Successful Treatment of Extensive Infantile Hemangiomatosis of the Small Bowel in a 3‐month‐old With Thalidomide and Somatostatin Analog

Abstract

Tumors of the small intestine are rare, constituting <5% of all gastrointestinal neoplasms (1). Gastrointestinal hemangiomas account for only 0.05% of all intestinal neoplasms (2). Patients with gastrointestinal hemangiomatosis can present with abdominal pain, intermittent bleeding, and anemia of varying severity, and sometimes obstruction or intussusception (2). Small-bowel hemangiomatosis usually is difficult to diagnose because of its relative rarity and the fact that the workup for gastrointestinal bleeding is initially focused on the stomach, duodenum, and colon. We present a rare case of a 3-month-old female with extensive infantile hemangiomatosis affecting two thirds of the small bowel managed medically with thalidomide and somatostatin analog bitherapy. CASE REPORT A 3-month-old girl presented with 4 episodes of melena during the previous month and failure to thrive. She was one of twins born by elective cesaerian section at 36 weeks' gestation weighing 2340 g. Her weight had fallen from the 25th centile at birth to below the 5th centile at presentation, when she weighed just 3700 g. Her twin was unaffected and was not investigated. On general examination, she was pale but systemically well, with normal observations. The physical examination was unremarkable. No cutaneous or mucous membrane vascular lesions were present. The patient's hemoglobin concentration on admission was 59 g/L (normal range, 100–135 g/L), and she received a blood transfusion. Her erythrocyte sedimentation rate and autoimmune screen were normal. Upper gastrointestinal endoscopy and biopsies of the esophagus, duodenum, and stomach were normal. Colonoscopy revealed fresh blood macroscopically with a normal histological report. Abdominal ultrasound was normal. She continued to have intermittent dark stools. Scintigraphy with technetium-99m–labeled red blood cells showed increased activity in the midabdomen, raising the suspicion of active bleeding in the small bowel. Angiography demonstrated an abnormal configuration of the superior mesenteric artery branches to the jejunum and ileum, which were dilated and tortuous (Fig. 1A). A marginal branch arising from the ileocolic artery replaced the normal ileal arteries. A marked capillary blush was seen at the end of the arterial phase in the jejunal and ileal branches of the superior mesenteric artery (Fig. 1B and 1C). There was no early venous filling to suggest an arteriovenous malformation, and no point of bleeding could be identified. No abnormality was detected in the celiac axis or inferior mesenteric artery territories.FIG. 1: A 3-mo-old girl presenting with melena and failure to thrive. a, Dilated and tortuous branches of the superior mesenteric artery to the ileum and jejunum, including an abnormal marginal branch of the ileocolic artery (arrows). b, c, Marked capillary blush at the end of the arterial phase in the jejunum and ileum.The patient underwent diagnostic laparoscopy and biopsy of the small bowel. Macroscopically, the entire distal two thirds of the small bowel appeared markedly abnormal (Fig. 2A). The bowel was grossly erythematous, with ecchymoses and enlarged, tortuous mesenteric vessels (Fig. 2B). Vessels on the antimesenteric surface were similarly enlarged throughout the affected length of bowel. There were dense networks of small blood vessels in the mesentery, immediately adjacent to the bowel wall (Fig. 2C), and prominent lacteals. The bowel itself was not friable and there was no contact bleeding or ulceration. No Meckel diverticulum was present.FIG. 2: Abnormal appearances of the small bowel at laparoscopy, with (A) ecchymoses and (B) dilated, tortuous vessels, as well as (C) dense networks of small blood vessels in the mesentery.Histopathological examination of the biopsied segment demonstrated essentially normal small-bowel architecture, but with an expanded lamina propria, partially replaced by large numbers of thin-walled vascular channels lined with a single layer of bland endothelium, which focally extended into the submucosa. Scattered larger muscular and thin-walled dilated vascular channels also were present within the submucosa. Immunohistochemical staining for CD34, an endothelial marker, was positive in the vessels, and staining for glucose transporter-1 was diffusely positive in the lesional endothelial cells (Fig. 3). The features indicated a diagnosis of infantile hemangiomatosis of the small bowel.FIG. 3: Small bowel from an infant with extensive intestinal hemangiomatosis, demonstrating (top) villus mucosa with lamina propria expansion by closely packed, thin-walled vessels (hematoxylin and eosin, original magnification ×40 [inset ×100]). Bottom, The lesional endothelial cells demonstrate strong expression of glucose transporter-1 (GLUT-1 immunostain with hematoxylin counterstain, original magnification ×40 (inset ×100).The patient was treated with 6.25 mg of the antiangiogenic agent thalidomide (dosing range, 1–2 mg/kg orally once daily) and a somatostatin analog (1 mg/kg lanreotide intramuscularly every 2 weeks). During the therapy regimen, she was reviewed regularly in the outpatient clinic and blood tests were conducted, including complete blood counts and liver and renal function tests. She also had peripheral nerve conduction studies at baseline and once every 3 months while she was receiving thalidomide. Since treatment began, the patient has been entirely asymptomatic and has been gaining weight normally. A repeat angiogram 6 months into treatment showed persistence of hemangiomatosis in the small bowel, but with no further proliferation of the vasculature that would otherwise have been expected. At her latest clinic visit at 2 years of age, her weight was 10.5 kg. Her growth, previously below the 5th centile at presentation, has steadily followed the 9th centile for age. She has not required any blood transfusions since starting treatment. Her hemoglobin was 125 g/dL and fecal occult bloods were negative. In view of her progress, thalidomide therapy was discontinued. She continues to take somatostatin analog for the time being. DISCUSSION Classical infantile hemangiomas are benign endothelial neoplasms with a generally predictable course of rapid proliferation that begins shortly after birth and continues for 6 to 10 months, followed by gradual involution during childhood (3). They are the most common tumors of infancy and have a female-to-male predominance ratio of 3:1. Histologically, hemangiomas are characterized by closely packed, thin-walled vascular channels. Conversely, vascular malformations are errors of vascular morphogenesis populated by a stable, mature endothelium (4), and are not neoplasms. Unlike hemangiomas, they are nonproliferative and do not regress with time, but rather grow in proportion to the child. By definition, vascular malformations are present at birth, although they may not present until childhood. The understanding of visceral vascular anomalies has been hindered by unclear descriptions in the literature relating to the difference between hemangiomas and vascular malformations. In 1982, Mulliken and Glowaki (5) described a classification system based on the physical findings, clinical behavior, and cellular kinetics of these entities. A modification of this classification system has since been adopted by the International Society for the Study of Vascular Anomalies (6). The tissue-specific vascular antigen, erythrocyte-type glucose transporter protein-1 is a diagnostically useful marker for infantile hemangiomas. It is highly expressed by the endothelium of hemangiomas, as was seen in this patient, and is not expressed by the normal vasculature of the skin or subcutis, or by vascular malformations (7). Distinguishing between a hemangioma and vascular malformation in a child is paramount because the treatment of these lesions differs. Involution of a hemangioma may be induced with angiogenesis inhibitors, but these treatments are ineffective for vascular malformations (3). Hemangiomas rarely will bleed after the proliferative phase has ended (3), and unlike vascular malformations, will regress spontaneously in the majority of cases. Surgical therapy for hemangiomas should be reserved for prolonged or uncontrolled bleeding (3). The diagnosis of vascular anomalies of the small bowel may be difficult and is often delayed. In this patient, the initial diagnostic workup tests for melena were nondiagnostic. Angiography, however, revealed an abnormal vascular pattern in the superior mesenteric artery territory. Together with the laparoscopic and histological findings, this permitted the diagnosis to be made. TREATMENT AND MANAGEMENT The generic approach for the treatment of children with extensive gastrointestinal vascular anomalies who are not candidates for surgical resection or embolization involves the use of strategies that either reduce the abnormal vascular proliferation or that reduce blood flow though the abnormal vasculature. The antiangiogenic actions of thalidomide result from ceramide-induced depletion of vascular endothelial growth factor receptors, and hemangiomas are known to overexpress vascular endothelial growth factor (8). Somatostatin also has been shown to have significant antiangiogenic properties by directly inhibiting endothelial cell line proliferation through a block of growth-factor–stimulated mitogen-activated protein kinase and endothelial nitric oxide synthase activities (9). At present, there are virtually no evidence-based studies to guide therapy for hemangiomas (10). Traditionally corticosteroids have been the mainstay of treatment; however, they have many potential side effects, including adrenal suppression, growth suppression, hyperglycaemia, osteoporosis, and gastric irritation, and their mechanism of action remains poorly understood (10). Interferon-α is not widely used for infantile hemangiomas because of the high incidence of neurotoxicity (10). Thalidomide is among the newer therapies emerging for hemangiomas (10). Its potent antiangiogenic and anti-inflammatory actions also have been used previously to treat children with refractory cancers and severe inflammatory bowel disease with promising results (11,12). However, the potential side effects of thalidomide, including peripheral neuropathy and thrombosis, are important clinical considerations. In this case, we opted to treat the patient with thalidomide and a somatostatin analog because of the extensiveness of the disease and the severity of her symptoms, and based on our previous experience of these agents. Conservative management was not an option in this case because the patient was experiencing life-threatening gastrointestinal bleeds and failing to grow. Additionally, at 3 months of age, the hemangiomatosis would still have been in the proliferative phase, meaning symptoms would have increased further without treatment. Although mesenteric angiography after 6 months of treatment showed persistence of hemangiomatosis, there was no evidence of further proliferation, which would otherwise have been expected based on the natural history of hemangiomas. The rationale for bitherapy with thalidomide and somatostatin analog over monotherapy with thalidomide was that thalidomide may take up to 3 weeks to take effect. In our experience, there also is a synergistic effect between these agents, and somatostatin analog therapy alone is sometimes associated with a degree of tachyphylaxis and waning of clinical effect. At our center, there is an established protocol for obtaining fully informed consent from the parents or legal guardian of all patients undergoing treatment with thalidomide. The duration of therapy is decided on an individual basis, and patients are monitored closely throughout the course of therapy. In this case, the patient did not experience any adverse effects from treatment. Conclusions We report an unusual case of medically managed extensive intestinal hemangiomatosis in a 3-month-old girl. Two thirds of her small bowel was affected, and she was suffering from life-threatening gastrointestinal bleeds, severe anemia, and failure to gain weight. Bitherapy with somatostatin analog and thalidomide resulted in rapid resolution of her clinical symptoms and resumption of normal growth, and she remains asymptomatic at 2 years of age.