Congenital Nonprogressive Hemangioma a Distinct Clinicopathologic Entity Unlike Infantile Hemangioma

STUDY Congenital Nonprogressive Hemangioma A Distinct Clinicopathologic Entity Unlike Infantile Hemangioma

Paula E. North, MD, PhD; Milton Waner, MD; Charles A. James, MD; Adam Mizeracki, BS; Ilona J. Frieden, MD; Martin C. Mihm, Jr, MD

Background: Infantile hemangiomas are common tu- Setting: A university-affiliated pediatric hospital. mors, distinctive for their perinatal presentation, rapid growth during the first year of life, and subsequent in- Main Outcome Measures: Histologic appearance, im- volution—and for their expression of a unique immu- munoreactivity for the infantile hemangioma–associated nophenotype shared by placental microvessels. Occa- antigens GLUT1 and LeY, and clinical behavior. sional “hemangiomas” differ from the classic form in presenting fully formed at birth, then following a static Results: Congenital nonprogressive hemangiomas dif- or rapidly involuting course. These congenitally fully de- fered from postnatally proliferating infantile hemangio- veloped lesions have generally been assumed to be clini- mas in histologic appearance and immunohistochemical cal variants of more typical, postnatally developing hem- profile. Distinguishing pathologic features of these tu- angiomas. This assumption has not been tested by rigorous mors were lobules of capillaries set within densely fi- histologic and immunophenotypic comparisons. brotic stroma containing hemosiderin deposits; focal lobular thrombosis and sclerosis; frequent association with Objective: To compare the histologic and immunohis- multiple thin-walled vessels; absence of “intermingling” tochemical features of congenital nonprogressive heman- of the neovasculature with normal tissue elements; and giomas with those of typical, postnatally proliferating, lack of immunoreactivity for GLUT1 and LeY. hemangiomas. Conclusion: Congenital nonprogressive hemangiomas Design: All cellular vascular tumors resected from in- are histologically and immunophenotypically distinct from fants younger than 4 months at Arkansas Children’s Hos- classically presenting hemangiomas of infancy, unlikely pital, Little Rock, over the past 20 years (43 lesions from to be related to the latter in pathogenesis. 36 patients) were first characterized histologically and immunohistochemically, then clinically by chart review. Arch Dermatol. 2001;137:1607-1620

NFANTILE (JUVENILE) hemangio- bers of our group2 have reported recently mas are the most common tu- that these congenital examples of other- mors of infancy, affecting ap- wise typical, postnatally proliferating, in- proximately 10% of children.1 fantile hemangiomas are histologically in- From the Departments of These benign vascular tumors distinguishable from classic, postnatally Pathology (Dr North and vary in location and extent of tissue in- presenting examples, including expres- Mr Mizeracki), Head and Neck I Surgery and Otolaryngology volvement, and thus in clinical impact, but sion of an unusual set of tissue-specific vas- (Dr Waner and Mr Mizeracki), share a remarkably predictable biological cular antigens uniquely shared by placen- 3 and Radiology (Dr James), the behavior. Lesions generally appear within tal microvessels. These antigens are not University of Arkansas for weeks after birth, proliferate rapidly dur- expressed by the normal vasculature of Medical Sciences and Arkansas ing the first year of life, and then sponta- skin or subcutis; or by a variety of benign Children’s Hospital, Little Rock; neously involute over a period of several vascular tumors that are histologically the Departments of Pediatrics years. Most begin as relatively inconspicu- similar to hemangioma (including pyo- and Dermatology, University of ous blanched or blushed macules, in some genic granuloma, tufted angioma, and in- California at San Francisco cases evident at birth, that then dramati- fantile kaposiform hemangioendothe- Medical Center, San Francisco cally expand as tumorlike masses. A mi- lioma); or by vascular malformations.3 Two (Dr Frieden); and the Department of Pathology, nority of infantile hemangiomas, per- of these antigens, the erythrocyte-type glu- Harvard University Medical haps 15%, are relatively prominent at birth, cose transporter protein GLUT1, and Lewis School and Massachusetts usually presenting as diffuse, plaquelike Y antigen (LeY), can be detected by im- General Hospital, Boston, Mass lesions that grow rapidly prior to their munohistochemical analysis using forma- (Dr Mihm). characteristic period of involution. Mem- lin-fixed, paraffin-embedded tissue speci-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 METHODS medical record review. These clinical features included patient sex and race; gestational history; age at resection; age when lesion was first noticed; biological behavior SPECIMENS (whether the lesion grew, regressed, or remained static postnatally); whether multiple lesions were present; gross con- We performed an initial database review, searching for all figuration of the lesion (eg, bulging tumor mass vs exo- surgical specimens archived at Arkansas Children’s Hos- phytic polyp vs diffuse infiltration or plaquelike expansion); pital, Little Rock, between January 1980 and December 2000, and whether the patient experienced complicating condi- for which the diagnosis contained the suffix “-angioma” (903 tions such as Kasabach-Merritt syndrome, heart failure, or cases). These were then restricted to examples resected from ulceration. patients younger than 4 months to exclude most noncon- genital lesions and enrich for “alarming” congenital le- IMMUNOHISTOCHEMICAL ANALYSIS sions, yielding a more manageable and focused group of 59 lesions from 50 patients. Hematoxylin-eosin–stained tis- Paraffin sections were deparaffinized, rehydrated, and sub- sue sections from these cases were then reviewed, and all jected to citrate buffer antigen retrieval, then protein- vascular and lymphatic malformations were excluded (15 blocked before incubation with primary antibodies to cases). This process yielded 44 cellular vascular lesions com- GLUT1 or LeY as previously described.3,4 Bound primary posed of proliferative, mitotically active vascular elements antibody was detected using a DAKO Corp (Carpinteria, resected from infants younger than 4 months. One case, Calif) LSAB+ peroxidase kit using DAB+ chromagen.4 Im- histologically consistent with infantile hemangioma, showed munoreactions for CD34 and ␣ smooth muscle actin were poor preservation of tissue antigenicity (GLUT1-positive performed similarly, but without antigen retrieval, using internal controls were nonreactive) and was subsequently monoclonal antibodies directed against CD34 (clone excluded, leaving a final total of 43 lesions from 36 pa- QBEnd/10, prediluted; Biogenex, San Ramon, Calif) or ␣ tients (1 patient had multiple lesions resected). smooth muscle actin (clone 1A4, DAKO N1584). Nega- During review of the hematoxylin-eosin–stained sec- tive controls were processed in parallel without primary tions, the lesions were comparatively evaluated by investi- antibody. Normal tissue immunoreactivities (perineu- gators blind to clinical history for a variety of general histo- rium and erythrocytes) provided internal positive con- logic features relevant to vascular proliferations, including trols for GLUT1. For LeY, sections of LeY-immunoposi- lobularity, endoneurial pseudoinvasion, lesional mitotic active oral mucosa were included in each run as positive tivity, endothelial cell atypia (eg, spindled or epithelioid shape controls. Immunoreactivities were scored blindly by the and/or abnormal mitotic figures), epithelial collarette forma- first author (P.E.N.) as none, weak, moderate,orintense tion, planes of tissue involvement, characteristics of the ac- (Ն controls). For LeY, occasional weak immunoreactivity companying larger vasculature, and the presence or absence in a perinuclear, hof-type pattern was discounted. Only of ulceration, thrombosis, hemorrhage, hemosiderin depo- membranous and/or diffuse cytoplasmic-membranous LeY sition, fibrosis, calcification, or necrosis. Histopathologic di- immunoreactivity was scored as positive. agnoses were rendered during the course of these reviews based on published criteria for infantile hemangioma,7 pyo- RADIOGRAPHIC ANALYSIS genic granuloma,8 vascular and lymphatic malformations,7 tufted angioma,9 and infantile kaposiform hemangioendo- Subsequent to the pathologic examinations, available ra- thelioma.10 No examples of infantile myofibromatosis (in- diographic imaging studies (ultrasound, computed tomog- fantile hemangiopericytoma), as defined by Mentzel et al,11 raphy, and magnetic resonance imaging) of all congenital were identified. Lesions that did not fit well into established nonprogressive lesions included in the study were re- diagnostic categories were initially grouped as other. viewed. Findings were compared with those characteris- Diagnoses, including other, were then correlated with tic of well-established vascular tumors and anomalies, in- GLUT1 and LeY immunoreactivites, and with selected clini- cluding infantile hemangiomas and vascular and lymphatic cal features determined (when available) by subsequent malformations, based on published criteria.12

mens, and thus are suitable for retrospective analyses of unusual, fully formed, congenital nonprogressive hem- archival material. Both GLUT1 and LeY are highly ex- angiomas have not been defined. They are typically cat- pressed by infantile hemangiomas at all stages of their egorized by surgical pathologists under the nonspecific evolution and represent intrinsic features of the com- term capillary hemangioma, using generic criteria that mitted endothelial phenotype of these lesions.3,4 Use of also apply to infantile hemangiomas. In this study, we these markers has increased diagnostic accuracy and al- describe the histologic, immunohistochemical, and clini- lowed focused study of infantile hemangioma as a sin- cal features of 6 such lesions from 6 patients treated in gular clinicopathologic entity. the last 20 years, and compare them with the features of There are descriptions in the clinical literature of rare, other vascular tumors of infancy collected during the same so-called congenital hemangiomas that are fully formed time period. at birth and sometimes diagnosed in utero. They do not show the postnatal proliferation characteristic of infan- RESULTS tile hemangioma. Some of these lesions have been reported to involute spontaneously at a pace much more Based on histopathologic and immunohistochemical find- rapid than is typical of classic hemangiomas.5,6 The ings, all 43 congenital and early neonatal cellular vascu- histologic and immunohistochemical features of these lar lesions could be classified into 5 coherent categories

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 1. Vascular Lesional Immunoreactivities and Patient Characteristics by Diagnostic Category

Vascular Patient Age Immunoreactivities,† Location Range When No. Positive/Total No. No. of Sex Ratio, of Lesion, Lesion Noticed Postnatal Behavior Patient Age Range Diagnosis Specimens F/M HN/T/UE/LE* (Mean) of Lesion at Resection (Mean) GLUT1 LeY Infantile hemangioma 25 17/8 24/1/0/0 Birth to 1 mo Rapid growth, all 22 d to 4 mo (3 mo) 25/25 25/25 (2.1:1) (10 d) cases Pyogenic granuloma 10‡ 3/0‡ 5/3/1/1 Birth to 1 mo Rapid growth, 2 37 d to 3 mo 29 d (3.1 mo) 0/10 0/10 (4 d)‡ cases; minimal growth, 8 cases‡ Tufted angioma 1 1 0/0/0/1 Birth Rapid growth 2 mo 4 d 0/1 0/1 Infantile kaposiform 1 1 1/0/0/0 Birth Rapid growth, with 3mo29d 0/1 0/1 hemangio- Kasabach-Merritt endothelioma syndrome Congenital 6 4/2 (2:1) 4/1/1/0 Birth, all cases No change 9 d to 2 mo 18 d (1 mo 24 d) 0/6 0/6 nonprogressive hemangioma

*HN/T/UE/LE indicates the number of specimens located on the head and neck, trunk, upper extremities, and lower extremities, respectively. †All immunopositive cases showed intense immunoreaction in more than 90% of lesional capillaries. GLUT1 indicates glucose transporter protein isoform 1; LeY, Lewis Y antigen. ‡Ten specimens from 3 patients. Two patients had singular lesions, appearing at 2 weeks and 1 month of age, that grew rapidly prior to resection at 3 months 27 days and 3 months 29 days of age, respectively. The third patient with pyogenic granuloma had a total of 8 lesions resected, all pyogenic granulomas by histologic examination, that were present at birth and showed only a small increase in size postnatally. One of these was resected at 1 month 7 days of age, and the other 7 were resected at 3 months 5 days of age.

(Table 1). For 4 of these categories, accounting for 37 between 1980 and 1997. However, low-magnification of the 43 lesions, subsequent chart review revealed post- views (eg, Figure 1B) revealed clear distinguishing fea- natal lesional growth (Table 1). These 4 categories were tures for these lesions. (1) infantile hemangioma (GLUT1/LeY immunoposi- In contrast to infantile hemangiomas, in which the tive), (2) pyogenic granuloma, (3) infantile kaposiform tumor lobules are separated by normal-appearing tissue hemangioendothelioma, and (4) tufted angioma. The fifth elements, the tumor nodules of congenital nonprogres- histologic category (originally classified as other) con- sive hemangiomas were separated by bands of abnor- sisted of 6 GLUT1/LeY–immunonegative lesions (from mal, dense fibrous tissue (Figure 1B-D; Figure 2A-B), 6 patients) that shared a singular, but previously unde- with epidermal atrophy and loss of dermal adnexal ap- scribed, histologic appearance. Subsequent chart re- pendages in overlying skin. In contrast, the epidermis view showed that all 6 of these lesions were fully formed covering infantile hemangiomas is, in our experience, atro- at birth and did not enlarge postnatally. We therefore re- phic only in involuted lesions, and is normal or hyper- named this category congenital nonprogressive heman- plastic in proliferative lesions. This latter observation is gioma. The differential clinical, histologic, and immu- confirmed by a recent study by Bielenberg et al,13 who nophenotypic findings that define these 5 distinctive found that the growth phase of infantile cutaneous hem- lesional types are described below. angiomas correlated with hyperplasia and angiogenesis in the adjacent epidermis. Congenital nonprogressive CONGENITAL NONPROGRESSIVE hemangiomas were further distinguished by occasional HEMANGIOMAS sclerosis of capillary lobules, either peripherally or glob- ally (Figure 2A), and acute fibrin thrombi were seen in These lesions, initially grouped in the other category un- 3 of the 6 lesions (Figures 2B). Hemosiderin granules (Fig- til their remarkably similar histologic appearance was rec- ure 1C and Figure 2C) and occasional small foci of dys- ognized, were cellular lesions consisting of multiple well- trophic calcification (Figure 1D) were also invariant find- defined lobules of proliferating capillaries, often flowing ings, within both the proliferating lobules and the fibrous into one another to form ribbons within subcutaneous septi of congenital nonprogressive hemangiomas, fur- tissue and, in some cases, overlying dermis. None in- ther suggesting a role for past hemorrhage or thrombo- vaded underlying skeletal muscle. High-magnification sis in the evolution of these lesions. No well-formed, hya- views of these proliferative lobules, considered without linized, or calcified phleboliths were present. reference to their greater context within the tissue, re- The cells comprising the cellular lobules within these vealed features reminiscent of infantile hemangioma lesions were confirmed to be endothelial and pericytic (Figure 1A): plump endothelial cells forming small cap- by CD34 and ␣ smooth muscle actin immunoreactions, illary lumina and surrounded by pericytes, moderate num- respectively (Figure 3). Mast cells were only occasion- bers of normal mitotic figures among both component ally evident in hematoxylin-eosin–stained sections of these cell types, and no alarming nuclear or cytoplasmic atypia. congenital lesions. Neither GLUT1 nor LeY expression Not surprisingly, all of these lesions had originally re- was immunohistochemically detectable in any of these ceived pathologic diagnoses of cellular, capillary, or ju- 6 lesions, despite consistently strong immunoreaction of venile hemangioma, reflecting various terminologies used internal positive controls (Figure 4). Small foci of ex-

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C D

Figure 1. Congenital nonprogressive hemangioma. Hematoxylin-eosin–stained sections of a bulging subcutaneous mass, fully formed at birth, resected from the forehead of 2-month-old girl (patient 3). A, High-magnification view shows dense capillary proliferation similar in appearance to that of infantile hemangioma, with occasional mitotic figures (black arrow). B, Lower magnification view reveals the distinguishing features of these lesions: numerous distinct lobules of capillary growth (black arrow) admixed with numerous thin-walled vessels, many suggestive of lymphatic vessels (white arrow). C, Some areas show a more dominant pattern of small vessels, with less capillary proliferation; note the golden brown deposits of hemosiderin in the lower-right corner. D, Foci of calcification are also occasionally present (black arrow).

tramedullary hematopoiesis were observed in 5 of 6 ules of infantile hemangioma that commonly show a cen- cases, and these immunoreacted positively for GLUT1 tral feeding artery in histologic sections (Figure 7B). A (Figure 5). All examples showed an irregular, sparse significant negative finding was the absence of intraneu- infiltrate of chronic inflammatory cells including occa- ral involvement by the neoplastic growths, in contrast sional eosinophils. to the frequent intraneural involvement in infantile hem- Some of these congenital lesions (in patients 4 and angiomas14 (Figure 8). The strongly lobular pattern of 5) contained large, thin-walled vascular structures com- capillary growth in some congenital nonprogressive hem- pressed between multiple tumor lobules (some of which angiomas was reminiscent of the “cannonball” pattern were several millimeters in diameter [Figure 6]). These of tufted angioma (Figure 1B). However, the densely vessels were typically collapsed and consequently easily packed capillary tufts with small, peripherally located cres- overlooked on casual examination. In some sections, lob- centic vascular clefts, characteristic of tufted angioma ules of capillary growth invaginated into these col- (Figure 9B), were absent. Spindled endothelial cells remi- lapsed lumina from broad, murally based pedicles (Fig- niscent of kaposiform hemangioendothelioma were also ure 6A), or appeared to “float” in their lumina (Figure notably absent. None of these lesions showed histologic 6B). In other sections from these same lesions, capillary evidence of ulceration or epithelial collarette formation. lobules were not associated with vessels (Figure 6C). For Retrospective review of patient medical records re- the patient whose lesion is depicted in Figure 6 (patient vealed that all of the lesions placed into this histologic 5), the surgeon’s operative note described a grossly lymph- category were clinically unusual (Table 1 and Table 2). angiomatous lesion with cystic, fluid-filled spaces and They invariably presented fully formed at birth, and they what looked like lymph nodes, which proved on micro- invariably did not enlarge between birth and the time of scopic examination to be capillary lobules. In other cases resection. Because all of these lesions, as mandated by (patients 1, 3, and 6), smaller-caliber vascular struc- the design of the study, were resected before the patient tures, consistent with veins or lymphatic vessels, were reached age 4 months (Tables 1 and 2), information about dispersed between lobules in numbers that appeared ab- their potential involutive behavior is limited. All of the normally high (Figure 1B-C). Small arterial feeders were 6 patients with lesions in this category had single, bulg- evident in many lesions, but showed no clear connec- ing, tumorlike lesions, all moderately large (2-5 cm); and tion to individual capillary lobules, in contrast to the lob- 3 patients showed at least focal red discoloration of the

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Figure 2. Congenital nonprogressive hemangioma. Hematoxylin-eosin–stained sections of 2.5-cm, moderately firm, submucosal mass resected from the labia majora of a 1-month-old girl (patient 6). A and B, Note the strongly lobular architecture and dense stromal background. Some lobules show peripheral sclerotic rims (A, black arrows) or central areas of fibrosis (C, white arrows). B, Intralobular thrombi are also multifocally present (black arrow); C, hemosiderin deposits, golden in color, are abundant (black arrows). D, High magnification reveals angulated capillary profiles lined by endothelial cells and surrounded by plump pericytes.

overlying skin. Patient photographs were available for 2 patients (patients 5 and 6) had only limited ultrasound im- of these lesions. Both of these were bossed lesions with aging performed that showed small, nonspecific oval soft peripheral rims of skin pallor (Figure 10A and Fig- tissue masses. No Doppler interrogation was available for ure 11A), remarkably similar to the clinical entity “con- these 2 patients. genital hemangioma” described by Boon et al6 and Mar- tinez-Perez et al.5 INFANTILE HEMANGIOMAS The 6 examples of congenital nonprogressive hemangioma showed no obvious anatomic sites of predi- Most of the cellular lesions in this study (25/43) met tra- lection. The resected examples described here arose on ditional, well-established histologic criteria for the diag- the forehead, cheek, posterior neck, posterior auricular nosis of proliferative-phase infantile hemangioma. These area, wrist, and labia majora. Based on history and his- appeared as nearly solid masses of small capillaries con- tologic analysis, none of the lesions was ulcerated. Of the sisting of plump endothelial cells and pericytes, admixed 6 affected infants, 4 were girls and 2 were boys; 5 were with numerous mast cells and grouped in delicately de- white, and 1 was African American. fined lobules separated by fine strands of connective tis- Radiologic imaging studies were available for 3 of the sue or by normal intervening tissue (Figure 7A). None of 6 patients with congenital nonprogressive hemangioma. the lobules was encapsulated or fibrotic, and many con- One of these (patient 3; Figure 10A) underwent head mag- tained normal tissue elements (Figure 7A) and a feeding netic resonance imaging for a bulging subcutaneous le- artery (Figure 7B), in contrast to congenital nonprogres- sion of the forehead to rule out intracranial involvement. sive hemangioma. All were subcutaneous or cutaneous, The lesion showed diffuse loss of signal throughout the and 3 of the 25 lesions showed histologic evidence of ac- lesion on T2-weighted imaging compatible with diffuse he- tive ulceration. Neural pseudoinvasion was a common mosiderin deposition, a finding not associated with in- feature (Figure 8B, Figure 13A), and occasional mi- fantile hemangiomas (Figure 12). This large soft tissue totic figures were present in all cases (Figure 7C). Hemo- mass also had internal high-signal hemorrhage on T1- siderin deposition and thrombosis were rare (2 cases), and weighted imaging, associated marked calvarial displace- were limited to ulcerated, acutely inflammed areas. ment at day 17 of life (implying intrauterine mass effect), Patient characteristics for the patients in the infan- and lack of a central arterial flow void (Figure 12). These tile hemangioma group are summarized in Table 1. Age findings are highly atypical for infantile hemangiomas. Two at which these lesions were first evident (25 lesions from

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CD34

B B LeY

αSMA

Figure 3. Immunoreactivities for CD34 (A) and ␣ smooth muscle actin Figure 4. Immunoreactivities for glucose transporter protein isoform 1 (␣SMA) (B) in congenital nonprogressive hemangioma. All congenital (GLUT1) (A) and Lewis Y antigen (LeY) (B) in congenital nonprogressive nonprogressive hemangiomas, typified by this labia majora lesion (patient 6) hemangioma. Lesional capillaries composing this congenital subcutaneous showed strong lobular immunoreactivity for CD34 and ␣SMA, confirming mass, resected from the wrist of a 2-month-old boy (patient 2) showed no composition by endothelial cells and pericytes, respectively. B, Note the immunoreactivity for GLUT1 or LeY. A, Note the positive internal controls peripheral rim of ␣SMA immunopositivity (black arrow), suggesting provided for GLUT1 by perineurium (white arrow) and luminal erythrocytes remnants of vascular smooth muscle. The pattern of endothelial (black arrow). immunoreactivity seen for CD34 was mimicked by immunoreactivities for other endothelial-associated antigens, including CD31 and von Willebrand factor (not shown). diffuse or segmental type at the time of patient presentation and showed a good response to aggressive oral and 25 patients) could be determined from available clinic intravenous steroid therapy begun at age 6 weeks. A small notes or photographs for 16 of the 25. Four were pres- portion of this extensive lesion, described as an enlarg- ent at birth, and all had appeared by age 1 month. The ing nodular area threatening the visual axis, was re- average age at presentation for these 16 patients was 10 sected and included in this study. It was histologically days. For all 25 of these lesions, including the 4 known indistinguishable from the other 24 more clinically typi- to be noticeable at birth, there was a well-documented cal infantile hemangiomas in our series. history of marked postnatal enlargement. Of the 25 pa- All 25 infantile hemangiomas showed strong lesional tients, 5 had multiple cutaneous hemangiomas by clini- endothelial immunoreactivity for GLUT1 and LeY (Table cal history (1 of these had multiple hepatic lesions also, 1; Figure 13), including the extensive, diffusely distributed, as evidenced by ultrasound), although each of these 5 right facial lesion described above, corroborating previous had only a single lesion each (all cutaneous) resected for reports.2-4 Native dermal and subcutaneous capillaries, pre- pathologic review and diagnosis. sent at the margins of many of these specimens, were in- Of the 4 congenitally evident lesions in this histo- variably immunonegative for both of these antigens. logic category, 3 appeared at birth as inconspicuous, blushed macules that rapidly expanded postnatally to form PYOGENIC GRANULOMAS much larger, tumorlike growths. The fourth of these congenitally evident lesions was a relatively flat lesion cov- Ten lesions, all immunonegative for GLUT1 and LeY ering much of the right face at birth, with irregular bright (Table 1), displayed the histologic and immunohisto- red surface discoloration that grew rapidly in thickness chemical features of pyogenic granuloma, including pro- thereafter. Patient photographs (not shown) document liferating lobules of capillaries set within edematous fi- diffuse involvement of the right forehead, cheek, upper bromyxoid stroma. Superficial, acute thrombosis was eyelid, chin, and lips. Magnetic resonance imaging re- found in 3 of these, all of which were ulcerated and in- vealed bilateral parotid gland involvement with exten- flamed. Two lesions (from 2 patients) were typical, small, sion into the pharyngeal space. This congenitally promi- exophytic eruptions. Both were pedunculated, papillo- nent, but nevertheless postnatally progressive lesion had matous upper-eyelid lesions, appearing between 2 weeks been clinically diagnosed as infantile hemangioma of the and 1 month after birth and growing rapidly. One bled

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 intermittently, but hemosiderin deposits were not present (Figure 9A). The remaining 8 lesions in this diag- A nostic category, all from a single patient, were some- what atypical histologically and clinically. This patient was born with more than 100 small, red, dome-shaped, pedunculated lesions that tended to bleed, scattered over her head, trunk, and upper and lower extremities. Al- though these were assumed to be hemangiomas, clinical notes indicate that all were present at birth and showed only a small increase in size thereafter. All 8 resected lesions were small (Ͻ1.5 cm), and many had a “lobulated” epidermal surface. Histologic examination showed a strongly lobular growth pattern of GLUT1 and LeY immunonegative capillaries within edematous stroma (Figure 14) flanked by epithelial collarettes con- B sistent with pyogenic granuloma. The lesions differed from more typical examples of pyogenic granuloma in the preva- lence of papillary endothelial hyperplasia found within dilated vessels in both the capillary lobules and the larger vessels at the base of many lesions. They were also located primarily subcutaneously. Although diagnosed at the time of resection as generic capillary hemangioma, none of these lesions demonstrated the delicate lobularity, mast cell density, or intermingling with normal tissue elements characteristic of infantile hemangioma, nor did they exhibit the hemosiderin deposition and expansive growth pattern of congenital nonprogressive hemangioma. Figure 5. Extramedullary hematopoiesis in congenital nonprogressive This unusual case also included a large erythematous hemangioma. Foci of extramedullary hematopoiesis were common in macule over the patient’s right buttock and upper leg. Com- congenital nonprogressive hemangioma (presumably reflective of the young puted tomography showed a contrast-enhancing nodule of age of these infants, all younger than 4 months). These could be seen in hematoxylin-eoxin–stained sections (black arrows) (A), but were accentuated the right lung, of uncertain significance, and a 6-cm contrast- by glucose transporter protein isoform 1 (GLUT1) immunoreaction enhancing, rounded mass deep within the right gluteal (black arrow) (B). Mature erythrocytes (white arrow) were also GLUT1 muscles directly beneath the erythematous macule. There immunopositive. Lesional capillaries, as also shown in Figure 4A, were not was no evidence of hepatic involvement. The lung and glu- immunoreactive for GLUT1. teal lesions were not examined histologically. Some of the untreated lesions were reported to have faded in color over INFANTILE KAPOSIFORM time. The patient was lost to follow-up at age 7 months. HEMANGIOENDOTHELIOMA

TUFTED ANGIOMA A previously reported lesion3,4 was diagnosed as infantile kaposiform hemangioendothelioma. This tumor con- A lesion resected from the thigh of a 2-month-old boy sisted of sheets and irregular lobules of relatively bland was histologically consistent with tufted angioma. The spindle cells defining slitlike spaces containing erythro- dermal portion of this lesion was composed of discrete cytes (Figure 9C) focally associated with lobules of better- vascular tufts of tightly packed capillaries with small, differentiated capillaries and many abnormal collec- round lumina indenting peripheral, crescentic, thin- tions of small, collapsed, thin-walled vessels suggestive walled vessels suggestive of lymphatics (Figure 9B). The of lymphatic channels. The lesion involved skin, subcu- bulk of the tumor, which measured 5 cm in greatest di- tis, and underlying deep skeletal muscle. None of the vas- mension, was located in the subcutis where the vascular cular elements was immunoreactive for GLUT1 or LeY tufts were larger and frequently coalescent, again in as- (Table 1).3 According to clinical history, this extensive sociation with dilated peripheral lymphatic-like vessels. facial lesion, analyzed by biopsy specimen at age 2 months, The outer rims of the capillary nodules displayed focal was prominent at birth and continued to grow rapidly spindled morphology similar to infantile kaposiform he- postnatally. The patient had Kasabach-Merritt phenom- mangioendothelioma. There was no lesional immuno- enon and died at age 6 months from intracranial hem- reactivity for GLUT1 or LeY (Table 1). orrhage secondary to profound thrombocytopenia com- The lesion first appeared at age 3 weeks as a dime- plicated by sepsis. sized, bruiselike growth on the thigh that became tender and swelled to 5 cm by the time of resection at age 8 weeks. COMMENT There was no evidence of coagulopathy. Preoperative magnetic resonance imaging results suggested a high-flow le- Congenital hemangiomas fully formed at birth have pre- sion, but the intraoperative gross appearance was that of viously been considered clinical variants of infantile he- a relatively discrete fibromyxoid mass, largely subcutane- mangioma, equivalent in the biological sense to more typi- ous, invading adjacent skin and muscle. It did not recur. cal, postnatally presenting hemangiomas, and differing

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Figure 6. Large, dilated, thin-walled vessels in congenital nonprogressive hemangioma. A and B, Hematoxylin-eosin–stained sections of this subcutaneous postauricular mass from a 2-month-old boy (patient 5) revealed large, partially collapsed thin-walled vessels suggestive of a lymphatic malformation (A, black arrow) containing cellular proliferations of capillaries within their lumina. Capillary lobules invaginated into these vessels from broad-based pedicles (A, white arrow) or thin stalks (B, black arrow). C, Other areas within this same lesion showed capillary lobules set in dense stroma without apparent association with large vessels.

A B C

Figure 7. The histologic appearance of infantile hemangioma. This hematoxylin-eosin–stained infantile hemangioma lesion from the cheek of a 3-month-old girl shows the delicate lobularity, delineated by fine strands of connective tissue (A, black arrow) and intralobular arterial supply (B, black arrow) characteristic of these postnatally developing lesions. Note also the inclusion of normal tissue elements within the capillary lobules, in this case fat (A), a feature not seen in congenital nonprogressive hemangiomas. B, Neural pseudoinvasion is also evident (white arrow). C, In a high-power magnification of infantile hemangioma, it is more difficult to differentiate the histologic features of these lesions from those of other benign vascular proliferations, including congenital nonprogressive hemangioma (compare with Figure 1A). Note the mitotic figure (black arrow).

from these primarily in the time (relative to birth) at which We have tested this assumption by rigorous histo- “full bloom” is reached and in the rapidity of involu- logic and immunohistochemical analysis, with sub- tion.6 This concept has been supported by histologic de- sequent clinical and radiologic correlation, of a large scriptions of biopsy specimens (and of rare resections) series of cellular vascular lesions of infants collected over of these lesions as proliferations of capillaries, pre- a 20-year period at Arkansas Children’s Hospital. We show sumed to be diagnostic of infantile hemangioma. here that congenital nonprogressive hemangiomas fully

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 formed at birth are histologically and immunophenotypically distinct from classically presenting hemangiomas of A infancy, and thus are unlikely to be pathogenically related to them. The 6 congenital nonprogressive hemangiomas described here demonstrated a singular histologic appearance that differed from that of classic infantile hemangiomas in (1) striking lobularity, defined by a densely fibrotic stroma; (2) ubiquitous presence of stromal hemosiderin deposits; (3) focal thrombosis and sclerosis of capillary lobules; (4) absence of intermingling of the neovasculature with normal tissue elements such as nerve, adipose tissue, and salivary gland; (5) relatively scarce mast cells; and (6) common association of the proliferating capillary lobules with multiple, thin-walled vessels. In addition, all of these congenital, nonprogressive lesions showed com- B plete lack of immunoreactivity for GLUT1 and LeY and thus were immunohistochemically distinct from typical infantile hemangiomas. Magnetic resonance imaging findings, available for one of the patients with congenital nonprogressive hemangioma, were also distinctive, and included internal hemorrhage with signal loss on T2-weighted imaging consistent with diffuse hemosiderin deposition (also evident in histologic sections). In addition, this large facial lesion with calvarial displacement lacked a central arterial flow void. These are not expected findings in infantile hemangiomas, which typically demonstrate central Figure 8. Lack of vessel-nerve intermingling in congenital nonprogressive flow voids and homogeneous, moderate to high signal hemangioma. A, Congenital nonprogressive hemangiomas showed no 12 on T2-weighted imaging. evidence of intermingling of lesional vascular elements (black arrow) with Recognition of congenital nonprogressive heman- peripheral nerves (white arrow) within their substance. This contrasts with the frequent nerve-vessel intermingling (B), seen in infantile hemangiomas, gioma as an entity biologically distinct from infantile accentuated by S100 immunostaining of schwannian neural elements hemangioma has important implications for patient (black arrow). management. Certainly the possibility of rapid involution in cases of this type should be considered, based on previous clinical reports that describe an unusually relevant to understanding temporal patterns of develop- rapid course of involution for lesions that are grossly ment for true, GLUT1-positive infantile hemangiomas. and clinically similar to those described here.5,6,15 Inter- Awareness of this distinction will help avoid potential estingly, other congenital lesions of similar clinical pre- misinterpretations. sentation have been described as persisting, and have The distinctive histologic appearance of congenital been called noninvoluting congenital hemangiomas. nonprogressive hemangioma reported here superficially Because all of the lesions in our study were resected be- resembles that of both tufted angioma and pyogenic granu- fore the patients reached age 4 months, it was not pos- loma, clinically distinct entities that are also represented sible to correlate histologic findings with involutional in the present study. In fact, the limited histologic over- behavior, only with clinical appearance and lack of dis- lap between tufted angioma and pyogenic granuloma has proportionate postnatal growth. Future comparative been noted16; both of these entities, like congenital non- studies of congenital nonprogressive hemangiomas of progressive hemangiomas, are strongly lobular in appear- rapidly involuting and noninvoluting types should ance and are immunonegative for GLUT1 and LeY.3 Be- clarify whether these are closely related or inherently yond these similarities, however, we found sufficient different entities distinguishable by biopsy findings. differences not only in clinical presentation, but also in Conservative management of congenital, fully formed histologic appearance, to confidently distinguish congen- hemangiomas may be indicated, at least until the invo- ital nonprogressive hemangiomas from tufted angiomas lutional potential of a given lesion is clear. However, as and pyogenic granulomas. pointed out by Boon et al,6 it may be wise early on to Tufted angiomas present as infiltrative, slowly grow- perform biopsies on unusually firm or otherwise atypi- ing macules or plaques, most commonly in the first few cal lesions to rule out more serious entities such as in- years of life, although rare lesions present at birth or in fantile sarcoma or myofibromatosis. adult life.16 Histologically, they show a widespread distri- Distinction between true infantile hemangiomas bution of distinct capillary lobules within the dermis and and congenital nonprogressive hemangiomas is also subcutis, creating a cannonball pattern when viewed at low important for any meaningful discussions of pathogen- magnification. These capillary lobules consist of densely esis concerning these disparate lesional types. For packed endothelial cells and pericytes forming tiny round instance, ultrasonographic detection of hemangiomas of lumina, and often display small, compressed vascular the congenital nonprogressive type early in utero is not crescents at their periphery. Hemosiderin deposits are not

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Figure 9. Pyogenic granuloma (A), tufted angioma (B), and infantile kaposiform hemangioendothelioma (C) were also represented in the study. A, The pyogenic granuloma shown was resected from the eyelid of a 3-month-old girl after appearing at age 1 month. Note the mildly edematous fibromyxoid stroma. B, This tufted angioma demonstrates the characteristic cannonball distribution of dense capillary lobules with peripheral vascular crescents (black arrows). C, A biopsy specimen taken at age 3 months revealed a proliferation of bland spindled cells forming slitlike spaces containing erythrocytes and occasional fibrin microthrombi. This infantile kaposiform hemangioendothelioma caused the patient’s death at age 6 months as a complication of Kasabach-Merritt syndrome.

Table 2. Summary of Clinical Data and Treatment for Patients With Congenital Nonprogressive Hemangiomas*

Patient Location Clinical Description Original Current Medical and Surgical No./Sex of Lesion of Lesion Pathologic Diagnosis Histologic Findings Interventions 1/F Midline posterior Moderately firm, freely movable Hemangioma, capillary type, Cellular capillary lobules within Resection en toto at cervical 5 ϫ 5 ϫ 3-cm subcutaneous with dilated lymphatic fibrotic stroma containing age9d mass covered by discolored channels numerous thin-walled vessels; skin and hair overlying skin atrophy; foci of hemosiderin, EMH† 2/M Radial aspect of 2 ϫ 2-cm bossed subcutaneous Capillary hemangioma Similar to patient 1, with addition Resection en toto at wrist mass of focal acute thrombosis age2mo6d within lobules 3/F Forehead 5 ϫ 5 ϫ 3-cm bulging, slightly Hemangioma mixed, Similar to patient 1, without Steroid trial, not tolerated; (see Figure 10A) pedunculated mass with predominantly juvenile obvious EMH (see Figures 1 resection en toto at peripheral rim of skin pallor; type and 10) age2mo18d freely movable, subcutaneous 4/F Preauricular 4 ϫ 4 ϫ 3-cm bulging Capillary hemangioma Similar to patient 1, with addition Resection en toto at (see Figure 11A) subcutaneous mass with of large pseudopapillary age2mo6d mottled, deep red skin capillary proliferations within discoloration and peripheral large vascular spaces, and pallor focal acute thrombosis (see Figure 11B-C); EMH and hemosiderin deposition marked; focal global hyalinizing sclerosis of lobules; skin atrophy 5/M Postauricular “Doughy” 3-cm, nodular Cellular hemangioma See Figure 6; similar to patient 1, Resection en toto at subcutaneous mass with with notable presence of very age2mo9d normal overlying skin large lymphatic spaces intertwined with the capillary lobules; hemosiderin and EMH present 6/F Labia majora 2.5-cm movable submucosal Lobular capillary See Figure 2; similar to patient 1, Resection en toto at mass, moderately firm in hemangioma wtih focal lobular sclerosis and age1mo9d consistency acute thrombosis; hemosiderin and EMH present

*All of the hemangiomas were congenital lesions, fully formed at birth (see Table 1 and the text). None were complicated by ulceration, cardiac failure,or coagulopathy. †EMH indicates extramedullary hematopoiesis.

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Figure 10. Congenital nonprogressive hemangioma. This subcutaneous forehead lesion was fully formed at birth and did not change in size prior to its resection at age 2.5 months (patient 3; hematoxylin-eosin–stained sections shown in Figure 1). A, Note the central skin discoloration and peripheral rim of skin pallor. B, This lesion, like all 6 congenital nonprogressive hemangiomas in this study, was immunonegative for glucose transporter protein isoform 1(GLUT1). Again, note the normal GLUT1 immunopositivity of luminal erythrocytes.

A B C

Figure 11. Congenital nonprogressive hemangioma. A, This preauricular mass (patient 4), like the forehead mass shown in Figure 10A, showed red skin discoloration with a peripheral rim of pallor. It was resected at age 2 months. B, A hematoxylin-eosin–stained section revealed lobules of capillaries surrounding and within the lumen of a large, ill-defined vascular space just beneath the skin. C, These lobules focally assumed a pseudopapillomatous architecture without true fibrinous or fibrous cores. B, Note the thinning of epidermis and loss of dermal appendages in the skin immediately overlying the vascular proliferation (left from center).

common, and thrombosis is generally limited to micro- Hemosiderin granules are sprinkled throughout con- thrombi within occasional capillary lumina. By contrast, genital nonprogressive hemangiomas, and thrombosis is congenital nonprogressive hemangiomas, as represented notably common, occasionally involving entire lobules, in the present study, present as bulging, tumorlike masses, some of which are sclerotic. Unlike congenital nonpro- largely subcutaneous and fully formed at birth; they are gressive hemangiomas, pyogenic granulomas (termed composed of capillary lobules and ribbons that vary widely lobular capillary hemangiomas by some pathologists in rec- in size—many very large—without the peripheral cres- ognition of their strongly lobular histologic appearance8) cents of tufted angioma. Large thin-walled vessels, some are relatively small, generally acquired lesions that lack a cystically dilated, are frequently present, and in some cases widespread growth pattern; most are exophytic erup- contain invaginated lobules of dense capillary growth tions of skin or mucosal surfaces, although rare subcuta- within their lumina. neous17 and intravascular18,19 forms have been described.

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B LeY

Figure 13. Immunoreactivities for glucose transporter protein isoform 1 (GLUT1) (A) and Lewis Y antigen (LeY) (B) in infantile hemangioma. Lesional endothelial cells of infantile hemangiomas, in marked contrast to those of Figure 12. Congenital nonprogressive hemangioma magnetic resonance congenital nonprogressive hemangiomas (Figure 4), consistently image. Axial T2-weighted imaging of the forehead mass shown in Figure 10A immunoreact strongly for both GLUT1 (A) and LeY (B, black arrow). Note the (patient 3) showed a large frontal subcutaneous mass (outer margins normal perineurial immunopositivity for GLUT1 and the pseudoinvasion of delineated by arrows) with underlying calvarial displacement. Widespread T2 an intralesional nerve by hemangiomatous capillaries (A, black arrow). signal loss throughout the mass is presumably secondary to hemosiderin Intralesional arterioles and arteries were nonreactive for both GLUT1 and deposition. These findings are not associated with infantile hemangiomas. LeY, shown here for LeY (B, white arrow).

Intravascular examples of pyogenic granuloma are described as solitary intravenous polyps composed of lobules of capillaries within a fibromyxoid stroma, attached to the wall of a vein by a fibrovascular stalk. In a study of 18 of such intravascular pyogenic granulomas, Cooper et al18 found only 5 lesions that contained thrombi, all of which were small and localized, and only 3 of which showed small deposits of iron. By contrast, thrombosis and hemorrhage were prominent in congenital nonprogressive hemangiomas, evident both radiologically and histologically and in the absence of complicating ulceration. The consistent presence of thrombosis and hemosiderin deposition in congenital nonprogressive hemangioma invites comparison with Masson lesion, currently Figure 14. An unusual case of multiple congenital lesions histologically termed intravascular papillary endothelial hyperplasia. This similar to pyogenic granulomas. The patient with this subcutaneous lesion peculiar histologic pattern, originally called vegetant intra- resected from her back was born with more than 100 small, red, vascular hemangioendothelioma by Masson20 in 1923, is seen dome-shaped or pedunculated lesions scattered over her trunk, head, and upper and lower extremities. These lesions showed limited postnatal growth. within many different types of vascular lesions. It is thought Eight were resected, all with histologic appearance highly reminiscent of to be an exuberant form of endothelial hyperplasia accom- pyogenic granuloma as shown here. Note the numerous, small lobules of panying organization of intravascular thrombi and con- capillaries set within a relatively loose fibromyxoid stroma. A well-defined sists of complex, spongelike ramifications of fibrinous or epithelial collarette was also present (not apparent here). fibrous papillae lined by endothelial cells.21 These are often seen in association with recognizable thrombus mate- derlying pathologic entity, but foci of this process are ex- rial and hemosiderin deposits, consistent with the pro- tremely common in venous malformations, reflecting the posed origin from organizing thrombus. high frequency of thrombosis in these slow-flow le- Intravascular papillary endothelial hyperplasia can sions.7 Foci are also occasionally seen in pyogenic granu- occur rarely as an isolated mass without a known un- lomas22 (including several in this study), hematomas,23

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 and venous lakes.21 Interestingly, a lymphatic vessel coun- notype displayed by infantile hemangiomas and placen- terpart has been described in cystic lymphatic malfor- tal vessels suggest a fundamental pathogenic link between mations.24 the vasculature of infantile hemangiomas and the micro- Five of the 6 cases of congenital nonprogressive vasculature of placenta, possibly involving either embo- hemangioma in this study clearly lacked the papillary lization of placental cells to fetal tissues during gesta- architecture that characterizes intravascular endothelial tion or birth, or aberrant differentiation of vascular hyperplasia. One case (patient 4; Figure 11A) included precursor cells within fetal tissues (skin and subcutis) a large central area of intravascular pseudopapillary toward the placental microvascular phenotype.3 The ab- capillary proliferation without true fibrinous or fibrous sence of GLUT1 and LeY expression in the congenital papillary cores (Figures 11B-C). nonprogressive lesions described here obviates these Congenital nonprogressive hemangiomas may rep- pathogenic considerations for these congenital lesions, resent primary capillary proliferations with secondary and suggests that their etiology is intrinsically different thrombosis or, alternatively, secondary endothelial from that of infantile hemangioma. hyperplasia in response to thrombosis or altered hemo- We have not excluded the possibility that rare non- dynamics (perhaps within malformed or damaged vas- progressive hemangiomas, similar in clinical and histo- cular or lymphatic beds). Multiple congenital heman- logic appearance to the congenital lesions reported in this giomas have been described in association with congenital study, may present in older children and adults or may protein C deficiency, a cause of severe thrombotic dis- show GLUT1 and/or LeY immunopositivity. We have ex- ease,25 and reactive angioendotheliomatosis has been re- amined only 6 of these unusual cases, restricted by study ported in adults in association with both antiphospho- design to neonatal samples. Similarly, we cannot ex- lipid syndrome26 and cryoglobulinemia.27 Abnormalities clude the possibility that rare GLUT1-positive infantile in coagulation during gestation, be they genetic, devel- hemangiomas may present fully formed at birth, with- opmental, or environmental in origin, might predispose out subsequent postnatal growth. However, we have not to development of congenital nonprogressive heman- identified any such lesions in the past 20 years at Arkan- gioma as a reactive phenomenon, perhaps engrafted on sas Children’s Hospital, suggesting that these lesions, if an underlying vascular or lymphatic malformation. they exist, must be exceedingly rare. In support of the idea that at least some of these le- As a final note, our study has uncovered another sions may have an underlying malformative nature is the point of diagnostic classification in need of clarification: fact that lesions from 5 of the 6 patients in this study with the concept of hemangiomatosis. We have demon- congenital nonprogressive hemangioma contained an un- strated that while some patients clinically diagnosed as usually high density of thin-walled channels, some large having diffuse hemangiomatosis have lesions that ex- and gaping, others small and numerous, throughout their hibit the histologic appearance and immunophenotypic substance. The rapid involution reported by others6,15 for features of true infantile hemangiomas (ie, the patient with some congenital hemangiomas might reflect extensive multiple cutaneous and hepatic hemangiomas de- postthrombotic sclerosis of lesional capillary beds, and scribed herein), other patients given this same clinical subsequent connective tissue contraction in the ab- diagnosis may have lesions of a different nature, similar sence of autonomous capillary proliferation. Noninvo- to infantile hemangiomas on casual clinical inspection luting examples of congenital hemangioma may be in- but distinct from hemangiomas histologically and im- trinsically different or may simply maintain a more even munophenotypically (ie, the unusual patient with hun- balance between reactive neovascularization and sclero- dreds of atypical pyogenic granuloma–type lesions and sis, perhaps affected by size and type (eg, lymphatic vs a large cutaneous stain described herein). Focused clini- venous) of the “parent” vessels of the malformation. Un- copathologic study of a larger series of these rare cases fortunately, resections and biopsies of these unusual le- of hemangiomatosis, with and without visceral involve- sions are very rare, making systematic comparison of non- ment, seems warranted. involuting and rapidly involuting examples at different In summary, we describe a distinct clinicopatho- stages of development difficult. Again, studies based on logic entity, the congenital nonprogressive hemangioma, multi-institutional collections of archival materials may that differs from classic infantile hemangioma in clinical be helpful. development, histologic and radiologic appearance, and Although the above discussion concerning the po- immunophenotype. Lesions of this type have been con- tential link between congenital nonprogressive heman- sidered clinical and morphological variants of infantile giomas and malformations remains speculative, our re- hemangioma. However, our findings show that these le- sults strongly suggest that congenital nonprogressive sions are pathogenically distinct from infantile heman- hemangiomas are not related in any meaningful biologi- gioma. The histologic features of these lesions suggest that cal sense to true infantile hemangiomas. The latter are thrombosis, possibly within lymphatic or vascular mal- invariably postnatally developing lesions, although they formations, may be important in their etiology. In the past, may be evident as nascent lesions at birth. True infan- the word hemangioma has been used to lump together a tile hemangiomas are not only histologically distinct from diverse group of vascular tumors and malformations. By congenital nonprogressive hemangiomas, but are uni- including so many different entities with differing clini- versally positive for an unusual set of vascular antigens: cal presentations, natural histories, and histologic fea- GLUT1, LeY, Fc␥RII, and merosin,3,4 that is shared by the tures, hemangioma has ceased to have any real diagnostic microvasculature of placenta. These striking and appar- meaning. As this article demonstrates, several clinically and ently unique similarities in microvascular immunophe- histologically distinct vascular tumors can be recog-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 nized. Hemangioma cannot function as a stand-alone di- 8. Mills SE, Cooper PH, Fechner RE. Lobular capillary hemangioma: the underlying agnosis for these tumors. Instead it must be modified with lesion of pyogenic granuloma: a study of 73 cases from the oral and nasal mu- cous membranes. Am J Surg Pathol. 1980;4:470-479. adjectives to indicate the specific clinicopathological en- 9. Padilla RS, Orkin M, Rosai J. Acquired “tufted” angioma (progressive capillary tity being described (ie, infantile hemangioma, congenital non- hemangioma): a distinctive clinicopathologic entity related to lobular capillary progressive hemangioma, tufted angioma, etc). Adoption of hemangioma. Am J Dermatopathol. 1987;9:292-300. this more specific terminology should help decrease diag- 10. Zukerberg LR, Nickoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of infancy and childhood. Am J Surg Pathol. 1993;17:321-328. nostic confusion and assist in patient management. 11. Mentzel T, Calonje E, Nascimento AG, Fletcher CD. Infantile hemangiopericy- Following submission of this article, an important toma versus infantile myofibromatosis: study of a series suggesting a continu- article was published by Enjolras et al,28 describing the ous spectrum of infantile myofibroblastic lesions. Am J Surg Pathol. 1994;18: clinical and histologic features of noninvoluting congen- 922-930. ital hemangiomas. These tumors, as beautifully de- 12. James CA. Diagnostic imaging of congenital vascular lesions. In: Waner M, Suen JY, eds. Hemangiomas and Vascular Malformations of the Head and Neck. New scribed in that article, are histologically distinct from the York, NY: John Wiley & Sons Inc; 1999:171-215. congenital nonprogressive hemangiomas described in the 13. Bielenberg DR, Bucana CD, Sanchez R, Mulliken JB, Folkman J, Fidler IJ. Pro- present article. Thus, these 2 tumor types probably rep- gressive growth of infantile cutaneous hemangiomas is directly correlated with resent different entities despite certain clinical similari- hyperplasia and angiogenesis of adjacent epidermis and inversely correlated with expression of the endogenous angiogenesis inhibitor, IFN-beta. Int J Oncol. 1999; ties. However, the etiologic relationship between these 14:401-408. tumors remains to be determined. 14. Calonje E, Mentzel T, Fletcher CD. Pseudomalignant perineurial invasion in cellular (“infantile”) capillary haemangiomas. Histopathology. 1995;26:159-164. Accepted for publication July 6, 2001. 15. Bonifazi E, Mileti F. Images in clinical medicine: congenital hemangioma. N Engl J Med. 1999;340:1080. This work was supported by the Departments of Pa- 16. Jones EW, Orkin M. Tufted angioma (angioblastoma): a benign progressive an- thology and Head and Neck Surgery, University of Arkan- gioma, not to be confused with Kaposi’s sarcoma or low-grade angiosarcoma. sas for Medical Sciences, Little Rock. J Am Acad Dermatol. 1989;20:214-225. Corresponding author and reprints: Paula E. North, 17. Cooper PH, Mills SE. Subcutaneous granuloma pyogenicum: lobular capillary hemangioma. Arch Dermatol. 1982;118:30-33. MD, PhD, Department of Pediatric Pathology, Arkansas 18. Cooper PH, McAllister HA, Helwig EB. Intravenous pyogenic granuloma: a study Children’s Hospital, 800 Marshall St, Little Rock, AR 72202 of 18 cases. Am J Surg Pathol. 1979;3:221-228. (e-mail: [email protected]). 19. Saad RW, Sau P, Mulvaney MP, James WD. Intravenous pyogenic granuloma. Int J Dermatol. 1993;32:130-132. 20. Masson P. Hemangioendotheliome vegetant intravasculaire. Bull Soc Anat Paris. REFERENCES 1923;93:517-532. 21. Clearkin KP, Enzinger FM. 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