Lymphovascular Anomalies Flashcards

Question

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.

Answer 1

A. Usually slow flow.

Answer 2

A. About 25 percent naturally undergo involution.

Answer 3

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.

Answer 4

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.

Answer 5

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.

Answer 6

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.

Answer 7

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)

Answer 8

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.

Answer 9

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

Answer 10

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]

Answer 11

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]

Answer 12

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

Answer 13

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.

Answer 14

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.

Answer 15

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.

Answer 16

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.

Answer 17

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.

Answer 18

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.

Answer 19

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.

Answer 20

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.

Answer 21

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.

Answer 22

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.

Answer 23

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.

Answer 24

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.

Answer 25

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.

Answer 26

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

Answer 27

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

Answer 28

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

Answer 29

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

Answer 30

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

Answer 31

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

Answer 32

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

Answer 33

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

Answer 34

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

Answer 35

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

Answer 36

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

Answer 37

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

Answer 38

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

Answer 39

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

Answer 40

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

Answer 41

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

Answer 42

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

Answer 43

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

Answer 44

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

Answer 45

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

Answer 46

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

Answer 47

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

Answer 48

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

Answer 49

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

Answer 50

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

Answer 51

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

Answer 52

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

Answer 53

E Arteriovenous malformation may be associated with hemi-hypertrophy of limb because of enhanced blood flow. Syed/MCQ

Answer 54

C Compression of renal arteries or its branches leads to hypertension because of renin angiotensin mechanism. Syed/MCQ

Answer 55

B Midaortic syndrome is associated with narrowing of aorta. Syed/MCQ

Answer 56

E Varicose vein is not a feature of Klippel-Trenaunay syndrome. Syed/MCQ

Answer 57

A Haemangioma is a localised condition, not a diffuse one. Syed/MCQ

Answer 58

A Arteriovenous malformation is usually fast flow, while complex combined vascular malformation is usually slow flow. Syed/MCQ

Answer 59

E Any of the above-mentioned sclerosing agents can be used in the management of lymphatic malformation. Syed/MCQ

Answer 60

B Haemangioma is the most common soft-tissue tumour in infancy, not the third-most common. Syed/MCQ

Answer 61

E Cystic hygroma is a variety of lymphatic malformation. Syed/MCQ

Answer 62

A Most haemangioma does not require treatment, and more than 50 per cent are naturally involute. Syed/MCQ

Answer 63

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

Answer 64

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

Answer 65

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

Answer 66

C 50–70 percent appears at birth. Syed/MCQ

Answer 67

E Parkes-Weber syndrome is a fast-flow vascular malformation. Syed/MCQ

Answer 68

E Ulceration and bleeding is common feature to both haemangioma and vascular malformation. Syed/MCQ

Answer 69

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)