Classification of vascular tumors/nevi Vascular tumors mainly of infancy and childhood • Hemangioma of infancy. • Congenital hemangioma. • Miliary hemangiomatosis of infancy. • Spindle cell hemangioma. • Kaposiform hemangioendothelioma. • Tufted angioma. • Sinusoidal hemagioma. Vascular malformation - Capillary: • Salmon patch. • Potr-wine stain. • Nevus anemicus.

- Mixed vascular malformation: • Reticulate vascular nevus. • Klipple ternaunay syndrome. • Venous malformation. • Blue rubber bleb nevus syndrome. • Maffucci syndrome. • Zosteriform venous malformation. • Other multiple vascular malformation syndrome. - Lymphatic malformations: • Microcystic/Macrocystic. • Rapid flow (arteriovenous malformation).

 Angiokeratoma: • Angiokeratoma circumscriptum naeviforme. • Angiokeratoma of Mibelli (or angiokeratoma acroasphyticum digitorum) . • Solitary papular angiokeratoma. • Angiokeratoma of fordyce (or angiokeratoma scroti). • Angiokeratoma corporis diffusum.  Cutanous vascular hyperplasia: • Lobular capillary hemangioma. • Epithelioid hemangioma. • Crisoid aneurysm. • Reactive angioendotheliomatosis. • Gromeruloid hemangioma.

• Hobnail hemangioma. • Microvascular hemangioma. Benign neoplasm: • Glomus tumors. Malignancy: • Kaposi sarcoma. • Angiosarcoma. • Retiform hemangioendothelioma. Modified classification of the International Society for the Study of Vascular Anomalies (Rome, Italy, 1996) :  Tumors: -Hemangiomas: • Superficial (capillary or strawberry haemangioma). • Deep (cavernous haemangioma). • Combined. - Others: • Kaposiform haemangioendothelioma. • Tufted angioma. • Hemangiopericytoma. • Spindle - cell hemangioendothelioma. • Glomangioma. • Pyogenic granuloma. • Kaposi sarcoma. • Angiosarcoma.

 Vascular malformation: • Single capillary (C): (port-wine stain or nevus flammeus). • Venous (V). • Lymphatic (L): (lymphangioma or cystic hygroma). • Arterial (A). • combined arteriovenous fistula (AVF). • Arteriovenous malformation (AVM). • CLVM(include most cases of Klippel-Trenaunay syndrome). • CVM(include most cases of Klippel-Trenaunay syndrome). • LVM. • CAVM. • CLAVM.

Difinition of angiokeratoma: The term angiokeratoma is applied to a number of quite distinct conditions that share a clinical presentation with asymptomatic hyperkeratotic vascular skin lesions and a histological combination of superficial dermal vascular ectasia and hyperkeratosis.

Aetiopathogenesis  The pathogenesis is still unknown. It is thought to be a telangiectatic lesion arising from local injury to capillaries in the papillary dermis, either from trauma or venous hypertension.

 In men, varicoceles have been implicated as a common cause. In women, increased venous pressure is noted during pregnancy and in vulval varicosity, post‐partum and post‐hysterectomy.

 Systemic angiokeratoma corporis diffusum (Anderson- Fabry disease) is an unusual X-linked lysosomal disorder characterized by deficiency of a-galactosidase.

Varieties of angiokeratoma  Angiokeratoma circumscriptum naeviforme.  Angiokeratoma of Mibelli (or angiokeratoma acroasphyticum digitorum) .  Solitary papular angiokeratoma.  Angiokeratoma of fordyce (or angiokeratoma scroti).  Angiokeratoma corporis diffusum.

Angiokeratoma circumscriptum naeviforme • The condition is rare. Usually but not always present from birth and occasionally they appear to extend during adolescence.

• The lesions are typically situated unilaterally on a lower leg or foot, but can occur on thigh, buttock or occasionally elsewhere.

• They are deep red to blue–black warty keratotic papules or nodules and tend to take on a streaky, banded or zosteriform configuration. They may bleed on trauma.

• There is no tendency to spontaneous improvement.

• It may associated with fordyce angiokeratoma and caviar spots. Similar lesions also may be a feature of the Klippel–Trenaunay syndrome and of Cobb’s syndrome.

Angiokeratoma of Mibelli • It is rare condition with a definite familial predisposition. It is transmitted as an AD trait .

• Females appear to be affected predominantly.

• The distribution and the regular association with acrocyanosis and chilblains appear to implicate cold injury as a provocative factor.

Clinical features • Age of 10 and 15 years, but both earlier and later onset has been recorded.

• A history of recurrent chilblains is usual.

• The earliest lesions are minute, bright-red macules, which slowly increase in size and become elevated, warty and darker in colour. Many attain a diameter of about 5 mm, but some may be larger.

• The dorsal and lateral aspects of fingers and toes are most often affected, but lesions also occur on the dorsa of hands and feet and occasionally on the knees ,elbows and buttocks . They may be associated with ulceration of the fingertips .

• There is little tendency to spontaneous resolution.

Solitary papular angiokeratoma • Appear usually between the age of 10 and 40 years.

• Local trauma and cold injury may be predisposing factors .

• They occur in both sexes and at any site, although the legs are the site of predilection.

• The lesions appear as single or multiple warty papules, generally between 2 and 10 mm in diameter, and dark red to blue-black in colour. Angiokeratoma of fordyce • The most common of the angiokeratomas.

• The pathogenesis of AKF may be due to injury the capillaries e.g ; trauma and chronic irritation.

• It is also believed that atrophy of dartos muscle and degeneration of elastic tissue incidental to senility also plays a role in loss of support of blood vessels. So It frequently appear with increasing age and considered as a degenerative disorder.

• Local venous hypertension as in varicocele plays a part in their development .

Clinical features • Small, 1–6 mm, bright-red vascular papules may develop on the scrotum as early as late adolescence. With increasing age they become larger, darker and more numerous.

• Patients may occasionally complain of itching, soreness or bleeding.

• Identical lesions may also occur on the glans or shaft of the penis, labia majora or even on the upper thighs and in the groins.

• Well circumscribed,macular, telangiectatic lesions have been described on the oral mucosa in patients with angiokeratomas of the scrotum.

Angiokeratoma corporis diffusum (Fabry’s disease) • It’s a generalized form of angiokeratoma.

• Males are primarily affected, females are carrriers.

• Incidence about 1:40 000 to 1:60 000.

Pathogenesis:

• X-linked recessive inborn error of glycosphingolipid metabolism due to deficiency of lysosomal enzyme α-glycosidase A.

• More than 200 mutations were identified in the long arm of chromosome X (Xq22).

• Deficiency of α-glycosidase A enzyme cause storage of 2 neutral uncleaved glycosphingolipids; trihexosylceramide (α-galactosyle- lactosyle-ceramide) and digalactosyle-ceramide ( galabiosylceramide) to ccumulate within lysosomes in a variety of cell types, including capillary endothelial cells, fibroblasts, pericytes, heart, kidneys and autonomic nervous system giving rise to the symptoms and signs of Fabry’s disease.

Clinical features: • Onset of the disease usually occurs during childhood or adolescence.

 Dermatological manifestations: • Angiokeratomas commonly seen in the lower half of the body namely lower abdomen, genitalia, buttock and lower limbs. It can also be seen in the lips. • Anhidrosis or hypohidrosis.

Neurological manifestations: Two types of pain • Episodic crises ("Fabry crises”) characterized by agonizing burning pain originating in the extremities and radiating inwards to the limbs and other parts of the body. • Chronic pain characterized by burning and tingling paraesthesias. Gastrointestinal manifestation: • Abdominal pain (often after eating),diarrhea, nausea, vomiting, and anorexia. • These gastrointestinal symptoms may be related to the deposition of Gb3 in the autonomic ganglia of the bowel and mesenteric blood vessels.

Cardiac manifestation: • Arrhythmias and cardiomyopathy.  Renal manifestation: • Proteinuria, renal impairment and renal faileur.  Cerebro vascular manifestation: • Transient ischemic attacks, ischemic strokes and more rarely vascular dementia. Auditory and vestibular manifestation : • Hearing loss, tinnitus and vertigo. Ocular manifestation: • Corneal opacities(cornea verticillata) and cataract.

• ACD is no longer regarded as specific to Fabry`s disease only, but also occur in patients with several enzyme deficiencies as; α-Fucosidase (fucosidosis), Neuraminidase (sialodosis) Aspartylglucosaminidase (aspartylglucosaminuria), β-Mannosidase (β-mannosidosis), α-N acetylgalactosaminidase (Kanski disease), β-galactosidase (adult onset GM1 gangliosidosis).

Differential Diagnosis

I. Clinical differential diagnosis:-  Melanocytic nevi.  Malignant melanomas.  Pigmented basal cell carcinomas.  Spitz nevi.  Lymphangioma circumscriptum.  Seborrheic keratoses.  Dermatofibromas.  Other vascular lesions such as angiomas, hemangiomas or pyogenic granulomas.  Wart.  Molluscum contagiosum.  Herpes zoster.  Acral pseudolymphomatous angiokeratoma.

Diagnosis 1. Clinical picture. 2. Dermoscopy. 3. Biopsy and histopathology. 4. In fabryʼs disease: Diagnosis is confirmed by:  Finding low levels of α galactosidase A in the leukocytes, serum, tears and skin fibroblasts.  Molecular genetic analysis of the GLA gene is the most accurate method of diagnosis in females.  ECG, MRI, echocardiography, eye examination, renal function tests and kidney biopsy may also be suggestive of Fabry disease if excessive lipid buildup is noted.  Prenatal diagnosis by enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is considered in male fetuses.

Dermoscopy Dermoscopy is an easily applicable non invasive in vivo technique for diagnosis of Aks

In the dermoscopic view

Dark lacunae well-demarcated, round dark blue, dark violaceous, or black structures which histologically represent dilated vessels with thrombosis is a strong diagnostic sign of AK.

Red lacunae refer to dilated vascular spaces without thrombosis in the upper dermis.

Whitish veil corresponds to acanthosis or hyperkeratosis.

 Peripheral erythema refer to a pinkish homogeneous area that could represent an inflamed lesion.

AKs were divided into three patterns by dermoscopic view.

All patterns include dark lacunae and whitish veil.

• Pattern 1 (sensitivity 84.4%, specificity 99.1%):- consists of no other features.

• pattern 2 (sensitivity 43.8%, specificity 100%) consists of peripheral erythema.

• pattern 3 (sensitivity 53.1%, specificity 99.6%) consists of hemorrhagic crusts.

II. Dermoscopic differential diagnosis:-  Hemangioma.  Lymphangioma.  Pyogenic granulomas.  Melanoma  BCC.  Spitz nevi.  Seborrheic keratoses.  Dermatofibroma.

BCC Malignant melanoma Cherry angioma Lymphangioma Spitz nevus Biopsy and Histopathology:-  Hyperkeratosis, irregular acanthosis and elongation of rete ridges.  Dilatation of papillary dermal vessels forming cavernous spaces.  Elongated rete ridges may surround the vessels.  Thrombosis of some of the vessels.  In Anderson Fabry disease, glycogen can be detected by Sudan black stain in the endothelial cells, pericytes, arrectores pilorum and sweat glands.

III. Histopathological differential diagnosis:-  Verrucous hemangiomas.  Lymphangiomas.  Angiomas.  Malignant melanomas. Haemangioma Lymphangioma Malignant melanoma Treatment

Treatment can range from conservative management such as reassurance with close monitoring and follow- up to more active approaches, especially for bleeding or discomfort.

Lines of Treatment of angiokeratoma: Electrocautery. . Cryotherapy. Surgical excision.  Laser therapy: Espcially Argon laser but CO2 laser, IPL and PDL also used. Sclerotherapy : Repeated local injections of 0.5% ethanolamine oleate or 0.25% sodium tetradecyl sulphate. Mild pain and epithelial sloughing with minimal scarring have been demonstrated.

Treatment methode Advantages side-effects

Surgical excision complitely removes the disfiguring scars, long lesions. recovery time.

recurrence, scarring, Laser therapy post treatment best cosmetic outcome. hypo- and hyperpigmentations.

Cryotherapy for very superficial recurrence, scars, many lesions. procedures.

Electrocautery for small superficial recurrence, scars. lesions. Treatment of fabryʼs disease  Psychological support.  Enzyme replacement therapy (Fabrazyme) with agalsidase alfa or beta. Reversal of the metabolic and pathological abnormalities in the cells and tissues are the key therapeutic goals. These changes should, in turn, result in improvement of symptoms and prevention of disease complications.  Gene therapy.  Symptomatic treatment as follow: • Pain: NSAIDS, carbamazepine and gabapentin. • Advanced renal disease: Dialysis and/or transplantation. • Antiplatelet agents or anticoagulants to prevent cerebrovascular disorders. • Treatment of hypertension and cardiac complications. Genetic Counseling Genetic counseling should be available to all individuals and their families. Medical Follow-up of Fabry disease: • All patients with Fabry disease should be followed regularly, with comprehensive medical evaluations at least once per year. • Asymptomatic females should be re-evaluated less frequently but at least every two years with particular emphasis on cardiovascular and cerebrovascular complications. Thank you