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88 Sangüeza and Requena / Pathology of Vascular Skin Lesions
disorders, but there is also an idiopathic form that presents with no other associated
anomalies. Among the different diseases associated with angiokeratoma corporis
diffusum, Fabry’s disease is the most common. Fabry’s disease is a rare error of the
metabolism that results in a deficiency of the lysosomal enzyme hydrolase α-galactosi-
dase A. It is transmitted as an X-linked recessive trait. The gene responsible for the coding
of α-galactosidase A has been localized to the middle of the long arm of the X chromo-
some. As an X-linked disease, Fabry’s disease exclusively affects males; females may be
asymptomatic carriers and may have corneal dystrophic changes that can be detected by
slit-lamp examination (18,19).
As a consequence of the enzymatic defect, glycosphingolipids, predominantly
trihexosylceramide, accumulate within the lysosomes of endothelial cells, fibroblasts,
pericytes, and smooth muscle fibers of the dermis. There is also an accumulation of this
material in other organs including ganglion cells, nerves, cornea, heart, and kidney,
resulting in cardiac, renal, ocular, and neurologic abnormalities (20). Angiokeratomas of
Fabry’s disease usually appear shortly before puberty. They are small, punctate, dark red
papules, some of them less than 1 mm, mainly located in the lower part of abdomen,
genitalia, buttocks, and thighs in a bathing-trunk distribution (Figs. 15, 16, and 17). A
frequent and asymptomatic finding is the so-called cornea verticillata, which is a super-
ficial corneal dystrophy. This finding is of diagnostic importance for the detection of mild
cases and female carriers. Other cutaneous manifestations include dry skin, anhidrosis,
hyperthermic crises (21), and acroparaesthesiae secondary to capillary changes in the nail
matrix (22). In rare instances patients with Fabry’s disease may also present with concur-
Fig. 13. Angiokeratomas of Fordyce involving the vulva of an elderly woman.
Fig. 14. Angiokeratomas of Mibelli in the inner border of the left hand.
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Chapter 6 / Cutaneous Lesions with Dilations 89
Fig. 15. Angiokeratoma corporis diffusum in a patient with Fabry’s disease. Multiple small red
papules involving the left flank.
rent Klippel-Trenaunay-Weber syndrome (23). Patients with Fabry’s disease who are
devoid of cutaneous lesions have been reported (24).

Angiokeratoma corporis diffusum is not exclusive to Fabry’s disease and has also been
described in association with other rare inherited lysosomal storage diseases such as
fucosidosis type II (25,26), galactosidosis type II (27), Kanzaki’s disease or deficiency
of α-N-acetylgalactosaminidase (28–30), aspartylglycosaminuria (31), sialidosis type II
(32), adult-onset GM
1
gangliosidosis (33), and β-mannosidase deficiency (34–36).
By the same token, rare cases of angiokeratoma corporis diffusum have been described
in patients without metabolic anomalies (37–40). In some of these patients the
angiokeratomas were multiple and presented in a zosteriform distribution (41). These
angiokeratomas have been described in patients with cutaneous and cerebral hemangio-
mas (42), tuberous sclerosis (43), blue rubber bleb nevus syndrome (44), and juvenile
dermatomyositis (45).
In a recent report, angiokeratoma corporis diffusum not associated with metabolic
disease was described in a three-generation family with autosomal dominant transmis-
sion. Some of the affected patients showed arteriovenous shunts with hypertrophy of the
affected limb (46).
H
ISTOPATHOLOGIC FEATURES
Histopathologically, all variants of angiokeratomas are identical under a conventional
microscope. Common features of all angiokeratomas include the presence of dilated thin-
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90 Sangüeza and Requena / Pathology of Vascular Skin Lesions
walled blood vessels lined by a layer of endothelial cells in the papillary dermis and a
variable degree of hyperkeratosis (1). Occasionally, angiokeratomas may be seen over-
lying deep vascular malformations (47). Hyperkeratosis is usually absent in Fordyce’s
angiokeratomas and in angiokeratoma corporis diffusum (Fabry’s disease). Ultrastruc-
Fig. 17. Angiokeratoma corporis diffusum in a patient with Fabry’s disease with small red papules
on the buttocks.
Fig. 16. Angiokeratoma corporis diffusum in a patient with Fabry’s disease. (A) Lesions of

angiokeratoma involved the dorsum of the foot. (B) Close-up view shows that small red papules
are also present in the spaces among the toes.
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Chapter 6 / Cutaneous Lesions with Dilations 91
tural studies have demonstrated quantitative alterations of cytoplasmic organelles within
the endothelial cells (48).
In patients with Fabry’s disease, there is vacuolization of the cytoplasm of the endot-
helial cells of the arterioles and smooth muscle cells of the arrector pili. The presence of
these vacuoles may be a clue to the specific diagnosis in sections stained with hematoxy-
lin and eosin. However, in most cases the amount of glycolipid in the skin is small,
making it extremely difficult, if not impossible, to identify them in routinely prepared
sections. Special stains such as Sudan black B (49) and PAS (50) highlight the presence
of glycolipid deposits within the vacuoles in patients with Fabry’s disease and related
disorders (Fig. 18). The lipid material is double refractile, which can be demonstrated by
means of polariscopic examination of unfixed, or formalin-fixed frozen sections. Depos-
its of glycolipids in patients with Fabry’s disease are not restricted to the lesions of
angiokeratoma but may also be seen in skin that appears to be normal (51). Electron
microscopy examination of the skin in Fabry’s disease shows large, electrodense lipid
deposits in endothelial cells, pericytes, fibroblasts, arrector pili muscles, and secretory,
ductal, and myoepithelial cells of the eccrine glands (52). These deposits show a charac-
teristic lamellar structure(53–58), not seen in other types of angiokeratomas or in lesions
of angiokeratoma corporis diffusum with no enzymatic anomalies (38–45). Other ultra-
structural findings in patients with Fabry’s disease consist of intersecting short, crescent-
shaped, tightly packed membranes in the endothelial cells of the small cutaneous blood
vessels (59) and cytoplasmic vacuoles in the epithelial cells of the eccrine glands (60).
T
REATMENT
Small angiokeratomas may be managed by diathermy, electrodessication and curet-
tage, or cryotherapy with liquid nitrogen. Good cosmetic results have been reported with
laser therapy (61–67). For larger lesions the preferred treatment is surgical excision if

treatment is required. Recombinant human α-galactosidase A replacement therapy has
been demonstrated to be safe and efficient in reversing the chief clinical manifestations
in patients with Fabry’s disease (68).
References
1. Imperial R, Helwig EB. Angiokeratoma: a clinicopathological study. Arch Dermatol 1967;95:166–75.
2. Kumar MV, Thappa DM, Shanmugam S, Ratnakar C. Angiokeratoma circumscriptum of the oral cavity.
Acta Derm Venereol 1988;78:472.
3. Foucar E, Mason WV. Angiokeratoma circumscriptum following damage to underlying vasculature.
Arch Dermatol 1986;122:245–6.
4. Goldman L, Gibson SH, Richfield DF. Thrombotic angiokeratoma circumscriptum simulating mela-
noma. Arch Dermatol 1981;117:138–9.
5. Imperial R, Helwig EB. Angiokeratoma of the scrotum (Fordyce type). J Urol 1967;98:379–87.
6. Agger P, Osmundsen PE. Angiokeratoma of the scrotum (Fordyce). Acta Derm Venereol
1970;50:221–4.
7. Patrizi A, Neri I, Trevisi P, Landi C, Bardazzi F. Congenital angiokeratoma of Fordyce. J Eur Acad
Dermatol Venereol 1998;10:195–6.
8. Bisceglia M, Carosi I, Castelvetere M, Nurgo R. Angiocheratomi multipli dello scroto, “tipo Fordyce.”
Su un cado ad insorgenza iatrogena. Pathologica 1998;90:46–50.
9. Carrasco L, Izquierdo MJ, Fariña MC, Martín L, Moreno C, Requena L. Strawberry glans penis: a rare
manifestation of angiokeratomas involving the glands penis. Br J Dermatol 2000;142:1256–7.
10. Novick NL. Angiokeratoma vulvae. J Am Acad Dermatol 1985;12:561–3.
11. Clark JR, Wheelock JB. Angiokeratoma of the vulva. A case report. J Reprod Med 1988;33:473–4.
12. Cohen PR, Young AW Jr, Tovell HM. Angiokeratoma of the vulva: diagnosis and review of the litera-
ture. Obstet Gynecol Surv 1989;44:339–46.
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Chapter 6 / Cutaneous Lesions with Dilations 93
13. Imperial R, Helwig EB. Angiokeratomas of the vulva. Obstet Gynecol 1967;29:307–12.
14. Novick NL. Angiokeratoma vulvae. J Am Acad Dermatol 1985;12:561–3.

15. Pringle JJ. Four cases of angiokeratoma from one family. Br J Dermatol 1913; 25:40–53.
16. Haye KR, Rebello DJA. Angiokeratoma of Mibelli. Acta Derm Venereol 1961;41:56–60.
17. Dave VK, Main RA. Angiokeratoma of Mibelli with necrosis of the fingertips. Arch Dermatol
1972;106:726–8.
18. Fox MF, Dutoit DL, Warnich L, et al. Regional localization of alpha-galactosidase (GLA) to Xpter→q22,
hexosaminidase B (HEXB) to 5 q13→qter and arylsulphatase B (ARSB) to 5 pter→q13. Cytogenet Cell
Genet 1984;38:45–9.
19. Bishop DF, Calhoun DH, Bernstein MS, et al. Structure of the human alpha-galactosidase A gene: 5'
control elements, intron/exon splice junction sequence and alternative 3' termination. Am J Hum Genet
1987;41(suppl):A208.
20. Wallace HJ. Anderson-Fabry disease. Br J Dermatol 1973;88:1–21.
21. Kang WH, Chun SI, Lee S. Generalized anhidrosis associated with Fabry’s disease. J Am Acad Dermatol
1987;17:883–7.
22. Jansen W, Lentner A, Genzel I. Capillary changes in angiokeratoma corporis diffusum Fabry. J Dermatol
Sci 1994;7:68–70.
23. Germain DP. Co-occurrence and contribution of Fabry disease and Klippel-Trenaunay-Weber syn-
drome to a patient with atypical skin lesions. Clin Genet 2001;60:63–7.
24. Clarke JTR, Knack J, Crawhall JC, et al. Ceramide trihexosidase (Fabry’s disease) without skin lesions.
N Engl J Med 1971;284:233–5.
25. Epinette WW, Norins AL, Zeman W, Patel V. Angiokeratoma corporis diffusum with alpha-L fucosidase
deficiency. Arch Dermatol 1973;107:754–7.
26. Patel V, Watanabe I, Zeman W. Deficiency of alpha-L-fucosidase. Science 1972;176:420–7.
27. Ishibashi A, Tsuboi R, Shinmei M. β-Galactosidase and neuraminidase deficiency associated with
angiokeratoma corporis diffusum. Arch Dermatol 1984;120:1344–6.
28. Kanzaki T, Yokota M, Mizuno N, Matsumoto Y, Hirabayashi Y. Novel lysosomal glycoaminoacid
storage disease with angiokeratoma corporis diffusum. Lancet 1989;1:875–7.
29. Kanzaki T, Wang AM, Desnick RJ. Lysosomal alpha-N-acetylgalactosaminidase deficiency: the enzy-
matic defect in angiokeratoma corporis diffusum with glycopeptiduria. J Clin Invest 1991;88:707–11.
30. Chabás A, Coll MJ, Aparicio M, Rodríguez E. Mild phenotypic expression of alpha-N-acetyl-
galactosaminidase deficiency in two adult siblings. J Inherit Metab Dis 1994;17:724–31.

31. Gehler J, Sewell AC, Becker C, Hartmann J, Spranger J. Clinical and biochemical delineation of
aspartylglycosaminuria as observed in two members of an Italian family. Helv Paediatr Acta
1981;36:179–89.
32. Miyatake T, Atsumi T, Obayashi T, et al. Adult type neuronal storage disease with neuraminidase
deficiency. Ann Neurol 1978;6:232–44.
33. Wenger DA, Sattler M, Mueller T, Myers GG, Schneimann RS, Nixon GW. Adult GM 1 gangliosidosis:
clinical and biochemical studies on two patients and comparison to other patients called variant or adult
GM 1 gangliosidosis. Clin Genet 1980;17:323–34.
34. Cooper A, Sarharwalla IB, Roberts MM. Human β-mannosidase deficiency. N Engl J Med
1986;315:1231.
35. Cooper A, Hatton C, Thornley M, Sardwalla IB. Human β-mannosidase deficiency: biochemical find-
ings in plasma, fibroblasts, white cells and urine. J Inherit Metab Dis 1988;11:17–29.
36. Rodríguez Serna M, Botella Estrada R, Chabás A, et al. Angiokeratoma corporis diffusum associated
with β-mannosidase deficiency. Arch Dermatol 1996;132:1219–22.
37. Holmes RC, Fenson AW, McKee P, Cairns RJ, Black MM. Angiokeratoma corporis diffusum in a
patient with normal enzyme activities. J Am Acad Dermatol 1984;10:384–7.
38. Crovato F, Rebora A. Angiokeratoma corporis diffusum and normal enzyme activities. J Am Acad
Dermatol 1985;12:885–6.
39. Marsden J, Allen R. Widespread angiokeratomas without evidence of metabolic disease. Arch Dermatol
1987;123:1125–7.
Fig. 18. (Opposite page) Histopathologic features of angiokeratoma in a patient with Fabry’s
disease. (A) Low-power view shows dilated vascular spaces in the papillary dermis. (B) Higher
magnification demonstrates the thin walls of the vascular channels. (C) PAS stain demonstrates
PAS-positive deposits within the endothelial cells.
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94 Sangüeza and Requena / Pathology of Vascular Skin Lesions
40. Frappaz A, Ferrier MC, Hermier C, et al. Angiokeratoma corporis diffusum avec activité enzimatique
normale. Ann Dermatol Venereol 1987;114:1383–7.
41. Eizaguirre X, Landa N, Raton JA, Díaz Pérez JL. Multiple angiokeratomas with zosteriform distribution
in two sisters. Int J Dermatol 1994;33:641–2.

42. Ostlere L, Hart Y, Misch KJ. Cutaneous and cerebral hemangiomas associated with eruptive
angiokeratomas. Br J Dermatol 1996;135:98–101.
43. Gil Mateo MP, Miquel FJ, Velasco AM, Pitarch A, Fortea JM, Aliaga A. Widespread angiokeratomas
and tuberous sclerosis. Br J Dermatol 1996;135:280–2.
44. Trattner A, Krichely D, David M. Blue rubber bleb nevus syndrome associated with diffuse
angiokeratoma. Cutis 1997;59:264–6.
45. Shannon PL, Ford MJ. Angiokeratomas in juvenile dermatomyositis. Pediatr Dermatol 1999;16:488–51.
46. Calzavara-Pinton P, Colombi M, Carlino A, et al. Angiokeratoma corporis diffusum and arteriovenous
fistulas with dominant transmission in the absence of metabolic disease. Arch Dermatol 1995;131:57–62.
47. Kraus MD, Lind AC, Alder SL, Dehner LP. Angiomatosis with angiokeratoma-like features in children:
a light microscopic and immunophenotypic examination of four cases. Am J Dermatopathol
1999;21:350–5.
48. Gioglio L, Porta C, Moroni M, Nastasi G, Gangarossa I. Scrotal angiokeratoma (Fordyce): histopatho-
logical and ultrastructural findings. Histol Histopathol 1992;7:47–55.
49. Frost P, Spaeth GL, Tanaka Y. Fabry’s disease. Glycolipid lipidosis. Arch Intern Med 1966;117:440–6.
50. Hashimoto K, Gross BG, Lever WF. Angiokeratoma corporis diffusum (Fabry). Histochemical and
electron microscopic studies of the skin. J Invest Dermatol 1965;44:119–28.
51. de Groot WP. Angiokeratoma corporis diffusum Fabry. Dermatologica 1964;128:321–49.
52. Nakamura T, Kaneko H, Nishino I. Angiokeratoma corporis diffusum (Fabry disease): ultrastructural
studies of the skin. Acta Derm Venereol 1981;61:37–41.
53. Hashimoto K, Lieberman P, Lamkin N Jr. Angiokeratoma corporis diffusum (Fabry’s disease): a lyso-
somal disease. Arch Dermatol 1976;112:1416–23.
54. Luderschmidt C, Wolff HH. Intracytoplasmic granules with lamellae as signs of heterozygous Fabry’s
disease. Am J Dermatopathol 1980;2:57–61.
55. Strayer DS, Santa Cruz D. Intracytoplasmic granules with lamellae in Fabry’s disease. Am J
Dermatopathol 1980;2:63–4.
56. Breathnach SM, Black MM, Wallace HJ. Anderson-Fabry disease. Characteristic ultrastructural fea-
tures in cutaneous blood vessels in a 1-year-old boy. Br J Dermatol 1980;103:81–4.
57. Voglino A, Paradisi M, Dompe G, Onetti Muda A, Faraggiana T. Angiokeratoma corporis diffusum
(Fabry’s disease) with unusual features in a female patient. Light and electron microscopic investigation.

Am J Dermatopathol 1988;10:343–8.
58. Lao LM, Kumakiri M, Mima H, et al. The ultrastructural characteristics of eccrine sweat glands in a
Fabry disease patient with hypohidrosis. J Dermatol Sci 1998;18:109–17.
59. Elleder M, Ledvinova J, Vosmik F, Zeman J, Stejskal D, Lageron A. An atypical ultrastructural pattern
in Fabry’s disease: a study on its nature and incidence in 7 cases. Ultrastruct Pathol 1990;14:467–74.
60. Idoate MA, Pardo-Mindan FJ, Gonzalez Alamillo C. Fabry’s disease without angiokeratomas showing
unusual eccrine gland vacuolation. J Pathol 1992;167:65–8.
61. Flores JT, Apfelberg DB, Maser MR et al. Angiokeratoma of Fordyce: successful treatment with the
argon laser. Plast Reconstr Surg 1984;74:835–8.
62. Newton JH, McGibbon DH. The treatment of multiple angiokeratomata with the argon laser. Clin Exp
Dermatol 1987;12:23–5.
63. Hobbs ER, Ratz JL. Argon laser treatment of angiokeratomas. J Dermatol Surg Oncol 1987;13:1319–20.
64. Pasyk KA, Argenta LC, Schelbert EB. Angiokeratoma circumscriptum: successful treatment with the
argon laser. Ann Plast Surg 1988;20:183–90.
65. Lapins J, Emtestam L, Marcusson JA. Angiokeratomas in Fabry’s disease and Fordyce’s disease: suc-
cessful treatment with Cooper vapour laser. Acta Derm Venereol 1993;73:133–5.
66. Occella C, Bleidl D, Rampini P, Schiazza L, Rampini E. Argon laser treatment of cutaneous multiple
angiokeratomas. Dermatol Surg 1995;21:170–2.
67. Meyer WR, Dotters DJ. Laser treatment of recurrent vulvar angiokeratomas associated with Noonan
syndrome. Obstet Gynecol 1996;87:863–5.
68. Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human alpha-galactosidase
A-replacement therapy in Fabry’s disease. N Engl J Med 2001;345:9–16.
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Chapter 6 / Cutaneous Lesions with Dilations 95
5. LYMPHANGIECTASES
CLINICAL FEATURES
Lymphangiectases are the lymphatic counterparts of angiokeratomas resulting from
the acquired permanent dilation of lymphatic capillaries. They develop in areas of the skin
affected by obstruction or destruction of lymphatic drainage. Clinically, lymphangiectases
localized on genital or plantar skin may mimic warts (1–4). Lymphangiectases have been

described as a result of interference of lymphatic vessels secondary to surgery (5,6),
scarring from scrofuloderma (7), photoaging and topical corticosteroid application (8),
porphyria cutanea tarda (9), hepatic cirrhosis with ascites (10), mastectomy (11,12), and
radiotherapy for breast carcinoma (13–17). In the penis and scrotum, lymphangiectases
develop as a complication of a surgical procedure for a sacrococcygeal tumor (18); on the
vulva and thigh they are usually secondary to Crohn’s disease (19,20), or they develop
after surgery and radiotherapy for cervical carcinoma (1,21–25). Lymphangiectases of
Fordyce may also appear in the genital region of elderly people without evidence of
damage of the lymphatic drainage (26). Lymphangiectases have also been described as
consequence of alterations in the collagen or elastic tissue, including penicillamine der-
mopathy (27).
Clinically, lymphangiectases appear as multiple, persistent, translucent, thick-walled
white vesicles, of 2–5 mm in diameter. Some lesions may have a polypoid shape, and
punction provokes the flow of a milky liquid (Fig. 19). The involved area appears to be
sprinkled with lymphangiectatic vesicles with areas of normal-appearing skin among them.
H
ISTOPATHOLOGIC FEATURES
Histopathologically, lymphangiectasias are characterized by the presence of dilated
lymphatic vessels positioned within papillary dermis (Fig. 20). Sometimes lymphan-
giectases rise above the level of the adjacent skin. The vessels lack contents or show a
homogeneous material within their lumina, and they are lined by a thin wall with a single
discontinuous layer of endothelial cells. The degree of epidermal hyperplasia in
lymphangiectases is usually less marked than in angiokeratomas. The differential diag-
nosis between lymphangiectases and superficial lymphatic malformations is established
by the absence of a deep lymphatic component; the dilated vessels are confined to the
papillary dermis, and they result from dilation of preexisting lymphatic capillaries.
Fig. 19. Lymphangiectases involving the inner aspect of the thigh. Punction provoked the flow of
a milky fluid.
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Authentic, superficial lymphatic malformations may show lymphangiectases as part of
their superficial component; however, they have a deep component with characteristic
valves in their walls (23).
T
REATMENT
Surgical excision of the superficial vesicles tends to be disappointing, and recurrences
are common. Palliative results have been achieved with sclerotherapy and (28) laser
therapy (29–32).
References
1. Harwood CA, Mortimer PS. Acquired vulval lymphangiomata mimicking genital warts. Br J Dermatol
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2. El Sayed F, Bazex J, Bouissou X, et al. Acquired cutaneous lymphangiectasia mimicking plantar warts.
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3. Darmstadt GL. Perianal lymphangioma circumscriptum mistaken for genital warts. Pediatrics
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Fig. 20. Histopathologic features of lymphangiectases. (A) Low-power view shows an exophytic
lesion that contains dilated vascular structures. (B) Higher magnification demonstrates that the
vascular channels are lined by a thin wall of a discontinous layer of endothelial cells.
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Chapter 6 / Cutaneous Lesions with Dilations 97
6. Moon SE, Youn JI, Lee YS. Acquired cutaneous lymphangiectasia. Br J Dermatol 1993;129:193–5.
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Acad Dermatol 1997;36:493–5.
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12. Kurwa A, Waddinton E. Post mastectomy lymphangiomatosis. Br J Dermatol 1968;80:840.
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tion therapy. Cancer 1978;42:1989–91.
14. Leshin B, Whitaker D, Foucar E. Lymphangioma circumscriptum following mastectomy and radiation
therapy. J Am Acad Dermatol 1986;15:1117–9.
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report of a case and review of the literature. Cutis 1996;58:276–8.
16. Bouzit N, Grezard P, Communal PH, Mironneau I, Balme B, Perrot H. Lymphangiectasies cutanées
acquises après traitement chirurgical et radiothérapie du cancer du sein. A propos de 2 cas. J Gynecol
Obstet Biol Reprod 1999;28:384–7.
17. Diaz Cascajo C, Borghi S, Weyers W, Retzlaff H, Requena L, Metze D. Benign lymphangiomatous
papules of the skin following radiotherapy: a report of five new cases and review of the literature.
Histopathology 1999;35:319–27.
18. Weakley DR, Juhlin EA. Lymphagiectases and lymphangiomata. Arch Dermatol 1961;84:574–8.
19. Dap RF, van der Meijden WI. Vulvaire lymphangiectasieen bij de ziekte Crohn. Ned Tijdschr Geneeskd
2000;26:1692–5.
20. Handfield-Jones SE, Prendiville WJ, Norman S. Vulval lymphangiectasia. Genitourin Med 1989;
65:335–7.
21. Young AW Jr, Wind RM, Tovell HM. Lymphangioma of vulva: acquired following treatment for
cervical cancer. NY State J Med 1980;80:987–9.
22. Kennedy CTC. Lymphangiectasia of the vulva following hysterectomy and radiotherapy. Br J Dermatol
1990;123 (suppl 37):92–3.
23. Fisher I, Orkin M. Acquired lymphangioma (lymphangiectasis): report of a case. Arch Dermatol
1970;101:230–4.
24. LaPolla J, Foucar E, Leshin B, et al. Vulvar lymphangioma circumscriptum: a rare complication of

therapy for squamous cell carcinoma of the cervix. Gynecol Oncol 1985;22:363–6.
25. Ambrojo P, Fernandez Cogolludo E, Aguilar A, Sanchez Yus E, Sanchez de Paz F. Cutaneous
lymphangiectases after therapy for carcinoma of the cervix: a case with unusual clinical and histological
features. Clin Exp Dermatol 1990;15:57–9.
26. Cecchi R, Bartoli L, Brunetti L, Pavesi M, Giomi A. Lymphangioma circumscriptum of the vulva of late
onset. Acta Derm Venereol 1995;75:79–93.
27. Goldstein JB, McNutt NS, Hambrick GW, Hsu MA. Penicillamine dermopathy with lymphangiectases.
A clinical, immunohistologic, and ultrastructural study. Arch Dermatol 1989;125:92–7.
28. Ahmed DD, Waldorf JC, Randle HW. Cutaneous lymphangiectasis: treatment with sclerotherapy. Plast
Reconstr Surg 1998;101:434–6.
29. Landthaler M, Hohenleutner U, Braun Falco O. Acquired lymphangioma of the vulva: palliative treat-
ment by means of laser vaporization carbon dioxide. Arch Dermatol 1990;126:967–8.
30. Egan CA, Rallis TM, Zone JJ. Multiple scrotal lymphangiomas (lymphangiectases) treated by carbon
dioxide laser ablation. Br J Dermatol 1998;139:561–2.
31. Novak C, Spelman L. Low energy fluence CO
2
laser treatment of lymphangiectasia. Australas J Dermatol
1998;39:277–8.
32. Loche F, Schwarze HP, Bazex J. Treatment of acquired cutaneous lymphangiectasis of the thigh and
vulva with a carbon dioxide laser. Acta Derm Venereol 1999;79:335.
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Chapter 7 / Cutaneous Vascular Hyperplasias 99
99
7
Cutaneous Vascular Hyperplasias
CONTENTS
ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA
PYOGENIC GRANULOMA

BACILLARY ANGIOMATOSIS
VERRUGA PERUANA
INTRAVASCULAR PAPILLARY ENDOTHELIAL HYPERPLASIA
(MASSON’S PSEUDO-ANGIOSARCOMA)
P
SEUDO-KAPOSI’S SARCOMA
REACTIVE ANGIOENDOTHELIOMATOSIS
1. ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA
Angiolymphoid hyperplasia with eosinophilia (AHE) was first described by Wells and
Whimster in 1969 (1). These authors considered the process to be a late stage of Kimura’s
disease, a disorder described in the Japanese literature 20 years earlier (2). Following this
description, the concept that AHE and Kimura’s disease were the same entity was widely
accepted. It later became clear that the entities are different, and currently most authors
believe that AHE and Kimura’s disease are two separate entities (3–8). To complicate the
issue further, different names have been used to describe AHE, to wit: atypical pyogenic
granuloma (9), pseudopyogenic granuloma (10), inflammatory angiomatous nodule (10),
papular angioplasia (11), inflammatory arteriovenous hemangioma (12), intravenous
atypical vascular proliferation (13), cutaneous histiocytoid hemangioma (7,14), and
epithelioid hemangioma (15). Many of these terms are confusing and in our opinion it is
best not to apply them to this particular entity. Take for example the term histiocytoid
hemangioma (14). This term has been used to describe a wide spectrum of vascular
proliferations, both benign and malignant, all of which are histopathologically character-
ized by the presence of endothelial cells with a histiocytoid appearance. Because this term
is not specific and does not designate a single entity it is better not to use it. Another
confusing term is epithelioid hemangioma (15), since it can be confused with epithelioid
hemangioendothelioma, an entirely different clinicopathologic entity. We believe that
the term AHE is the most appropriate denomination for this entity because it is well
established in the literature (1,16–19), it adequately describes the lesion from a histo-
pathologic point of view, and it does not lead to confusion with other terms.
C

LINICAL FEATURES
Clinically, AHE is characterized by nodules or papules of angiomatoid appearance
predominantly located on the head, especially around the ears (Fig. 1), forehead, and
scalp. Less commonly lesions of AHE have been described in the mouth (20,21), trunk,
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100 Sangüeza and Requena / Pathology of Vascular Skin Lesions
Fig. 1. Angiolymphoid hyperplasia with eosinophilia. Multiple nodules with angiomatous appear-
ance involving the posterior aspect of the ear.
extremities (16,17,19,22,23), vulva (24,25), penis (26), and inner canthus of the eye (27).
Most of the time AHE is not associated with other diseases; however, there is a report of
a patient with AHE associated with pachydermoperiostosis (28). AHE has also been
described in HIV-infected patients (29). When the lesions are multiple, they tend to be
grouped or confluent. Symptomatic lesions may be painful, pruritic, or pulsatile (19).
Lesions do not involute spontaneously and often recur after excision (30). Some patients
have peripheral eosinophilia, but this feature is less frequent and less marked than in
Kimura’s disease.
H
ISTOPATHOLOGIC FEATURES
Histopathologically, AHE consists of well-circumscribed nodules involving the der-
mis and/or the subcutaneous fat (Fig. 2). Under scanning magnification two distinct
components are seen, irregular blood vessels and a dense inflammatory infiltrate. The
vascular component comprises irregular, thick-walled blood vessels lined by plump
endothelial cells, which protrude into the lumen. The walls of the vessels often have
thickened bundles of smooth muscle and abundant mucin. The endothelial cells lining the
vessels are plump, with large round to oval nuclei and abundant eosinophilic cytoplasm,
which often contains prominent vacuoles as an expression of primitive vascular differ-
entiation. The endothelial cells can form solid sheets, and the angiomatous nature of the
lesion becomes less evident. Occasionally the proliferation of endothelial cells is so
prominent, especially within the lumina of large vessels, that it can be confused with
malignant neoplasms (13). In some cases, the endothelial cells cluster together, giving the

appearance of multinucleated cells with immature vascular lumina (31). The presence of
plump endothelial cells is quite characteristic of AHE, and different names have been
employed to describe them, including histiocytoid (14), epithelioid (15), or hobnail
endothelial cells. The stroma consists of fibrovascular tissue that invariably contains
lymphocytes, eosinophils, mast cells, and sometimes mucin deposits. In some cases,
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Chapter 7 / Cutaneous Vascular Hyperplasias 101
Fig. 2. Histopathologic features of angiolymphoid hyperplasia with eosinophilia. (A) Scanning
power shows an exo-endophytic lesion involving the entire thickness of the dermis. (B) The
vascular channels are lined by plump endothelial cells, some of them with vacuoles in their
cytoplasm. (C) The inflammatory infiltrate is mostly composed of lymphocytes and eosinophils.
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102 Sangüeza and Requena / Pathology of Vascular Skin Lesions
lymphoid follicles with germinal centers are present, but usually they are not as promi-
nent as in Kimura’s disease. Immunohistochemical studies have demonstrated that the
endothelial cells are positive for factor VIII-related antigen (19,20,32–35), Ulex
europaeus I lectin (26,32), actin, and vimentin (32). The lymphocytes present within the
infiltrate consist primarily of polytypic B-lymphocytes (33). Ultrastructurally, the char-
acteristic endothelial cells contain Weibel-Palade bodies (20,32–34,36,37).
The true nature of AHE is uncertain. Human herpesvirus 8 (HHV8) has been detected in
some lesions of AHE (38,39), but these findings could be not confirmed by other authors
(23,40,41). In some cases there is an antecedent of trauma (15,19,42). When the biopsy is large
and deep enough, an arteriovenous shunt is found in a significant percentage of cases
(15,19,43). These features suggest that AHE is not a true neoplasm, but a reactive hyperplastic
process that occurs probably secondary to damage and repair of an artery or vein (15,42).
D
IFFERENTIAL DIAGNOSIS
The differential diagnosis with Kimura’s disease can be established on the basis of
both the clinical and histopathologic features (3–8). Clinically, Kimura’s disease consists
of skin-colored subcutaneous masses that in extreme cases distort the outline of the face

dramatically, as a consequence of the presence of large infiltrates of inflammatory cells
within the dermis and subcutaneous tissues. Usually patients also show intense peripheral
eosinophilia and lymphadenopathy. Histopathologically Kimura’s disease is devoid of
the vascular abnormalities seen in AHE, and when plump endothelial cells are present in
the blood vessels they are a focal finding. The main findings are represented by the
presence of numerous, closely packed lymphoid follicles that extend throughout the
dermis and subcutaneous fat, and sometimes into the lymph nodes and internal organs.
Within these infiltrates there are numerous eosinophils. In brief, Kimura’s disease is not
a disorder of blood vessels, but an inflammatory systemic process of unknown etiology.
T
REATMENT
Surgery, cryotherapy, or laser therapy (44–49) can adequately manage lesions of
AHE, but larger lesions show a tendency to persist (30), unless the arteriovenous shunt
is excised. Partial improvement of the lesions of AHE has been reported after intralesional
injection of interferon-α-2a (50) or interferon-α-2b (51), as well as after oral administra-
tion of pentoxifylline (52), indomethacin (53), or isotretinoin (54).
References
1. Wells GC, Whimster IW. Subcutaneous angiolymphoid hyperplasia with eosinophilia. Br J Dermatol
1969;81:1–15.
2. Kimura T, Yoshimura S, Ishikawa E. Abnormal granuloma with proliferation of lymphoid tissue. Trans
Soc Pathol Jpn 1948;37:179–80.
3. Chan JKC, Hui PK, Ng CS, Yuen NWF, Kung ITM, Gwi E. Epithelioid hemangioma (angiolymphoid
hyperplasia with eosinophilia) and Kimura’s disease in Chinese. Histopathology 1989;15:557–74.
4. Googe PB, Harris NL, Mihm MC Jr. Kimura’s disease and angiolymphoid hyperplasia with eosino-
philia: two distinct histopathological entities. J Cutan Pathol 1987;14:263–71.
5. Kung ITM, Gibson JB, Bannatyne PM. Kimura’s disease: a clinico-pathological study of 21 cases and
its distinction from angiolymphoid hyperplasia with eosinophilia. Pathology 1984;16:39–44.
6. Kuo TT, Shih LY, Chan HL. Kimura’s disease. Involvement of regional lymph nodes and distinction
from angiolymphoid hyperplasia with eosinophilia. Am J Surg Pathol 1988;12:843–54.
7. Rosai J. Angiolymphoid hyperplasia with eosinophilia of the skin. Its nosological position in the spec-

trum of the histiocytoid hemangioma. Am J Dermatopathol 1982;4:175–84.
07/Sangüeza/99-132/F 01/14/2003, 12:12 PM102
Chapter 7 / Cutaneous Vascular Hyperplasias 103
8. Urabe A, Tsuneyoshi M, Enjoji M. Epithelioid hemangioma versus Kimura’s disease. A comparative
clinicopathologic study. Am J Surg Pathol 1987;11:758–66.
9. Peterson WC Jr, Fusaro RM, Goltz RW. Atypical pyogenic granuloma: a case of benign hemangio-
endotheliomatosis. Arch Dermatol 1964;90:197–201.
10. Wilson Jones E, Bleehen SS. Inflammatory angiomatous nodules with abnormal blood vessels occuring
about the ears and scalp (pseudo- or atypical pyogenic granuloma). Br J Dermatol 1969;81:804–16.
11. Wilson Jones E, Marks R. Papular angioplasia: vascular papules of the face and scalp simulating
malignant vascular tumors. Arch Dermatol 1970;102:422–7.
12. Girard C, Graham JH, Johnson WC. Arteriovenous hemangioma (arteriovenous shunt): a clinicopatho-
logical and histochemical study. J Cutan Pathol 1974;1:73–87.
13. Rosai J, Akerman LR. Intravenous atypical vascular proliferation: a cutaneous lesion simulating a
malignant blood vessel tumor. Arch Dermatol 1974;109:714–7.
14. Rosai J, Gold J, Landy R. The histiocytoid hemangiomas: a unifying concept embracing several previously
described entities of the skin, soft tissue, large vessels, bone, and heart. Hum Pathol 1979;10:707–30.
15. Fetsch JF, Weiss SW. Observations concerning the pathogenesis of epithelioid hemangioma
(angiolymphoid hyperplasia). Mod Pathol 1991;4:449–55.
16. Mehregan AH, Shapiro L. Angiolymphoid hyperplasia with eosinophilia. Arch Dermatol 1971;103:50–7.
17. Reed RJ, Terazakis N. Subcutaneous angioblastic lymphoid hyperplasia with eosinophilia (Kimura’s
disease). Cancer 1972;29:489–97.
18. Castro C, Winkelmann RK. Angiolymphoid hyperplasia with eosinophilia in the skin. Cancer
1974;34:1696–705.
19. Olsen TG, Helwig EB. Angiolymphoid hyperplasia with eosinophilia: a clinopathologic study of 116
patients. J Am Acad Dermatol 1985;12:781–96.
20. Masa FC, Fretzin DF, Chowdhury L, et al. Angiolymphoid hyperplasia demonstrating extensive skin
and mucosal lesions controlled with vinblastine therapy. J Am Acad Dermatol 1984;11:333–9.
21. Tsuboi H, Fujimura T, Katsuoka K. Angiolymphoid hyperplasia with eosinophilia in the oral mucosa.
Br J Dermatol 2001;145:365–6.

22. Imbling FD Jr, Viegas SF, Sanchez RL. Multiple angiolymphoid hyperplasia with eosinophilia of the
hand: report of a case and review of the literature. Cutis 1996;58:345–8.
23. Arnold M, Geilen CC, Coupland SE, et al. Unilateral angiolymphoid hyperplasia with eosinophilia
involving the left arm and hand. J Cutan Pathol 1999;26:436–40.
24. Aguilar A, Ambrojo P, Requena L, Olmos L, Sanchez Yus E. Angiolymphoid hyperplasia with eosino-
philia limited to the vulva. Clin Exp Dermatol 1990;15:65–7.
25. Scurry J, Dennerstein G, Brenan J. Angiolymphoid hyperplasia with eosinophilia of the vulva. Aust N
Z Obstet Gynaecol 1995;35:347–8.
26. Srigley JR, Ayala AG, Ordoñez NG, et al. Epithelioid hemangioma of the penis: a rare and distinctive
vascular lesion. Arch Pathol Lab Med 1985;109:51–4.
27. Mariatos G, Gorgoulis VG, Laskaris G, Kittas C. Epithelioid hemangioma (angiolymphoid hyperplasia
with eosinophilia) in the inner canthus. J Eur Acad Dermatol Venereol 2001;15:90–1.
28. Kanekura T, Mizumoto JI, Kanzaki T. Pachydermoperiostosis with angiolymphoid hyperplasia with
eosinophilia. J Dermatol 1994;21:133–4.
29. D’Offizi G, Ferrara R, Donati P, Bellomo P, Paganelli R. Angiolymphoid hyperplasia with eosinophilia
in HIV infection. AIDS 1995;9:813–4.
30. Bendl BJ, Asano K, Lewis RJ. Nodular angioblastic hyperplasia with eosinophilia and lympho-
folliculosis. Cutis 1977;19:327–9.
31. Sakamoto F, Hashimoto T, Takenouchi T, Ito M, Nitto H. Angiolymphoid hyperplasia with eosinophilia
presenting multinucleated cells in histology: an ultrastructural study. J Cutan Pathol 1998;25:322–6.
32. Angervall L, Kindblom LG, Karlsson K, et al. Atypical hemangioendothelioma of venous origin: a
clinicopathologic angiographic immunohistochemical, and ultrastructural study of two endothelial
tumors within the concept of histiocytoid hemangioma. Am J Surg Pathol 1985;9:504–16.
33. Wrigth DH, Padley NR, Judd MA. Angiolymphoid hyperplasia with eosinophilia simulating lymphad-
enopathy. Histopathology 1981;5:127–40.
34. Ose D, Vollmer R, Shelburne J, et al. Histiocytoid hemangioma of the skin and scapula: a case report
with electron microscopy and immunohistochemistry. Cancer 1983;51:1656–62.
35. Burgdorf WHC, Mukai K, Rosai J. Immunohistochemical identification of factor VIII related antigen
in endothelial cells of cutaneous lesions of alleged vascular nature. Am J Clin Pathol 1981;75:167–71.
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36. Daniels DG, Schrodt GR, Fliegelman MT, et al. Ultrastructural study of a case of angiolymphoid
hyperplasia with eosinophilia. Arch Dermatol 1974;109:870–2.
37. Eady RAJ, Wilson Jones E. Pseudopyogenic granuloma: enzyme histochemical and ultrastructural
study. Hum Pathol 1977;8:653–68.
38. Gyulai R, Kemeny L, Adam E, Nagy F, Dobozy A. HHV8 DNA in angiolymphoid hyperplasia of the
skin. Lancet 1996;347:1837.
39. Oksenhendler E, Cazals-Hatem D, Schulz TF, et al. Transient angiolymphoid hyperplasia and Kaposi’s
sarcoma after primary infection with human herpesvirus 8 in a patient with human immunodeficiency
virus infection. N Engl J Med 1998;338:1585–90.
40. Lebbe C, Pellet C, Flageul B, et al. Sequences of human herpesvirus 8 are not detected in various non-
Kaposi sarcoma vascular lesions. Arch Dermatol 1997;133:919–20.
41. Jang KA, Ahn SJ, Choi JH, et al. Polymerase chain reaction (PCR) for human herpesvirus 8 and
heteroduplex PCR for clonality assessment in angiolymphoid hyperplasia with eosinophilia and
Kimura’s disease. J Cutan Pathol 2001;28:363–7.
42. Vadlamudi G, Schinella R. Traumatic pseudoaneurism: a possible early lesion in the spectrum of epithe-
lioid hemangioma/angiolymphoid hyperplasia with eosinophilia. Am J Dermatopathol 1998;20:113–7.
43. Onishi Y, Ohara K. Angiolymphoid hyperplasia with eosinophilia associated with arteriovenous mal-
formation: a clinicopathological correlation with angiography and serial estimation of serum levels or
renin, eosinophil cationic protein and interleukin 5. Br J Dermatol 1999;140:1153–6.
44. Hobbs ER, Bailin PL, Ratz JL, Yarbrough CL. Treatment of angiolymphoid hyperplasia of the external
ear with carbon dioxide laser. J Am Acad Dermatol 1988;19:345–9.
45. Letzman BH, McMeekin T, Gaspari AA. Pulsed dye laser treatment of angiolymphoid hyperplasia with
eosinophilia lesions. Arch Dermatol 1997;133:920–1.
46. Rohrer TE, Allan AE. Angiolymphoid hyperplasia with eosinophilia successfully treated with a long-
pulsed tunable dye laser. Dermatol Surg 2000;26:211–4.
47. Papadavid E, Krausz T, Chu AC, Walker NP. Angiolymphoid hyperplasia with eosinophilia success-
fully treated with the flash-lamp pulsed-dye laser. Br J Dermatol 2000;142:192–4.
48. Gupta G, Munro CS. Angiolymphoid hyperplasia with eosinophilia: successful treatment with pulsed
dye laser using the double pulse technique. Br J Dermatol 2000;143:214–5.

49. Fosko SW, Glaser DA, Rogers CJ. Eradication of angiolymphoid hyperplasia with eosinophilia by
copper vapor laser. Arch Dermatol 2001;137:863–5.
50. Shenefelt PD, Rinker M, Caradonna S. A case of angiolymphoid hyperplasia with eosinophilia treated
with intralesional interferon alfa-2a. Arch Dermatol 2000;136:837–9.
51. Rampini P, Semino M, Drago F, Rampini E. Angiolymphoid hyperplasia with eosinophilia: successful
treatment with interferon alpha 2b. Dermatology 2001;202:343.
52. Person JR. Angiolymphoid hyperplasia with eosinophilia may respond to pentoxifylline. J Am Acad
Dermatol 1994;31:117–8.
53. Nomura K, Sasaki C, Murai T, Mitsuhashi Y, Sato S. Angiolymphoid hyperplasia with eosinophilia:
successful treatment with indomethacin farnesil. Br J Dermatol 1996;134:189–90.
54. Oh CW, Kim KH. Is angiolymphoid hyperplasia with eosinophilia a benign vascular tumor? A case
improved with oral isotretinoin. Dermatology 1998;197:189–91.
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Chapter 7 / Cutaneous Vascular Hyperplasias 105
2. PYOGENIC GRANULOMA
Pyogenic granuloma (PG) is a fairly common lesion that is still the subject of contro-
versy. Most authors regard PG as a hyperplastic process; the lesion grows rapidly at sites
of superficial trauma, and in some cases lesions of PG are associated with endocrine
alterations or medication and usually involute upon cessation of the stimuli. Other authors,
however, prefer to include PG with the group of vascular neoplasms. Among the
arguments used to support the neoplastic nature of PG is the presence of a lobular archi-
tecture, similar to that seen in other neoplastic processes including tufted hemangioma.
Mills et al. (1) noted that a lobular pattern is a repeatable finding in some stages of the
development of all variants, including both the subcutaneous and intravenous forms.
These authors coined the term lobular capillary hemangioma for such lesions and con-
sidered them to be benign neoplasms, based on their microscopic morphology. However,
capillaries arranged in a lobular pattern can be seen in different vascular proliferations,
both hyperplasias and neoplasias (2); therefore, this is not a compelling argument in favor
of either the hyperplastic or neoplastic nature of PG. An additional issue is the name
pyogenic granuloma. Semantically, it is obviously an unfortunate term, because the

lesion does not contain pus and it is not composed of granulomas.
We consider PGs to be hyperplasias rather than neoplasias for the following reasons:
the lesion often appears as a response to trauma, hormonal factors (3), or retinoid therapy;
(4–7); in the early stages it is indistinguishable from granulation tissue, and it resolves
into a nubbin of scar tissue; widespread lesions appear in an eruptive fashion, but they
usually resolve spontaneously within a few months (8); and lesions in pregnant women
as well as lesions secondary to oral contraceptive pills or retinoid therapy usually regress
following parturition (9) or withdrawal of the responsible drug (4–7,10–13). In our
opinion, these are all compelling reasons that militate against the neoplastic nature of PG
and in favor of a hyperplastic one. Thus PG is discussed along with other hyperplastic
processes in this part of the book. We agree that there is a problem with the name, but
unfortunately it is firmly entrenched in the dermatologic literature and for that reason we
continue to use it in this monograph. Furthermore, the term lobular capillary hemangioma
is also problematic, because some of the lesions are composed almost exclusively of
veins. In sum, PG is neither a hemangioma nor a neoplasm; the lesion is an inflammatory
and hyperplastic condition, better interpreted as a florid expression of granulation tissue
proliferation.
C
LINICAL FEATURES
PG affects both the skin and the mucous membranes. Clinically, these lesions typically
present as a papule or polyp with a glistening surface, which bleeds easily. It preferen-
tially affects the gingiva, lips (Fig. 3), mucosa of the nose, fingers, and face (1,9,14), but
examples of PG have been described in all parts of the skin and mucous membranes
including the vulva (15), scrotum (16), penis (17), and glans penis (18). In a epidemio-
logic study of 325 cases (9), cutaneous lesions accounted for 86% of the lesions, with
mucosal lesions representing only 12% of the cases. Overall, male patients outnumbered
female patients. The peak incidence for PG is around the second decade of life. PG
usually develop at the site of a preexisting injury, where they evolve rapidly over a period
of weeks to a maximum size and then shrink and become replaced by fibrous tissue, which
eventually disappears within a few months. PG is especially common in children and

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106 Sangüeza and Requena / Pathology of Vascular Skin Lesions
young adults. The gingival lesions that develop during pregnancy, known as epulis
gravidarum, are identical to PG (2). In rare instances, PG may develop within a preex-
isting lesion such as a nevus flammeus (19–22) or in a spider angioma (23). When the
lesions are multiple, these tend to be grouped in a localized area (23–34) (Fig. 4), but they
can also extend in a eruptive and disseminated fashion (8,35–39). With a few exceptions,
multiple recurrent lesions are more common in adolescents and young adults, and they
occur after attempts at electrodesiccation or surgical removal of the primary single lesion.
Multiple lesions can also occur after removal of melanocytic lesions (40) or in burns (41).
The most common site for multiple lesions is the trunk, especially the interscapular
region. Eruptive widespread lesions of PG have been described as a paraneoplastic
manifestation in a patient affected with Hodgkin’s disease (38), but in most cases no
underlying disease is identified (8,35–37). Rare variants of PG include the subcutaneous
(42,43) and intravenous (44–48) forms. Lesions quite similar to PG have been reported
in patients receiving oral retinoid therapy for acne or psoriasis (4–7), oral indinavir
(10,11), as well as topical applications of tretinoin (12) or tazarotene creams (13).
H
ISTOPATHOLOGIC FEATURES
Early lesions of PG are identical to granulation tissue, to wit, numerous capillaries and
venules disposed radially to the skin surface, which is often eroded and covered with
scabs (Fig. 5). The stroma is edematous and contains a mixed inflammatory infiltrate with
lymphocytes, histiocytes, plasma cells, neutrophils, and an increased number of mast
cells (49). Fully developed lesions of PG are polypoid and show a lobular pattern with
fibrous septa intersecting the lesion, hence the name lobular capillary hemangioma (1)
used by some authors for this stage of the lesion. Each lobule is composed of aggregations
of capillaries and venules lined by plump endothelial cells. At this stage the lesion has
reepithelialized entirely, and it is covered by epidermis with collarettes of hyperplastic
adnexal epithelium partially embracing the lesion at the periphery. The inflammatory
infiltrates are sparse, and edema of the stroma has disappeared. In the late stages of PG

there is a steady increase in the amount of fibrous tissue, so as the fibrotic struts widen,
the lobules of capillaries become smaller and, with time, PG evolves into a fibroma.
When the specimen is deep enough, a small feeding artery and one or more veins may be
seen ascending from the subcutaneous fat throughout the reticular dermis to enter the base
of a PG directly. The histopathologic findings are the same in all variants.
Fig. 3. Pyogenic granuloma, a dome-shaped papule with angiomatous appearance, involving the
lower lip of a boy.
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Chapter 7 / Cutaneous Vascular Hyperplasias 107
Uncommon histopathologic features in lesions of PG include intravascular papillary
endothelial hyperplasia (50) and extramedullary hematopoiesis (51). When the lesions of
PG recur, they may show some atypical features and in some cases even resemble an
angiosarcoma. In recurrent lesions there are anastomosing vascular channels lined by
endothelial cells that infiltrate and dissect between the dermal collagen bundles, vaguely
mimicking an angiosarcoma, specially in the deeper areas of the lesion (24). When
lesions of PG develop within a vein (Fig. 6), they are usually attached to the wall of the
vein by a stalk, and the lobular pattern is less prominent than in their extravascular
counterparts (44).
Immunoperoxidase investigations have documented factor VIII-related antigen posi-
tivity in the endothelial cells lining large vessels but negativity in the cellular areas (52),
whereas Ulex europaeus I lectin binds to the endothelial cells in both large vessels and
cellular aggregates (53). Ultrastructural studies have demonstrated the capillary nature
of most of the blood vessels that make up PG (45,54,55).
Polymerase chain reaction (PCR) investigations for human papillomavirus (56) and
HHV8 (57) have yielded negative results. Immunohistochemical studies have dem-
onstrated the expression of inducible nitric oxide synthase (58), increased expression of
vascular endothelial growth factor (59), low apoptotic rate expression of Bax/Bcl-2
proteins (60), and strong expression of phosphorylated mitogen-activated protein kinase
(61) in PG lesions.
Fig. 4. Multiple recurrent lesions after electrodesiccation of a PG on the scalp of an elderly patient.

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108 Sangüeza and Requena / Pathology of Vascular Skin Lesions
Fig. 5. Histopathologic features of PG. (A) Low power shows a polypoid lesion with eroded
surface. (B) Higher magnification demonstrates capillary blood vessels surrounded by inflamma-
tory infiltrate of neutrophils and lymphocytes. (C) Blood vessels lined by uniform cuboidal
endothelial cells without atypia.
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Chapter 7 / Cutaneous Vascular Hyperplasias 109
TREATMENT
The pedunculated lesions of PG are easily removed by electrodesiccation and curet-
tage. Other therapies that are successful include sclerotherapy with monoethanolamine
oleate (62) and laser therapy (63–65). When the proliferating vessels extend deep within
the reticular dermis, recurrences are frequent. In these cases, an excision including a
narrow ellipse of normal adjacent tissue should be performed.
References
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granuloma: a study of 73 cases from the oral and nasal mucous membranes. Am J Surg Pathol
1980;4:471–9.
2. LeBoit PE. Lobular capillary proliferation: The underlying process in diverse benign cutaneous vascular
neoplasms and reactive conditions. Semin Dermatol 1989;8:298–310.
3. Musalli NG, Hopps RM, Johnson NW. Oral pyogenic granuloma as a complication of pregnancy and
the use of hormonal contraceptives. Int J Gynecol Obstet 1976;14:187–91.
4. Campbell JP, Grekin RC, Ellis CN, Matsuda-John SS, Swanson NA, Voorhes JJ. Retinoid therapy is
associated with excess granulation tissue responses. J Am Acad Dermatol 1983;9:708–13.
5. Blumental G. Paronychia and pyogenic granuloma like lesions with isotretinoin. J Am Acad Dermatol
1984;10:677–8.
6. Hodak E, David M, Feverman EJ. Excess granulation tissue during etretinate therapy. J Am Acad
Dermatol 1984;11:1166–7.
7. Miller RAW, Ross JB, Martin J. Multiple granulation tissue lesions occurring in isotretinoin treatment
of acne vulgaris—successful response to topical corticosteroid therapy. J Am Acad Dermatol

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Fig. 6. (Opposite page) Histopathologic features of intravascular PG. (A) Low power shows a
blood vessel with obliterated lumen. (B) Higher magnification demonstrates that the lumen is
obliterated by a capillary blood vessel proliferation.
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110 Sangüeza and Requena / Pathology of Vascular Skin Lesions
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112 Sangüeza and Requena / Pathology of Vascular Skin Lesions
3. BACILLARY ANGIOMATOSIS
In 1983, Stoler et al. (1) called attention to an unusual infection occurring in patients
affected with AIDS. These authors described their cases as “An atypical subcutaneous
infection associated with acquired immune deficiency syndrome.” Four years later
Cockerell et al. (2) reported on similar cases, using the term “epithelioid angiomatosis,”
to emphasize the vascular nature of these proliferations. A year later, LeBoit et al. in San
Francisco, suggested the possibility of an infectious agent as the cause of the disease.
These authors also suggested the possibility of a relationship between the agent of bacil-
lary angiomatosis and the causative agent of cat scratch disease (3). A few months later,
the same group confirmed the infectious nature of the disease utilizing the Warthin-Starry
technique to demonstrate the organism (4).
C
LINICAL FEATURES
Bacillary angiomatosis preferentially affects patients with AIDS (2–4), but it has also
been described in patients with other immunodeficiency disorders including leukemic
patients (5), patients receiving systemic steroid therapy (6), and renal transplant recipi-
ents receiving cyclosporine and prednisone (7). Several recent reports have also docu-
mented bacillary angiomatosis in immunocompetent patients, both children (8,9) and
adults (10–12) without HIV infection and without risk factors for the disease. The caus-
ative microorganisms of bacillary angiomatosis are of the genus Bartonella (formerly
Rochalimaea) (13). Two species of Bartonella cause bacillary angiomatosis: B. quintana
and B. henselae. Because of the difficulty in culturing these organisms, the diagnosis of
bacillary angiomatosis was initially established based on the clinical features of the

disease combined with serologic studies, molecular biology studies, or tissue demonstra-
tion of the organisms using the Warthin-Starry staining technique.
Currently, the diagnosis of Bartonella infection can be established based on the results
of blood, cutaneous, or visceral cultures (14) or PCR methods for the detection of Bar-
tonella sp (15). Despite numerous attempts HHV-8 has not been demonstrated in lesions
of bacillary angiomatosis (16,17). The vast majority of patients with bacillary angiomatosis
are advanced AIDS patients with CD4
+
lymphocytic counts of less than 200 cells/mm
3
.
There is a strong association between a cat scratch or bite and bacillary angiomatosis;
furthermore, B. henselae has been isolated from the blood and fleas of infected cats,
supporting the notion that cats may serve as a reservoir of the disease in some patients.
It is also possible that humans may act as reservoirs of the disease; chronic B. quintana
bacteremia has been demonstrated in homeless patients in different geographic areas (18).
Bacillary angiomatosis can involve the skin and/or internal organs. It is usually accom-
panied by systemic symptoms (19). Cutaneous lesions are either single or multiple; some
patients have a widespread eruption with a myriad of lesions. Lesions on the skin usually
begin as small, red to purple, pinpoint-size papules that increase in size to form nodules
and tumors. Individual lesions often resemble PG (Fig. 7). When deep lesions are present,
they appear as erythematous subcutaneous nodules that may attain several centimeters in
diameter (20). In other occasions the subcutaneous nodules present as violaceous plaques
and tumors resembling Kaposi’s sarcoma. Atypical clinical presentations include large
fungating masses (21) and ulcers (22). Involvement of the oral and genital mucous
membranes is fairly common (23).
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