Lymphovascular Anomalies Flashcards
A one-year old patient is brought to you for evaluation. According to the parents the patient developed a raised erythematous lesion a month ago. It was noted that the lesion doubled in size since. On physical examination, you have a 2 cm elevated reddish lesion with well-defined borders that is non-tender on palpation. What would you recommend for this patient?
a. do angiography
b. inject intralesional steroids
c. excision
d. observation
d. observation
How are vascular anomalies classified?
In 1996 the International Society for the Study of Vascular Anomalies (ISSVA) adopted a classification system proposed in 1982 by Mulliken and Glowacki, and most recently expanded it at the General Assembly in Amsterdam, the Netherlands in 2018.
The ISSVA classification system (Fig. 15.1) divides lesions into two categories—tumors and vascular malformations—and then further categorizes them based on endothelial characteristics.
Tumors are further divided, into benign, locally aggressive or borderline, and malignant categories.
This classification system can be used to aid providers in predicting the disease course.
Vascular malformations can be simple, combined, associated with major named blood vessels, or associated with other anomalies such as congenital syndromes.
What causes vascular anomalies to develop?
Vascular anomalies usually arise sporadically and are generally not due to germline mutations.
The exceptionally inherited vascular malformation syndromes typically follow an autosomal dominant inheritance pattern.
What is the standard for diagnosing vascular malformations?
Thanks to advances in gene mapping abilities such as next generation sequencing (NGS), many different genes have been identified as the primary mutations that lead to the development of vascular malformations.
A biopsy of the affected tissue should be sent for pathologic evaluation and gene testing, as many vascularmalformation malformations are due to somatic mutations and mosaicism and not germ line mutations.
Many diagnoses are made with a combination of phenotype, radiology studies and clinical history and exam.
What is the best imaging technique for lymphovascular anomalies?
MRI has been recently suggested to be the standard for diagnostic imaging of these complex lesions, especially involving the extremity. Advanced imaging should be performed prior to any invasive procedure such as biopsy, debulking, or sclerotherapy.
What type of vascular malformations are high-flow?
Arteriovenous malformations are characteristically high-flow lesions, similar to flow dynamics seen in surgically created arteriovenous fistulas.
What is Kasabach-Merritt syndrome?
Kasabach-Merritt syndrome is a phenomenon associated primarily with KHE lesions which can create a consumptive coagulopathy and severe thrombocytopenia with platelet count of <30,000.
KMP was first reported in 1940 in a case of profound thrombocytopenia, petechiae, and bleeding in conjunction with a “giant hemangioma.” As with many terms in the field of vascular anomalies, this term has been often misused in connection with coagulopathy and other vascular lesions, most prominently VM. However, the profound and persistent thrombocytopenia that occurs with KMP does not occur with either VM or IH.
The only known true associations are with TA and KHE.
The platelet count with KMP is typically <10,000/μL and may be associated with decreased fibrinogen levels, increased d-dimer, and mildly elevated partial prothrombin time (PT) and partial thromboplastin time (PTT). Bleeding can result from this platelet trapping coagulopathy at many sites, including intracranial, GI, peritoneal, pleural, and pulmonary.
A microangiopathic hemolytic anemia is also present.
Treatment for KHE with KMP is primarily medical as the tumor is usually too large and extensive to be resected.
Corticosteroids and interferon-alfa have been effective in about 50% of cases.
Actinomycin, antiplatelet therapy, cyclophosphamide, doxorubicin, gemcitabine, propranolol, sirolimus, and vincristine have also been found to be beneficial in several case series, as single drugs or in combination, but none of these agents have been shown to be consistently successful.
Platelet transfusions are ineffective and should be avoided unless there is active bleeding.
Additionally, heparin may stimulate tumor growth and worsens the thrombocytopenia of KMP and should likewise be avoided.
Mortality rates with KHE and TA remain high at 20–30%.
KHE not associated with KMP can be followed without treatment as long as the size and location of tumor are limited.
Which vascular tumors are typically benign?
Infantile, congenital hemangiomas, spindle-cell hemangiomas, epithelioid hemangiomas, pyogenic granulomas, and tufted angiomas are typically benign tumors.
Some vascular tumors are locally aggressive and therefore borderline malignant, but classically do not have a risk of distant metastases.
These include Kaposiform hemangioendothelioma (KHE), retiform hemangioendothelioma, Dabska tumor or papillary intralymphatic angioendothelioma, composite hemangioendothelioma, and Kaposiform sarcoma.
Angiosarcoma and epithelioid type hemangioendotheliomas are considered malignant tumors.
What are the stages of growth of infantile hemangiomas?
Infantile hemangiomas classically present at birth or soon after birth as a flat or raised vascular stain that can even be mottled or bruise-like in appearance.
The lesions can be deep or superficial. Soon after the appearance of the lesion, a rapid growth phase occurs with the lesion reaching 80% of its maximal size by 3 months of life.
This is typically followed by a rapid involuting phase.
Most lesions will involute gradually over a period of years and are usually completely involuted by 10 years old.
The dysregulation of angiogenesis can be seen during the proliferation and involution of hemangiomas, and is suspected to be a cause of the disease.
IHs in the proliferative phase express high levels of fibroblast growth factor (FGF), TIE-2, angiopoietins, matrix metalloproteinases (MMPs), and vascular endothelial growth factor A (VEGF-A) and its receptor (VEGFR), all of which play critical roles in the formation of blood vessels during and after embryogenesis. The tumor during this phase is composed of plump, rapidly dividing endothelial cells forming a mass of sinusoidal vascular channels. Enlarged feeding arteries and draining veins often vascularize the tumor. Markers for mature endothelium, CD-31 and von Willebrand factor, are present on these neoplastic endothelial cells.
Involuted hemangiomas express normal levels of these factors but elevated levels of tissue inhibitor of TIMP1, a metalloproteinase that inhibits new blood vessel formation, and interferon-β. The endothelial cells of the tumor flatten as apoptosis progresses, the vascular channels dilate, and the tumor assumes a lobular architecture with replacement by fibrofatty stroma. All that remains in the involuted phase is a residuum of fibrofatty tissue with tiny capillaries and mildly dilated draining vessels.
What are treatment modalities for infantile hemangiomas (IH)?
The majority of IHs do not require any specific treatment other than observation and reassurance of the parents. Even tumors that exhibit rapid growth or fiery red skin will spontaneously regress and leave behind little to no evidence of their presence. However, regular follow-up is important as the potential complications have few clinical indicators. Serial photographs are very helpful in documenting progression and subsequent improvement.
Reasons for treatment or referral to a vascular anomalies specialist or center include dangerous locations (impinging on a vital structure such as the airway or eye), unusually large size or rapid growth, and local or endangering complications (skin ulceration or high-output heart failure).
Hemangiomas exhibiting the aforementioned risk factors or complications should be considered for treatment. As hemangiomas are tumors of pure angiogenesis, pharmacologic therapy involves angiogenesis inhibition.
Systemic corticosteroids, which inhibit the expression of VEGF-A by hemangioma-derived stem cells and thus angiogenesis, were first-line therapy for decades. Oral prednisone is given at a dose of 2–3 mg/kg/day. Doses up to 5 mg/kg/day have been used for life-threatening complications of large hemangiomas causing airway obstruction or heart failure. The overall response rate is 80–90%, with initial improvement in the color and tension of the mass usually noted within 1 week. The steroids are maintained with a very gradual taper every 2–4 weeks with the goal of discontinuation around age 10–11 months.
Live vaccines such as polio, measles, mumps, rubella, and varicella should be withheld while children are taking prednisone. Hemangiomas will have rebound growth if steroids are tapered or stopped too quickly. Return to the initial dosage and slower tapering will usually help manage this problem.
Potential complications of steroid use in infants and children include impaired growth and weight gain in about one-third of cases. Almost all children will have “catch up” growth and return to pretreatment growth curves by age 14–24 months.
Cushingoid facies occur in almost all patients and normalizes on tapering.
In rare circumstances, steroids may induce hypertension or hypertrophic cardiomyopathy, both of which are indications to wean or change therapy.
Intralesional corticosteroids are used for small cutaneous hemangiomas that cause local deformity or ulceration, especially for lesions of the eyelid, nose, cheek, or lip. A total of two to four injections of triamcinolone acetate are typically given at intervals of 6–8 weeks at a dose of 2–3 mg/kg/ injection.
The response rate approaches that of systemic steroids.
Subcutaneous atrophy is a potential complication of steroid injection, but is usually temporary. There have been reported cases of blindness following intralesional steroid injection for periorbital hemangiomas. This is presumed to be secondary to particle embolization into the retinal artery through feeding vessels. Manual compression around the periphery of the tumor is recommended during injection to minimize embolization through draining veins.
Propranolol, a nonselective beta blocker, has recently been recognized as an important treatment option for hemangiomas. In most centers, it has become first-line pharmacotherapy. A child with a nasal capillary hemangioma treated with propranolol for steroid-induced cardiomyopathy had regression of his lesion. This revelation led to the publication of several more studies supporting this finding. Propranolol is given orally at 2–3 mg/kg/day, in two or three divided doses, and discontinued following regression of the lesion. Treatment often leads to a consistent, rapid, therapeutic effect with softening of the lesion on palpation and color shift from intense red to purple. Propranolol is well tolerated but can cause rare side effects such as bradycardia, gastroesophageal reflux, hypoglycemia, hypotension, rash, somnolence, and wheezing. Several mechanisms of action have been proposed. Propranolol inhibits β-adrenoreceptors, which are activated by adrenaline, causing vasoconstriction of capillaries supplying the hemangioma. This likely leads to the visible changes in color and palpable softening. Blockage of β-adrenoreceptors also results in decreased expression of VEGF and MMPs, thereby inhibiting angiogenesis, and induces apoptosis in endothelial cells.
Recombinant interferon was once considered as a second-line agent but has fallen out of favor except in very limited circumstances. A small subset of patients (5–12%) may develop a severe complication known as spastic diplegia. Spasticity usually resolves if the drug is terminated quickly. Children receiving interferon should be followed carefully by a neurologist. Though experience is limited, low-dose, high-frequency antiangiogenic regimens using vincristine can be effective. The use of interferon and vincristine has waned since the introduction of propranolol as first-line therapy.
Although attractive in concept, laser therapy is not often beneficial for IHs, except for a few specific indications. The flash lamp pulse-dye laser penetrates the dermis to a depth of only 0.75–1.2 mm. Most cutaneous hemangiomas are deeper than this and therefore not affected by laser treatment. In addition, laser therapy carries risks of scarring, skin hypopigmentation, and ulceration, which may lead to a poor result compared with observation alone. One instance in which the laser is advantageous is the treatment of telangiectasias that often remain in the involuted phase of hemangioma. The use of endoscopic continuous wave carbon dioxide laser has been shown to be a good strategy for controlling proliferative phase hemangiomas in the unilateral subglottic location. Lastly, intralesional photocoagulation with bare fiber Nd:YAG laser can be useful for hemangiomas in certain locations, such as the upper eyelid when visual obstruction is a concern.
Indications for resection of IHs vary with patient age. During the proliferative phase in infancy, well-localized or pedunculated tumors can be expeditiously resected with linear closure, especially for tumors complicated by bleeding and ulceration. Sites that are most amenable to resection are the scalp, trunk, and extremities. Other modalities to treat ulceration include wound care with dressing changes, topical antibiotics, and topical steroids, which can accelerate healing. Tumors of the upper eyelid that obstruct vision and that do not respond to pharmacologic therapy may also require excision or debulking. Focal lesions of the GI tract with bleeding that fail medical management may require enterotomy and resection, or endoscopic band ligation. Diffuse, patchy involvement is the more common presentation of GI hemangiomas. Management is difficult, but most lesions eventually involute and stop bleeding. Preoperative localization with capsule endoscopy and/or intraoperative endoscopy may be necessary to identify lesions in the small bowel.
During the involuting phase, resection may be needed for hemangiomas that are large and protuberant and therefore likely to create excess and lax overlying skin. Indications for resection include (1) it is obvious that resection will be necessary sooner or later; (2) the scar will be identical regardless of timing of operation; and (3) the scar can easily be hidden. Lesions of the nose, eyelids, lips, and ears require special expertise. It is often preferable to perform the operation for the foregoing indications during the preschool years before children become aware of and focus on body image differences that may lead to low self-esteem.
After complete involution of hemangioma, cosmetic distortion often becomes the primary indication for resection. Fibrofatty residuum and redundant skin can be excised in staged operations if necessary. Occasionally, extensive scarring from tissue destruction may necessitate reconstructive techniques.
Finally, for the difficult to treat and life-threatening large hemangiomas, especially in the liver, angiographic embolization may be required to manage high-output cardiac failure. Arterial catheterization in infants carries significant risks and should generally be limited to those situations with cardiac compromise in which there is the capacity and intent to perform simultaneous embolization. In these rare cases, antiangiogenic pharmacotherapy remains the first line of therapy and should continue along with angiographic procedures. Repeat embolization procedures may be required. Success with embolization is dependent on occlusion of macrovascular shunts within the tumor rather than occlusion of feeding vessels.
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Multidisciplinary management is typically required for complex hemangiomas.
Propranolol is a widely accepted oral medication to treat hemangiomas.
It is generally well tolerated, even by infants, with few side effects.
It is given in the proliferative phase of the lesions and may be continued for 1–2 years of life or more.
Propranolol may be contraindicated in PHACE syndrome patients who have underlying cardiac or cerebral lesions.
Local therapy includes timolol cream, laser treatment and surgical debulking or excision.
What are the complications of hemangiomas?
Hemangiomas can ulcerate, become infected, and cause disfigurement due to dermal thickening and permanent skin changes.
Lesions involving the periorbital area can lead to cortical blindness in infant if left untreated.
Airway lesions can lead to airway obstruction or compromise. Liver hemangiomas can cause organ compromise, hypothyroidism, and high output cardiac failure (dependent on type and number of lesions) [2].
What are the subtypes of congenital hemangiomas?
Congenital hemangiomas are fully grown at birth (Fig. 15.2), and have recently been subdivided based on their involution characteristics.
These include rapidly involuting congenital hemangiomas (RICH) which involute shortly after birth, and non-involuting congenital hemangiomas, called NICH.
Additionally, congenital hemangiomas that have focal areas which display some involution and other areas in the same lesion which do not involute are called partially involuting congenital hemangiomas (PICH) [2].
What are capillary malformations and how do they present?
Capillary malformations are composed of a large network of cutaneous capillary redundancies and have historically been referred to as “port-wine stains”.
Typically, these sporadic anomalies manifest as flat, red lesions on the head and neck with a characteristic blush on physical examination. They can be associated with underlying venous or lymphatic malformations, as well as overgrowth of a limb.
What are venous malformations and where are they found?
Venous malformations are lesions that display characteristic radial distribution with venous endothelium that has a markedly dilated channel (Fig. 15.3). Can be found throughout the body—within the subcutaneous fat, muscle and bone.
Venous malformations (VMs), often mistermed “cavernous hemangiomas,” are slow-flow lesions consisting of venous channels that can develop anywhere in the body, most commonly in the skin and soft tissues. VMs may be seen at birth or become apparent later, depending on the anatomic location. A wide spectrum of presentations is possible, including simple varicosities and ectasias, discreet spongy masses, and complex channels that can permeate any tissue or organ system.
VMs are probably the most common of the vascular malformations and are more likely to be multiple as well. They tend to slowly enlarge with normal growth of the patient, but can dilate and become symptomatic at any time.
As with other VMs, the proportional growth that occurs may become exaggerated during puberty. On examination, these soft, bluish, compressible lesions can expand with dependent position and Valsalva maneuver.
Episodes of phlebothrombosis secondary to stasis may lead to acute pain and swelling.
Phleboliths can be palpated in many VMs.
Associated local overgrowth and limb length discrepancy are not uncommon. Involvement of bones and joints creates risk for pathologic fractures and hemarthroses, with subsequent arthritis.
Histologically, VMs most often consist of sinusoidal vascular spaces with variable communication to adjacent veins. The dilated venous channels are thin walled, compared with normal veins, and smooth muscle actin staining reveals abnormal smooth muscle architecture that may be responsible for the gradual expansion seen over time with these lesions. Calcified phleboliths can be seen that provide evidence of prior clot formation within the VM.
A variant of VM, glomuvenous malformation (GVM, also incorrectly called “glomangioma”), has the additional presence of ballshaped glomus cells that line the vascular channels.
Approximately 90% of VMs are sporadic; half of those result from a mutation in the vascular endothelial cell-specific receptor tyrosine kinase TIE-2 and its associated TEK gene. The TIE-2 signaling pathways play an important role in angiogenic remodeling and vessel stabilization during development. Cutaneomucosal VMs, inherited through autosomal dominant transmission, are caused by a gain-of-function mutation in TIE-2 and represent 1–2% of VMs.
GVM, also autosomal dominant, represents 5% of VMs and results from loss-of-function mutations in glomulin, which affects vascular smooth muscle differentiation.
VMs of the GI tract are often multiple as well, and can affect every part from mouth to anus. They are more common in the left colon and rectum when associated with VM of the pelvis and perineum. GI bleeding, typically chronic in nature, can result. Blue rubber bleb nevus syndrome (or “Bean syndrome”) represents a specific rare disorder consisting of multifocal VMs that affect the skin and GI tract primarily.
The skin lesions are unique in that they are often quite numerous and resemble tiny “blue rubber nipples.” These skin lesions present diffusely and are classically seen on the palms and soles of the feet.
As with other GI VMs, chronic bleeding and intussusception can result.
Diagnosis of a GI VM is generally based on endoscopy.
Patients with rectal VMs can have associated ectatic mesenteric veins and are at risk for developing portomesenteric venous thrombosis.
Large VMs can also be complicated by localized intravascular coagulopathy caused by stasis and stagnation of blood within the malformation, leading to consumption of coagulation factors.
The clotting profile consists of prolonged prothrombin time, decreased fibrinogen, and elevated d-dimers.
The PTT is often normal.
Thrombocytopenia can occur with a typical platelet range of less than 100,000/μL.
The distinction between this coagulopathy and KMP is important. Lesions causing KMP are treated with antiangiogenic agents, while VMs will not respond to pharmacotherapy.
Radiologic modalities useful for the diagnosis of VMs include US, MRI, and venography. MRI is most informative and demonstrates hyperintense lesions with T2 sequences. Contrast enhancement of the vascular spaces distinguishes VM from LM, as does the presence of pathognomonic phleboliths. Intralesional bleeding within LMs can represent an exception to this rule. In contrast to AVMs, VMs do not demonstrate evidence of arterial flow on MRI.
Indications for treatment include appearance, pain, functional impairment, and bleeding. Unfortunately, cure for VMs, as with LMs, is difficult to achieve for all but the most localized, and therefore less problematic lesions.
For extensive VMs of the extremities, conservative management with the use of graded compression stockings can achieve significant improvement in size and symptoms. Patient satisfaction with this treatment depends on a proper customized fit, but can be elusive, especially for children and teenagers. In order to prevent phlebothrombosis of VMs with resultant pain and swelling, low-dose aspirin may be beneficial.
Intralesional sclerotherapy is the mainstay of treatment for most VMs. Sclerosing agents, most commonly ethanol and sodium tetradecyl sulfate, cause direct endothelial damage, thrombosis, and scarring. For small VMs, the injection process is similar to that for simple varicosities. Larger lesions are accessed by direct puncture, and the therapeutic agents are injected under fluoroscopy, with the use of tourniquets and compression of venous drainage to prevent systemic administration of the sclerosants.
General anesthesia is required in most instances. Staged therapy and occasional embolization of large venous channels are useful for more complex VMs. The more complex lesions are best treated by a skilled interventional radiologist who has experience with vascular anomalies.
VMs have a propensity for recanalization and reenlargement. Cure with sclerotherapy is rare. Given that recurrence is so prevalent, results from treatment are often stated in terms of patient satisfaction with decreased pain and appearance. Resection is typically reserved for well-localized lesions, but is marked by procedural morbidity and recurrence, especially for complex VMs.
Preoperative sclerotherapy is recommended preceding operations for extensive VMs to shrink the lesion and decrease bleeding during the resection.
Unifocal GI lesions can be excised. Diffuse colorectal malformations causing significant bleeding may be treated by colectomy, anorectal mucosectomy, and coloanal pull-through.
For multifocal VMs in the blue rubber bleb nevus syndrome, complete resection of all lesions, combined with endoscopy of the entire GI tract at the time of operation, provides the only chance for possible cure. Bowel resection for these lesions is rarely indicated. Rather, wedge excision and polypectomy by intussusception of successive lengths of intestine are the preferred methods of resection.
What is the most common treatment for venous malformations?
They are commonly treated with compression garments.
Function threatening malformations can be treated with sclerotherapy or a combination of embolization and excision or surgical debulking alone.
What are lymphatic malformations?
Lymphatic malformation can occur anywhere in the body, but are most commonly (50% of lesions) seen in the head and neck as these areas are rich in lymphatic tissue.
In general, these are divided into macrocystic and microcystic lesions based on their size.
Lesions smaller than 2 cm are microcystic and larger than 2 cm are considered macrocystic.
How are lymphatic malformations treated?
Lymphatic malformations can be treated with multiple modalities either alone or in combination.
Compression therapy is a mainstay of treatment with all patients with significant malformations being prescribed a compression garment.
If symptoms are ongoing, sclerotherapy is the next step in management.
Surgical resection of lymphatic malformations can be done if form or function is threatened.
Medical therapy with sirolimus should be also be used for significant lesions.
What is CLOVES syndrome?
Congenital Lipomatous Overgrowth, Vascular malformations, and Epidermal Nevi Syndrome, or CLOVES Syndrome, is a genetic disorder caused by mutation of the gene PIK3CA on chromosome 3q26, which can be attributed to postzygotic, somatic mosaicism.
The hallmark sign of this disorder is hemi-hypertrophy and overgrowth.
These vascular anomalies are generally low-flow, with the exception of peri-spinal vascular malformations which have been documented as high-flow in some individuals.
There are also several skeletal and spinal anomalies associated with this condition as well as extremity hamartomas and epidermal nevi.
What is sclerotherapy and how is it used?
Sclerotherapy can be used for symptomatic lymphatic and venous malformations.
Common agents used for lymphatic malformations include doxycycline and bleomycin.
Sodium tetradecyl sulfate (STS) is used most commonly for venous malformations.
The mechanism of action is postulated by initiation of an inflammatory reaction mediated by exposure of the sclerosant to the endothelium of the abnormal vascular tissue, response to percutaneous sclerotherapy can be affected by the open or closed-cell architecture of the malformations.
Sclerotherapy tends to be more efficacious with macrocystic lesions rather than microcystic lymphatic malformations.
What are compression garments and when do you use them?
Compression garments allow for compression of vascular malformations—venous or lymphatic which are symptomatic.
They decrease edema and venous distension associated with these anomalies.
Custom garments can be fit for infants and children and should be remeasured every 6 months to adjust for growth of the child and wear of the garment.
Garment compression should start at 20–30 mmHg and titrate upward to maximize therapeutic effect.
What surgical therapies are used to treat vascular malformations?
Surgical therapy can be divided into a few classifications based on the goal of intervention: debulking procedures, resection, and sclerotherapy.
Surgery should take into account the complex anatomy of these malformations, a judicious use of sealants and post-operative drains.
Advances in interventional radiology have led to the development of minimally invasive techniques of obliterating flow through lesions through angioembolization techniques which can be an excellent adjunct to surgical procedures.
Glue embolization of venous malformations prior to debulking procedures to reduce blood loss and allow for vascular control for resection of venous malformations.
What are the indicated for use of sirolimus?
Sirolimus is indicated in PIK3CA associated overgrowth syndromes and complicated vascular malformations which are limb, life, or function threatening, or disfiguring.
Clinical trials have demonstrated sirolimus is effective particularly for lymphatic malformations and well tolerated.
Side effects include headaches, mouth ulcers, hypertriglyceridemia, hyperglycemia, and bone marrow toxicity.
Sirolimus levels, lipid levels, and liver function should be assessed with labs every 3 months.
Are there any novel drugs to treat PIK3CA associated overgrowth syndromes?
There are now multiple targeted drug therapies for patients with PIK3CA asso- ciated overgrowth syndromes such as CLOVES syndrome.
Newer drugs specifically targeting the genetic mutations involved have been developed, a drug called BYL719 has been studied in a CLOVES mouse model and is now in clinical trials in patients with PIK3CA related overgrowth syndromes including CLOVES.
The results have been promising.
Other drugs inhibiting the AKT pathway are also being tested in clinical trials.
Lymphangioma is different from mesenteric or omental cyst, as it has the following features, except:
A. Small lymphatic spaces
B. Lymphoid tissues
C. Smooth muscles
D. Cuboidal or columnar lining of epithelium
E. Thin wall
D
Mesenteric or omental cysts contain cuboidal or columnar epithelium, while cystic lymphangia has endothelial lining. A, B, C and E are features of lymphangioma.
Syed/MCQ
About arteriovenous malformations, all of the following are correct, except:
A. Usually slow flow.
B. Present at birth.
C. Évident on infancy.
D. Skin becomes red or violaceous.
E. Local warmth, thrill or bruit.
A. Usually slow flow.
Regarding the management of hemangioma, which is false?
A. About 25 percent naturally undergo involution.
B. Corticosteroid is one method of treatment.
C. Alpha interferon is used for serious and life-threatening hemangioma.
D. Laser therapy is only used in cutaneous hemangioma.
E. Excision should be performed in involution phase.
A. About 25 percent naturally undergo involution.
How do you differentiate pyogènic granulomas from hemangiomas?
Pyogenic granulomas may be differentiated from hemangiomas by their rare appearance before 6 months (mean age is 6–7 years), and their frequent association with minor trauma.
What is PHACES association?
PHACES (posterior fossa malformations, hemangioma of the face, arterial abnormalities, cardiac defects and coarctation, eye abnormalities, and sternal nonunion or supraumbilical raphe) association describes facial hemangiomas associated with congenital ocular abnormalities such as microphthalmia, cataracts, optic nerve hypoplasia, posterior fossa cystic malformations, hypoplasia or absence of carotid and vertebral vessels, as well as malformation of the aortic arch.
Females are affected in 90% of cases.
Facial hemangiomas in these patients usually start as a small red macule and progress rapidly to a plaque-like or reticular pattern, though deeper hemangiomas can also occur.
These patients are at risk for stroke in the neonatal period and migraines in older ages.
Imaging findings expected for hemangiomas?
US and MRI are the most useful imaging modalities.
US of proliferative phase hemangiomas demonstrates a mass with dense parenchyma exhibiting fast-flow vascularity.
This distinguishes deep IHs from VMs, which exhibit slow-flow vascularity and larger blood-filled spaces.
MRI of proliferating hemangiomas shows a lobulated solid mass of intermediate intensity with T1 spin-echo sequences, and moderate hyperintensity on T2 spin-echo. Flow voids that represent fast flow and shunting are seen in and around the tumor.
During the involuting phase, MRI demonstrates decreased flow voids and vascularity, with the mass taking on a more lobular and fatty appearance.
What is the recommended treatment for infantile hemangiomas?
The majority of IHs do not require any specific treatment other than observation and reassurance of the parents.
Even tumors that exhibit rapid growth or fiery red skin will spontaneously regress and leave behind little to no evidence of their presence.
However, regular follow-up is important as the potential complications have few clinical indicators. Serial photographs are very helpful in documenting progression and subsequent improvement.
Reasons for treatment or referral to a vascular anomalies specialist or center include dangerous locations (impinging on a vital structure such as the airway or eye), unusually large size or rapid growth, and local or endangering complications (skin ulceration or high-output heart failure).
Hemangiomas exhibiting the aforementioned risk factors or complications should be considered for treatment. As hemangiomas are tumors of pure angiogenesis, pharmacologic therapy involves angiogenesis inhibition. Systemic corticosteroids, which inhibit the expression of VEGF-A by hemangioma-derived stem cells and thus angiogenesis, were first-line therapy for decades.
Oral prednisone is given at a dose of 2–3 mg/kg/day. Doses up to 5 mg/kg/day have been used for life-threatening complications of large hemangiomas causing airway obstruction or heart failure. The overall response rate is 80–90%, with initial improvement in the color and tension of the mass usually noted within 1 week.
The steroids are maintained with a very gradual taper every 2–4 weeks with the goal of discontinuation around age 10–11 months.
Live vaccines such as polio, measles, mumps, rubella, and varicella should be withheld while children are taking prednisone.
Hemangiomas will have rebound growth if steroids are tapered or stopped too quickly. Return to the initial dosage and slower tapering will usually help manage this problem.
Potential complications of steroid use in infants and children include impaired growth and weight gain in about one-third of cases. Almost all children will have “catch up” growth and return to pretreatment growth curves by age 14–24 months.
Cushingoid facies occur in almost all patients and normalizes on tapering. In rare circumstances, steroids may induce hypertension or hypertrophic cardiomyopathy, both of which are indications to wean or change therapy.
Intralesional corticosteroids are used for small cutaneous hemangiomas that cause local deformity or ulceration, especially for lesions of the eyelid, nose, cheek, or lip. A total of two to four injections of triamcinolone acetate are typically given at intervals of 6–8 weeks at a dose of 2–3 mg/kg/ injection. The response rate approaches that of systemic steroids.
Subcutaneous atrophy is a potential complication of steroid injection, but is usually temporary. There have been reported cases of blindness following intralesional steroid injection for periorbital hemangiomas. This is presumed to be secondary to particle embolization into the retinal artery through feeding vessels. Manual compression around the periphery of the tumor is recommended during injection to minimize embolization through draining veins.
Propranolol, a nonselective beta blocker, has recently been recognized as an important treatment option for hemangiomas. Propranolol is given orally at 2–3 mg/kg/day, in two or three divided doses, and discontinued following regression of the lesion. Treatment often leads to a consistent, rapid, therapeutic effect with softening of the lesion on palpation and color shift from intense red to purple. Propranolol is well tolerated but can cause rare side effects such as bradycardia, gastroesophageal reflux, hypoglycemia, hypotension, rash, somnolence, and wheezing.
Propranolol inhibits β-adrenoreceptors, which are activated by adrenaline, causing vasoconstriction of capillaries supplying the hemangioma. This likely leads to the visible changes in color and palpable softening.
Blockage of β-adrenoreceptors also results in decreased expression of VEGF and MMPs, thereby inhibiting angiogenesis, and induces apoptosis in endothelial cells.
Recombinant interferon was once considered as a second-line agent but has fallen out of favor except in very limited circumstances. A small subset of patients (5–12%) may develop a severe complication known as spastic diplegia. Spasticity usually resolves if the drug is terminated quickly. Children receiving interferon should be followed carefully by a neurologist. Though experience is limited, low-dose, high-frequency antiangiogenic regimens using vincristine can be effective. The use of interferon and vincristine has waned since the introduction of propranolol as first-line therapy.
Although attractive in concept, laser therapy is not often beneficial for IHs, except for a few specific indications. One instance in which the laser is advantageous is the treatment of telangiectasias that often remain in the involuted phase of hemangioma. The use of endoscopic continuous wave carbon dioxide laser has been shown to be a good strategy for controlling proliferative phase hemangiomas in the unilateral subglottic location.
Lastly, intralesional photocoagulation with bare fiber Nd:YAG laser can be useful for hemangiomas in certain locations, such as the upper eyelid when visual obstruction is a concern.
During the proliferative phase in infancy, well-localized or pedunculated tumors can be expeditiously resected with linear closure, especially for tumors complicated by bleeding and ulceration.
Sites that are most amenable to resection are the scalp, trunk, and extremities.
Other modalities to treat ulceration include wound care with dressing changes, topical antibiotics, and topical steroids, which can accelerate healing.
Tumors of the upper eyelid that obstruct vision and that do not respond to pharmacologic therapy may also require excision or debulking.
Focal lesions of the GI tract with bleeding that fail medical management may require enterotomy and resection, or endoscopic band ligation.
Diffuse, patchy involvement is the more common presentation of GI hemangiomas. Management is difficult, but most lesions eventually involute and stop bleeding. Preoperative localization with capsule endoscopy and/or intraoperative endoscopy may be necessary to identify lesions in the small bowel.
During the involuting phase, resection may be needed for hemangiomas that are large and protuberant and therefore likely to create excess and lax overlying skin.
Indications for resection include (1) it is obvious that resection will be necessary sooner or later; (2) the scar will be identical regardless of timing of operation; and (3) the scar can easily be hidden. Lesions of the nose, eyelids, lips, and ears require special expertise. It is often preferable to perform the operation for the foregoing indications during the preschool years before children become aware of and focus on body image differences that may lead to low self-esteem.
After complete involution of hemangioma, cosmetic distortion often becomes the primary indication for resection. Fibrofatty residuum and redundant skin can be excised in staged operations if necessary. Occasionally, extensive scarring from tissue destruction may necessitate reconstructive techniques.
Finally, for the difficult to treat and life-threatening large hemangiomas, especially in the liver, angiographic embolization may be required to manage high-output cardiac failure. Arterial catheterization in infants carries significant risks and should generally be limited to those situations with cardiac compromise in which there is the capacity and intent to perform simultaneous embolization. In these rare cases, antiangiogenic pharmacotherapy remains the first line of therapy and should continue along with angiographic procedures. Repeat embolization procedures may be required. Success with embolization is dependent on occlusion of macrovascular shunts within the tumor rather than occlusion of feeding vessels.
How do you differentiate RICH from NICH?
Two types of rare congenital hemangiomas exist that are fully developed at birth and that do not usually exhibit postnatal tumor growth. These have been termed rapidly involuting congenital hemangioma (RICH) and the noninvoluting congenital hemangioma (NICH).
Lesions are solitary and affect both genders equally. Unlike IHs, they do not stain positive for GLUT-1.
The diagnosis is typically made on physical exam at birth, although some can be diagnosed prenatally as early as 12 weeks of gestation. Most do not require therapy.
As opposed to IH, RICH is more common on the extremities. Also, RICH will spontaneously regress, much more quickly than IH, by 6–14 months; NICHs do not involute and grow with the child.
RICHs appear raised and violaceous, often with a central depression or scar, ulceration, telangiectasia, or surrounding pale rim. MRI will show enhancing hyperintense masses, high-flow vessels within and adjacent to the mass, and the presence of vascular flow voids on T2-weighted imaging.
NICHs are well-circumscribed, plaque-like lesions, often with coarse telangiectasias, areas of pallor, or a white to bluish rim. They appear on MRI as homogeneous lesions with isointense signal on T1-weighted imaging and hyperintense on T2-weighted sequences.
Both lesions are fast flow on Doppler US. If treatment is needed for NICH, arterial embolization may be beneficial, as these lesions have significant flow to them.
Operative excision is reserved for cases with equivocal diagnosis; poor cosmetic appearance; or for complications such as ulceration, bleeding, obstruction, or congestive heart failure.
(Top: RICH; Bottom: NICH)
How are hepatic hemangiomas classified?
Hepatic hemangiomas (HHs) in infants should be differentiated from “hepatic hemangiomas” that present in adulthood. Adult “hepatic hemangiomas,” which are sometimes called “cavernous hemangiomas,” are in fact VMs. In contrast, HHs of infancy are true tumors and have a pattern of involution similar to that of cutaneous IHs. Contrary to popular belief, not all liver hemangiomas are life-threatening. The classic triad of heart failure, anemia, and hepatomegaly is unusual, and most involute without long-term sequelae.
Focal HH
- Hepatic equivalent of RICH
- Do NOT stain positive for GLUT-1
- Histologically distinct from IH
- Fully grown at birth, regress much faster than IH
- Asymptomatic (transient anemia and moderate thrombocytopenia from intralesional thrombosis)
- A subset will have macrovascular shunts from hepatic arteries/portal veins to hepatic veins (May close as tumor involutes, but can lead to high output cardiac failure)
- Steroids may be attempted.
Multifocal HH
- True IH, biologically distinct from focal HH
- Undergo involution, stain positive for GLUT-1
- Females, Caucasians
- Born earlier and are asymptomatic, but diagnosed later
- With cutaneous IH, identified following screening for visceral hemangiomas
- Some with hypothyroidism - a serum TSH should be checked
- High output cardiac failure possible from macrovascular shunting - treatment with steroid or propanolol can close these shunts.
- Embolization can be employed in those who fail medical therapy. Serial abdominal US should be performed in infants with multifocal HH until the lesions involute.
Diffuse HH
- True IHs, but far more serious lesions
- Diagnosed weeks after birth
- Females, Caucasians
- Associated with cutaneous IH, involute, express GLUT-1
- All develop severe hypothyroidism from high levels of type 3 iodothyronine deiodinase, which inactivâtes circulating thyroid hormones.
- Aggressive exogenous thyroid hormone replacement is essential.
- Can develop respiratory compromise from compression of diaphragm and thoracic cavity, ACS and multisystem organ failure.
- Aggressive pharmacotherapy with propranolol, steroids, and occasionally low-dose vincristine is warranted in those with cardiac failure, hemodynamically significant shunting, or hypothyroidism to hasten involution.
- Hepatic transplantation is the last resort for critically ill infants.
What is the dose for propanolol use in hemangiomas?
Propranolol use in Hemangioma (Harriet):
5wk old to 5mo old and >2kg
0.6mg/kg/dose BID PO x 7 days
1.1mg/kg/dose BID PO X 14 days
1.7mg/kg/dose BID PO X 6months
> 5month old
1mg/kg/24hrs ÷ 3 PO
2mg/kg/24hrs ÷3 PO
Contraindications: Asthma, heart failure, heart block
Findings suggestive of lymphatic malformation on antenatal ultrasound?
Increasingly, mass lesions and vascular anomalies are detected on antenatal ultrasound.
The term cystic hygroma is used in perinatology to describe a lymphatic anomaly distinct from LMs seen in postnatal pediatrics.
A fetal cystic hygroma consists of collections of lymphatic fluid due to a maldevelopment of the cervical lymphatic sacs. Nuchal thickness greater than or equal to 2.5 mm, measured between 10 and 14 weeks gestation, is considered abnormal.
A fetal cystic hygroma ranges from 6.5 to 7.9 mm.
The finding of a first-trimester septated cystic hygroma has definitively been shown to be associated with a higher risk of aneuploidy, cardiac malformation, and perinatal death over simple increased nuchal translucency.
Chromosomal abnormalities such as Down syndrome or Turner syndrome are observed in 50% of fetuses with cystic hygroma; however, 17% to 25% of these pregnancies will result in the birth of a healthy newborn.
Resolution of a fetal cystic hygroma improves the chance of a normal outcome to as high as 95%.
Fetal cystic hygroma and simple increased nuchal translucencies are always situated in the posterior neck and can extend down the entire dorsum of the fetus. This posterior location is distinct from cervical LMs located in the submandibular, supraclavicular, and anterior/lateral neck regions. LMs are usually not detected until the second or third trimesters, unlike the more concerning fetal cystic hygroma, which is seen by 14 weeks.
Unfortunately, because of continued use of the imprecise term cystic hygroma, some families receive misinformation regarding their true diagnosis and conclude incorrectly that their fetus cannot survive or will have chromosomal abnormalities. Antenatal consultation with pediatric specialists knowledgeable about vascular malformations can benefit families.
Reassurance can be given that a lateral or anterior LM is not associated with chromosomal or developmental disorders. It also provides an educational opportunity to discuss the concerns facing a child with a cervicofacial LM.
[Coran]
When is the EXIT procedure indicated?
Large cervicofacial LMs detected in utero should raise concern about potential airway obstruction leading to asphyxia in postnatal life.
Results from prenatal ultrasound and fetal MRI allow for assessment of potential airway difficulties at birth.
When the risk of airway obstruction is high, consideration should be given to delivery of the fetus via an ex-utero intrapartum treatment (EXIT) procedure.
Although the EXIT procedure had early popular appeal, experience has shown that most LMs are compressible, allowing for intubation after delivery in the face of airway compromise.
Differentiating LM from teratoma, which is usually firm and noncompressible, is an important distinction in delivery planning.
[Coran]
The purpose of the EXIT procedure is to maintain the baby on placental circulation until the airway is secured. Otherwise, immediate asphyxia and death are likely to occur. The EXIT procedure involves the collaboration of an entire team that includes anesthesiologists, obstetricians, pediatric surgeons, neonatologists, and cardiologists. The procedure should therefore be planned and rehearsed well in advance so that all those participating are aware of the condition and progress of the mother and fetus and have clearly assigned roles.
[Sherif]
What is Proteus syndrome?
Proteus syndrome is probably diagnosed more often than it actually occurs.
Many patients diagnosed with this syndrome likely have CLOVES syndrome. This overgrowth disorder is associated with activating mutations in the oncogene AKT-1 and is progressive over time.
Vascular, skeletal, and soft tissue anomalies tend to be asymmetric and variably expressed. Common features include lipomas or lipomatosis, macrocephaly, and gigantism of the hands or feet (or both).
[Ashcraft]
- https://www.nejm.org/doi/full/10.1056/nejmoa1104017
When should infantile hemangiomas be worked up for other anomalies?
IH are rarely associated with other anomalies. However, a few such anomalies have been described, more commonly IH are rarely associated with other anomalies. However, a few such anomalies have been described, more commonly with larger and midline hemangiomas.
Cervicothoracic hemangiomas can be seen in conjunction with sternal nonunion.
Tumors of the lumbosacral area have been noted to occur along with spinal dysraphism abnormalities such as meningocele and tethered spinal cord.
Hemangiomas of the pelvis and perineum have been found in association with urogenital and anorectal anomalies.
PHACES (posterior fossa malformations, hemangioma of the face, arterial abnormalities, cardiac defects and coarctation, eye abnormalities, and sternal nonunion or supraumbilical raphe) association describes facial hemangiomas associated with congenital ocular abnormalities such as microphthalmia, cataracts, optic nerve hypoplasia, posterior fossa cystic malformations, hypoplasia or absence of carotid and vertebral vessels, as well as malformation of the aortic arch. Females are affected in 90% of cases.
Facial hemangiomas in these patients usually start as a small red macule and progress rapidly to a plaque-like or reticular pattern, though deeper hemangiomas can also occur. These patients are at risk for stroke in the neonatal period and migraines in older ages.
What work up should be done for hemangiomatosis?
The presence of multiple disseminated hemangiomas is termed hemangiomatosis.
The cutaneous tumors are usually tiny (<5 mm) and dome-like.
When five or more lesions are present, occult visceral lesions, most commonly in the liver, may also be present.
Screening patients with ultrasound (US) and/or magnetic resonance imaging (MRI) may be indicated for these patients.
Which vascular tumors of childhood are more aggressive and invasive than infantile hemangiomas?
Tufted angioma (TA) and Kaposiform hemangioendothelioma (KHE) probably exist within the same spectrum as they share many overlapping clinical and histologic features. Both tumors typically present at birth, although they occur postnatally as well. Males and females are affected equally.
The tumors are unifocal and are most often located on the trunk, shoulder, thigh, or retroperitoneum.
TAs present as erythematous or brownish macules or plaques, and histology reveals small tufts of capillaries.
KHEs are typically more extensive tumors that present with deep, red-purple skin discoloration and overlying and surrounding ecchymosis.
The natural history of these tumors is one of continued proliferation into early childhood followed by subsequent, but incomplete regression. These tumors usually persist, albeit in a smaller form. Fortunately, they are usually asymptomatic in later stages, though may cause musculoskeletal pain.
Histology of these lesions reveals infiltrating sheets of spindleshaped endothelial cells in the form of irregular lobules, sheets, and lacy network.
Imaging of KHE depicts an enhancing lesion on MRI with poorly defined margins that extend across tissue planes.
This is in contrast to IHs, which are well-circumscribed and respective of tissue planes.
Which vascular tumors of childhood have metastatic potential?
Epithelioid hemangioendothelioma (EHE) is a locally aggressive tumor with the potential for metastasis. It is a tumor arising from medium to large blood vessels that has features intermediate between the benign epithelioid hemangiomas and the more aggressive angiosarcomas.
The most common presentations are in the liver, lung, and bone, though they may occur in many other sites including the soft tissues of the extremities and rarely the head and neck.
Histology of these lesions shows epithelioid cells arranged in nests, strands, and trabecular patterns.
A WWTR1–CAMTA1 fusion gene has been found in the majority of cases (around 90%) while a smaller subset have a YAP1–TFE3 fusion gene.
Cutaneous lesions are either nodular or plaque-like while bony lesions are osteolytic on bone films.
Hepatic nodules have central vascularity on US and enhance with contrast on CT.
Given its rarity, there is no standard for treatment for this disease. Observation can be done in indolent cases while more aggressive lesions are treated.
Often, when the lesions are small and limited in number, then surgical resection is suggested. The effect of adjuvant radiation therapy or chemotherapy is unknown, but they are sometimes used for the control of residual disease in localized tumors or for widespread disease respectively.
—
Angiosarcoma is a rare and aggressive vascular tumor that is most commonly seen in the soft tissue but that can be seen in any part of the body. It is extremely rare in children and more often occurs in older adults, most commonly in the 60–70-year age range.
It is typified by an irregular network of channels along dermal collagen bundles.
Local disease is treated with operative resection while chemotherapy and radiation can be added for metastatic disease.
Prognosis is poor with a median overall survival of 16 months. Poor prognostic factors include metastatic disease at presentation, visceral or deep soft tissue location of tumor, tumor size, and presence of necrosis.
What is Gorham-Stout Disease?
A rare but very difficult problem arises with GorhamStout disease, in which soft tissue and skeletal LMs lead to progressive osteolysis and “disappearing bone disease”.
It presents most frequently in the second and third decades of life and is seen slightly more often in males.
Presenting symptoms include pain, limping, extremity weakness, and spontaneous fractures, most commonly involving the shoulder, facial, spine, and pelvic bones.
The clinical course is variable, ranging from mild disability to paraplegia.
On imaging, well-circumscribed intramedullary and subcortical lucencies resembling osteoporosis are seen early.
Biopsy typically demonstrates a matrix of thin-walled vessels lined with a single layer of endothelium surrounded by extensive fibrovascular connective tissue, but without signs of inflammation or malignancy.
A variety of treatments have been reported. Interferon alfa-2b is believed to have antiangiogenic activity and has been shown to induce remission.
Bisphosphonates can also stabilize disease, presumably by inhibition of osteoclasts.
Surgery, reserved for symptomatic lesions, involves resection of affected areas and reconstruction.
What is congenital lymphedema?
Lymphedema, which occurs when protein-rich fluid leaks into the subcutaneous tissue, should be considered a type of LM. It can be inherited or acquired.
Milroy disease is an autosomal dominant, congenital lymphedema caused by a mutation in the VEGR3 gene.
Bilateral, below-the-knee swelling is a consistent phenotypic feature of the disorder and is usually present at birth.
Cellulitis, dilated lower extremity veins, up slanting toenails, and papillomatosis are also present.
Males may often develop a hydrocele.
In contrast, Meige disease and lymphedemadistichiasis (LD) syndrome present in puberty or later in adulthood with lymphedema.
Both are autosomal dominant disorders.
Meige disease is more common in females. No genetic cause has been found.
LD patients can also present with distichiasis (double rows of eyelashes), varicose veins, ptosis, cleft palate, and cardiac abnormalities.
A mutation in the FOXC2 forkhead/winged-helix transcription factor, which plays a role in somite formation, is responsible for the disease.
What are arteriovenous malformations?k
AVMs are fast-flow vascular malformations characterized by abnormal connections or shunts between feeding arteries and draining veins, without an intervening capillary bed. These shunts define the nidus of the malformation.
Lesions tend to be localized but can be extensive as well.
AVMs are one of the most common vascular anomalies that occur in the CNS and are more frequent than extracranial AVM.
A clinical staging system has been developed to describe the natural history of progression.
At birth, they appear as a pink cutaneous blemish that can be confused with both a CM and the premonitory sign of an IH. The fast flow through the shunt becomes more evident in childhood and adolescence as the lesion expands and develops into a mass.
Lesions will feel warm to the touch, often with a bruit or thrill. With continued expansion, they become more red and prominent. Puberty, pregnancy, or local trauma tends to trigger more rapid expansion. Skin ischemia can develop from expansion or local steal phenomenon, leading to pain, ulceration, and bleeding. Large AVMs can cause high-output cardiac failure.
Most AVMs are sporadic, but heritable forms exist. Mutations in RASA1 cause the autosomal dominant disorder CM-AVM.
The CMs are multifocal, small, round-to-oval, pinkish-to-red lesions and are usually randomly distributed. They can be associated with an AVM or arteriovenous fistula.
Recently, mutant MAP2K1 alleles were identified in a large proportion of extracranial AVM specimens studied. It is thought that somatic mutations in this gene cause dysfunction in endothelial cells due to increased MEK1 activity, therefore making MEK1 inhibitors a potential therapy for AVMs in the future.
US and Doppler imaging can elucidate the fast flow of these lesions and distinguish them from VMs.
On CT, dilated feeding arteries and veins are seen as areas of contrast enhancement.
MRI and MRA are the most useful modalities to demonstrate the full extent of lesions. They appear as signal flow voids (black tubular structures) on MRI or areas of contrast enhancement (white tubular structures) on MRA.
Superselective angiography can clearly identify the nidus when treatment is planned.
The majority of AVMs require treatment because of continued expansion, which can lead to local tissue ischemia and pain. The mainstays of treatment are angiographic embolization alone or in combination with excision.
Local recurrence following early intervention can complicate future procedures.
Very well-localized stage I AVMs may be amenable to excision. Intervention is often delayed until symptoms (focal pain, ulceration, and bleeding) develop, which is indicative of stage III.
Treatment during infancy is indicated in cases of heart failure. The proximal feeding arteries should not be embolized or ligated during treatment as they provide the only avenue by which to reach the nidus of the AVM for subsequent embolization. The nidus will recruit other nearby arteries after the primary feeding vessels are occluded, and the AVM will recur and continue to enlarge.
Embolization should be directed to the nidus itself and the arteriovenous fistulae at the epicenter of the lesion. Direct puncture sclerotherapy of the AVM nidus can be an adjunct to embolization, especially when the feeding arteries are too tortuous or have been previously ligated. Retrograde transvenous embolization is often the best strategy for AVMs with few venous outflow channels. Repeated and staged embolization procedures are typically necessary for these lesions, but often provide only temporary improvement. The quantity and microscopic nature of the arteriovenous fistulae that comprise the nidus of the AVM make it difficult to achieve complete occlusion of these microscopic shunts. Nonetheless, patients often have significant improvement in their symptoms, and cures with embolization alone have occurred.
The preferred treatment strategy for an AVM typically consists of resection carried out 2–3 days following preoperative embolization of the nidus. Angiographic embolization facilitates the operation by decreasing bleeding, but does not decrease the extent of tissue to be resected. Whenever possible, the goal should be complete excision of the lesion. Both the nidus of the AVM and the involved skin should be removed. The most important factor for success is the extent of resection. Review of radiologic imaging, including the earliest available MRI scans and angiograms before any other treatment, is important.
Intraoperatively, observation of the pattern of bleeding at the resection margins can also guide the extent of excision, as can intraoperative frozen section analysis.
Primary closure is sometimes not possible without tissue transfer techniques. Vacuum-assisted closure devices can also be useful in areas with large soft tissue loss that precludes linear closure. The best results are seen with an AVM that is well localized. Yet, even in these cases, it is prudent to follow these patients for years to evaluate for recurrence.
Unfortunately, most AVMs are extensive and often not amenable to an operative approach. For these difficult lesions, embolization is used for palliation. For difficult AVMs of the extremities, if distal in location, amputation becomes an option.
What is Klippel-Trenaunay Syndrome?
Klippel–Trenaunay syndrome (KTS) is a slow-flow combined vascular malformation involving abnormal capillaries, veins, and lymphatics. This capillary-lymphaticovenous malformation (CLVM) usually involves one or more extremities, most often a lower limb, and is associated with prominent soft tissue and bony hypertrophy.
This syndrome is sporadic and obvious at birth, with a wide range in severity. The CM component can be multiple and typically presents as a large geographic pattern affecting the extremity, buttock, and trunk. It is macular at birth and develops lymphatic vesicles over time.
The lymphatic anomalies have a variable presentation including hypoplasia, lymphedema, and macrocystic LM, and are common in the buttock, pelvis, and perineum.
Anomalous lateral superficial veins in the extremity, usually dilated with incompetent valves, are persistent embryonic vessels, the most common being the marginal vein of Servelle.
There are anomalous deep system veins as well that may be hypoplastic or even absent. Thrombophlebitis of the anomalous veins occurs with a frequency of 20–45%, and pulmonary emboli are found in up to one-quarter of the patients.
Limb hypertrophy is also obvious at birth and tends to be progressive over time. Though the affected extremity is generally larger, it is occasionally shorter. With CLVM of the legs, pelvic involvement with LMs and VMs can also occur, but is often asymptomatic. Alternatively, problems with recurrent infections, hematuria, hematochezia, and bladder outlet obstruction can develop. With CLVM of the superior trunk and arms, the mediastinum or retropleural space can harbor the vascular malformation as well.
Imaging plays an important role in the evaluation of patients with KTS. Plain films are used to serially document limb length discrepancies. MRI provides the foundation for describing the type and extent of each of the vascular malformation components. Hypertrophic fatty tissue is often seen in areas of overgrowth.
A common pattern seen with LMs of the lower extremity is macrocystic lesions in the pelvis and thigh, and microcystic LMs affecting the abdominal wall, buttock, and distal extremity. These LMs can be localized to the subcutaneous tissues or extend into the intramuscular compartments.
Magnetic resonance venography can elucidate the anatomy of the deep system veins. Identification of a subcutaneous vein coursing along the lateral calf and thigh, the marginal vein of Servelle, is typical for KTS.
Treatment for KTS is often conservative. Symptoms of pain and deformity secondary to venous anomalies and oozing from the LM can often be improved with compression stockings. Alternatively, sclerotherapy can treat certain components of CLVM such as focal VMs, macrocystic LMs, and bleeding lymphatic vesicles. Recurrence after sclerotherapy, however, is often a problem. Endovenous laser ablation or resection can treat persistent embryonic veins, and also veins with direct connections to the inferior vena cava or femoral or iliac veins, as these are at risk for causing pulmonary embolism (PE). Sirolimus may be considered especially in patients with a larger lymphatic component as disease response has been shown in other studies.
Operative therapies, mainly debulking procedures, can manage some of the specific problems encountered, primarily for overgrowth. Staged contour resection can be used to treat areas of soft tissue overgrowth and lymphedema.
It is critical to determine the location of the overgrowth, which can be either extrafascial or intrafascial. Intrafascial overgrowth should not be debulked secondary to the risk of injury to major neurovascular structures and immobility. Debulking of the trunk and thoracic wall is feasible, but excision of intrathoracic and mediastinal malformations should generally not be undertaken, especially if asymptomatic.
Tissue with poor lymphatic drainage and altered circulation makes for poor tissue flaps, leading to delayed postoperative healing and protracted use of closed-suction drains.
Perioperative management during significant resections should include consideration for anticoagulation and temporary inferior vena cava filter placement to help prevent deep venous thrombosis and PE.
Gross foot enlargement, which can impair ambulation and the ability to wear shoes, requires orthopedic corrective procedures and partial amputations to permit the use of regular or even custom footwear.
Limb length discrepancy should be followed annually by an orthopedic surgeon to document and predict severity; differences <0.5 cm do not require therapy. Children with discrepancies >1.5 cm should use shoe lifts to prevent limping and scoliosis. Epiphysiodesis of the distal femoral and/or proximal tibial growth plates are sometimes performed around the age of 11–12 years to correct overgrowth. Correction for arm length discrepancies is unnecessary. Resection of anomalous veins producing pain or potential sources of PE can be considered if too large for endovenous approaches.
What is Cloves Syndrome?
This syndrome is named for its phenotypic features: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, seizures, scoliosis, and skeletal/ spinal anomalies.
These patients may be misdiagnosed as having Proteus syndrome.
Truncal lipomatous masses are present at birth, typically with an overlying capillary malformation, and may be identified on prenatal imaging.
The masses can extend into the mediastinum, pleural cavity, retroperitoneum, and paraspinalintraspinal space. Both low-flow and high-flow vascular malformations are seen in CLOVES.
Musculoskeletal abnormalities usually involve the extremities and include macrodactyly, large hands, wide triangular feet, or widened sandal gap.
Management options are similar to those for KTS.
Recently, mutations in PIK3CA, which encodes for a subunit of PI3K, are the cause of CLOVES.
Activation of PI3K eventually leads to phosphorylation of AKT, levels of which are increased by the PI3K mutations seen in CLOVES. Mutations in this gene have been shown to induce angiogenesis and malignant cell growth.
What is Maffucci Syndrome?
This syndrome consists of exophytic VMs of the soft tissue and bones, bony exostoses, and endochondromas. This sporadic disorder is not usually evident at birth and can be unior bilateral.
The bony lesions and endochondromas manifest first in childhood, while the venous anomalies appear later.
Spindle cell hemangioendotheliomas commonly occur and denote reactive vascular proliferation within the preexisting VM, rather than true tumors.
The endochondromas can undergo malignant transformation in 20–30% of cases, leading to chondrosarcomas.
Two studies have identified somatic mosaic mutations in IDH-1 and IDH-2, which code for different forms of the enzyme isocitrate dehydrogenase, as the cause of Maffucci syndrome.
What is Parkes Weber Syndrome?
Parkes Weber syndrome is a sporadic, combined fast-flow vascular malformation affecting the limb and trunk, with the lower extremity being the most common site.
Capillary arteriovenous fistulae (CAVF) and CM-AVM are combined with hypertrophy of the bone and muscle of the affected limb.
CM-AVM is obvious at birth, appearing as overgrowth with a large geographic macular pink stain. In contrast to CLVM seen with KT syndrome, the limb hypertrophy is symmetric along the length and substance of the extremity.
The macular stain associated with CM-AVM has much greater cutaneous warmth than the typical CM.
The finding of bruits or thrills on examination confirms the diagnosis.
MRI demonstrates symmetric muscular and bony overgrowth, with generalized enlargement of the normal named arteries and veins within the affected limb.
Angiography depicts the discrete arteriovenous fistulae. In rare cases, superselective embolization is used to occlude the arteriovenous shunts if symptoms of ischemia, pain, or high-output congestive heart failure occur.
What is FAVA?
Fibro-adipose vascular anomaly (FAVA) is a newly recognized complex mesenchymal malformation.
It consists of fibrofatty replacement of an affected muscle with associated slow-flow vascular malformations. It usually affects the extremities with the calf (usually the gastrocnemius muscle) and forearm most commonly involved.
Phlebectasia of the affected muscle or the adjacent subcutaneous tissue is most commonly seen, though minor LMs are also possible.
The typical presentation involves a progressively painful limb with motor dysfunction and eventual joint contracture.
The muscle can be either focally or diffusely involved with the degree of involvement often predictive of the level of pain.
US can be used to differentiate a compressible common VM from the solid FAVA lesion.
MRI demonstrates a moderately hyperintense signal on T2-weighted images and enhancement on postcontrast T1-weighted images.
Orthopedic involvement is needed for these patients, and resection of the lesion is often required.
Cryotherapy can also be used for focal lesions not involving the neurovascular bundles.
What is PTEN Hamartoma Syndrome?
Bannayan–Riley–Ruvalcaba (BRRS) and Cowden syndromes (CS) are autosomal dominant disorders caused by mutations of the tumor-suppressor gene PTEN (phosphatase tensin homolog on chromosome 10), collectively termed PTEN hamartoma tumor syndrome (PHTS).
BRRS is primarily an overgrowth syndrome that has vascular malformations as a minor component.
The more prominent clinical features are macrocephaly, developmental delay, multiple lipomas, hamartomatous polyps of the ileum and colon, genital lentiginosis, and Hashimoto thyroiditis.
CS is characterized by mucocutaneous and papillomatous lesions, lipomas, hamartomatous intestinal lesions, and an increased risk for thyroid, breast, and endometrial cancer.
Multifocal fast-flow vascular anomalies associated with ectopic fat are seen in about half of patients with PTEN mutations.
Macrocephalic patients with fast-flow vascular anomalies or multiple intracranial developmental venous anomalies should be tested for PTEN mutations.
Identifying PTEN mutations is important as these patients are at increased risk of developing tumors of the breast, thyroid, and endometrium, and need appropriate surveillance.
Large or symptomatic hamartomas can be resected while AVMs can undergo embolization with or without resection.
A 14-day-old neonate presents to the emergency department with difficulty breathing. The infant is found to have massive hepatomegaly and is in distributive shock. Radiography reveals near-total displacement of the liver parenchyma with innumerable heman-giomas. Given the likely diagnosis, which of the following is the most likely complication of this neonate’s condition?
Choices:
1. Hypothyroidism
2. Gastrointestinal bleeding
3. Spontaneous bacterial peritonitis
4. Cerebrovascular accident
Answer: 1 - Hypothyroidism
Explanations:
• Diffuse infantile hepatic hemangiomas can present with massive hepatomegaly and cardiac failure. Cardiac failure may be due to high output failure from extensive arteriovenous and portosys-temic venous shunting. Cardiac failure may also occur secondary to poor contractility due to acquired hypothyroidism in these patients.
• Patients with diffuse infantile hepatic hemangioma may present with severe consumptive hypothyroidism due to increased production of type 3 iodothyronine deiodinase. Type 3 iodothyronine deiodinase converts thyroxine to its inactive forms leading to hypothyroidism.
• Diffuse liver hemangiomas are rare and may occur in the absence of skin hemangiomas. Patients may present with hypothyroidism and cardiac failure as described in this case. They may also present with massive hepatomegaly, abdominal compartment syndrome, impaired ventilation, and renal vein compression.
• Other complications include gastrointestinal hemorrhage if visceral hemangiomas are present, but this is exceedingly rare.
StatPearls
A well-appearing, 4-month-old infant presents to her primary care provider. The medical history is pertinent for premature birth at 35 weeks. Physical exam reveals multiple cutaneous hemangiomas involving the extremities, trunk, and one on the forehead but none adjacent to the eyes. Exam is otherwise within normal limits. Six hemangiomas are counted in total. What additional evaluation should the infant undergo?
Choices:
1. None
2. Thyroid function testing
3. Liver ultrasound
4. Ophthalmologic evaluation
Answer: 3 - Liver ultrasound
Explanations:
• Infants with greater than five cutaneous infantile hemangiomas have an increased risk of infantile hepatic hemangioma and should undergo liver ultrasound to evaluate the hepatic parenchyma.
• Risk factors for infantile hemangiomas include prematurity, low birth weight, and family history.
• Infants with diffuse infantile hepatic hemangioma may overproduce type III iodothyronine deiodinase, leading to acquired hypothyroidism. The absence of symptoms of hypothyroidism or hepatomegaly on exam makes this less likely in this question and would not be the next step in evaluation.
• Infantile hemangiomas of the skin, when located near the eye, may cause complications in vision including amblyopia, astigmatism, or strabismus.
StatPearls
A one-week-old baby is brought by her mother for a check-up. She was born vaginally, and the delivery was uncomplicated.
Apgar scores were 8 and 10 at 1 and 5 minutes, respectively. The patient was born with a mass protruding from her left sternocleidomastoid.
On examination, the mass is soft, measures 5 cm in diameter, appears to contain fluid, and is unilocular. What underlying condition is most likely present in this newborn?
Choices:
1. Fragile X syndrome
2. Turner syndrome
3. Von Hippel-Lindau syndrome
4. Angelman syndrome
Answer: 2-Turner syndrome
Explanations:
• The mass present in the newborn is most likely a lymphangioma.
• Congenital lymphangiomas form due to blockage of the lymphatic system during fetal development, though the cause remains unknown. Cystic lymphangiomas are associated with genetic dis-orders, including trisomies 13, 18, and 21, Noonan syndrome,
Turner syndrome, and Down syndrome.
• Lymphangiomas are soft, with varying sizes and shapes, and will typically grow if not surgically excised. When posterior neck lesions are present, there may be an association with Turner syn-drome, hydrops fetalis, or other congenital abnormalities.
• Lymphangiomas result from congenital or acquired abnormalities of the lymphatic system. The congenital form typically occurs before the age of 5 years. Acquired lymphangiomas occur as a sequela of any interruption of previously normal lymphatic drainage such as surgery, trauma, malignancy, and radiation therapy.
StatPearls
A 5-year-old healthy male has an asymptomatic, enlarged upper lip at birth. The skin is normal. The lip has continued to steadily increase in size over the course of his lifetime. Which of the following is the most likely diagnosis?
A infantile haemangioma
B congenital haemangioma
C pyogenic granuloma
D lymphatic malformation
E kaposiform haemangioendothelioma (KHE).
D
lymphatic malformation is present at birth and slowly enlarges over time.
Infantile haemangioma is usually noted 2 weeks after birth and grows rapidly over the first few months of life; by 1 year of age the tumour begins to regress.
Congenital haemangioma is fully grown at birth and does not enlarge postnatally.
Pyogenic granuloma does not appear at birth. It usually appears in early childhood as a rapidly growing, red lesion that frequently bleeds.
KHE often presents at birth or in infancy and nearly 90% have cutaneous, reddish-purple lesions. KHE is frequently associated with Kasabach–merritt’s phenomenon (severe thrombocytopenia due to intralesional trapping).
SPSE 1
A 3-month-old girl has a rapidly enlarging, 10 cm facial haemangioma causing ulceration and a nasal deformity. Which of the following is the most appropriate treatment?
A interferon
B corticosteroid
C resection
D pulsed dye laser
E sclerotherapy
B
First-line treatment for a large, problematic infantile haemangioma is prednisolone, a corticosteroid.
Almost all infantile haemangiomas will respond as long as the correct dose is given (3 mg/kg/day).
Response is considered either stabilisation (the tumour no longer enlarges) or accelerated regression (the lesion becomes smaller).
Corticosteroid is very safe. unlike patients who receive chronic, high-dose corticosteroid for transplants or autoimmune disorders, infants with infantile haemangioma are treated for only a few months and the dose is rapidly weaned as they gain weight and the physician lowers the dose.
Interferon is no longer used for patients with infantile haemangioma because it causes spastic diplegia.
Resection of this large, proliferating tumour is contraindicated; during infancy the tumour is highly vascular and the patient is at risk for major blood loss and facial nerve injury.
Pulsed dye laser treatment for a cutaneous, proliferating infantile haemangioma is contraindicated; the laser cannot penetrate into the deep dermis or subcutaneous tissue and thus has minimal efficacy. In addition, the laser delivers a thermal injury to the already compromised skin and has been shown to increase the risk of ulceration, pain and scarring.
Sclerotherapy is effective treatment for lymphatic or venous malformations, not for infantile haemangioma.
SPSE 1
What is first-line management of a painful, diffuse venous malformation involving the left cheek, orbit and lip?
A resection
B embolisation
C corticosteroid
D interferon
E sclerotherapy
E
Sclerotherapy, the injection of the malformation with a sclerosant (e.g. sodium tetradecyl sulphate, ethanol), causes endothelial damage, scarring and shrinkage of the lesion. It is first-line treatment for a large, symptomatic venous malformation.
Resection of a diffuse venous malformation of the face would leave a worse deformity than the lesion, and the patient would be at risk for major blood loss and facial nerve injury.
Resection is reserved for small venous malformations that may be removed for cure, or when sclerotherapy is no longer possible because all vascular spaces have been obliterated.
Corticosteroid and interferon are indicated for some vascular tumours. Embolisation is used to treat high-flow arteriovenous malformations.
SPSE 1
Each of the following is a possible treatment for KHE except:
A resection
B sclerotherapy
C vincristine
D corticosteroid
E interferon
B
Sclerotherapy is used to treat venous and lymphatic malformations, not vascular tumours.
Resection is rarely indicated for KHE, but is possible for small or localised lesions.
Vincristine and corticosteroids are first-line options for KHE, though steroids are much less efficacious than vincristine.
Interferon may be used to treat KHE, but as a second-line agent because of side effects such as spastic diplegia in infants.
SPSE 1
A mutation in each of the following genes is associated with inherited vascular anomalies except:
A RASA1
B PTEN
C BRCA1
D VEGFR3
E TIE2.
C
mutations in BRCA1 have not been found to cause vascular anomalies.
RASA1 mutation causes capillary malformation-arteriovenous malformation.
PTEN mutations can cause arteriovenous malformations.
VEGFR3 mutations can cause primary lymphoedema.
mutations in TIE2 may result in venous malformations.
SPSE 1
First-line operative management for a symptomatic child with a moderately enlarged lower extremity from primary lymphoedema is:
A liposuction
B excision and skin grafting
C lymphaticovenous anastomosis
D staged skin/subcutaneous excision
E omental flap transfer.
A
Liposuction effectively removes, with low morbidity, the subcutaneous adipose tissue that develops from lymphoedema.
Excision and skin grafting is a radical approach and is only considered in extreme disease because the procedure is associated with significant morbidity.
lymphaticovenous anastomosis may improve lymphatic flow in patients with secondary lymphoedema, but has minimal effects on limb size because the subcutaneous adipose tissue is not removed.
Staged skin/subcutaneous excision is indicated for patients with severely enlarged legs when significant skin excess would be expected following liposuction.
omental flap transfer has not been shown to improve lower extremity lymphoedema and is associated with significant complications.
SPSE 1
An infant has a large facial haemangioma and cannot be treated with corticosteroid because of a severe pulmonary infection. What is the next step in management?
A vincristine
B cyclophosphamide
C propranolol
D thalidomide
E interferon
C
Propranolol, a beta blocker, recently has been shown to have activity in infantile haemangioma. However, its efficacy and safety compared with corticosteroid has not been studied.
Complications such as hypotension and hypoglycaemia have been reported, and infants require close monitoring after the initiation of therapy.
Vincristine and cyclophosphamide have been reported to slow haemangioma growth, but they require intravenous administration and have greater toxicity and less efficacy than propranolol.
Thalidomide has antiangiogenic activity but has not been used to treat infantile haemangioma.
Although interferon is effective, it is avoided in infants because it can cause spastic diplegia.
SPSE 1
A 5-year-old male has a large upper lip microcystic lymphatic malformation causing a deformity. What is the most appropriate management?
A corticosteroid
B pulsed dye laser
C sclerotherapy
D resection
E embolisation
D
Resection is the only current treatment for microcystic lymphatic malformation; the cysts are too small to be accessed for sclerotherapy.
Sclerotherapy is first-line treatment for macrocystic lymphatic malformation.
Corticosteroid is used to treat problematic infantile haemangioma.
Pulsed dye laser can effectively lighten capillary malformations.
Embolisation is indicated for arteriovenous malformations.
SPSE 1
A 3-month-old healthy female has a 1 cm superficial infantile haemangioma on the buttock. What is the most appropriate management?
A corticosteroid
B resection
C observation
D embolisation
E sclerotherapy
C
more than 90% of infantile haemangiomas are non- problematic and are observed; lesions will regress after 12 months of age.
Corticosteroid is reserved for problematic lesions threatening vital structures or at risk for causing a significant deformity.
Resection is rarely indicated for proliferating lesions during infancy, but may be performed in early childhood to correct residual deformities caused by the tumour.
Embolisation is rarely used for large haemangiomas causing congestive heart failure.
Sclerotherapy is indicated for lymphatic or venous malformations.
SPSE 1
A 7-year-old female has a 4 cm, pedunculated infantile haemangioma of the right cheek. What is the most appropriate management?
A corticosteroid
B pulsed dye laser
C sclerotherapy
D resection
E embolisation
D
After involution, infantile haemangiomas often leave behind fibrofatty residuum, redundant skin or damaged structures that require resection and/or reconstruction.
Corticosteroid is effective for problematic infantile haemangiomas during the proliferative phase in infancy.
Pulsed dye laser is used to treat residual cutaneous telangiectases following involution.
Sclerotherapy is indicated for lymphatic or venous malformations.
Embolisation is rarely indicated for large haemangiomas in infancy causing congestive heart failure.
SPSE 1
You are planning to biopsy a large, firm, purple cutaneous mass on the chest of a 6-month-old and notice a platelet count of 8 × 109 /L. Immediately after platelet transfusion, the mass painfully enlarges and becomes dark purple. What is the diagnosis of the mass?
A infantile haemangioma
B KHE
C arteriovenous malformation
D venous malformation
E epithelioid haemangioendothelioma
B
KHE is a vascular tumour typically presenting in infancy. KHE may behave aggressively, crossing adjacent tissue planes. The majority of lesions manifest severe thrombocytopenia known as Kasabach–merritt’s phenomenon, due to intralesional platelet trapping. Platelet transfusions are rapidly consumed by trapping in the lesion, as described in this case. Venous malformations may have localised intralesional coagulation leading to low fibrinogen, high D-dimer, prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), but the platelet count is usually normal. Infantile haemangioma, arteriovenous malformations and epithelioid haemangioendothelioma are not associated with thrombocytopenia.
SPSE 1
Possible complications from infantile haemangiomas include all of the following except:
A ulceration
B visual impairment
C airway compromise
D hypothyroidism
E hypokalaemia.
E
Infantile haemangiomas are benign, self-resolving tumours identified in 4%–8% of Caucasian infants.
Despite their self-resolving natural history, certain locations are at risk of complications during the rapid proliferative phase.
Infantile haemangioma in locations susceptible to incidental trauma, such as lips, nasal tip, perineum and hand are prone to ulceration.
Periorbital lesions can occlude vision during a critical developmental period, leading to strabismus, amblyopia and even monocular blindness.
Subglottic lesions may present with stridor and can progress to airway obstruction if untreated.
Very large haemangiomas, often including diffuse hepatic haemangiomas, overproduce type III iodothyronine deiodinase leading to severe consumptive hypothyroidism requiring aggressive repletion.
Electrolyte abnormalities are not associated with infantile haemangiomas.
SPSE 1
Soon after menarche, a 12-year-old girl develops an enlarging painful mass over her right deltoid. Imaging confirms a high-flow lesion and you suspect an arteriovenous malformation. Which of the following is recommended prior to excision?
A CO2 -laser therapy
B embolisation
C sclerotherapy
D pulsed dye laser therapy
E bevacizumab (antiangiogenic medical therapy)
B
Arteriovenous malformations are often present at birth and present with periods of rapid growth, onset of pubertal hormones or pregnancy or after trauma.
These high-flow, densely vascular lesions are surgically challenging to remove and require wide, complete excision to prevent recurrence.
Preoperative embolisation of feeding arteries may shrink the malformation, reduce intraoperative bleeding and increase the chance of curative surgery.
SPSE 1
Which of the following best describes the natural history of an infantile haemangioma?
A present at birth, proliferation for 5 months, slow involution over several years
B prenatal diagnosis, proliferation for 5 months, rapid involution by 1 year
C presenting 2 weeks after birth, proliferation for 5 months, slow involution over several years to residuum of fibrous and adipose tissue
D presenting weeks after birth, proliferation for 5 months, rapid involution by 1 year
E presenting any time through childhood, variable progression and involution
C
Infantile haemangioma may have a faint precursor lesion visible at birth, though prenatal or fully formed tumours at birth exclude this diagnosis.
The median age of presentation for infantile haemangioma is 2 weeks after birth.
Infantile haemangiomas exhibit rapid proliferation for 3–5 months and then slowly involute from 12–15 months through 5–7 years of age, leaving behind skin with reduced elasticity, increased fibrofatty tissue, scarring and hypopigmentation.
lesions varying from this natural history require further evaluation.
SPSE 1
Complications of extensive, diffuse hepatic haemangioma in a 3-month-old include all of the following except:
A poor growth
B severe consumptive hypothyroidism
C restrictive lung disease due to poor diaphragm excursion
D severe thrombocytopenia
E massive hepatomegaly and abdominal compartment syndrome.
D
Hepatic haemangiomas may be focal, multifocal or diffuse.
Focal hepatic haemangiomas are Glut-1 negative, may be present prenatally and undergo rapid spontaneous involution.
multifocal hepatic haemangiomas are Glut-1 positive and may include arteriovenous shunting leading to high-output cardiac failure.
Diffuse hepatic haemangiomas are Glut-1 positive and may efface the entire liver.
Hepatomegaly can lead to inferior vena cava compression, respiratory compromise, abdominal compartment syndrome, multiorgan system failure and rarely lead to hepatic transplantation.
Diffuse hepatic haemangiomas overproduce an enzyme that consumes thyroid hormone.
The resulting severe hypothyroidism requires aggressive replacement to prevent mental retardation associated with congenital hypothyroidism.
Thrombocytopenia is not associated with infantile haemangioma.
SPSE 1
Which of the following statements regarding vascular malformations is not true?
A Vascular malformations form during embryologic vasculogenesis.
B Vascular malformations may present at any age.
C Vascular malformations are more amenable to interventional or surgical therapies than to medical therapies.
D Vascular malformations may include combinations of venous, arterial, capillary and/or lymphatic structures.
E Haemangiomas are one type of vascular malformation.
E
Vascular anomalies are currently classified into tumours and malformations.
Tumours are proliferative and present at different ages, though often in infancy.
malformations represent dysfunctional embryologic vasculogenesis.
While malformations may enlarge, it is currently unclear if this occurs through enlargement of existing channels, angiogenesis or vasculogenesis. Because they are less proliferative than tumours, they are less amenable to antiangiogenic and antiproliferative therapies and are generally managed by sclerotherapy, embolisation and/or resection.
SPSE 1
You are evaluating a dark-red cutaneous chest lesion in a healthy 4-month-old infant. Which of the following features supports the diagnosis of infantile haemangioma?
A initial presentation at 1 month of age
B no significant change in appearance throughout infancy
C needle biopsy evaluation reveals negative Glut-1 staining
D platelet count 12 × 109 /L
E slow vascular flow on Doppler evaluation
A
Infantile haemangioma typically presents in the first few weeks of life, though presentation in early infancy is not diagnostic.
Not following the natural history of infantile haemangioma (proliferation, slow involution and fibrofatty residuum), the absence of Glut-1 positive immunostaining, and severe thrombocytopenia, each rule out infantile haemangioma.
Infantile haemangiomas are often warm and are invariably high-flow lesions during the proliferative phase of growth.
SPSE 1
You are evaluating a 12-year-old boy with a large lipovascular hamartoma in his thigh with associated arteriovenous malformations. You notice frontal bossing and penile freckling on exam and recommend testing for what genetic syndrome and why?
A Li–Fraumeni’s syndrome (p53) – high risk of adenocarcinomas early in life
B Fanconi’s anaemia – risk of aplastic anaemia and haematological malignancies
C PTEN mutation – risk of thyroid, breast and other malignancies through life
D trisomy 21 (Down’s syndrome) – risk of congenital heart disease, cognitive impairment and leukaemias
E Beckwith–Wiedemann’s syndrome – risk of hemihypertrophy, Wilms’s tumour, hypoglycaemia and hepatoblastoma
C
Among these cancer predisposition choices, benign vascular hamartomas with significant lipomatous composition, associated arteriovenous malformations, frontal bossing and penile freckling are distinctive phenotypically for patients with PTEN mutations.
multiple syndromes in the literature are now known to be allelic, including PTEN hamartoma tumour syndrome, Cowden’s syndrome, Bannayan–Riley–Ruvalcaba’s syndrome, Proteus and Proteus-like syndrome and adult-onset lhermitte–Duclos’s disease.
Increased risk of breast and thyroid cancer require regular screening.
macrocephaly, intestinal hamartomatous polyps and mucocutaneous lesions are very common.
SPSE 1
The following patterns of infantile haemangioma warrant additional consideration of associated underlying or associated anomalies except:
A nasal tip haemangioma
B extensive facial haemangioma
C submandibular ‘beard’ distribution haemangioma
D midline haemangioma overlying the lumbosacral spine
E more than 20 multifocal cutaneous haemangiomas.
A
Nasal tip haemangiomas are associated with ulceration, but not with any underlying or associated anomalies.
Extensive facial haemangiomas should be evaluated for PHACE syndrome (Posterior cranial fossa abnormalities, Haemangioma, Arterial anomalies, Cardiovascular defects and Eye abnormalities).
‘Beard’ distribution haemangiomas are associated with subglottic haemangiomas and risk of airway compromise.
lumbosacral midline haemangiomas are associated with underlying spinal cord dysraphisms.
multifocal cutaneous infantile haemangiomas (>5) are associated with visceral haemangiomas, particularly hepatic.
SPSE 1
The best initial therapy for a newborn with a large, prenatally identified, submandibular macrocystic lymphatic malformation (previously called ‘cystic hygroma’) is:
A elective tracheostomy
B aspiration of fluid followed by sclerotherapy
C close observation without intervention until older than 5 years
D treatment with either corticosteroid or propranolol
E simple aspiration of fluid.
B
Some prenatal macrocystic lymphatic malformations cause concern around methods of delivery and protection of the neonatal airway.
Tracheostomy is rarely indicated since needle aspiration will decompress these macrocysts effectively.
These malformations tend to be compressible and wrap around structures without compressing them.
Aspirated fluid will simply re-accumulate if a sclerosant is not administered.
Deferral of sclerotherapy allows intralesional haemorrhage to convert these to solid, scarred masses no longer treatable with sclerotherapy and instead, require more difficult surgical resection/debulking.
Corticosteroid or propranolol therapy is used for some patients with infantile haemangioma, but these therapies have no role in macrocystic lymphatic malformations.
SPSE 1
A 1-month-old with a severely swollen and purple right leg, severe thrombocytopenia (8000 × 109 /L), is referred to you with the diagnosis of ‘haemangioma’. What is the cause of the thrombocytopenia?
A autoimmune idiopathic thrombocytopenia with purpura
B sepsis with disseminated intravascular coagulation
C intralesional platelet trapping
D alloimmune (maternal antibody against fetal platelet) thrombocytopenia
E congenital amegakaryocytic thrombocytopenia
C
The case describes Kasabach–merritt’s phenomenon associated with KHE.
This consumptive thrombocytopenia is due to intralesional platelet trapping and may be seen in some biopsy samples.
Platelet transfusion leads to rapid painful expansion of the vascular tumour due to engorgement behind occlusive platelet thrombi.
Sepsis should always be considered in a young infant with thrombocytopenia, though prolonged PT and aPTT are the main laboratory findings in sepsis and disseminated intravascular coagulation, thrombocytopenia is rarely this severe.
other choices are rare causes of neonatal/infant thrombocytopenia with no association to vascular anomalies.
SPSE 1
A 3-month-old presents with a purple 6 cm cutaneous chest lesion with a surrounding halo present at birth and now much smaller and paler. What is the diagnosis?
A infantile haemangioma
B non-involuting congenital haemangioma (NICH)
C congenital lymphoedema
D KHE
E rapidly involuting congenital haemangioma (RICH)
E
The natural history of this lesion is critical to making the diagnosis of RICH.
The pale halo signifies involution.
NICH does not change over time.
Infantile haemangiomas proliferate over the first 3 months of life and do not have a halo present at birth.
KHE lesions may involute spontaneously over a few years and would not have a halo present at birth.
Congenital lymphoedema presents with swollen legs and genitalia and some cases are caused by autosomal dominant inheritance of VEGFR3 mutations.
SPSE 1
Which of the following is the most likely cause of progressive osteolysis involving bone cortex, sparing joints between involved bones and often affecting the skull and cervical spine?
A Gorham–Stout’s syndrome
B metastatic neuroblastoma
C microcystic lymphatic malformation
D multiple myeloma
E Langerhans’s cell histiocytosis
A
This is a classic definition of Gorham–Stout’s disease, also called ‘disappearing bone disease’ because of the loss of bony cortex and, therefore, even entire bones.
metastatic malignancies, such as neuroblastoma or multiple myeloma, may manifest ‘punched-out’ lytic bone lesions, but the cortex is preserved.
langerhans’s cell histiocytosis has painful lytic bone lesions with a sclerotic or inflammatory rim.
microcystic lymphatic malformations are typically confined to soft tissue, although generalised lymphatic anomalies or lymphangiomatosis may involve bone, though again with preserved bone cortex.
SPSE 1
An adolescent with massive right leg and overlying port-wine discoloured stain, leg-length discrepancy, limited range of knee movement and elevated D-dimer is most consistent with which diagnosis?
A microcystic lymphatic malformation
B CLOVES syndrome
C diffuse capillary malformation with overgrowth (DCMO)
D mixed capillary- lymphatic- venous malformation (Klippel Trénaunay)
E PTEN syndrome
D
microcystic lymphatic malformations may present with enlarged extremities, but do not have overlying capillary stains.
CloVES is a recently described syndrome with Congenital lipomatous overgrowth, Vascular anomalies, Epidermal naevi and Spinal arteriovenous malformations and Scoliosis.
DCmo comprises limb overgrowth secondary to diffuse capillary malformation. Enlarged veins may be associated with DCmo, but elevated D-dimers and joint problems are not.
Klippel–Trénaunay’s describes a mixed capillary–lymphatic–venous malformation. Extremity overgrowth can be massive and severely debilitating. Involvement of the knee with venous or lymphatic malformations may cause pain and haemarthrosis.
Intralesional thrombosis is common, leading to elevated D-dimers, low fibrinogen, prolonged PT and aPTT and these patients may have significant thromboembolic risk because of large-calibre draining veins.
PTEN syndrome is associated with lipovascular hamartomas with unusual arteriovenous malformations, breast and thyroid cancer risk, penile freckling and frontal bossing.
SPSE 1
Regarding arteriovenous malformation, which of the following is false?
A. Most occur in peripheral vessels.
B. Macro fistulous are obvious and easily seen on angiography.
C. Mostly seen in lower limbs.
D. Can be classified as micro-fistulous and macro-fistulous.
E. May be associated with hemi-atrophy of limb.
E
Arteriovenous malformation may be associated with hemi-hypertrophy of limb because of enhanced blood flow.
Syed/MCQ
Regarding congenital aneurysm, which one of the following is false?
A. Usually involves visceral arteries.
B. Rupture is unusual.
C. Hypotension is common when renal artery branches are involved.
D. Common in spleen and liver.
E. Repair is indicated for more than 2 cm.
C
Compression of renal arteries or its branches leads to hypertension because of renin angiotensin mechanism.
Syed/MCQ
Features of midaortic syndrome include all except:
A. Fibromuscular dysplasia.
B. Aortic aneurysm.
C. Malignant hypertension.
D. Congestive cardiac failure.
E. Renal failure.
B
Midaortic syndrome is associated with narrowing of aorta.
Syed/MCQ
Regarding Klippel-Trenaunay syndrome, all of the following are correct except:
A. Limb hypertrophy.
B. Lymphatic dysplasia.
C. Port wine stain.
D. Venous hypertension.
E. Varicose vein.
E
Varicose vein is not a feature of Klippel-Trenaunay syndrome.
Syed/MCQ
The following are diffuse congenital Malformations of venous predominance except:
A. Haemangioma.
B. Klippel-Trenaunay syndrome.
C. Proteus syndrome.
D. Parkes-Weber syndrome.
E. Maffucci syndrome.
A
Haemangioma is a localised condition, not a diffuse one.
Syed/MCQ
About arteriovenous malformation all of the following are correct except:
A. Usually slow flow.
B. Present at birth.
C. Evident on infancy.
D. Skin becomes red or violaceous.
E. Local warmth, thrill or bruit.
A
Arteriovenous malformation is usually fast flow, while complex combined vascular malformation is usually slow flow.
Syed/MCQ
The best sclerosing agent used to manage lymphatic malformation is:
A. One hundred per cent ethanol.
B. Sodium tetradecyl sulphate.
C. Bleomycin.
D. OK432.
E. Any of the above.
E
Any of the above-mentioned sclerosing agents can be used in the management of lymphatic malformation.
Syed/MCQ
What is false about haemangioma?
A. They are tumours of vascular tissue.
B. They are the third most common soft tumour of infancy.
C. They are the most common congenital anomaly in humans.
D. Incidence is 1–3 percent.
E. Female to male ratio 3:1.
B
Haemangioma is the most common soft-tissue tumour in infancy, not the third-most common.
Syed/MCQ
The following are variety of capillary haemangioma except:
A. Salmon pink.
B. Strawberry nevus.
C. Port wine stain.
D. Spider nevus.
E. Cystic hygroma.
E
Cystic hygroma is a variety of lymphatic malformation.
Syed/MCQ
Regarding management of haemangioma, which is false?
A. About 25 percent naturally undergo involution.
B. Corticosteroid is one method of treatment.
C. Alpha interferon is used for serious and life-threatening haemangioma.
D. Laser therapy is only used in cutaneous haemangioma.
E. Excision should be performed in involution phase.
A
Most haemangioma does not require treatment, and more than 50 per cent are naturally involute.
Syed/MCQ
Which of the following is not true about lymphangioma?
A. Majority apparent at birth.
B. OK432 is helpful in treatment.
C. Mortality in general is less than 10 percent.
D. Intrathoracic has higher mortality than cervicomediastinal.
E. Lymphangioma of extremities has low mortality.
D
Cervicofacial and cervicomediastinal has about 33 percent mortality.
Intrathoracic, intraabdominal, trunk and extremities have low mortality. Mortality in general is 3.5–5.7 percent.
About 65 percent are apparent at birth and 90 percent are apparent by the end of second year of life.
Syed/MCQ
Regarding lymphatic disorders, all of the following are false except:
A. Fluid in chylothorax contains more than 20 percent of lymphocytes.
B. Cavernous lymphangioma comprises of capillary-sized lymphatic channels.
C. Cystic hygroma undergoes malignancy.
D. Bleomycin is one of the treatment of lymphangioma.
E. In chylous ascites, internal drainage by percutaneous shunt is not possible.
D
Fluid in chylothorax contains more than 60 percent lymphocytes.
Lymphangioma simplex is composed of small (capillary-sized) lymphatic channels, while cavernous lymphangioma comprises dilated lymphatic channels.
Cystic hygroma and other variety of lymphatic malformation do not undergo malignancy.
Bleomycin, OK432, serial laser therapy and surgery are all different ways of treating lymphangioma.
In chylous ascites, internal drainage by percutaneous shunt is a possible treatment.
Syed/MCQ
Regarding lymphedema, which statement is false?
A. There is increase lymph in interstitial tissue.
B. Primary lymphedema is more common than secondary.
C. Lymphedema Praecox is secondary type of lymphedema.
D. Lymphedema Tarda presents after 35 years of age.
E. Excision surgery by Charles method involves removal of skin and subcutaneous tissues down to the muscle and covering the nude surface with split-thickness skin graft.
C
Primary lymphedema is one in which there is lymphatic aplasia.
There are three primary types: congenital is at birth, praecox presents before 35 years of age and Tarda presents after 35 years of age.
Secondary variety of lymphedema is caused by radiation, tumours, fibrosis, or inflammation.
Primary lymphedema is more common than secondary.
In Charles method, skin and subcutaneous tissues are removed down to the muscles and denuded surface is covered by split-thickness skin graft. In
Homan’s method of excision surgery, excision of subcutaneous tissues and deep fascia and creation of thick skin flaps, which are used to cover the excised area, rather than skin grafts.
Syed/MCQ
Regarding cystic hygroma, all of the following are correct except:
A. It is lined by endothelial cells.
B. It is a cluster of lymphatic channels that fails to connect to normal lymphatic pathway.
C. Fifty to seventy per cent appear one month after birth.
D. It appears as lump at lower third of neck.
E. Cystic lymphangioma is same as cystic hygroma.
C
50–70 percent appears at birth.
Syed/MCQ
The following are the slow flow vascular malformation except:
A. Telangiectasia.
B. Klippel-Trenaunay syndrome.
C. Proteus syndrome.
D. Solomon syndrome.
E. Parkes-Weber syndrome.
E
Parkes-Weber syndrome is a fast-flow vascular malformation.
Syed/MCQ
Vascular malformation is different from haemangioma by all of the following features except:
A. It is a developmental error of vessels.
B. It is composed of dysplastic vessels.
C. It almost never regresses.
D. It is present at birth.
E. It is marked by ulceration and bleeding.
E
Ulceration and bleeding is common feature to both haemangioma and vascular malformation.
Syed/MCQ
What are the different sclerosing agents used for sclerotherapy?
1) OK-432 (Picibanil)
0.1 - 0.2mg/dose
OK-432, though not currently approved by the US Food and Drug Administration (FDA), has been reported to be capable of successfully treating LM. The mechanism of action is proposed to be an inflammatory response to the inactive bacteria, leading to fibrosis. OK-432 may be a viable option for large unilocular cysts.
Currently, OK-432 is available in the United States only by protocol. It does not work well for small cysts.
Because the procedure for using OK-432 involves aspiration prior to injection of the sclerosant, some have hypothesized that the true effect is from the aspiration.
2) Bleomycin
0.5mg/kg (not exceeding 10u at a time)
Bleomycin, a cytotoxic antibiotic, has been considered a poor choice because of its toxicity (pulmonary fibrosis); LM is a benign disease, and other less toxic treatment options are available. Niramis et al studied 70 patients who underwent sclerotherapy with bleomycin; 83% obtained an excellent or good result, 43% had adverse reactions, and three patients died.
Sainsbury et al studied 75 patients, 83% of whom had a complete or significant response. Five adverse reactions were reported, with no severe morbidity or mortality (including pulmonary fibrosis).
3) Alcohol
0.5ml/kg
Absolute alcohol as a sclerosing agent has been used with some success in some patients; alcohol works well in vascular malformations. Imperizzilli et al studied computed tomography (CT)-guided ethanol injection and obtained complete resolution in seven of eight patients without complications. [22]
Interferon alfa-2a
This has been used in the treatment of hemangiomas, and its use has been proposed in lymphangiomas. However, its efficacy has never been documented, and it carries a serious side-effect profile.
4) Fibrin sealant
The use of a fibrin sealant after aspiration of LM has been reported in the literature.
5) Doxycycline
10mg/mL (max 20mg/kg or 1000mg)
Doxycycline has been reported as a potential sclerotherapy agent, with both safety and efficacy. Like most other sclerosant agents, it has shown the highest efficacy in macrocystic lesions and the lowest efficacy in microcystic ones.
6) Sildenafil
A limited case series has been reported using sildenafil for severe lymphatic malformations. A prospective trial has been performed, which did not demonstrate a significant effect on LM.
7) Sirolimus
Sirolimus (rapamycin) is a mammalian target of rapamycin (mTOR) inhibitor that may be helpful in treating LMs. It works through deregulation of the mTOR pathway, which is suspected of playing a role in the pathogenesis of vascular anomalies. Sirolimus causes a decrease in vascular endothelial growth factor (VEGF), which is a known regulator in lymphangiogenesis.
Sirolimus has been studied in several small series, but the optimal dose and duration have not been identified. [26, 27, 28, 29] In a systematic review, treatment results from 105 patients with LM were reported, with more than 91% of patients showing at least a partial response to treatment.
Although complete response was seldom seen, many patients did benefit from the partial response and pain-relieving action. In complex cases where surgical therapy or sclerotherapy is difficult, sirolimus may be a useful option.
A multicenter clinical trial is under way to assess the safety and efficacy of sirolimus in treating LMs; the hope is that sirolimus may become the new first-line therapy.
Medscape
Table from Bagrodia, et Al (2015, Management of lymphatic malformations in children. Current Opinion in Pediatrics)
