eISSN: 2084-9869
ISSN: 1233-9687
Polish Journal of Pathology
Current issue Archive Manuscripts accepted About the journal Supplements Editorial board Abstracting and indexing Subscription Contact Instructions for authors Ethical standards and procedures
SCImago Journal & Country Rank
2/2021
vol. 72
 
Share:
Share:
more
 
 
Case report

Bean’s syndrome (blue rubber bleb nevus syndrome – BRBNS) as a gastrointestinal bleeding – case report and review of the literature

Małgorzata Lenarcik
1
,
Jacek Pachlewski
1
,
Andrzej Mróz
2

1.
Department of Gastroenterology, Hepatology and Clinical Oncology, Centre of Medical Postgraduate Education, Warsaw, Poland
2.
Department of Pathomorphology, Centre of Medical Postgraduate Education, Warsaw, Poland
Pol J Pathol 2021; 72 (2): 190-194
Online publish date: 2021/09/30
Article file
- 13-PJP-Answers_Quiz.pdf  [2.75 MB]
Get citation
ENW
EndNote
BIB
JabRef, Mendeley
RIS
Papers, Reference Manager, RefWorks, Zotero
AMA
APA
Chicago
Harvard
MLA
Vancouver
 
 

Introduction

Bean’s syndrome (blue rubber bleb nevus syndrome – BRBNS) is a rare morbidity associated with the venous malformations of vascular bed. In majority of cases BRBNS is caused by sporadic mutations of TEK gene which encode TIE2 – endothelial cell tyrosine kinase receptor of angiopoetins [1, 2, 3], few cases of germline mutations located on chromosome 9p has been also described [4, 5]. TEK mutation has also contributed to establishing BRBNS as a separate entity in international society for the study of vascular anomalies classification ISSVA [6]. The diagnosis of BRBNS is based on multidisciplinary approach with CT and MRI studies, endoscopic and histopathological examinations (supported by immunohistochemical stainings CD34, GLUT1, SMA, Ki67). Vascular malformations in BRBNS develop mostly in the skin and gastrointestinal tract and sporadically in CNS, liver, spleen, air tract, heart, urinal bladder and visceral spaces [7, 8, 9, 10]. BRBNS affects men and women equally with skin vascular lesion developing in early childhood followed by other localizations in adolescence. Up to 300 cases of BRBNS have been described in the literature thus far [4, 8, 11, 12].

Pathophysiology

The somatic double (cis) TEK (TIE2) gene mutations encoding angiopoetin receptor have been proved to cause BRBNS [2, 4]. The vascular bed of patients with BRBNS is malformed with the presence of venous vascular malformations accompanied by vascular fistulas. The vessels are malformed and irregularly located and blood flow systems are dysregulated. The blood flow is turbulent, diameter’s and resistance’s dependent which cause thrombi formation and vascular autoamputations and ruptures. Significant bleedings mainly of gastrointestinal tract occur with secondary inflammation, ulceration and life threatening perforation. As a result of autoamputations or vascular malformation sclerotization neighboring vascular channels are overloaded and the blood stream is redirected to form new lesions. In addition some of new lesions are formed from mutated precursors cells mandating perpetuated nature of the diseases [2].

Case report

A 41-year-old man with recurrent gastrointestinal bleeding and secondary anemia requiring multiple blood transfusions, with protracted and increasing weakness. Physical examination revealed both flat and protruded bluish, fading under pressure skin lesions with a slightly wrinkled surface in the perioral area, forearms and the left knee. In addition, postsurgical deformation of the right foot was found due to skin lesion excision in the childhood. In laboratory tests a low level of Hb 3.9 g/dl and iron deficiency were present. In the endoscopic examination of the gastrointestinal tract numerous, bluish submucosal lesions were found in esophagus, stomach (Fig. 1B), duodenum, small and large intestines (Fig. 1A). The size of the lesions was estimated from 0.2 mm to 4 cm. The patient was treated locally endoscopically, surgically and also received empiric chemotherapy without significant clinical improvement. The reemergence of new changes was observed. Histopathological biopsies revealed wide vascular spaces, thin-walled, lined with a single layer of endothelial cells with no atypia located within the submucosa of the gastrointestinal tract (Figs. 2 A-D, 3A). There were signs of fibrosis and hyalinosis in the surrounding tissue. The mucosa above the lesions revealed no significant pathological changes. Immunohistochemistry of vascular spaces lining: SMA+ CD34+, GLUT1– (Fig. 3B-D).

Discussion

BRBNS is a clinicopathological diagnosis [2, 10, 12, 14] and the morphological differential diagnosis include vascular malformations and vascular tumors (Table I). Unlike vascular malformations tumors generate hyperplasia of neoplastic cells. These cells differ metabolically from nonneoplastic lesions (Warburg effect) [15]. In the neoplastic cells overexpression of GLUT1 (erythrocyte type glucose transporter) is displayed in immunohistochemical stainings [16]. This reaction has both diagnostic and prognostic significance differentiating vascular malformations form vascular tumor mainly hemangiomas [16, 17]. BRBNS was initially described in 1860 by George Gascoyen [18] but the full description of the entity was introduced by William Bennet Bean in 1958 [19].
Vascular malformations in BRBNS are classically observed from the birth, particularly on hands and feet and gradually gastrointestinal tract lesions reveal. These lesions are in form of flat or protruded polyps growing slowly with acceleration in puberty which may indicate the association with hormonal factors. BRBNS is currently established based on the mutation in TEK (TIE2) gene and included in III category (simple vascular malformations named Blue rubber bleb naevus (Bean) syndrome VM TK (TIE2) of ISSVA classification for vascular anomalies (Amsterdam, Netherlands 2018) [20]. BRBNS is a phenotypic variant of TEK (TIE2) mutations and should be differentiated from other vascular malformations including multiple cutaneous and mucosal venous malformations (VMCS), multifocal venous malformations (MVM) and sporadical venous malformation (VM). The aforementioned entities belong to the TEK mutation spectrum and cannot be diagnosed solely on histopathological picture. The final diagnosis depends on inheritance mode, localization of the lesion and their number and size [2, 21]. In order to determine the extension of vascular lesion radiological techniques (US, CT, MRI, echocardiography) and endoscopy are utilized also to exclude the bone and soft tissue lesion which are not characteristic for Bean syndrome.
Outside the scope of TEK mutated syndromes the differential diagnosis of BRBNS include: Osler Weber Rendu syndrome of arterio-venous malformations (AVM) in the mucosa of oral and nasal cavities and minute pinpoint cutaneous teleangiectasies [10, 21], Klippel-Trenaunay syndrome of capillary-venous vascular malformation connected with hypertrophy or hypotrophy of the limbs [10, 22, 23] and Maffucci syndrome of vascular venous malformations and hemangiomas in gastrointestinal tract, bones, meninges accompanied by enchondromas or oteochondromas [10, 22, 24]. These patients are also at increased risk of developing cholangiocarcinomas, gliomas, acute leukemias and malignant transformation of vascular and chondral lesions [14, 25]. The treatment of patients with Bean syndrome has to be individualized based on severity of symptoms. In case of sporadic gastrointestinal bleedings iron supplementation and blood transfusions are usually sufficient. In case of severe bleeding the surgical or endoscopical procedure must be considered [10]. Different modes of BRBNS therapy has have been described in the literature with corticosteroids, interferon and propranolol, somatostatin analogues (octreotide) and sirolimus (rapamycin) [4, 9, 12, 26]. Sirolimus was proved to decrease gastrointestinal lesions, severe bleedings episodes and to increase the intervals between blood transfusions which all improve patients quality of life [3, 12].
The authors declare no conflict of interest.

References

1. Ochiai D, Miyakoshi K, Yakubo K, et al. Familial Blue Rubber Bleb Nevus Syndrome in Pregnancy with Spinal Epidural Involvement, Case Reports. Obstetrics and Gynecology 2013; Article ID 141506: 3 pages.
2. Soblet J, Kangas J, Natynki M, et al. Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations. J Invest Dermatol 2017; 137: 207-216.
3. Mayba JN, Cullingham K. Blue rubber bleb nevus syndrome. CMAJ 2019; 191: E841;
4. Ke-Ling Wang, Shu-Fang Ma, Ling-Yu Pang, et al. Sirolimus alternative to blood transfusion as a life saver in blue rubber bleb nevus syndrome. Medicine (Baltimore) 2018; 97: e9453.
5. Gallione Cj, Pasyka KA, Boon LM, et al. A gene for familial venous malformations maps to chromosome 9p in a second large kindred J. Med Genet 1995; 32: 197-199.
6. https://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf.
7. Baigrie D, Rice AS; In C. An. Blue Rubber bleb nevus syndrome. StatPearls Publishing; 2021.
8. Sullivan CA. Blue Rubber Bleb Nevus Syndrome. Anesthesiology 2018; 129: 1169.
9. Isoldi S, Belsha D, Yeop I, et al. Diagnosis and management of children with Blue Rubber Bleb Nevus Syndrome:
10. A multi-center case series. Dig Liver Dis 2019; 51: 1537-1546.
11. Xue-Li Jin, Zhao-Hong Wang, Xi-Bin Xiao, et al. Blue rubber bleb nevus syndrome: A case report and literature review. World J Gastroenterol 2014; 20: 17254-17259.
12. Zahedi MJ, Moghadam SD, Mirzaei SM, et al. Blue Rubber Bleb Nevus Syndrome as a rare Cause of Iron Deficiency Anemia: a Case Report and Review of Literature. Middle East
13. J Dig Dis 2013; 5: 235-239.
14. Xu Y, Zhou B, Zhang M, Luo D. An unusual case of blue rubber bleb nevus syndrome with unilateral linear distribution. Indian J Dermatol Venereol Leprol 2013; 79: 269-270.
15. Wyrzykowski D, Bukowski M, Jaœkiewicz J. Cancer burgery 2011. Guzy naczyniowe i wrodzone malformacje naczyniowe.
16. El Abiad JM, Robbins SM, Cohen B, et al. Natural history of Ollier disease and Maffucci syndrome: Patient survey and review of clinical literature. Am J Med Genet A 2020; 182: 1093-1103.
17. Luc R, Tortorella SM, Ververis K, et al. Lactate as an insidious metabolite due to the Warburg effect. Molecular Biology Reports 2015; 42: 835-840.
18. Zambrano A , Molt M, Uribe E, et al. Glut 1 in Cancer Cells and the Inhibitory Action of Resveratrol as A Potential Therapeutic Strategy. Int J Mol Sci 2019; 20: 3374.
19. Wnêk A, Kobos J, Przewratil P. Controversies on the histopathological classification of vascular anomalies in children. Nowotwory Journal of Oncology 2015; 65: 214-220.
20. Gascoyen GG. Case of naevus involving the parotid gland and causing death from suffocation: naevi of the viscera. Trans Pathol Soc London 1860; 11: 267.
21. Bean WB. Vascular spiders and related lesions of the skin. Springfield, Illinois: Charles C. Thomas 1958; 178-185.
22. Boon LM, Vikkula M. Multiple Cutaneous and Mucosal Venous Malformations. Gene Revievs [Internet] 2018.
23. Tortora A, Riccioni ME, Gaetani E, et al. Rendu-Osler-Weber disease: a gastroenterologist’s perspective. Orphanet Journal of Rare Diseases 2019; 14: 130.
24. Franco M, Santino F, Paiva Lopes MJ. Inverse Klippel-Trenaunay syndromecase report. Rev Paul Pediatr 2020: 38: e2020091.
25. Brandigi E, Torino G, Messina M, et al. Combined capillary venous-lymphatic malformations without overgrowth in patients with Klippel-Trenaunay syndrome. J Vasc Surg Venous Lymphat Disord 2018; 6: 230-236.
26. Prokopchuk O, Andres S, Becker K, et al. Maffucci syndrome and neoplasms: a case report and review of the literature. BMC Research Notes 2016; 9: 126.
27. Salloum R, Fox CE, Alvarez-Allende CR, et al. Response of Blue Rubber Bleb Nevus Syndrome to sirolimus treatment. Pediatr Blood Cancer 2016; 63: 1911-1914.
Copyright: © 2021 Polish Association of Pathologists and the Polish Branch of the International Academy of Pathology This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Quick links
© 2021 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe