Benign Vascular Proliferations in Irradiated Skin

Home , Angioma, Angiosarcoma, Hemangioendothelioma, Lymphangiomatosis

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 been This immunohistochemical profile also supported the lym- described in areas of irradiated skin, including both benign phatic nature of these vascular proliferations developed in ir- lesions, such as benign lymphangiomatous papules, atypical radiated skin. Although some of these lesions may mimic his- vascular lesions, or benign lymphangioendothelioma, and ma- topathologically patch-stage Kaposi’s sarcoma or well- lignant neoplasms such as high-grade angiosarcomas. This re- differentiated angiosarcoma, the follow-up of the patients of port describes the clinicopathologic features of 15 cases of this series demonstrated that the vascular proliferations arisen different types of benign cutaneous vascular proliferations in irradiated skin invariably showed a benign biologic behavior. arisen within irradiated skin. All patients were female ranging Key Words: Benign lymphangiomatous papules—Atypical in age from 33 to 72 years, and they had received postoperative vascular proliferations—Benign lymphangioendothelioma— external radiotherapy for treatment of breast carcinoma (14 Kaposi’s sarcoma—Angiosarcoma—Radiotherapy. cases) or ovarian carcinoma (one case). In those cases in which the latency interval period between radiotherapy and the devel- Am J Surg Pathol 26(3): 328–337, 2002. opment of the vascular lesion was known from the clinical records, the latency interval period elapsed between radiotherapy and diagnosis of the vascular lesion ranged from 3 to 20 years. The most common clinical presentation of the cuta- The occurrence of vascular proliferations arisen in neous lesions consisted of papules, small vesicles, or erythem- previously irradiated areas of the skin is well known. atous plaques on the irradiated field. Histopathologically, most These cutaneous vascular proliferations after radio- lesions consisted of irregular dilated vascular spaces, with a branching and anastomosing pattern, thin walls, and lymphatic therapy include both benign lesions, such as benign 1,10,13,15,21,22,25,27,28,30,38,40,55 appearance involving the superficial dermis. A discontinuous lymphangiomatous papules, single layer of endothelial cells with flattened nuclei lined these atypical vascular lesions,12 or benign lymphangioendo- vascular channels, and numerous small stromal papillary for- thelioma (also named acquired progressive lymphangio- mations also lined by endothelial cells projected into the lumina ma),44 and malignant neoplasms such as high-grade an- of the dilated lymphatic vessels. These cases were classified as 2,3,5,7,9,11,12,16,17,20,31,34–37,39,45–47,49 benign lymphangiomatous papules or plaques. Two cases giosarcomas. These showed different histopathologic findings because they con- vascular lesions appear within the field of radiation sisted of poorly circumscribed and focally infiltrating irregular therapy, and the latency interval time elapsed between jagged vascular spaces involving the entire dermis and lined by radiotherapy and the onset of the cutaneous lesions is inconspicuous endothelial cells. In some areas these irregular usually of several years. Some of the benign lesions, slit-like vascular spaces dissected collagen bundles of the der- 12 mis. These cases were classified as atypical vascular prolifera- such as atypical vascular proliferations and benign 44 tions mimicking benign lymphangioendothelioma or patch- lymphangioendothelioma, may mimic histopathologi- stage Kaposi’s sarcoma. All cases showed similar immunohis- cally patch-stage Kaposi’s sarcoma or well-differentiated tochemical findings and the endothelial cells lining the vascular angiosarcoma and thus may cause problems in the his- spaces expressed immunoreactivity for CD31, but they stained topathologic differential diagnosis. only focally positive for CD34 or were negative for this marker. Immunohistochemical investigations for ␣-smooth muscle ac- In this study 15 patients with several types of benign tin failed to demonstrate a complete peripheral ring of actin- vascular proliferations arisen within the area of irradiated positive pericytes in most of the neoformed vascular structures. skin were investigated from clinical, histopathologic, and immunohistochemical standpoints. Benign lymphangi- From the Department of Dermatology (L.R.), Fundación Jiménez Díaz, omatous papules and plaques were the most common Universidad Autónoma, Madrid, Spain; Dermatohistopathologisches lesions. Prominent intravascular papillary projections Gemeinschaftslabor (H.K., T.M.), Friedrichshafen, Germany; the Department of Pathology (R.D.), Hospital de Elda, Alicante, and lined by endothelial cells were seen in some of the di- the Department of Pathology (J.L.R.-P.), Hospital 12 de Octubre, lated lymphatic vessels. Other patients showed more Universidad Complutense, Madrid, Spain. atypical vascular proliferations mimicking benign lym- Address correspondence and reprint requests to Luis Requena, MD, Department of Dermatology, Fundación Jiménez Díaz, Avda. Reyes phangioendothelioma, patch-stage Kaposi’s sarcoma, or Católicos 2, 28040-Madrid, Spain; e-mail: [email protected] Dabska’s tumor in miniature. This report expands the

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

Case Age (y)/ Primary Latency Clinical Histopathologic no. sex disease interval (y)* presentation Site Treatment findings Follow-up (mo)

1 72/F Breast 20 Two papules Axillary Local BLAPa NERM 6 mo carcinoma fold excision after diagnosis 2 — Breast 10 Two papules Chest BLAPa, nodular NERM 13 y carcinoma wall lymphocytic after diagnosis infiltrates 3 64/F Breast – Single papule Chest Local BLAPa, nodular NERM 5 y carcinoma wall excision lymphocytic after diagnosis infiltrates 4 44/F Breast – Erythematous Chest Local BLAPl NERM 4 y carcinoma plaque wall excision after diagnosis 5 49/F Breast – Several papules Chest Local BLAPl NERM 3 y carcinoma wall excision after diagnosis 6 62/F Breast 11 Several papules Chest Local BLAPa in upper NERM 3 y carcinoma wall excision areas, atypical after diagnosis vascular proliferation in deeper areas 7 62/F Breast 6 Several papules Chest Local BLAPa NERM 2 y carcinoma wall excision after diagnosis 8 61/F Ovarian – Erythematous Inguinal Local BLAPa NERM1yafter carcinoma plaque with area excision diagnosis overlying papular lesions 9 33/F Breast 3 Single papule Chest Local BLAPl NERM 6 mo carcinoma wall excision after diagnosis 10 44/F Breast – Single papule Chest Local BLAPl NERM 6 y carcinoma wall excision after diagnosis 11 70/F Breast 4 Single papule Chest Local Atypical vascular NERM 5 y carcinoma wall excision proliferation with after diagnosis endothelial tufts 12 54/F Breast 12 Single papule with Chest Local Atypical vascular NERM 2 y carcinoma appearance of wall excision proliferation after diagnosis dermatofibroma 13 68/F Breast 10 Single papule Chest Local BLAPa NERM 4 y carcinoma wall excision after diagnosis 14 67/F Breast 6 Erythematous Chest Biopsy BLAPl NERM1yafter carcinoma plaque wall diagnosis 15 58/F Breast 14 Single Chest Local BLAPa in upper NERM1yafter carcinoma pedunculated wall excision areas, atypical diagnosis lesion vascular proliferation in deeper areas

* 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. histopathologic spectrum of vascular proliferations able, for each patient: age, sex, primary disease, time arisen within previously irradiated skin. latency interval elapsed between radiotherapy and diagnosis of the vascular lesion, clinical appearance, and lo- MATERIALS AND METHODS cation of the lesions. Where possible, follow-up information was obtained from the laboratory request forms Fifteen cases of cutaneous vascular proliferations and referring dermatologists or pathologists. arisen in areas of previously irradiated skin were re- For conventional light microscopy, tissue was fixed in trieved from the files of Dermatohistopathologisches 4% formalin, embedded in paraffin wax, and cut and Gemeinschaftslabor, Friedrichshafen, Germany (10 stained with hematoxylin and eosin. For immunohisto- cases), the Department of Dermatology, Fundación chemical studies representative sections of 10 cases Jiménez Díaz, Universidad Autónoma, Madrid, Spain were examined by the alkaline phosphatase anti-alkaline (three cases), the Department of Pathology, Hospital 12 phosphatase technique using appropriate positive and de Octubre, Universidad Complutense, Madrid, Spain negative controls throughout. Automated immunostain- (one case), and the Department of Pathology, Hospital de ing was performed on a BioTek Solutions Tech Mate Elda, Alicante, Spain (one case). Clinical information (TechMate 500, Biotech Solutions, Dako, Glostrup, Den- was obtained from the hospital records or laboratory re- mark). The following antibodies were used: CD31 quest forms. The following data were recorded, if avail- (JC/70A, 1:30, Dako, Hamburg, Germany), CD34

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(HPCA-1, 1:100, Becton-Dickinson, San Jose, CA, USA), ␣-smooth muscle actin (1A4, 1:80, Dako), and Ki67 (MIB-1, 1:100, Dako).

RESULTS Clinical Findings Table 1 summarizes the clinical data of the 15 patients. Briefly, all of them were female. Fourteen patients had a history of breast carcinoma, and one (case no. 8) had an ovarian carcinoma. Age range of the patients was 33–72 years (median 52 years). All patients with breast carcinoma underwent partial or radical mastectomy, and an ovarian carcinoma was excised in case no. 8. All patients received postoperative external radiotherapy. In those cases in which the latency interval period between radiotherapy and the development of the vascular lesion was known from the clinical records (10 cases), the latency interval period elapsed between radiotherapy and diagnosis of the vascular lesion ranged from 3 to 20 years (median 9 years). All lesions were located on the anterior chest wall, except those of the case no. 8, who received radiotherapy for ovarian carcinoma and the cutaneous lesions appeared on the inguinal area. The most common clinical presentation of the cutaneous lesions consisted of FIG. 1. Clinical appearance of the lesions. (A) Papules or papules, small vesicles, or erythematous plaques on the small vesicles. (B) Erythematous plaques on the irradi- irradiated field (Fig. 1). Case no. 12 showed a single ated field. papule that was clinically considered as dermatofibroma.

FIG. 2. Case no. 1. (A) A dome-shaped, exophytic lesion projecting over the skin surface in a case of benign lymphangiomatous papule. (B) Irregular dilated vascular spaces, with a branching and anastomosing pattern, thin walls, and lymphatic appearance, were seen in the superficial dermis. (C) A discontinuous single layer of endothelial cells with spindled 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 ring of actin-positive pericytes. Note the actin-positive internal control of the smooth muscle fibers of the arrector pili muscle in the deeper dermis in G and the walls of the adjacent capillary blood vessels containing erythrocytes within their lumina in I. BENIGN VASCULAR PROLIFERATIONS 331

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 jagged lumina 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.

Only one patient (case no. 3) showed clinical evidence of years (median 3.4 years), and none of the patients devel- lymphedema in the left arm. In all cases the lesions were oped recurrent lesions or metastatic disease. removed by local excision. In each patient a single lesion was histopathologically studied, except case no. 2 with Histopathologic Features two lesions excised and case no. 8 from whom five le- At low power all lesions appeared as relatively well- sions were removed. Follow-up ranged from 0.5 to 13 circumscribed vascular proliferations involving the der-

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showed a “back-to-back” arrangement, with the two vascular lumina separated only by a thin layer of endothelial cells. Numerous small papillary projections, also lined by a single layer of endothelial cells, projected into the lumina of the dilated lymphatic vessels. The papillary projections were especially prominent in case no. 13 (Fig. 4). The stroma of the lesions consisted of fibrillary collagen, numerous spindled or stellate fibroblasts, and in some cases abundant deposits of interstitial mucin between the dilated vascular channels. Two cases (case nos. 2 and 3) showed dense nodular infiltrates of lymphocytes with germinal centers in the vicinity of the dilated vascular channels (Fig. 5). The stroma of one of the lesions of case no. 8 showed striking metaplasia of mature adipocytes intermingled with the dilated vascular spaces (Fig. 6). All these cases were classified as benign

FIG. 4. Case no. 13. (A) A benign lymphangiomatous papule showing an exophytic and pedunculated morphology 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 projections of endothelial cells protruded within the lumina of the dilated lymphatic vessels. mis, without extension to the subcutaneous fat. The epi- dermis was normal. Eight lesions presented as dome- shaped, exophytic papules projecting over the skin surface (case nos. 1–3, 6–8, 13, and 15) (Fig. 2) and the other seven cases (case nos. 4, 5, 9–12, and 14) were flat with a plaque-like morphology (Fig. 3). In most lesions (case nos. 1–10 and 13–15), irregular dilated vascular spaces, with a branching and anastomosing pattern, thin walls, and lymphatic appearance, were seen in the superficial dermis (Figs. 2 and 3). A discontinuous single FIG. 5. Case no. 2. (A) A benign lymphangiomatous papule with dense nodular infiltrates of lymphocytes in the layer of endothelial cells with spindled or flattened nu- stroma. (B) Irregular dilated vascular channels with lym- clei lined these vascular channels and their lumina ap- phatic appearance. (C) Dense nodular infiltrates of lym- peared empty. In many areas adjacent vascular channels phocytes close to the dilated lymphatic vessels.

Am J Surg Pathol, Vol. 26, No. 3, 2002 BENIGN VASCULAR PROLIFERATIONS 333 lymphangiomatous papules or benign lymphangiomatous plaques. Two lesions (case nos. 11 and 12) showed different histopathologic findings. They consisted of poorly circumscribed and focally infiltrating irregular jagged vascular spaces involving the entire dermis, lined by inconspicuous endothelial cells. In some areas these irregular slit-like vascular spaces dissected collagen bundles of the dermis. Erythrocytes were not seen in the lumina of the vascular channels, and a few lymphocytes were present in the stroma. Case no. 11 also showed conspicuous tufts of endothelial cells protruding into the lumens of neoformed vessels. These striking endothelial tufts resembled those of Dabska’s tumor in miniature, although in contrast with authentic Dabska’s tumor, the endothelial tufts of this lesion had no connective tissue core and they were grape-like papillary formations exclusively composed of endothelial cells. Therefore, we classified this lesion as atypical vascular proliferation with dabskoid features (Fig. 7). Case no. 12 showed irregular jagged vascular spaces dissecting collagen bundles of the dermis and abundant interstitial hemosiderin deposits, mimicking patch-stage Kaposi’s sarcoma (Fig. 8). Case nos. 6 (Fig. 9) and 15 combined features of benign lymphangiomatous papules in the upper dermis and atypical vascular proliferations with focally infiltrative pattern in deeper dermis.

Immunohistochemical Findings

All cases showed similar immunohistochemical findings. Endothelial cells lining the vascular spaces expressed immunoreactivity for CD31, but they stained only focally positive for CD34 or were negative for this marker. Although a few vessels showed an attenuated FIG. 6. Case no. 8. (A) A benign lymphangiomatous pap- muscle layer stained for ␣-smooth muscle actin antibody ule with prominent metaplasia of adipocytes in the stroma. surrounding the endothelial cells, this marker was essen- (B) Mature adipocytes intermingled with dilated vascular tially negative in most vascular structures. Ki67 stained spaces in the dermis. (C) The dilated vascular spaces showed thin walls and empty lumina and were lined by a some keratinocytic nuclei of the epidermal basal layer, single layer of endothelial cells. but it was negative in the nuclei of the endothelial cells lining the vascular structures. ripheral ring of actin-positive pericytes, also supports a lymphatic nature for these neoformed vessels. Benign DISCUSSION lymphangiomatous papules and plaques seem to be the most common vascular lesions developed in areas of irra- The histopathologic characteristics of these cases of diated skin. They have been erroneously named “lymphan- vascular proliferations arisen in irradiated skin were gioma circumscriptum” by some authors,28,30,40,55 but those of lymphatic vessels because they consisted of di- this is an inaccurate term because lymphangioma cir- lated vascular spaces with thin walls lined by a single cumscriptum refers to localized malformations of lym- discontinuous layer of flat endothelial cells and arranged phatic vessels of the superficial dermis.42 Benign lymph- in a “back-to-back” fashion. Furthermore, the immuno- angiomatous papules and plaques are the lymphatic histochemical profile of the endothelial cells lining the counterpart of telangiectases, and they result from ac- neoformed vessels, which expressed immunoreactivity quired permanent dilatation of lymphatic capillaries. for CD31, but not for CD34, and the absence of a pe- They may appear in areas of skin affected by obstruction

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FIG. 7. Case no. 11. (A) Atypical vascular proliferation with dabskoid features in miniature. (B) Poorly circumscribed and focally infiltrating irregular jagged vascular spaces involving the entire dermis and lined by inconspicuous endothelial cells. (C) In some areas conspicuous tufts of endothelial cells protruded into the lumina of neoformed vessels. These endothelial tufts resembled those of Dabska’s tumor in miniature, although in contrast with authentic Dabska’s tumor, the endothelial tufts had no connective tissue core and they were grape-like papillary formations exclusively composed of endothelial cells. or destruction of the lymphatic drainage and have been The cases of this series classified as atypical vascular described as a result of interference of lymphatic vessels proliferations showed histopathologic similarities with secondary to radiotherapy1,13,15,21,22,25,27,28,30,38,40,55 or benign lymphangioendothelioma, also named acquired surgery.57 Benign lymphangiomatous papules and progressive lymphangioma, and with patch-stage Kaposi’s plaques, however, may also appear in the skin of elderly sarcoma. Indeed, a case of acquired progressive lymphan- persons without any evidence of secondary lymphatic gioma of the skin after radiotherapy has been previously damage.4 Clinically, benign lymphangiomatous papules described,44 although this case more likely represents an arisen in areas of irradiated skin appear as multiple, per- example of postirradiation atypical vascular proliferation. sistent, translucent, thick-walled, whitish vesicles or Benign lymphangioendothelioma is a rare lymphatic neo- small papules. Some lesions may have polypoid shape plasm originally described by Wilson Jones et al.53,54 Ap- and punction provokes the flow of a milky liquid. Benign proximately 40 cases of this uncommon neoplasm have lymphangiomatous plaques appear as erythematous flat been reported in the literature.6,18,19,23,24,32,33,41,48,50–54,56 areas of indurated skin. Histopathologically, both lesions Clinically, lesions of benign lymphangioendothelioma consist of dilated lymphatic vessels positioned within appear as a solitary reddish or bruise-like slowly growing papillary dermis, although some dilated lymphatic ves- plaque that does not have a site of predilection. Histo- sels may also be seen involving the reticular dermis. The pathologically, benign lymphangioendothelioma is com- lumina of the dilated vessels show no contents or are posed of delicate, thin-walled, endothelium-lined dilated filled by homogeneous eosinophilic material, and they vascular spaces involving the superficial dermis. In some are lined by a thin wall composed of a single discontinu- areas intravascular papillary stromal projections are pres- ous layer of endothelial cells. A striking histopathologic ent, resembling papillary endothelial hyperplasia. As feature in our cases consisted of the presence of promi- the lesion descends within deeper dermis, the vascular nent papillary projections of stroma lined by endothelial spaces collapse and dissect the collagen bundles, mim- cells or tufts of endothelial cells without stroma axis icking patch-stage Kaposi’s sarcoma, especially the protruding within the lumina of the dilated lymphatic lymphangioma-like variant of Kaposi’s sarcoma,8,14,29,43 vessels. These intravascular papillary projections have and well-differentiated angiosarcoma. Preexisting ves- been previously described in vascular proliferations of sels and adnexal structures of the dermis also appear irradiated skin10,12 as well as in lymphatic malforma- dissected by the neoformed vascular channels. These tions,26 and they are interpreted as the lymphatic coun- vascular spaces appear empty or to contain proteinaceous terpart of Masson’s intravascular papillary endothelial material. Erythrocytes and hemosiderin deposits are hyperplasia.26 characteristically absent. The endothelial cells in the le-

Am J Surg Pathol, Vol. 26, No. 3, 2002 BENIGN VASCULAR PROLIFERATIONS 335 sional vessels are present in greater numbers than in normal lymphatic channels, and in some places they are crowded together. However, no nuclear atypia is found in the endothelial cells lining the cleft-like vessels. In contrast with patch-stage Kaposi’s sarcoma, lesions of benign lymphangioendothelioma show no erythrocytes or hemosiderin deposits, and there are no plasma cells in the stroma. With the exception of the case reported by Rosso et al.,44 which probably is better interpreted as an example of postradiotherapy atypical vascular proliferation, no other examples of benign lymphangioendothelioma have been reported in irradiated skin. To the best of our knowledge, the striking tufts of endothelial cells, seen in our case no. 11, which protruded within the irregular jagged vascular channels resembling the features of Dabska’s tumor in miniature, have not been previously described in the vascular proliferations arisen in irradiated skin. Case no. 12 showed irregular jagged vascular channels and abundant hemosiderin deposits in the stroma, mimicking patch-stage Kaposi’s sarcoma. How- ever, in contrast with authentic Kaposi’s sarcoma, the so-called promontory sign that results from the dissec- tion of preexisting capillaries by the proliferating endothelial cells and an inflammatory infiltrate of plasma cells were not seen in case no. 12. Histopathologic differential diagnosis between the atypical vascular proliferations in areas of irradiated skin also includes well-differentiated angiosarcoma. In contrast with angiosarcoma, atypical vascular proliferations in irradiated skin do not involve the subcutaneous tissue, and there is not substantial cytologic atypia because the nuclei of endothelial cells lining the vascular channels are monomorphous, with inconspicuous nucleoli and no mitotic figures. Another frequent histopathologic finding in angiosarcoma consists of the presence of multilayer- FIG. 8. Case no. 12. (A) Irregular jagged vascular spaces ing of atypical endothelial cells lining irregular vascular involving the full thickness of the dermis. (B) These and anastomosing channels, the so-called piling-up phe- jagged vascular spaces dissected the collagen bundles of the dermis, and the stroma contained abundant interstitial nomenon, and this feature is not seen in atypical vascular hemosiderin deposits, mimicking patch-stage Kaposi’s proliferations in irradiated skin. Usually, many nuclei of sarcoma. (C) A single layer of endothelial cells lined the neoplastic endothelial cells of angiosarcoma express pro- irregular vascular channels. liferation markers such as Ki67, and this marker was essentially negative in our cases. Furthermore, there is not evidence that these atypical vascular proliferations and usually appear after a latent period of several years represent premalignant lesions for the development of after radiotherapy. Although these vascular proliferations postirradiation angiosarcoma, and the follow-up of our in irradiated skin may raise problems in the histopatho- patients has demonstrated that these lesions have a be- logic differential diagnosis with malignant vascular nign biologic behavior. proliferations, they invariably show a benign biologic In summary, vascular proliferations arisen in areas behavior. ᮀ of irradiated skin comprise a wide spectrum of lesions. The most common lesions are benign lymphangiomatous papules and plaques, but more atypical vascular REFERENCES proliferations resembling benign lymphangioendothelioma, patch-stage Kaposi’s sarcoma, and well- 1. Ambrojo P, Fernández-Cogolludo E, Aguilar A, et al. Cutaneous lymphangiectases after therapy for carcinoma of the cervix: a case differentiated angiosarcoma may also appear. All these with unusual clinical and histological features. Clin Exp Dermatol vascular lesions arise within the field of irradiated skin 1990;15:57–9.

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FIG. 9. Case no. 6. (A) This lesion combined features of a benign lymphangiomatous papule in the upper dermis and an atypical vascular proliferation in the deeper dermis. (B) Dilated lymphatic vessels in the superficial areas. (C) In the deeper dermis irregular jagged vascular spaces dissected the collagen bundles. (D) Endothelial cells lined these jagged irregular vascular spaces.

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