due to the common association of CM with systemic lesion. In patients with KTS, leg length is evaluated radiologically after the age of 2 years and, if abnormal, followed once a year until the end of puberty. Doppler ultrasound evaluation of the venous status is mandatory to identify varicose veins in KTS. MRI is sometimes useful before management of the lesion.27

Differential Diagnosis

(Box 172-1)

AVF = arteriovenous fistula; AVM = arteriovenous malformation; CM = capillary malformation; CM-AVM = capillary malformation-arteriovenous malformation; CMTC = cutis marmorata telangiectatica congenita; HHT = hereditary hemorrhagic telangiectasia; M-CM = macrocephaly cutis marmorata

Complications

The major concern for a patient affected with CM is cosmetic due to the visible discoloration. Hypertrophy of soft tissue can occur with time, especially when CM is located on V2 and V3 dermatomes or on the extremities. In rare instances, CM can be the stigmata of underlying anomalies such as lumbar dysraphism when located at sacrum.

Prognosis and Clinical Course

CM never regresses. It is present at birth, and slowly thickens and darkens with time. It often becomes raised and nodular.35 Pyogenic granuloma can occur with time as well as soft tissue or bony hypertrophy.36 (Fig. 172-6).

Treatment

Many therapeutical approaches have been used for CM, such as electrocoagulation, tattooing, dermabrasion, cryosurgery, and cosmetic makeup. Camouflage using Covermark is still effectively used (see eFig. 172-6.1). Laser treatment is the gold standard for most CM. Pulsed-dye laser with its specific wavelength (585 nm) and a short pulse duration (400 ms) currently gives the best results in infants and children. There are few complications. Multiple sessions (6–12) are needed, and general anesthesia may be necessary as the procedure is painful. Laser treatment is more efficient on the cervicofacial and trunk area than on the extremities. Early treatment during childhood does not reduce the number of laser sessions.37 The use of a dynamic cooling system to avoid heating the epidermis allows increasing of laser fluences, resulting in optimal lightening of the lesion.38 Recurrence can occur after cessation of therapy. Laser has no impact on associated hypertrophy. Contour resection is needed mainly to treat complications such as pyogenic granuloma or lip hypertrophy.

Treatment of patients with KTS is conservative and mainly consists of elastic stockings to alleviate pain due to venous congestion. Surgical resection of varicose veins cannot be done if the deep venous system is abnormal (aplasia, incompetence). In the presence of leg discrepancy, an early-adapted shoe lift is needed to prevent scoliosis, and is followed by epiphysiodesis. If cutaneous bleeding occurs from capillary-lymphatic cutaneous vesicles, neodymium:yttrium-aluminum-garnet laser coagulation, sclerotherapy, or skin grafting can be helpful.

Prevention

In patients with SWS, ophthalmic follow-up, started immediately after birth and continued until the end of puberty, is essential, as visual impairment will depend on the promptness of treatment. Prophylactic antiepileptic medication to prevent neural cell death has been advocated by some clinicians.39,40

Epidemiology

Venous anomalies are the most common vascular malformations referred to specialized center 41. They are mainly sporadic, although 1% are inherited (VMCM) and 5% are inherited glomuvenous malformations (GVM). No sex preponderance is reported.42 Both VMCM and GVM have an age-dependant variation in penetrance, which reaches its maximum by 20 years of age (87% for VMCM and 92.7% for GVM).43 Large VMCMs and GVMs are present at birth. However, 17% of affected individuals develop new small lesions over time.42

VM is a congenital defect on the skin or mucosa, but can involve any structure (subcutis, muscles, bones, and nerves) and any organ [central nervous system, gastrointestinal (GI) tract]. Fifty percent of VMs are located in the cervicofacial area and 37% on the extremities. VMs are mainly isolated, but can be part of complex vascular disorders of unknown etiology, such as KTS, and Maffucci and blue rubber bleb nevus (BRBN) syndromes.44

Histology

VMs consist of ectatic vascular channels of venous type with flat endothelium and thin walls due to a variable number of mural smooth muscle cells that stain positive for smooth muscle cell-α-actin.45 In contrast, GVM is characterized by distended venous channels surrounded by mural glomus cells that are aberrant smooth muscle cells. Glomus cells are round or polygonal, instead of elongated like the normal vascular smooth muscle cells.46 By immunohistochemistry, glomus cells stain positively for smooth muscle-α-actin and vimentin, whereas they are negative for desmin, von Willebrand factor and S100 neuronal marker.47 By in situ hybridization, they are also negative for glomulin.48

Pathogenesis

The etiopathogenesis of at least 50% of sporadic VM are due to somatic mutations in the tyrosine kinase domain of the angiopoietin receptor TIE2, which was previously identified as the causative gene for inherited mucocutaneous VM (VMCM).49 However, the mutations differ from the inherited ones, as the most common one (L914F) has never been identified as an inherited mutation and vice versa, the most common inherited mutation (R849W) has never been identified as a sporadic one, suggesting that sporadic mutations probably cause lethality in germline and that inherited one have weaker effects that require additional changes.49

VMCM is caused by amino acid substitutions in the TIE2 gene. These gain-of-function mutations induce phosphorylation of the receptor.50,51 GVM is genetically linked to a locus on 1p21, and caused by loss-of-function mutations in the glomulin gene.43 Currently, there is no correlation between the position of a mutation in the glomulin gene and the characteristics of the disorder, such as the number of glomus cells in the lesion, the extent of the lesion, or the number of lesions. Moreover, for the same mutation, the expressivity is variable from patient to patient.52 So far, a mutation in glomulin has been found in almost all GVM families tested, demonstrating locus homogeneity (Brouillard et al, unpublished).48,52 Among the 30 different mutations found, eight are detected in several families, making efficient genetic diagnosis possible in more than 75% of patients. Several observations suggest a paradominant mode of inheritance for GVM, instead of a simple autosomal dominant transmission. A somatic double-hit mutation has been identified in one GVM resected from a patient with a known inherited glomulin mutation (Aerts et al, in preparation).43 The combination of an inherited and a somatic mutation in the tissue suggests that a complete loss of glomulin is needed for GVM development.43 This could explain the variation in size and location of GVMs, depending on the time of occurrence of the postzygotic second-hit mutations. The low frequency of extensive lesions (>5 cm) and the high frequency of localized lesions (<5 cm) support this model.42

Clinical Findings

(Table 172-3; Fig. 172-7; and see eFig. 172-7.1)

VMs are usually solitary, but can be multifocal, suggesting an inheritable disorder. Cutaneous VMs are congenital light-to-dark bluish lesions. Deep VM has a normal overlying skin color and is often diagnosed only at puberty or later in life with the onset of pain. Cutaneous VMs are detected early because they are usually clinically visible. Size varies from small spongy blebs to large lesions of several centimeters in diameter. VMs can easily be emptied by compression or by positioning in a nondependent position. Skin temperature is normal. There is no thrill or bruit. Depending on size and location, VMs can cause pain, particularly in the morning on awakening, anatomic distortion, and even threaten life because of bleeding, expansion, or obstruction of vital structures. Palpation is not painful unless thrombosis occurs.42 Local thrombosis is responsible for acute pain that lasts for 10 days and causes phleboliths, which can be identified by palpation or by radiography. VM never cause pulmonary embolism. Facial VM is usually unilateral causing asymmetry and progressive deformation and possibly dental malalignment (see Fig. 172-7 and eFig. 172-7.1). Migraine is a common feature, if VM is located in the temporal muscle. Oropharyngeal VM can impair speech, whereas pharyngeal or laryngeal location will compromise the airway and cause snoring and even sleeping apnea. On extremities, VMs often involve muscles and joints (see eFig. 172-7.1). They cause muscle weakness, hypotrophy, and sometimes hypertrophy, resulting in leg length discrepancy, which is less severe than in KTS. Intra-articular bleeding, if the malformation is located in the knee joint, lead to early-onset arthrosis.53 Genital VM often occurs with limb VM and can be responsible for dyspareunia. GI VM is often diagnosed in patients with chronic anemia.

Familial Venous Malformations Cutaneomucosal (VMCM)

One percent of venous malformation are inherited as an autosomal dominant trait [Online Mendelian Inheritance in Man (OMIM) #600195]. Cutaneous lesions are dome shaped, multiple, and small in diameter (<5 cm). Presence of an oral mucosal lesion in a patient with family history of VMs strongly suggests VMCM. In contrast to sporadic VMs, VMCMs are more superficial, seldom invade muscle, and never joint, or bone. Due to their size, they are often asymptomatic.51,54

Glomuvenous Malformations (GVM)

(eFig. 172-7.2)

Five percent of patient with venous anomalies seen at multidisciplinary vascular anomaly centers are GVMs (OMIM #138000). GVM, previously known as glomangioma or (multiple) glomus tumor, is a vascular malformation of venous type. It should not be confused with solitary glomus tumor, a painful 3–6-mm papule commonly located in the nail bed. Clinically, these lesions resemble VM, but can often be distinguished by color, appearance, consistency, and painfulness to palpation.42 GVM varies from pink to purplish-dark blue in color. They are usually raised, nodular, hyperkeratotic, and multifocal. They are present at birth and slowly expand during childhood. Plake-like GVM can be present at birth as a telangiectatic, red, flat lesion, which is only slightly bluish at the periphery. Thus, they mimic capillary-venous malformations. Within months, the lesion will become more raised and purple, like typical GVM.55 GVMs are mainly located on the extremities (see eFig. 172-7.2), involve skin and subcutis, rarely mucosa. In contrast to VM, GVM cannot be completely emptied by compression. They do lead to intestinal hemorrhage, which distinguishes them from patients with blue rubber bleb nevus (BRBN) syndrome (OMIM #112200).56

Blue Rubber Bleb Nevus Syndrome (Bean Syndrome)

When a patient has both cutaneous and visceral VMs, the diagnosis of blue rubber bleb nevus syndrome is most likely. This syndrome is usually sporadic, although some families with autosomal inheritance have been reported. They could be familial VMCM. The cutaneous VMs of BRBN are distinct, characterized by multiple small (0.1–0.5 cm), spongy, and rubbery blebs often located on the palms and soles (eFig. 172-7.3).57 Often a patient has one large VM that is present at birth and multiple small lesions disseminated all over the body. More lesions appear with time. The VMs are usually asymptomatic but occasionally they can become tender and painful. GI lesions, commonly located in the small intestine, are sessile or polypoid, causing chronic and severe iron-deficiency anemia. In rare instances, BRBN can involve other organs, such as lungs, spleen, liver, kidneys, bladder, or even the brain.

Familial Cerebral “Cavernous” Malformation (CCM)

Familial cerebral “cavernous” malformation (CCM, OMIM #116860) is a rare autosomal inherited disorder that consists of multiple cerebral capillary-venous malformations. Patients with CCM can present headache, epilepsy, or acute intracranial bleeding with a risk of sudden death.58,59 Often these go unnoticed for years, and CCMs are discovered at autopsy. Some families with Krit1 mutations also have cutaneous vascular lesions. They include lesions with minor hyperkeratosis and a dark red color that resemble morphologically and histologically the intracranial lesions and are called hyperkeratotic cutaneous capillary-venous malformations (HCCVM), capillary malformations (CM), and small punctate venous malformations.60–63 Such lesions are rare in CCM2 and CCM3 patients.63 CCM has been linked to three chromosomal loci: on 7q (CCM1), 7p15–p13 (CCM2), and 3q25.2–27 (CCM3).64,65 The defective genes have been identified: KRIT1 (Krev1 interaction trapped 1) for CCM161, Malcavernin on CCM2, and PDCD10 on CCM3.66 All mutations seem to cause loss-of-function 2. Forty percent of families studied show linkage to CCM1, 20% to CCM2, and 40% to CCM3. Important differences were identified in penetrance: 88% for CCM1, 100% for CCM2, and 63% for CCM3.65,67

Maffucci Syndrome

Maffucci syndrome is a rare sporadic disorder that associates venous-type lesions with multiple enchondromas and a high incidence of malignancy (30%–90%). There is no gender predilection. Enchondromas that are abnormal intraosseous and subperiosteal cartilaginous overgrowths in the hand, foot, and long bones, usually appear first, leading to an initial diagnosis of Ollier disease.68 The venous-type lesions are multiple, located more commonly on the hand (89%) and foot (61%) but can be anywhere (eFig. 172-7.4). They are bluish exophytic nodules. These venous ectasias are often characterized as hemangioendotheliomas with spindle cells.7 Skeletal deformation and spontaneous fracture, as well as secondary dwarfism are common in patients with Maffucci syndrome. Although the (genetic) cause of Maffucci syndrome is not known, it differs from that of Ollier disease, in which dysfunction of the parathyroid hormone receptor PTHR1 has been reported in five patients.69,70

Cerebral Developmental Venous Anomaly

Cerebral developmental venous anomaly is not a VM but an unusual cerebral drainage that occurs in 0.05%–0.5% of the general population. It can be seen in 20% of patients with extensive craniofacial VM and in 89% of patients with PTEN hamartoma tumor syndrome.71 As cerebral developmental venous anomaly is asymptomatic and does not need treatment, it must be differentiated from CCM that can cause epilepsia, bleeding, and migraine.

Laboratory Tests

Localized intravascular coagulopathy (LIC) is associated with 42% of VMs. This phenomenon is characterized by elevated d-dimers, split fibrin degradation products, normal-to-low fibrinogen, and normal platelet counts. d-dimer measurement has become a useful biomarker for the diagnosis of a VM. In patients with vascular anomalies and elevated d-dimer level, a VM is present in 96.5%.72,73 In contrast, a normal d-dimer level cannot rule out a VM. Although LIC is usually well tolerated during everyday life, it can decompensate into disseminated intravascular coagulopathy (DIC) after, for example, surgery, sclerotherapy, pregnancy, and puberty, resulting in severe bleeding due to consumption of clotting factors.74,75 This is especially true for patients with extensive venous malformations, mainly affecting an extremity and who have a severe LIC with a very high d-dimer level (>1.8 μg/mL) and a low fibrinogen level. Therefore, measurement of d-dimer levels is mandatory for the diagnosis and management of VMs.44,72,73

This coagulation disorder is different from the Kasabach–Merritt phenomenon seen with kaposiform hemangioendothelioma (see Chapter 126).76,77

Imaging Study

Doppler ultrasound is the easiest way to confirm the clinical diagnosis of a VM by demonstrating a slow-flow, ill-defined vascular lesion that is compressible on palpation, in contrast to lymphatic malformation (LM) or hemangioma. Presence of phleboliths, easily identified on plain radiography, is the hallmark of VM and, in contrast, never present in GVM (see eFig. 172-7.5).78 Computed tomography scan detects skeletal defects that can be seen in about 20% of craniofacial VM. MRI with spin-echo T1- and T2-weighted sequences is the gold standard to evaluate extension and exact location of VMs (see eFig. 172-7.5).79 Arteriography is normal, as arteries are not affected by the malformation. The VM lesion is seen in late venous phase. Phlebography, always done before sclerotherapy, has limited diagnostic use compared with Doppler and MRI.

Differential Diagnosis

(Box 172-2)

Cutaneous VMs are usually diagnosed by clinical examination on the basis of their bluish color and the fact that they are compressible on palpation. However, not all bluish lesions are VMs.

Prognosis/Clinical Course

VMs are present at birth and exhibit progressive ectasia with age. A rapid expansion can be observed after trauma, partial resection, or hormonal modulation at puberty or during pregnancy or antiovulatory therapy. Deep VMs often become painful at puberty. If not treated, cervicofacial VM can cause chronic respiratory obstructive syndrome.

Treatment

Indications for treatment include esthetic preference, pain or functional impairment. VMs can be treated conservatively or medically and, more aggressively with either sclerotherapy and/or surgical resection. VM in an extremity is conservatively managed by a custom-made elastic compressive garment. Aspirin (80 mg/day) can alleviate chronic pain due to local and painful thrombosis. Low-molecular-weight heparin is much more efficient in case of LIC (high d-dimer). The commonly used dosage is 100 anti-Xa/kg/day for adults and 30 anti-Xa/kg/day in children. Reduction of pain and d-dimers are seen within 10 days. The treatment can be continued for several months and is mandatory before any surgery to avoid decompensation into DIC during or after surgery.44 It will also improve sclerotherapy results.

Small cutaneous VMs can be injected, at any site, with a sclerosant, such as 1% sodium tetradecyl sulfate. For large VMs, fluoroscopic guidance and general anesthesia are mandatory during percutaneous sclerotherapy. Sclerotherapy is potentially dangerous and requires the skills of an experienced interventional radiologist.80 Several sessions are commonly necessary (see eFig. 172-7.6). For GVM, sclerotherapy is less effective (Dompmartin et al, submitted).

Small, well-localized symptomatic VMs can be surgically excised (see eFig. 172-7.7). The risk of recurrence after subtotal surgery can be reduced by preoperative sclerotherapy.53 Laser (argon, pulsed dye, neodymium:yttrium-aluminium-garnet (Nd-YAG)) has been used with variable results.81 Gastrointestinal VM of BRBN can be managed by endoscopic cauterization, sclerosis, or bowel resection if necessary.82 GVMs are best treated by surgical resection.56

Epidemiology

Lymphatic malformation (LM) is a congenital disorder of unknown incidence. It consists of vesicles or large cysts filled with lymphatic fluid. Macrocystic LM can be diagnosed in utero as early as the first trimester of pregnancy.83 However, most LMs are diagnosed during infancy, before the age of 2 years. Some can manifest only at puberty or during adulthood. Macrocystic LMs are often located on the neck, axilla, chest wall, or groin, whereas microcystic lesions are commonly seen in the face. LMs occur sporadically in contrast to primary lymphedema that can be inherited as an autosomal dominant trait in up to 20% of cases. Rare families with recessive inheritance have also been identified.84 Primary lymphedema is divided into congenital (present at or soon after birth) (Milroy disease, OMIM #153100) and late onset (present at puberty) (Meige disease OMIM #153200). It can be isolated or part of a syndrome, such as Turner and Noonan syndromes.85

Etiology and Pathogenesis

LMs are errors in morphogenesis of the lymphatic vessels. The etiology is unknown. In contrast, several genes have been identified that lead to or cause lymphedema. Milroy disease is caused by a mutation that leads to loss of phosphorylation of vascular endothelial growth factor receptor 3 (VEGFR3),86,87 whereas lymphedema distichiasis is caused by loss-of-function mutations in the FOXC2 transcription factor. Hypotrichosis-lymphedema-telangiectasia (HLT) that has an autosomal dominant or recessive pattern of inheritance, is caused by mutations in SOX18.84 Hennekam syndrome is an autosomal recessive generalized lymphatic dysplasia, which is characterized by intestinal lymphangiectasia with severe and progressive lymphedema of the limbs, genitalia, and face and sever mental retardation (OMIM #235510).88 Mutations in the Ccbe1 (collagen and calcium-binding EGF domains 1) have been identified.89,90

Histologically, LMs are characterized by dilated flat endothelium-lined channels of variable wall thickness. No blood cells are seen in these spaces, except after intracystic bleeding (Fig. 172-8) or in the presence of a combined lymphaticovenous malformation. Macrocystic LM shows single or multiple lymphatic cysts surrounded by thick fibrous membrane. These cysts do not communicate with each other. Endothelial vessels express specific lymphatic markers, such as podoplanin, D2-40, VEGFR-3.91 Lymphedema is characterized by abnormalities in collecting lymphatic vessels in the affected limb (VEGFR3 and FOXC2 patients) and extensive dermal fibrosis.

Clinical Findings

LMs are composed of microcysts (previously lymphangioma circumscriptum; Fig. 172-9) and/or macrocysts (larger than 1-cm diameter, previously known as cystic hygroma) that grow proportionally with the child. They are filled with clear or serosanguineous fluid (see Fig. 172-9). Macrocystic LM manifests as a soft, multilobulated, well-defined mass, whereas microcystic LMs are ill defined and often invade adjacent structures. Skin can be normal in color or, due to intracystic bleeding, have a bluish discoloration (see eFig. 172-9.1). Dermal LMs can manifest as small millimeter-sized vesicles, clear (see Fig. 172-9 and eFig. 172-9.1) or dark red (if intracystic bleeding) that can bleed and become purple and nodular.

Facial asymmetry, especially of the mandibule, is commonly associated with microcystic LM (see eFig. 172-9.1). Intraorbital LM is responsible for ocular dystopia and exophthalmia as well as orbital enlargement. LM on the tongue impairs speech and produces oozing and halitosis. Airway obstruction is common when affecting the base of the tongue or the cervicofacial area.92 Extension into the pleura can occur and cause chylothorax. Abdominal lesions are associated with chylous ascites. Extensive limb LM can cause elephantiasis.

Angiokeratoma Circumscriptum

Angiokeratoma circumscriptum, or capillary-lymphatic malformation (CLM), is a combined, well-demarcated lesion often located on the extremity. This lesion is pink to bluish red in color, slightly raised, and usually hyperkeratotic (Fig. 172-10). Dilated capillaries and lymphatic vessels located on the superficial dermis and associated with hyperkeratosis can be seen histologically. Clinically, angiokeratoma circumscriptum (see Fig. 172-10), angiokeratoma of Mibelli (circumscribed, dark-red, and hyperkeratotic plaques on the distal extremities; see eFig. 172-10.1), and angiokeratoma of Fordyce (very common hyperkeratotic, blue–black papules on the scrotum of elderly males; see eFig. 172-10.2) are recognized (see Table 136-2). They have to be differentiated from the angiokeratomas of Fabry disease (see Chapter 136).

Gorham–Stout Syndrome

Gorham–Stout syndrome (“vanishing bone disease”) is an osteolytic disorder characterized by progressive demineralization and destruction of bones, which are replaced by lymphatic vessels and capillaries.93 Depending on the location, this syndrome manifests as bone pain, muscular atrophy, fractures, pleural effusion, ascites, and cerebrospinal fluid rhinorrhea. Lethality occurs in 16% of cases.

Lymphedema

Lymphedema is characterized by swelling of the affected body part, usually the lower extremity, and caused by accumulation of lymphatic fluid into the extracellular space due to intrinsic lymphatic dysfunction (Fig. 172-11). Various phenotypes depending on the age of onset, location and associated anomalies.90

Congenital Lymphedema

Congenital lymphedema or Milroy disease is suspected in the presence of swelling of the dorsum of the feet with familial history of lymphedema. Lymphedema is present at birth, often bilateral and affects the lower limbs, below the knees.94 Other features can be associated with congenital lymphedema, such as hydrocele (37% of males), prominent veins (23%), upslanting toenails (14%), papillomatosis (10%), or urethral abnormalities in males (4%). Cellulitis is a common complication affecting 20% of cases.94 Rare occurrence of pleural effusion even in utero, hydrops fetalis, and chylous ascites have been observed.95,96 Spontaneous resorption of limited localized lymphedema has also been noted.87,95 Moreover, in some patients (n = 2/12), sporadic hydrops fetalis and/or generalized subcutaneous edema was caused by a VEGFR3 mutation.97 At birth, they had only limited edema of the lower extremities. The presence of a VEGFR3 mutation in this frequently lethal fetal condition may thus be a positive prognostic factor.

Meige Disease

Meige disease or pubertal onset of lymphedema, represents 80% of primary lymphedema. It is usually isolated and more common in women. In two specific forms, the causative genetic alterations have been identified.

Lymphedema-Distichiasis Syndrome

Lymphedema-distichiasis syndrome is characterized by lower extremity lymphedema of variable age-at-onset associated with an abnormal growth of a second row of eyelashes from the Meibomian glands (OMIM #153400). Lymphedema is usually asymmetric. Due to distichiasis, ocular symptoms, such as corneal irritation, photophobia, ptosis, and recurrent conjunctivitis are common. These patients sometimes have signs and symptoms in other organs, too, such as a ptosis, a cardiac anomaly or a cleft lip.98

Hypotrichosis-Lymphedema-Telangiectasia Syndrome

Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS; OMIM #607823) is characterized by the triad of (1) sparse hair, (2) lymphedema, and (3) cutaneous telangiectasias. The hair usually has a normal appearance at birth, but becomes sparse during infancy. Eyebrows and eyelashes are missing, and the patients do not develop axillary or pubic hair. Lymphedema mostly affects lower limbs and is unilateral but can be bilateral, and has a variable age at onset from congenital to puberty. Telangiectasia or cutis marmorata-like lividity of the skin can be present at palms, soles, scalp, scrotum, or legs; however, it is not observed in all patients. One patient presented with hydrops fetalis.84,99

Turner Syndrome

Turner syndrome is clinically characterized by short stature that is disproportionate, neck webbing, and congenital lymphedema of hands and feet. Other symptoms include primary amenorrhea, high-arched palate, scoliosis, hearing difficulties, cardiac and renal abnormalities, and hypothyroidism.85 Lymphedema tends to improve with time.

Lymphedema with Yellow Nails

Lymphedema with yellow nails (yellow nail syndrome) associates chronic lymphedema with specific nail anomalies. These nails are very slow growing, with transverse overcurvature, and hardening of the nail plate. Yellow nails are often seen in patients with FOXC2 mutations.

Imaging Studies

Doppler ultrasound shows anechoic or hypoechoic and homogeneous cysts that are not compressible. On MRI, macrocystic LMs are hypointense on T1 and hyperintense on T2-weighted sequences. In the presence of a large cyst, fluid level is seen, showing intracystic bleeding. Microcystic LM shows an ill-defined mass with abnormal enhancement.79

Laboratory Test

LIC, like in VM, can be seen in extensive LM.

Differential Diagnosis

(Box 172-3)

Complications

LM can suddenly enlarge in response to fever, cough, or viral or bacterial infection or to intralesional bleeding (see eFig. 172-11.1). Recurrent cellulitis is the major complication, as it can evolve into septicemia if not promptly treated. Local redness and warmth will appear and the lesion will become painful. Visceral LM can cause protein-loosing enteropathy and hypoalbuminemia.

Prognosis and Clinical Course

LM usually grows with the child. LM often causes asymmetry with bony overgrowth. Increase in size can be seen during infection of intralesional bleeding. Episodic reports of spontaneous involution exist. As the regression is usually seen after local infection, it could be that this evolution is due to postinflammatory pseudosclerosis.

Treatment

Intralesional bacterial infection as well as early cellulitis should be monitored with prolonged antibiotics first given intravenously. Pain medication and anti-inflammatory drugs may be required. Immune-modifying medications, such as interferon and corticosteroids, are not effective. Neodymium:yttrium-aluminum-garnet laser or carbon dioxide laser photocoagulation has been used to treat dermal LM vesicles that cause oozing (see eFig. 172-11.2). Macrocystic LM is treated with fluid aspiration followed by percutaneous, intralesional injection of sclerosing agents performed by an interventional radiologist. Several sclerosing agents have been used, such as sodium tetradecyl sulfate, pure ethanol, OK432 (extract from a killed strain of group A Streptococcus pyogenes: picibanil), doxycycline, or bleomycin. Side effects include fever, erythema, and oedema.102,103

Surgical resection is another alternative for LM.104 Results depend on the anatomical site and extension of the lesion (See eFig. 172-11.3). Recurrence is frequent since it is difficult to differentiate microcystic LM from adjacent normal tissue. This leads to either incomplete resection or unnecessary sacrifice of normal structures. One should always try to treat completely one region at a time.105

Lymphedema is best treated with elastic stocking, massage, and pneumatic compression devices. Family and patient education regarding the etiology and treatment is necessary, as lymphedema can be inherited.

Fast-flow cutaneous vascular malformations are mainly AVM and rarely arteriovenous fistula (AVF). AVF is usually traumatic. AVM is characterized by the presence of a “nidus,” the epicenter of the lesion that is composed of direct communications between multiple feeding arteries and draining veins without intervening the normal capillary bed. Histologically, AVM consists of distorted arteries and veins with thickened muscle walls due to arteriovenous shunting and fibrosis (Fig. 172-12).

Epidemiology

The incidence of AVM is unknown. It is a rare, usually sporadic, fast-flow vascular malformation. It can affect any tissue and any organ. Seventy percent of AVMs are located on the head and neck area. AVMs are present at birth, but often manifest later in life during puberty or after trauma. They never regress. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal inherited disorder with a prevalence of 1 in 10,000 individuals.

Etiology and Pathogenesis

The etiology of AVM is currently unknown. An underlying predisposing genetic defect exists for these fast-flow vascular malformations when part of CM-AVM (OMIM #608354), HHT (OMIM #187300), or PTHS (OMIM #153480 and 158350). CM-AVM associates multiple, small, atypical CMs with fast-flow lesions (AVM or AVF). It is inherited as an autosomal dominant disorder with a penetrance of about 95%.16,17,19 It is caused by loss-of-function mutations in the RASA1 gene.16,18 The high intrafamilial phenotypic variability could be explained by the necessity of a second hit, a somatic mutation, to occur. Prevalence of CM-AVM is unknown.

Molecules implicated in the transforming growth factor-β signaling pathway predispose to the formation of AVM/AVF, as loss-of-function mutations in endoglin and activin-like receptor tyrosine kinase cause hereditary hemorrhagic telangiectasia with fast-flow lesions in skin, mucosa and viscera (lung, brain, and liver) (OMIM # 187300).106,107

AVM can also be caused by loss-of-function mutation in PTEN, a tumor suppressor gene, as seen in most patients with PTHS (OMIM # 158350 & 153480).108 This rare congenital, autosomal dominant disorder is characterized by the triad of macrocephaly, multiple lipomas and AVMs, which are often multifocal, associated with ectopic fat, and cause destruction of tissue architecture.109,110

Clinical Findings

During childhood, AVM is often mistaken for a CM or a hemangioma, as, at birth, AVM usually manifests as a faint, ill-defined, macular red stain. However palpation reveals its fast-flow component as it is warm. About one third of AVMs are present at birth, another one-third appear during childhood or at puberty, and the rest in adulthood. Puberty and trauma usually trigger the growth of an AVM. AVMs are staged using the Schobinger classification (Table 172-4). AVMs manifest as cutaneous, red-to-purple warm masses with a thrill, a bruit, or a pulsation of increased amplitude. They worsen with time evolving from stage I to III or even IV, never regressing spontaneously (Fig. 172-13).

CM-AVM

CM-AVM manifests as multiple atypical CM associated with fast-flow lesions in 18% to 20% of patients: AVM, AVF, Parkes Weber syndrome. The expressivity is highly variable within families, from small, asymptomatic CMs to life-threatening AVM. In contrast to sporadic CM, CMs in CM-AVM are often multiple and randomly distributed. Their size is variable: from a few millimeters to several centimeters in diameter. They are round-to-oval, pink, red or brown, and sometimes with a narrow pale halo (Fig. 172-14). The lesions are well-circumscribed and blanch on pressure with a glass. Some of them are present at birth, whereas others appear later. They grow with the child and are asymptomatic. Fast-flow lesions (AVM or AVF) are either cutaneous, subcutaneous with or without intramuscular and intraosseous involvement, intraspinal (A novel association between RASA1 mutations and spinal arteriovenous anomalies111, or intracerebral.16,17,19 About 10%–15% of the CM-AVM individuals have Parkes Weber syndrome either on the lower (two-thirds) or the upper extremity (one-third). The AVMs can be asymptomatic but complications occur depending on their location and size.

Hereditary Hemorrhagic Telangiectasia

Hereditary Hemorrhagic Telangiectasia (HHT) manifests as multiple cutaneous and mucosal telangiectasias that are associated with visceral, pulmonary, and cerebral fast-flow lesions. Epistaxis is a common clinical sign and can be life-threatening (ref 25).

PTEN Hamartoma Tumor Syndrome

PTEN hamartoma tumor syndrome (PTHS) regroup patients with Bannayan–Riley–Ruvalcaba syndrome (BRRS) and Cowden syndrome, as 60% and 81% of them, respectively, have a mutation in the PTEN gene.110 These patients typically have macrocephaly, penile freckling, multiple developmental venous anomalies in the brain, fast-flow vascular malformations (54%) and an increased risk of malignancy. The vascular malformations are often multifocal (57%) and musculoskeletal, and associated with ectopic fat deposition and disruption of the normal tissular architecture.

Parkes Weber Syndrome

Parkes Weber syndrome (OMIM # 608355) was first described by F. Parkes Weber in 1918. This condition is characterized by a large, congenital, cutaneous, vascular stain on an extremity in association with soft tissue and skeletal hypertrophy of the affected limb, and with underlying multiple arteriovenous microfistulas.10 The affected extremity is longer and larger than the contralateral one. The signs and symptoms worsen with age. When young, these patients can develop congestive heart failure.

Bonnet–Dechaume–Blanc or Wyburn–Mason Syndrome

Bonnet–Dechaume–Blanc or Wyburn–Mason syndrome, is a sporadic syndromic AVM located in the centrofacial and/or hemifacial area, with oculo-orbital and cerebral involvement.112 AVM is present at birth and worsens with time. Patients can exhibit epistaxis, exophthalmos, and hemianopia. Mental retardation can occur.

Cobb Syndrome

Cobb syndrome is another sporadic syndromic AVM that associates cutaneous and spinal cord AVMs of the same metamere.113 It manifests in childhood with neurological complications (pain, sensory and motor disturbances and a neurogenic bladder) that depend on the location and extension of the AVM. Treatment consists of complete surgical resection of the spinal cord AVM nidus, whenever possible.

Imaging Study

Ultrasonography and Color Doppler show no mass, but an aggregation of high-velocity arterial and pulsatile venous flow with low resistance. Vessels are tortuous. On extremities, noninvasive follow-up is performed by comparing the arterial outflow of the affected limb with the unaffected one. Computed tomography scan has been replaced by MRI, which better shows the extent of AVM and allows differentiation from hemangioma and VM. Flow voids, corresponding to fast-flow vessels, are pathognomonic of AVM. Arteriography is needed before any treatment to determine feeding arteries and the nidus (see Fig. 172-12).

Differential Diagnosis

(Box 172-4)

Prognosis and Clinical Course

AVMs tend to worsen with time, causing local destruction and/or life-threatening bleeding. Puberty and trauma trigger growth. Bony hypertrophy is a common feature that causes common facial asymmetry. AVM of an extremity commonly causes peripheral ischemia due to blood flow steel phenomenon. Cardiac failure is rare (Schobinger stage IV), especially during childhood. Improper management, often due to misdiagnosis, such as ligation of feeding arteries, or partial resection of the nidus, can have dramatic consequences and expansion of the AVM (see Fig. 172-13). The CMs in CM-AVM are harmless, and usually of only cosmetic importance.

Treatment

This fast-flow vascular malformation is the most complex and difficult vascular anomaly to treat. Its management is multidisciplinary. AVM should be followed by periodic evaluation. In a limb AVM or multiple AVFs, elastic stockings can stabilize the lesion and protect the skin. The goal of cure of an AVM is based on obliteration (by embolization) and complete removal of the nidus or the epicenter. Early intervention for “quiescent AVM” (Schobinger Stage I) is debatable but should be considered only if complete resection is possible.114 In contrast to AVF, superselective arterial embolization alone is only palliative and is done only in unresectable complicated AVM. The embolized particles need to reach the epicenter of the lesion to avoid refilling of the nidus through new collaterals.115 Direct puncture of the nidus is another possibility in patients with previous arterial ligation or embolization.116 Surgical resection is usually done only after embolization, to minimize perioperative bleeding.117 AVM needs to be widely excised. Reconstruction often necessitates microsurgical free flap transfer.118 At least 5-year follow-up by annual Doppler ultrasound and/or MRI is mandatory after any treatment. For patients with Parkes Weber syndrome, the treatment should be as conservative as possible (e.g., elastic stockings). Epiphysiodesis may be necessary to control leg length discrepancy. However, this procedure can sometimes aggravate the AVM.10

For patients with HHT, multiple treatments have been tried to reduce bleeding, for example, topical application of anti-inflammatory drugs, laser, or surgery. Due to the extensiveness of the lesions, they all give limited free symptoms-intervals. Thalidomide has recently been successfully used to reduce the frequency and duration of nosebleeds in patients with HHT.119