Postradiation Cutaneous Angiosarcoma After Treatment of Breast Carcinoma is Characterized by MYC Amplification in Contrast to Atypical Vascular Lesions After Radiotherapy and Control Cases

Clinicopathological, Immunohistochemical and Molecular Analysis of 66 Cases

T Mentzel; H U Schildhaus; G Palmedo; R Büttner; H Kutzner

Disclosures

Mod Pathol. 2012;25(1):75-85. 

In This Article

Results

The clinical details of the affected patients are summarized in Table 1, and selected results of immunohistochemical investigations and of FISH analysis are listed in Table 2.

Control Group (Cases 1–5)

Five patients (2 M, 3 F, age ranged between 20 and 76 years) were included into the control group. In Case 1, a hemangioma arising on the buttock was completely excised. The patient in Case 2 developed a well-circumscribed hobnail hemangioma in the popliteal fossa, showing a biphasic growth of superficially dilated, lymphangioma-like vascular structures, and deeper rather narrow vessels lined by hobnail endothelial cells containing enlarged but uniform nuclei. Cases 3 and 4 contained biopsies from the rectum showing moderate postradiation colitis after radiotherapy of rectal and prostatic cancers. The patient in Case 5 is a 70-year-old female who developed a basal cell carcinoma in the postradiation area, who previously received radiotherapy for breast cancer with dermal fibrosis, slight vascular proliferation, and scattered inflammatory cells. Immunohistochemically, the endothelial cells of the hobnail hemangioma in Case 2 stained focally positive for prox-1, whereas the remaining cases were negative, and endothelial cells did not stain positively for MYC. In none of the control cases, an amplification of MYC was detected by FISH analysis.

Cases Showing Radiation-Induced Vascular Proliferation (Cases 6–17)

This group comprised 12 female patients (age ranged between 48 and 79 years), who received radiotherapy for breast cancer. All carcinomas were excised completely, and the vascular proliferation developed within 1 and 12 years after radiotherapy. The patients presented clinically with ill-defined, sometimes slightly indurated and erythematous skin areas in the postradiation areas, and skin ulceration was seen in two cases (Cases 8 and 13). Histologically, a slight and diffuse increase of dilated or narrow vessels associated with dermal fibrosis and scattered inflammatory cells was seen in all cases, and in Cases 9–16 the dermal fibrosis was more intense. Immunohistochemically, all cases were negative for MYC, and focal expression of prox-1 was noted in only one case (Case 7). No MYC amplification was detected by FISH analysis.

Atypical Vascular Proliferations after Radiotherapy (Cases 18–33)

In this group 16 female patients were included (age ranged between 29 and 81 years), who received radiotherapy for breast cancer and developed an atypical vascular proliferation within 2 and 8 years after radiotherapy. In Case 21 two lesions were seen, and in Cases 27 and 31 multiple lesions developed within a short time period (Figure 1), the remaining patients presented with solitary lesions. The lesions were excised completely and no progression to an angiosarcoma was reported. Follow-up information was available in 11 patients (range from 12 to 144 months) and revealed a local recurrence in Case 25 who was treated with complete excision.

Figure 1.

The patient in Case 31 presented with multiple lesions. Numerous lesions were excised, and no progression within 12 months was noted.

Cases 19 and 26 showed features of benign lymphangiomatous papule with superficially located, well-circumscribed, lymphangioma-like vascular structures lined by slightly enlarged endothelial cells with enlarged but uniform 'hobnail'-like nuclei. No endothelial multilayering, no formation of papillary structures, and no increased proliferative activity were seen in these lesions (Figure 2). Immunohistochemically, the vascular spaces were not or only incompletely surrounded by actin-positive (myo)pericytes, and no increased Ki-67 activity was detected. Both cases showed a focal expression of prox-1 by endothelial tumor cells, whereas MYC was negative. No MYC amplification was detected in both cases (Figure 2).

Figure 2.

Case 19 showed morphological features of benign lymphangiomatous papule with dilated, lymphangioma-like vascular structures (a). Higher power view reveals dilated vascular structures lined by bland endothelial cells (b). Immunohistochemically, no expression of MYC was seen in endothelial tumor cells (c). No MYC amplification was detected by FISH analysis (d).

The other 14 patients in this group developed atypical vascular lesions showing a broad morphological variation. The lesions in Cases 20 and 32 resembled an ill-defined lymphangioma, and the lesion in Case 28 was composed of hemangioma-like vascular structures with stromal fibrosis. The remaining cases were composed of rather ill-defined, superficially located dermal vascular lesions composed of dilated and narrow vascular structures. In Case 31, multiple lesions were excised showing features of either well-circumscribed lymphangioma or of ill-defined vascular lesions composed of narrow vascular structures. The lining endothelial cells contained slightly enlarged but relatively uniform, sometimes hyperchromatic, nuclei, and no increased proliferative activity was detected. In Cases 18, 22, 23, 25, 27, 30, and 33 more worrisome morphological features were present. At least focally, anastomosing vascular spaces were noted, and focal endothelial multilayering was present in these lesions (Figure 3). Immunohistochemically, only few endothelial cells showed Ki-67 expression. Whereas a focal expression of prox-1 was noted in 10 cases (Cases 18, 20, 22, 24, 25, 26, 27, 30, 32, and 33), only few endothelial cells in Case 28 stained positively for MYC, the remaining cases were negative. No MYC amplification was detected in any case (Figure 3).

Figure 3.

An atypical vascular lesion was seen in Case 18. The rather ill-defined dermal neoplasm is composed of narrow and dilated vascular structures dissecting the dermis (a). The vascular spaced are lined by endothelial cells with enlarged but uniform nuclei. No endothelial multilayering and no significant atypia are present (b). A focal expression of prox-1 by endothelial cells was noted (c). No MYC amplification was detected by FISH analysis (d).

Angiosarcomas of Skin and Soft Tissues Unrelated to Radiotherapy (Cases 34–41)

Three male and five female patients (age ranged between 25 and 92 years) in this group developed an angiosarcoma unrelated to previous radiotherapy. The neoplasms of Cases 34, 36, 37, 38, and 41 arose in subcutaneous and deep soft tissues of the trunk, the neck and the extremities, Case 35 represented a cutaneous angiosarcoma arising on the lower leg, and Cases 39 and 40 arose in deep tissue of the breast. Histologically, the neoplasms showed a broad morphological spectrum ranging from well-differentiated angiosarcoma in Case 40 to poorly differentiated angiosarcoma composed of sheets of atypical endothelial tumor cells with numerous mitoses and areas of tumor necrosis in Case 34. A predominantly spindle cell angiosarcoma was seen in Case 36. Unfortunately, follow-up information was available in only two patients. A local recurrence at 18 months occurred in Case 38, and the patient of Case 39 developed multiple liver and peritoneal metastases at 110 months. Immunohistochemically, focal expression of prox-1 was noted in Case 41. No MYC amplification was detected in any case.

Angiosarcomas after Radiotherapy (Cases 42–66)

In this group 25 female patients, who developed a cutaneous angiosarcoma after radiotherapy for breast cancer, were included. In all cases the breast carcinoma had been excised completely, and the vascular neoplasms developed within 1.5 and 13 years after radiotherapy (Figure 4). The age of the affected patient ranged from 46 to 95 years. Follow-up information of 19 patients (range from 5 to 60 months) revealed local recurrences in seven cases (Cases 42, 44, 49, 50, 51, 57, and 61), lymph node metastases in Case 57, multiple metastases in two patients (Cases 51 and 53), and six patients died of disease (Cases 44, 51, 52, 53, 54, and 57).

Figure 4.

The patient in Case 66 developed an erythematous and indurated plaque with numerous papules and nodules of varying size.

In 21 patients a dermal angiosarcoma was seen, whereas in Cases 48, 52, 58, and 62 the dermis and the subcutis were involved. Histologically, a broad morphological spectrum was present ranging from well-differentiated, BLAP- or AVL-like cutaneous angiosarcomas in Cases 55 and 59 to poorly differentiated neoplasms, i.e., in Case 62. The neoplasms were composed of dissecting, infiltrating, and anastomosing vascular structures lined by enlarged endothelial tumor cells containing enlarged vesicular or hyperchromatic nuclei (Figure 5). A solid growth was present in Cases 46, 52, 62, and 65. Whereas mild cytologic atypia was present in Case 55, severe atypia was noted in Cases 45, 52, 62, 64, and 65. Interestingly, numerous vascular tufts resembling morphological features of tufted hemangioma were noted in Cases 43 and 61 (Figure 6). Intravascular papillary structures lined by atypical endothelial cells were detected in Case 58. A predominantly epithelioid cytomorphology of neoplastic endothelial cells was noted in Cases 62 and 64, whereas spindle-shaped tumor cells predominated in Case 65. The mitotic rate ranged from 2 mitoses in 10 high-power fields in Cases 55 and 59 to 65 mitoses in 10 high-power fields in Case 62, and the Ki-67 index ranged from 10% in Case 59 to 90% in Case 64. Ulceration of the overlying epidermis was present in Cases 45, 50, 52, and 60, and areas of confluent tumor necrosis were seen in Cases 52 and 62. Numerous lymphocytes were seen in Cases 51, 53, 60, and 63.

Figure 5.

The biopsy of Case 42 shows features of a moderately differentiated cutaneous angiosarcoma. The neoplasm is composed of infiltrating and anastomosing vascular structures lined by atypical endothelial cells (a). Endothelial tumor cells contain enlarged and hyperchromatic nuclei. Note focal endothelial multilayering (b). Immunohistochemically, a strong nuclear staining of endothelial tumor cells for MYC is seen (c), and FISH analysis reveals MYC amplification (d).

Figure 6.

Cellular tufts composed of narrow vascular structures are seen in Case 43 (a). Numerous tumor cells stain positively for MYC (b), and FISH analysis reveals MYC amplification (c). Small vessels in the vicinity of the obvious angiosarcomatous areas were lined by slightly atypical endothelial cells (d), which stained strongly positive for MYC (e).

Immunohistochemically, positive nuclear staining of neoplastic endothelial cells for MYC was seen in all but one case (Case 55), and for prox-1 in all but five cases (Cases 44, 46, 58, 62, and 63). Interestingly, the endothelial cells in small vascular structures in the vicinity of the obvious cutaneous angiosarcoma, that were lined by atypical endothelial cells, stained positively for MYC as well (Figure 6). In contrast, cytologically uniform endothelial cells lining small and dilated vascular structures in the periphery showed no expression of MYC. FISH analysis of all cases detected amplification of MYC in the vast majority of tumor cell nuclei (Table 2). In four cases (Cases 43, 45, 51, and 52), small and dilated vessels in the periphery, lined by cytologically uniform endothelial cells, were examined by FISH analysis as well; however, no MYC amplification was detected in these vessels.

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