Infantile hemangioma as cause of neonatal gastrointestinal bleeding

Journal of Pediatric Surgery Case Reports 31 (2018) 71–76

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Infantile hemangioma as cause of neonatal gastrointestinal bleeding a,∗

a

a

b

Francesca Destro , Luciano Maestri , Claudio Vella , Vittoria Baraldini , Giovanna Riccipetitoni a b

T a

Paediatric Surgery Unit, Paediatric Surgery Department, V. Buzzi Children's Hospital, Milan, Italy Vascular Anomalies Unit, Pediatric Surgery Department, V.Buzzi Children's Hospital, Milan, Italy

A R T I C L E I N F O

A B S T R A C T

Keywords: Gastrointestinal hemangioma Neonates Laparoscopy Vascular anomalies Gastrointestinal bleeding

Introduction: Gastrointestinal infantile hemangiomas (IHs) are extremely rare and represent a diagnostic challenge, especially in newborns for the limited applicability of diagnostic approaches. We report two cases of neonates with gastrointestinal bleeding from intestinal hemangioma and a literature review of gastrointestinal IHs. Case 1: Full-term baby, asymptomatic at birth. On the seventh day of life she experienced failure to thrive, weight loss and hypotonus followed by melena and vomit. The imaging showed an intestinal vascular anomaly. We performed exploratory laparotomy and intestinal resection to remove the lesion. No complication occurred. Case 2: A 20-day old girl had melena and severe anaemia. The scintigraphic evaluation excluded gastric heterotopia. We opt for explorative surgery and we performed a laparoscopy that showed a congested and oedematous intestinal segment that was resected. Post-operative course was uneventful. Discussion: Gastrointestinal IHs may cause intractable bleeding, intussusception and intestinal perforations with bad prognosis. A prompt and accurate diagnosis is vital but not always easy. Colour-coded Duplex Scan are a good first-line imaging, MRI and CT give a better definition but the latter exposes to radiation. In the “era” of minimally invasive surgery, laparoscopy can have a role in the management of patients with gastrointestinal IHs. Conclusions: Gastrointestinal IHs should be considered in the differential diagnosis of neonates with anemia and gastro-intestinal bleeding. In selected cases, the minimally invasive approach permits diagnosis and treatment.

1. Introduction Infantile hemangiomas (IHs) are common benign vascular tumours affecting 4–10% of infants [1,2]. The cutaneous localized (focal) and the segmental forms account respectively for 67,5% and 13% of cases, whereas the remainder are indeterminate (16,5%) or multifocal (3,6%) [3]. Extracutaneous intestinal manifestations are extremely rare and represent a diagnostic challenge, especially in neonates and small infants for the limited applicability of diagnostic approaches [1,4,5]. We report two cases of neonates with intestinal bleeding that were found to have infantile intestinal hemangioma. 2. Case reports 2.1. Case 1 A Caucasian female was born at 38 weeks of gestational age. The pregnancy was complicated by intrauterine death of one twin. The girl was asymptomatic at birth and discharged home after standard

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observation period. At 7 days she was admitted to the hospital with failure to thrive, weight loss and hypotonus. Laboratory tests showed high inflammatory makers (reactive C protein and white blood cell count) with negative infection screening. After two days she had liquid malodorous stools, vomit and painful abdomen. Blood samples showed progressive reduction of haemoglobin: after 18 days there was abundant melena. MRI showed enhancement of part of the small bowel with increased calibre of the superior mesenteric vein, splenic vein and portal vein at the hepatic hilum. CT scan was performed for a better definition: the proximal ileum was involved by a vascular anomaly that leaded to increased venous blood flow through the superior mesenteric and portal veins (Fig. 1). Systemic corticosteroids were administered but the episodes of melena frequently recurred causing persistent severe anaemia. The decision was to perform explorative laparotomy through a midline incision: the middle ileum had a thickened and red wine wall that extended for about 40 cm. The lesion appeared well marked (Fig. 2a) and was resected leaving a residual normal intestine of 57 cm. A termino-

Corresponding author. Via Castelvetro 32, 20154, Milano, Italy. E-mail address: [email protected] (F. Destro).

https://doi.org/10.1016/j.epsc.2018.02.004 Received 25 January 2018; Accepted 11 February 2018 Available online 13 February 2018 2213-5766/ © 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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associated symptoms. Colour-Coded Duplex scan showed a large solid vascular mass with regular margins and deep extension covered by normal skin. The intralesional flow pattern was characterized by high vascularization density and presence of multiple arterio-venous shunts, consistent with the diagnosis of deep infantile hemangioma in proliferative phase. Total body MRI (Fig. 4) was performed for a better definition of the clinical picture: the cervical mass measured 7 × 5.5 × 7 cm and extended towards the deep cervical sheath and in the opposite side of the body. The abdominal scans showed a hepatic mass (4 × 3,5 cm) in the right lobe, multiple alterations in the mesentery surrounding the vascular branches (9 × 6x5 cm) and a focal diaphragmatic lesion (1,6 × 0,7 × 1 cm). These lesions had rapid and diffuse signal enhancement during the arterial phase, persisting also in late acquisitions. The anomalies had the characteristics of multifocal infantile hemangioma. Propranolol therapy (2 mg/kg/die) was administered after cardiological evaluation. The response occurred in a few days. After one month there was a huge clinical and US improvement.

Fig. 1. CT evaluation showing increased venous blood flow through the superior mesenteric and portal veins.

terminal anastomosis was performed after resection. Post-operative course was uneventful. Feeding stared after 5 days and the girl was discharged after 23 days. Histology permitted to diagnose a benign vascular tumour with features of infantile hemangioma (GLUT1 positive) (Fig. 2b). The girl had a regular follow-up without evidence of disease.

3. Discussion Vascular tumours include IHs, congenital hemangiomas, tufted angioma, pyogenic granuloma, and hemangioendotheliomas (Table 1) [6]. These entities were grouped together by Mulliken and Glowacki because they share the endothelial cell hyperplasia with increased proliferation activity and aberrant blood vessel architecture [7]. In contrast, vascular malformations are not true neoplasms but localized defects of vascular morphogenesis caused by embryogenetic and vasculogenetic dysphunctions. IHs are the most common tumours of infancy and have a female predominance [1,8]. Their natural history includes a developmental phase between 2 and 8 weeks of life with rapid growth for approximately 6–12 months. Afterwards they undergo slow involution in the first years of life. During the proliferative phase, IHs variably deepen into soft tissues producing superficial, deep and combined forms. IHs may also be localized/focal (67,5% of total IHs, arising from a single focal point), segmental (13%, covering a cutaneous territory derived from a specific neuroectodermal placode), indeterminate (16,5%) and multifocal (3,6%). The spectrum of manifestations includes the most common cutaneous forms and extracutaneous localizations (e.g. hepatic, gastrointestinal, mediastinum, brain …) [9]. The liver is the second most common localization. Hepatic involvement should be suspected when there are multifocal (> 5 lesions), large (> 5 cm) and segmental cutaneous IHs or in case of hepatomegaly and congestive heart failure [1,10,11]. Gastrointestinal IHs are extremely rare, accounting for only 0,05% of all intestinal neoplasms [8]. They are usually located in the intestinal

2.2. Case 2 A Caucasian female was born full term after regular pregnancy. Twenty days after birth she presented with melena and severe anemia (Hb 6.4 g/dL) requiring red blood cells transfusion. Screening for infections (CMV, rotavirus, adenovirus, enterovirus) and coproculture were negative. Inflammatory markers were normal. There was no sign of milk protein allergy. A scintigraphy with Tc99m was performed to rule out Meckel diverticulum: the exam showed impregnation of contrast means in the small intestine. Meanwhile melena and anaemia recurred and the girl became instable. We performed a laparoscopic exploration that permitted to identify an intestinal loop with red wine serosa 20 cm far from the ileo-cecal valve (Fig. 3a). The small bowel was exteriorized through the umbilical wound and inspected and palpated outside the abdomen. The affected segment was dilated and edematous and well-demarcated separation (Fig. 3b). We performed an intestinal resection completely removing the lesion and a terminoterminal anastomosis to restore canalization. Histology concluded for infantile hemangioma with GLUT1 positivity. Imaging evaluation performed soon after the operation included abdominal and cerebral ultrasounds: both evaluations were negative. Two months after surgery a right cervical mass appeared without

Fig. 2. Intraoperative identification of the affected bowel segment (a) and histological evaluation (b).

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Fig. 3. Intraoperative findings: laparoscopic visualization of the intestinal loop with red wine serosa (a) that was exteriorized (b).

Table 1 ISSVA Classification updated in 2014 [6]. 2014 ISSVA Classification of Vascular Anomalies Vascular malformations Simple Venous malformations Lymphatic malformations Capillary malformations Arteriovenous malformations and fistulae Mixed (combined) malformations Combined Vascular malformations associated with other anomalies Klipplel-Treaunay syndrome Parkes-Weber syndrome Sturge-Weber syndrome Maffucci syndrome CLOVES syndrome Proteus syndrome Bannayan-Riley-Ruvalcaba syndrome Others Vascular tumours Benign Infantile hemangioma (IH) Congenital hemangioma (rapidly, RICH or non-involuting NICH, partially involuting PICH) Lobulated capillary hemangioma (pyogenic granuloma) Tufted angioma Spindle cell hemangioma Epithelioid hemangioma Pyogenic granuloma Others Locally aggressive or borderline Kaposiform hemangioendothelioma (KHE) Retiform hemangioendothelioma Dabska tumour Composite hemangioendothelioma Kaposi sarcoma Others Malignant Angiosarcoma Epithelioid hemangioendothelioma Others

Fig. 4. MRI evaluation for multifocal infantile hemangioma.

segments supplied by branches of the superior mesenteric artery (midgut) [5]. The typical distribution is a segmental one but in severe cases diffuse involvement may be present being responsible for intractable bleeding, intestinal perforations and overall bad prognosis [12]. Perforation is a common complication during the proliferative phase probably for a reduced integrity of the bowel wall with vascular compromise that makes the mucosa susceptible to erosion and bleeding [5,12]. Gastrointestinal bleeding with subsequent anaemia is the main presenting symptom, followed by obstruction and intussusception [5,12]. The lesions are usually founded in the small bowel. Gastric and colonic involvement has been described too, even if doubts remain regarding the diagnostic appropriateness of these reports [5,13]. In fact, there is still confusion in classifying and diagnosing vascular tumours in infancy; vascular malformations are often misinterpreted as vascular tumour and the presence of various terms indicating IHs has resulted in huge confusion. For instance the term “cavernous hemangiomas” indicates deep IHs or venous malformations, “diffuse neonatal hemangiomatosis” was used to include IHs, multifocal lymphangioendotheliomatosis with thrombocytopenia and other multifocal conditions [1,14]. The accurate diagnosis is mandatory for appropriate evaluation, treatment and prognosis (e.g. involution of IHs may be obtained with angiogenesis inhibitors that are ineffective for vascular

malformations) [4]. In neonates and infants, an additional complication is that some diagnostic tolls are not recommended or not applicable. Colour-coded Duplex Scan are a good first-line imaging showing thickened bowel loops and vessel enlargement [4]. Esophagogastroduodenoscopy and colonoscopy identify only lesions of the foregut and hindgut but can exclude alternative etiologies. MRI is optimal for retroperitoneal evaluation but it is less useful in defining intestinal lesions and vascular anomalies than CT scanning. On the other hand, CT should be used cautiously for the well known radiological exposure. Nuclear scintigraphy shows alterations only in case of active bleeding, it cannot differentiate the type of vascular anomalies and it is difficult to interpret in children [15]. According to Soukoulis, the clinical suspicion and the results of radiologic studies (including US, CT and MRI) 73

74

1 (F)

1 (F)

1 (M)

1 (M)

1 1 (F)

(2010) [12]

Jarvi (2008) [8]

Scafidi (1998) [19]

Attash (2012) [13]

Arafa (2002) [20] Pascual-Castroviejo (2010) [21]

1

36

1

3

1

3

Stomach Small bowel and colon

Stomach

Small bowel

Small bowel

Small bowel

Colon (1)

Upper gastrointestinal bleeding

Gastrointestinal bleeding

Emesis, chronic constipation, failure to thrive Melena, failure to thrive

Gastrointestinal bleeding (2)

Surgery: laparotomy (two intestinal perforations) Endoscopy Surgery: laparotomy CT

Thalidomide and Somatostatin analogue Corticosteroid and Interferon-α 2b –

–

Surgery: laparotomy (multiple intestinal perforations) Surgery: VLS

–

– Corticosteroid (8) Propraolol (5) Vincristine (4) Interferon-α 2b (1) Octreotide (1) Corticosteroid (3) Interferon-α 2a (2)

NED

Cutaneous IHs –

– Partial gastrectomy, omentectomy and splenectomy Endoscopic removal

Cutaneous IHs PHACE

Died

–

NED

NED

–

NED Intestinal perforation (1) Recurrent bleeding (2) Unknown (4) NED (3) Died (1) Cutaneous IHs

– Cutaneous IHs (10) Liver IHs (3) Retroperitoneal IHs (4) Other IHs (3) PHACE (9) Cutaneous IHs (2) Liver IHs (1)

NED

Intestinal perforation (2) Short bowel syndrome (1)

Outcomes (number of patients)

Endoscopic banding (1) Embolization of portal hepatic shunts (1) Intestinal resection

– Intestinal resection (2)

Intestinal resection

Cutaneous IHs (9) Liver IHs (3) PHACE (1) Retroperitoneal IHs (2) Other IHs (2) –

Intestinal resection (3)

Corticosteroid (12) Propranolol (4) Vincristine (2)

–

Comorbidities (number of patients)

Surgery (number of patients)

Medical therapy (number of patients)

MRI, endoscopy Surgery: laparotomy (4)

Surgery: VLS and laparotomy (8) MRI/US (4) CT (2) Endoscopy (2) Surgery: TULA

Diagnosis (number of patients)

a The authors also report 43 additional cases of segmental, cutaneous hemangiomas associated with internal organ involvement: 16/43 were gastro-intestinal localizations. Four deaths were the result of extensive gastrointestinal involvement and subsequent bleeding.

4 (3 F)

Gastrointestinal bleeding Gastrointestinal bleeding (10)

– Small bowel (6) Colon (3) Never identified (2)

7 2

1a (F) 10 (all F)

Fishman (1998) [4]

Gastrointestinal bleeding

Small bowel

–

Gastrointestinal bleeding (16)

Symptoms (number of patients)

1 (−)

Papparella (2014) [18] Metry (2004) [9] Drolet (2012) [15]

Location (number of patients) Small bowel (15) Colon (2)

16 (14 F)

Soukoulis (2015) [5]

Mean age (months)

4

Number of patients (sex)

Author (year)

Literature review: paediatric gastrointestinal IHs (2007–2017)

Table 2 Main published series on paediatric gastrointestinal IHs of the last 20 years. F = female, M = male; VLS = laparoscopy; MRI = magnetic resonance imaging; US = ultrasounds; CT = computed tomography; IHs = infantile hemangiomas; TULA = trans umbilical laparoscopic assisted; PHACE = posterior fossa defects, hemangiomas, cerebrovascular arterial anomalies, cardiovascular anomalies, eye anomalies; NED = no evidence of disease.

F. Destro et al.

Journal of Pediatric Surgery Case Reports 31 (2018) 71–76

Journal of Pediatric Surgery Case Reports 31 (2018) 71–76

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Disclosure statements

can be diagnostic without the need for endoscopy or surgical exploration [4]. Other authors experienced some problems in obtaining the diagnosis using only imaging studies [1,8,16]. The reduced invasiveness of new surgical technologies that are now applicable also in neonates and infants makes surgery a valid complementary approach. The lack of tactile feedback, complained by some authors, may be overcome by the use of hybrid and video-assisted techniques. In our “Case 2” the clinical picture and the positivity of the scintigraphic scan led us to perform emergency surgery. The operation was performed with a minimally invasive approach and permitted both the diagnosis and the treatment. Regarding the diagnosis we observed the following features of the affected bowel:

There are no prior publications or submissions with any overlapping information, including studies and patients. We do not have any conflict of interest. Patient consent Patient consent was obtained although this report does not contain any personal information that could lead to the identification of the patient. Funding

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well-defined lesions red wine serosa edema and dilatation numerous afferent congested mesenteric vessels

No funding or grant support. Authorship All authors attest that they meet the current ICMJE criteria for Authorship.

We could discuss on the utility of MRI, that requires sedation, and of CT, that exposes to radiation, in the “era of minimally invasive surgery”. First line therapy for gastrointestinal IHs is propranolol [4]. Corticosteroids can be used as complementary therapy and they are shown to be effective in 2/3 of patients [1,6,17]. In complex multi-resistant cases an alternative is the use of combined approaches or Vincristine [6,17]. Surgery is indicated when medical therapy fails, in case of prolonged or recurrent bleeding and intestinal complications (e.g. perforation). Minimally invasive approaches reduce surgical comorbidities: laparoscopy may aid in achieving a diagnosis and laparo-assisted procedures permit to handle the affected bowel combining the advantages of the open techniques [4,12]. Small isolated lesions of the stomach and colon can be banded endoscopically, as performed by Fishman t al. in one of their patients [4]. However the procedure carries the risk of perforation and accelerated haemorrhage [4]. Table 2 resumes the main published series on paediatric gastrointestinal IHs of the last 20 years. Thirty-eight patients (mainly females) presented with gastrointestinal bleeding at a mean age of 6 months. The most frequent location was the small intestine; the colon was involved in 7 cases and the stomach in 2. Surgery was performed to obtain a definitive diagnosis in 17 cases while in 8 patients it permitted the removal of the lesions. Endoscopic treatment was described in 2 cases. The following events were recorded during follow-up: intestinal perforations (n = 3), short bowel syndrome (n = 1) and recurrent bleeding (n = 2). Two patients died. Analysing the published literature, three elements may be proposed to suggest the presence of intestinal IHs: patient's age (bleeding occurs during the proliferative phase in the first months of life), clinical presentation and the evidence of cutaneous IHs [4]. In fact, it has been observed that gastrointestinal IHs are associated with large segmental hemangiomas [14] and distinctive clinical phenotype (female Hispanic or Caucasian infant with aortic abnormalities) [15]. However, the absence of cutaneous hemangioma does not exclude gastrointestinal IHs, as previously suggested and as shown by our “Case 1” [4].

Conflict of interest The following authors have no financial disclosures: FD, LM, CV, VB, GR References [1] Darrow DH, Greene AK, Mancini AJ, Nopper AJ. SECTION on dermatology, section on otolaryngology–head and neck surgery, and section on plastic surgery. Diagnosis and management of infantile hemangioma. Pediatrics 2015 Oct;136(4):e1060–104. http://dx.doi.org/10.1542/peds.2015-2485. [2] Belen B, Oguz A, Okur A, Dalgic B. A complication to be aware of: hyperkalaemia following propranolol therapy for an infant with intestinal haemangiomatozis. BMJ Case Rep 2014 May;19. [3] Jinnin M, Medici D, Park L, Limaye N, Liu Y, Boscolo E, Bischoff J, Vikkula M, Boye E, Olsen BR. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med 2008 Nov;14(11):1236–46. [4] Fishman SJ, Burrows PE, Leichtner AM, Mulliken JB. Gastrointestinal manifestations of vascular anomalies in childhood: varied etiologies require multiple therapeutic modalities. J Pediatr Surg 1998 Jul;33(7):1163–7. [5] Soukoulis IW, Liang MG, Fox VL, Mulliken JB, Alomari AI, Fishman SJ. Gastrointestinal infantile hemangioma: presentation and management. J Pediatr Gastroenterol Nutr 2015 Oct;61(4):415–20. [6] Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, Burrows P, Frieden IJ, Garzon MC, Lopez-Gutierrez JC, Lord DJ, Mitchel S, Powell J, Prendiville J, Vikkula M, ISSVA Board and Scientific Committee. Vascular anomalies classification: recommendations from the international society for the study of vascular anomalies. Pediatrics 2015 Jul;136(1):e203–14. [7] Mulliken JB, Glowacki J. Classification of pediatric vascular lesions. Plast Reconstr Surg 1982 Jul;70(1):120–1. [8] Jarvi K, Roebuck DJ, Sebire NJ, Lindley K, Shah N, Salomon J, Curry JI. Successful treatment of extensive infantile hemangiomatosis of the small bowel in a 3-monthold with thalidomide and somatostatin analog. J Pediatr Gastroenterol Nutr 2008 May;46(5):593–7. [9] Metry DW, Hawrot A, Altman C, Frieden IJ. Association of solitary, segmental hemangiomas of the skin with visceral hemangiomatosis. Arch Dermatol 2004 May;140(5):591–6. [10] Dickie B, Dasgupta R, Nair R, Alonso MH, Ryckman FC, Tiao GM, Adams DM, Azizkhan RG. Spectrum of hepatic hemangiomas: management and outcome. J Pediatr Surg 2009 Jan;44(1):125–33. [11] Hughes JA, Hill V, Patel K, Syed S, Harper J, De Bruyn R. Cutaneous haemangioma: prevalence and sonographic characteristics of associated hepatic haemangioma. Clin Radiol 2004 Mar;59(3):273–80. [12] Rao AB, Pence J, Mirkin DL. Diffuse infantile hemangiomatosis of the ileum presenting with multiple perforations: a case report and review of the literature. J Pediatr Surg 2010 Sep;45(9):1890–2. [13] Attash SM, Ali MS, Al-Nuaimy HA. Isolated cavernous haemangioma of the stomach in a 3-year-old child: an unusual cause of upper GI bleeding. BMJ Case Rep 2012 Oct;6. [14] Glick ZR, Frieden IJ, Garzon MC, Mully TW, Drolet BA. Diffuse neonatal hemangiomatosis: an evidence-based review of case reports in the literature. J Am Acad Dermatol 2012 Nov;67(5):898–903. [15] Drolet BA, Pope E, Juern AM, Sato T, Howell B, Puttgen KB, Lara-Corrales I, Gilliam A, Mancini A, Powell J, Siegel D, Metry D, Stevenson DA, Grimmer JF, Frieden IJ. Gastrointestinal bleeding in infantile hemangioma: a complication of segmental, rather than multifocal, infantile hemangiomas. J Pediatr 2012 Jun;160(6).

4. Conclusions Gastrointestinal IHs are rare but should be kept in mind in differential diagnosis of neonates and infants with gastrointestinal bleeding of obscure origin, especially when there are segmental cutaneous IHs. In selected cases the laparo-assisted approach permits the diagnostic confirmation and the definitive therapy. The procedure allows for direct bowel manipulation and gives all the advantages of a minimally invasive surgery.

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Laparoscopic approach to Meckel's diverticulum. World J Gastroenterol 2014 Jul 7;20(25):8173–8. [19] Scafidi DE, McLeary MS, Young LW. Diffuse neonatal gastrointestinal hemangiomatosis: CT findings. Pediatr Radiol 1998 Jul;28(7):512–4. [20] Arafa UA, Fujiwara Y, Shiba M, Higuchi K, Wakasa K, Arakawa T. Endoscopic resection of a cavernous haemangioma of the stomach. Dig Liver Dis 2002 Nov;34(11):808–11. [21] Pascual-Castroviejo I, Pascual-Pascual SI, Velazquez-Fragua R, García-Guereta L, López-Gutiérrez JC, Olivares P, Tovar J. Association of cutaneous red-to-purple hemangiomas with leptomeningeal hemangiomas. a clinical study of two patients. Neuropediatrics 2010 Feb;41(1):7–11.

1021–1026.e3. [16] Kim SH, Cho YH, Kim HY. Vascular malformations of the small intestine manifesting as chronic anemia: two pediatric cases managed by single-site umbilical laparoscopic surgery. Int J Surg Case Rep 2017;31:233–6. [17] Stillo F, Baraldini V, Dalmonte P, El Hachem M, Mattassi R, Vercellio G, Amato B, Bellini C, Bergui M, Bianchini G, Diociaiuti A, Campisi C, Gandolfo C, Gelmetti C, Moneghini L, Monti L, Magri C, Neri I, Paoloantonio G, Patrizi A, Rollo M, Santecchia L, Vaghi M, Vercellino N, Italian Society for the study of Vascular Anomalies (SISAV). Vascular anomalies guidelines by the Italian society for the study of vascular anomalies (SISAV). Int Angiol 2015 Apr;34(2 Suppl 1):1–45. [18] Papparella A, Nino F, Noviello C, Marte A, Parmeggiani P, Martino A, Cobellis G.

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