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.
—
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 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)
