Benign Vascular Proliferations in Irradiated Skin

Benign Vascular Proliferations in Irradiated Skin

Luis Requena, M.D., Heinz Kutzner, M.D., Thomas Mentzel, M.D.,Rafael Durán, M.D., and José Luis Rodríguez-Peralto, M.D.

Several types of cutaneous vascular proliferations have beendescribed in areas of irradiated skin, including both benignlesions, such as benign lymphangiomatous papules, atypicalvascular lesions, or benign lymphangioendothelioma, and ma-lignant neoplasms such as high-grade angiosarcomas. This re-port describes the clinicopathologic features of 15 cases ofdifferent types of benign cutaneous vascular proliferationsarisen within irradiated skin. All patients were female rangingin age from 33 to 72 years, and they had received postoperativeexternal radiotherapy for treatment of breast carcinoma (14cases) or ovarian carcinoma (one case). In those cases in whichthe latency interval period between radiotherapy and the devel-opment of the vascular lesion was known from the clinicalrecords, the latency interval period elapsed between radio-therapy and diagnosis of the vascular lesion ranged from 3 to20 years. The most common clinical presentation of the cuta-neous lesions consisted of papules, small vesicles, or erythem-atous plaques on the irradiated field. Histopathologically, mostlesions consisted of irregular dilated vascular spaces, with abranching and anastomosing pattern, thin walls, and lymphaticappearance involving the superficial dermis. A discontinuoussingle layer of endothelial cells with flattened nuclei lined thesevascular channels, and numerous small stromal papillary for-mations also lined by endothelial cells projected into the luminaof the dilated lymphatic vessels. These cases were classified asbenign lymphangiomatous papules or plaques. Two casesshowed different histopathologic findings because they con-sisted of poorly circumscribed and focally infiltrating irregularjagged vascular spaces involving the entire dermis and lined byinconspicuous endothelial cells. In some areas these irregularslit-like vascular spaces dissected collagen bundles of the der-mis. These cases were classified as atypical vascular prolifera-tions mimicking benign lymphangioendothelioma or patch-stage Kaposi’s sarcoma. All cases showed similar immunohis-tochemical findings and the endothelial cells lining the vascularspaces expressed immunoreactivity for CD31, but they stainedonly focally positive for CD34 or were negative for this marker.Immunohistochemical investigations for �-smooth muscle ac-tin failed to demonstrate a complete peripheral ring of actin-positive pericytes in most of the neoformed vascular structures.

This immunohistochemical profile also supported the lym-phatic nature of these vascular proliferations developed in ir-radiated skin. Although some of these lesions may mimic his-topathologically patch-stage Kaposi’s sarcoma or well-differentiated angiosarcoma, the follow-up of the patients ofthis series demonstrated that the vascular proliferations arisenin irradiated skin invariably showed a benign biologic behavior.Key Words: Benign lymphangiomatous papules—Atypicalvascular proliferations—Benign lymphangioendothelioma—Kaposi’s sarcoma—Angiosarcoma—Radiotherapy.

Am J Surg Pathol 26(3): 328–337, 2002.

The occurrence of vascular proliferations arisen inpreviously irradiated areas of the skin is well known.These cutaneous vascular proliferations after radio-therapy include both benign lesions, such as benignlymphangiomatous papules,1,10,13,15,21,22,25,27,28,30,38,40,55

atypical vascular lesions,12 or benign lymphangioendo-thelioma (also named acquired progressive lymphangio-ma),44 and malignant neoplasms such as high-grade an-giosarcomas.2,3,5,7,9,11,12,16,17,20,31,34–37,39,45–47,49 Thesevascular lesions appear within the field of radiationtherapy, and the latency interval time elapsed betweenradiotherapy and the onset of the cutaneous lesions isusually of several years. Some of the benign lesions,such as atypical vascular proliferations12 and benignlymphangioendothelioma,44 may mimic histopathologi-cally patch-stage Kaposi’s sarcoma or well-differentiatedangiosarcoma and thus may cause problems in the his-topathologic differential diagnosis.

In this study 15 patients with several types of benignvascular proliferations arisen within the area of irradiatedskin were investigated from clinical, histopathologic, andimmunohistochemical standpoints. Benign lymphangi-omatous papules and plaques were the most commonlesions. Prominent intravascular papillary projectionslined by endothelial cells were seen in some of the di-lated lymphatic vessels. Other patients showed moreatypical vascular proliferations mimicking benign lym-phangioendothelioma, patch-stage Kaposi’s sarcoma, orDabska’s tumor in miniature. This report expands the

From the Department of Dermatology (L.R.), Fundación Jiménez Díaz,Universidad Autónoma, Madrid, Spain; DermatohistopathologischesGemeinschaftslabor (H.K., T.M.), Friedrichshafen, Germany; theDepartment of Pathology (R.D.), Hospital de Elda, Alicante, andthe Department of Pathology (J.L.R.-P.), Hospital 12 de Octubre,Universidad Complutense, Madrid, Spain.

Address correspondence and reprint requests to Luis Requena, MD,Department of Dermatology, Fundación Jiménez Díaz, Avda. ReyesCatólicos 2, 28040-Madrid, Spain; e-mail: [email protected]

The American Journal of Surgical Pathology 26(3): 328–337, 2002 © 2002 Lippincott Williams & Wilkins, Inc., Philadelphia

328

histopathologic spectrum of vascular proliferationsarisen within previously irradiated skin.

MATERIALS AND METHODS

Fifteen cases of cutaneous vascular proliferationsarisen in areas of previously irradiated skin were re-trieved from the files of DermatohistopathologischesGemeinschaftslabor, Friedrichshafen, Germany (10cases), the Department of Dermatology, FundaciónJiménez Díaz, Universidad Autónoma, Madrid, Spain(three cases), the Department of Pathology, Hospital 12de Octubre, Universidad Complutense, Madrid, Spain(one case), and the Department of Pathology, Hospital deElda, Alicante, Spain (one case). Clinical informationwas obtained from the hospital records or laboratory re-quest forms. The following data were recorded, if avail-

able, for each patient: age, sex, primary disease, timelatency interval elapsed between radiotherapy and diag-nosis of the vascular lesion, clinical appearance, and lo-cation of the lesions. Where possible, follow-up infor-mation was obtained from the laboratory request formsand referring dermatologists or pathologists.

For conventional light microscopy, tissue was fixed in4% formalin, embedded in paraffin wax, and cut andstained with hematoxylin and eosin. For immunohisto-chemical studies representative sections of 10 caseswere examined by the alkaline phosphatase anti-alkalinephosphatase technique using appropriate positive andnegative controls throughout. Automated immunostain-ing was performed on a BioTek Solutions Tech Mate(TechMate 500, Biotech Solutions, Dako, Glostrup, Den-mark). The following antibodies were used: CD31(JC/70A, 1:30, Dako, Hamburg, Germany), CD34

TABLE 1. Clinical data of the patients with benign vascular proliferations within irradiated skin

Caseno.

Age (y)/sex

Primarydisease

Latencyinterval (y)*

Clinicalpresentation Site Treatment

Histopathologicfindings Follow-up (mo)

1 72/F Breastcarcinoma

20 Two papules Axillaryfold

Localexcision

BLAPa NERM 6 moafter diagnosis

2 — Breastcarcinoma

10 Two papules Chestwall

BLAPa, nodularlymphocyticinfiltrates

NERM 13 yafter diagnosis


– Single papule Chestwall

Localexcision

BLAPa, nodularlymphocyticinfiltrates



– Erythematousplaque

Chestwall

Localexcision

BLAPl NERM 4 yafter diagnosis


– Several papules Chestwall

Localexcision



11 Several papules Chestwall

Localexcision

BLAPa in upperareas, atypicalvascular proliferationin deeper areas



6 Several papules Chestwall

Localexcision

BLAPa NERM 2 yafter diagnosis

8 61/F Ovariancarcinoma

– Erythematousplaque withoverlyingpapular lesions

Inguinalarea

Localexcision

BLAPa NERM 1 y afterdiagnosis


3 Single papule Chestwall

Localexcision

BLAPl NERM 6 moafter diagnosis


– Single papule Chestwall

Localexcision




Localexcision

Atypical vascularproliferation withendothelial tufts



12 Single papule withappearance ofdermatofibroma

Chestwall

Localexcision

Atypical vascularproliferation




Localexcision

BLAPa NERM 4 yafter diagnosis


6 Erythematousplaque

Chestwall

Biopsy BLAPl NERM 1 y afterdiagnosis


14 Singlepedunculatedlesion

Chestwall

Localexcision

BLAPa in upperareas, atypicalvascular proliferationin deeper areas

NERM 1 y afterdiagnosis

* Latency interval refers to the time elapsed between radiotherapy and diagnosis of the vascular lesion.BLAPa, benign lymphangiomatous papule; BLAPl, benign lymphangiomatous plaque; NERM, no evidence of recurrence or metastatic

disease.

BENIGN VASCULAR PROLIFERATIONS 329

Am J Surg Pathol, Vol. 26, No. 3, 2002

(HPCA-1, 1:100, Becton-Dickinson, San Jose, CA,USA), �-smooth muscle actin (1A4, 1:80, Dako), andKi67 (MIB-1, 1:100, Dako).

RESULTSClinical Findings

Table 1 summarizes the clinical data of the 15 patients.Briefly, all of them were female. Fourteen patients had ahistory of breast carcinoma, and one (case no. 8) had anovarian carcinoma. Age range of the patients was 33–72years (median 52 years). All patients with breast carci-noma underwent partial or radical mastectomy, and anovarian carcinoma was excised in case no. 8. All patientsreceived postoperative external radiotherapy. In thosecases in which the latency interval period between ra-diotherapy and the development of the vascular lesionwas known from the clinical records (10 cases), the la-tency interval period elapsed between radiotherapy anddiagnosis of the vascular lesion ranged from 3 to 20 years(median 9 years). All lesions were located on the anteriorchest wall, except those of the case no. 8, who receivedradiotherapy for ovarian carcinoma and the cutaneouslesions appeared on the inguinal area. The most commonclinical presentation of the cutaneous lesions consisted ofpapules, small vesicles, or erythematous plaques on theirradiated field (Fig. 1). Case no. 12 showed a singlepapule that was clinically considered as dermatofibroma.

FIG. 1. Clinical appearance of the lesions. (A) Papules orsmall vesicles. (B) Erythematous plaques on the irradi-ated field.

FIG. 2. Case no. 1. (A) A dome-shaped, exophytic lesion projecting over the skin surface in a case of benign lymphan-giomatous papule. (B) Irregular dilated vascular spaces, with a branching and anastomosing pattern, thin walls, andlymphatic appearance, were seen in the superficial dermis. (C) A discontinuous single layer of endothelial cells withspindled or flattened nuclei lined these vascular channels and their lumina appeared empty. (D, E, and F) Immunohisto-chemical demonstration of CD31 immunoreactivity of endothelial cells lining the vascular structures. (G, H, and I) Immu-nohistochemical study for �-smooth muscle actin antibody demonstrated that the dilated vessels lacked a peripheral ringof actin-positive pericytes. Note the actin-positive internal control of the smooth muscle fibers of the arrector pili musclein the deeper dermis in G and the walls of the adjacent capillary blood vessels containing erythrocytes within their luminain I.

L. REQUENA ET AL.330

Only one patient (case no. 3) showed clinical evidence oflymphedema in the left arm. In all cases the lesions wereremoved by local excision. In each patient a single lesionwas histopathologically studied, except case no. 2 withtwo lesions excised and case no. 8 from whom five le-sions were removed. Follow-up ranged from 0.5 to 13

years (median 3.4 years), and none of the patients devel-oped recurrent lesions or metastatic disease.

Histopathologic Features

At low power all lesions appeared as relatively well-circumscribed vascular proliferations involving the der-

FIG. 3. Case no. 4. (A) A benign lymphangiomatous plaque mimicking benign lymphangioendothelioma. (B) Irregular,thin-walled, endothelium lined dilated vascular spaces involving the dermis. (C) These vascular channels showed jaggedlumina lined by a single layer of endothelial cells and in some areas dissected the collagen bundles of the dermis. (D, E,and F) Immunohistochemical demonstration of the CD31 positivity of the endothelial cells lining the vascular channels.



mis, without extension to the subcutaneous fat. The epi-dermis was normal. Eight lesions presented as dome-shaped, exophytic papules projecting over the skinsurface (case nos. 1–3, 6–8, 13, and 15) (Fig. 2) and theother seven cases (case nos. 4, 5, 9–12, and 14) were flatwith a plaque-like morphology (Fig. 3). In most lesions(case nos. 1–10 and 13–15), irregular dilated vascularspaces, with a branching and anastomosing pattern, thinwalls, and lymphatic appearance, were seen in the su-perficial dermis (Figs. 2 and 3). A discontinuous singlelayer of endothelial cells with spindled or flattened nu-clei lined these vascular channels and their lumina ap-peared empty. In many areas adjacent vascular channels

showed a “back-to-back” arrangement, with the two vas-cular lumina separated only by a thin layer of endothelialcells. Numerous small papillary projections, also linedby a single layer of endothelial cells, projected into thelumina of the dilated lymphatic vessels. The papillaryprojections were especially prominent in case no. 13(Fig. 4). The stroma of the lesions consisted of fibrillarycollagen, numerous spindled or stellate fibroblasts, andin some cases abundant deposits of interstitial mucinbetween the dilated vascular channels. Two cases (casenos. 2 and 3) showed dense nodular infiltrates of lym-phocytes with germinal centers in the vicinity of thedilated vascular channels (Fig. 5). The stroma of one ofthe lesions of case no. 8 showed striking metaplasia ofmature adipocytes intermingled with the dilated vascularspaces (Fig. 6). All these cases were classified as benign

FIG. 4. Case no. 13. (A) A benign lymphangiomatouspapule showing an exophytic and pedunculated morphol-ogy with prominent intravascular papillary formations.(Large arrow indicates the area enlarged in B and C.Small arrow indicates the area enlarged in D and E). (B,C, D, and E) In some areas prominent papillary projec-tions of endothelial cells protruded within the lumina of thedilated lymphatic vessels.

FIG. 5. Case no. 2. (A) A benign lymphangiomatous pap-ule with dense nodular infiltrates of lymphocytes in thestroma. (B) Irregular dilated vascular channels with lym-phatic appearance. (C) Dense nodular infiltrates of lym-phocytes close to the dilated lymphatic vessels.



lymphangiomatous papules or benign lymphangioma-tous plaques.

Two lesions (case nos. 11 and 12) showed differenthistopathologic findings. They consisted of poorly cir-cumscribed and focally infiltrating irregular jagged vas-cular spaces involving the entire dermis, lined by incon-spicuous endothelial cells. In some areas these irregularslit-like vascular spaces dissected collagen bundles of thedermis. Erythrocytes were not seen in the lumina of thevascular channels, and a few lymphocytes were presentin the stroma. Case no. 11 also showed conspicuous tuftsof endothelial cells protruding into the lumens of neo-formed vessels. These striking endothelial tufts re-sembled those of Dabska’s tumor in miniature, althoughin contrast with authentic Dabska’s tumor, the endothe-lial tufts of this lesion had no connective tissue core andthey were grape-like papillary formations exclusivelycomposed of endothelial cells. Therefore, we classifiedthis lesion as atypical vascular proliferation with dab-skoid features (Fig. 7). Case no. 12 showed irregularjagged vascular spaces dissecting collagen bundles of thedermis and abundant interstitial hemosiderin deposits,mimicking patch-stage Kaposi’s sarcoma (Fig. 8). Casenos. 6 (Fig. 9) and 15 combined features of benignlymphangiomatous papules in the upper dermis andatypical vascular proliferations with focally infiltrativepattern in deeper dermis.

Immunohistochemical Findings

All cases showed similar immunohistochemical find-ings. Endothelial cells lining the vascular spaces ex-pressed immunoreactivity for CD31, but they stainedonly focally positive for CD34 or were negative for thismarker. Although a few vessels showed an attenuatedmuscle layer stained for �-smooth muscle actin antibodysurrounding the endothelial cells, this marker was essen-tially negative in most vascular structures. Ki67 stainedsome keratinocytic nuclei of the epidermal basal layer,but it was negative in the nuclei of the endothelial cellslining the vascular structures.

DISCUSSION

The histopathologic characteristics of these cases ofvascular proliferations arisen in irradiated skin werethose of lymphatic vessels because they consisted of di-lated vascular spaces with thin walls lined by a singlediscontinuous layer of flat endothelial cells and arrangedin a “back-to-back” fashion. Furthermore, the immuno-histochemical profile of the endothelial cells lining theneoformed vessels, which expressed immunoreactivityfor CD31, but not for CD34, and the absence of a pe-

ripheral ring of actin-positive pericytes, also supports alymphatic nature for these neoformed vessels. Benignlymphangiomatous papules and plaques seem to be themost common vascular lesions developed in areas of irra-diated skin. They have been erroneously named “lymphan-gioma circumscriptum” by some authors,28,30,40,55 butthis is an inaccurate term because lymphangioma cir-cumscriptum refers to localized malformations of lym-phatic vessels of the superficial dermis.42 Benign lymph-angiomatous papules and plaques are the lymphaticcounterpart of telangiectases, and they result from ac-quired permanent dilatation of lymphatic capillaries.They may appear in areas of skin affected by obstruction

FIG. 6. Case no. 8. (A) A benign lymphangiomatous pap-ule with prominent metaplasia of adipocytes in the stroma.(B) Mature adipocytes intermingled with dilated vascularspaces in the dermis. (C) The dilated vascular spacesshowed thin walls and empty lumina and were lined by asingle layer of endothelial cells.



or destruction of the lymphatic drainage and have beendescribed as a result of interference of lymphatic vesselssecondary to radiotherapy1,13,15,21,22,25,27,28,30,38,40,55 orsurgery.57 Benign lymphangiomatous papules andplaques, however, may also appear in the skin of elderlypersons without any evidence of secondary lymphaticdamage.4 Clinically, benign lymphangiomatous papulesarisen in areas of irradiated skin appear as multiple, per-sistent, translucent, thick-walled, whitish vesicles orsmall papules. Some lesions may have polypoid shapeand punction provokes the flow of a milky liquid. Benignlymphangiomatous plaques appear as erythematous flatareas of indurated skin. Histopathologically, both lesionsconsist of dilated lymphatic vessels positioned withinpapillary dermis, although some dilated lymphatic ves-sels may also be seen involving the reticular dermis. Thelumina of the dilated vessels show no contents or arefilled by homogeneous eosinophilic material, and theyare lined by a thin wall composed of a single discontinu-ous layer of endothelial cells. A striking histopathologicfeature in our cases consisted of the presence of promi-nent papillary projections of stroma lined by endothelialcells or tufts of endothelial cells without stroma axisprotruding within the lumina of the dilated lymphaticvessels. These intravascular papillary projections havebeen previously described in vascular proliferations ofirradiated skin10,12 as well as in lymphatic malforma-tions,26 and they are interpreted as the lymphatic coun-terpart of Masson’s intravascular papillary endothelialhyperplasia.26

The cases of this series classified as atypical vascularproliferations showed histopathologic similarities withbenign lymphangioendothelioma, also named acquiredprogressive lymphangioma, and with patch-stage Kaposi’ssarcoma. Indeed, a case of acquired progressive lymphan-gioma of the skin after radiotherapy has been previouslydescribed,44 although this case more likely represents anexample of postirradiation atypical vascular proliferation.Benign lymphangioendothelioma is a rare lymphatic neo-plasm originally described by Wilson Jones et al.53,54 Ap-proximately 40 cases of this uncommon neoplasm havebeen reported in the literature.6,18,19,23,24,32,33,41,48,50–54,56

Clinically, lesions of benign lymphangioendotheliomaappear as a solitary reddish or bruise-like slowly growingplaque that does not have a site of predilection. Histo-pathologically, benign lymphangioendothelioma is com-posed of delicate, thin-walled, endothelium-lined dilatedvascular spaces involving the superficial dermis. In someareas intravascular papillary stromal projections are pres-ent, resembling papillary endothelial hyperplasia. Asthe lesion descends within deeper dermis, the vascularspaces collapse and dissect the collagen bundles, mim-icking patch-stage Kaposi’s sarcoma, especially thelymphangioma-like variant of Kaposi’s sarcoma,8,14,29,43

and well-differentiated angiosarcoma. Preexisting ves-sels and adnexal structures of the dermis also appeardissected by the neoformed vascular channels. Thesevascular spaces appear empty or to contain proteinaceousmaterial. Erythrocytes and hemosiderin deposits arecharacteristically absent. The endothelial cells in the le-

FIG. 7. Case no. 11. (A)Atypical vascular proliferationwith dabskoid features in min-iature. (B) Poorly circum-scribed and focally infiltratingirregular jagged vascularspaces involving the entiredermis and lined by incon-spicuous endothelial cells. (C)In some areas conspicuoustufts of endothelial cells pro-truded into the lumina of neo-formed vessels. These endo-thelial tufts resembled those ofDabska’s tumor in miniature,although in contrast with au-thentic Dabska’s tumor, theendothelial tufts had no con-nective tissue core and theywere grape-like papillary for-mations exclusively composedof endothelial cells.



sional vessels are present in greater numbers than innormal lymphatic channels, and in some places they arecrowded together. However, no nuclear atypia is foundin the endothelial cells lining the cleft-like vessels. Incontrast with patch-stage Kaposi’s sarcoma, lesions ofbenign lymphangioendothelioma show no erythrocytesor hemosiderin deposits, and there are no plasma cells inthe stroma. With the exception of the case reported byRosso et al.,44 which probably is better interpreted as anexample of postradiotherapy atypical vascular prolifera-tion, no other examples of benign lymphangioendothe-lioma have been reported in irradiated skin. To the bestof our knowledge, the striking tufts of endothelial cells,seen in our case no. 11, which protruded within the ir-regular jagged vascular channels resembling the featuresof Dabska’s tumor in miniature, have not been previ-ously described in the vascular proliferations arisen inirradiated skin. Case no. 12 showed irregular jagged vas-cular channels and abundant hemosiderin deposits in thestroma, mimicking patch-stage Kaposi’s sarcoma. How-ever, in contrast with authentic Kaposi’s sarcoma, theso-called promontory sign that results from the dissec-tion of preexisting capillaries by the proliferating endo-thelial cells and an inflammatory infiltrate of plasmacells were not seen in case no. 12.

Histopathologic differential diagnosis between theatypical vascular proliferations in areas of irradiated skinalso includes well-differentiated angiosarcoma. In con-trast with angiosarcoma, atypical vascular proliferationsin irradiated skin do not involve the subcutaneous tissue,and there is not substantial cytologic atypia because thenuclei of endothelial cells lining the vascular channelsare monomorphous, with inconspicuous nucleoli and nomitotic figures. Another frequent histopathologic findingin angiosarcoma consists of the presence of multilayer-ing of atypical endothelial cells lining irregular vascularand anastomosing channels, the so-called piling-up phe-nomenon, and this feature is not seen in atypical vascularproliferations in irradiated skin. Usually, many nuclei ofneoplastic endothelial cells of angiosarcoma express pro-liferation markers such as Ki67, and this marker wasessentially negative in our cases. Furthermore, there isnot evidence that these atypical vascular proliferationsrepresent premalignant lesions for the development ofpostirradiation angiosarcoma, and the follow-up of ourpatients has demonstrated that these lesions have a be-nign biologic behavior.

In summary, vascular proliferations arisen in areasof irradiated skin comprise a wide spectrum of lesions.The most common lesions are benign lymphangioma-tous papules and plaques, but more atypical vascularproliferations resembling benign lymphangioendo-thelioma, patch-stage Kaposi’s sarcoma, and well-differentiated angiosarcoma may also appear. All thesevascular lesions arise within the field of irradiated skin

and usually appear after a latent period of several yearsafter radiotherapy. Although these vascular proliferationsin irradiated skin may raise problems in the histopatho-logic differential diagnosis with malignant vascularproliferations, they invariably show a benign biologicbehavior. �

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Benign Vascular Proliferations in Irradiated Skin

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