BJD
British Journal of Dermatology
S C H O L A R L Y R E V IE W
Vascular tumours in infants. Part II: vascular tumours of intermediate dignity and malignant tumours I. Colmenero1 and P.H. Hoeger2 1 2
Histopathology Department, Birmingham Children’s Hospital, Birmingham, U.K. Paediatric Dermatology Department, Catholic Children’s Hospital Wilhelmstift, Hamburg, Germany
Summary Correspondence Peter Hoeger. E-mail: [email protected]
Accepted for publication 2 November 2013
Funding sources None.
Conflicts of interest None declared. DOI 10.1111/bjd.12835
Malignant cutaneous vascular tumours are very uncommon in children. As in adults, they are aggressive neoplasms with metastatic potential and a high mortality rate. Some nonmalignant vascular tumours may exhibit a locally aggressive behaviour and some of them can be associated with life-threatening systemic complications such as Kasabach–Merritt syndrome. Early diagnosis of these aggressive neoplasms in children is very important in order to start appropriate therapy as soon as possible, as this can have a significant impact on the prognosis of these patients. This review focuses on cutaneous vascular tumours of intermediate dignity (tufted angioma, kaposiform haemangioendothelioma, multifocal lymphangioendotheliomatosis with thrombocytopenia, papillary intralymphatic angioendothelioma, retiform haemangioendothelioma, adult-type haemangioendotheliomas) and malignant vascular tumours in young children (Kaposi sarcoma, angiosarcoma).
What’s already known about this topic?
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Malignant vascular tumours can mimic infantile haemangiomas, but need to be differentiated as soon as possible.
What does this study add?
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This is a comprehensive review of vascular tumours of intermediate dignity and malignant vascular tumours presenting during infancy and early childhood. We present clinical and histological criteria for differential diagnosis and discuss treatment options.
True malignant cutaneous vascular neoplasms are very rare in children and, as in adults, they show a high capacity to metastasize and a high mortality rate. Nevertheless, some nonmalignant vascular tumours may behave in a locally aggressive fashion or may be associated with serious systemic complications such as Kasabach–Merritt syndrome. Both malignant tumours and those of intermediate dignity may initially be misdiagnosed as infantile haemangiomas or other benign neoplasms. The early identification of these aggressive tumours is essential to start the appropriate treatment as soon as possible.
Tufted angioma/kaposiform haemangioendothelioma spectrum The significant degree of clinical and histological overlap between tufted angioma (TA) and kaposiform haemangioen© 2014 British Association of Dermatologists
dothelioma (KHE) and the association of these two entities with Kasabach–Merritt syndrome (KMS) suggest that TA is a milder, more superficial form of KHE.1 The expression of endothelial lymphatic-associated antigens displayed by TA and KHE supports the concept that these tumours have at least a partial lymphatic endothelial phenotype.2–4 Kasabach–Merritt syndrome is characterized by profound thrombocytopenia due to platelet trapping within the tumour, sometimes accompanied by microangiopathic haemolytic anaemia and secondary consumption of coagulation factors. It is different from the consumptive coagulopathy that may develop in large venous or lymphatic malformations.5 KHE and TA account for the vast majority of KMS cases.1 Recent findings have shed new light on the molecular mechanisms underlying KHE and tufted haemangioma, as well as on the coagulation phenomena associated with multifocal British Journal of Dermatology (2014)
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lymphangioendotheliomatosis with thrombocytopenia (MLT). These vascular lesions share a common podoplanin-positive lymphatic endothelial immunophenotype. Podoplanin (D2-40) is a mucin-type transmembrane glycoprotein and may be found, albeit not exclusively, in endothelial cells of lymphatic lineage. Podoplanin is the only known endogenous ligand for CLEC-2, a C-type lectin receptor that is highly expressed on platelets.6–9 CLEC-2 is known to elicit powerful platelet activation upon engagement by podoplanin.7–9 Binding of podoplanin to CLEC-2 appears to be the predominant initiator of the blood clotting phenomena observed in various tumours with a podoplanin-positive lymphatic immunophenotype.7–11 Consequently, CLEC-2 could be an ideal novel target for an antiplatelet drug that would inhibit pathological thrombus formation but not physiological haemostasis.12–15 Tufted angioma Tufted angioma was first described as such by Wilson-Jones and Orkin in1989.16 Identical lesions had been described earlier as angioblastoma and progressive capillary haemangioma.17,18 Approximately 15% are congenital, and most of them present before 5 years of age,19 but some cases have been reported in adults.20 No racial predilection is recognized for TA and its prevalence is equal in both sexes. Most reported tumours occur on the upper trunk, neck and shoulders, and fewer cases occur on the face, scalp and proximal extremities. Involvement of the feet and oral mucosa has been observed only in rare cases.21,22 Tufted angioma is typically a solitary lesion, but multiple tumours have been described.23 Lesions present as enlarging pink-red, purple or red-brown patches and plaques with superimposed papules or nodules that spread slowly, then stabilize, and rarely regress (Fig. 1).24 The lesion diameter generally ranges from < 1 cm to several centimetres. On palpation, TA often has a rubbery consistency, and may be painful. Tenderness and hyperhidrosis are commonly associated symptoms.25 Hypertrichosis may also be observed in some cases.26 TA may be associated with KMS, and also with a chronic consumptive coagulopathy with normal platelet counts.27
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Tufted angioma is histologically described as a poorly demarcated lesion in the dermis and subcutis, consisting of multiple discrete, cannonball-like lobules of capillaries. Crescent-shaped thin-walled lymphatic vessels peripherally surround some of these lobules. A second component of lymphangioma-like anastomosed vessels is a prominent feature in some cases.28 Intervening dermis and subcutis are sometimes fibrotic, but may be histologically normal. The surrounding appendageal structures of the dermis are unaffected, although hypertrophy of neighbouring eccrine sweat glands can be seen.29 The pinpoint-like capillary lumina that form the lobules occasionally contain fibrin and platelet microthrombi. Endothelial cells may appear spindled at the periphery of lobules, but this is never a prominent feature. By immunohistochemistry, endothelial cells are focally positive for the lymphothelial markers podoplanin, lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1) and prospero homeobox-containing 1 (PROX1) transcription factor, but less extensively than is often seen in KHE.3,4 Similarly to other vascular tumours, TA is positive for Wilms tumour 1.30 Tumour endothelial cells are glucose transporter 1 (GLUT1) negative.31 The management of TA is difficult, and treatment guidelines have yet to be established. Several treatment regimens for TA with or without KMS have been reported, including compression therapy, surgery, laser, topical or systemic corticosteroids, interferon, propranolol and chemotherapy.1,26,32,33 A waitand-see policy seems appropriate because of the benign nature of this tumour and the possibility of spontaneous regression. Overall 95% of the cases found to regress did so within a period of 2 years.24 However, careful follow-up should be implemented, especially in early childhood, to detect complications such as KMS.27 No malignant transformation has been described to our knowledge. Kaposiform haemangioendothelioma Kaposiform haemangioendothelioma was first discussed under this name in the literature by Zukerberg et al.34 It is most commonly seen in infancy and childhood and is strikingly associated with KMS. Most cases of KHE1,2,35,36 present in
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Fig 1. Tufted angioma. (a) An indurated plaque with light pink nodular areas and hypertrichosis, (b) cannonball-like lobules of capillaries in the dermis, (c) crescent-shaped thin-walled lymphatic vessels peripherally surround some of the lobules. British Journal of Dermatology (2014)
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early childhood, especially in the first 2 years of life, and are occasionally detected prenatally.37,38 The prevalence of KHE is estimated at about 091 per 100 000 children.39 In a series of 107 patients published recently,39 93% manifested in infancy and 60% in the neonatal period. The lesions range from superficial, locally infiltrative maculopapules and plaques to deep-seated bulky masses. The latter may occur in the soft tissue of the extremities, trunk or the head and neck, or may be diagnosed as large-body cavity or retroperitoneal masses, often followed by a complicated course with KMS and adverse outcome. Cutaneous manifestations occur in 75% of cases.39 Skin manifestations include vascular tumours, purpura and ecchymoses (Fig. 2a). Magnetic resonance imaging usually demonstrates a diffusely enhancing, T2 hyperintense lesion with ill-defined margins that cross tissue planes. Untreated tumours do not regress.37 KMS occurs in 71% of cases, and thrombocytopenia in 56%.39 Kaposiform haemangioendothelioma has been termed a haemangioendothelioma in order to reflect early uncertainty regarding possible borderline malignant behaviour, as regional lymph node metastases have been reported in two cases.34 However, accumulated evidence suggests that true metastasis is unlikely in KHE.31 Multifocal development along a regional lymphatic chain or in separate regions has been proposed as an alternative explanation for the above phenomenon. No distant metastases have been reported. Histologically,1,2,35–37 KHEs are composed of infiltrative, ill-defined, frequently coalescing lobules of spindled endothelial cell fascicles (Fig. 2b,c). The moderately plump spindle cells form elongated, slit-like lumina that contain erythrocytes. Nodular pericyte-rich epithelioid nests with pinpoint vascular lumina often surround platelet-rich microthrombi. The epithelioid nodules are rich in pericytes and contain cytoplasmic hyaline globules and erythrocyte fragments. Dilated lymphatic
Fig 2. Kaposiform haemangioendothelioma. (a) Enlarging violaceous tumour in the arm of a neonate associated with Kasabach–Merritt syndrome, (b) infiltrative coalescing lobules of spindled endothelial cell fascicles and dilated lymphatic vessels surrounding the nodules, (c) slit-like lumina containing erythrocytes, (d) intense and diffuse staining with D2-40. Picture (a) cortesy of Dr Antonio Torrelo, Madrid, Spain. © 2014 British Association of Dermatologists
vessels surround and intermingle with nodules, most prominently at the margins of lesions. Areas with a lobular pattern indistinguishable from TA are sometimes seen at the periphery of the tumour. At the margin of the lesion, the spindle cells may freely infiltrate into the surrounding adipose tissue and between collagen bundles, or they may be encased by desmoplastic stroma. By immunohistochemistry31,40 the spindled endothelial cells are positive for the panendothelial marker CD31, as well as for CD34 and lymphothelial markers (D240, LYVE1, PROX1).3 All endothelial cells comprising KHE are completely negative for infantile haemangioma markers such as GLUT1 and Lewis Y antigen. Wide local excision, when possible, is curative. Medical treatment is warranted in case of KHE-associated KMS and when the lesion is not resectable. Platelet transfusions have sometimes paradoxically worsened the coagulopathy. Platelet activation and release of angiogenic factors, such as plateletderived growth factor, may stimulate vascular proliferation in KHE. No single regimen has yielded consistent results either in terms of tumour size reduction or correction of thrombocytopenia. Vincristine has emerged as a preferred treatment of choice. Efficacy of interferon alfa-2a and 2b has been reported, but these have fallen out of favour due to risk of permanent spastic paraplegia when administered in infancy. Corticosteroid monotherapy has been advocated by some,41 but it is generally considered not to be effective.42 Although a case of KHE successfully treated with propranolol has been described, a subsequent study has shown that only a small proportion of cases respond to this treatment.33 Recent reports suggest that sirolimus, a mammalian target of rapamycin inhibitor with antiangiogenic activity, might be active against KHE.43 Rapid response to low-dose sirolimus (01 mg kg 1 per day) was demonstrated, but prospective controlled studies are not yet available.
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Multifocal lymphangioendotheliomatosis with thrombocytopenia MLT is a rare disorder that was first described in 2004 by North et al.44 MLT is characterized by a proliferation of multiple congenital and progressive vascular lesions usually associated with mild-to-moderate thrombocytopenia. It is debatable whether MLT lesions are best considered tumours or malformations. MLT involves skin and the gastrointestinal system, but in some cases it can also involve lungs, brain, spleen, bone, synovium or muscle. Boys and girls are equally affected. Gastrointestinal bleeding is almost universally present and may be life threatening.45 The lethality of MLT is high (63% in a recent meta-analysis).46 Cutaneous lesions are flat or indurated, red-brown to burgundy papules or plaques, which range in size from a few millimetres to 5 cm. They are present in variable numbers, with more than 100 lesions in some cases. Appearance of new lesions and slow progression of existing lesions, without evidence of regression, is typical.45 It is difficult on clinical grounds alone to separate MLT from diffuse neonatal haemangiomatosis.46 MLT lesions involving the skin consist of delicate vessels scattered throughout the dermis and subcutis. They are lined by a monolayer of slightly hobnailed endothelial cells that form complex papillary projections that seem to float within the lumina. Mitotic figures are rare or absent. The endothelial cells show strong reactivity for CD31, CD34 and LYVE1, and light or absent positivity for D2-40. They are negative for GLUT1.44 The lack of effective therapeutic interventions for MLT makes the clinical management and treatment of this disease extremely challenging. Attempts to treat MLT with medications including corticosteroids, thalidomide, interferon alfa-2a and vincristine have failed to demonstrate any sustained efficacy in controlling bleeding from the gastrointestinal lesions, whereas a combination of propranolol (3 mg kg 1 per day), prednisolone (2 mg kg 1 per day) and aminocaproic acid (loading dose 100 mg kg 1, 2-week infusion at 33 mg kg 1) was recently reported to be successful in one case.47 The endoscopic management of gastrointestinal bleeding from MLT has shown limited efficacy and complications.48
Papillary intralymphatic angioendothelioma/ retiform haemangioendothelioma spectrum Papillary intralymphatic angioendothelioma (PILA) and retiform haemangioendothelioma (RHE) are closely related lesions considered within the group of vascular tumours known as ‘haemangioendotheliomas’ to imply that they are borderline between benign haemangiomas and conventional angiosarcomas. This term reflects their ability to recur but their limited capacity for metastasis compared with angiosarcoma. Some authors have suggested that PILA is the juvenile variant of RHE. In the current literature, it has been suggested that both tumours probably develop from lymphatic endothelial cells. British Journal of Dermatology (2014)
Papillary intralymphatic angioendothelioma Papillary intralymphatic angioendothelioma, also known as Dabska tumour, is a low-grade vascular tumour of childhood first described in 1969 by the Polish pathologist Marıa Dabska.49 Based on the observation that the lesion is often associated with lymphatic vessels, Fanburg-Smith et al.50 proposed the name ‘papillary intralymphatic angioendothelioma’, which has since been adopted by the World Health Organization (WHO).51 PILA/Dabska tumours occur almost exclusively in children and young adults; some cases are congenital. Most PILA tumours originate in the skin and superficial soft tissues of the head and neck, trunk or extremities.50,52 Rarely, unusual sites such as bone53 and spleen54 are affected. Typically, PILA/Dabska tumours are ill-defined masses of the dermis and subcutaneous tissue that may impart a violaceous hue to the overlying skin (Fig. 3a). Some arise from a bona fide lymphatic or vascular malformation.55–57 At low power, lesions resemble a vascular malformation with large, irregular, thick-walled vessels surrounded by lymphoid aggregates (Fig. 3b). Smaller lymphatic channels can also be identified. Vessels are lined by ‘hobnail’ endothelial cells, which represent a characteristic feature of this tumour, and the diagnosis should not be made in their absence. They are identified by their cuboidal shape, high nuclear-to-cytoplasmic ratio, finely stippled chromatin pattern, nuclear clefts and cytoplasmic vacuoles (Fig. 3c). Intravascular endothelial papillary projections lined by these hobnail cells and containing a central hyaline core of accumulated basement membrane material are seen within small and large vessels. While intravascular endothelial tufts can be seen in other tumours, notably angiosarcoma, only the ‘hobnail’ endothelium is specific for the Dabska tumour. The endothelial cells within the Dabska tumour exhibit an immunophenotype that resembles normal lymphatic endothelium. They usually express von Willebrand factor, CD31 and CD34, although staining of the first two is usually significantly less intense than the last. They also express the lymphatic markers vascular endothelial growth factor receptor 3 (VEGFR3) and podoplanin, and lack an actin-positive cuff of pericytes.50,51 Papillary intralymphatic angioendothelioma/Dabska tumours metastasize to regional lymph nodes, but only an exceptional case has given rise to disseminated disease. Of the six cases reported by Dabska, two developed regional lymph node metastases and one died of metastatic disease.49 On the other hand, none of the eight cases with follow-up information reported by Fanburg-Smith et al.50 developed either recurrence or metastasis. Several other anecdotal cases in the literature also had a benign course. As PILA/Dabska tumours are so rare, it has been difficult to develop an understanding of their long-term behaviour and a rational approach to treatment. Usually an extended local or wide excision with clear margins is recommended coupled with follow-up care with attention to regional lymph nodes. © 2014 British Association of Dermatologists
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Fig 3. Papillary intralymphatic angioendothelioma/Dabska tumour. (a) Reddish infiltrated plaque-like tumours on the calf of a 20-monthold infant, (b) large irregular vascular channels resembling a vascular malformation, (c) intravascular papillae lined by ‘hobnail’ endothelial cells. Pictures (b) and (c) courtesy of Dr Carlos Diaz, Freiburg, Germany.
Retiform haemangioendothelioma Retiform haemangioendothelioma is a superficially located tumour that occurs mainly in adults and is characterized by vessels having an elongated shape resembling the rete testis (Fig. 4).58 Similarly to the PILA/Dabska tumour these vessels
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Fig 4. Retiform haemangioendothelioma. (a) A poorly circumscribed dermal lesion, (b) elongated vessels resembling the rete testis, (c) vessels lined by hobnail endothelial cells. Pictures cortesy of Dr Heinz Kutzner, Fiedrichshafen.
are lined by hobnail endothelial cells and are associated with lymphocytes in a dense hyaline-like background. Intravascular papillary projections are either absent or few in number and lymphatic vessels are usually less prevalent. Retiform haemangioendothelioma and PILA/Dabska tumours are closely related, and there are overlapping cases. This has resulted in the suggestion to label both lesions as ‘hobnail haemangioendotheliomas’.
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Other adult-type haemangioendotheliomas Haemangioendotheliomas can be further broken down into three subgroups. The first group of lesions, which nearly always occur in children and young adults, displays at least a partially lymphatic differentiation. KHE, PILA and RHE are members of this subgroup, and have been discussed above. The second, more aggressive group, largely confined to older children or adults, displays vascular differentiation. The epithelioid haemangioendothelioma is the principal member of this group, although the WHO considers it to be a variant of angiosarcoma. The t(1;3)(p36;q23–25) translocation is unique to epithelioid haemangioendothelioma.59 This translocation fuses the WWTR1 gene in 3q23–24 with the CAMTA1 gene in 1p36, creating the WWTR1–CAMTA1 fusion gene that is the hallmark of epithelioid haemangioendothelioma. The t(1;3)(p363;q23–25) translocation is specific to epithelioid haemangioendothelioma, regardless of its location, and has not been detected in any of the other epithelioid cell vascular neoplasms, including epithelioid haemangioma/angiolymphoid hyperplasia with eosinophilia, epithelioid angiosarcoma or pseudomyogenic haemangioendothelioma. Cytogenetic studies using appropriate fluorescence in situ hybridization probes for t(1;3)(p36;q23–25) are helpful for differential diagnosis, and they could show that multicentric epithelioid haemangioendothelioma is in fact a metastatic vascular tumour originating from a single neoplasm. The last group is incompletely characterized, and provisionally considered haemangioendotheliomas. Epithelioid sarcomalike haemangioendothelioma60 and pseudomyogenic haemangioendothelioma,61 which are closely related, along with composite haemangioendothelioma,62 are examples of this subgroup. Of these, only the latter has been reported to be congenital.63,64 We saw one congenital case of composite haemangioendothelioma in the subcutaneous tissue of the leg in a girl with congenital hemihypertrophy (I. Colmenero, personal observation) (Fig. 5). Composite haemangioendothelioma is composed of various histological components, including epithelioid haemangioendothelioma, RHE, spindle cell haemangioma and angiosarcoma. These components are frequently associated with malformative elements of blood vascular and lymphatic origin.
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Malignant vascular tumours Kaposi sarcoma Kaposi sarcoma (KS) is a low-grade malignant vascular neoplasm with four known clinical subtypes – classic, iatrogenic, AIDS-associated and African/endemic.65,66 All clinical subtypes of KS are caused by human herpesvirus 8 (HHV8) (also called KS-associated herpesvirus) and are rarely observed in children. Most African children who progress from latent HHV8 infection to KS do so in the context of untreated HIV. Immunosuppression is speculated to facilitate progression to clinical KS by uncoupling viral surveillance from HHV8 replication. British Journal of Dermatology (2014)
Fig 5. Composite haemangioendothelioma. (a) Violaceous nodule on the leg showing areas of (b) spindle cell haemangioma, (c) retiform haemangioendothelioma and (d) angiosarcoma. Picture (a) cortesy of Dr Enriquez de Salamanca, Madrid, Spain.
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Infection of differentiated blood vascular endothelial cells with Kaposi sarcoma-associated HHV8 leads to their lymphatic reprogramming, induction of approximately 70% of the main lymphatic lineage-specific genes (including PROX1, a master regulator of lymphatic development) and downregulation of blood vascular genes.67 It is remarkable that induction of the lymphatic marker genes for podoplanin and VEGFR3 is mediated by upregulation of the transcription factor PROX1. Furthermore, it might be shown that PROX1 plays an important, previously unanticipated role in mediating the aggressive behaviour of vascular neoplasms such as KS.68 Kaposi sarcoma lesions are characterized by multiple violaceous dermal patches, plaques and/or nodules. Clinicopathological variants of KS include anaplastic, telangiectatic, lymphangioma-like, bullous, hyperkeratotic, keloidal, micronodular, pyogenic granuloma-like, ecchymotic and intravascular KS.69,70 It has been suggested that certain variants, such as anaplastic KS and possibly lymphangioma-like KS, might have prognostic relevance.69 In children, cervical and oropharyngeal lymphadenopathy and visceral involvement are more common than cutaneous involvement. Histology provides the most efficient and cost-effective definitive diagnosis (Fig. 6). Patch lesions can be misinterpreted at low-power magnification as some form of inflammatory dermatosis. On closer examination, a subtle vasoformative process composed of slit-like vascular spaces dissecting between dermal collagen is present. The protrusion of native vascular structures into the lumina of ectatic neoplastic channels results in the characteristic ‘promontory’ sign. A mild inflammatory infiltrate comprising lymphocytes and plasma cells, often accompanied by iron-laden macrophages, is usually noticed. In the plaque stage numerous dissecting vascular channels containing erythrocytes occupy the dermis. Vessels are more irregular in shape, and fascicles or solid sheets of spindle cells with slit-like vascular lumina and extravasated erythrocytes are demonstrated. Hyaline globules are seen within solid areas of the tumour. Mitotic figures are sparse and there is no significant nuclear or cytological pleomorphism. Nodular KS exhibits dermal expansion by a relatively circumscribed proliferation of monomorphic neoplastic spindled cells (with some mitotic figures) arranged in fascicles. Erythrocytes are contained within slit-like channels between the individual spindled cells. HHV8 latent nuclear antigen-1 protein can be demonstrated by immunohistochemistry in KS. HHV8 can also be assessed by polymerase chain reaction analysis in tissues processed for conventional histopathology.71 HHV8 is not specific for KS as the virus has been detected in other vascular and nonvascular neoplasms.72 CD31, CD34, Friend leukaemia virus integration 1 and D2-40 are variably expressed in HIV- and non-HIVrelated KS.73 Differential diagnosis in children includes spindle cell haemangioma, KHE, hobnail angioma and microcystic lymphatic malformation; clinical features and absence of HHV8 staining help in the differentiation of these lesions from KS. There are no randomized controlled studies of chemotherapy in KS.74 AIDS-associated KS responds markedly to highly © 2014 British Association of Dermatologists
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Fig 6. Kaposi sarcoma, nodular type. (a) Dermal expansion of a circumscribed proliferation of neoplastic spindled cells arranged in fascicles; (b) erythrocytes within slit-like channels between the individual spindled cells. The proliferating cells are relatively monomorphic, but some mitotic figures can be identified. Hyaline globules and intracytoplasmic red cells are present. Pictures courtesy of Prof. Luis Requena, Madrid, Spain.
Fig 7. Angiosarcoma. Papillary formations lined by atypical epithelioid endothelial cells.
active antiretroviral therapy. Iatrogenic KS responds best to stopping immunosuppressants. Sirolimus may also improve iatrogenic KS.75 Systemic chemotherapy is employed to treat British Journal of Dermatology (2014)
8 Vascular tumours in infants, I. Colmenero and P.H. Hoeger Table 1 Clinical clues for differentiation between benign and intermediate/malignant cutaneous vascular tumours
Criteria Palpation Delineability Infiltration of surrounding tissuea Association with DIC/ thrombocytopenia
Benign vascular tumours
Intermediate risk and malignant vascular tumours
Soft Yes No
Coarse No Yes
Nob
Yes
DIC, disseminated intravascular coagulation. aBeyond visible parts of the tumour. bExcept for rare cases of rapidly involuting congenital haemangioma (Baselga et al.).82
patients with extensive skin involvement or disseminated or systemic disease. Cutaneous angiosarcoma Cutaneous angiosarcoma (CA) is a rare tumour that predominantly arises in the sun-exposed skin of the head and neck of adults and elderly patients. Rarely, these tumours have been observed in children, mostly in association with a pre-existing condition such as xeroderma pigmentosum, Aicardi syndrome or radiation therapy. Most paediatric cases of angiosarcoma are seen in late childhood and adolescence, and congenital and infantile angiosarcomas are very rare.76 Cutaneous angiosarcoma in children differs significantly from disease in adults. In adults, CA usually develops in male patients on the face and scalp, and is often large, multifocal and secondary to sun exposure.77,78 In contrast, paediatric CA
Table 2 Characteristic immunochemical markers of vascular tumours
Characteristic positive markers
Characteristic negative markers
GLUT1, LeY, merosin, WT1 Endothelial markers,b WT1
Lymphothelial markersa GLUT1
Endothelial markers, WT1
GLUT1
Pyogenic granuloma
Endothelial markers, WT1
Glomangioma
Endothelial markers
Verrucous haemangioma
Endothelial markers, GLUT1, WT1 Spindle cells: actin, vimentin
GLUT1, lymphothelial markers GLUT1, WT1, lymphothelial markers Lymphothelial markers
Disease Benign tumours Infantile haemangioma Rapidly involuting congenital haemangioma Noninvoluting congenital haemangioma
Spindle cell haemangioma
Tumours of intermediate dignity Tufted angioma Lymphothelial, endothelial, WT1 Kaposiform Lymphothelial, endothelial, haemangioendothelioma WT1 MLT Endothelial, LYVE1 PILA Endothelial and lymphothelial
Malignant tumours Kaposi sarcoma Angiosarcoma
Endothelial, lymphothelial, HHV8 Endothelial
Comments
Lymphothelial markers positive in malformative lymphatic channels between the lobules Lymphothelial markers positive in malformative lymphatic channels between the lobules
Glomus cells express SMA
Spindle cells: CD34
Cells lining vascular spaces express endothelial markers. Lymphothelial markers are sometimes expressed
GLUT1
vWF weak or negative
GLUT1
vWF weak or negative
GLUT1 GLUT1
D2-40 weak or negative Retiform haemangioendothelioma = same marker spectrum
GLUT1 HHV8
GLUT1 and lymphothelial markers can be positive
GLUT1, glucose transporter 1; HHV8, human herpesvirus 8; LeY, Lewis Y antigen; MLT, multifocal lymphangioendotheliomatosis with thrombocytopenia; PILA, papillary intralymphatic angioendothelioma; SMA, smooth muscle actin; WT1, Wilms tumour 1. aLymphothelial markers: podoplanin (D2-40), human lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1), prospero homeobox protein 1 (PROX1), vascular endothelial growth factor receptor 3 (VEGFR3). bEndothelial markers: CD31, CD34, friend leukaemia insertion site 1 (FLI1), von Willebrand factor (vWF).
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Vascular tumours in infants, I. Colmenero and P.H. Hoeger 9
is more common in female patients and in the lower extremities, and tends to be small and unifocal.76 Histologically, paediatric CA is similar to the adult form, although there seem to be a disproportionate number of purely epithelioid variants (90%).77 Diagnostic criteria include the presence of racemose and arborizing vessels, significant cytological atypia and endothelial stratification or areas of solid morphology (Fig. 7). Well-differentiated areas and poorly differentiated foci may alternate. Immunohistochemical analysis reveals expression of endothelial markers (CD31, CD34, Ulex europaeus and von Willebrand factor). There is variable reactivity for lymphatic markers such as VEGFR3 and D2-40,79,80 but HHV8 is absent in CA.81 Therapy consists of surgical excision wherever possible.
Conclusions The multitude of different vascular tumours presented in this series of review articles may at first seem confusing to the general dermatologist. However, there are some straightforward clinical cues, presented in Table 1, which should facilitate the principal question of whether the tumour is benign or potentially malignant. All vascular tumours with no clearcut clinical diagnosis and those with a potentially malignant character should be biopsied. Histological assessment of vascular tumours is a complicated matter requiring specific expertise. In addition to the assessment of architecture and extension of the tumour, immunohistological markers are essential for the correct categorization of individual vascular lesions. Key markers relevant for vascular tumours are summarized in Table 2.
References 1 Enjolras O, Wassef M, Mazoyer E et al. Infants with Kasabach-Merritt syndrome do not have ‘true’ hemangiomas. J Pediatr 1997; 130:631–40. 2 Lyons LL, North PE, Mac-Moune Lai F et al. Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma. Am J Surg Pathol 2004; 28:559–68. 3 Le Huu AR, Jokinen CH, Rubin BP et al. Expression of PROX1, lymphatic endothelial nuclear transcription factor, in Kaposiform hemangioendothelioma and tufted angioma. Am J Surg Pathol 2010; 34:1563–73. 4 Arai E, Kuramochi A, Tsuchida T et al. Usefulness of D2-40 immunohistochemistry for differentiation between kaposiform hemangioendothelioma and tufted angioma. J Cutan Pathol 2006; 33: 492–7. 5 Cohen MM. Vascular update: morphogenesis, tumors, malformations, and molecular dimensions. Am J Med Genet 2006; 140:2013– 38. 6 Astarita JL, Acton SE, Turley SJ. Podoplanin: emerging functions in development, the immune system, and cancer. Front Immunol 2012; 3:283. 7 Navarro-N un ~ez L, Langan SA, Nash GB, Watson SP. The physiological and pathophysiological roles of platelet CLEC-2. Thromb Haemost 2013; 109:991–8.
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8 Ozaki Y, Suzuki-Inoue K, Inoue O. Novel interactions in platelet biology: CLEC-2/podoplanin and laminin/GPVI. J Thromb Haemost 2009; 7(Suppl. 1):191–4. 9 Bertozzi CC, Schmaier AA, Mericko P et al. Platelets regulate lymphatic vascular development through CLEC-2–SLP-76 signaling. Blood 2010; 116:661–70. 10 Lowe KL, Navarro-Nunez L, Watson SP. Platelet CLEC-2 and podoplanin in cancer metastasis. Thromb Res 2012; 129(Suppl. 1): S30–7. 11 Suzuki-Inoue K. Essential in vivo roles of the platelet activation receptor CLEC-2 in tumour metastasis, lymphangiogenesis and thrombus formation. J Biochem 2010; 150:127–32. 12 Ogasawara S, Kaneko MK, Price JE, Kato Y. Characterization of anti-podoplanin monoclonal antibodies: critical epitopes for neutralizing the interaction between podoplanin and CLEC-2. Hybridoma (Larchmt) 2008; 27:259–67. 13 Suzuki-Inoue K, Inoue O, Ozaki Y. Novel platelet activation receptor CLEC-2: from discovery to prospects. J Thromb Haemost 2011; 9 (Suppl. 1):44–55. 14 Kato Y, Kaneko MK, Kunita A et al. Molecular analysis of the pathophysiological binding of the platelet aggregation-inducing factor podoplanin to the C-type lectin-like receptor CLEC-2. Cancer Sci 2008; 99:54–61. 15 Suzuki-Inoue K, Inoue O, Ding G et al. Essential in vivo roles of the C-type lectin receptor CLEC-2: embryonic/neonatal lethality of CLEC-2-deficient mice by blood/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets. J Biol Chem 2010; 285:24494–507. 16 Wilson-Jones E, Orkin M. Tufted angioma (angioblastoma). A benign progressive angioma, not to be confused with Kaposi’s sarcoma or low-grade angiosarcoma. J Am Acad Dermatol 1989; 20:214–25. 17 Nakagawa K. Case report of angioblastoma of the skin. Nihon Hifuka Gakkai Zasshi 1949; 59:92–4. 18 Macmillan A, Champion RH. Progressive capillary haemangioma. Br J Dermatol 1971; 85:492–3. 19 Heagerty AH, Rubin A, Robinson TW. Familial tufted angioma. Clin Exp Dermatol 1992; 17:344–5. 20 Hebeda CL, Scheffer E, Starink TM. Tufted angioma of late onset. Histopathology 1993; 23:191–3. 21 Fukunaga M. Intravenous tufted angioma. APMIS 2000; 108:287– 92. 22 Kleinegger CL, Hammond HL, Vincent SD, Finkelstein MW. Acquired tufted angioma: a unique vascular lesion not previously reported in the oral mucosa. Br J Dermatol 2000; 142: 794–9. 23 Maronn M, Chamlin S, Metry D. Multifocal tufted angiomas in 2 infants. Arch Dermatol 2009; 145:847–8. 24 Ishikawa K, Hatano Y, Ichikawa H et al. The spontaneous regression of tufted angioma. A case of regression after two recurrences and a review of 27 cases reported in the literature. Dermatology 2005; 210:346–8. 25 Suarez SM, Pensler JM, Paller AS. Response of deep tufted angioma to interferon alfa. J Am Acad Dermatol 1995; 33:124–6. 26 Herron MD, Coffin CM, Vanderhooft SL. Tufted angiomas: variability of the clinical morphology. Pediatr Dermatol 2002; 19:394–401. 27 Osio A, Fraitag S, Hadj-Rabia S et al. Clinical spectrum of tufted angiomas in childhood: a report of 13 cases and a review of the literature. Arch Dermatol 2010; 146:758–63. 28 Sadeghpour M, Antaya RJ, Lazova R, Ko CJ. Dilated lymphatic vessels in tufted angioma: a potential source of diagnostic confusion. Am J Dermatopathol 2012; 34:400–3.
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10 Vascular tumours in infants, I. Colmenero and P.H. Hoeger 29 Ban M, Kamiya H, Kitajima Y. Tufted angioma of adult onset, revealing abundant eccrine glands and central regression. Dermatology 2000; 201:68–70. 30 Trindade F, Tellechea O, Torrelo A et al. Wilms tumor 1 expression in vascular neoplasms and vascular malformations. Am J Dermatopathol 2011; 33:569–72. 31 North PE, Waner M, Mizeracki A, Mihm MC. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 2000; 31:11–22. 32 Hall GW. Kasabach-Merritt syndrome: pathogenesis and management. Br J Haematol 2001; 112:851–62. 33 Chiu YE, Drolet BA, Blei F et al. Variable response to propranolol treatment of kaposiform hemangioendothelioma, tufted angioma, and Kasabach-Merritt phenomenon. Pediatr Blood Cancer 2012; 59:934–8. 34 Zukerberg LR, Nickoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of infancy and childhood. An aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. Am J Surg Pathol 1993; 17:321–8. 35 North PE, Waner M, Buckmiller L et al. Vascular tumors of infancy and childhood: beyond capillary hemangioma. Cardiovasc Pathol 2006; 15:303–17. 36 Sarkar M, Mulliken JB, Kozakewich HP et al. Thrombocytopenic coagulopathy (Kasabach–Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg 1997; 100:1377–86. 37 Enjolras O, Mulliken JB, Wassef M et al. Residual lesions after Kasabach-Merritt phenomenon in 41 patients. J Am Acad Dermatol 2000; 42:225–35. 38 Walsh MA, Carcao M, Pope E, Lee KJ. Kaposiform hemangioendothelioma presenting antenatally with a pericardial effusion. J Pediatr Hematol Oncol 2008; 30:761–3. 39 Croteau SE, Liang MG, Kozakewich HP et al. Kaposiform hemangioendothelioma: atypical features and risks of Kasabach-Merritt phenomenon in 107 referrals. J Pediatr 2013; 162:142–7. 40 Debelenko LV, Perez-Atayde AR, Mulliken JB et al. D2-40 immunohistochemical analysis of pediatric vascular tumors reveals positivity in kaposiform hemangioendothelioma. Mod Pathol 2005; 18:1454–60. 41 Beaubien ER, Ball NJ, Storwick GS. Kaposiform hemangioendothelioma: a locally aggressive vascular tumor. J Am Acad Dermatol 1998; 38:799–802. 42 Adams DM, Wentzel MS. The role of the hematologist/oncologist in the care of patients with vascular anomalies. Pediatr Clin North Am 2008; 55:339–55. 43 Blatt J, Stavas J, Moats-Staats B et al. Treatment of childhood kaposiform hemangioendothelioma with sirolimus. Pediatr Blood Cancer 2010; 55:1396–8. 44 North PE, Kahn T, Cordisco MR et al. Multifocal lymphangioendotheliomatosis with thrombocytopenia: a newly recognized clinicopathological entity. Arch Dermatol 2004; 140:599–606. 45 Maronn M, Catrine K, North P et al. Expanding the phenotype of multifocal lymphangioendotheliomatosis with thrombocytopenia. Pediatr Blood Cancer 2009; 52:531–4. 46 Glick ZR, Frieden IJ, Garzon MC et al. Diffuse neonatal hemangiomatosis: an evidence-based review of case reports in the literature. J Am Acad Dermatol 2012; 67:898–903. 47 Esparza EM, Deutsch G, Stanescu L et al. Multifocal lymphangioendotheliomatosis with thrombocytopenia: phenotypic variant and course with propranolol, corticosteroids, and aminocaproic acid. J Am Acad Dermatol 2012; 67:e62–4. 48 Noel RJ, Duffy KJ, Kelly ME et al. Endoscopic management of gastrointestinal bleeding from multifocal lymphangioendotheliomato-
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sis with thrombocytopenia: limited efficacy and complications. J Pediatr Gastroenterol Nutr 2012; 54:822–4. Dabska M. Malignant endovascular papillary angioendothelioma of the skin in childhood. Clinicopathologic study of 6 cases. Cancer 1969; 24:503–10. Fanburg-Smith JC, Michal M, Partanen TA et al. Papillary intralymphatic angioendothelioma (PILA): a report of twelve cases of a distinctive vascular tumor with phenotypic features of lymphatic vessels. Am J Surg Pathol 1999; 23:1004–10. Fletcher C, Unni K, Mertens F, eds. Vascular tumours. In: Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon: IARC Press, 2002; 155–78. Neves RI, Stevenson J, Hancey MJ et al. Endovascular papillary angioendothelioma (Dabska tumor): underrecognized malignant tumor in childhood. J Pediatr Surg 2011; 46:25–8. McCarthy EF, Lietman S, Argani P, Frassica FJ. Endovascular papillary angioendothelioma (Dabska tumor) of bone. Skeletal Radiol 1999; 28:100–3. Rodgers B, Zeim S, Crawford B et al. Splenic papillary angioendothelioma in a 6-year-old girl. J Pediatr Hematol Oncol 2007; 29:808– 10. Emanuel PO, Lin R, Silver L et al. Dabska tumor arising in lymphangioma circumscriptum. J Cutan Pathol 2008; 35:65–9. Argani P, Athanasian E. Malignant endovascular papillary angioendothelioma (Dabska tumor) arising within a deep intramuscular hemangioma. Arch Pathol Lab Med 1997; 121:992–5. Quecedo E, Martınez-Escribano JA, Febrer I et al. Dabska tumor developing within a preexisting vascular malformation. Am J Dermatopathol 1996; 18:302–7. Calonje E, Fletcher CD, Wilson-Jones E, Rosai J. Retiform hemangioendothelioma. A distinctive form of low-grade angiosarcoma delineated in a series of 15 cases. Am J Surg Pathol 1994; 18:115– 25. Errani C, Zhang L, Sung YS et al. A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosom Cancer 2011; 50:644–53. Billings SD, Folpe AL, Weiss SW. Epithelioid sarcoma-like hemangioendothelioma. Am J Surg Pathol 2003; 27:48–57. Hornick JL, Fletcher CDM. Pseudomyogenic hemangioendothelioma: a distinctive, often multicentric tumor with indolent behavior. Am J Surg Pathol 2011; 35:190–201. Nayler SJ, Rubin BP, Calonje E et al. Composite hemangioendothelioma: a complex, low-grade vascular lesion mimicking angiosarcoma. Am J Surg Pathol 2000; 24:352–61. Reis-Filho JS, Paiva ME, Lopes JM. Congenital composite hemangioendothelioma: case report and reappraisal of the hemangioendothelioma spectrum. J Cutan Pathol 2002; 29:226–31. Fukunaga M, Suzuki K, Saegusa N, Folpe AL. Composite hemangioendothelioma: report of 5 cases including one with associated Maffucci syndrome. Am J Surg Pathol 2007; 31:1567–72. Sahin G, Palanduz A, Aydogan G et al. Classic Kaposi sarcoma in 3 unrelated Turkish children born to consanguineous kindreds. Pediatrics 2010; 125:704–8. Abbas AAH, Jastaniah WA. Extensive gingival and respiratory tract Kaposi sarcoma in a child after allogenic hematopoietic stem cell transplantation. J Pediatr Hematol Oncol 2012; 34:53–5. Hong Y-K, Foreman K, Shin JW et al. Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet 2004; 36:683–5. Dadras SS, Skrzypek A, Nguyen L et al. Prox-1 promotes invasion of kaposiform hemangioendotheliomas. J Invest Dermatol 2008; 128:2798–806.
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Vascular tumours in infants, I. Colmenero and P.H. Hoeger 11 69 Cossu S, Satta R, Cottoni F, Massarelli G. Lymphangioma-like variant of Kaposi’s sarcoma: clinicopathologic study of seven cases with review of the literature. Am J Dermatopathol 1997; 19:16–22. 70 Grayson W, Pantanowitz L. Histological variants of cutaneous Kaposi sarcoma. Diagn Pathol 2008; 3:31. 71 Pak F, Pyakural P, Kokhaei P et al. HHV-8/KSHV during the development of Kaposi’s sarcoma: evaluation by polymerase chain reaction and immunohistochemistry. J Cutan Pathol 2005; 32:21–7. 72 Pantanowitz L, Pinkus GS, Dezube BJ, Tahan SR. HHV8 is not limited to Kaposi’s sarcoma. Mod Pathol 2005; 18:1148. 73 Rosado FGN, Itani DM, Coffin CM, Cates JM. Utility of immunohistochemical staining with FLI1, D2-40, CD31, and CD34 in the diagnosis of acquired immunodeficiency syndrome-related and non-acquired immunodeficiency syndrome-related Kaposi sarcoma. Arch Pathol Lab Med 2012; 136:301–4. 74 Molyneux E, Davidson A, Orem J et al. The management of children with Kaposi sarcoma in resource limited settings. Pediatr Blood Cancer 2013; 60:538–42. 75 Yuksekkaya HA, Arikan C, Yazici A et al. Successful treatment of a child having generalized Kaposi’s sarcoma after living donor liver transplantation with conversion to sirolimus. Pediatr Transplant 2009; 13:375–8.
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76 Deyrup AT, Miettinen M, North PE et al. Pediatric cutaneous angiosarcomas: a clinicopathologic study of 10 cases. Am J Surg Pathol 2011; 35:70–5. 77 Deyrup AT, McKenney JK, Tighiouart M et al. Sporadic cutaneous angiosarcomas: a proposal for risk stratification based on 69 cases. Am J Surg Pathol 2008; 32:72–7. 78 Morgan MB, Swann M, Somach S et al. Cutaneous angiosarcoma: a case series with prognostic correlation. J Am Acad Dermatol 2004; 50:867–74. 79 Kahn HJ, Bailey D, Marks A. Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi’s sarcoma and a subset of angiosarcomas. Mod Pathol 2002; 15:434–40. 80 Folpe AL, Veikkola T, Valtola R, Weiss SW. Vascular endothelial growth factor receptor-3 (VEGFR-3): a marker of vascular tumors with presumed lymphatic differentiation, including Kaposi’s sarcoma, kaposiform and Dabska-type hemangioendotheliomas, and a subset of angiosarcomas. Mod Pathol 2000; 13:180–5. 81 Lasota J, Miettinen M. Absence of Kaposi’s sarcoma-associated virus (human herpesvirus-8) sequences in angiosarcoma. Virchows Arch 1999; 434:51–6. 82 Baselga E, Cordisco MR, Garzon M et al. Rapidly involuting congenital haemangioma associated with transient thrombocytopenia and coagulopathy: a case series. Br J Dermatol 2008; 158:1363–70.
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S C H O L A R L Y R E V IE W
Vascular tumours in infants. Part II: vascular tumours of intermediate dignity and malignant tumours I. Colmenero1 and P.H. Hoeger2 1 2
Histopathology Department, Birmingham Children’s Hospital, Birmingham, U.K. Paediatric Dermatology Department, Catholic Children’s Hospital Wilhelmstift, Hamburg, Germany
Summary Correspondence Peter Hoeger. E-mail: [email protected]
Accepted for publication 2 November 2013
Funding sources None.
Conflicts of interest None declared. DOI 10.1111/bjd.12835
Malignant cutaneous vascular tumours are very uncommon in children. As in adults, they are aggressive neoplasms with metastatic potential and a high mortality rate. Some nonmalignant vascular tumours may exhibit a locally aggressive behaviour and some of them can be associated with life-threatening systemic complications such as Kasabach–Merritt syndrome. Early diagnosis of these aggressive neoplasms in children is very important in order to start appropriate therapy as soon as possible, as this can have a significant impact on the prognosis of these patients. This review focuses on cutaneous vascular tumours of intermediate dignity (tufted angioma, kaposiform haemangioendothelioma, multifocal lymphangioendotheliomatosis with thrombocytopenia, papillary intralymphatic angioendothelioma, retiform haemangioendothelioma, adult-type haemangioendotheliomas) and malignant vascular tumours in young children (Kaposi sarcoma, angiosarcoma).
What’s already known about this topic?
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Malignant vascular tumours can mimic infantile haemangiomas, but need to be differentiated as soon as possible.
What does this study add?
• •
This is a comprehensive review of vascular tumours of intermediate dignity and malignant vascular tumours presenting during infancy and early childhood. We present clinical and histological criteria for differential diagnosis and discuss treatment options.
True malignant cutaneous vascular neoplasms are very rare in children and, as in adults, they show a high capacity to metastasize and a high mortality rate. Nevertheless, some nonmalignant vascular tumours may behave in a locally aggressive fashion or may be associated with serious systemic complications such as Kasabach–Merritt syndrome. Both malignant tumours and those of intermediate dignity may initially be misdiagnosed as infantile haemangiomas or other benign neoplasms. The early identification of these aggressive tumours is essential to start the appropriate treatment as soon as possible.
Tufted angioma/kaposiform haemangioendothelioma spectrum The significant degree of clinical and histological overlap between tufted angioma (TA) and kaposiform haemangioen© 2014 British Association of Dermatologists
dothelioma (KHE) and the association of these two entities with Kasabach–Merritt syndrome (KMS) suggest that TA is a milder, more superficial form of KHE.1 The expression of endothelial lymphatic-associated antigens displayed by TA and KHE supports the concept that these tumours have at least a partial lymphatic endothelial phenotype.2–4 Kasabach–Merritt syndrome is characterized by profound thrombocytopenia due to platelet trapping within the tumour, sometimes accompanied by microangiopathic haemolytic anaemia and secondary consumption of coagulation factors. It is different from the consumptive coagulopathy that may develop in large venous or lymphatic malformations.5 KHE and TA account for the vast majority of KMS cases.1 Recent findings have shed new light on the molecular mechanisms underlying KHE and tufted haemangioma, as well as on the coagulation phenomena associated with multifocal British Journal of Dermatology (2014)
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2 Vascular tumours in infants, I. Colmenero and P.H. Hoeger
lymphangioendotheliomatosis with thrombocytopenia (MLT). These vascular lesions share a common podoplanin-positive lymphatic endothelial immunophenotype. Podoplanin (D2-40) is a mucin-type transmembrane glycoprotein and may be found, albeit not exclusively, in endothelial cells of lymphatic lineage. Podoplanin is the only known endogenous ligand for CLEC-2, a C-type lectin receptor that is highly expressed on platelets.6–9 CLEC-2 is known to elicit powerful platelet activation upon engagement by podoplanin.7–9 Binding of podoplanin to CLEC-2 appears to be the predominant initiator of the blood clotting phenomena observed in various tumours with a podoplanin-positive lymphatic immunophenotype.7–11 Consequently, CLEC-2 could be an ideal novel target for an antiplatelet drug that would inhibit pathological thrombus formation but not physiological haemostasis.12–15 Tufted angioma Tufted angioma was first described as such by Wilson-Jones and Orkin in1989.16 Identical lesions had been described earlier as angioblastoma and progressive capillary haemangioma.17,18 Approximately 15% are congenital, and most of them present before 5 years of age,19 but some cases have been reported in adults.20 No racial predilection is recognized for TA and its prevalence is equal in both sexes. Most reported tumours occur on the upper trunk, neck and shoulders, and fewer cases occur on the face, scalp and proximal extremities. Involvement of the feet and oral mucosa has been observed only in rare cases.21,22 Tufted angioma is typically a solitary lesion, but multiple tumours have been described.23 Lesions present as enlarging pink-red, purple or red-brown patches and plaques with superimposed papules or nodules that spread slowly, then stabilize, and rarely regress (Fig. 1).24 The lesion diameter generally ranges from < 1 cm to several centimetres. On palpation, TA often has a rubbery consistency, and may be painful. Tenderness and hyperhidrosis are commonly associated symptoms.25 Hypertrichosis may also be observed in some cases.26 TA may be associated with KMS, and also with a chronic consumptive coagulopathy with normal platelet counts.27
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Tufted angioma is histologically described as a poorly demarcated lesion in the dermis and subcutis, consisting of multiple discrete, cannonball-like lobules of capillaries. Crescent-shaped thin-walled lymphatic vessels peripherally surround some of these lobules. A second component of lymphangioma-like anastomosed vessels is a prominent feature in some cases.28 Intervening dermis and subcutis are sometimes fibrotic, but may be histologically normal. The surrounding appendageal structures of the dermis are unaffected, although hypertrophy of neighbouring eccrine sweat glands can be seen.29 The pinpoint-like capillary lumina that form the lobules occasionally contain fibrin and platelet microthrombi. Endothelial cells may appear spindled at the periphery of lobules, but this is never a prominent feature. By immunohistochemistry, endothelial cells are focally positive for the lymphothelial markers podoplanin, lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1) and prospero homeobox-containing 1 (PROX1) transcription factor, but less extensively than is often seen in KHE.3,4 Similarly to other vascular tumours, TA is positive for Wilms tumour 1.30 Tumour endothelial cells are glucose transporter 1 (GLUT1) negative.31 The management of TA is difficult, and treatment guidelines have yet to be established. Several treatment regimens for TA with or without KMS have been reported, including compression therapy, surgery, laser, topical or systemic corticosteroids, interferon, propranolol and chemotherapy.1,26,32,33 A waitand-see policy seems appropriate because of the benign nature of this tumour and the possibility of spontaneous regression. Overall 95% of the cases found to regress did so within a period of 2 years.24 However, careful follow-up should be implemented, especially in early childhood, to detect complications such as KMS.27 No malignant transformation has been described to our knowledge. Kaposiform haemangioendothelioma Kaposiform haemangioendothelioma was first discussed under this name in the literature by Zukerberg et al.34 It is most commonly seen in infancy and childhood and is strikingly associated with KMS. Most cases of KHE1,2,35,36 present in
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Fig 1. Tufted angioma. (a) An indurated plaque with light pink nodular areas and hypertrichosis, (b) cannonball-like lobules of capillaries in the dermis, (c) crescent-shaped thin-walled lymphatic vessels peripherally surround some of the lobules. British Journal of Dermatology (2014)
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Vascular tumours in infants, I. Colmenero and P.H. Hoeger 3
early childhood, especially in the first 2 years of life, and are occasionally detected prenatally.37,38 The prevalence of KHE is estimated at about 091 per 100 000 children.39 In a series of 107 patients published recently,39 93% manifested in infancy and 60% in the neonatal period. The lesions range from superficial, locally infiltrative maculopapules and plaques to deep-seated bulky masses. The latter may occur in the soft tissue of the extremities, trunk or the head and neck, or may be diagnosed as large-body cavity or retroperitoneal masses, often followed by a complicated course with KMS and adverse outcome. Cutaneous manifestations occur in 75% of cases.39 Skin manifestations include vascular tumours, purpura and ecchymoses (Fig. 2a). Magnetic resonance imaging usually demonstrates a diffusely enhancing, T2 hyperintense lesion with ill-defined margins that cross tissue planes. Untreated tumours do not regress.37 KMS occurs in 71% of cases, and thrombocytopenia in 56%.39 Kaposiform haemangioendothelioma has been termed a haemangioendothelioma in order to reflect early uncertainty regarding possible borderline malignant behaviour, as regional lymph node metastases have been reported in two cases.34 However, accumulated evidence suggests that true metastasis is unlikely in KHE.31 Multifocal development along a regional lymphatic chain or in separate regions has been proposed as an alternative explanation for the above phenomenon. No distant metastases have been reported. Histologically,1,2,35–37 KHEs are composed of infiltrative, ill-defined, frequently coalescing lobules of spindled endothelial cell fascicles (Fig. 2b,c). The moderately plump spindle cells form elongated, slit-like lumina that contain erythrocytes. Nodular pericyte-rich epithelioid nests with pinpoint vascular lumina often surround platelet-rich microthrombi. The epithelioid nodules are rich in pericytes and contain cytoplasmic hyaline globules and erythrocyte fragments. Dilated lymphatic
Fig 2. Kaposiform haemangioendothelioma. (a) Enlarging violaceous tumour in the arm of a neonate associated with Kasabach–Merritt syndrome, (b) infiltrative coalescing lobules of spindled endothelial cell fascicles and dilated lymphatic vessels surrounding the nodules, (c) slit-like lumina containing erythrocytes, (d) intense and diffuse staining with D2-40. Picture (a) cortesy of Dr Antonio Torrelo, Madrid, Spain. © 2014 British Association of Dermatologists
vessels surround and intermingle with nodules, most prominently at the margins of lesions. Areas with a lobular pattern indistinguishable from TA are sometimes seen at the periphery of the tumour. At the margin of the lesion, the spindle cells may freely infiltrate into the surrounding adipose tissue and between collagen bundles, or they may be encased by desmoplastic stroma. By immunohistochemistry31,40 the spindled endothelial cells are positive for the panendothelial marker CD31, as well as for CD34 and lymphothelial markers (D240, LYVE1, PROX1).3 All endothelial cells comprising KHE are completely negative for infantile haemangioma markers such as GLUT1 and Lewis Y antigen. Wide local excision, when possible, is curative. Medical treatment is warranted in case of KHE-associated KMS and when the lesion is not resectable. Platelet transfusions have sometimes paradoxically worsened the coagulopathy. Platelet activation and release of angiogenic factors, such as plateletderived growth factor, may stimulate vascular proliferation in KHE. No single regimen has yielded consistent results either in terms of tumour size reduction or correction of thrombocytopenia. Vincristine has emerged as a preferred treatment of choice. Efficacy of interferon alfa-2a and 2b has been reported, but these have fallen out of favour due to risk of permanent spastic paraplegia when administered in infancy. Corticosteroid monotherapy has been advocated by some,41 but it is generally considered not to be effective.42 Although a case of KHE successfully treated with propranolol has been described, a subsequent study has shown that only a small proportion of cases respond to this treatment.33 Recent reports suggest that sirolimus, a mammalian target of rapamycin inhibitor with antiangiogenic activity, might be active against KHE.43 Rapid response to low-dose sirolimus (01 mg kg 1 per day) was demonstrated, but prospective controlled studies are not yet available.
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4 Vascular tumours in infants, I. Colmenero and P.H. Hoeger
Multifocal lymphangioendotheliomatosis with thrombocytopenia MLT is a rare disorder that was first described in 2004 by North et al.44 MLT is characterized by a proliferation of multiple congenital and progressive vascular lesions usually associated with mild-to-moderate thrombocytopenia. It is debatable whether MLT lesions are best considered tumours or malformations. MLT involves skin and the gastrointestinal system, but in some cases it can also involve lungs, brain, spleen, bone, synovium or muscle. Boys and girls are equally affected. Gastrointestinal bleeding is almost universally present and may be life threatening.45 The lethality of MLT is high (63% in a recent meta-analysis).46 Cutaneous lesions are flat or indurated, red-brown to burgundy papules or plaques, which range in size from a few millimetres to 5 cm. They are present in variable numbers, with more than 100 lesions in some cases. Appearance of new lesions and slow progression of existing lesions, without evidence of regression, is typical.45 It is difficult on clinical grounds alone to separate MLT from diffuse neonatal haemangiomatosis.46 MLT lesions involving the skin consist of delicate vessels scattered throughout the dermis and subcutis. They are lined by a monolayer of slightly hobnailed endothelial cells that form complex papillary projections that seem to float within the lumina. Mitotic figures are rare or absent. The endothelial cells show strong reactivity for CD31, CD34 and LYVE1, and light or absent positivity for D2-40. They are negative for GLUT1.44 The lack of effective therapeutic interventions for MLT makes the clinical management and treatment of this disease extremely challenging. Attempts to treat MLT with medications including corticosteroids, thalidomide, interferon alfa-2a and vincristine have failed to demonstrate any sustained efficacy in controlling bleeding from the gastrointestinal lesions, whereas a combination of propranolol (3 mg kg 1 per day), prednisolone (2 mg kg 1 per day) and aminocaproic acid (loading dose 100 mg kg 1, 2-week infusion at 33 mg kg 1) was recently reported to be successful in one case.47 The endoscopic management of gastrointestinal bleeding from MLT has shown limited efficacy and complications.48
Papillary intralymphatic angioendothelioma/ retiform haemangioendothelioma spectrum Papillary intralymphatic angioendothelioma (PILA) and retiform haemangioendothelioma (RHE) are closely related lesions considered within the group of vascular tumours known as ‘haemangioendotheliomas’ to imply that they are borderline between benign haemangiomas and conventional angiosarcomas. This term reflects their ability to recur but their limited capacity for metastasis compared with angiosarcoma. Some authors have suggested that PILA is the juvenile variant of RHE. In the current literature, it has been suggested that both tumours probably develop from lymphatic endothelial cells. British Journal of Dermatology (2014)
Papillary intralymphatic angioendothelioma Papillary intralymphatic angioendothelioma, also known as Dabska tumour, is a low-grade vascular tumour of childhood first described in 1969 by the Polish pathologist Marıa Dabska.49 Based on the observation that the lesion is often associated with lymphatic vessels, Fanburg-Smith et al.50 proposed the name ‘papillary intralymphatic angioendothelioma’, which has since been adopted by the World Health Organization (WHO).51 PILA/Dabska tumours occur almost exclusively in children and young adults; some cases are congenital. Most PILA tumours originate in the skin and superficial soft tissues of the head and neck, trunk or extremities.50,52 Rarely, unusual sites such as bone53 and spleen54 are affected. Typically, PILA/Dabska tumours are ill-defined masses of the dermis and subcutaneous tissue that may impart a violaceous hue to the overlying skin (Fig. 3a). Some arise from a bona fide lymphatic or vascular malformation.55–57 At low power, lesions resemble a vascular malformation with large, irregular, thick-walled vessels surrounded by lymphoid aggregates (Fig. 3b). Smaller lymphatic channels can also be identified. Vessels are lined by ‘hobnail’ endothelial cells, which represent a characteristic feature of this tumour, and the diagnosis should not be made in their absence. They are identified by their cuboidal shape, high nuclear-to-cytoplasmic ratio, finely stippled chromatin pattern, nuclear clefts and cytoplasmic vacuoles (Fig. 3c). Intravascular endothelial papillary projections lined by these hobnail cells and containing a central hyaline core of accumulated basement membrane material are seen within small and large vessels. While intravascular endothelial tufts can be seen in other tumours, notably angiosarcoma, only the ‘hobnail’ endothelium is specific for the Dabska tumour. The endothelial cells within the Dabska tumour exhibit an immunophenotype that resembles normal lymphatic endothelium. They usually express von Willebrand factor, CD31 and CD34, although staining of the first two is usually significantly less intense than the last. They also express the lymphatic markers vascular endothelial growth factor receptor 3 (VEGFR3) and podoplanin, and lack an actin-positive cuff of pericytes.50,51 Papillary intralymphatic angioendothelioma/Dabska tumours metastasize to regional lymph nodes, but only an exceptional case has given rise to disseminated disease. Of the six cases reported by Dabska, two developed regional lymph node metastases and one died of metastatic disease.49 On the other hand, none of the eight cases with follow-up information reported by Fanburg-Smith et al.50 developed either recurrence or metastasis. Several other anecdotal cases in the literature also had a benign course. As PILA/Dabska tumours are so rare, it has been difficult to develop an understanding of their long-term behaviour and a rational approach to treatment. Usually an extended local or wide excision with clear margins is recommended coupled with follow-up care with attention to regional lymph nodes. © 2014 British Association of Dermatologists
Vascular tumours in infants, I. Colmenero and P.H. Hoeger 5
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Fig 3. Papillary intralymphatic angioendothelioma/Dabska tumour. (a) Reddish infiltrated plaque-like tumours on the calf of a 20-monthold infant, (b) large irregular vascular channels resembling a vascular malformation, (c) intravascular papillae lined by ‘hobnail’ endothelial cells. Pictures (b) and (c) courtesy of Dr Carlos Diaz, Freiburg, Germany.
Retiform haemangioendothelioma Retiform haemangioendothelioma is a superficially located tumour that occurs mainly in adults and is characterized by vessels having an elongated shape resembling the rete testis (Fig. 4).58 Similarly to the PILA/Dabska tumour these vessels
© 2014 British Association of Dermatologists
Fig 4. Retiform haemangioendothelioma. (a) A poorly circumscribed dermal lesion, (b) elongated vessels resembling the rete testis, (c) vessels lined by hobnail endothelial cells. Pictures cortesy of Dr Heinz Kutzner, Fiedrichshafen.
are lined by hobnail endothelial cells and are associated with lymphocytes in a dense hyaline-like background. Intravascular papillary projections are either absent or few in number and lymphatic vessels are usually less prevalent. Retiform haemangioendothelioma and PILA/Dabska tumours are closely related, and there are overlapping cases. This has resulted in the suggestion to label both lesions as ‘hobnail haemangioendotheliomas’.
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6 Vascular tumours in infants, I. Colmenero and P.H. Hoeger
Other adult-type haemangioendotheliomas Haemangioendotheliomas can be further broken down into three subgroups. The first group of lesions, which nearly always occur in children and young adults, displays at least a partially lymphatic differentiation. KHE, PILA and RHE are members of this subgroup, and have been discussed above. The second, more aggressive group, largely confined to older children or adults, displays vascular differentiation. The epithelioid haemangioendothelioma is the principal member of this group, although the WHO considers it to be a variant of angiosarcoma. The t(1;3)(p36;q23–25) translocation is unique to epithelioid haemangioendothelioma.59 This translocation fuses the WWTR1 gene in 3q23–24 with the CAMTA1 gene in 1p36, creating the WWTR1–CAMTA1 fusion gene that is the hallmark of epithelioid haemangioendothelioma. The t(1;3)(p363;q23–25) translocation is specific to epithelioid haemangioendothelioma, regardless of its location, and has not been detected in any of the other epithelioid cell vascular neoplasms, including epithelioid haemangioma/angiolymphoid hyperplasia with eosinophilia, epithelioid angiosarcoma or pseudomyogenic haemangioendothelioma. Cytogenetic studies using appropriate fluorescence in situ hybridization probes for t(1;3)(p36;q23–25) are helpful for differential diagnosis, and they could show that multicentric epithelioid haemangioendothelioma is in fact a metastatic vascular tumour originating from a single neoplasm. The last group is incompletely characterized, and provisionally considered haemangioendotheliomas. Epithelioid sarcomalike haemangioendothelioma60 and pseudomyogenic haemangioendothelioma,61 which are closely related, along with composite haemangioendothelioma,62 are examples of this subgroup. Of these, only the latter has been reported to be congenital.63,64 We saw one congenital case of composite haemangioendothelioma in the subcutaneous tissue of the leg in a girl with congenital hemihypertrophy (I. Colmenero, personal observation) (Fig. 5). Composite haemangioendothelioma is composed of various histological components, including epithelioid haemangioendothelioma, RHE, spindle cell haemangioma and angiosarcoma. These components are frequently associated with malformative elements of blood vascular and lymphatic origin.
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Malignant vascular tumours Kaposi sarcoma Kaposi sarcoma (KS) is a low-grade malignant vascular neoplasm with four known clinical subtypes – classic, iatrogenic, AIDS-associated and African/endemic.65,66 All clinical subtypes of KS are caused by human herpesvirus 8 (HHV8) (also called KS-associated herpesvirus) and are rarely observed in children. Most African children who progress from latent HHV8 infection to KS do so in the context of untreated HIV. Immunosuppression is speculated to facilitate progression to clinical KS by uncoupling viral surveillance from HHV8 replication. British Journal of Dermatology (2014)
Fig 5. Composite haemangioendothelioma. (a) Violaceous nodule on the leg showing areas of (b) spindle cell haemangioma, (c) retiform haemangioendothelioma and (d) angiosarcoma. Picture (a) cortesy of Dr Enriquez de Salamanca, Madrid, Spain.
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Vascular tumours in infants, I. Colmenero and P.H. Hoeger 7
Infection of differentiated blood vascular endothelial cells with Kaposi sarcoma-associated HHV8 leads to their lymphatic reprogramming, induction of approximately 70% of the main lymphatic lineage-specific genes (including PROX1, a master regulator of lymphatic development) and downregulation of blood vascular genes.67 It is remarkable that induction of the lymphatic marker genes for podoplanin and VEGFR3 is mediated by upregulation of the transcription factor PROX1. Furthermore, it might be shown that PROX1 plays an important, previously unanticipated role in mediating the aggressive behaviour of vascular neoplasms such as KS.68 Kaposi sarcoma lesions are characterized by multiple violaceous dermal patches, plaques and/or nodules. Clinicopathological variants of KS include anaplastic, telangiectatic, lymphangioma-like, bullous, hyperkeratotic, keloidal, micronodular, pyogenic granuloma-like, ecchymotic and intravascular KS.69,70 It has been suggested that certain variants, such as anaplastic KS and possibly lymphangioma-like KS, might have prognostic relevance.69 In children, cervical and oropharyngeal lymphadenopathy and visceral involvement are more common than cutaneous involvement. Histology provides the most efficient and cost-effective definitive diagnosis (Fig. 6). Patch lesions can be misinterpreted at low-power magnification as some form of inflammatory dermatosis. On closer examination, a subtle vasoformative process composed of slit-like vascular spaces dissecting between dermal collagen is present. The protrusion of native vascular structures into the lumina of ectatic neoplastic channels results in the characteristic ‘promontory’ sign. A mild inflammatory infiltrate comprising lymphocytes and plasma cells, often accompanied by iron-laden macrophages, is usually noticed. In the plaque stage numerous dissecting vascular channels containing erythrocytes occupy the dermis. Vessels are more irregular in shape, and fascicles or solid sheets of spindle cells with slit-like vascular lumina and extravasated erythrocytes are demonstrated. Hyaline globules are seen within solid areas of the tumour. Mitotic figures are sparse and there is no significant nuclear or cytological pleomorphism. Nodular KS exhibits dermal expansion by a relatively circumscribed proliferation of monomorphic neoplastic spindled cells (with some mitotic figures) arranged in fascicles. Erythrocytes are contained within slit-like channels between the individual spindled cells. HHV8 latent nuclear antigen-1 protein can be demonstrated by immunohistochemistry in KS. HHV8 can also be assessed by polymerase chain reaction analysis in tissues processed for conventional histopathology.71 HHV8 is not specific for KS as the virus has been detected in other vascular and nonvascular neoplasms.72 CD31, CD34, Friend leukaemia virus integration 1 and D2-40 are variably expressed in HIV- and non-HIVrelated KS.73 Differential diagnosis in children includes spindle cell haemangioma, KHE, hobnail angioma and microcystic lymphatic malformation; clinical features and absence of HHV8 staining help in the differentiation of these lesions from KS. There are no randomized controlled studies of chemotherapy in KS.74 AIDS-associated KS responds markedly to highly © 2014 British Association of Dermatologists
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Fig 6. Kaposi sarcoma, nodular type. (a) Dermal expansion of a circumscribed proliferation of neoplastic spindled cells arranged in fascicles; (b) erythrocytes within slit-like channels between the individual spindled cells. The proliferating cells are relatively monomorphic, but some mitotic figures can be identified. Hyaline globules and intracytoplasmic red cells are present. Pictures courtesy of Prof. Luis Requena, Madrid, Spain.
Fig 7. Angiosarcoma. Papillary formations lined by atypical epithelioid endothelial cells.
active antiretroviral therapy. Iatrogenic KS responds best to stopping immunosuppressants. Sirolimus may also improve iatrogenic KS.75 Systemic chemotherapy is employed to treat British Journal of Dermatology (2014)
8 Vascular tumours in infants, I. Colmenero and P.H. Hoeger Table 1 Clinical clues for differentiation between benign and intermediate/malignant cutaneous vascular tumours
Criteria Palpation Delineability Infiltration of surrounding tissuea Association with DIC/ thrombocytopenia
Benign vascular tumours
Intermediate risk and malignant vascular tumours
Soft Yes No
Coarse No Yes
Nob
Yes
DIC, disseminated intravascular coagulation. aBeyond visible parts of the tumour. bExcept for rare cases of rapidly involuting congenital haemangioma (Baselga et al.).82
patients with extensive skin involvement or disseminated or systemic disease. Cutaneous angiosarcoma Cutaneous angiosarcoma (CA) is a rare tumour that predominantly arises in the sun-exposed skin of the head and neck of adults and elderly patients. Rarely, these tumours have been observed in children, mostly in association with a pre-existing condition such as xeroderma pigmentosum, Aicardi syndrome or radiation therapy. Most paediatric cases of angiosarcoma are seen in late childhood and adolescence, and congenital and infantile angiosarcomas are very rare.76 Cutaneous angiosarcoma in children differs significantly from disease in adults. In adults, CA usually develops in male patients on the face and scalp, and is often large, multifocal and secondary to sun exposure.77,78 In contrast, paediatric CA
Table 2 Characteristic immunochemical markers of vascular tumours
Characteristic positive markers
Characteristic negative markers
GLUT1, LeY, merosin, WT1 Endothelial markers,b WT1
Lymphothelial markersa GLUT1
Endothelial markers, WT1
GLUT1
Pyogenic granuloma
Endothelial markers, WT1
Glomangioma
Endothelial markers
Verrucous haemangioma
Endothelial markers, GLUT1, WT1 Spindle cells: actin, vimentin
GLUT1, lymphothelial markers GLUT1, WT1, lymphothelial markers Lymphothelial markers
Disease Benign tumours Infantile haemangioma Rapidly involuting congenital haemangioma Noninvoluting congenital haemangioma
Spindle cell haemangioma
Tumours of intermediate dignity Tufted angioma Lymphothelial, endothelial, WT1 Kaposiform Lymphothelial, endothelial, haemangioendothelioma WT1 MLT Endothelial, LYVE1 PILA Endothelial and lymphothelial
Malignant tumours Kaposi sarcoma Angiosarcoma
Endothelial, lymphothelial, HHV8 Endothelial
Comments
Lymphothelial markers positive in malformative lymphatic channels between the lobules Lymphothelial markers positive in malformative lymphatic channels between the lobules
Glomus cells express SMA
Spindle cells: CD34
Cells lining vascular spaces express endothelial markers. Lymphothelial markers are sometimes expressed
GLUT1
vWF weak or negative
GLUT1
vWF weak or negative
GLUT1 GLUT1
D2-40 weak or negative Retiform haemangioendothelioma = same marker spectrum
GLUT1 HHV8
GLUT1 and lymphothelial markers can be positive
GLUT1, glucose transporter 1; HHV8, human herpesvirus 8; LeY, Lewis Y antigen; MLT, multifocal lymphangioendotheliomatosis with thrombocytopenia; PILA, papillary intralymphatic angioendothelioma; SMA, smooth muscle actin; WT1, Wilms tumour 1. aLymphothelial markers: podoplanin (D2-40), human lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1), prospero homeobox protein 1 (PROX1), vascular endothelial growth factor receptor 3 (VEGFR3). bEndothelial markers: CD31, CD34, friend leukaemia insertion site 1 (FLI1), von Willebrand factor (vWF).
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Vascular tumours in infants, I. Colmenero and P.H. Hoeger 9
is more common in female patients and in the lower extremities, and tends to be small and unifocal.76 Histologically, paediatric CA is similar to the adult form, although there seem to be a disproportionate number of purely epithelioid variants (90%).77 Diagnostic criteria include the presence of racemose and arborizing vessels, significant cytological atypia and endothelial stratification or areas of solid morphology (Fig. 7). Well-differentiated areas and poorly differentiated foci may alternate. Immunohistochemical analysis reveals expression of endothelial markers (CD31, CD34, Ulex europaeus and von Willebrand factor). There is variable reactivity for lymphatic markers such as VEGFR3 and D2-40,79,80 but HHV8 is absent in CA.81 Therapy consists of surgical excision wherever possible.
Conclusions The multitude of different vascular tumours presented in this series of review articles may at first seem confusing to the general dermatologist. However, there are some straightforward clinical cues, presented in Table 1, which should facilitate the principal question of whether the tumour is benign or potentially malignant. All vascular tumours with no clearcut clinical diagnosis and those with a potentially malignant character should be biopsied. Histological assessment of vascular tumours is a complicated matter requiring specific expertise. In addition to the assessment of architecture and extension of the tumour, immunohistological markers are essential for the correct categorization of individual vascular lesions. Key markers relevant for vascular tumours are summarized in Table 2.
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