Vascular proliferations of the skin after radiation therapy for breast cancer: Clinicopathologic analysis of a series in favor of a benign process

A study from the French Sarcoma Group

Abstract

BACKGROUND.

Cutaneous vascular proliferations that occur in the field of prior radiotherapy include angiosarcoma and small, cutaneous lesions with a pseudosarcomatous pattern that previously were reported as atypical vascular lesions or benign lymphangiomatous papules.

METHODS.

The objective of this study was to investigate the clinicopathologic features and outcomes of 56 radiation-induced vascular proliferations that occurred in 36 patients who received previous treatment for breast carcinoma. Data from all patients were retrieved from the files of the French Sarcoma Group. Immunostaining with D2.40 antibody was performed in 24 lesions.

RESULTS.

All patients (median age, 52 years) had received external radiotherapy. Small papules developed within the field of prior radiotherapy (median latency interval, 66 months). Microscopically, the lesions were relatively well circumscribed, and they were located mostly in the superficial/middermis. They were composed of dilated or irregular-jagged vascular channels that were lined by a single layer of bland endothelial cells, and they demonstrated either a predominately lymphangioendothelioma-like or lymphangioma/lymphangioma circumscriptum-like growth pattern. Micropapillary tufts were common findings. Ten lesions showed additional cytologic and/or architectural atypia. Twenty of 24 lesions showed D2.40 positivity. Follow-up information was available for 31 patients (median follow-up, 48 months): Five women developed new cutaneous lesions, and 1 woman had spontaneous regression of her lesions. None of the patients developed cutaneous angiosarcoma. Five patients were lost to follow-up.

CONCLUSIONS.

Although vascular proliferations in irradiated skin may mimic angiosarcoma morphologically, the large majority of these lesions showed a benign clinical outcome. Despite relatively limited follow-up, the current results indicate the benign nature of these vascular proliferations. Cancer 2007. © 2007 American Cancer Society.

Vascular proliferations of the breast may occur either spontaneously or in the context of predisposing conditions, including chronic lymphoedema (Stewart-Treves syndrome, congenital lymphoedema) and radiation therapy. In the past 10 years, a significant number of vascular lesions have been reported that occurred in women after they received radiation therapy.1–12 These included conventional angiosarcomas5–13 and small, cutaneous, superficial, vascular proliferations that initially were believed to be incipient angiosarcomas.1–4 Although a few cases have been reported previously in the literature under various designations, such as acquired lymphangectasies,14 acquired progressive lymphangioma,4 or lymphangioma circumscriptum,15 it was only in 1994 that Fineberg and Rosen introduced the concept of atypical vascular lesions of the skin after radiation therapy.1 In their study, those authors reported that these atypical vascular lesions had a benign clinical course, suggesting that they actually were not incipient angiosarcomas. Subsequently, 2 clinicopathologic studies2, 3 confirmed these results, and the term benign lymphangiomatous papules after radiotherapy was proposed to designate these lesions. In the French Sarcoma Group, we came across several of these unusual vascular lesions, most of them resembling either benign lymphangioendothelioma16 (so-called acquired progressive lymphangioma) or superficial lymphangioma (benign lymphangioma circumscriptum or lymphangioma).

Herein we report our experience in a series of 36 patients who presented with small, cutaneous, vascular proliferations in a field of prior radiation after surgery for breast carcinoma. Our results suggest that most of these postradiation vascular lesions have no malignant potential and are not incipient angiosarcomas.

MATERIALS AND METHODS

Between 1982 and 2004, 56 vascular lesions that occurred in the irradiated field of 36 patients who were treated previously for breast carcinoma were retrieved from the files of some members of the French Sarcoma Group (see the list of authors and acknowledgments). Clinical data and follow-up information were obtained from referring pathologists. For light-microscopy examination, 4-μm-thick formalin- or Bouin-fixed, paraffin-embedded sections were stained with hematoxylin and eosin. All lesions were reviewed by 2 of the authors (C.G. and L.G.). Problematic lesions were discussed within the Histopathology Committee of the French Sarcoma Group, comprising 12 pathologists with experience in soft tissue tumor pathology. Based on their predominant growth pattern, the lesions were subclassified as benign lympangioendothelioma-like/hobnail hemangioma-like lesions and superficial lymphangioma-like (benign lymphangioma circumscriptum or lymphangioma) lesions.

Benign lymphangioendothelioma-like lesions (Figs. 1, 2) and hobnail hemangioma-like lesions were characterized by the presence of anastomotic, angulated, vascular spaces dissecting the dermal collagen. In the superficial dermis, vascular spaces often were dilated; whereas, in the deep dermis, they tended to be narrower with a slit-like, pseudoangiosarcomatous appearance (Fig. 2).

Figure 1. Lymphangioendothelioma-like lesion: A superficial dermal lesion composed of slit-like vascular spaces with a pseudoangiosarcomatous pattern (Patient 8).

Figure 2. Lymphangioendothelioma-like lesion: Narrow vascular spaces intermixed with a moderate, chronic inflammatory infiltrate (Patient 4).

The superficial lymphangioma-like pattern (Figs. 3, 4) consisted of dilated, regular, vascular spaces located in the superficial/papillary dermis, often forming dome-shaped, exophytic papules (lymphangioma circumscriptum-like) (Fig. 3). For all lesions, the presence or absence of papillary endoluminal projections, cellular spindling, nuclear atypia (nuclear hyperchromasia and prominent nucleoli), mitoses, and areas of necrosis and hemorrhage were noted.

Figure 3. Lymphangioma circumscriptum-like appearance: Dilated vascular spaces filled with a proteinaceous material are located in the superficial dermis, resulting in a dome-shaped, exophytic papule (Patient 32).

Figure 4. Lymphangioma-like lesion: More or less dilated vascular channels with small stromal projections protruding into lumina (Patient 15).

An immunohistochemical analysis with the D2.40 antibody (mouse monoclonal clone D2.40; 1:400 dilution; Signet Laboratories, Dedham, Mass) without antigen retrieval was performed on 24 of the 56 lesions. Positive and negative controls consisted of nonlesional lymphatics and veins, respectively. Immunostaining using anti-CD31 antibody (mouse monoclonal clone JC70A; 1:200 dilution; Dakopatts, Glostrup, Denmark) was performed in 19 lesions, including 17 that also were stained with an anti-CD34 antibody (mouse monoclonal clone QBEND10; 1:300 dilution; Immunotech, Marseille, France).

RESULTS

Clinical Findings

Clinical data are summarized in Table 1. There were 56 postradiation, atypical vascular proliferations that occurred in 36 patients. All patients were women between ages 39 years and 75 years (median, 52 years). Thirty-four patients underwent surgery for their primary breast malignancy. Twenty-four patients received radiotherapy in the setting of breast-conserving therapy. For 10 patients, the treatment consisted of modified radical mastectomy followed by external radiotherapy, including 1 patient who underwent bilateral mastectomy followed by external radiotherapy for bilateral, metachronous, mammary carcinoma (Patient 36). Seventeen patients received neoadjuvant or adjuvant chemotherapy. Two patients did not undergo surgery, including 1 woman (Patient 29) who received a combination of radiotherapy and chemotherapy and another woman (Patient 24) who received radiotherapy alone. Cumulative doses were known in 28 patients and ranged from 45 grays (Gy) to 60 Gy (median dose, 50 Gy). The cutaneous vascular lesions that occurred subsequently arose in the irradiation field, including the skin of the breast (n = 22 patients), of the axillary region (n = 4 patients), and of the thorax (n = 10 patients). Postradiation intervals ranged from 11 months to 216 months (median, 66 months). The 1 patient who underwent bilateral mastectomy for metachronous mammary carcinoma (Patient 36) developed bilateral vascular lesions on the thorax 12 months and 78 months after radiation therapy. Clinically, the lesions presented as solitary (26 patients) or multiple (10 patients), bluish or reddish nodules (n = 23 patients) or small papules and/or vesicles (n = 12 patients). One woman (Patient 1) presented with a small, erythematous plaque, and 1 woman had a lesion that was described as a small cutaneous cyst (Patient 22). For the patients who presented with multiple lesions, the number of lesions ranged from 2 to 6, and all lesions were grouped on the thorax. Tumors ranged in size from 1 mm to 15 mm (median size, 5 mm). Large, ecchymotic plaques were not observed. Two women presented with clinical evidence of lymphoedema at the affected site (Patients 9 and 23). Clinical preoperative diagnoses were known for only 14 patients. A local recurrence of breast carcinoma was suspected in 7 patients, and the possible occurrence of an angiosarcoma was suspected in 1 patient. Clinically, 2 lesions (Patients 2 and 16) that presented as a single papule or nodule were considered to represent dermatofibromas, 3 lesions were considered to be lymphangiomas (Patients 24, 32, and 33), and 1 lesion was considered an epidermal cyst (Patient 22). For 6 patients, the cutaneous lesions were present from 6 months to 60 months prior to biopsy or excision. One woman (Patient 10) experienced a spontaneous regression of multiple papules before she developed a single nodule that measured 6 mm and underwent histologic examination. Two women (Patients 32 and 33) developed several papules 12 months to 48 months after undergoing complete excision of similar cutaneous lesions (histologic samples were not available for review).

Table 1. Clinical and Histologic Features of Vascular Lesions After Radiotherapy for Breast Carcinoma in 36 Patients

Patient	Age, years	Surgery (breast cancer)	RTX Dose, Gy	Latency interval, months	Site of vascular cutaneous lesion	Clinical presentation prior to excision	Predominant histologic pattern	Nuclear/ architectural atypia	Treatment	F/U
RTX indicates radiotherapy; Gy, grays; F/U, follow-up; M, mastectomy; LE, lymphangioendothelioma-like; CE, complete excision with negative margins; AWTD, alive without disease; T, tumorectomy; HO, hobnail hemangioma-like; H, hemangioma-like; MI, mixed histologic patterns; IB, incisional biopsy (with positive margins); NA, not available; AWD, alive with disease; LY, lymphangioma-like; LC, lymphangioma circumscriptum-like.
Patients with solitary cutaneous lesions at presentation
1	44	M	55	28	Chest wall	One nodule present for 10 mo, changing into an 5-mm erythematous plaque	LE	No	CE	AWTD at 36 mo
2	48	M	50	84	Axilla	Five-mm nodule present for 19 mo	LE	No	CE	AWTD at 120 mo
3	58	T	50	24	Axilla	One vesicle, 4 mm	HO	No	CE	Dead of metastatic breast carcinoma at 53 mo; no recurrent vascular lesion
4	40	T	50	72	Axilla	One papule, 7 mm	LE	Yes	CE	AWTD at 48 mo, metastatic breast carcinoma
5	61	T	60	63	Breast	Six-mm nodule present for 12 mo	LE	No	CE	AWTD at 81 mo
6	44	T	50	67	Breast	One nodule, 3 mm	LE	No	CE	Dead of ovarian carcinoma at 152 mo
7	59	T	50	55	Breast	One nodule, 6 mm	H	No	CE	Dead of metastatic breast carcinoma at 94 mo
8	51	T	50	72	Breast	One nodule, 6 mm	LE	Yes	CE	AWTD at 54 mo
9	65	M	45	216	Chest wall	One nodule, 15 mm	MI	Yes	CE	AWTD at 7 mo
10	67	T	50	72	Breast	Multiple papules regressing spontaneously 3 mo before development of a 6-mm nodule	LE	Yes	IB	Spontaneous regression 12 mo after biopsy; AWTD at 28 mo
11	53	T	60	65	Breast	Eight-mm clinically stable nodule present for 44 mo	LE	No	CE	AWTD at 14 mo
12	50	T	NA	108	Breast	One nodule, 6 mm	HO	No	Present on mastectomy specimen (recurrent breast carcinoma)	Lost to F/U
13	58	T	NA	84	Chest wall	One nodule, 7 mm	HO	No	CE	Lost to F/U
14	46	T	NA	36	Breast	One nodule, 5 mm	LE	No	IB	Lost to F/U
15	72	T	60	60	Breast	One papule, 4 mm	LY	No	IB	AWD at 71 mo, no additional cutaneous lesions
16	53	M	46	45	Chest wall	One papule, 6 mm	LE	No	CE	AWTD at 24 mo
17	48	T	NA	72	Breast	One nodule, 4 mm	LE	No	Incomplete excision (R1)	AWD at 65 mo, no additional cutaneous lesions
18	51	T	NA	96	Breast	One nodule, 4 mm	HO	No	CE	Recurrent lesion at 38 mo treated by CE; AWTD at 48 mo
19	52	M	45	12	Chest wall	One nodule, 2 mm	LY	Yes	CE	Recurrent and persistent telangectasis at 60 mo
20	75	T	50	153	Breast	One nodule, 4 mm	LE	No	IB	AWD at 61 mo, no additional cutaneous lesions
21	49	T	50	36	Breast	One papule, 5 mm	LY	No	IB	AWD at 28 mo, no additional cutaneous lesion. (Continued)
22	42	M	50	24	Chest wall	One cyst, 5 mm	LE	No	IB	AWD at 36 mo, no additional cutaneous lesions
23	52	T	50	135	Breast	One nodule, 4 mm	LE	No	CE	AWTD at 7 mo
24	53	No surgery	50	NA	Breast	One papule, 6 mm	LE	Yes	CE	Lost to F/U
25	64	T	50	63	Breast	Four-mm stable nodule present for 6 mo	LE	No	CE	AWTD at 40 mo
26	39	T	60	52	Breast	One nodule, 5 mm	LY	No	CE	AWTD at 12 mo
Patients with multiple cutaneous lesions at presentation
27	63	T	60	120	Breast	Six papules (1–2 mm) present for 5 y; development of an additional 6-mm nodule	LE	No	IB (6-mm nodule)	AWTD at 92 mo
28	52	T	50	36	Breast	Two nodules, 7 mm	HO	Yes	CE	Died of breast carcinoma at 48 mo, no recurrence of vascular cutaneous lesion
29	52	No surgery	NA	108	Breast	Two nodules, 8 mm	LE	Yes	Present on mastectomy specimen (recurrent breast carcinoma)	Lost to F/U
30	50	M	46	11	Chest wall	Multiples papules, 1–6 mm	LY	Yes (1 recurrent lesion)	IB (1 papule)	Three efflorescences of new vascular lesions at 6 mo, 12 mo, and 24 mo (up to 40 papules); excision with tumor-free margins; recurrent nodule 4 mo after surgery; AWD at 48 mo
31	56	T	NA	118	Breast	Two nodules, 4 mm	LE	Yes (1 nodule)	CE	AWTD at 67 mo
32	57	M	NA	61	Chest wall	Six papules (4 mm) occurring 48 mo and 24 mo after CE of clinically similar cutaneous lesions	LE (2 of 4 specimens examined), and LC (2 specimens)	No	CE	AWTD at 3 mo
33	51	T	60	104	Chest wall	Several papules (7–10 mm) developing 42 mo and 12 mo after CE of a single cutaneous papule	LE	No	CE	Two episodes of new cutaneous lesions at 4 mo and 15 mo treated by CE; AWTD at 64 mo
34	50	T	50	72	Breast	Papules, 3–6 mm	LE	No	CE	AWTD at 8 mo
35	61	M	50	17	Axilla	Nodules, 3–5 mm	LE	No	CE	AWTD at 6 mo
36	57	M (left)	50	12	Chest wall	One vesicule, 2 mm	LY	No	CE	Recurrent polypoid lesion at 14 mo (incisional biopsy); alive with persistent telangectasis at 24 mo
36	57	M (right)	50	78	Chest wall	Multiple nodules, 2–3 mm	LE	No	CE	Alive with persistent telangectasis at 88 mo

The treatment modalities were as follows: Twenty patients underwent local excision of their vascular lesions, and all but 1 woman (Patient 17) achieved tumor-free surgical margins. The maximal dimension of the excisional specimen was known for 6 patients and ranged from 1.3 cm to 20 cm. In 14 patients, lesions were removed by using a simple biopsy-excision procedure, and 6 patients achieved with tumor-free margins; in those patients, the biopsy specimens measured from 0.4 cm to 1 cm. For 2 of those 14 women (Patients 10 and 27), a biopsy was performed only after development of additional vascular lesions 3 months and 60 months, respectively, after the occurrence of the first vascular lesions. In 2 women, the vascular lesions were detected on the mastectomy specimen (Patients 29 and 12) from recurrent breast carcinoma.

Pathologic Features

One lesion per patient was available for histopathologic examination, except for 5 patients. For these 5 patients (case nos. 30–32, 34, and 36), 2, 3 (n = 2), 4 and 13 lesions were available for review. At low power, skin lesions were circumscribed relatively well and were confined to the dermis. Twenty-nine lesions extended into the deep dermis, but none involved the subcutaneous fat. The overlying epidermis was normal (n = 43 lesions) or showed mild acanthosis (n = 13 lesions). On microscopic examination, 2 major growth patterns were recognized: a benign lymphangioendothelioma-like pattern (n = 28 lesions) (Figs. 1, 2) and a superficial, lymphangioma-like architecture (n = 18 lesions) (Figs. 3, 4). Five patients (Patients 3, 12, 13, 18, and 28) showed morphologic features similar to those of hobnail hemangioma. Four lesions, including 1 at initial presentation (Patient 9) (Fig. 5a,b), showed combined features of lymphangioma circumscriptum and lymphangioendothelioma with a readily visible, dissecting growth pattern in the deep dermis (Fig. 5b). One lesion (Patient 7), which presented as a well-circumscribed dermal nodule, was composed of regular, dilated vascular spaces filled with red blood cells, resulting in a hemangioma-like appearance.

Figure 5. Lesion with mixed histologic patterns (Patient 9): Dilated vascular spaces are visible in the superficial dermis (a); slit-like vascular spaces dissect collagen fibers in deep dermis (b).

In all lesions, the thin-walled, irregular vascular spaces were lined by a discontinuous, single layer of flat-to-plump cells. In most lesions, endothelial cells were bland cytologically with homogeneous chromatin and inconspicuous nucleoli. Endothelial cell piling-up was observed in 2 lesions (Patients 26 and 33). Thin projections of endothelium-covered stroma protruding into lumina were a constant finding. In 19 lesions, small micropapillary tufts were noted. Mitoses were not observed. Vascular spaces were empty or were filled with a proteinaceous material (n = 36 lesions). In some instances, they contained a variable amount of erythrocytes (n = 17 lesions) or scattered lymphocytes (n = 8 lesions). Rare clumps of endothelial cells lying freely in the lumen were observed (n = 9 lesions). In 27 lesions, the vascular channels that dissected the dermal collagen surrounded preexisting adnexal structures or vessels. Arrector pili muscles were infiltrated by the vascular structures in a few instances (n = 8 lesions).

All lesions contained a sparse-to-moderate, chronic inflammatory infiltrate with variable numbers of mast cells. Plasma cells were observed in 4 lesions. Minimal amounts of hemosiderin were present in the stroma of 18 lesions. In all but 8 lesions, a varying proliferation of spindle-shaped or bizarre stromal cells was admixed with the vascular component.

Ten lesions presented with nuclear and/or architectural atypia in the form of focal nuclear hyperchromasia of endothelial cells (Fig. 6a,b), prominent nucleoli, or an angiosarcomatous-like pattern with infiltrating, irregular, jagged vascular spaces (Figs. 1, 2). One recurrent vascular lesion (Patient 36) showed prominent papillary projections protruding within the lumina of the vascular channels that resembled a Dabska tumor or a retiform hemangioendothelioma (Fig. 7).

Figure 6. a) Well-circumscribed, dermal, vascular proliferation with a lymphangioendothelioma-like appearance. b) At high-power magnification, some vascular spaces are lined by endothelial cells with enlarged, hyperchromatic nuclei (Patient 29).

Figure 7. Prominent papillary projections lined by nonhyperchromatic endothelial cells, resembling Dabska tumor/retiform hemangioendothelioma (recurrent vascular lesion; Patient 36).

Immunohistochemical Findings

Of the 24 lesions that were examined for D2.40 expression, 20 showed focal or diffuse, positive staining of endothelial cells (Fig. 8). The proportion of positive vessels varied from <25% (n = 15 lesions) to 25% to 50% (n = 2 lesions); 3 tumors showed diffuse and strong reactivity for D2.40 (100% reactivity). In almost all lesions, the intensity of staining was less pronounced than in nonlesional lymphatic vessels. Lesions that were formed only by D2.40-negative vascular channels contained a few clusters of nonlesional, small, vascular channels in the superficial dermis, which reacted strongly with D2.40. Endothelial cells of arteries and veins were not stained by D2.40. Diffuse CD31 expression was observed in all lesions (19 of 19). Seven of 17 lesions also showed focal (n = 6 lesions) or diffuse CD34 reactivity, all of which also expressed D2.40 at least focally. All CD34-negative lesions except 1 were positive for D2.40.

Figure 8. Lymphangioma-like lesion: Slit-like vascular spaces lined by a layer of D2.40-positive endothelial cells.

Outcome

Follow-up information (summarized in Tables 1 and 2) was available for 31 patients with a median follow-up of 48 months (range, 3–152 months). Twelve patients had a follow-up >60 months, and 5 patients were lost to follow-up.

Table 2. Clinical Outcome in 31 Patients with Postradiation Vascular Proliferations of the Skin

Subset of patients	No. of patients	No. with multiple vascular lesions at presentation	No. with atypical histologic features	Treatment modalities		Median FU (range), mo
				CE, R0	IB or incomplete excision, R1
CE indicates complete excision with negative margins; IB, incisional biopsy with positive margins; FU, follow-up.
Patients without recurrent vascular disease	26	6	4	19	7	44 (3–152)
Patients with recurrent vascular disease	5	3	2	4	1	48 (24–64)

Of the 26 patients who did not experience recurring vascular disease, 3 patients died of breast carcinoma, and 1 patient died of International Federation of Gynecology and Obstetrics stage IV ovarian carcinoma. Five women (Patients 18, 19, 30, 33, and 36) developed new cutaneous vascular lesions in the same area or at a distance (n = 1 woman) from 4 months to 60 months after they underwent removal of their primary vascular lesion. One of these women (Patient 30) experienced 3 efflorescences of vascular lesions at 6 months, 12 months, and 24 months, respectively, and subsequently developed up to 40 cutaneous papules, which were excised completely with tumor-free margins. Four months later, she developed another nodule in the same region. A second women (Patient 33) experienced 2 recurrences 4 months and 15 months, respectively, after complete excision of the primary cutaneous lesion. The woman who was treated for bilateral, metachronous, mammary carcinoma (Patient 36) and who subsequently developed bilateral, vascular, cutaneous lesions had persistent bilateral disease with telangectasies at last follow-up.

For the subgroup of patients (n = 10 women) who had vascular lesions that displayed atypical histologic features (including 9 primary lesions and 1 recurrent lesion; Patient 30), the median follow-up was 48 months (range, 7–67 months). For 2 women (Patients 19 and 31), the follow-up was ≥60 months. One patient experienced spontaneous regression of her lesion 12 months after the biopsy (Patient 10) and was alive without disease at 28 months. Two of the vascular lesions with atypical histologic features recurred, and these women were alive with disease at 48 months (Patient 30) and 60 months (Patient 19), respectively. One woman (Patient 28) died of breast carcinoma at 48 months and did not develop any new cutaneous, vascular lesions prior to death. Four patients who underwent local excision and achieved tumor-free margins remained disease free after 7 months, 48 months, 54 months, and 67 months, respectively. Two patients were lost to follow-up.

At their last medical examination, none of our patients had obvious cutaneous angiosarcoma or metastatic vascular disease.

DISCUSSION

Conventional angiosarcoma, which remains an uncommon complication after radiation therapy with an overall incidence estimated at 0.09% to 0.16%,9 is not the only radiation-associated, cutaneous, vascular lesion. Recently, attention has been drawn to the possible occurrence of clinically benign vascular changes in irradiated fields.1–7 In 1994, Fineberg and Rosen1 reported the clinicopathologic features of 4 unusual angiomatous proliferations arising in previously irradiated skin after breast-conserving treatment and introduced the concept of atypical vascular lesions of the skin after radiotherapy. Despite the presence of cytologic abnormalities and/or a pseudoangiosarcomatous growth pattern, all 4 lesions had a benign outcome. One year later, a similar lesion4 was reported as acquired progressive lymphangioma of the skin after radiotherapy for breast cancer. In 1999, Diaz-Cascajo et al2 described 5 new examples of these unusual, radiation-induced, vascular proliferations and proposed the name benign lymphangiomatous papules after radiotherapy. More recently, Requena et al3 examined the clinicopathologic features of 15 clinically benign vascular proliferations that occurred within the field of irradiated skin, and Brenn and Fletcher7 identified 16 similar vascular proliferations in a series of 42 patients with cutaneous, radiation-associated, vascular lesions.

In the current study, we examined the clinicopathologic features of 56 vascular lesions of the skin that occurred after radiotherapy for breast carcinoma, all of which had a benign clinical course despite their sometimes atypical histologic features. A review of the literature on vascular lesions of the skin occurring after radiotherapy reported between 1994 and 2005, to which our cases (n = 56 lesions in 36 women) are added, provides the following data: All patients were women, and the large majority had received adjuvant radiotherapy for breast carcinoma. Less frequently, the vascular, cutaneous lesions developed in the field of radiation therapy in the setting of gynecologic malignancies (ovarian,7 endometrial,2 and cervical carcinomas15) or other malignant tumors, such as multiple myeloma.7 The median patient age was 55 years (range, 52–68.5 years). In our series, the median radiation dose delivered was 50 Gy, which was comparable to the median total dose in previous reports.1, 2, 4, 7 The median interval latency period after radiotherapy varied from 3 years to 5 years (range, 0.5–17 years). Cutaneous lesions were either single or multiple and presented as papules, plaques, or nodules.

Although it is always difficult and somewhat arbitrary to compare lesions from 1 study to another, it appears that all lesions can be classified roughly into 2 histologic categories: lesions that resemble superficial lymphangioma or lymphangioma circumscriptum (also reported as benign lymphangiomatous papules in the study by Requena et al3) and lesions that resemble benign lymphangioendothelioma or hobnail hemangioma (reported as benign lymphangiomatous plaques by Requena et al3), although some lesions may display combined features (ie, the appearance of benign lymphangiomatous papules in the upper dermis and a more infiltrative, lymphangioendothelioma-like growth pattern in the deep dermis). The term atypical was used in previously reports to underline the possible presence in those lesions of cytologic and/or architectural abnormalities in terms of nuclear hyperchromasia, partially anastomotic or infiltrative growth patterns, possible extension of the lesion into superficial subcutaneous tissue, the presence of papillary endothelial hyperplasia resembling Dabska tumor, and the presence of abundant interstitial hemosiderin deposits mimicking patch-stage Kaposi sarcoma. In our experience, these worrisome features are part of the histologic spectrum and were observed in approximately 50% of our lesions. Thin projections of endothelial-covered stroma are not rare and have been considered by some authors17 as an indirect expression of their lymphatic nature.

The occurrence of postradiation vascular lesions raises important questions for the patient and the clinician. Are these lesions benign or malignant in nature? Do they represent precursors of angiosarcoma or, worse, incipient angiosarcomas? What is the best treatment for them?

Most data on outcomes reported previously, including ours, favored a benign process. With the exception of 3 recently reported angiosarcomas,7, 10, 11 which had developed in a background of postradiation atypical vascular lesions, all other postradiation vascular lesions reported in the literature had a benign clinical outcome,1–5 including those that showed atypical histologic features. In our study, none of the 12 patients who were followed for ≥60 months (the median interval for the development of radiation-associated angiosarcoma)13 developed angiosarcoma. Because most of our vascular lesions with atypical histologic features were excised completely, data are not available regarding their natural clinical behavior; thus, we cannot definitively rule out the possibility that some of these lesions may have been incipient angiosarcomas that were cured by complete excision. Two lesions that displayed atypical histologic features were excised incompletely and, nevertheless, behaved in a benign manner. Atypical vascular lesions may recur. In our study, 5 patients developed new papules at the site of previous excision, and 2 of those patients had several local recurrences. It is our impression, however, that these new lesions are not true recurrences but, instead, new lesions that develop in the same irradiated field: a sort of field-effect phenomenon.

D2.40 is an O-linked sialoglycoprotein that targets an oncofetal antigen, M2A. D2.40 is a marker of normal and neoplastic lymphatic endothelial cells, although accumulated experience indicates that D2.40 is less specific to endothelial cells of lymphatic vessels than was believed previously. D2.40 positivity also has been reported in various nonendothelial cells.8, 19 Eighty-three percent of atypical vascular lesions in our series expressed D2.40, at least focally, thus favoring a lymphatic nature. Because positive D2.40 staining also has been reported in a subset of angiosarcomas,8 this antibody is not helpful in distinguishing between benign and malignant, radiation-associated vascular lesions.

Although the term atypical may not be adequate to designate these postradiation vascular lesions, it does emphasize that they easily may be misdiagnosed as angiosarcomas. However, as opposed to angiosarcomas, postradiation vascular lesions are relatively small (≤1 cm), well circumscribed, and frequently restricted to the superficial dermis. Most of them lack significant nuclear atypia, and endothelial cell multilayering (so-called piling-up phenomenon); blood lakes, and necrosis are not observed. Differential diagnosis can be very difficult in some patients, and clinicopathologic correlation is highly desirable. Cutaneous angiosarcomas usually present as multifocal, heterogeneous, variably large, cutaneous lesions with a bluish/ecchymotic appearance. Nevertheless, careful clinical follow-up is advisable, because some postradiation angiosarcomas may have a deceptively benign appearance. Recently, 4 women who had radiation-associated angiosarcoma with potentially misleading, benign-appearing capillary lobules were reported.12, 20

Although the rare lymphangioma-like variant of Kaposi sarcoma shares some histologic features with postradiation vascular lesions, the clinical presentation is quite different. Kaposi sarcoma is a vascular disease associated with herpes virus 8 (HHV-8) infection and has no relation to radiotherapy. It is noteworthy that the dissection of preexisting capillaries (the so-called promontory sign) should not be considered as pathognomonic of Kaposi sarcoma, because it was observed in 32% of our postradiation vascular lesions. In contrast to Kaposi sarcoma, areas of cell spindling were not observed. Immunostaining with anti-HHV-8 antibody also helps in distinguishing 1 lesion from the other.

In summary, cutaneous vascular proliferations that develop within the field of prior radiotherapy include rare tumors, such as angiosarcomas, and also benign lymphangiomatous proliferations, which are reported by some as benign lymphangiomatous papules/plaques. Histologically, the latter present either as a predominantly lymphangionendothelioma-like lesion or have the appearance of a lymphangioma circumscriptum. Although postradiation vascular lesions occasionally may show worrisome histologic features and some potential for multiplicity and/or recurrence, at least in the current study, they showed a benign clinical course and, thus, differed from angiosarcoma. On that point, heretofore, there is no or little evidence that postradiation vascular lesions have the capacity to transform into well-differentiated angiosarcomas or represent incipient (baby) angiosarcomas. Accordingly, we believe that these lesions are treated best conservatively. One should keep in mind, nevertheless, that irradiated patients are at risk for developing angiosarcoma and that some well-differentiated angiosarcomas may have a misleading benign appearance. Thus, any vascular lesion that occurs in a previously irradiated field should be excised completely with tumor-free margins and examined histologically.

Acknowledgements

We thank Drs. F. Mishellany, R. Kerdraon, P. Terrier, F. Collin, C. Ribaux, I. Orain Tours, J. Gallier, E. Arav, J. F. Henninger, and E. Mégevand for providing case material and follow-up information.