PATHOLOGY OF VASCULAR SKIN LESIONS - PART 9 potx

258 Sangüeza and Requena / Pathology of Vascular Skin Lesions
7. CUTANEOUS ANGIOSARCOMA ASSOCIATED
WITH LYMPHEDEMA
Stewart and Treves (1) first described the development of cutaneous angiosarcoma in
lymphedematous areas in 1948. Since then, this disorder has been known as Stewart-
Treves syndrome. In their original report, these authors reported six patients with
postmastectomy lymphedema on the ipsilateral arm in whom angiosarcomas developed
several years after this procedure. A large number of additional cases rapidly appeared
in the literature (2–10). In addition to lymphedema secondary to mastectomy, this type
of angiosarcoma has also been described in areas of lymphedema secondary to a variety
of other mechanisms, including axillary node dissection for metastatic melanoma in
males (11), lymphedema of the abdominal wall following lymph node dissection for
carcinoma of the penis (12), congenital lymphedema (3,4,13–16), lymphedema secondary
to a filarial infection (17–22), chronic idiopathic lymphedema (3,15,18,22–27), morbid
obesity with lymphedema(28), and angiosarcoma complicating elephantiasis (29).
Angiosarcomas arising in areas of lymphedema have been designated lymphangiosa-
rcomas on the presumption that the neoplasms originated from dilated lymphatic vessels.
However, this assertion has not been definitively proved, and immunohistochemical and
ultrastructural studies support a hemangiomatous differentiation. Therefore at this time
the term angiosarcoma is justified for neoplasms that develop in lymphedematous
areas (30).
More than 90% of all angiosarcomas associated with chronic lymphedema occur
following mastectomy for breast carcinoma (3). The mastectomy invariably includes
removal of the axillary lymph nodes, and in some patients, but not all, there is also the
antecedent of adjuvant radiotherapy to the affected area. The risk of developing angiosa-
rcoma in postmastectomy patients who have a survival of 5 years or more is approxi-
mately 0.5% (19). The interval between the mastectomy and the development of
angiosarcoma ranges from 1 to 30 years. The arm, most often the upper inner aspect, is
the most frequent site for early involvement. Less commonly, the tumor appears more
distally, on the elbow or on the forearm. In rare instances, postmastectomy angiosarcoma
has been reported in patients who have experienced little or no lymphedema.

C
LINICAL FEATURES
Clinically, these lesions appear as bruise-like areas or violaceous nodules superim-
posed on the brownish nonpitting edema of the affected limb (31) (Fig. 21). After the
appearance of the lesions, there is a rapid increase in their number and size, and they may
undergo ulceration. In advanced cases, they spread distally to the hands and proximally
to the chest wall. The clinical appearance and the histologic behavior of angiosarcomas
in lymphedematous extremities unassociated with mastectomy are essentially identical
to those of postmastectomy angiosarcoma.
H
ISTOPATHOLOGIC FEATURES
Angiosarcomas that originate in areas of chronic lymphedema exhibit similar histo-
pathologic features to those of angiosarcoma of the scalp and face (30,32). They appear
as irregular vascular spaces that form an intricate network of freely anastomosing vessels
containing erythrocytes with extensive dissection of collagen. Endothelial cell nuclei are
plump and hyperchromatic. Patchy lymphoid infiltrates are sometimes present around
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Chapter 9 / Malignant Neoplasms 259
Fig. 21. Cutaneous angiosarcoma associated with chronic postmastectomy lymphedema (Stewart-
Treves syndrome). (A) The entire upper extremity appears edematous, with multiple angiomatous
nodules. (B) In addition to the nodules, there are ill-delimited angiomatous plaques.
the newly formed vessels. In some cases, there is a verrucous epidermal hyperplasia,
presumably caused by lymphedema and the involvement of the papillary dermis (33).
From a histogenetic point of view, the relationship between chronic lymphedema and
angiosarcoma is enigmatic. Stewart and Treves, in their original report (1), postulated
that unknown carcinogens within lymphatic fluid, acting in a locus minoris resistentia ,
induced the neoplastic change, a view that was also held by other authors (2). More
recently, it has been suggested that the lymphedema modifies the biochemical or immu-
nologic status of the affected limb fostering, the development of angiosarcoma (5,14).
The notion that areas with chronic lymphedema are “immunologically privileged sites”

is supported by the observation that skin grafts survive for long periods when they are
transferred to lymphedematous extremities (20,21).
Immunohistochemical studies in cutaneous angiosarcomas developing in lymph-
edematous extremities have documented positivity for factor VIII-related antigen (8,34),
and ultrastructural examination has demonstrated the presence of pericytes and Weibel-
Palade bodies in some cases (7,8,35,36). These special studies are useful in establishing
a differential diagnosis between Stewart-Treves angiosarcoma and metastatic breast
carcinoma in a lymphedematous arm, since both entities may show similar clinical and
histopathologic features. In metastatic breast carcinoma, the neoplastic cells express
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260 Sangüeza and Requena / Pathology of Vascular Skin Lesions
immunoreactivity for cytokeratin owing to their epithelial nature, whereas factor VIII-
related antigen is negative (37).
T
REATMENT
Survival in angiosarcoma associated with lymphedema may be worse than in other
forms of cutaneous angiosarcoma. Woodward et al. (3) reported a mean survival time of
patients with angiosarcoma following mastectomy of 19 months, compared with 34
months for cutaneous angiosarcomas not related to lymphedema. Sordillo et al. (6)
reported a mean survival time of 31 months. A longer survival time has been reported in
patients initially treated with radical surgery, including limb disarticulation, or hindquar-
ter or forequarter amputation (30). Other studies have found no significant difference in
survival when cases initially treated with wide excision were compared with those treated
with amputation (38).
References
1. Stewart FW, Treves N. Lymphangiosarcoma in postmastectomy lymphedema. Cancer 1948;1:64–81.
2. Herrmann JB. Lymphangiosarcoma of the clinically edematous extremity. Surg Gynecol Obstet
1965;121:1107–15.
3. Woodward AH, Ivins JC, Soule EH. Lymphangiosarcoma arising in chronic lymphedematous extremi-
ties. Cancer 1972;30:562–72.

4. Taswell HF, Soule HE, Coventry MB. Lymphangiosarcoma arising in chronic lymphedematous
extremities. J Bone Joint Surg 1962;44A:277–94.
5. Schreiber H, Barry FM, Russell WC, Macon WL IV, Ponsky JL, Pories WJ. Stewart-Treves syndrome.
A lethal complication of postmastectomy lymphedema and regional immune deficiency. Arch Surg
1979;114:82–5.
6. Sordillo PP, Chapman R, Hajdu DI, Magill GB, Golbey RB. Lymphangiosarcoma. Cancer 1981;
48:1674–9.
7. Silverberg SG, Kay S, Koss LG. Postmastectomy lymphangiosarcoma: utrastructural observations.
Cancer 1971;27:100–8.
8. Kanitakis J, Bendalac A, Marchand C, et al. Stewart-Treves syndrome: a histogenetic (ultrastructural
and immunohistochemical) study. J Cutan Pathol 1986;13:30–9.
9. Hultberg BM. Angiosarcoma in chronically lymphedematous extremities: two cases of Stewart-Treves
syndrome. Am J Dermatopathol 1987;9:406–12.
10. Hildebrandt G, Mittag M, Gutz U, Kunze ML, Haustein UF. Cutaneous breast angiosarcoma after
conserving treatment of breast cancer. Eur J Dermatol 2001;11:580–3.
11. Chen KTK, Bauer V, Flam MS. Angiosarcoma in postsurgical lymphedema. An unusual occurrence in
a man. Am J Dermatopathol 1991;13:488–92.
12. Calnan J, Cowdell RH. Lymphangioendothelioma of the anterior abdominal wall: report of a case.
Br J Surg 1959;46:375–9.
13. Dubin HU, Creehan EP, Headington JT. Lymphangiosarcoma and congenital lymphedema of the
extremity. Arch Dermatol 1974;110:608–14.
14. Laskas JJ Jr, Shelley WB, Wood MG. Lymphangiosarcoma arising in congenital lymphedema. Arch
Dermatol 1975;111:86–9.
15. Mackezie DM. Lymphangiosarcoma arising in chronic congenital and idiopathic lymphedema. J Clin
Pathol 1971;24:524–9.
16. Merrick T, Erlandson RA, Hajdu SI. Lymphangiosarcoma of a congenitally lymphedematous extremity.
Arch Pathol 1971;91:365–71.
17. Muller R, Hajdu SI, Brenan MF. Lymphangiosarcoma associated with chronic filarial lymphedema.
Cancer 1987;59:179–83.
18. Alessi E, Sala F, Berti E. Angiosarcomas in lymphedematous limbs. Am J Dermatopathol 1986;8:371–8.

19. Shirger A. Postoperative lymphedema: etiologic and diagnostic factors. Med Clin North Am
1962;46:1045–50.
20. Stark RB, Dwyer EM, DeForest M. Effect of surgical ablation of regional lymph nodes on survival of
skin homographs. Ann NY Acad Sci 1960;87:140–5.
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Chapter 9 / Malignant Neoplasms 261
21. Lambert PB, Frank HA, Bellman S, et al. The role of the lymph trunks in the response to allogenic skin
transplants. Transplantation 1965;3:62–73.
22. Sordillo EM, Sordillo PP, Hadju SI, et al. Lymphangiosarcoma after filarial infection. J Dermatol Surg
Oncol 1981;7:235–9.
23. Baes H. Angiosarcoma in a chronic lymphedematous leg. Dermatologica 1967;134:331–6.
24. Sinclair SA, Sviland L, Natarajan S. Angiosarcoma arising in a chronically lymphoedematous leg. Br
J Dermatol 1998;138:692–4.
25. Simonetti V, Folgaresi M, Motolese A. Angiosarcoma of the lower leg in chronic lymphoedema. Acta
Derm Venereol 1999;79:251–2.
26. Azurdia RM, Guerin DM, Verbov JL. Chronic lymphoedema and angiosarcoma. Clin Exp Dermatol
1999;24:270–2.
27. Nakazono T, Kudo S, Matsuo Y, et al. Angiosarcoma associated with chronic lymphedema (Stewart-
Treves syndrome) of the leg: MR imaging. Skeletal Radiol 2000;29:413–6.
28. Azam M, Saboorian H, Bieligk S, Smith T, Molberg K. Cutaneous angiosarcoma complicating morbid
obesity. Arch Pathol Lab Med 2001;125:531–3.
29. Hallel-Haevy D, Yerushalmi J, Grunwald MH, Avinoach I, Halevy S. Stewart-Treves syndrome in a
patient with elephantiasis. J Am Acad Dermatol 1999;41:349–50.
30. Enzinger FM, Weiss SW. Malignant vascular tumors. In: Soft Tissue Tumors, 3rd ed. St. Louis, MO,
Mosby, 1995:641–77.
31. Bisceglia M, Attino V, D’Addeta C, Murgo R, Fletcher CD. Le sindrome di Stewart e Treves in fase
precoce: presentazione di due casi e revisione della letteratura. Pathologica 1996;88:483–90.
32. Cooper PH. Angiosarcomas of the skin. Semin Diagn Pathol 1987;4:2–17.
33. Diaz-Cascajo C, Weyers W, Borghi S, Reichel M. Verrucous angiosarcoma of the skin: a distinct variant
of cutaneous angiosarcoma. Histopathology 1998;32:556–61.

34. Capo V, Ozello L, Fenoglio CM, et al. Angiosarcomas arising in edematous extremities. Hum Pathol
1985;16:144–50.
35. McWilliam LJ, Harris M. Histogenesis of postmastectomy angiosarcoma: an ultrastructural study.
Histopathology 1985;9:331–43.
36. Kindblom L-G, Stenman G, Angervall L. Morphological and cytogenetic studies of angiosarcoma in
Stewart-Treves syndrome. Virchows Arch A Pathol Anat Histopathol 1991;419:439–45.
37. Hashimoto K, Hatsumoto M, Eto H, et al. Differentiation of metastatic breast carcinoma from Stewart-
Treves angiosarcoma. Arch Dermatol 1985;121:742–6.
38. Grobmyer SR, Daly JM, Glotzbach RE, Grobmyer AJ. Role of surgery in the management of
postmastectomy extremity angiosarcoma (Stewart-Treves syndrome). J Surg Oncol 2000;73:1182–8.
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8. RADIATION-INDUCED CUTANEOUS ANGIOSARCOMA
Postirradiation cutaneous angiosarcoma is a rare condition that has been described
following the use of radiotherapy for the treatment of diverse conditions. These include
cutaneous hemangiomas (1,2), acne (3), hand eczema (4), X-ray depilation for scalp
ringworm during childhood (5), and malignant neoplasms such as carcinoma of the
cervix (6–9), endometrium (10), ovary (11), and breast (12–26), Hodgkin’s disease (27),
penile squamous cell carcinoma (28), or peripheral primitive neuroectodermal tumor
(29). The ensuing angiosarcoma usually manifests after a long interval, ranging from 4
to 40 years (mean 23.3 years) when radiation therapy was administered for benign con-
ditions, and from 4 to 25 years (mean 12.3 years), for patients in whom radiation therapy
was used for malignant tumors. These differences are probably related to the higher
dosage and harder radiation in the group of patients with previous malignancy. Preexist-
ing radiodermatitis of the involved area has been described in some cases (3,8,15,30,31).
C
LINICAL FEATURES
The clinical appearance of postirradiation cutaneous angiosarcoma varies from case
to case. Diffuse infiltrative plaques (Fig. 22), papulo-nodules, and ulcerated lesions have
been described. All lesions occurred in the area of irradiation or its immediate vicinity,

and because most of the cases appeared following radiation for breast and genitourinary
malignant tumors, the chest wall and the lower abdominal wall are the sites most fre-
quently involved by postirradiation angiosarcomas. Most of these patients had no evi-
dence of lymphedema, suggesting that radiation is the most important etiologic factor.
H
ISTOPATHOLOGIC FEATURES
Postirradiation angiosarcoma shows a histopathologic picture similar to that of other
variants of cutaneous angiosarcoma (Fig. 23). In early lesions, neoplastic vessels infil-
trate collagen bundles of the entire thickness of the dermis and often extend to the
subcutaneous tissue. The endothelial cells lining these vessels show variable atypia, but
at least some have large hyperchromatic nuclei and protrude into the lumina of the
irregular vascular channels. Sometimes papillations lined by protuberant endothelial
cells are present. As the lesions become increasingly cellular, aggregations of epithelioid
neoplastic cells develop. In these aggregations, vacuoles within the cytoplasm of neo-
plastic cells are seen as an expression of primitive luminal differentiation. Mitotic figures
are frequently seen in the solid-appearing zones. A frequent finding is the presence of
lymphoid nodules in both the superficial and deep areas of the dermis. In the advancing
edges of these solid areas there are jagged vessels similar to those seen in earlier lesions
infiltrating between collagen bundles of the dermis.
Cutaneous angiosarcoma originating in irradiated areas of the skin should be distin-
guished histopathologically from the benign vascular proliferations arising in irradiated
skin (see Chapter 8, Subheading 15.), which have received different names in the litera-
ture, including lymphangiectases (32), benign lymphangiomatous papules (33), lym-
phangioma (34–44), atypical vascular lesions (45), benign lymphangioendothelioma
(46), or benign vascular proliferations in irradiated skin (47). Histopathologically, they
consist of relatively well-circumscribed vascular proliferations involving the dermis,
without extension to the subcutaneous fat, and they do not involve the epidermis. Most
lesions show irregular dilated vascular spaces, with a branching and anastomosing pat-
tern, and a lymphatic appearance in the superficial dermis. A discontinuous single layer
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Chapter 9 / Malignant Neoplasms 263
Fig. 22. (A) Angiosarcoma of the breast appeared after radiation for breast carcinoma. (B) Close-up
view showing the angiomatous appearance of the plaques of angiosarcoma.
of endothelial cells with spindled or flattened nuclei lines the vascular channels, and their
lumina appear empty. In many areas, adjacent vascular channels show a “back-to-back”
arrangement, with the two vascular lumina only separated by a thin layer of endothelial
cells. Numerous small papillary projections, also lined by a single layer of endothelial
cells, are seen projecting into the lumina of the dilated lymphatic vessels. The stroma of
the lesions consists of fibrillary collagen and numerous spindled or stellate fibroblasts.
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Chapter 9 / Malignant Neoplasms 265
In some cases, dense nodular infiltrates of lymphocytes with germinal centers are present
in the vicinity of the dilated vascular channels.
Furthermore, in contrast to well-differentiated angiosarcomas, benign vascular prolif-
erations in irradiated skin do not involve the subcutaneous tissue, and there is no substan-
tial cytologic atypia because the nuclei of endothelial cells lining the vascular channels
are monomorphous, with inconspicuous nucleoli and no mitotic figures. In contrast,
angiosarcomas may present with multiple layers of atypical endothelial cells lining ir-
regular vascular and anastomosing channels, the so-called piling-up phenomenon; this is
not seen in atypical vascular proliferations in irradiated skin.
T
REATMENT
In general, the prognosis for angiosarcoma originating in irradiated areas is poor (6),
although there are cases of radiation-induced low-grade cutaneous angiosarcomas with
multiple recurrences. However, they did not produce metastasis (11). Treatment consists
of radical surgery with wide margins of noninvolved tissue. The neoplasm usually extends
far beyond the clinically visible boundaries of the lesion, and metastases have already
developed by the time surgery is performed.

References
1. Caldwell JB, Ryan MT, Benson PM, James WD. Cutaneous angiosarcoma arising in the radiation site
of a congenital hemangioma. J Am Acad Dermatol 1995;33:865–70.
2. Cabo H, Cohen ES, Casas GJ, Allevato M, Woscoff A. Cutaneous angiosarcoma arising on the radiation
site of a congenital facial hemangioma. Int J Dermatol 1998;37:638–9.
3. Seo IS, Warner TFCS, Warren JS, Bennett JF. Cutaneous postirradiation sarcoma. Ultrastructural evi-
dence of pluripotential mesenchymal cell derivation. Cancer 1985;56:761–7.
4. Girard C, Johnson WC, Graham JH. Cutaneous angiosarcoma. Cancer 1970;26:868–83.
5. Stone NM, Holden CA. Postirradiation angiosarcoma. Clin Exp Dermatol 1997;22:46–7.
6. Goette EK, Detlefs RL. Postirradiation angiosarcoma. J Am Acad Dermatol 1985;12:922–6.
7. Maddox JC, Evans HL. Angiosarcoma of skin and soft tissue. A study of forty-four cases. Cancer
1981;48:1907–21.
8. Krasagakis K, Hettmannsperger U, Tebbe B, Garbe C. Cutaneous metastatic angiosarcoma with a lethal
outcome, following radiotherapy for a cervical carcinoma. Br J Dermatol 1995;133:610–4.
9. Kim MK, Huh SJ, Kim DY, et al. Secondary angiosarcoma following irradiation—case report and
review of the literature. Radiat Med 1998;16:55–60.
10. Paik HH, Komorowski R. Hemangiosarcoma of the abdominal wall following irradiation therapy of
endometrial carcinoma. Am J Clin Pathol 1976;66:810–4.
11. Chen TK, Goffman KD, Hendricks EJ. Angiosarcoma following therapeutic irradiation. Cancer
1979;44:2044–8.
12. Edeiken S, Russo DP, Knecht J, et al. Angiosarcoma after tylectomy and radiation therapy for carcinoma
of the breast. Cancer 1992;70:644–7.
13. Rubin E, Maddox WA, Mazur MT. Cutaneous angiosarcoma of the breast 7 years after lumpectomy and
radiation therapy. Radiology 1990;174:258–60.
14. Sessions SC, Smenk RD. Cutaneous angiosarcoma of the breast after segmental mastectomy and radia-
tion therapy. Arch Surg 1992;127:1362–3.
15. Stokkel MPM, Peterse HL. Angiosarcoma of the breast after lumpectomy and radiation therapy for
adenocarcinoma. Cancer 1992;69:2965–8.
Fig. 23. (Opposite page) Histopathologic features of postirradiation angiosarcoma of the breast.
(A) Scanning power shows dense cellular aggregates at the superficial dermis. (B) Higher

magnification demonstrates that these cellular aggregates are surrounding elongated, slit-like
vascular spaces. (C) Still higher magnification shows that neoplastic cells are pleomorphic, with
hyperchromatic nuclei and numerous mitotic figures.
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16. Moskaluk CA, Merino MJ, Danforth DN, Medeiros LJ. Low-grade angiosarcoma of the skin of the
breast: a complication of lumpectomy and radiation therapy for breast carcinoma. Hum Pathol
1992;23:710–4.
17. Bolin DJ, Lukas GM. Low-grade dermal angiosarcoma of the breast following radiotherapy. Am Surg
1996;62:668–72.
18. Autio P, Kariniemi AL. Angiosarcoma. A rare secondary malignancy after breast cancer treatment. Eur
J Dermatol 1999;9:118–21.
19. Majeski J, Austin RM, Fitzgerald RH. Cutaneous angiosarcoma in an irradiated breast after breast
conservation therapy for cancer: association with chronic breast lymphedema. J Surg Oncol
2000;74:208–12.
20. Cafiero EF, Gipponi M, Peressini A, et al. Radiation-associated angiosarcoma: diagnostic and therapeu-
tic implications: two cases reports and review of the literature. Cancer 1996;77:2496–502.
21. Cancellieri A, Eusebi V, Mambellin V, et al. Well-differentiated angiosarcoma of the skin following
radiotherapy. Pathol Res Pract 1991;187:301–6.
22. Givens SS, Ellerbroek NA, Butler JJ, et al. Angiosarcoma arising in an irradiated breast: a case report
and review of the literature. Cancer 1989;64:2214–6.
23. Marchal C, Weber B, de Lafontan B. Nine breast angiosarcomas after conservative treatment for breast
carcinoma: a survey from French comprehensive cancer centers. Int J Radiat Oncol Biol Phys
1999;44:113–9.
24. Otis CN, Peschel R, McKhann C et al. The rapid onset of cutaneous angiosarcoma after radiotherapy for
breast cancer. Cancer 1986;57:2130–4.
25. Parham DM, Fisher C. Angiosarcomas of the breast developing post radiotherapy. Histopathology
1997;31:189–95.
26. Shaikh NA, Beaconsfield T, Walker M, et al. Postirradiation angiosarcoma of the breast: a case report.
Eur J Surg Oncol 1988;14:449–51.

27. Richards PG, Bessell EM, Goolden AWG. Spinal extradural angiosarcoma occurring after treatment for
Hodgkin’s disease. Clin Oncol 1983;9:165–8.
28. Prescott RJ, Mainwaring AR. Irradiation-induced penile angiosarcoma. Postgrad Med J 1990;66:576–9.
29. Coffin CM, Vietti TJ, Land VJ, et al. Cutaneous angiosarcoma as a second malignant neoplasm after
peripheral primitive neuroectodermal tumor. Med Pediatr Oncol 1992;20:352–6.
30. Hodgkinson DJ, Soule EH, Woods JE. Cutaneous angiosarcoma of the head and neck. Cancer
1979;44:1106–13.
31. Calnan J, Cowdell RH. Lymphangioendothelioma of the anterior abdominal wall: report of a case. Br J Surg
1959;46:375–9.
32. Ambrojo P, Fernández-Cogolludo E, Aguilar A, et al. Cutaneous lymphangiectases after therapy for
carcinoma of the cervix: a case with unusual clinical and histological features. Clin Exp Dermatol
1990;15:57–9.
33. Díaz-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.
34. Fisher I, Orkin M. Acquired lymphangioma (lymphangiectasis). Arch Dermatol 1970;101:230–4.
35. Gianelli V, Rockley PF. Acquired lymphangiectases following mastectomy and radiation therapy.
Report of a case and review of the literature. Cutis 1996;58:276–8.
36. Handfield-Jones SE, Prendville WJ, Norman S. Vulval lymphangiectasia. Genitourin Med 1989;65:335–7.
37. Harwood CA, Mortimer PS. Acquired vulvar lymphangiomata mimicking genital warts. Br J Dermatol
1993;129:334–6.
38. Kennedy CTC. Lymphangiectasia of the vulva following hysterectomy and radiotherapy. Br J Dermatol
1990;123(suppl. 37):92–3.
39. Kurwa A, Waddinton E. Post mastectomy lymphangiomatosis. Br J Dermatol 1968;80:840.
40. 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.
41. Leshin B, Whitaker D, Foucar E. Lymphangioma circumscriptum following mastectomy and radiation
therapy. J Am Acad Dermatol 1986;15:1117–9.
42. Plotnick H, Richfield D. Tuberous lymphangiectatic varices secondary to radical mastectomy. Arch
Dermatol Syphilol 1956;74:466–8.

43. Prioleau PG, Santa Cruz DJ. Lymphangioma circumscriptum following radical mastectomy and radia-
tion therapy. Cancer 1978;42:1989–91.
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Chapter 9 / Malignant Neoplasms 267
44. Young AW Jr, Wind RM, Tovell HM. Lymphangioma of vulva: acquired following treatment for
cervical cancer. NY State J Med 1980;80:987–9.
45. Finenberg S, Rosen PP. Cutaneous angiosarcoma and atypical vascular lesions of the skin and breast
after radiation therapy for breast carcinoma. Am J Clin Pathol 1994;102:757–63.
46. Rosso R, Gianelli U, Carnevali L. Acquired progressive lymphangioma of the skin following radio-
therapy for breast carcinoma. J Cutan Pathol 1995;22:164–7.
47. Requena L, Kutzner H, Mentzel T, Durán R, Rodríguez-Peralto JL. Benign vascular proliferations in
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9. EPITHELIOID ANGIOSARCOMA
CLINICAL FEATURES
This is a rare variant of the cutaneous angiosarcoma recently described (1–7). Clini-
cally, lesions of cutaneous epithelioid angiosarcoma are indistinguishable from conven-
tional angiosarcoma (Fig. 24). Perhaps the preferential location of these lesions on the
lower extremities is the only distinctive clinical feature, although lesions on the scalp and
face have also been described (1,5). Radiation exposure (3), a reaction to a foreign body
(7), and chronic immunosuppression in the setting of renal transplantation (8) have been
implicated as possible causes.
H
ISTOPATHOLOGIC FEATURES
Histopathologically, cutaneous epithelioid angiosarcoma mimics an epithelial neo-
plasm. The tumor is composed of sheets of rounded epithelioid cells with a large cyto-
plasm, vesicular nuclei, and prominent nucleoli (Fig. 25). Areas of irregular vascular
channels lined by atypical endothelial cells that dissect the collagen bundles are not
prominent, but the finding of such areas has high diagnostic value. In some areas, epithe-

lioid cells exhibit cytoplasmic vacuoles as an expression of primitive luminal differen-
tiation. Immunohistochemistry corroborates the vascular nature of this epithelioid
neoplasm because expression of factor VIII-related antigen, Ulex europaeus I lectin,
CD31, and CD34 have been documented in examples of cutaneous epithelioid angiosa-
rcoma (1–5). However, these tumors also consistently express cytokeratins (3–6,9),
attributable to the abundance of intracytoplasmic intermediate filaments in neoplastic
cells, and this phenomenon may result in the misinterpretation of this type of angiosar-
coma as carcinoma. Ultrastructural studies have documented a prominent cytoskeleton
of intermediate filaments, numerous pinocytotic vesicles, and scarce (1,3) or no (2,5,7)
Weibel-Palade bodies in neoplastic cells of cutaneous epithelioid angiosarcoma.
Fig. 24. Clinical features of epithelioid angiosarcoma. Erythematous nodules with angiomatous
appearance.
Fig. 25. (Opposite page) Histopathologic features of epithelioid angiosarcoma. (A) Low power
shows a cellular proliferation involving the entire dermis. (B) Higher magnification demonstrates
solid aggregations of neoplastic cells with some inconspicuous vascular lumina. (C) Still higher
magnification demonstrates that neoplastic cells have an epithelioid appearance, and many of
them exhibit prominent vacuolization of their cytoplasm as an expression of primitive luminal
differentiation.
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Chapter 9 / Malignant Neoplasms 269
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270 Sangüeza and Requena / Pathology of Vascular Skin Lesions
TREATMENT
Wide surgical excision of the neoplasm is necessary. Despite claims of a better prog-
nosis for this variant of cutaneous angiosarcoma (2), these have a highly aggressive
course, and most of the patients develop widespread metastatic disease within a year of
presentation (3).
References
1. Perez Atayde AR, Achenbach H, Lack EE. High-grade epithelioid angiosarcoma of the scalp. An
immunohistochemical and ultrastructural study. Am J Dermatopathol 1986;8:411–8.

2. Marrogi AJ, Hunt SJ, Santa Cruz DJ. Cutaneous epithelioid angiosarcoma. Am J Dermatopathol
1990;12:350–6.
3. Fletcher CDM, Beham A, Bekir S, Clarke AMT, Marley NJE. Epithelioid angiosarcoma of deep soft tissue:
a distinctive tumor readily mistaken for an epithelial neoplasm. Am J Surg Pathol 1991;15:915–24.
4. Maiorana A, Fante R, Fano RA, Collina G. Epithelioid angiosarcoma of the buttock. Case report with
immunohistochemical study on the expression of keratin polypeptides. Surg Pathol 1991;4:325–32.
5. Prescott RJ, Banerjee SS, Eyden BP, Haboubi NY. Cutaneous epithelioid angiosarcoma: a clinicopatho-
logical study of four cases. Histopathology 1994;25:421–9.
6. McCluggage WG, Clarke R, Toner PG. Cutaneous epithelioid angiosarcoma exhibiting cytokeratin
positivity. Histopathology 1995;27:291–4.
7. Jennings TA, Peterson L, Axiotis CA, Friedlaender GE, Cooke RA, Rosai J. Angiosarcoma associated
with foreign body material. Cancer 1988; 62:2436–44.
8. Wehrli BM, Janzen DL, Shokeir O, Masri BA, Byrne SK, O’Connell JX. Epithelioid angiosarcoma
arising in a surgically constructed arteriovenous fistula: a rare complication of chronic immuno-
ssuppression in the setting of renal transplantation. Am J Surg Pathol 1998;22:1154–9.
9. Ng WK, Collins RJ, Law D, Gwi E. Cutaneous epithelioid angiosarcoma: a potential diagnostic trap for
cytopathologists. Diagn Cytopathol 1997;16:160–6.
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Chapter 9 / Malignant Neoplasms 271
10. MALIGNANT GLOMUS TUMOR (GLOMANGIOSARCOMA)
Glomangiosarcomas are exceptionally rare, to the point that some authors doubt their
existence. The most controversial issue is the recognition and acceptance of malignant
glomus tumors in which no benign component is present. In the literature there are only
a few reports of this neoplasm (1–14). The first report of a malignant variety of glomus
tumor (MGT) was by Lumley and Stansfeld in 1972 (1). A year later, Anagnostou et al. (15)
identified 1 MGT in a series of 20 subcutaneous glomus tumors studied. In most instances,
there was no recurrence of the tumor, and the few recurrences were usually classified as
locally infiltrating glomus tumors with indistinct capsular borders (4,5,7).
C
LINICAL FEATURES

The lesions of glomangiosarcomas are larger and deeper than conventional glomus
tumors, and they are predominantly located on the extremities, where they appear as
subcutaneous masses. The tumors affect men and women equally (12). Metastatic disease
has been documented in only 10 cases of histopathologically defined MGT, and in 8 of
these patients, death was a consequence of the widespread metastases from the
glomangiosarcoma (6,10,12). Locally aggressive behavior appears to be more common
in these neoplasms.
H
ISTOPATHOLOGIC FEATURES
There are three proposed categories for malignant glomus tumors: (1) locally infiltra-
tive glomus tumor—these are neoplasms that lack atypical features but show locally
aggressive behavior (LIGT); (2) glomangiosarcomas that result from the transformation
of a glomus tumor (GABG)—these are the most common type of MGT, and remaining
areas of typical GT can be identified (Fig. 26); and (3) de novo glomangiosarcoma
(GADN), the most unusual form of MGT (4).
In the second group, there are sarcomatous areas intermingled with areas of benign
glomus tumor. In these cases it is important to identify the benign component, as it is the
most important clue to the diagnosis of glomangiosarcoma. The malignant areas appear
as poorly circumscribed and infiltrative neoplasms composed of fascicles of spindle cells
or aggregations of round glomoid cells with nuclear pleomorphism, frequent mitotic
figures, and foci of necrosis en masse. In some neoplasms, there is a peculiar arrangement
of neoplastic cells, with small round glomus cells at the periphery and central areas of
spindle cells (12). A diagnosis of glomangiosarcoma should be not misconstructed in
cases of long-standing glomus tumors, in which it is possible to see glomus cells with
large hyperchromatic nuclei, probably as result of degenerative changes similar to those
seen in ancient schwannoma. Some authors have proposed the name symplastic glomus
tumor for these benign glomus tumors with nuclear atypia (12).
In the absence of the benign glomus tumor component, the diagnosis of glomangio-
sarcoma nearly always presupposes the use of immunohistochemistry. Immunohis-
tochemical studies in cases of glomangiosarcoma have demonstrated immunoreactivity

of neoplastic cells for vimentin, collagen type IV, muscle-specific actin, and smooth
muscle actin, whereas neuron-specific enolase, desmin, Leu-7, CD34, and S-100 protein
positivities are detected focally in only some cases (2,12). Some neoplastic cells express
caldesmon and calponin (12). Factor VIII-related antigen was negative in neoplastic cells
(3). In one example of a glomangiosarcoma derived from a benign glomus tumor, immu-
nohistochemical studies demonstrated that bcl-2, an inhibitor of apoptosis, was strongly
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Chapter 9 / Malignant Neoplasms 273
expressed in the glomangiosarcoma areas, with only weak staining in the benign areas.
The proliferation index of glomangiosarcoma was almost 10-fold higher than that of the
benign glomus tumor. Numerous nuclei of glomangiosarcoma were intensely stained for
the tumor suppressor protein p53 (11). Ultrastructural studies (2,3) have demonstrated
that neoplastic cells of glomangiosarcoma show prominent nucleoli, poorly developed
organelles, and some bundles of tonofilaments. Micropinocytotic vesicles have also been
identified in some cases (3).
Histopathologically the differential diagnosis of glomangiosarcoma includes nodular
hidradenoma, leiomyosarcoma, and hemangiopericytoma. Nodular hidradenomas are
neoplasms with sweat gland differentiation that are usually well circumscribed. Leiomyo-
sarcomas are usually poorly circumscribed, large, asymmetrical neoplasms with muscle
differentiation. Hemangiopericytomas are composed of branching vessels of variable
size and shape, which give the neoplasm a characteristic “staghorn” configuration.
T
REATMENT
Complete removal by surgical excision is essential if local recurrence and eventual
metastasis are to be avoided. Wide excision of the lesion has been found to be adequate
therapy.
References
1. Lumley JSP, Stansfeld AG. Infiltrating glomus tumour of lower limb. BMJ 1972;1:484–5.

2. Aiba M, Hirayama A, Kuramochi S. Glomangiosarcoma in a glomus tumor. An immunohistochemical
and ultrastructural study. Cancer 1988;61:1467–71.
3. Gould EW, Manivel JC, Albores-Saavedra J, Monforte H. Locally infiltrative glomus tumors and
glomangiosarcomas. A clinical, ultrastructural, and immunohistochemical study. Cancer 1990;65:310–8.
4. Noer H, Krogdahl A. Glomangiosarcoma of the lower extremity. Histopathology 1991;18:365–6.
5. Watanabe K, Hoshi N, Tsu-Ura Y, et al. A case of glomangiosarcoma. Fukushima J Med Sci 1995;41:
71–7.
6. Brathwaite CD, Poppiti RJ Jr. Malignant glomus tumor. A case report of widespread metastases in a
patient with multiple glomus body hamartomas. Am J Surg Pathol 1996;20:233–8.
Fig. 26. Malignant glomus tumor (glomangiosarcoma). (A) Low-power magnification shows a
large, asymmetric neoplasm involving the entire dermis. (B) The superficial part of the neoplasm
reveals vascular structures of a glomus tumor. (C) Other areas of the neoplasm demonstrate a
cellular neoplasm, composed of cuboidal cells with some degree of nuclear pleomorphism. (D) At
this power there are necrotic cells and an increased number of mitotic figures.
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274 Sangüeza and Requena / Pathology of Vascular Skin Lesions
7. Hiruta N, Kameda N, Tokudome T, et al. Malignant glomus tumor: a case report and review of the
literature. Am J Surg Pathol 1997;21:1096–103.
8. Wetherington RW, Lyle WG, Sangueza OP. Malignant glomus tumor of the thumb: a case report. J Hand
Surg [Am] 1997:22:1098–102.
9. López Rios F, Rodriguez Peralto JL, Castaño E, Ballestin C. Glomangiosarcoma of the lower limb: a case
report with a literature review. J Cutan Pathol 1997;24:571–4.
10. Watanabe K, Sugino T, Kusakabe T, Suzuki T. Glomangiosarcoma of the hip: report of a highly aggres-
sive tumour with widespread distant metastases. Br J Dermatol 1998;139:1097–1101.
11. Hegyi L, Cormack GC, Grant JW. Histochemical investigation into the molecular mechanisms of
malignant transformation in a benign glomus tumour. J Clin Pathol 1998;51:872–4.
12. Folpe AL, Fanburg-Smith JC, Mietinen M, Weiss SW. Atypical and malignant glomus tumors. Analysis
of 52 cases, with a proposal for the reclassification of glomus tumors. Am J Surg Pathol 2001;25:1–12.
13. Rodríguez-Justo M, Aramburu-González JA, Santoja C. Glomangiosarcoma of abdominal wall.
Virchows Arch 2001;438:418–20.

14. Kayal JD, Hampton RW, Sheehan DJ, Washington CV. Malignant glomus tumor: a case report and
review of the literature. Dermatol Surg 2001;27:837–40.
15. Anagnostou GD, Papademetriou DG, Toumazani MN. Subcutaneous glomus tumor. Surg Gyn Obstet
1973;136:45–50.
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Chapter 10 / Other Neoplasms 275
275
10
Other Cutaneous Neoplasms
With a Significant Vascular Component
CONTENTS
MULTINUCLEATE CELL ANGIOHISTIOCYTOMA
ANGIOFIBROMA
ANGIOLEIOMYOMA
ANGIOLIPOMA
CUTANEOUS ANGIOLIPOLEIOMYOMA
CUTANEOUS ANGIOMYXOMA
AGGRESSIVE ANGIOMYXOMA
Table 1 summarizes the cutaneous neoplasms with a significant vascular component
that are included in this section.
Table 1
Cutaneous Neoplasms
with a Significant Vascular Component
Multinucleate cell angiohistiocytoma
Angiofibroma
Angioleiomyoma
Angiolipoma
Cutaneous angiolipoleiomyoma
Cutaneous angiomyxoma
Aggressive angiomyxoma

1. MULTINUCLEATE CELL ANGIOHISTIOCYTOMA
CLINICAL FEATURES
Multinucleate cell angiohistiocytoma was first described by Smith and Wilson Jones
in 1985 (1). To our knowledge, 44 examples of this lesion have been reported in the
literature (1–18). The lesions develop more frequently in women than in men (ratio,
36:8). The age range of these patients was 24 to 75, with a mean of 56 years. The lesions
were most often located on the limbs, especially on the dorsal parts of the hands or wrists
(13 cases) and the thighs (4 cases), although lesions on the face (2–4,6,8) and chest (3)
have also been described. Bilateral lesions occurred in some patients (3), and a 24-year-
old man presented with generalized multinucleate cell angiohistiocytoma, with multiple
papules on the trunk and extremities (11).
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276 Sangüeza and Requena / Pathology of Vascular Skin Lesions
Clinically, multinucleate cell angiohistiocytoma is characterized by multiple dome-
shaped papules, from 2 to 15 mm in diameter and of an erythematous or violaceous color
(Fig. 1). The lesions appear grouped on an anatomic area, are usually asymptomatic, and
show slow progression over years without associated disease. One patient had a multinucle-
ate cell angiohistiocytoma that appeared clinically as a large cutaneous plaque (15), and
another patient with multinucleate cell angiohistiocytoma also had mycosis fungoides (16).
H
ISTOPATHOLOGIC FEATURES
Histopathologically, multinucleate cell angiohistiocytoma consists of a proliferation
of capillaries and venules involving the full thickness of the dermis. These vessels exhibit
round lumina surrounded by a sparse inflammatory infiltrate composed mainly of lym-
phocytes and plasma cells (5). Characteristically, there are multinucleated cells with
geometric shapes and scalloped or angulated cytoplasm sparsely scattered throughout the
lesion (Fig. 2). The collagen bundles tend to be slightly coarse and are arranged haphaz-
ardly or vaguely parallel to the skin surface. The overlying epidermis is often hyperplas-
tic(2,3). Immunohistochemical studies have demonstrated that cells lining the vascular
component of the lesion are clearly labeled with endothelial markers including factor

VIII-related antigen (2–4,9), PAL-E (2,4), EN4 (2), BMA120 (2–4), and Ulex europaeus
I lectin (3,4), whereas the mononuclear interstitial cells were positive for factor XIIIa
(3,4,9,12), lisozyme (3), and α1-antitrypsin (3) but were negative for MAC387 (3) and
S-100 protein (3). The multinucleated giant cells only labeled positively with vimentin
(3) . The lymphocytes present interstitially were predominantly T-lymphocytes (2–4,9).
Investigations for human herpesvirus-8 (HHV-8) in lesions of mutinucleate cell
angiohistiocytoma yielded negative results (18).
Ultrastructural studies have shown that the multinucleated cells of multinucleate cell
angiohistiocytoma exhibit characteristics of cells in transitional stages between activated
fibroblasts and fully developed multinucleated giant cells (2).
The main differential diagnosis of multinucleate cell angiohistiocytoma is with der-
matofibroma. Even though some authors believe that these are different entities (5), on
the basis of the clinical, histopathologic, immunohistochemical and ultrastructural char-
Fig. 1. Clinical appearance of multinucleate cell angiohistiocytoma. Multiple small papules with
an angiomatous appearance on the anterior thigh of an adult woman.
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Chapter 10 / Other Neoplasms 277
acteristics of multinucleate cell angiohistiocytoma, it is considered a histopathologic
variant of dermatofibroma with a prominent vascular component and peculiar multi-
nucleated cells. Furthermore, we have seen examples of stereotypical dermatofibroma
that showed focally histopathologic features of multinucleate cell angiohistiocytoma.
T
REATMENT
Multinucleate cell angiohistiocytoma is an entirely benign condition, and cases of
spontaneous regression of the lesions have been described (3,5). In some patients, mul-
tiple lesions were successfully treated with argon laser (7).
References
1. Smith NP, Wilson Jones E. Multinucleate cell angiohistiocytoma—a new entity [Abstract]. Br J Dermatol
1985;113(suppl 29):15.
2. Smolle J, Auboeck L, Gogg-Retzer I, Soyer HP, Kerl H. Multinucleate cell angiohistiocytoma: a clini-

copathological, immunohistochemical and ultrastructural study. Br J Dermatol 1989;121:113–21.
Fig. 2. (A) Low power shows a combination of dilated vascular spaces, mild fibrosis, and slight
hyperplasia of the epidermis. (B) At higher magnification, there are dilated vascular spaces and
multinucleated fibrocytes.
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278 Sangüeza and Requena / Pathology of Vascular Skin Lesions
3. Wilson Jones E, Cerio R, Smith NP. Multinucleate cell angiohistiocytoma: an acquired vascular anomaly
to be distinguished from Kaposi’s sarcoma. Br J Dermatol 1990;122:651–3.
4. Annesi G, Girolomo G, Gianetti A. Multinucleate cell angiohistiocytoma. Am J Dermatopathol
1992;14:340–4.
5. Shapiro PE, Nova MP, Rosmarin LA, Halperin AJ. Multinucleate cell angiohistiocytoma: a distinct
entity diagnosable by clinical and histologic features. J Am Acad Dermatol 1994;30:417–22.
6. Jones AC, Mullins D, Jimenez F. Multinucleate cell angiohistiocytoma of the upper lip. Oral Surg Oral
Med Oral Pathol 1994;78:743–7.
7. Kopera D, Smolle J, Kerl H. Multinucleate cell angiohistiocytoma: treatment with argon laser. Br J
Dermatol 1995;133:308–10.
8. Shields JA, Eagle RC Jr, Shields CL, Sohmer KK. Multinucleate cell angiohistiocytoma of the orbit. Am
J Ophthalmol 1995;120:402–3.
9. Cribier B, Gambini C, Rainero M, Grosshans E. Multinucleate cell angiohistiocytoma. A review and
report of four cases. Acta Derm Venereol 1995;75:337–9.
10. Duncan LM, Baden HP. Vascular papules on the dorsum of the hands. Multinucleate cell angio-
histiocytoma (MCAH). Arch Dermatol 1996;132:703.
11. Chang SN, Kim HS, Kim SC, Yang WI. Generalized multinucleate cell angiohistiocytoma. J Am Acad
Dermatol 1996;35:320–2.
12. Le Cam-Savin C, Dallot A, Chemaly P, Martin A, Choudat L, Amoroux J. Angiohistiocytome à cellules
multinuclées. A propos de six cas. Ann Pathol 1996;16:435–8.
13. Romiti R, Perniciaro C, White JW Jr. Multinucleate cell angiohistiocytoma. Cutis 1997;59:190–2.
14. Aloi F, Solaroli C, Tomasini C, Pippione M. Multinucleate cell angiohistiocytoma: a report of two cases.
J Eur Acad Dermatol Venereol 1998;11:51–4.
15. Issa AA, Lui H, Shapiro J, Trotter MJ. Plaque-type multinucleate cell angiohistiocytoma. J Cutan Med

Surg 1998;3:112–4.
16. Bader RS, Telang GH, Vonderheid EC. Multinucleate-cell angiohistiocytoma occurring in a patient with
mycosis fungoides. Cutis 1999;63:145–8.
17. Belgodere X, Wechsler J, Pasqualini G, Paoli M. Angiohistiocytome à cellules multinuclées. Ann
Dermatol Venereol 1999;126:431–2.
18. Sass U, Noel JC, Andre J, Simonart T. Multinucleate cell angiohistiocytoma: report of two cases with
no evidence of human herpesvirus-8 infection. J Cutan Pathol 2000;27:258–61.
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Chapter 10 / Other Neoplasms 279
2. ANGIOFIBROMA
CLINICAL FEATURES
Angiofibroma is considered by some authors to be a generic term encompassing
lesions described as fibrous papules of the nose, facial lesions of tuberous sclerosis,
pearly penile papules, oral fibromas, and perifollicular fibromas (1) . However, other
authors believe that at least some of these entities have enough distinguishing histopatho-
logic features to be considered distinct lesions (2–5). Still others believe there is an
angiofibromatous reactive pattern that is common to the lesions described under the
names of facial lesions of tuberous sclerosis, subungual and periungual fibromas, acquired
acral fibrokeratomas, fibrous papules of the nose, and pearly penile papules (6).
The angiofibromas of the face seen in patients with tuberous sclerosis consist of
several papules and nodules with a predilection for the butterfly area of the face and
nasolabial grooves (7) (Fig. 3). They develop in childhood and in many cases are the
presenting sign of the disease (8). Cases with unilateral agminated facial angiofibromas
have been considered as forme fruste or segmental expression of tuberous sclerosis
(9,10). Patients with tuberous sclerosis may also have angiofibromas in the genital region
(11). However, multiple angiofibromas are not exclusive to tuberous sclerosis and have
also been described in patients with neurofibromatosis type 2 (12) and in patients with
Fig. 3. Multiple facial angiofibromas in a patient with tuberous sclerosis.
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multiple endocrine neoplasia type 1 (MEN-1). This consists of a heritable tendency to
develop tumors of parathyroid, pituitary, and entero-pancreatic endocrine tissues and
results from a germline mutation in the MEN-1 gene (13–17). Solitary giant facial
angiofibroma can be seen in patients without any associated disease (18). Fibrous papule
of the nose is a fairly common lesion that occurs in adults nearly always as a solitary lesion
on the lower portion of the nose or on the adjacent skin of the face (1–5). It is usually
dome-shaped, firm, and small, not exceeding 5 mm in diameter (Fig. 4). In most cases,
it is skin-colored and clinically can be confused with a melanocytic nevus or a basal cell
carcinoma. Acral fibrokeratomas include lesions reported as acquired digital fibro-
keratomas (19–22), acquired periungual fibrokeratomas (23), and periungual fibromas
(Köenen tumors) of tuberous sclerosis (24). Pearly penile papules are persistent asymp-
tomatic, white papules, 1–3 mm in diameter, occurring circumferentially on the coronal
margin and sulcus of the penis (25,26). They are found in about 10% of young adult males
and are more common in the uncircumcised (25).
H
ISTOPATHOLOGIC FEATURES
Histopathologically, all these lesions share several features and have been thought by
some authors to represent hyperplasias of the papillary and adventitial dermis (27). The
common characteristic pattern of all these lesions consists of an increased number of
small blood vessels associated with perivascular and periadnexal fibrosis arranged con-
Fig. 4. Clinical appearance of a solitary angiofibroma. Small, dome-shaped papule close to the nose.
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Chapter 10 / Other Neoplasms 281
Fig. 5. Histopathologic features of angiofibroma. (A) Scanning power shows a well-circum-
scribed and exophytic lesion. (B) Dilated vascular structures are one of the main components of
the lesion. Distorted hair follicles, such as those seen in this particular case, are also frequent
findings. (C) Large bizarre fibroblasts, some of them multinucleated, are present in the stroma of
the lesion.
centrically in an onion skin-like fashion (6) (Fig. 5). The fibrous tissue usually contains
stellate fibroblasts, some of them multinucleated. Some of the features have been pro-

posed to be characteristic for the different lesions. Thus, bizarre cells in the dermis and
melanocytic hyperplasia at the dermoepidermal junction are seen more commonly in
fibrous papule of the nose; compact hyperkeratosis and vertical arrangement of thick
Fig. 5
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collagen bundles in acral fibrokeratomas and an absence of folliculosebaceous units in
pearly penile papules. Uncommon histopathologic variants of fibrous papule of the face
include fibrous papule with granular cells (28) and clear cell fibrous papule (29). Immu-
nohistochemical studies have shown that the large stellate fibroblastic cells that char-
acterize these lesions express factor XIIIa but not S-100 protein (30–34). α1-antitrypsin
and lysozyme were detected in one study (35). Factor XIIIa appears to be important in
the promulgation of the fibroplasias (30). Ultrastructural studies have suggested that the
stellate cells are fibroblastic or fibrohistiocytic (5,36,37).
T
REATMENT
Cutaneous angiofibromas are entirely benign lesions and may be removed by shave
excision and dermabrasion (38,39). Excellent cosmetic results have been reported in
facial angiofibromas of tuberous sclerosis managed with laser therapy (40–43).
References
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2. Pinkus H. Perifollicular fibromas. Pure periadnexal adventitial tumors. Am J Dermatopathol
1979;1:341–2.
3. Reed R. Fibrous papule of the face. Melanocytic angiofibroma. Am J Dermatopathol 1979;1:343–4.
4. McGibbon DH, Wilson Jones E. Fibrous papule of the face (nose). Fibrosing nevocytic nevus. Am J
Dermatopathol 1979;1:345–8.
5. Santa Cruz DJ, Prioleau PG. Fibrous papule of the face. An electron microscopic study of two cases. Am
J Dermatopathol 1979;1:349–52.
6. Weedon D. In: Symmers WSC, ed. The Skin. Edinburgh, Churchill Livingstone, 1992:25.
7. Sanchez NP, Wick MR, Perry HO. Adenoma sebaceum of Pringle: a clinicopathologic review, with a

discussion of related pathologic entities. J Cutan Pathol 1981;8:395–403.
8. Nickel WR, Reed WB. Tuberous sclerosis: special reference to the microscopic alterations in the cuta-
neous hamartomas. Arch Dermatol 1962;85:209–24.
9. Anliker MD, Dummer R, Burg G. Unilateral agminated angiofibromas: a segmental expression of
tuberous sclerosis. Dermatology 1997;195:176–8.
10. Garcia Muret MP, Pujol RM, de Moragas JM. Angiofibromes multiples et unilateraux de la face: forme
fruste de la sclerose tubereuse de Bourneville. Ann Dermatol Venereol 1998;125:325–7.
11. Nico MM, Ito LM, Valente NY. Genital angiofibromas in tuberous sclerosis: two cases. J Dermatol
1999;26:111–4.
12. Jaffe AT, Heyman WR, Schnur RE. Clustered angiofibromas on the ear of a patient with neurofibroma-
tosis type 2. Arch Dermatol 1998;134:760–1.
13. Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM, Turner M. Multiple facial angiofibro-
mas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol
1997;133:853–7.
14. Pack S, Turner ML, Zhuang Z, et al. Cutaneous tumors in patients with multiple endocrine neoplasia type
1 show allelic deletion of the MEN1 gene. J Invest Dermatol 1998;110:438–40.
15. Boni R, Vortmeyer AO, Pack S, et al. Somatic mutations of the MEN1 tumor suppressor gene detected
in sporadic angiofibromas. J Invest Dermatol 1998;110:539–40.
16. Hoang-Xuan T, Steger JW. Adult-onset angiofibroma and multiple endocrine neoplasia type I. J Am
Acad Dermatol 1999;41:890–2.
17. Sakurai A, Matsumoto K, Ikeo Y, et al. Frequency of facial angiofibromas in Japanese patients with
multiple endocrine neoplasia type 1. Endocr J 2000;47:569–73.
18. Stough DB, Metheny R. Giant angiofibroma without accompanying tuberous sclerosis. Cutis
1988;42:429–32.
19. Kint A, Baran R, De Keyser H. Acquired (digital) fibrokeratoma. J Am Acad Dermatol 1985;12:816–21.
20. Herman PS, Datnow B. Acquired (digital) fibrokeratomas. Acta Derm Venereol 1974;54:73–6.
21. Bart RS, Andrade R, Kopf AW, Leider M. Acquired digital fibrokeratomas. Arch Dermatol
1968;97:120–9.
22. Hare PJ, Smith PAJ. Acquired (digital) fibrokeratoma. Br J Dermatol 1969;81:667–70.
23. Cahn RL. Acquired periungual fibrokeratoma. Arch Dermatol 1977;113:1564–8.

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