The utility of GLUT1 as a diagnostic marker in cutaneous vascular anomalies: A review of literature and recommendations for daily practice

doi:10.1016/j.prp.2017.04.023

Pathology - Research and Practice

Volume 213, Issue 6, June 2017, Pages 591-597

https://doi.org/10.1016/j.prp.2017.04.023 Get rights and content

Abstract

Objective

To assess the utility of GLUT1 as an immunohistochemical marker in the diagnostics of cutaneous vascular anomalies.

Methods

A systematic literature search was conducted for studies on GLUT1 staining patterns in cutaneous vascular lesions. Data was grouped according to the latest ISSVA classification for vascular anomalies.

Results

Vascular tumors: GLUT1 staining was positive in 368/386 (95%) of infantile hemangiomas. Congenital hemangiomas (16 cases) and kaposiform hemangioendotheliomas (62 cases) were all negative for GLUT1. Angiosarcomas were GLUT1 positive in 12/39 (31%) and epithelioid hemangioendotheliomas in 2/27 (7%) of cases. Vascular malformations: All vascular malformations (33 arteriovenous malformations, 16 capillary malformations, 64 lymphatic malformations, 54 venous malformations, 3 venous-lymphatic malformations and 3 capillary venous-lymphatic malformations) were negative for GLUT1 staining. Unclassified vascular anomalies: Angiokeratomas were GLUT1 positive in 1/15 (7%) and verrucous hemangiomas in 71/100 (71%) of cases. Microvenular hemangiomas were negative for GLUT1 in all 9 cases.

Conclusions

GLUT1 can be used as an additional diagnostic tool in cutaneous vascular lesions. A negative GLUT1 stain renders a diagnosis of infantile hemangioma unlikely. A positive GLUT1 stain excludes vascular malformations and is suggestive of infantile hemangioma. One must be cautious, however, that the final diagnosis is made through interpretation of all clinical and diagnostic features, and not based on GLUT1 staining alone.

Introduction

‘Vascular anomalies’ is an umbrella term used for lesions that stem from abnormalities in either blood vessels, lymphatic vessels, or both. Historically, the nomenclature for these vascular lesions has been vague and contradicting [1]. The first organized classification was published by Mulliken and Glowacki in 1982, distinguishing vascular tumors (lesions growing by endothelial hyperplasia, likehemangiomas) from vascular malformations (lesions with quiescent endothelium, considered localized defects of vascular morphogenesis) [2]. This basic classification system was adopted by the International Society for the Study of Vascular Anomalies (ISSVA) in 1993 [3]. Over the years, imaging techniques, immunohistochemistry and genetic studies have allowed for new diagnostic and classification opportunities in vascular anomalies, leading to various ISSVA classification updates [4], [5], [6]. Nonetheless, unambiguous classification of vascular anomalies remains a challenge. Wassef et al. published an introduction into the latest ISSVA classification update in 2015, striving for uniform classification of vascular anomalies by pathologists, clinicians, and researchers [6].

In 2000, North et al. found that the endothelial cells of infantile hemangiomas (IH) are immunoreactive for the Glucose Transporter Type 1 (GLUT1), contrary to the vascular endothelium in normal skin. They did not find comparable immunostaining in vascular malformations, rendering GLUT1 a potential marker for IH [7]. This led to new hypotheses regarding the origin of infantile hemangiomas, translating into the placental embolization theory of IH that still has supporters this day [8]. Although of undisputed scientific value, the clinical applicability of GLUT1 staining in infantile hemangiomas has not been addressed. Therefore, we aimed to define the utility of GLUT1 in the diagnostics of cutaneous vascular anomalies.

Section snippets

Materials and methods

The objective of this study was to assess the utility of GLUT1 staining in the diagnostics of cutaneous vascular anomalies. We searched PubMed for studies reporting on GLUT1 immunostaining patterns for different types of vascular anomalies (primary outcome). The search strategy was designed to entail all entities recognized by the latest ISSVA classification [Table 1] in combination with “GLUT1”. Exclusion criteria were: studies of non-cutaneous vascular anomalies; studies where GLUT1 was not

Results

Our search rendered 197 results. Title and abstract screening led to the exclusion 156 citations. Out of the 41 remaining citations, 21 relevant papers were included [Table 2]. The results of data extraction are discussed below. Findings are summarized in Table 3.

Discussion

In order to clarify the role of GLUT1 as a diagnostic tool in cutaneous vascular lesions, we reviewed published cases reporting on GLUT1 staining in vascular anomalies. Infantile hemangiomas were investigated most frequently, and nearly all tumors (95%) were positive for GLUT1. With this near ubiquitous GLUT1 immunoreactivity, it can be suspected that IH endothelium might inherently possess the Glucose Transporter Type 1. Similarly, North et al. argue that at least two out of four lesions that

Funding

None.

Conflicts of interest

None to declare.

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In the field of vascular anomalies, distinguishing between vascular malformations and tumors has become crucial for a correct therapeutic approach. However, the differential diagnosis between these two groups is not always well explained in classical texts, mainly because many vascular malformations are still known with old names that suggest a tumoral nature. Also, genetic and pathogenic knowledge of these entities has greatly increased in recent decades, so researchers and clinicians now have a better understanding of vascular malformations. In this paper, we present the main histopathological tips to recognize and identify a vascular malformation as such. We also contextualize such information in the clinical and pathogenic knowledge for a better understanding of these entities.
En el campo de las anomalías vasculares, distinguir entre malformaciones vasculares y tumores vasculares se ha vuelto esencial para un enfoque terapéutico correcto. Sin embargo, el diagnóstico diferencial entre estos dos grupos no está siempre correctamente explicado en los textos clásicos, principalmente porque a muchas malformaciones vasculares se las conoce todavía con nombres antiguos que sugieren tumores vasculares. Asimismo, el conocimiento genético y patogénico de estas entidades se ha incrementado notablemente en las décadas recientes, de tal manera que investigadores y clínicos tienen ahora una mejor comprensión de las malformaciones vasculares. En este artículo, presentamos las principales claves histopatológicas para reconocer las malformaciones vasculares e identificarlas como tal. También contextualizamos tal información en el conocimiento clínico y patogénico para mejor comprensión de estas entidades.
Digital subtraction angiography and trans arterial embolization in preventing massive hemorrhage of Kaposiform hemangioendothelioma: A case report
2022, Radiology Case Reports
Citation Excerpt :
This may have been caused by sporadic somatic mutations which occurred due to vascular malformations. These findings show that the diagnosis of the disease cannot be based on one positive or negative finding on Immunohistochemistry examination [11]. Options for therapy in KHE are systemic or intralesional steroids, low dose radiotherapy, excisional surgery, and chemotherapy with vincristine, cyclophosphamide, and sirolimus.
The management of hypervascularity tumor in infants and children is challenging due to its hemorrhage risk which can be life threatening. A proper and precise approach should be performed in preventing massive bleeding. A one-month-old male infant came with hypovolemic shock due to intratumor hemorrhage on the right chest that presented at birth and grew progressively with a size of 20 × 15 × 7 cm. After stabilization, Magnetic resonance imaging and Doppler ultrasonography of the tumor showed a solid lesion with an increase in vascular flow. He underwent two rounds of digital subtraction angiography (DSA) and trans arterial embolization (TAE) on the internal mammary, superior thoracic, and right thoracoacromial arteries. On the sixth day after second embolization and ensure significantly reduced vascularity using the ultrasound Doppler modality, he performed tumor removal surgery and skin grafted closure. There were no post-embolization or post-operative complications. Histopathological examination with immunohistochemistry staining on the tumor tissue indicated as Kaposiform hemangioendothelioma. Fluoroscopic technique of DSA and TAE should be considered prior to the tumor removal surgery has been proven to be safe and effective options in progressive large mass with high vascular flow management.
Advances in Pediatric Periocular Vascular Neoplasms
2022, Advances in Ophthalmology and Optometry
Citation Excerpt :
They consist of intravenous lobular capillary hemangioma and have a tendency to bleed, and surgical curettage/excision is definitive (Fig. 2) [15]. Tufted angioma and Kaposiform hemangioendothelioma are considered to be part of a spectrum of the same disease and exhibit lymphatic antigens, while being negative for GLUT-1 [16]. These lesions involve extremities, and their presence in head and neck region is rare.
Infantile hemangioma. Part 1: Epidemiology, pathogenesis, clinical presentation and assessment
2021, Journal of the American Academy of Dermatology
Citation Excerpt :
Involuting IHs show a reduction in vessel number, with a flattened, less mitotically active endothelium and apoptotic debris in a more conspicuous fibrous and fatty stroma.85 GLUT-1 staining of the endothelium is a sensitive marker for IH, absent in most other vascular tumors and malformations (Fig 7).86 Investigations and recommendations about referral to other specialists are summarized in Table III.
Infantile hemangioma (IH) is the most common pediatric vascular tumor. Its pathogenesis is poorly understood but thought to represent an aberrant response of pluripotent stem cells to stimuli such as hypoxia and the renin-angiotensin system. IH usually appears during the first few weeks of life and follows a characteristic natural trajectory of proliferation and involution. Their clinical appearance depends on their depth and distribution. Classification comprises superficial, mixed, and deep IH as well as IH with minimal or arrested growth. Multifocal IHs are more likely to be associated with infantile hepatic hemangioma and, although the need for screening based on a specific number of IH has been recently debated, 5 remains the most widely acceptable cutoff point. Large facial IHs warrant investigation for posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects or aortic coarctation and eye anomalies (PHACE) syndrome. Lumbar IHs warrant investigation for lower body IH and other cutaneous defects, urogenital anomalies, ulceration, myelopathy, bony deformity, anorectal malformations, arterial anomalies, and renal anomalies (LUMBAR) syndrome. Complications of IH include ulceration, obstruction or functional impairment, hypothyroidism, and cosmetic sequelae. Differential diagnoses mostly consist of other vascular tumors and vascular malformations, although IH may sometimes mimic nonvascular tumors or developmental anomalies. Diagnosis is usually clinical and biopsy is rarely indicated. High-frequency ultrasonography may help with the differential diagnosis, particularly with subcutaneous lesions. Referral to other specialists may be required in specific cases.
Imaging of Vascular Anomalies in the Pediatric Musculoskeletal System
2021, Seminars in Roentgenology
Citation Excerpt :
IHs are more common among girls (4:1) and premature infants, especially those with a birth weight <1500 g. These lesions are composed of tight clusters of plump capillary endothelium that almost always (approximately 95%) stain positive for glucose transporter-1 (GLUT-1).6,20 The majority of lesions involve the skin with a characteristic clinical appearance as a soft bright red papule, nodule or plaque raised above clinically normal skin, resulting in the classic “strawberry lesion.”
Vascular anomalies represent a spectrum of commonly encountered pediatric soft tissue masses, ranging from a localized cutaneous “birthmark” to systemic and/or life-threatening entities. Many of these lesions have specific implications for the growing musculoskeletal system, potentially affecting lifelong function. Establishing the correct diagnosis can be challenging, but an awareness of typical radiologic and clinical features of the most common entities will expedite the workup and enable appropriate family counseling and therapeutic implementation. This review will focus on the most commonly encountered vascular anomalies, including neoplasms and malformations, affecting the pediatric musculoskeletal system.

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ReviewThe utility of GLUT1 as a diagnostic marker in cutaneous vascular anomalies: A review of literature and recommendations for daily practice

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Materials and methods

Results

Discussion

Funding

Conflicts of interest

Hum. Pathol.

Br. J. Plast. Surg.

Hum. Pathol.

Semin. Pediatr. Surg.

Postcricoid vascular lesions: histopathological and immunohistochemical diagnosis

Laryngoscope

Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics

Plast. Reconstr. Surg.

Introduction: ISSVA Classification Excerpt from ‘Color Atlas of Vascular Tumors and Vascular Malformations’

Vascular tumors and vascular malformations (new issues)

Adv. Dermatol.

Update on the classification of hemangioma

J. Oral Maxillofac. Pathol.

Vascular anomalies classification: recommendations from the International Society for the Study of Vascular Anomalies

Pediatrics

Does hypoxia play a role in infantile hemangioma?

Arch. Dermatol. Res.

Congenital nonprogressive hemangioma: a distinct clinicopathologic entity unlike infantile hemangioma

Arch. Dermatol.

A unique microvascular phenotype shared by juvenile hemangiomas and human placenta

Arch. Dermatol.

Extracutaneous infantile haemangioma is also Glut1 positive

J. Clin. Pathol.

Usefulness of D2-40 immunohistochemistry for differentiation between kaposiform hemangioendothelioma and tufted angioma

J. Cutan. Pathol.

Wilms tumor 1 expression in vascular neoplasms and vascular malformations

Am. J. Dermatopathol.

Benign vascular proliferations–an immunohistochemical and comparative study

Pol. J. Pathol.

Visceral and mucosal involvement in neonatal haemangiomatosis

J. Eur. Acad. Dermatol. Venereol.

Dilated lymphatic vessels in tufted angioma: a potential source of diagnostic confusion

Am. J. Dermatopathol.

Clinicopathological features of Kaposiform hemangioendothelioma

Int. J. Clin. Exp. Pathol.

Review
The utility of GLUT1 as a diagnostic marker in cutaneous vascular anomalies: A review of literature and recommendations for daily practice