Peripheral vascular tumors are rare, yet some physicians encounter patients with these tumors regularly and most physicians encounter them at least several times in the course of their practice. The clinical significance of vascular tumors ranges from trivial to cosmetically and psychosocially burdensome to life threatening. Some have characteristic clinical manifestations while many are found incidentally but have characteristic imaging findings. However, rare lesions and variable clinical presentations can result in delayed or misdiagnosis. This chapter will provide an overview of primary vascular tumors, emphasizing those affecting arteries and capillaries.

Primary vascular neoplasms are defined as those arising from vascular elements, such as endothelial cells and pericytes. Most involve the microvasculature and manifest in the skin, but others affect deep structures and occasionally manifest in large vessels.

Historically, clinicians and pathologists have used conflicting descriptions and schemes in classifying vascular tumors and vascular malformations (VM). In some cases, different labels have been used to describe the same disease while in other cases the same label has been applied to vastly different diseases.

In 1982, Mulliken and Glowacki¹ published a classification system based on endothelial characteristics and biologic behavior, in part to address this confusion (Table 50-1). A subsequent revision of their classification system broadened the category of vascular tumors of infancy to include pyogenic granuloma, tufted angioma, kaposiform hemangioendothelioma (KH), and hemangiopericytoma.² This revised classification has become the standard for distinguishing hemangiomas from VM and is the official classification schema of the International Society for the Study of Vascular Anomalies.

Despite the current acceptance of this standard, imprecise terminology remains widespread in the scientific literature.³ Furthermore, pathologists, who are often unaware of a patient’s clinical presentation, still use histopathologic diagnoses and classify vascular lesions by the type of vessel that predominates (arterial, venous, or lymphatic). In contrast, clinicians often make the diagnosis without relying on biopsy or histopathology.

Hemangioma

Hemangiomas are benign tumors of vascular endothelium and, by far, the most common form of primary vascular tumor. They most commonly affect the skin, but can occur in nearly any organ (Table 50-2). Hemangiomas are often without clinical significance, but they can cause complications such as disfigurement, ulceration, bleeding, organ failure, and death. Most hemangiomas present early in life. In some cases, hemangiomas are inherited as part of rare syndromes. Newly diagnosed superficial hemangiomas are uncommon after 30 years of age, but deep hemangiomas are often discovered incidentally in adults during imaging studies.

Hemangiomas have often been confused with VM.¹ The clinical distinction between hemangiomas and VM is not always initially apparent, but the diagnosis usually becomes clear with time. There are several features that distinguish hemangiomas from VM. Hemangiomas are more common in Caucasians than other races, more common in females than males, have early growth that is disproportionate to that of the patient, are composed of immature hyperplastic endothelial cells, have increased numbers of mast cells, and have upregulated expression of proliferative cell markers (see Pathophysiology below) (Table 50-3).

In contrast to hemangiomas: VM have equal sex distribution, are often present and fully formed at birth, grow proportionately with the child, are composed of mature and often combined arterial, venous, or lymphatic vascular elements, have normal numbers of mast cells, have no increase in proliferative cell markers, and unlike hemangiomas, endothelial cells from VM do not grow in tissue culture.

Pathophysiology

Although theories abound, the etiology of hemangiomas and the mechanisms that control their proliferation and involution are not well understood. At least four general theories predominate, as discussed below.

Chorionic Villi. There is strong evidence of a relationship between hemangiomas and placental chorionic villi. The gene expression profiles of hemangiomas and placentae are similar and they share a tissue-specific marker called GLUT-1.⁴ It has been hypothesized that hemangiomas represent the embolization of placental tissue to the fetus.⁵ However, contrary to popular belief, it has recently been shown that chorionic villous sampling is probably not a contributing factor to the development of hemangiomas.⁶

Angiogenesis. Hemangiomas have long been thought to represent a localized derangement of angiogenesis (the growth of new vessels from existing vessels). As evidence for this theory, proliferating hemangiomas have upregulated expression of angiogenic factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (BFGF), fibroblast growth factor (FGF), and type-IV collagenase.^7,8,9 Furthermore, therapy directed at inhibiting angiogenesis, such as corticosteroids and interferons, is often effective in causing involution of hemangiomas.

Vasculogenesis. More recently, however, some have argued that hemangiomas are mediated not by angiogenesis, but instead, by an error in vasculogenesis (the formation of blood vessels from angioblasts). This theory postulates that hemangiomas represent an incomplete maturation of the endothelial component of the fetal vasculature. The supporters of this theory point to the clonality of proliferating hemangioma endothelial cells.^10,11

Immune-Mediated. Immunohistochemical staining suggests a causal role for hematopoietic cells of myeloid origin.¹² Expression of specific clusters of differentiation (CD83, CD32, CD14, CD15), possibly triggered by local tissue hypoxia, have been demonstrated in hemangioma endothelial cells.

The evidence for these differing putative mechanisms suggests either a multifactorial process or the presence of different disease entities under the umbrella diagnosis of “hemangioma.”

Pathologic Classifications

Hemangiomas are classified by pathologists as being capillary, cavernous, or pyogenic granuloma (lobular capillary hemangioma).¹³ However, the American Academy of Dermatology refers to capillary hemangiomas as “superficial hemangiomas” and cavernous hemangiomas as “deep hemangiomas.”¹⁴ Hemangiomas that involve both superficial and deep tissue are called combined (or compound) lesions.

Capillary Hemangioma. Capillary (“strawberry”) hemangiomas represent the major common form of hemangioma. Most often, they are located in the skin or subcutaneous tissue. Grossly, these lesions appear red to purple in color (Figure 50-1). Histologically, one sees a proliferation of capillary-sized vessels surrounding a feeder vessel (Figure 50-2). This architecture has been referred to as “lobular” and has also been used to describe pyogenic granuloma and epithelioid hemangioma. The sine qua non of capillary hemangiomas is the presence a proliferating phase and an involuting phase.

Cavernous Hemangioma. Cavernous (deep) hemangiomas are less common than capillary (superficial) hemangiomas. They are generally larger, less well circumscribed, and more likely to involve deep structures, such as solid organs (e.g., liver). Grossly, they appear as indistinct purplish-blue nodules or masses in the skin (Figure 50-3). Histologically, they appear as massively engorged capillary hemangiomas (Figure 50-4), but unlike capillary hemangiomas, cavernous hemangiomas tend not to involute or do so more slowly and incompletely. They are also more likely to cause local tissue destruction.

Many cavernous hemangiomas are discovered incidentally on imaging studies. Both computed tomography (CT) and magnetic resonance (MR) imaging show an enhancing heterogeneous mass resulting from fibrous, vascular and fat components. There may be erosion of adjacent bones. The most characteristic imaging findings, however, are phleboliths, which are small rounded calcifications or ring calcifications of venous walls or thrombi. Phleboliths are found in up to one-third of cavernous hemangiomas (Figures 50-5 and 50-6).¹⁵ Complex hemangiomas with thrombus, hemosiderin, and hyalinization may resemble neoplasms.

Pyogenic Granuloma. See next section.

Pediatric Hemangiomas

Hemangioma of infancy (HOI) is the most common soft tissue tumor in the pediatric population, occurring in nearly 10% of Caucasian infants. Although the etiology and pathophysiology of hemangiomas remains unclear (see above), a number of risk factors have been identified (Table 50-4). Of those affected, 20% have multiple lesions.¹⁶ The vast majority of HOI occur sporadically, although familial autosomal dominant cases have been reported.¹⁷

Most HOI are superficial (capillary type). Many are not evident at birth, in contrast to VM, but become noticeable within the first few days or months of life. HOI can involve nearly any organ, but most are cutaneous on the head and neck (Figure 50-1A and 50-1B) (Table 50-2). Superficial hemangiomas appear as red papules, nodules, or plaques. Deep tissue hemangiomas often have a bluish hue (Figure 50-3).

Hemangiomas are characterized by a phase of proliferation followed by phase of involution and regression. They typically grow to maximal size by age 6 to 18 months and their growth is disproportionate to that of the infant. With few exceptions, they range in size from a few millimeters to several centimeters in diameter. Most will spontaneously involute. As a general rule, approximately 10% involute per year after 1 year of age. By 7 years of age, 75% to 90% will have involuted. However, even when a lesion fully involutes and regresses, a residual hypopigmented scar with redundant skin is evident in 50% of cases. The risk of scarring increases with larger combined lesions, and with lesions of the nose, ear, lip, or breast.

Congenital Hemangiomas. Congenital hemangiomas are rare and of two types: Rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH).¹⁸ RICH is similar to HOI but is fully developed at birth, lacks female preponderance, and pursues a course of rapid involution. Imaging studies can aid in making a diagnosis and differentiating this tumor from other entities, but occasionally biopsy is necessary. Accurate diagnosis of RICH is important in order to avoid unnecessary interventional therapy for this rapidly regressing lesion. NICH is so called because it is fully formed at birth and never involutes. Enjolras et al.¹⁹ published a series of 53 patients and found that all NICH lesions were single, averaged 5 cm in size, and more than 40% were on the head and neck.

Hemangiomatosis. Most hemangiomas are single and cutaneous, but 20% of patients will have more than one lesion.¹⁶ Hemangiomatosis is a syndrome that mostly affects neonates and is defined by the presence of multiple small hemangiomas (≥5 lesions).^13,20 Most cases are confined to the skin. Sometimes, hundreds of lesions are present and envelop an entire extremity (Figure 50-7).

A more severe variant can result in significant morbidity and rarely mortality because of systemic involvement.^21,22 In order of decreasing frequency, the liver, GI tract, brain, and lung may be affected. Hepatomegaly, congestive heart failure (CHF) and anemia appear early in severely affected infants, and death may result from heart failure. Despite its potentially aggressive nature, there are no reports of hemangiomatosis progressing to malignancy, and it remains a benign lesion that is often histologically identical to other common manifestations of hemangioma. Ultrasound (US) is a useful imaging modality for screening infants with more than five cutaneous hemangiomas for visceral lesions. Tumors in patients with hemangiomatosis recur in 90% of cases, so treatment should be as conservative as possible.²²

Syndromes. Aside from hemangiomatosis, there are several other rare clinical syndromes associated with hemangiomas (Table 50-5).¹³ Gorham disease (vanishing bone disease) is a syndrome of massive osteolysis that can occur with hemangiomatosis. Maffucci syndrome is a nonhereditary mesodermal dysplasia that manifests with multiple cavernous hemangiomas and enchondromas, most of which affect the phalanges and long bones (Figure 50-8). Patients with blue rubber bleb nevus syndrome (Bean syndrome), Peutz-Jeghers syndrome, and Klippel-Trenaunay-Weber syndrome may have multiple bowel hemangiomas that bleed and cause iron-deficient anemia. PHACE syndrome affects multiple organ systems and is discussed separately (see below). The Kasabach-Merritt syndrome (KMS) is a consumptive coagulopathy associated with specific hemangiomas, especially KH and tufted angioma (see below). Contrary to reports in older literature, KMS is rarely, if ever, associated with infantile hemangioma.

Complications and Regionally Important Lesions. Most hemangiomas are asymptomatic. However, lesions affecting the face often cause psychosocial distress (Figure 50-1A and Figure 50-1B). An additional 10% of pediatric hemangiomas will result in structural, coagulopathic, or metabolic complications (Table 50-6).

psychologic issues. Psychosocial distress, both for the patient and the family, is the most common complication of pediatric hemangiomas. Much has been published on this topic.^14,16,23,24 These issues are best dealt with by educating the parents and patient as to the natural course of the disease, explaining the treatment plans, and discussing reasonable expectations. Frequent and regular office follow-up is often necessary. Contact with other families through support groups and via the Internet may also be helpful.

ulceration and bleeding. Ulceration and bleeding are common complications of rapidly proliferating cutaneous hemangiomas and those located in areas of friction and pressure, such as the intertriginous areas.²⁵ These lesions are generally painful, susceptible to secondary infection and often result in larger residual scaring and discoloration.

soft tissue lesions. Soft tissue hemangiomas may present as a mass, with pain and discomfort, or as an incidental finding on an imaging study. Functional impairment may arise when a hemangioma interferes with a vital structure. Physical examination findings are often subtle. Generally, there is no discoloration of the overlying skin. The size of the lesion cannot be reliably assessed by palpation. Thrills and bruits are rarely present. Therefore, imaging studies (e.g., plain films, CT, MR, US, angiography) are especially useful in establishing the diagnosis (Figures 50-9,50-10,50-11,50-12). Biopsy should be performed if there is uncertainty regarding the diagnosis, particularly if there is a question of malignancy.

skeletal lesions. Hemangiomas are the most common benign vascular tumor of bone in children and adults, but constitute only 1% of bone tumors.^26,27 Most skeletal hemangiomas occur in the vertebrae (Figure 50-13) and skull (Figure 50-14) and are asymptomatic. Most of these tumors are discovered incidentally on routine imaging tests where they have a characteristic appearance. Appendicular skeletal lesions (Figure 50-15) are much less common, difficult to diagnose on imaging studies, and more likely to present with pain, swelling, or pathologic fracture.²⁸

periorbital lesions. Periorbital hemangiomas are among the most complicated lesions, as the visible portion often represents only the tip of the iceberg (Figure 50-1A). Periorbital hemangiomas can compromise visual axis maturation, resulting in a range of functional disabilities.^29,30 Patients may present with exophthalmos, proptosis, astigmatism, ptosis, strabismus, or visual impairment. MR is useful to assess the extent of the lesion and potential compromise to vital structures. Vision may be compromised by even small lesions so early pediatric ophthalmologic consultation is crucial.

upper airway lesions. Hoarseness or stridor in an infant patient of 6 to 12 weeks of age may herald a subglottic hemangioma.³¹ Patients at highest risk for this complication have hemangiomas affecting the “beard” region of the face, which corresponds to the cranial nerve V3 trigeminal distribution (preauricular, anterior neck, chin, and lower lip). Early consultation with ENT is advisable. Bronchoscopy may be necessary to establish the diagnosis and/or treat the lesion.

PHACE syndrome. The PHACE syndrome (Online Mendelian Inheritance in Man [OMIM] No. 606519) describes patients with: (1) Posterior fossa malformation; (2) Hemangioma; (3) Arterial abnormalities (including coarctation of the Aorta); (4) Cardiac defects; and (5) Eye abnormalities (Figure 50-16).^32,33,34 It is thought to be caused by an unknown embryonic insult that occurs during the first trimester of gestation. However, a strong female predominance exists, suggesting X-linked inheritance, but no familial cases have been reported.

Infants with PHACE syndrome present a spectrum of anomalies and disease severity. The diagnosis should be considered in any infant presenting with a large plaque-like lesion on the face. The vascular lesion, which is a true hemangioma, can be confused with the port wine stain (a VM) associated with the Sturge-Weber syndrome. Affected patients require an extensive work-up and consultation with a dermatologist, ophthalmologist, neurologist, cardiologist, and radiologist familiar with the syndrome.

MR of the head and neck should be considered to evaluate for posterior fossa abnormalities (e.g., the Dandy-Walker complex, cerebellar hypoplasia, and abnormalities of the vermis). Cerebral vascular compromise and stroke can result from compression of the carotid arteries or circle of Willis by hemangioma.^35,36,37 Carotid and vertebral anomalies are best evaluated by MR angiography or traditional (invasive) angiography with digital subtraction. The aortic arch can be evaluated by CT angiography, MR angiography, or more invasively by angiography. Transthoracic echocardiography should be performed to evaluate for congenital heart disease, such as atrial septal defect, or ventricular septal defect.

visceral lesions. In the general population, most visceral hemangiomas occur in the absence of cutaneous hemangiomas. However, in the pediatric population, the presence of large or multiple (≥5) cutaneous hemangiomas is a significant risk factor for the presence of visceral (especially hepatic) and brain hemangiomas. US is an effective noninvasive and relatively inexpensive method for screening the abdomen. In patients younger than 5 months of age, US may also be used to screen for the presence of brain hemangiomas.

The liver is the most common site of visceral hemangiomas (affecting 5% of the general population), and hemangioma is the most common benign hepatic tumor. Most liver hemangiomas are without clinical significance and are discovered incidentally during abdominal imaging studies (Figures 50-17 and 50-18). Most liver hemangiomas have characteristic imaging findings on CT, MR, and US (Figure 50-19A, 50-19B, 50-19C and 50-19D). Angiography is rarely used to establish the diagnosis, but classically shows highly vascular lesions with parallel arterial feeders and late venous stain. Technetium-99 m-labeled red blood cell (RBC) nuclear imaging can also be helpful when the diagnosis is in doubt based on other imaging studies (Figure 50-19E and 50-19F).³⁸

When significant arterial–venous shunting occurs within a liver hemangioma, high-output CHF may result. Massive liver hemangiomas sometimes compress adjacent structures, such as renal veins and the inferior vena cava (IVC), causing abdominal compartment syndrome. In very rare instances, liver hemangiomas can cause a consumptive hypothyroidism as a result of high expression of the thyroid hormone inactivating enzyme type-3 iodothyronine deiodinase (D3).³⁹

The presence of iron-deficient anemia or bowel obstruction in the pediatric population should prompt the consideration of gastrointestinal (GI) hemangioma. GI hemangiomas may present focally within the bowel wall, diffusely as intestinal hemangiomatosis, or as an extrinsic abdominal or pelvic cavernous hemangioma with direct invasion of the GI tract.⁴⁰ In these cases, a gastroenterology consult is warranted. The diagnosis may be established with endoscopy, tomographic imaging of the abdomen and pelvis (e.g., CT, MR), or angiography. GI hemangiomas are often associated with clinical syndromes (Table 50-5) and, when encountered, should raise the possibility of blue rubber bleb nevus syndrome (Bean syndrome), Klippel-Trenaunay-Weber syndrome, or Peutz-Jeghers syndrome.⁴¹

Congestive Heart Failure. High-output CHF as a result of arteriovenous (AV) shunting is an occasional complication of hemangiomas. In these cases, the offending lesion(s) is most often hepatic (see above). These patients should be evaluated by a cardiologist. An initial evaluation should include an electrocardiogram (ECG), an echocardiogram, a chest X-ray and basic laboratory work. Cardiac catheterization is often unnecessary in patients younger than 30 years of age, but may be useful in establishing the severity of the shunt. The liver, and potentially other viscera, should be evaluated for hemangioma by imaging studies (US, CT, MR, nuclear).