Are You Confident of the Diagnosis?
What you should be alert for in the history
Kaposiform hemangioendothelioma (KHE) is an uncommon to rare vascular tumor. The diagnosis of KHE should be considered in rapidly or slowly growing vascular tumors presenting in early childhood, or in patients with red-brown stain-like areas with induration (another relatively common presentation). KHE tumors have a predilection for certain sites, particularly the proximal extremities and trunk, but other locations such as the lateral face and neck, the retroperitoneum, and mediastinum are not uncommon.
Characteristic findings on physical examination
The morphology of KHE is varied and may include poorly defined solitary nodules or infiltrating thick plaques. Cutaneous lesions most often initially present as pink “bruise-like” or brown-red patches that spread centrifugally to form dusky red to violaceous-hued or even purple, indurated plaques (Figure 1, Figure 2). Multifocal presentations are extremely rare.
The most important complication of KHE is Kasabach-Merrit phenomena (KMP). KHE is more likely to have associated KMP than tufted angioma. KMP in the setting of KHE can occur in any site, but the risk is greater in larger, more infiltrative, tumors and those in visceral locations, e.g. retroperitoneal or mediastinal sites (although this may be an ascertainment bias, as these tumors might not be noticed without KMP).
Small superficial KHE, especially those less than 5cm, are less likely to result in KMP. You should be particularly suspicious of KMP in KHE when there is a history of increasing size, tenderness, or firmness, with change to a more plum/purple color, or if bruising develops in apparently unaffected surrounding skin (Figure 3, Figure 4).
KHE may be congenital or can be acquired later in life, but most often, KHE appears during infancy or early childhood. In adult onset, KHE tumors seem to be limited to the skin and are unlikely to manifest KMP.
Many KHE tumors are initially noted as a bruise-like patch, but the evolution of the disease varies considerably. Some lesions remain stable in size over time. Most grow in an indolent fashion, extending their surface area slowly over time, but occasionally they expand rapidly, particularly in the setting of KMP As noted, not all KHE lead to KMP.
Some KHE grow to a stable size and are then quiescent. Others have a low-grade chronic coagulopathy without full-blown KMP. A minority may partially regress with time. This is more common in small superficial cutaneous lesions than in those KHE that are larger, subcutaneous, or occur in the viscera, mediastinum, or retroperitoneum.
Malignant transformation with distant metastasis has never been reported. Local metastasis to regional lymph nodes has rarely been reported, and it is likely that this represents local invasion, rather than true metastatic spread. Thus, KHE is considered a hemangioendothelioma rather then a hemangioma, connoting locally aggressive behavior without true malignant potential. In contrast to infantile hemangioma, local aggressive growth into muscle, visceral tissue (such as pleural), and other structures may occur.
Expected results of diagnostic studies
When KHE is suspected by exam and history, a skin biopsy is required to confirm the diagnosis.
Biopsy and histopathologic evaluation usually reveal infiltrating nodules or sheets of slit-like or crescentic vessels that are poorly canalized and lined by spindled endothelium cells within zones of fibrosis. These small vascular channels infiltrate and entrap normal tissues and show microthrombi, extravasation of blood cells, and hemosiderin deposits. The spindled cells have pale cytoplasm and oval nuclei. There are also areas of nests of rounded epitheloid cells of vascular origin, as well as aggregates of capillaries with irregularly shaped lumens containing fibrin thrombi with platelets.
There may be associated “lymphangiomatosis,” which likely represents a background of lymphatic malformation, manifesting as dilated hyperplastic lymphatic channels that can surround vascular tumor nodules (Figure 5, Figure 6, Figure 7).
The high-power microscopic features of KHE may share many features with tufted angioma (TA), although immunostains for the endothelial markers CD34 and HHF-35 actin, as well as the lymphatic marker of D2-40, may help separate the two diagnoses.
D2-40, in particular, seems to be markedly reactive in KHE lesions, whereas it is usually only partially positive in surrounding vessels and negative in the cannonball-like proliferative capillaries that classically occur in TA. However, most authors feel that TA and KHE are part of the same spectrum. Prox1 staining may be increased in the neoplastic spindle cells of KHE and TA, and its presence may reflect a more aggressive biologic behavior in terms of growth and local infiltration.
As reflected in its title, KHE can mimic Kaposi’s sarcoma (KS) histologically, even demonstrating intracellular and extracellular hyaline bodies. However, KHE manifests less nuclear atypia than KS, and mitotic activity is generally lower (2-3/10 high-power field). KS lacks the lobularity of KHE under the microscope, characteristically shows a few plasma cells among the tumor cells, and stains positively for human herpes virus 8 (HHV-8), whereas KHE does not.
Infantile hemangioma (IH) tumors usually have a distinct architecture, with lobules of endothelial channels separated by fibrous septa, and the endothelial cells stain positively with Glut-1, whereas KHE and TA do not manifest Glut-1 positivity.
When Enjolras et al. (JAAD 2000) reviewed histologic specimens fromforty-one patients with KMP, the authors found that KHE was more common during the active phase of KMP, while TA was more common in early stages of KMP or after resolution of KMP.
The clinical and histologic similarities between KHE and TA, as well as their simultaneous presence within the same tumor, has led some to believe that these entities may actually represent one condition with a spectrum of histologic findings based on anatomic location, depth of biopsy, or stages of evolution of the tumor. Cases of TA transforming into KHE and vice versa also support that these tumors lie closely within the same neoplastic spectrum; however, in both the current pathological and dermatological classifications of vascular tumors, KHE and TA are described as two separate disease entities.
In practice, the management of these tumors is quite similar, and their distinction perhaps more academic than practical. That said, features of KHE are more likely to be found in visceral locations, e.g. mediastinal and retroperitoneal, with a higher risk for invasion of major vital organs, infiltrative growth, local aggressiveness, and regional metastasis. KHE also seem to have less likelihood of spontaneous regression than TA.
In general, systemic complications are more common in KHE, with higher rates of KMP and reports of lymphangiomatosis associated with the tumor, even at distant sites . Growth is more aggressive than in TA, more often involving the subcutis, even invading muscle and bone, with rare reports of KHE causing pathologic fractures.
Morbidity and mortality, mostly related to associated KMP, but also infiltrative growth, is greater in KHE than TA. In contrast, TA is usually confined to the skin as a solitary noninfiltrative or locally invasive tumor. TA tumors rarely invade beyond the skin or subcutaneous tissues and have only been reported to metastasize in the setting of prior irradiation.
Laboratory tests important in the workup of KHE include a basic screen of coagulation factors (particularly platelets), D-dimers, and fibrinogen, but also prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR). Also, a peripheral smear should be done to look for evidence of a microangiopathic hemolytic anemia.
Identification of an associated coagulopathy can support, but is not specific to, the diagnosis of KHE or TA. Venous malformations and other benign vascular proliferations can manifest a similar, but more low grade, coagulopathy. The presence, absence, or character of the coagulopathy associated with KHE has important implications for management.
If one suspects KMP within the lesion, then these labs should be done prior to biopsy to rule out KMP and assess bleeding risk. If KMP is present, then platelets can be decreased to the point that an in-office procedure may carry unacceptable risk and you may want to consider obtaining tissue in a more controlled setting such as the operating room.
Magnetic resonance imaging (MRI), with and without contrast, is the best study to delineate the size and extent of the tumor. This may be helpful to evaluate for encroachment into vital structures, assess for risk of KMP (larger and more infiltrative lesions have higher risk), and plan surgical intervention.
MRI of KHE demonstrates a diffuse enhancing T2 hyperintense lesion with ill-defined margins. In contrast to IH, KHE characteristically involves multiple tissue planes, with cutaneous thickening, subcutaneous stranding, edema, draining vessels, and signal voids representing involvement of the septal fat by tumor. Gradient-echo images may demonstrate hemosiderin.
Superficial feeding and draining vessels are less frequent and less prominent than with common hemangioma. On the other hand, clinical correlation is often required to radiographically differentiate KHE from various other slow-flow benign vascular proliferations such as venous malformation, mixed venous-lymphatic malformation, or IH (Figure 8).
Other vascular proliferations can have a similar clinical presentation. The differential diagnosis includes IH, port wine stain, lymphatic malformation, hemangiompericytoma, myofibroma, or other benign vascular proliferations. KS or other malignant vascular tumors may resemble TA. Infantile fibrosarcoma and rhabdomyosarcoma can also present in early infancy as growths with a violaceous or highly vascular appearance, but are usually more exophytic and have different histopathologic appearances.
IH is much more common than KHE, occurring in at least 1%-2% percent of neonates. The clinical course of IH is somewhat different from KHE. While both can be present at or soon after birth as a red macule or patch, the color of IH is usually much brighter red than KHE and often there are telangiectatic components or adjacent blanched areas not typically present in KHE; however, there are exceptions, particularly when comparing very superficial KHE (which can be more red) and hemangiomas with less of a superficial component (which can have a subtle bluish hue) or those that begin as a pseudoecchymotic stain.
With palpation, IH tumors are often softer or more “doughy” feeling compared to KHE tumors, which are typically firmer with palpation (except in patients within the first few weeks of life). KHE may also continue to slowly expand, even beyond an age when most IH have completed their growth (12-18 months).
KHE is most often a solitary lesion, whereas IH tumors, while often solitary, can occur in multiple locations. Of course, the histology of KHE is distinct from IH and they can easily be differentiated with immunostaining, since KHE does not stain positive for GLUT-1, as IH does. This can be helpful in differentiating these entities when analyzing small tissue samples.
The MRI findings of IH show well-defined margins, a lobulated architecture, and uniform enhancement with flow voids versus the ill-defined margins, diffuse enhancement, tissue stranding, and crossing of tissue planes that is observed for KHE. IH never demonstrates associated KMP, although in rare cases, mild thromboctypenia has been reported in the setting of very large or multiple intrahepatic or visceral hemangiomas. However, it is prudent to re-evaluate a clinical diagnosis of IH and consider KHE, TA, or other vascular anomalies in the setting of a patient with a vascular tumor and rapidly falling platelets.
Two other hemangiomas, rapidly involuting congenital hemangiomas (RICH) and non-involuting congenital hemangiomas (NICH), are also considerations in the differential diagnosis. Unlike KHE tumors, which often enlarge after birth if present congenitally, RICH and NICH are present at birth but do not increase in size postnatally. They usually occur on the head, neck, and extremities, and can look somewhat similar to KHE. These lesions are also Glut-1 negative with immunostaining, like KHE; however, they can usually be distinguished on clinical exam.
RICH lesions usually have a distinct appearance, presenting as a well-demarcated elevated soft-tissue tumor with radiating telangectatias and a surrounding rim of pallor. Central eschar or depression may be present. NICH lesions are usually flatter than RICH lesions, and present as a well-circumscribed, round-to-oval, slightly indurated or raised soft-tissue mass with a blue-purple collar or with coarse superficial telengectasia and rim of pallor (Figure 9, Figure 10).
Both NICH and RICH have high-flow components evident on Doppler interrogation. They can be associated with cardiac overload and transient thrombocytopenias and anemias that do not reach the low nadirs that occur in KMP. Neither RICH nor NICH manifest true coagulopathy, but a mild to moderate thrombocytopenia can occur occasionally. This is most likely related to shear forces of these high-flow lesions resulting in platelet destruction.
Spindle cell hemangiomas usually present on the extremities, often within pre-existing vascular malformations such as a venous malformation. Their histology is distinct, with cavernous vascular spaces that do not occur in KHE.
Venous malformations are soft blue compressible nodules or plaques that may slowly expand with time. They usually do not grow as quickly in a radial fashion. Venous malformations can also manifest a low-grade localized intravascular coagulopathy with elevated D-dimers and decreased fibrinogen; however, this usually occurs only in larger lesions and venous malformations that do not exhibit true KMP .
The coagulopathy in these lesions results from stasis. With extensive venous malformations, localized intravascular clotting can lead to evidence of a systemic coagulopathy, but low platelet counts are rare and virtually never drop below 50,000-60,000 per cubic millimeter). D-dimers may be elevated and fibrinogen low in both conditions.
A rare, but interesting entity that should be considered on the differential diagnosis of vascular malformations with an associated KMP-like coagulopathy and thrombocytopenia is multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT). In this disease, multifocal red-brown to burgundy flat plaques or indurated papules are usually present on the skin, sometimes with overlying scale; in other cases, small red and blue papules predominate.
The lesions have a unique histology with dilated LYVE-1 (a lymphatic marker) positive vessels that often contain characteristic endothelium-lined intraluminal projections. Most cases describe hundreds of similar lesions, some with scar-like central areas, and others with a central pallor. Usually, many lesions are present on the skin at birth with subsequent progression in number over time, without regression. In the cases described thus far, gastrointestinal (GI) bleeding in infancy is also characteristic.
Patients with MLT often present with the cutaneous lesions, GI bleeding, and a coagulopathy that resembles KMP in its features, with moderate to severe fluctuating thrombocytopenia. This entity can easily be differentiated from KHE by its multifocal nature (which is unusual in KHE), the characteristic GI involvement, and its unique histology.
Who is at Risk for Developing this Disease?
KHE is quite rare. It most often occurs during the first year of infancy or early in childhood. There are occasional reports of congenital and adult onset. The incidence in males and females is approximately equal, and no ethnic skewing has been noted in reported cases thus far.
What is the Cause of the Disease?
KHE is a benign vascular tumor that is thought to originate from stem cells possessing the characteristics of both blood and lymphatic vessel lineages. Some have postulated that KHE represents a lymphatic differention of these cells, while TA tumors represent the more endothelial differentiation of the progenitor cells. Studies demonstrating immunoreactivity for the lymphatic endothelium-associated antigen VEGFR-3 and other lymphatic markers support this concept.
It is thought that KHE may emit lymphatic endothelial growth factors that initiate the growth of associated lymphatic vessels (lymphangiomatosis) that often surround or anatomically connect to KHE tumors. The reasons for, and mechanisms of, vascular and lymphatic proliferation are unclear.
Some have interpreted the behavior of KHE as more of a reactive process (akin to pyogenic granuloma), related to changes in vascular growth factor milieu caused by trauma or other triggers.
The association of KHE and KMP is postulated to occur because of platelet activation and trapping related to turbulence arising from blood flow patterns related to the abrupt linear pattern with which smaller convoluted capillaries arise from larger vessels.
Systemic Implications and Complications
The clinical implications of KHE vary widely depending on the anatomic location, size of the tumor, and biologic behavior. Almost certainly, the disease-associated mortality of 15%-30% quoted in the literature results from a strong ascertainment bias for more dramatic presentations of KHE with associated KMP, visceral or intra-thoracic location, and morbidity related to aggressive local invasion.
Mediastinal or retroperitoneal KHE seems to present earlier (usually in the first year of life) and be associated with higher morbidity and mortality. This is in contrast to cutaneous lesions, which seem to present later and have decreased mortality. Again, this may well represent an ascertainment bias, as small retroperitoneal and visceral tumors may be asymptomatic and go undetected.
Lymphangiomatosis is an important systemic association of KHE. It is thought that KHE may release lymphangiogenic factors, which can reach sufficient levels to incite proliferation of lymphatic vessels on susceptible vessels. Others believe that KHE may actually arise within a bed of abnormal lymphatics. Interestingly, while lymphedema or abnormal lymphatics typically occur in close proximity to the primary KHE tumor, there have been reports of distant lymphangiomatosis in sites such as the lung and mediastinum, leading to patient morbidity and mortality by compromising the airways.
An associated coagulopathy may be present, ranging in severity from mild and low-grade coagulation abnormalities to full-blown KMP. For this reason, patients with KHE should have laboratory studies, including fibrinogen, D-dimer, and platelet count, as well as PT, PTT, and INR. These can help can determine which of the following three clinical scenarios a patient with KHE falls within.
1. KHE without thrombocytopenia or coagulopathy
In this scenario, KHE is present, with no associated systemic abnormalities in coagulation factors or platelets.
2. KHE without thrombocytopenia but with chronic low-grade coagulopathy (due to low-level chronic clotting within the tortuous vessels of the KHE)
In this scenario, KHE is present and mild low-level chronic clotting occurs within the lesion. This will be reflected by an elevated D-dimer and a decrease in fibrinogen, sometimes with slightly low or low-normal platelet levels. This is presumably due to vascular sludging or mild platelet trapping within the abnormal and tortuous endothelial-lined channels of the tumor. In this setting, KHE does not always acutely change in appearance or firmness, but may become more tender, painful, “lumpy,” or indurated than in patients without coagulopathy.
3. KHE with associated KMP
In the scenario of a true KMP, platelet trapping within the KHE results in a severe consumptive coagulopathy with profound thrombocytonia, hypofibrinogenemia, elevated D-dimers, and microangiopathic hemolytic anemia or anemia due to red blood cell trapping. Most KMP in the setting of KHE occurs in the first few weeks of life, but the condition can present later in infancy and childhood as well. This rare condition was originally described by Kasabach and Merritt in 1941, and was thought to be a complication of IH. However, in the 1990s it was recognized that KMP does not occur in IH, but rather, specifically in KHE and TA.
Multiple case series have shown that perhaps 90% of KMP are secondary to KHE, with most others related to TA . KHE that develops KMP will often undergo one or more of the following clinical signs: marked enlargement, increased tenderness, and increased intensity of violaceous color and/or purpura extending beyond the apparent clinical borders of the tumor. Bleeding from even small scratches to the lesion can be copious.
KHE with KMP has high mortality (15%, up to 30% in some series), particularly in tumors of the viscera, retroperitoneum, neck, and mediastinum. This is perhaps because in lesions at these locations, the KMP may not be clinically apparent early on and acute changes are more difficult to detect. This underscores the need for vigilance regarding the complication of KMP in the setting of KHE.
Petechiae on the skin (usually occurs when platelet levels fall to near 10,000 per cubic millimeter) or mucous membranes, easy bruising, bleeding of the gums, bloody stools, or frequent epistaxis in the presence of a mediastinal, retroperitoneal, or visceral tumor should prompt concern for KMP.
Lab abnormalities in KMP reflect the consumptive coagulopathy occurring within the tumor and include: severely decreased platelets (usually below 50,000-60,000 per cubic millimeter), increased D-dimer, decreased fibrinogen, and in severe cases, changes in the PT or PTT. Associated anemias can be caused by sequestration of red cells in the tumor, or a microangiopathic hemolytic anemia can be deduced from abnormalities of the peripheral smear such as red cell fragmentation or schistocytes.
Pharmacologic therapy is always indicated when the diagnosis of KMP in KHE is made. It is unclear why KMP so preferentially develops in KHE versus other vascular malformations, but theories center around the unique architecture and endothelial characteristics of KHE. The small convoluted capillaries and lymphatic vessels arising directly from large vessels are thought to cause turbulence, leading to platelet activation and aggregation.
Refer to below and to the CDS chapter specifically dedicated to Kasabach Merritt phenomena for further information regarding the management of KMP.
Treatment options are summarized in Table I.
|Medical Therapy||Surgical Therapy||Physical Modalities|
|Aspirin, dipyridamole or ticlodipine—for symptoms and prevention of coagulopathy/KMP|
|Systemic corticosteroids—successful in less than 10% of tumors (actually decreased tumor bulk)||Surgical excision||Embolization—sometimes combined with surgery|
|Vincristine||Pulsed dye laser|
|Interferon alpha-2a—after the age of 1, vincristine||Argon laser|
|Rapamycin (sirolimus) is in clinical trials||Radiotherapy—if risk outweighs benefit|
|Other chemotherapy or anti-angiogenic therapy||Cryotherapy—usually not effective|
KMP: Kasabach Merritt phenomena
Optimal Therapeutic Approach for this Disease
Consider location, rapidity of growth, and coagulation profile when choosing a therapeutic approach. Unlike TA, which will occasionally spontaneously regress, KHE almost never resolves spontaneously, even if it shrinks slightly over time. Therefore, surgical, systemic, or other physical modalities are usually indicated in larger or symptomatic lesions.
For localized KHE lesions, early excision is the most effective treatment. Unfortunately, recurrences are common, and often, definitive resection is not possible because of tumor infiltration across tissue planes and the risk of bleeding. Therapy with systemic agents has shown variable efficacy and no standard of care has been established.
Cryotherapy and electrocautery have been attempted in individual cases, with little success and high rates of recurrence. Radiotherapy has been used successfully but is not considered first line because of the risks of secondary malignancy and side effects.
Embolization or sclerotherapy of KHE can sometimes be effective, particularly preoperatively, or if the lesion is very symptomatic and not amenable to surgical resection. Unfortunately, in many cases it can be difficult to cannulate the very small feeder vessels of KHE.
Pulsed dye laser has been used with variable results for TA, and may have some efficacy for small superficial KHE. In one reported case, five treatments with a 585nm pulse dye laser using a 7mm spot size, 0.45 microsecond pulse width, and fluences increasing from 6.5-8 joules/cm2 resulted in noticeable lightening of the lesion, decrease in pain, and no recurrence for 2 years in a 7-year-old with TA. Some atrophic scarring did result at these settings.
One article mentions successful lightening and resolution of TA (in an adult patient) with an argon tunable dye laser after failure with pulsed dye laser; another article details a good response to intense pulsed light. Other reports describe lesions treated with pulsed dye laser without success, likely due to deeper involvement that was not accessible to laser therapy.
Aspirin, typically in doses of 5-10mg/kg/day, has also been effective and can diminish pain, and in some cases soft-tissue swelling, in KHE, even in the absence of laboratory evidence of a coagulopathy. Aspirin may help prevent platelet trapping and KMP as well. Adverse side effects such as hemorrhage, gastritis, and rare anaphylactic reactions must be considered.
In pediatric patients, Reyesyndrome is also a concern. This syndrome—involving mitochondrial dysfunction—leads to liver failure, encephalopathy, and death in 30%-40% of cases. It has usually been reported with higher doses of aspirin (much greater than 5-10mg/kg/day) in use or with aspirin use in association with influenza or varicella. Consequently, children utilizing chronic aspirin therapy should have varicella vaccination prior to initiating therapy, a yearly flu shot, and close monitoring during a flu-like illness.
If these precautions are taken, we believe the risk of Reye syndrome is outweighed by the benefit to most patients in this setting; however, prospective trials evaluating the risks and benefits of aspirin in the treatment of KHE or other vascular malformations have not been conducted on a large enough scale to definitively answer this question.
Reports of efficacy with similar antiplatelet agents such as ticlodipine (10mg/kg/day) indicate that these responses are likely related to improvement in local platelet trapping rather than true decrease in lesion size. Multiple reports seem to indicate that sometimes KMP in KHE can be averted or even reversed using antiplatelet agents alone.
Dipyridamole (1.5mg/kg/day) has also been shown in some series to be effective in bringing platelet levels up in the face of KMP. There are also multiple case reports in which antiplatelet agents such as aspirin, ticlodipine, dipyridamole, pentoxphylin, and heparin are used as monotherapy, in combination or as adjuncts to the systemic agents discussed below. This combination therapy is used to improve consumptive coagulopathy, hypothetically by decreasing platelet trapping and clotting.
However, Mueller and Mulliken state in one review (Seminars in Perinatology, 1999) that “heparin administration, the standard treatment for disseminated intravascular coagulopathy, has been shown to incite growth of KHE and can actually worsen the clinical situation. In the animal model, heparin mobilizes basic fibroblast growth factor, a potent angiogenic protein and induces tumor angiogenesis.”
Similarly, giving platelet transfusions can expand the tumor because of rapid trapping and intralesional consumption; however, some experts recommend correcting fibrinogen below 50mg/dL when platelets fall below 10,000 per cubic millimeter to help prevent spontaneous bleeding. The addition of an antifibrinolytic agent such as aminocaproic acid or tranexamic acid may be helpful if there is significant bleeding from a particular source.
In many reports, oral steroids such as prednisone are attempted as first-line monotherapy; however, the failure rate for systemic steroids alone is quite high (perhaps on the order of 85%-90%); therefore, other interventions are often required.
As with IH, the doses utilized are 2-5mg/kg/day during the initiation phase of therapy. Most reports start at doses of approximately 2-3mg/kg of prednisolone, given orally. This treatment approach seems to be more successful in the setting of coagulopathy and/or platelet trapping and KMP ; however, it is often not effective in resolving or reducing actual tumor volume of KHE.
If there is systemic coagulopathy requiring acute debulking of the tumor, or if the patient fails a 1-2 week trial, then other systemic agents may be required. Of course, steroid dosing at these levels can quickly lead to Cushing syndrome, fussiness, bone changes, and other steroid-associated side effects, but these usually reverse when steroids are stopped. Many children have inhibition of growth; however, most correct and regain the “lost” growth relatively quickly when the steroids are tapered. A very slow taper from this sort of high-dose therapy is required to allow for adrenal recovery.
Vincristine has also been utilized as a therapy for KHE, particularly in the setting of KMP. It has emerged as an early second-line therapy, to use if corticosteroids are not effective, and indeed some have advocated starting both treatments at the same time for full-blown KMP.
While numerous potential side effects can occur, vincristine is usually well tolerated, even in young infants; however, it cannot be used in very young infants with jaundice. Vincristine is a vinca alkaloid, which has antimitotic properties that inhibit the formation of microtubules in cells.
The main toxicity is peripheral neuropathy which, in infants, can result in cranial nerve palsy, loss of deep tendon reflexes, and abdominal autonomic disturbance with constipation and abdominal pain. Neurotoxicity, as well as alopecia, rash, and constipation, may resolve if dosing is decreased.
Myelosuppression can occur but is generally fairly mild. Syndrome of inappropriate antidiuretic hormone (ADH) secretion has rarely been reported from vincristine. Indwelling venous access is typically needed for administration of vincristine, increasing risk for iatrogenic infections. Vincristine therapy requires close monitoring of blood counts, electrolytes, and liver function tests (its metabolism is mostly hepatic). Vincristine has been used as monotherapy or (often more effectively) in combination with steroids, or even steroids and interferon or other agents, in life-threatening KMP.
Vincristine can also be used in conjunction with excision to prevent recurrence and shrink remaining tumor burden. Typical dosing is 0.05-0.25mg/kg/weekly for many weeks, depending on response. Vincristine can also be dosed by surface area. A typical regimen would be 1.5mg/meter squared for patients older than 1 year, or 0.05mg/meter squared for patients younger than 1 year, for twelve weekly cycles, followed by twelve cycles every other week.
One case report details good response of a KHE lesion with associated KMP (in a 2-month old) to intravenous vincristine (0.05mg/kg/week), along with aspirin (10mg/kg/day) and ticlodipine (10mg/kg/day). The vincristine was stopped (there was significant tumor shrinkage) after 12 weeks, and the antiplatelet therapy continued until the patient was 1 year of age. It is important to note that the time to clinical response with vincristine therapy can be 3-5 weeks before platelet response and tumor shrinkage begin .
Interferon alpha-2a or 2b, at a dose of 1-3 million international units (MU) per meter squared per day subcutaneously, has often been described as second-line treatment for systemic therapy when lesions are not amenable to local excision; however, in children less than 1 year old, it may be third or even fourth line behind vincristine due to the risk of neurotoxicity, specifically spastic diplegia. In addition, some preparations of interferon contain a significant amount of benzyl alcohol, which can be toxic in very young infants.
The exact mechanism of IFN-alpha-2a is unknown, but it seems to have anti-angiogenic properties that inhibit endothelial cell proliferation. Interferon seems to stop proliferation in some cases, and has even led to tumor shrinkage in other reports, but there are also multiple case reports describing KHE as unresponsive to this therapy.
Spastic diplegia and motor disturbances are a major risk of interferon therapy in children that are less than 1 year old. In one meta-analysis, 27 out of 441 children treated with interferon alpha developed neuromotor complications, and all of these children were less than 1 year of age.
Although minor motor disturbances usually correct after stopping treatment, spastic diplegia is not reversible. Therefore, interferon should only be considered in this age group (<1 year old) if risk from the tumor is felt to outweigh risk of motor disturbance/spastic diplegia. If utilized, baseline neurologic assessment and serial examinations are essential during interferon treatment.
The side effects of interferon treatment can be uncomfortable in older patients. Adults often report flu-like symptoms, headache, abdominal pain, fatigue, nausea, and weakness. Patients of all ages will often manifest a reversible increase in liver enzymes (up to 5-fold normal), transient neutropenia, and mild anemia.
A few cases of autoantibody-induced interferon-associated hypothyroidism have been reported. Interferon responses do not always seem to correlate with markers of vascular proliferation such as urinary basic fibroblast growth factor levels in the setting of KHE treatment. About half of lesions treated with interferon alpha therapy have a clinical or hematologic response, as defined by tumor shrinkage or normalization of coagulation factors and platelets.
Cyclophosphamide (10mg per kg IV for 3 days) has been used adjunctively with vincristine or interferon alfa-2a (or both), when a rapid response is needed due to systemic complications.
A 2004, Case Records of the Massachusetts General Hospital (Case 13-2005), gives a nice “real world” discussion of a case of KHE with KMP in a newborn girl that was treated with a combination of cyclophosphamide, vincristine, and interferona alfa-2a after a failure with corticosteroids (the patient had rapidly declining platelet levels and severe systemic complications).
One interesting therapeutic strategy that will likely become more common in the future is the use of anti-angiogenic agents to prevent recurrence or shrink vascular tumors such as KHE. These could be used alone or, more likely, in concert with surgical interventions.
Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR), an important player in angiogenesis. In 2010, sirolimus was used successfully by a group from the University of North Carolina to shrink a life-threatening KHE that had failed multiple other interventions, including prednisone, propanolol, serial embolization, sclerotherapy, and another anti-angiogenic agent, avastin (5-15mg/kg/week, every 1-3 weeks). The sirolimus was dosed at 0.1mg/kg/day, divided twice a day (to maintain trough levels of 8-15ng/ml). A correction of platelet count and tumor response was observed after 2 weeks of therapy.
Since then, Cincinnati Children’s Hospital has begun an ongoing trial with a protocol based on treatment with sirolimus (clinicaltrials.gov NCT00975819). Early indications are that this medication shows great promise, leading to greater tumor shrinkage and less fibrosis than vincristine or other older therapies ).
Cincinnati Children’s Hospital is using rapamycin (sirolimus) oral suspension 1mg/ml at a dose of 0.8 mg/m2 per dose given every 12 hours orally. The target levels of sirolimus are 10-13ng/ml. Complete blood counts with differential, metabolic panel, fasting lipid profile, and creatinine, as well as a urinalyisis are done at baseline and weekly along with plasma levels of drug. One advantage of rapamycin over vincristine is the oral route of administration, obviating the need for a central line.
The main therapeutic approach to treating or preventing recurrent KMP in the setting of KHE is to try to shrink, or at least induce fibrosis in, the underlying KHE lesion. This can be accomplished with prednisone or methylprednisone, IFN-alpha, vincristine, or combinations thereof .
In the setting of KMP, more aggressive medical chemotherapy regimens are sometimes warranted to quickly destroy as much lesion mass as possible as a way to decrease the nidus for platelet trapping that is underlying the consumptive coagulopathy of KMP. Combination regimens are usually administered by hematology-oncology, and can include agents such as vincristine, actinomycin D, and cyclophosphamide (VAC).
Radiation, while not appropriate in smaller asymptomatic lesions, may also be warranted in this setting (of a tumor with KMP unresponsive to systemic agents), as well to quickly shrink tumor mass. There are reports of local and global growth retardation, neuroendocrine dysfunction, and secondary malignancy, so the risks and benefits should be weighed carefully.
KMP is a life-threatening complication of KHE, with mortality rates reported around 25%. When KMP does occur in a KHE lesion, the KMP must be managed first and foremost. The treatment of KMP centers around treatment of the underlying lesion, but involves multiple and complex peripheral issues. Reference the KMP chapter of Decision Support in Medicine for more in-depth discussion regarding treatment of the acute severe platelet trapping and consumptive coagulopathy involved in KMP.
KHE usually appears in early childhood, most often in infancy. Most KHE expand slowly, in a mostly radial fashion, for a period of months to years and then stabilize. They rarely shrink or regress on their own, in contrast to TA . Close clinical follow up is of the utmost importance to characterize the trajectory of growth and changes in appearance of the lesion that may portend KMP. Photographic documentation can be quite helpful in this respect.
Surgical excision at an early time is the intervention of choice, if possible, in order to prevent larger procedures later. Embolization may be a good choice in some settings; however, it is almost always combined with other modalities.
If the diagnosis is made in a lesion at an early stage, and if the size is small and the lesion is in a cosmetically sensitive area or an area that may lead to functional issues in the future, one might attempt a trial of pulsed dye laser or argon laser to try to eliminate or slow the growth of the lesion. However, this is less likely to be successful in KHE as compared to TA.
All patients with KHE, particularly those with symptoms or larger lesions, deserve screening for coagulopathy, with coagulation studies to guide management .
Parents or patients should be particularly warned about the signs and symptoms of KMP in a KHE. These include: rapid expansion of the lesion; acute increase or change in symptoms (particularly pain) in the lesion; sudden change in texture with increased fullness and firmness of the TA; signs of coagulopathy such as nosebleeds, bleeding gums, blood in the stool, easy bruising, and petechiae. KMP is a medical emergency and if these signs or symptoms occur, the patient should be immediately evaluated in the emergency room.
Aspirin or ticlodipine may be appropriate treatment for less acute presentations (e.g. slow swelling, pain, or mild coagulopathy). Topical or injected steroids (kenalog 10mg/ml) may also be effective for symptom control in this setting, but in our experience do not work as well as aspirin. These therapies can be helpful to manage symptoms and prevent KMP until definitive treatment of the tumor is undertaken.
The management of KHE is often complex and multimodal. Therefore, if the resource is available, evaluation of the patient in a multispecialty vascular anomalies clinic is recommended. This will allow experts in medical or pediatric dermatology, lasers, interventional radiology, plastic surgery, hematology, and other relevant specialties to confer and tailor the therapeutic plan to this diversely presenting vascular tumor.
Unusual Clinical Scenarios to Consider in Patient Management
There are multiple reports of visceral presentations or invasion of viscera in KHE. These include involvement of the scrotum, spleen, thymus, thyroid, pancreas, deltoid muscle, and even one report of an intracranial presentation in the brain.
Multifocal presentations of KHE are extremely unusual. There are case reports in the literature, and these KHE seem to behave in a manner similar to other KHE. In multifocal disease, the differential should carefully be considered and histology carefully evaluated to make sure it is consistent.
KHE commonly presents in early infancy or childhood. Rarely, it first presents in an adult with no preceding lesion; however, these adult KHE patients seem to be less likely to have KMP or lymphangiomatosis. The behavior of adult KHE seems to be less invasive and results in less morbidity and mortality.
What is the Evidence?
Fernández, Y, Bernabeu-Wittel, M, García-Morillo, JS. “Kaposiform hemangioendothelioma”. Eur J Intern Med. vol. 20. 2009 Mar. pp. 106-13. (A nice review encompassing all aspects of KME— , its classification, clinical features, diagnostic work-up, and treatment)
Gruman, A, Liang, MG, Mulliken, JB, Fishman, SJ, Burrows, PE, Kozakewich, HP. “Kaposiform hemangioendothelioma without Kasabach-Merritt phenomenon”. J Am Acad Dermatol. vol. 52. 2005 Apr. pp. 616-22. (It is important to remember that KHE is not always complicated by KMP. This article points out that cutaneous KHE is probably much less likely to develop KMP than subcutaneous, retroperitoneal, mediastinal, cervico fascial, or KHE presenting in the viscera; however, it does point out that KMP has developed in tumors as small as less than 5cm. In this series, two of the lesions even slowly regressed, which was previously thought to occur very rarely in KHE)
Mac-Moune Lai, F, To, KF, Choi, PC, Leung, PC, Kumta, SM, Yuen, PP. “Kaposiform hemangioendothelioma: five patients with cutaneous lesion and long follow-up”. Mod Pathol. vol. 14. 2001 Nov. pp. 1087-92. (Similar to the above paper, this series points out the marked diversity in clinical behavior of superficial KHE limited to skin and skin lesions that represent a “tip of the iceberg” marker of deep subcutaneous involvement. The importance of MRI in making this determination is key)
Lyons, LL, North, PE, Mac-Moune Lai, F, Stoler, MH, Folpe, AL, Weiss, SW. “Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma”. Am J Surg Pathol. vol. 28. 2004 May. pp. 559-68. (This case series is one of the larger and more recent. The study details the complications of KMP and lymphangiomatosis, which occur in association with KHE, and opines on their possible pathogenesis. The study also confirms the locally aggressive but not malignant behavior of this hemangioendothelioma)
Vetter-Kauczok, CS, Ströbel, P, Bröcker, EB, Becker, JC. “Kaposiform hemangioendothelioma with distant lymphangiomatosis without an association to Kasabach-Merritt-Syndrome in a female adult!”. Vasc Health Risk Manag. vol. 4. 2008. pp. 263-6. (This article points out the association of KHE and lymphangiomatosis. This case is unusual because of the occurrence in an adult; however, it is important to remember that lymphangiomatosis can occur both local to the lesion and at distant sites in both adults and [probably more often] in children. Lymphangiomatosis can have severe clinical consequences and has caused morbidity and even mortality in some cases involving the lung and mediastinum)
Enjolras, O, Wassef, M, Mazoyer, E, Frieden, IJ, Rieu, PN, Drouet, L. “Infants with Kasabach-Merritt syndrome do not have “true” hemangiomas”. J Pediatr. vol. 130. 1997 Apr. pp. 631-40. (Hallmark article that helped us understand that KMP occurs in the setting of KHE and TA rather than in “true” infantile hemangiomas)
Enjolras, O, Mulliken, JB, Wassef, M, Frieden, IJ, Rieu, PN, Burrows, PE. “Residual lesions after Kasabach-Merritt phenomenon in 41 patients”. J Am Acad Dermatol. vol. 42. 2000 Feb. pp. 225-35. (This study of the pathology of the lesions remaining after KMP showed that the lesions are most likely to be KHE, when taken during the active phase of KMP, whereas TA was more often found in the early beginning of KMP or after KMP has totally resolved. This article re-emphasizes that KMP is a feature of KHE and TA, not infantile hemangiomas. It also discusses the likely relationship of KHE and TA histologically and the role of KMP in perhaps modifying lesions towards one or the other end of the KHE/TA spectrum)
Mulliken, JB, Anupindi, S, Ezekowitz, RA, Mihm, MC. “Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 13-2004. A newborn girl with a large cutaneous lesion, thrombocytopenia, and anemia”. N Engl J Med. vol. 350. 2004 Apr 22. pp. 1764-75. (This is a very instructive discussion of a how to manage KHE with associated KMP. The format gives good insight into the “real world” management of these complex intertwined entities)
Mueller, BU, Mulliken, JB. “The infant with a vascular tumor”. Semin Perinatol. vol. 23. 1999 Aug. pp. 332-40. (This article gives provides a nice discussion regarding practical aspects of using systemic agents for the treatment of multiple vascular tumors, including KHE. The side effect profiles and dosing regimens of multiple agents are outlined in detail)
Fernandez-Pineda, I, Lopez-Gutierrez, JC, Ramirez, G, Marquez, C. “Vincristine-ticlopidine-aspirin: an effective therapy in children with Kasabach-Merritt phenomenon associated with vascular tumors”. Pediatr Hematol Oncol. vol. 27. 2010 Nov. pp. 641-5. (Another good “real world” article containing a case report detailing this therapeutic approach to treating KHE with KMP. This may be a good strategy, particularly in children under 1 year of age, whose risk with regard to interferon may be unacceptable)
Blatt, J, Stavas, J, Moats-Staats, B, Woosley, J, Morrell, DS. “Treatment of childhood kaposiform hemangioendothelioma with sirolimus”. Pediatr Blood Cancer. vol. 55. 2010 Dec 15. pp. 1396-8. (This article is likely a window into the future of treatment of vascular tumors with new classes of anti-angiogenic and antiproliferative agents used to shrink tumors and prevent recurrence after other interventions)
Chen, YJ, Wang, CK, Tien, YC, Hsieh, TJ. “MRI of multifocal kaposiform haemangioendothelioma without Kasabach-Merritt phenomenon”. Br J Radiol. vol. 82. 2009 Mar. pp. e51-4. (This article nicely summarizes various appearances of KHE on MRI )
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