Kaposiform Hemangioendothelioma Associated With Milroy’sDisease (Primary Hereditary Lymphedema)

By Roberto Mendez, Ana Capdevila, Manuel G. Tellado, Ivan Somoza, Jorge Liras,Ernesto Pais, and Diego Vela

A Coruna, Spain

Kaposiform infantile hemangioendothelioma (KHE) is a rarerecently characterized, locally aggressive, endothelial-de-rived neoplasm that occurs exclusively in the pediatric agegroup. Milroy-Nonne disease (primary hereditary lymphed-ema) is an uncommon congenital entity with familiar historyof lower limb edema as typical clinical features. An 8-year-old boy developed a hard painless mass in the right leg 7years after the diagnosis of congenital primary lymphedemaof the right lower extremity. Histopathological analysis of the

tumor showed the typical findings of the KHE. To our knowl-edge this is the first reported case of a KHE engrafting on thisinfrequent benign lymphatic anomaly.J Pediatr Surg 38:E19. © 2003 Elsevier Inc. All rights re-served.

INDEX WORDS: Kaposiform infantile hemangioendotheli-oma, Milroy’s disease, primary lymphedema, vascular tu-mors.

TSANG AND CHAN1 reported in 1991 a distinctivevascular tumor previously incompletely character-

ized that combined Kaposi-like and hemangioendotheli-oma features, the so-called infantile kaposiform heman-gioendothelioma (KHE).1 These tumors involve the deepsoft tissues of retroperitoneum and extremities duringinfancy and can be associated with thrombocytopeniccoagulopathy (Kasabach-Merritt syndrome).2

Primary hereditary lymphedema is a rare disease thatmay present in either the congenital form (Milroy-Nonne) or the delayed onset variety (Letessier-Meige).Its typical findings include lower limb edema, familiarhistory of edema of lower extremities, lymphangio-graphic abnormalities, and no other causes of secondaryedema.3-6

KHE has been reported to be associated with lym-phatic malformations (anomalous lymphatic channels) inthe majority of patients occurring in association withKasabach-Merritt phenomenon.2,7

To our knowledge, this is the first reported case ofprimary hereditary lymphedema associated with focalKHE without Kasabach-Meritt syndrome in pediatricpatients.

CASE REPORT

Our patient is an 8 year-old boy with Milroy-Nonne’s diseaseoriginally diagnosed at the age of 18 months when he presentedprimary and progressive lymphedema on his right leg with familiarhistory of edema of the lower limbs (mother and daughter affected).The entire right extremity was involved compared with the contralat-eral normal leg. The patient was referred to our hospital when henoticed a solid, noninflammatory soft tissue mass in the right lowerextremity at the age of 8 years. The lesion progressed slowly during thelast 3 months. On clinical examination, a hard deeply and painlesstumor 6 � 6 cm in size located in right proximal thigh was seen. Theskin was apparently normal. Sonography showed a complex heteroge-

neous solid mass with low resistance arterial signal in Doppler studies(Fig 1). On computed tomography (CT) scan, a soft tissue mass withvascular components enhanced after contrast administration was seen.Magnetic resonance imaging (MRI) (Fig 2) showed a well-delimitedintramuscular tumor with typical hemangioma features (heterogeneouslesion with low signal intensity mass on T1-weighted images and veryhigh signal intensity caused by vascular tissue on T2-weighted images).The suspected diagnosis was hemangioma, and the patient underwentoperated surgery. The surgical resection was difficult because of thesurrounding vascular weft, but all the mass could be excised. The skinover the mass was not affected, and resection was not necessary. Thehistopathologic examination showed a well-circumscribed mass (6 �5 � 6 cm in size) macroscopically resembling a cavernous hemangi-oma. The histologic appearance was of cavernous endothelium-linedblood spaces interconnecting sheets of irregular nodules of slitlike andcapillary-type vessels. There were some nests of endothelial epithelioidwith eosinophilic cytoplasm containing vacuoles and hyaline droplets.Nuclear atypia was minimal, and mitotic figures were infrequent (Fig3). The immunophenotypic profile of the endothelium and pericytes ofthese vessels expressed a strong reactivity with CD34, factor VIII-AGand muscle-specific actin, desmin and vimentin. No staining of thetumor cells could be seen with antibodies to S-100 protein, cytokeratin,or HMB45. The tumor was diagnosed as infantile Kaposiform heman-gioendothelioma after a thorough review of the previously reportedcases. The patient is now 12 years of age, and there is no recurrence ofthe lesion at the site of the excision 4 years after the surgery. Lymphed-ema of the right leg has improved because of press therapy manage-ment. Follow-up is made with clinical examination and ultrasound scanof the extremity every 6 months.

From the Departments of Pediatric Surgery and Pathology, Chil-dren’s Hospital “Teresa Herrera,” Complexo Hospitalario “JuanCanalejo,” A Coruna, Spain.

Address reprint requests to Roberto Mendez, MD, Department ofPediatric Surgery, Children’s Hospital “Teresa Herrera,” UniversityHospital “Juan Canalejo,” As Xubias 84. 15006. A Coruna, Spain.

© 2003 Elsevier Inc. All rights reserved.1531-5037/03/3807-0036$30.00/0doi:10.1016/S0022-3468(03)00213-6

1Journal of Pediatric Surgery, Vol 38, No 7 (July), 2003: E19

DISCUSSION

Kaposi-like infantile hemangioendothelioma (KHE)is a rare but distinctive vascular neoplasm completelycharacterised by Tsang and Chan in 19911 and originallydescribed in the retroperitoneum of young infants. Sincethen, more than 60 cases have been reported in thereviewed literature.2,8,9,10 This tumor apparently occursonly in children, and most of the previously reportedcases have been published under a wide variety ofnames including hemangioma with kaposiform fea-tures, infantile hemangioendothelioma, spindle-cell in-fantile hemangioendothelioma locally metastasizing,congenital retroperitoneal hemangioendothelioma, andhemangioendothelioma epithelioid Kaposi-like.2,11 Al-though previous articles emphasize the location on ret-roperitoneum, nearly 75% of the reported cases havebeen described recently in other sites including extrem-ities, skin, scalp, and chest wall.10,12

Histologic appearance of KHE is quite different fromother vascular neoplasms during childhood, but there aresome difficulties in the differential diagnosis with other

newly characterized vascular tumors. The criss-crossspindle cell fascicles simulate the nodular lesions ofKaposi’s sarcoma without the clinical implications ofthis kind of tumor. KHE can be distinguished from

Fig 1. Ultrasound showed a heterogeneous solid mass with small

calcifications.

Fig 2. MRI T2-weighted images show the typical signal of a vas-

cular tissue mass.

Fig 3. Kaposiform infantile hemangioendothelioma pathologic

features: (a) spindle-cells intertwined with slit-like vascular spaces

showing uniform oval nuclei with fine chromatin; (b) reticulin fibers

are present around the vessels and between the spindle-cell fasci-

cles; (c) ectatic capillaries and lymphatics lined by flat endothelial

cells in the periphery of the mass.

2 MENDEZ ET AL

angiosarcoma by the absence of infiltrative endothelialchannels, the infrequent mitosis or atypias, and the pres-ence of the lobulated pattern.9 Some areas of this tumorvaguely resemble spindle cell hemangioendothelioma,but KHE does not contain the typical cavernous vascularspaces present in the latter.13

Immunohistochemical studies are essential for the def-inition of the neoplasm, and some endothelial antigenshave been identified. The tumor cells usually show im-munoreactivity to CD34, factor VIII-AG, actin, desmin,vimentin, and C31.14

KHE is a locally aggressive vascular tumor oftenassociated with locally extensive disease and Kasabach-Merritt syndrome (thrombocytopenic coagulopathy asso-ciated with vascular neoplasms), but no distant metasta-sis have been reported.9,10 Regardless of this fact, we stillare uncertain about the biologic behavior and metastaticpotential: follow-up information of the previously re-ported cases has been limited to a few years only.

This tumor also may engraft itself on lymphangioma-tosis, a phenomenon that has been noted only in 3 casesreported by Zukerberg et al.2,15 We found only one casein the literature in which the identification of the lym-phatic anomaly preceded the diagnosis of the tumor.16 Inour particular case, the underlying lymphatic malforma-tion (Milroy’s disease) had been diagnosed 7 years be-fore onset of the mass. Although the relationship be-tween chronic lymphedema and neoplasms likelymphoma, lymphangiosarcoma (Stewart-Treves syn-drome), melanoma, or metastatic carcinoma has beendefined clearly, no reports had been published concern-ing KHE and primary lymphedema.17

Milroy’s disease (primary hereditary lymphedema) isan uncommon disease typically characterized by lowerlimb edema (uni or bilateral) affecting various familialmembers.3,18 Genetic mapping of the autosomal domi-

nant form of primary hereditary lymphedema suggeststhat this disease can be ascribed to a mutation thatinactives the vascular endothelial growth factor recep-tor–3 (VEGFR-3), a tyrosine kinase signalling mecha-nism that is felt to be specific to lymphatic vessels.19,20

VEGFR-3 is a tyrosine kinase receptor expressed almostexclusively by lymphatic endothelium, and this mono-clonal antibody has been shown to react with a smallnumber of cases of Kaposi’s sarcoma, cutaneous lym-phangiomas, and KHE.21,22 Recent research with trans-genic mouse models has identified a variety of moleculeslike VEGF and their receptors involved in the normalvascular development and angiogenesis.7 Disruption ofthe normal function of some of these factors couldgenerate abnormalities in vasculogenesis.23

The definitive pathogenesis mechanism of this non–previously described association is unclear, but probablythe most consistent theory implies chronic lymphaticstasis that may cause a local dysfunction of the immunesystem that predisposes to the induction of the neopla-sia.17 Some chemical mediators derived from abnormalendothelial cells and VEGFs may be the crucial factorsin the induction of the endothelial cell neoplasia.22

Awareness of the risk of lymphedema-related malig-nant tumors is mandatory for long-term follow-up ofpatients diagnosed as having Milroy’s disease. The ap-propriate management of KHE is controversial becauseof the locally aggressive behavior and the typical diffuse(nonfocal) presentation. The absence of documented dis-tant metastasis enforce to adopt a radical surgical ap-proach for the treatment of these masses. In some re-ported examples, other different interventions such asradiation, interferon, and chemotherapy have modifiedthe natural history of the tumor attaining partial regres-sions.10

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3. Milroy WF: Chronic hereditary edema: Milroy’s disease. JAMA91:1172, 1928

4. Kinmouth JR, Taylor GW, Tracy GD: Primary lymphedema:Clinical and lymphangiographic studies of a series of 107 patients inwhich the lower limbs were affected. Br J Surg 45:1-5, 1957

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9. Tsang WY, Chan JK, Fletcher CD: Recently characterized vas-cular tumours of skin and soft tissues. Hystopathology 19:489-501,1991

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11. Niedt GW, Greco MA, Wieczorek R, et al: Hemangioma withkaposi’s sarcoma-like features: report of two cases. Pediatr Pathol9:567-575, 1989

12. Lalaji TA, Haller JO, Burgess RJ: A case of head and neckkaposiform hemangioendothelioma simulating a malignancy on imag-ing. Pediatr Radiol 31:876-878, 2001

13. Weiss SW, Enzinger FM: Spindle-cell hemangioendothelioma,a low grade angiosarcoma resembling a cavemous hemangioma andKaposi’s sarcoma. Am J Surg Pathol 10:521-530, 1986

14. Costa MA, Sousa A, Vieira E: Hemangioendothelioma: A rarevascular tumour in childhood and adolescence. Pediatr Hematol Oncol13:333-337, 1996

3HEMANGIOENDOTHELIOMA AND MILROY’S DISEASE

15. Zukerberg LR, Weiss SW: Infiltrative kaposiform vascular tu-mour of infancy and childhood. Mod Pathol 5:12, 1992

16. Kerhoas Nicolas CK, Le Bidaut M, Dosquet C, et al: Kasabach-Merritt syndrome of the leg associated with osteolysis or Gorham sign.Ann Dermatol Venereol 124:852-854, 1997

17. Torres-Paoli D, Sanchez JL: Primary cutaneous B-cell lym-phoma of the leg in a chronic lymphedematous extremity. Am JDermatopathol 22:257-260, 2000

18. Ersek RA, Danese CA, Howard JM: Hereditary congenitallymphedema (Milroy’s disease). Surgery 60:1098, 1966

19. Rockson SG: Lymphedema. Am J Med 110:288-295, 200120. Irrthum A, Karkkainen MJ, Devriendt K, et al: Congenital

hereditary lymphedema caused by a mutation that inactivates VEGFR3tyrosine kinase. Am J Hum Genet 67:295-301, 2000

21. Folpe AL, Veikkola T, Valtola R, et al: Vascular endothelialgrowth factor receptor-3 (VEGFR-3): A marker of vascular tumorswith presumed lymphatic differentiation, including Kaposi’s sarcoma,kaposiform and Dabska-type hemangioendotheliomas, and a subset ofangiosarcomas. Mod Pathol 13:180-186, 2000

22. Partanen TA, Alitalo K, Miettinen M: Lack of lymphatic vas-cular specificity of vascular endothelial growth factor receptor 3 in 185vascular tumors. Cancer 86:2406-2412, 1999

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