Hemangiomas and Vascular Malformations in Infants and Children: A Classification Based on Endothelial Characteristics John B. Mulliken, M.D., and J ‘Bos, Mas Glowacki, Ph.D. ‘Those difculies which have hitherto amused philosophers, and blocked up the way t0 knowledge, are emiely owing to ourselves. That we have fst raised a dust and then complain ‘The management of cutaneous vascular lesions is hampered by a bewildering nomenclature that has evolved from ignorance of pathophysiology. ‘Textbook classifications offer an array of admixed histologic and descriptive terms. Hemangioma has been used as a generic word to describe a variety of vascular lesions with different etiologies and natural histories. The most common tumor of infancy, known as “strawberry,” “capillary,” “ju- venile,” or “cellular” hemangioma, predictably undergoes involution. Yet, port-wine stains, which never regress, also are classified as capillary Hemangiomas®® Unforcunatly, the. histologic term cavernous has been used clinically to describe vascular lesions that involute’ and rarely invo- lute.* Lesions of lymphatic origin, called dymphan- ‘giomas, grow commensurately with the child, sometimes enlarge,’ or may improve with time or ven disappear.® 22 Hybrid termoy such as capil lary-caverous hemangioma and ymphangioheman- ‘gioma, permeate the literature and further add to the confusion, Hamartia (Greek, hamarta, “to sin”) is defined as any developmental defect. Albrecht introduced hamartoma to describe proliferative le- sions of developmental origin, such as neurofibro- ‘matosis and hepatic vascular lesions."" However, ‘hamartoma is too comprehensive a term—it could be applied to any lesion that histologically shows Gorge Bekley (1685-1753) a proliferation of cells normally present in a tissue. Contemporary terminology of vascular lesions is enough to befuddle pathologist and clinician alike Historical, Perspective It has been argued whether vascular lesions are developmental malformations or types of neopla- sia, Dupuytren called them “erectile tumors.” * Other nineteenth century expressions, such as “naevus maternus” and “stigma metrocelis,” in- dicted the mother. Vascular lesions were thought to be “produced by the longing of the mother for particular things, or her aversion to them; hence these marks resemble mulberries, strawberries, grapes, pines, bacon, etc.” ® Virchow considered these lesions to be vascular tumors and classified them based on channel architecture as angioma simplex, angioma cavernosum, and angioma racemo- sun." He believed that one type could transform into another by cither cellular proliferation or vessel dilation. Wegner, after studying with Vi chow at the Berlin Pathological Institute, pro- posed a similar histomorphologic classification of lymphatic swellings that is still used today: /ym- ‘phangioma simplex, cavernosum, and cystoides."” Weg- ner believed that these lesions resulted from either lymphatic inflammation and dilation, malfor- From the Division of Platic Surgery a the Harvard Medial School, the Children's Hespial Medical Center, and the Bigham and ‘Wormen't Hop Preeed Londen rt atthe Third International Workshop forthe Study of Vacalar Anomalies, on June 6 180, at St. Thomas’ HospiVol. 69, No. 3 / HEMANGIOMAS AND VASCULAR MALFORMATIONS, 413 TABLE Clasitication of Vasewlar Lesions in Infants and TABLE th 1d Clinical Features of Pediatric Vascular Catutar Lesions ary power present at bith Ni. peroit erie at Rapid penal gow sid Grane ommerately with ‘ o mation, or endothelial proliferation, ‘With an increased appreciation of cardiovas- cular embryology, it was suggested lesions originated from persistent angioblastic tis- sue that normally reorganized and regressed." ‘Thus “angiomas” could be either capillary, ve- nous, of arterial with or without fistulae, depend- ing on the stage at which morphogenesis. was disturbed." ‘The histopathologic classifications of Stout and. Lattes include a variety of lesions, both congenital, and acq red, under the title of “angiomato- ses."® These authors called the proliferative le sion of infants “benign hemangioendothelioma” and reserved Mallory’s term," “hemangioendo- thelioma,” for malignant neoplasia, ‘This prospective investigation was undertaken. to define the cellular features of cutaneous vas ‘cular lesions in infants and children in relation to history and clinical course. Surgical specimens were analyzed by selected histochemical, autora- diographic, and electron microscopic techniques. This study presents a simplified classification of pediatric vascular lesions that clarifies clinical diagnosis and therapeutic approaches. Mareriats asp Meriops ine fresh operative specimens were ob- na variety of cutaneous vascular le- sions in 35 females and 14 males. Patient age range was from 2 months to 16 years (mean 6.9 years). Sixty percent of the lesions were from, the head and neck region; the rest were from the extremities or trunk Formaldehyde-fixed specimens were embedded in paraffin, sectioned to 4 um, and stained by H&E, reticulin, van Gieson, periodic acid-Schiff (PAS), and Masson trichrome techniques. As markers of endothelial maturation, alkaline phos- phatase activity (Sigma Technical Bulletin No. 85) was determined, and in some specimens, fac: tor VIII antigen was localized with a fixed pe oxidase method.”* In order to demonstrate DNA synthesis by the tissues, we performed radioautog: raphy after 18 hours of incubation at 37°C: of 2 mm’ pieces with 4 pCi/ml ["H]thymidine in Me. v Fic. 1. Ue) Newborn child. (Right) Fiye months later, hemangiomatous. proliferation involves the face and neck, necesitating tracheostomy and systemic steroid administration,414 Pe ae fat Left Pevifeative hemangioma shoscing endothelial hyperplane and witht lumen formation (HSE, TOD) (Right) Astoradogsaph of a early proliferative hemangioma Grains repeeset endothelial cell DNA syste (720, dium 199 (Grand Island Biologicals Inc.). Frag. ments of tissue also were prepared for el microscopy by fixation in 2.6% glutaraldeh 0.1 M cacodylate buller followed by bul cosmic acid. Specimens were embedded in Epon 812. Thick sections were cut on an LKB ultra microtome, stained with toluidine blue, and ex: amined by light microscopy. Thin sections were stained with uranyl acetate and lead citrate and examined in a JEOL-JEM-1 scope. The slides were interpreted and grouped. without knowledge of the patient’s identity. or history. The clinical histories were later reviewed and correlated with the cellular features Resvurs ‘These cellular studies revealed two major types of vascular lesions (Tables I and 11): (1) those yi Fu. 4. La) Electeon micrograph of a 2-year-old hemangioma showing nnditamination of the basement membeane (2). endothelial cell), lune (2), and peieyte (P) COW). (Right ‘Thikenedl basement membranes inthe se lesion seen with PAS stan (OHO).Vol. 69, No. 3 / MEMANGIOMAS AND_VASC exhibiting a history of rapid neonatal growth and slow involution were characterized by hypercel- Iularity during the proliferating phase and fibro- sis and diminished cellularity during the involut- ing phase (hemangiomas): and (2) those present at birth which grew commensurately with the child were characterized by a normal rate of endothe- lial cell turnover (malformations) Hemangiomas ‘These lesions were present at birth in 40 per- cent of the patients in ths series (7 = 22 females: n= 4 males), usually only as a small red mark They characteristically grew rapidly for 6 to 8 months (Fig. 1) and regressed to a variable extent Specimens were studied from both the prolifer- ating and involuting phases. Proljraing phase. Fourteen lesions were dis Linguished by’ increased endothelial cell activity with the formation of syneytial masses withyand without lumens (Fig. 2?) Alkaline phosphyfiase was localized throughout the areas of hyperce!- as well as in mature vessels. Factor VILL was present in endothelial cells of the hemangioma and in cells of normal adjacent vessels in specimens from patients as early as 2 months of age ‘Autoradiograms showed labeling of endothe: lium both in the presence and absence of vascular AR MALFORMATIONS 415 lumens (Fig. 2, right). OF 12 specimens prepared, 9 were interpretable; endothelial cells were las beled at an index of 27 12 per high power field. (HPF) in early proliferative lesions (I year, n = 4). Electron microscopic characterization will be described in detail elsewhere. In brief, there were multiple laminas of basement membranes under lying the endothelium in hemangiomas (Fig. 3, Ue). This thickening also was evident on light microscopy by PAS stain (Fig. 3. right). There was an active rough endoplasmic reticulum and mi- crotubular bodies of Weibel and Palade” within the endothelial eytoplasm, Involuting phase. Twelve specimens showed di- minished cellularity with islands of fatty deposits intermingled with fibrous tissue (Fig. 4, dt) ‘There were prominent vascular channels lined by plump endothelium: these channels were devoid of smooth-muscle coating. Involured lesions demonstrated no ["H)thymi: dine incorporation (1 = 6), Hemangiomas that failed to undergo complete regression showed fox of endothelial proliferation coexistent with areas of fibrofatty infiltration (Fig. 4, right) Faseular Malformations Twenty-three lesions (from 13 fen males) grew cor les and 10, snsurately with the child, none Fie, 4. (Le) Hemangioma in cluting phase showing fibrofatty infiltration liminished cellularity (trichrome tain, 300%). (Right) Hemangioma with foc af ["Haymidine Incorporation (anne) coexistent with fbrofate infieration (610%)416 regressed, and several expanded with onset of puberty. Ninety percent of these had been ree: ognized at birth. Most of these lesions were pre~ dominantly venous in type, six were lymphatic, and two were port-wine stai The specimens were not hypercellular, but rather were composed of vascular channels lined by flat “mature” endothelium (Fig. 5). Normal reticulin networks surrounded the vessels, Alka line phosphatase and factor VIII antigen were localized to the endothelium of the abnormal channels. ‘The endothelial lin in the vascular malfor- mation group, including the Iymphatie lesions and port-wine stains, was not proliferative on the basis of [H]thymidine radioautography (v= 13) Fig. 6). Electron microscopy showed typical Weibel Palade bodies and smooth endoplasmic reticulum within endothelium overlying single-layered base ment membrane (Fig. 7). From this analysis of cellular features, child hood vascular lesions could be classified as either Fro. 5. Vascular channels of a venous malformation of the eek (HAE, 30%). "LASTIC AND RECONSTRUCTIVE SURGERY, March 1982 0. Abloradiograph of portaine sain shineng 1 corporation af [H]ibyeatdine ls) in epidermis bt not in abnormal vascular channels in dermis (HD)Val, 69, No. 3 / HEMANGIOMAS AND VASCULAR MALFORMATIONS 417 hemangiomas or malformations, The suffix -oma, from the Greck dkas, meaning “a mass or swelling,” should be restricted to lesions that exhibit cellular proliferation. Thus we propose that the term, ‘hemangioma be limited to those lesions that show increased mitotic activity ‘These are the most common tumors of infancy. They make the appearance during the late fetal or early neonatal life, grow rapidly, and usually undergo regression. ies to demonstrate whether or not the endo- thelium in such lesions is embryonal in type showed the cells to be differentiated enough to contain Weibel-Palade bodies, factor VIII anti- gen, and alkaline phosphatase. The multilami- nated basement membrane in hemangiomas! may be the result of cellular proliferation and death, as suggested for similar ultrastructural vas- cular alterations in diabetes." Vascular lesions that grow pari passu with the child, fail to regress, and show normal endothelial mitotic activity should be called malformations i A Teyentald boy: with eens 0 the neck that expanded with V Sse in Figure 3 IMarmation of (Fig. 8). They may have any combination of capillary, venous, arterial, and lymphatic com- ponents, with or without fistulae. The colorful claret or port-wine stain belongs to the malfor- ‘mation category and consists of venule-like chan: nels located within the dermis (Fig. 9). Although from a cellular standpoint, vascular malforma tions are stable, clinically they can be devastating, particularly when there is arteriovenous shunt ing.®” Most investigators agree that congenital atic lesions are true malformations with a normal cell replication eycle;®"" only Goetsch presented contrary findings.” The term bmphan- -gioma should be reserved for a hypercellular tumor that can be documented to be of lymphatic prove- nance. The hybrid terms hmphangiohemangioma or hemangiolymphangiona should not be used to de- scribe congenital vascular anomalies. ‘These words imply a potential for growth by cell prolif eration (Fig. 10). Our studies confirm the view that such lesions are combined deformities of blood and lymphatic vessels.” ‘The shrinking of lymphatic malformations should be called resolu- tuon, or deflation, rather than involution until the mechanism is elucidated, Because lymphatic uc. 9. Porcine sain involving the skin innervated by all bree divisions of the trigeminal nerve. Autoradiograph Of this type of malformation fs sen in Figute 6418 Fre. 10, Lymphatic malformation of the forehead and orbit n a 2-year gil Since fan the chil aga has been “Iymphangisbemat channels develop in association with the venous. plexus," venolymphatic shunts may play a role in the natural history of lymphatic anomalies, A classification is justifiable only if it has di agnostic applicability, helps in planning therapy, and guides studies of pathogenesis, Vascular le sions are perceived differently on the basis of this, simplified, cell-oriented terminology. Not all he- mangiomas look like strawberries. Hemangionias may grow deep in subcutaneous tissue and muscle and not involve the papillary dermis (Fig, 11) The characteristic bright red color of a hema: gioma is a reflection of subepidermal endothelial penetration. Lesions that clinically appear to be “mixed,” with “capillary” (superficial) “cavern ous” (deep) components (Figs. 12 and 13), pre. sent_a uniform histologic picture. Much of the confusion lies in the fact that with the aid of a microscope, mature or late involuting phase he- mangiomas can look “cavernou the term cav ‘emous should be restricted to the histologic de scription of large channel (venous or lymphatic) malformations, or perhaps the term should be discarded altogether. Sophisticated laboratory techniques are not necessary to assign a lesion to either of the two major categories, hemangioma or malformation, March 1982 Hic. I. A Samantha child with 4 deep, rapidly grow ing hemangiona of the right sipratrochkar region Gat noted at J weeks of ge howe is Figure 2 gh Avtoradiograph of thy leisy The diagnosis ean usually be made by an accurate history and physical examination. Hemangiomas should be approached as problems of increased proliferation, ever, are structural abnormalities, errors of vas cular morphogenesis, the enlargement of which can occur with changes in pressure and flow, ectasia, collateral formation, shunting, and hor- monal modulation, ‘Therapy of vascular malfor- ations should be on a rheologic basis. This classification does not exclude the possi bility of lesions that appear to be combinations of neoplasia and malformation, For example, en: dothelial proliferation may establish a vascular network within a hemangioma that could mimic a malformation or function as a physiologic shunt." Perhaps, flow or pressure triggers en: dothelial cell growth within anomalous vessel ic. reactivation of dormant angiopoietic cells." Yet, to date, evidence for stimulation of endothe- lial proliferation by hemodynamic factors has not been convincing. Folkman and co-workers have demonstrated, in fact, that capillary endothelial proliferation” and migration,” as well as lumen endothelial Malformations, how-Vol. 69, No. 3 / HEMANCIOMAS AND VASCULAR MALFORMATIONS 419 = Fic, 12, Proliferative hemangioma in a 2-year-old child: it was not present at birth. In the past, theve lesions were called "mixed" or “eapillary-cavernous” hemangiomas. His: tology of this lesion is shown in Figure 2 (ef Hic. 13. A 2yearold giel with a large, deep heman: siom, showing central regrewion of the superficial element ‘Autoradiogeaph ofthis lesion is shown in Figure 4 (ng) formation,*' can occur ex vivo in the absence of blood flow. Sunowany Forty-nine specimens from a variety of vascular lesions were analyzed for cellular characteristics Two major categories of lesions emerged from this investigation: hemangiomas and vascular malfor mations. This classification and its implications are justified by several considerations. Hemangiomas in the proliferating phase (n = 14) were distin- guished by (1) endothelial hyperplasia with in- corporation of ['H]thymidine, (2) multilaminated basement membrane formation beneath the en- dothelium, and (3) clinical history of rapid growth during early infancy. Hemangiomas in the involuting phase (n = 12) exhibited (1) his- tologie fibrosis and fat deposition, (2) low to absent [H]thymidine labeling of endothelial cells, and (3) rapid growth and subsequent regres- sion. The endothelium in hemangiomas had many characteristics of differentiation: Weibel- Palade bodies, alkaline phosphatase, and factor VIII production, ‘Vascular malformations (n = 23) demonstrated no tritiated thymidine incorporation and normal ultrastructural characteristics. These lesions were usually noted at birth, grew proportionately with the child, and consisted of abnormal, often com- bined, capillary, arterial, venous, and lymphatic vascular elements. This cell-oriented analysis provides a simple yet comprehensive classification of vascular le- sions of infancy and childhood and serves as a ‘guide for diagnosis, management, and further research, John B. Mulliken, M.D. Division of Plastic Surgery Children’s Hospital Medical Center 500 Longwood Avenue Boston, Mass. 02115 AcknowLe ‘The authors wish 10 thank De. Joseph E. Murray for rtimolating our interes in hemangiomas and Dr. Judah Folkman for helping us to ask the right questions. We also are grateful to Dr. Rama S, Cotran and his sa for helpful tritici and to Dr, M. Belicaa forthe electron microscopy: Ms, Nancy A. Healey deserves recognition for her technical ‘These studies were supported by Funds from the Massa chusetts Cosmetologists Asvociation, Inc, the Harry Dochla Foundation, and the Brigham Surgical Group, Ine REFERENCES 1, Berkeley, G, A Theat Concerning the Pricples of Human “Knaledge. Dublin: Jeremy Pepyat, 1710. P- 4420 2 3 2. Lister, W. 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