Vascular Anomalies: From the Dermatologist s Perspective

Transcription

1 Vascular Anomalies: From the Dermatologist s Perspective Aimee Smidt, MD, FAAD, FAAP University of New Mexico School of Medicine, Depts. of Dermatology & Pediatrics April 2018 No conflict of interest to declare

2 Objectives Become familiar with the updated ISSVA classification system for vascular anomalies. Explain the quality of life (QoL) impact of vascular anomalies as a consideration for management.

3 Lecture Overview ISSVA Classification What s New? Illustrative Cases Challenges Genetics Quality of Life

4 issva.org/classification New classification approved in 2014

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6 ISSVA Abbreviated Classification

7 2014 Classification System (Revised from Mulliken & Glowacki, 1982) TUMORS = NEOPLASMS Benign Infantile Hemangioma Congenital Hemangioma Rapidly involuting* Non- and partially involuting Tufted (Hem)angioma* Pyogenic granuloma/lobular Capillary Hemangioma Others Locally aggressive Kaposiform hemangioendothelioma (KHE) Retiform hemangioendothelioma Kaposi s Others Malignant Angiosarcoma Epithelioid hemangioendothelioma

8 Pediatrics Jan. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Drolet BA 1, et al. Infantile Hemangiomas What s New? GLUT1+ on pathology Typical rapid proliferation Earlier than previously thought, by 8 weeks Treat for prevention of sequelae Active non-intervention Topical timolol (0.5% gel-forming solution BID) Oral propranolol (2-3 mg/kg/day div BID) FIRST LINE Pediatrics Aug. Early growth of infantile hemangiomas: what parents' photographs tell us. Tollefson MM1, Frieden IJ. JAMA Jan. Safety of Propranolol Therapy for Severe Infantile Hemangioma. Prey S, et al. N Engl J Med Feb A randomized, controlled trial of oral propranolol in infantile hemangioma. (FDA Approval) Léauté-Labrèze C, et al.

9 Propranolol for Infantile Hemangiomas Indications: Function-threatening/severe disfigurement Risk of complications (ulceration) Outpatient if >8 wks old (corrected) Screen for risk of cardiac dz or asthma (EKG not required if none) Baseline + 1 st dose HR/BP ALWAYS w feeds, hold if ill (risk hypoglycemia) Different dosing guidelines Start at 1 mg/kg div BID-TID Increase to 2 mg/kg (if needed) after 3-5 days Continue with dose adjustment for weight until 6+ months old, taper/dc therapy at 12 months

10 12 mo girl Enlarging left labial mass Growing since 6 months of age US: Probable left labial vascular malformation (aka hemangioma) Recommended: Propranolol vs watchful waiting, vs excision Re-evaluated at 2 yo, still growing US: No change MRI: Large heterogeneous mass Numerous flow voids Uniformly enhancing after contrast Feeding vessels from fem artery Draining vessels into fem vein c/w Hemangioma (?other neoplasm) Path: Hemangioma, GLUT-1+

11 Rapidly Involuting Congenital Hemangiomas (RICH) GLUT1 negative, high flow Present and largest at birth Can be associated with thrombocytopenia and heart failure but NOT Kasabach-Merritt/DIC Treatment is close monitoring

12 Non-Involuting Congenital Hemangiomas (NICH) What s New? PICH = Partially Involuting Present at birth Rim of pallor No proliferative phase nor rapid involution GLUT1 negative Persist over time May be painful

13 NICH/PICH Treatment: Reassurance/monitoring Pulsed dye laser Excision?Medical

14 Kaposiform Hemangioendothelioma (KHE) Very rare (1/100K) Head/neck common Early infancy- childhood Genetics still unknown Expansile Kasabach-Merritt (life threatening) Usually biopsy-proven Relapsing course Multidisciplinary (Heme-Onc) Treatment: Sirolimus (mtor inhibition) Steroids Vincristine Surgical Excision

15 2014 Classification System (Revised from Mulliken & Glowacki, 1982) MALFORMATIONS = ANOMALOUS VESSELS Capillary (CM) Venous (VM) Lymphatic (LM) Arterial (AM) Arteriovenous (AVM or AVF) Combined (CVM, LVM, GVM, etc.)

16 Capillary Malformations What s New J Hum Genet Dec; The somatic GNAQ mutation c.548g>a (p.r183q) is consistently found in Sturge-Weber syndrome. Nakashima M, et al. GNAQ also in non-syndromic CM Treatment typically PDL +/- NdYag laser Early + frequent Ophtho exams Risk SWS only if V1 upper lid/forehead (<10%) In SWS Close neurodevelopmental monitoring Neuro consult/anti-epileptics if indicated +/- early MRI Pediatr Dermatol Jan. Screening for Sturge-Weber syndrome: A state-of-theart review. Zallmann M, et al.

17 7 month girl dx d w Klippel-Trenaunay Multiple vascular patches, becoming darker Asymmetric hypertrophy left foot/toes Developmentally normal, normocephalic s/p PDL with EMLA at outside institution toxicity necessitating PICU admission* MRI: CMs, LLE hypertrophy LLE dilated, tortuous veins (not true VM) No evidence of high flow AM Diffuse Capillary Malformation w Overgrowth (DCMO) Pediatr Emerg Care Seizures and methemoglobinemia in an infant after excessive EMLA application. Larson A, Stidham T, Banerji S, Kaufman J.

18 Venous Malformations Slow-flow Relatively rare Sporadic> familial Present at birth but not always evident Soft, compressible, blue Enlarge with dependency, activity May extend (much) deeper than appear! Aberrant vascular development Path: Poorly circumscribed, irregular endothelial-lined thin-walled vascular channels, few/no smooth muscle cells Genetics: Endothelial cell receptor TIE2 (somatic)/tek - VMCM,?Angiopoietin 1&2

19 Venous Malformations: Complications Head/Neck Cosmetic Bleeding Airway Vision Speech, nutrition Dentition Sleep Soft tissue, bone hypo > hypertrophy Pathologic fractures Pain Extremity Phleboliths Localized intravascular coagulation (D-dimer) Trunk Pulmonary hypertension

20 Venous Malformations: Dx & Management History & Clinical Coagulation profile ( D-dimer, Fibrinogen) MRI: Confirm diagnosis Delineate extent Multidisciplinary approach: Sclerotherapy (Bleomycin) Surgery Laser (NdYag)? Role of aspirin/anticoagulants Compression for extremity lesions: Decreases pain Limits edema Protects epidermis Decreases phlebolith formation

21 Familial Cerebral Cavernous Malformation Syndrome AD w incomplete penetrance CCM1, CCM2, CCM3 KRIT1 Northern NM Q455X mutation Hyperkeratotic VMs Screen w Brain MRI for intracranial involvement

22 Blue Rubber Bleb Nevus Syndrome VMs of skin, GI > other organs Deep blue rubbery blebs, range in size GI bleeding Unknown genetics to date Treatment: Surgery Yag/ablative laser?sirolimus

23 2 yo girl born w blue patch, slowly enlarging over time Asymptomatic but becomes noticeably larger at times s/p multiple IL steroid injections without benefit MRI: Contrast-enhancing c/w hemangioma isolated to lip Underwent surgical excision and laser

24 1 mo baby boy Bluish mass since birth Enlarging, tense at 2 months

25 Lymphatic Malformations No-flow Subtypes: Macrocystic (aka Cystic Hygroma) Microcystic (aka Lymphangioma circumscriptum, Frog Spawn ) Both LYVE-1, VEGFR-3, PROX1 all involved in lymphatic differentiation PIK3CA isolated in majority of both isolated LM and syndromes Likely de novo somatic or germline mosaic mutations J Pediatr Apr; Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. Luks VL, Kamitaki N, Vivero MP, et al.

26 6 yo boy Lifelong facial asymmetry, unchanged Ptosis, superior visual field defect No other ophthalmologic issues Affecting QoL MRI: Mostly microcystic LM No clear cyst >1.5 cm Preseptal in R eyelid Does not involve posterior orbit Extends into infratemporal fossa Flow void? More vascular component

27 Lymphatic Malformations: Diagnosis & Management History & PE Ultrasound with Doppler MRI with contrast Coagulation profile usually normal Sequelae of large lesions depend on location Common complications: Oozing, bleeding Recurrent infection Management based on site & extent Sclerotherapy (Doxycycline, STS foam) Sirolimus Surgery (Laser) Lymphatic Anomalies Registry - Boston Childrens lymphaticregistry@childrens.harvard.edu

28 Sirolimus for LM Disorders of inappropriate activation of the PI3K/AKT/mTOR pathway 2010 Off-label use 2011 Hammill et al. Sirolimus for the Treatment of Complicated Vascular Anomalies in Children 2015 Phase 2 Clinical Trial results Cincinnati Childrens Protocol (Heme-Onc) 0.8 mg/m2 per dose BID, adjusted by checking trough levels Indications? LM, KHE, VM Early impressions: Works best when initiated young Length of ideal treatment unknown

29 Klippel-Trenaunay Syndrome (KTS) Superficial vascular stain (CM) + Soft tissue/bony hypertrophy + Varicose veins, +/- deep anomalies Ie CVM or CLM or CVLM PE, auscultation, palpation & limb lengths Doppler/Duplex MRI (minor or no muscle involvement) Sporadic, PIK3CA NOT Parkes-Weber : Assoc d micro-avf(s) = RASA1 Servelle-Martorell: VM + bone UNDERgrowth Treatment: Ortho evaluation if LLD (>2cm or progressive) Compression PDL/NdYag laser Surgery for symptomatic varicosities Micro-sclerotherapy interventions

30 Teenage girl Larger R buttock at birth by mom Limb hypertrophy early in childhood R leg continued length and girth 2004 Genetics eval: Klippel-Trenaunay Followed by Ortho, s/p Numerous procedures including R tibia wedge osteotomy 6/10 Now pain, fatigue, heaviness Referred by IR: concerning MRI & exam Warm to touch, Doppler +

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32 Arteriovenous Malformations Fast-flow Arterial & venous vessels connected w/o capillary bed Many present at birth, but may not be evident until childhood Head/neck, especially ear/cheek Increased warmth, bruit or thrill is highly suggestive Stages: 1: Quiescent/asymptomatic 2: Progressive/invasive (puberty, trauma, pregnancy) 3: Deep destruction, bone involvement (after yrs) 4: Cardiac decompensation

33 AVM: Diagnosis & Management? Predominance in CNS due to apoptosis-inhibiting milieu? Failure of retiform plexus arteriovenous channels to regress in early fetal development (Angiotensin1) Am J Hum Genet Mar Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation (MEK1 pathway) History & PE (Attention to pain, warmth, hyperkeratosis, bleeding) Auscultation, bedside Doppler MRI with contrast (MRA: confirm fast-flow, extent) Angiography prior to intervention Multidisciplinary approach: Embolization +/- surgery Indications: Pain, enlargement, ulceration, bleeding? Avoid partial treatment - May recur & more difficult to manage? Better results if treat Stage I?

34 15 yo girl born with red patches on L foot to leg Dx d w Klippel-Trenaunay in Mexico Recent profuse bleeding after minor injury in PE On exam, warm-hot, hypertrophic, Doppler + Multiple foci of AVM in ankle, knee and thigh S/p Onyx embolization; subsequent amputation Ongoing treatment

35 15 month old boy LLE overgrowth + CM Warm, nontender, Doppler + L foot very slightly cooler than R AVM: intramuscular arteriolovenular microshunting CM-AVM RASA1+ Risk of intra- and extracranial AVM Variable expressivity Brain/spine imaging normal

36 10-year-old boy Multiple vascular malformations, lipomas Overgrowth of the hands, feet, trunk s/p surgical debulking/excision symptomatic lesions Most consistent with CLOVES syndrome

37 CLOVES Syndrome Congenital, Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis/Skeletal/Spinal anomalies Somatic mosaicism postzygotic activating mutations in PIK3CA Extremely rare (n 100?), variable signs/symptoms 1. Fatty Truncal Mass: Usually at birth Back, abdomen, groin, may extend in chest, abd, spinal canal Covered with red-pinkish CM 2. Vascular Anomalies: Abnormal lymphatic and venous channels Sometimes more aggressive AVM (spinal) 3. Abnormal extremities and scoliosis : Very wide hands or feet, large fingers or toes, wide space between digits and uneven size of extremities 4. Skin abnormalities: Prominent veins, capillary/venous/lymphatic malformations, and epidermal nevi 5. Other abnormalities: Small or absent kidney, abnormal patella, knee and hip joints. Dx can be established right after birth; possibly prenatal with imaging

38 It can be very challenging 1 month old baby boy Referred from pediatrician 3 hours away Extensive capillary/venous malformations, lipomatous hypertrophy, epidermal nevi, normal head size CLOVE syndrome Staged discussion with parents Required building relationship over time Gatekeeper Role for Dermatology Multidisciplinary care IR ablation of anomalous vessels CO2 laser of surface bleeding plaques Sirolimus ongoing Partial amputation

39 9 yo boy Multiple CMs over face, trunk and extremities (R leg) since birth R leg progressively smaller and shorter Numerous pulsed dye laser with benefit at another institution Macrocephaly, truncal dysmorphology, learning disability Previous diagnosis Klippel-Trenaunay M-CM

40 Macrocephaly-Capillary Malformation (MCM) aka Megalencephaly-Capillary Malformation- Polymicrogyria Syndrome (MCAP) Macrocephaly Congenital macrosomia Extensive cutaneous CMs Body asymmetry (lipomatous) Extra/fused fingers/toes Lax joints Doughy skin Variable dev delays Other neuro, eg seizures, hypotonia PIK3CA

41 SOME THINGS I VE LEARNED MIMICKERS

42 11 mo boy Isolated mass since birth Progressively enlarging, nontender Outside MRI: c/w LM

43 US-guided sclero x 2, some improvement Lesion refilling Surgical excision Path demonstrated Dermoid Cyst

44 Teenage girl Lifelong h/o hemangioma Progressively enlarging, affecting QoL Multiple cutaneous lesions NF1

45 QoL & Vascular Anomalies Little objective data on QoL and vascular birthmarks other than hemangiomas Marked QoL impact in multiple domains Better more specific data/indices needed Consider parental/patient response, different at different ages Need to ask (or project empathy) in order to know! Validate concerns Recognize/confirm parental reaction(s) as a normal phenomenon Project confidence, knowledge, experience; misinformation is a common situation Express commitment to long term care Seek outside help within dermatology, behavioral health, online, and multidisciplinary

46 Lifelong chronicity and Multidisciplinary care Often our role as dermatologists is: Appropriate diagnosis Parental assistance Organizing and/or executing on referrals Ensuring multispecialty care when needed Critical role of radiologic interpretation Vascular anomalies centers for more complex situations Outside resources National Organization of Vascular Anomalies (NOVA) ISSVA Vascular Birthmarks Foundation Ideally QoL (both parental and patient) should be a metric assessed at each visit Treatments should be undertaken to alleviate QoL impairments

47 Dermatopathology ENT- Facial Plastic Surgery Pediatric ENT Who we are Dermatology Neuro- Surgery Pediatric Heme-Onc Pediatric Radiology Interventional Radiology Genetics Plastic Surgery Neuro- Interventional Radiology Pediatric Ortho Oculo- Plastics

48 Tell them what you told them Vascular Tumors Infantile vs Congenital Hemangiomas Propranolol guidelines KHE Vascular Malformations Low or no flow: CM (DCMO, SWS), VM, LM (Macro vs Micro), Combined High flow: AVM/AVF Emerging role of sirolimus Genetic Syndromes PIK3CA-overgrowth CLOVE MCM Klippel-Trenaunay (CLVM) RASA (CM-AVM) TIE2 (VM, MCVM) Beware mimickers Know your radiologist/pathologist Remember QoL as a driver for treatment Need for multidisciplinary care

49 ISSVA Abbreviated Classification

50 It takes a village Thank You! asmidt@salud.unm.edu