Chapter 462. Vascular Neoplasms

Vascular tumors comprise a small percentage of tumors in children and adults. Classifying these tumors can be difficult because of the rarity of these lesions and their diverse morphologic appearance and clinical behavior. In the pediatric population, these tumors are not independently stratified, leading to further problems with diagnosis. The most common vascular tumors (hemangiomas) are benign and have a diverse spectrum of clinical phenotypes. Similarly, the rarer vascular tumors can be benign or malignant with some overlap adding to diagnostic and treatment dilemmas (Table 462-1).

Infantile hemangiomas are discussed in more detail in Chapter 364. Hemangiomas are composed of a proliferating, clonal population of endothelial-like cells.1 These tumors can involve any organ; can occur as single, diffuse, or disseminated lesions; and can be associated with complicated syndromes.1,2 Tumor endothelial cells express GLUT1 as determined by immunohistochemistry.4 Most hemangiomas are uncomplicated and do not require therapeutic intervention. However, a significant percentage of hemangiomas produce clinical symptoms because of lesion size, location, or hemodynamic effects.5

Treatment of infantile hemangiomas is designed to control growth, minimize deformity, and preserve function. Systemic pharmacotherapy is used to treat large lesions, those that present a surgical challenge, or lesions causing functional or life-threatening problems. Steroids used at high doses (2–5 mg/kg/day) for long periods of time (3–12 months) have been the mainstay of therapy for symptomatic hemangiomas.6-10 Other agents with reported activity in treating hemangiomas include vincristine and α-interferon.11-19

Infants with multiple (> 5) cutaneous hemangiomas can have focal visceral tumors involving the liver, spleen, lung, brain, and intestines. The liver is the organ most commonly affected and its involvement can lead to serious complications such as hepatomegaly with liver dysfunction, compartment syndrome (intraparenchymal hypertension), congestive heart failure, and anemia/mild thrombocytopenia.20-22 Therefore, infants presenting with multiple cutaneous hemangiomas should undergo further evaluation, including ultrasound evaluation of the abdomen. If liver lesions are found, magnetic resonance imaging (MRI) is indicated to better characterize and quantify the lesions. Liver hemangiomas can also occur without cutaneous lesions, which make them more difficult to diagnose. Symptomatic liver hemangiomas have been treated successfully with steroids, vincristine, and interferon therapy.

A recent report demonstrated an association between infantile hemangiomas and severe hypothyroidism.23 High levels of type 3-iodothyronine deiodinase activity were found in the hemangioma tissue, causing an accelerated uptake of thyroid hormone. Infants with large hemangiomas, particularly hepatic hemangiomas, should therefore be screened for hypothyroidism. Since such patients may require extraordinarily high doses of thyroid replacement, they should be followed by a pediatric endocrinologist. Unidentified, severe hypothyroidism can lead to heart failure and death.

Spindle cell hemangiomas (SCH) often occur as superficial, painful lesions involving distal extremities in adolescents and young adults.24,25 Tumors often begin as a single nodule, but most patients develop multifocal lesions within an anatomic region over years. These tumors are well circumscribed, occasionally contain phleboliths, and consist of cavernous blood spaces alternating with areas of nodular spindle cell proliferation. A significant percentage of SCH are completely intravascular. The vein containing the tumor is abnormal, as are blood vessels apart from the tumor mass, supporting the contention that SCH are true vascular neoplasms. SCH has been described in association with Maffucci syndrome, Klippel-Trenaunay syndrome, early-onset varicosities, and congenital lymphedema. Metastases have not been reported, although local recurrence following surgical excision is 50% to 60%.24

Pyogenic granuloma is a vascular tumor that predominantly affects children and young adults.26-28 The precise mechanism for the development of pyogenic granuloma is unknown. These lesions can arise spontaneously, in sites of trauma, and within capillary malformations. Pyogenic granulomas have also been associated with medications, including oral contraceptives and retinoids. Most occur as solitary growths, but multiple (grouped) or, rarely, disseminated lesions have been described. These lesions appear as small vascular papules that grow rapidly over weeks and tend to bleed spontaneously. Histologically, these lesions are composed of capillaries and venules with plump endothelial cells separated into lobules by fibromyxoid stroma. Untreated lesions eventually atrophy, become fibromatous, and slowly regress. Surgery is restricted for problematic lesions; however, recurrences can be as high as 40% to 50%.

Angiofibromas are rare benign neoplasms in the pediatric population. Specifically challenging are juvenile nasopharyngeal angiofibromas (JNA), which account for 0.5% of all head and neck tumors.29 Histologically, JNA are vascular benign tumors, but they can be locally destructive, spreading from the nasal cavity to the nasopharynx, paranasal sinuses, orbit and skull base with intracranial extension. Some reports have suggested a hormonal influence on JNA with present emphasis on the molecular mechanisms involved. Surgical excision is the treatment of choice but can be very challenging. JNA have also been treated with radiation therapy, chemotherapy, and α-interferon therapy.

Retiform hemangioendotheliomas are slow-growing, exophytic, flat tumors found in young adults and teenagers.30 They are usually located in the limbs and trunk. Local recurrences are common, but distant metastases are extremely rare. Pathologically, they are located in the dermis and subcutaneous tissue planes of the skin. Vessels exhibit a pattern resembling the rete testis and are lined by protruding endothelial cells. Treatment is usually surgical excision.

Kaposiform hemangioendothelioma (KHE) is a rare tumor noted by Zukerberg in 1993 to have features similar to but distinct from juvenile hemangiomas.31 This tumor is often associated with Kasabach-Merritt phenomenon, which is characterized by consumptive coagulopathy associated with profound thrombocytopenia, hypofibrinogenemia, and elevated fibrin split products.32,33 KHE is usually present at birth but can appear in children and young adults, affecting both sexes equally. Lesions are firm, indurated, and purpuric; they are usually unifocal but can be very diffuse. Initially, lesions may not be evident, but with trauma and worsened coagulopathy, they become violaceous and larger. These tumors have a predilection for the upper trunk, extremities, thigh, sacrum, and retroperitoneum. MRI reveals a hyperintense lesion on T2 with ill-defined margins involving several tissue layers. Histologically, tumors consist of irregular infiltrating nodules of compressed vessels showing characteristics of both capillary hemangioma and Kaposi sarcoma. The vessels are lined by spindled endothelial cells with dilated hyperplastic lymphatic channels staining positive for CD31, CD34, and FLI1 and staining negative for GLUT1 and Lewis Y antigen (LeY). Epithelioid islands reveal CD61-positive fibrin thrombi.34

A number of therapies have been reported in the treatment of these tumors, but none have been uniformly effective.35,36 These therapies include the use of steroids, α-interferon, antifibrinolytic agents, and chemotherapy, including vincristine, cyclophosphamide, actinomycin, and methotrexate. These agents have been used singularly or in combination. Initial treatment is steroid therapy followed by vincristine and interferon. Other more experimental antiangiogenic agents are available and have been tried with varied response. There are no prospective studies available to assess efficacy. If initial therapy is not effective, additional medications or regimens that are more aggressive are used. Because the majority of these lesions are not resectable, tissue evaluation for research is limited.

Surgical excision, when possible, is the most effective treatment for kaposiform hemangioendothelioma; however, with large lesions or when Kasabach-Merritt phenomenon is present, multi-modality treatment is necessary. Even with therapy, these lesions do not fully regress, and they can recur.37 The mortality associated with this tumor is primarily from the extensive coagulopathy (Kasabach-Merritt phenomenon). Long-term effects include chronic pain, lymphedema, heart failure, and orthopedic issues. These lesions prove to be a difficult dilemma for the practitioner because they have varying degrees of clinical spectrum and varying responses to therapy. They should not be confused with hemangiomas and require supervision by a multidisciplinary team.

Hemangiopericytomas (HPC) are soft tissue tumors derived from mesenchymal cells with pericytic differentiation.38-42 They are very uncommon in children, who account for 10% of HPC cases. They usually present as a deep soft tissue mass with insidious growth and can occur in any part of the body, with the extremities being the most common location. They have a characteristic architectural pattern (pericytoma pattern) with tightly packed cells around thin-walled endothelium-lined vascular channels, ranging from small, capillary fixed vessels to large, gaping sinusoidal spaces.

In childhood, 2 distinct clinical entities are described: the adult type and the infantile type. The adult type occurs in children older than 1 year and is similar to HPC in adults. The infantile type occurs in the first year of life with focal and multifocal disease and is commonly associated with spontaneous regression and an overall favorable prognosis. This entity represents a third of all pediatric HPC cases and is considered congenital. There are few published data on clinical management of either entity in children. Surgical resection is the mainstay of treatment. The effectiveness of chemotherapy and radiotherapy remains to be established, but some reports have suggested a significant role for adjuvant treatments when complete resection is not possible.

Epithelioid hemangioendotheliomas arise from medium to large blood vessels and involve the soft tissue of the extremities, liver, lung, bone, and, rarely, the head and neck.38,39 They are more common in middle age but have been reported in children. Epithelioid hemangioendotheliomas can metastasize to lymph nodes, brain, and liver. Thirty percent of soft tissue cases are associated with metastases and, when present, portend a very aggressive course with limited response to chemotherapy. Histologically, these lesions are characterized as epithelioid lesions arranged in nests, strands, and trabecular patterns with infrequent vascular spaces. Features that may be associated with aggressive clinical behavior include cellular atypia, 1 or more mitoses per 10 high-power fields, an increased proportion of spindled cells, focal necrosis, and metaplastic bone formation.

Angiosarcomas are rare neoplasms that can occur in any region of the body (liver, breast, spleen, bone, heart) but are more frequent in skin and soft tissue.43-45 The tumors may develop as a complication of previous radiation therapy, from preexisting conditions such as chronic lymph edema, or following environmental exposures. Angiosarcomas are characterized by rapidly proliferating, extensively infiltrating anaplastic cells derived from blood vessels that line irregular, blood-filled spaces. Angiosarcomas are aggressive and tend to recur locally, spread widely, and have a high rate of lymph node and systemic metastases. The rate of tumor-related death is high. Doxorubicin-based therapies and newer antiangiogenic agents have been used in small numbers of patients with some success.