Lymphovascular lesions

Question 1

Define vascular malformation vs. vascular tumors.

Outline 4 differences between vascular malformation and vascular tumors

Answer 1

Vascular Malformation: Early embryonic disorder in vasculogenesis that contains all vessel types and may be associated with genetic defecits.

Vascular tumors: Mostly benign (but some malignant) disorder of vascular development that may contain some neoplastic features.

Vascular Malformations are:
1. Present at birth
2. Grow with child
3. Do NOT involute
4. Grow by cellular hyperTROPHY (increase in cell size)

Vascular Tumors are:
1. Present AFTER birth
2. Rapid EARLY growth phase
3. Generally involute (at least partially)
4. Grow by cellular hyperPLASIA (increase in cell number) and proliferation

Question 2

What are some syndromes or conditions that are associated with vascular tumors?

Answer 2

PHACE syndrome
Kasobach-Merritt phenomenon - profound thrombocytopenia

Question 3

What are some syndromes associated with vascular malformations?

Answer 3

1. HHT
2. Sturge-Weber
3. Maffuci
4. Von Hippel Lindau
5. PHACES
6. Blue rubber bleb
7. Klippel Trenaunay

Question 4

Describe the classification system for vascular anomalies

Answer 4

Vascular Anomalies –> Vascular tumors vs. Vascular Malformations

Vascular tumors:
- Benign:
— Hemangiomas (infantile hemangioma, RICH, NICH, PICH)
— Pyogenic granuloma (lobular capillary hemangioma)
— KHE/TA (Aggressive/low-grade malignant)
- Malignant:
— Angiosarcoma
— Hemangiopericytoma

Vascular Malformations:
- Capillary malformations
- Venous malformations
- Lymphatic malformations
- Arteriovenous malformations
- Combined/mixed malformations (AVM, CL, VL, CVL)
- Low flow (lymphatic, venous)
- High flow (AVM)

Question 5

What are high flow vs. low flow vascular malformations

Answer 5

Low flow - lymphatic, venous
High flow - AVM (anything with artery)

LOW FLOW:
1. Capillary
2. Venous
3. Lymphatic (microcystic, macrocystic, mixed)
4. Combinations

HIGH FLOW:
1. Arterial
2. Arteriovenous

Question 6

What is the ISSVA classification of vascular tumors?

Answer 6

Benign vascular tumors
- Infantile hemangioma/hemangioma of infancy
- Congenital hemangioma (RICH - Rapidly involuting RICH, NICH non-involuting, PICH - Partially involuting
- Tufted angioma
- Spindle-cell hemangioma
- Epithelioid hemangioma
- Pyogenic granuloma (aka lobular capillary hemangioma)
- Others

Locally aggressive or borderline vascular tumors
- Kaposiform hemangioendothelioma
- Retiform hemangioendothelioma
- Papillary intralymphatic angioendothelioma (PILA), Dabska tumor
- Composite hemangioendothelioma
- Kaposi sarcoma
- Others

Malignant vascular tumors
- Angiosarcoma
- Epithelioid hemangioendothelioma
- Hemangiopericytoma
- Others

Question 7

What is the ISSVA classification of vascular malformations?

Answer 7

SIMPLE
- Capillary malformations (C)
- Lymphatic malformations (LM)
- Venous malformations (VM)
- Arteriovenous malformations (AVM)
- Arteriovenous fistula

COMBINED
- CVM, CLM
- CLM, CLVM, CAVM
- CLAVM

Question 8

What is the most common vascular tumor?

Answer 8

Hemangioma of infancy (HOI) aka. Infantile hematioma - affects 1 in 10 white infants in North america

Question 9

What is the most common vascular malformation?

Answer 9

Lympahtic malformation

Question 10

Differentiate Hemangioma and Vascular malformations with respect to:
1. Seen at birth
2. Gender distribution
3. Race distribution
4. Growth pattern
5. Exam feature
6. Bony involvement
7. Histology

Answer 10

1. Seen at birth
   - Hemangioma: Usually No
   - VM: Always
2. Gender distribution
   - Hemangioma: Female > Male
   - VM: Equal
3. Race distribution
   - Hemangioma: White
   - VM: Equal
4. Growth pattern
   - Hemangioma: Rapid growth, slow regression
   - VM: Proportional with child
5. Exam feature
   - Hemangioma: Firm and rubbery
   - VM: Compressible
6. Bony involvement
   - Hemangioma: Rarely involves bone or cartilage
   - VM: May cause significant hypertrophy and distortion of craniofacial skeleton
7. Histology
   - Hemangioma: Proliferating endothelial cells and increased mast cells
   - VM: Mature endothelium with normal mitotic activity and no mast cells

Question 11

What are 9 risk factors for hemangioma of infancy?

Answer 11

1. Female (3-6:1)
2. Low birth weight
3. Premature
4. Hereditary component
5. White
6. Advanced maternal age
7. Multiple gestation
8. CV sampling history
9. Placental anomalies

Question 12

1. What is the epidemiology of infantile hemangioma?
2. What are the clinical characteristics/categories of how infantile hemangiomas present?
3. How does it usually present?

Answer 12

Epidemiology:
1. F:M 3-6:1
2. 20% multiple
3. 50% with subglottic lesion will have cutaneous lesion, but only 1% true in reverse

Appears ~2 weeks of age, absent at birth

Appearance: Superficial vs. Deep vs. Combined “Compound”
- Superficial: Soft, red, raised
- Deep: Spectrum of appearance and consistency (soft and supple; raised and firmer warm masses with bluish color)
- Combined “Compound”: Both red epidermal colouration and subcutaneous mass that is either blue or flesh coloured

Number: Focal vs. Segmental vs. Diffuse/multifocal
- Focal: single discrete lesion (H/N focal lesions relate to embryonic fusion lines)
- Segmental: Dermatome distribution (usually superficial, related to neural crest cells), increased morbidity
- Diffuse/multifocal

Question 13

What are two warning signs to be concerned about for infantile hemangioma?

Answer 13

1. ≥ 6 cutaneous hemangiomas = increased risk of visceral hemangiomas, increased risk of hepatomegaly, GI bleeding, profound hypothyroidism, anemia, or congestive heart failure
2. Beard Distribution or lesion of Hyoid = 60% risk airway lesion

Question 14

What are the 3 stages of infantile hemangioma? Describe them.

Answer 14

1. Proliferation/Active growth (2 weeks to 4-10 months; deep lesions up to 2 years; segmental lesions ~18 months)
   - Proliferating endothelial cells (that eventually apoptosis -> vascular network eventually replaced by fibrofatty tissue)
   - Large number of pericytes, mast cells, and fibroblasts
2. Quiescence: Growth stabilizes
3. Involution/Tumor Regression
   - ~12-18 months and can last up to 5-6 years
   - Colour fades (grayish or dull purple)
   - Maximum involution occurs in 50% of children by 5 years, 70% by 7 years, and 90% by 9 years
   - Segmental lesions do not completely regress

Question 15

What are the specific markers of infantile hemangioma proliferation?

Answer 15

1. Serum and urinary vascular endothelial growth factor (VEGF)
2. Urinary beta-fibroblast growth factor (b-FGF)
3. Urinary matrix metalloproteinases (MMPs)

Question 16

What are 4 immunohistochemical markers of infantile hemangiomas (endothelium surface markers)? What are the other histology features?

Answer 16

1. GLUT-1- Present only in infantile hemangiomas and placenta, which differentiates from other types of hemangioma
2. Lewis Y antigen (LeY: present but not specific)
3. Fcy-RIIb
4. Merosin

Other histology features:
- Proliferating endothelial cells
- Increased mast cells

Question 17

Describe the MRI characteristics (T1, T2, Contrast, Gradient) of the following vascular anomalies:
1. Hemangioma
2. Venous malformation
3. Lymphatic malformation
4. Arteriovenous malformation

Answer 17

Hemangioma:
1. T1-Weighted: Soft tissue mass, isointense or hypointense, with flow voids
2. T2-Weighted: Lobulated soft tissue mass, increased signal (bright), flow voids
3. Contrast: Uniform intense enhancement
4. Gradient: High-flow vessels within and around soft tissue mass

Venous Malformation:
1. T1-Weighted: Isointence to muscle, possible high-signal thrombi
2. T2-Weighted: Septated soft tissue mass, high signal, signal voids (phleboliths)
3. Contrast: Diffuse or inhomogeneous enhancement
4. Gradient: No high-flow vessels

Lymphatic Malformation:
1. T1-Weighted: Septated soft tissue mass, low signal
2. T2-Weighted: Soft tissue mass, high signal, fluid levels
3. Contrast: RIm enhancement or no enhancement
4. Gradient: No high-flow vessels

Arteriovenous malformation:
1. T1-Weighted: Soft tissue thickening, flow voids
2. T2-Weighted: Variable increased flow voids
3. Contrast: Diffuse enhancement
4. Gradient: High-flow vessels through abnormal tissue

*Arterial and hemangioma are high flow; venous and lymphatics are low flow

Question 18

Describe PHACES Syndrome.
For patients with hemangiomas, when should you workup for PHACES syndrome?
How should patients with PHACES be managed?
What are the risks of PHACES syndrome?

Answer 18

PHACES SYNDROME:
P: Posterior fossa or intracranial abnormalities (e.g. cerebellar hypoplasia, Dandy-walker malformation)
H: Hemangioma (segmental at high risk of PHACES, especially if on forehead, temple, upper cheek, periorbital area; or airway hemangioma); Note: Segmental lower face + PHACES = 50% risk of airway hemangioma
A: Arterial lesions (aneurysms, congenital valvular aortic stenosis)
C: Cardiac abnormalities/aortic coarctation (e.g. TOF, MVR, VSD)
E: Eye abnormalities (e.g. Esotropia, congenital cataract, micropthalmia, abnormal retinal vessels)
S: Sternal cleft or supraumbilical raphes, or other ventral clefts
Other signs: Cranial neuropathies, rarely CPA lesions (hearing loss)

High Risk for consideration of PHACES workup:
1. Large segmental hemangioma
2. Facial hemangioma > 5cm

Workup of PHACES patients:
1. Ophthalmology referral
2. Neurology referral
3. ECHO
4. MRI or MRA of head/neck/chest

Risks of PHACES:
- >50% have neurologic sequelae (e.g. seizures, stroke, developmental delay, migraines)
- Some recommend antiplatelet treatment if abnormal cerebral vasculature to prevent stroke

Question 19

What are complications that can be associated with hemangioma of infancy? What presentation of HOIs are these complications greater?

Answer 19

Greater risk of complications = large, segmental, multifocal

Complications:
1. Life-threatening obstruction (e.g. airway, nasal)
2. Functional obstruction: Swallowing (feeding difficulties), Vision (deprivation amblyopia, astigmatic amblyopia), Ears
3. Bleeding, ulceration, infection/chronic wound
4. Scarring (early proliferation - excess tissue/altered bone - can cause permanent disfiguration)
5. Psychosocial
6. High-output cardiac failure if large (especially for parapharyngeal or scalp regions, due to increased blood flow)
7. Consumptive Coagulopathy (Kasabach-Merritt syndrome) - leading to profound thrombocytopenia

Question 20

Describe conservative and medical management options for hemangioma of infancy.

Answer 20

Conservative: Observation (if no complications) - most involute

MEDICAL OPTIONS:
1. First line for HOI that impair function or if observation undesirable = Propranolol 1mg/kg BID x 6-18 months or 2mg/kg/day TID (should see response within days of treatment)
- MOA: Speculative, may involve downregulation of angiogenic factors and upregulation of apoptosis (decrease blood vessel density)
- Risks (thus require monitoring for first 48 hours): Hypoglycemia, hypotension, bradycardia, asthma attack/severe bronchospasm
- Side effects: Sleep disturbances, agitation, peripheral coldness
- Indications for initiating treatment as an inpatient: Airway lesions, young patients < 2 yo, Abnormal cerebral vasculature 2o PHACES, Comorbidities

2. Topical Beta-Blocker (e.g. Timolol)
   - Useful for small superficial hemangiomas
3. Steroids
   - Indications: Patients who fail propranolol
   - Application: Intralesional injection in small focal hemangioma (especially periorbital region, nasal tip, subglottis)
   - Preparation: Combining long-acting (triamcinolone acetonide) and short-acting (betamethasone acetate) to a volume ≤ 2.5mL (depending on size of lesion)
   - Complications: adrenal suppression, FTT, periorbital injection - risk of retinal artery embolization and thrombosis –> blindness (use fundoscopic retinal examination as injecting)
   - Dosage PO: 2-3mg/kg/d x 7 d, if responsive then taper 4-6 weeks up to 10 months)
   - Dosage Intralesional: Triamcinolone 40mg or Betamethasone 6mg q4-6 weeks x 1-5 times, avoid periorbital
4. Interferon-a
   - Risks: Spastic Diplegia
   - CNS is more vulnerable under 1 year old
   - Can be daily SQ x 6+ months
   - Significant side effects - largely replaced now by Vincristine
5. Vincristine
   - For beta blocker or steroid unresponsive disease (replacing IFN-alpha)
   - Risks: Polyneuropathy (e.g. HL, facial nerve palsy, vocal cord paralysis)
6. Cyclophosphamide

Question 21

Discuss surgical options for treatment of hemangioma of infancy

Answer 21

1. Laser (PDL):
   - Purpose: Reduce coloration, not bulk
   - Timing: Used at the end of the involution phase to reduce residual vascular markings
   - Type of HOI: Superficial (ineffective for deep)
   - MOA: Promote healing, reepithelialization, and pain for control for ulcerated hemangiomas
   - Laser: CO2 and Nd:YAG (Neodymium-doped yttrium aluminum garnet) for airway hemangiomas –> risk of scarring and subglottis stenosis
   - Risks: Often need multiple treatments, scarring and ulceration if age < 6 months
2. Surgical Excision:
   - Indications: Unresponsive to medical treatment, complications of HOI or functional compromise (vision, hearing), poor scarring, ulcerated or bleeding lesions, incomplete resolution (especially by school age - psychosocial), large hemangiomas (large amounts of fibrofatty tissue or excessive skin), high output cardiac failure
   - Timing: Defer until proliferation phase is complete
3. Photocoagulation (q4-6 weeks, early proliferative phase and superficial lesions
4. Cryotherapy
5. Tracheostomy
6. Laryngotracheoplasty

Question 22

What is the protocol to iniate propranolol therapy for hemangiomas of infancy. Describe the inpatient and outpatient protocols

Answer 22

Inpatient protocol:
1. Preadmission diagnostic testing: ECG to rule out arryhthmia; ECHO if family history of murmur, FTT, or significant comorbidity
2. Admit to telemetry unit with continuous HR and BP monitoring
3. Initiate Propranolol at 0.5mg/kg PO BID x 2 doses, then increase to 1mg/kg for 2 doses, then finally to 2mg/kg PO BID (as long as no side effects)
4. Check blood glucose 2h after each dose
5. Check ECG 24h after initiation
6. Discharge after second dose at 2mg/kg with contact information
7. Parents are instructed to maintain strict feeding regimen. If < 6 months, feeding should be every 2-4h. Older children can be spaced to every 6-8h
8. Parents instructed to hold medication if child becomes ill or has decreased PO intake

Outpatient Protocol:
1. Diagnostic testing: ECG/ECHO as above
2. Monitor on unit for 6h with BP and HR monitoring
3. Initiate propranolol at 0.5mg/kg
4. Check blood glucose 2h dose of propranolol
5. Discharge instructions provided
6. Continue propranolol at 0.5mg/kg PO BID x 1 week
7. Return to hospital for 6h admission on telemetry to increase propranolol to 1mg/kg. ECG done prior, glucose checked 2h after. Discharge home at this dose for a week
8. Repeat the same process with 2mg/kg; then follow up in 4 weeks

Question 23

What are the side effects of Propranolol therapy for HOI?

What are the contraindications?

Answer 23

SIDE EFFECTS:
1. Bradycardia
2. Hypotension
3. Hypoglycemia
4. Bronchospasm
5. Rash
6. Gastrointestinal discomfort/reflux

CONTRAINDICATIONS:
1. Cardiogenic shock
2. Sinus bradycardia
3. Hypotension
4. > 1st degree heart block
5. Heart failure
6. History of bronchospasm or wheezing (Reactive airways/bronchial asthma)
7. Hypersensitivity to propranolol
8. Preterm infants with corrected age < 5 weeks
9. Caution in PHACES syndrome (can have cardiac/stroke complications)

Question 24

What is the most common location for an airway hemangioma?

Answer 24

Left posterolateral subglottis

Question 25

Regarding subglottic hemangiomas, discuss:
1. What % of airway hemangiomas also have cutaneous hemangiomas?
2. What type of subglottic hemangioma is safest to biopsy and use CO2 laser for resection?
3. What is the potential complication of laser of subglottic hemangioma?

Answer 25

SUBGLOTTIC HEMANGIOMA:
- 50% of airway hemangiomas also have cutaneous hemangiomas

TYPES OF SUBGLOTTIC HEMANGIOMA:
- Capillary: Less color to lesion, smaller vessel size, able to use laser and safer to biopsy
- Cavernous: Dark red/blue, bleed with biopsy, difficult to control with CO2 laser

COMPLICATION:
1. Subglottic stenosis

Question 26

What % of cutaneous hemangiomas also have airway lesions?
What factors increase the risk?
When do they usually occur?
What are the typical symptoms?
How is it diagnosed?
What is the treatment for airway hemangiomas?

Answer 26

1-2% cutaneous hemangiomas also have airway lesions

Risk Factors:
1. Hemangioma of infancy in beard distribution
2. Lesion overlying hyoid

Usually occur within first 6 months of life; the earlier the presentation the more likely will require surgical intervention

Symptoms: Progressive stridor/retractions

Diagnosis: Rigid Bronchoscopy

Treatment:
1. Emergent = secure airway + avoid trach if possible (compressible with a small ETT)
2. Propranolol
3. Focal: steroid injection, laser ablation, surgical excision
4. Circumferential/segmental ± adjacent cervicofacial –> possible trach (difficult); Steroid injection or laser one side at a time to prevent stenosis

Question 27

Regarding congenital hemangiomas, discuss:
1. What type of vascular anomaly are they?
2. What are the types?
3. What is the difference between congenital hemangiomas and hemangioma of infancy?
4. How do they typically present?
5. What is the treatment?

Answer 27

What is it?
- High flow vascular tumor

How does it differ from infantile hemangioma?
- Present at birth (vs. absent for HOI)
- Absent GLUT-1, but otherwise histologically similar
- Medical treatmnet less effective

Types of Congenital Hemangiomas:
1. Rapidly Involuting (RICH): Involute by 12-14 months of age, leaves residual patch of thin skin with prominent veins and little to none subcutaneous fat
2. Non-involuting (NICH): Does not involute
3. Partially involuting (PICH)

Clinical Presentation:
- Predilection for head or limbs
- Present as solitary violaceous lesions at birth
- Rarely co-exist with infantile hemagnaiomas
- < 3% of all hemangiomas
- Grow proportionally with patient

Histology:
1. GLUT-1 negative (HOI is positive)

Treatments:
1. Observation
2. Laser
3. Surgery
*Typically don’t respond to medical treatment; RICH tend to observe, NICH may need laser/surgery

Question 28

Regarding Kaposiform Hemangioendothelioma (KH), discuss:
1. What is it?
2. What is the clinical presentation?
3. How is it diagnosed?
4. What are the treatment options?
5. What are the possible complications associated with this entity? How is it worked up and treated?

Answer 28

• Aggressive non-hemangioma vascular tumor, therefore considered low-grade malignant
• Other non-hemangioma vascular tumor = tufted angioma (TA)

Clinical Presentation:
- Rarely occur in head/neck area (usually in extremities
- KH can occur anywhere on H/N with significant lymphatic component in addition to vascular endothelium
- TA typically more localized ± skin involvement
- Violaceous nodules extending into deep tissues
- Lymphatic and vascular component

Diagnosis/Workup:
1. Radiographically: Diffuse infiltrative vascular process
2. Incisional biopsy ± Immunohistochemical staining

Treatment:
1. Curative surgical resection
2. Chemotherapy (antiangiogenic): Sirolimus, Rapamycin

Complications:
1. Bone Resorption/Osteopenia (Gorham Syndrome –> proliferation of vasculature and lymphatics overtaking bone causing local bony destruction)
2. Kasabach-Merritt Phenomenon (KMP) - associated with KH and TA, and also HOI
- Tumor traps (sequesters) and destroys platelets
- Associated coagulopathies
- As tumor increases in size –> increase platelet trapping (consumptive coagulopathy) –> profound thrombocytopenia
- Workup: CBC, smear, coagulopathy profile (factors, fibrinogen, d-dimer, protein c/s), r/o SLE (APA), r/o other coagulopathies (e.g. factor V leiden)
- Treatment: Chemotherapy - Vincristine, Sirolimus (replacing IFN-A2a); AVOID PLATELET TRANSFUSION (consumptive); supportive care, steroids, pRBCs for anemia (limit unless bleeding), RT or embolization may be used

Question 29

Regarding pyogenic granulomas, discuss:
1. What are they?
2. Where are they commonly located?
3. What are the risk factors?
4. What are the typical symptoms?
5. What are the imaging findings on MRI? Histology findings?
6. What is the typical treatment?

Answer 29

What is it?
- More accurate name: Lobular capillary hemangioma
- Benign vascular tumor of skin or mucous membranes
- Proliferation of capillaries arranged in lobules and separated by loose connective tissue strome
- Small capillary hemangioma arising on skin and mucosal surfaces (e.g. gingiva, fingers, lips, face, nasal cavity 60% septum, and tongue)

Most common location = oral cavity/lip 40%; 10-30% nasal cavity

Causes unknown but may be triggered by trauma, meds, hormones.
Risk Factors:
- Pregnancy
- Hormonal changes (e.g. puberty, OCP)
- Chronic trauma
- Underlying microscopic AVMs
- Local angiogenic growth fator production
- M > F in children (F > M in adults)
- More common in adolescent males

Symptoms:
- Rapid growth, friable surface that frequently ulcerates and bleeds, red to purple mass, < 1cm
- Epistaxis/bleeding
- Nasal obstruction
- Pain

Imaging:
- T2 hyperintense, T1 hypointense
- Enhancing with GAD (T1)

Histology: Aggregate of capillaries in lobules

Treatment:
1. Observation: often spontaneously involute
2. Excision: often recur
- Surgical excision with cautery of the base
- Pulse dye laser or CO2 laser for cosmetically sensitive areas

Vancouver Page 29

Question 30

Regarding Capillary Malformations, Discuss:
1. What is the common clinical presentation?
2. What are the Grades of capillary malformation?
3. What is the treatment?
4. What are the common associations? List and describe 3 syndromes

Answer 30

Capillary malformations = cutaneous capillary dilatations
*Most common occuring subgroup of vascular malformations

Clinical Presentation:
- Two most common capillary malformations = salmon patches (nervus simplex) and port-wine stain (nevus flammeus)
- Frequently mid+upper face
- Progressively darker + thicker with age (due to local tissue hypertrophy, hamartomatous nodule)
- 85% limited to single dermatome
- 0.3% newborns have port-wine stains
- M=F

Grades:
1) Light pink macule = vessel diameter < 80µm
2) Pink macule < 120 µm
3) Red macule < 150 µm
4) Thick purple macule, may be papular (“cobblestoning) > 150 µm

Treatment:
1. Serial pulsed-dye laser

ASSOCIATIONS:
1. Wyburn-Mason Syndrome
- Port-wine stains associated with unilateral AVM of the retina and intracranial optic pathway

2. Sturge-Weber Syndrome (aka. Trigeminal Encephaloangiomatosis)
   - Genetics: Sporadic (not hereditary) mutation in GNAQ gene (Ch. 9)
   - Signs: trigeminal V1 CM, retinal and choroidal CM (glaucoma - 10-30%), leptomeningeal angiomas and vascular malformations (leads to ischemic cortical atrophy)
   - CM mature endothelial lining without hypercellularity - present at birth and grows proportionally
   - Symptoms: Progressive neurologic problems, migraines, stroke-like episodes, learning difficulties, mental retardation, visual field impairment, hemiparesis, seizures
   - Workup: Ophthalmology consult, brain MRI or CT (especially if patient has upper face/eyelid CM)

MRI findings (usually appear > 2 years):
- Leptomeningeal enhancement

CT Findings (usually begin to appear > 2 years):
- “Tram Tracking” cortical calcifications = parallel calcification of cortex
- Brain atrophy/volume loss
- Overgrowth of the craniofacial skeleton = “Cross-bite” deformity

Treatment:
- Symptomatic/supportive
- PDL - halt progression, mitigate the red colouration
- Nd:YAG laser
- Surgical debulking
- Medication treat comorbidities

3. Klippel-Trenaunay Syndrome (aka. Angio-Osteohypertrophy)
   Triad of:
   - Port wine stain / vascular nevi
   - Varicose veins
   - Osteohypertrophy (hypertrophy/hyperplasia of local soft tissue + bone)
   Genetics: Sporadic, PIK3C4 (some say unknown?
   Symptoms: Extensive extremity CMs (port-wine stain) with associated limb overgrowth
   Treatment: Symptomatic/supportive (pressure garments, debulking, clot prevention)

Pics: Kevan’s Question 9
Vancouver 493 Sturge Webber

Question 31

Regarding Venous Malformations, discuss:
1. What are they?
2. How do they typically present?
3. Any associations?
3. What are the symptoms?
4. Imaging findings?
5. Treatment?

Answer 31

What are venous malformations?
- Defect in smooth muscle layer of vessels
- Tangled abnormal blood vessels with low-flow blood

Clinical Presentation:
1. Superficial (intradermal or subcutaneous) vs. Deep (intramuscular or intraosseous)
2. Spectrum from very subtle (“stork bite”, “angel-kiss”, “salmon patch”) to severe

Venular Malformation (e.x. Stork bite)
- Pale pink patch, often mistaken for capillary malformation
- Disappears by 1 year (as overlying skin thickens)
- No treatment

Venous Malformation
1. Genetics: Associated with Tyrosine kinase receptor dysfunction (TEK gene mutation)

2. Symptoms:
   - Present at birth, slowly enlarge, can be inflamed/painful and enlarge quickly with puberty/trauma
   - Intracranial/skull base extension may occur, especially with periorbital lesions
   - Bluish compressible mass with no palpable thrill or audible bruit
   - Enlarge in a dependent position (e.g. Valsalva, high cardiac output)
   - Pain may be secondary to adjacent nerve irritation, or localized intravascular coagulation (LIC) - this can be diagnosed via increased D-dimer and decreased Fibrinogen, and treated with ASA/antiinflammatory or heparin + Heme consult
3. Imaging: MRI - low flow, bright T2, signal voids (phleboliths - calcified areas within veins)
4. Treatment
   - Sclerotherapy (only for low flor - washes away in high-flow lesions)
   - Laser (PDL for shallow, ND:YAG for deep)
   - Surgical excision with pre-op embolization (need to r/o coagulopathy first)
   *Difficult to eradicate, bleeds easily, often recurs

Question 32

Regarding Sclerotherapy, discuss:
1. What is it/how does it work?
2. List 5 different agents that can be used and their main risks of use
3. What type of lesions are best suited for sclerotherapy?
4. List the toxicities, minor, and major complications

Answer 32

Sclerotherapy = injection of locally irritating substances to promote irritation and sclerosing of cavity endothelium; often requires multiple treatments

AGENTS:
1. Sodium Tetradecyl Sulface (Sotradecol) - risk hyperpigmentation
2. Pure EtOH - effective but ++ burning pain with injection, neuropathy
3. Doxycycline
4. Bleomycin - risk pulmonary fibrosis
5. OK-432 (Picibanil - low virulence Strep pyogenes strain + penicillin) - less toxicity and scarring

Best types of lesiosn for use:
- Sclerotherapy only used for low-flow lesions, as high flow lesiosn would wash it away
- Macrocystic lesions > 2cm (ineffective for microcystic lesions)

Toxicity:
1. Pulmonary fibrosis (bleomycin)
2. Permanent nerve injury (ethanol)

Minor complications:
1. Skin blistering/loss
2. Fever
3. Erythema
4. Pain at injection site

Major complications:
1. Sepsis
2. Stroke
3. Shock
4. Seizures

Question 33

Regarding lymphatic malformations, discuss:
1. What is the epidemiology in the head/neck
2. What is the genetics? What are the common associated syndromes?
3. What are the common symptoms?
4. What is the histology?

Answer 33

Epidemiology:
- Most common type of vascular malformation
- 45-52% in H/N

Symptoms:
- Soft doughy bulge, normal overlying skin
- Mucosa: small white vesicles
- Present from birth, but may not be initially apparent
- May grow or worsen with infection/trauma
- Posterior cervical lesions arising in perinatal period may be associated with Turner syndrome
- Prenatal lymphatic malformations associated with chromosomal abnormalities (post-nasal are generally not)

Genetics: P1K3CA gene –> P13K enzyme

Associated syndromes:
- Turner syndrome
- Down syndrome
- Klinefelter syndrome
- Trisomy 18, 13
- Noonan syndrome
- Fryns syndrome
- Multiple pterygium syndrome
- Achondroplasia

Histology: Abnormally dilated lymphatic channels

Question 34

What are the types of lymphatic malformations and how do they differ in their clinical presentation?

Answer 34

A. MACROCYSTIC (Spaces ≥ 2cm)
- Smooth, translucent masses under normal or bluish skin
- Usually infrahyoid, below mylohyoid
- If suprahyoid, usually lateral to lateral canthus
- Large suprahyoid lesions often behave unpredictably and have most problematic dysfunction
- Involves the anterior and posterior cervical triagles
- Macrocystic + posterior neck + no septations + infrahyoid = possibly self-resolving

B. MICROCYSTIC (spaces < 2cm)
- Clear, tiny vesicles
- Permeate subcutaneous tissue and muscles
- Suprahyoid (above the mylohyoid), commonly in oral cavity, oropharynx, tongue, parotid, submandibular gland, and pre-epiglottic space
- Clinical presentation (common): Recurrent tongue swelling, persistent tongue hypertrophy, mucosal bleeding, speech difficulty, airway symptoms
- More difficult to treat
- Greater risk of airway compromise
- If suprahyoid + bilateral, tend to be microcystic or mixed with poor treatment response (consider sirolimus)

C. MIXED (>50% macrocystic)
- Commonly medial midface lesions

Question 35

What is the staging system for lymphatic malformations and what is the practical significance of the staging?

Answer 35

De Serres Staging (increasing complication rates)
1. 1 - Unilateral infrahyoid
2. 2 - Unilateral suprahyoid
3. 3 - Unilateral infra + suprahyoid
4. 4 - Bilateral suprahyoid
5. 5 - Bilateral infra + suprahyoid

Seattle modification adds to the above
6. 6 - Bilateral infrahyoid
7. 7 - Retropharyngeal
8. M = Mediastinal

Question 36

How are lymphatic malformations typically diagnosed? What is typically seen on MRI imaging?

Answer 36

Diagnosis:
- 60% detected by in utero ultrasound (nuchal thickening and lucency)
- May be followed by pre-natal MRI (planning for delivery)
- No indication for CT (radiation risk with no significant information acquired)

MRI Findings:
- Low flow, therefore no flow voids
- Low intensity on T1
- Bright on T2 (no feeding or draining vessels)
- Septated
- May see fluid-fluid levels (proteinaceous fluid precipitates to bottom)

*All patients with cervical cystic lesions should have a CXR to rule out mediastinal involvement

Question 37

What are complications of lymphatic malformations in the head/neck?
What complications are specific to lymphatic malformations found in-utero?

Answer 37

1. Bony (especially mandibular) overgrowth - cause unknown
2. Lymphocytopenia (especially with large) - cause unknown
3. Bilateral Suprahyoid - risk of airway obstruction (FOM/tongue swelling)
4. Acute cellulitis and/or recurrent cellulitis
5. Airway obstruction
6. Dysphagia
7. Chylothorax
8. Chylopericardium
9. Nerve compression - paresthesia and pain

Large LM found intra-uterine:
- Swallowing obstruction: gastric hypoplasia
- Airway obstruction: pulmonary hypoplasia
- Polyhydramnios
- Often too big to deliver vaginally: required planned (or emergent) C-section
- May require EXIT procedure (Ex-utero intrapartum treatment): Maintain placental connection (max 20min, give mom PGE) while securing airway (ETT, tracheostomy, ECMO, rapid surgical removal of lesion)

Question 38

What are the treatment options for lymphatic malformations in general?

Answer 38

1. Observation
   - Acceptable for unilocular (or near-unilocular), small-ish, non-obstructing, infrahyoid lesions –> may spontaneously involute
   - May also be considered for macrocystic posterior lesions
2. Sclerotherapy
   - Low toxicity, low scarring
   - Good for macrocystic; ineffective for microcystic
   - Aspirate the macrocyst, then inject agent under fluoroscopy
3. Laser
   - CO2 for small microcystic tongue lesions
4. Surgery ± Trach
   - Delayed and/or staged excision (one side at a time) often necessary (especially for Stage II-V) to avoid complications (e.g. post-op obstructing tongue edema)
   - Used if unresponsive to sclerotherapy
   - Cold knife vs. laser if oral cavity/tongue (CO2, Nd:YAG, pulsed dye)
   - Complications: CN injury, great vessel injury, tongue edema, trach, bleeding, infection, lymphorrhea, recurrence (common - 40%)
5. Antibiotics & steroids for acute infection
   - Minimize swelling/inflammation
6. Sirolimus
   - Mammalian target of rapamycin (mTOR) involved in P13K/AKT pathway
   - Early trials - 82% partial response
   - 27% blood/bone marrow toxicity
7. Radiofrequency ablation (e.g. coblation)
8. Radiotherapy (historical)
9. Dildenafil (new trials)
10. Other surgical techniques: BARDACH procedure (ring of absorbable sutures placed to occlude vascular supply)
11. If detected on prenatal US with possible airway issues = EXIT procedure

Question 39

Discuss the treatment options for microcystic tongue lymphatic malformations

Answer 39

1. CO2 laser
2. Excision
3. Radiofrequency ablation
4. Potentially necessitates tracheostomy
5. Sclerotherapy only for macrocystic

*Intralesional steroid injection is ineffective!

Question 40

Regarding Arteriovenous Malformations, discuss:
1. What is it?
2. What is the genetics?
3. What are the causes?
4. What is the clinical presentation?
5. How is it diagnosed? What is seen on MRI?
6. Discuss the clinical stages/natural history
7. What are the complications
8. What are the treatment options?

Answer 40

What is an arteriovenous malformation?
- High flow congenital vascular malformation
- Variable degree of arteriovenous shuting
- Abnormal communication of arteries & veins that bypass capillary bed (nidus of blood vessels)
- Different than an AV fistula (solitary abnormal communication between an artery and vein, usually acquired secondary to trauma)

Genetics: RAS1 (seen in conjunction with atypical capillary malformations)

Causes:
1. Congenital
2. Traumatic

Clinical Presentation:
- Most common location = cheek, auricle
- Firm, warm, pink/red/purple pulsatile mass
- High flow –> may cause bruit/thrill, tinnitus

Diagnosis: Requires MRI or CT Angiography
MRI Angio findings:
- High flow with flow voids
- Low intensity on T1 & T2
- “Early venous filling” on arteriography = diagnostic

CLINICAL STAGES/NATURAL HISTORY: SCHOBINGER STAGING
1. Quiescent phase (dormant): may be mistaken for another vascular anomalies at this stage (Presents as warm, pink macules)
2. Expansion phase (bruit, thrill, throbbing)
3. Destruction phase (ulcers, bleeding, bony changes)
4. Decompensation phase (LVH, CHF)

COMPLICATIONS:
1. Bleeding, ulceration, skin necrosis, scarring
2. Large, high-flow –> high-output cardiac failure
3. Consumptive coagulopathy
4. Bony destruction (pressure erosion)
*without treatment, will continue to grow and eventually become problematic

TREATMENT:
1. Pre-op embolization (maximum 48 hours in advance otherwise will revascularize)
2. Embolization: Metal coils, particles, and glue (N-butyl cyanoacrylate)
- Lesions only within bone may be treated with just embolization and no surgery
- Surgery often required if involved soft tissues
3. Surgical excision
4. Amputation - may be needed for extremity lesions
*Recurrence is common

Question 41

Regarding Mafucci syndrome, discuss:
1. What are the classic features?

Answer 41

MAFUCCI SYNDROME:
1. Mulitple venous malformations / hemangiomas, occasional visceral vascular lesions
2. Dyschondroplasia & shortening/deformity of involves bones
3. Chondrosarcoma in 25%

Question 42

Regarding Von-Hippel Lindau syndrome (VHL), discuss:
1. What is the inheritence and genetics?
2. What are the features?

Answer 42

GENETICS/INHERITANCE:
1. Autosomal dominant
2. Gene: Mutation in VHL gene, chromosome 3p25

FEATURES:
1. Hemangioblastomas of CNS + retinas
2. Renal cysts/Carcinoma
3. Pheochromocytoma
4. Pancreatic cysts
5. Epididymal papillary cystadnome
6. Endolymphatic sac tumors in 11% (if hearing loss present = 60% chance)

One of the few syndromes that can have paraganglioma and pheochromocytoma. Others are:
1. MEN2
2. NF1
3. Familial paraganglioma pheochromocytoma syndrome

Vancouver 494