Path. Res. Pract. 187,301-306 (1991)
Well-Differentiated Angiosarcoma of the Skin Following Radiotherapy Report of two Cases A. Cancellieri and V. Eusebi Istituto di Anatomia e Istologia Patologica, University, Bologna, Italy
V. Mambelli Istituto di Anatomia e Istologia Patologica, Ancona, Italy
G. Ricotti Clinica Dermosifilopatica, Ospedale Regionale, Torrette, Ancona, Italy
G. Gardini Istituto di Anatomia, Istologia Patologica e di Citodiagnostica, Ospedale S. Maria Nuova, Reggio Emillia, Italy
G. Pasquinelli Istituto di Microscopia Elettronica Clinica, PoliC/inico S. Orsola, Bologna, Italy
SUMMARY Two cases of well-differentiated angiosarcoma following radiotherapy together with an immunocytochemical and electron-microscopical study are reported. Both cases occurred in young females (16- and 22-yr-old respectively) who had been irradiated after birth for an "angiomatous" lesion. These cases have to be added to 34 similar cases reported in the literature.
Introduction Angiosarcomas are rare malignant tumours of soft tissues, which arise most frequently in elderly patients 10 . In addition to chronic lymphoedema and other rare conditions 10 , therapeutic irradiation is known to be a rare additional etiological factor lO • In the present paper, two cases of well-differentiated angiosarcoma are described. Both cases appeared in young © 1991 by Gustav Fischer Verlag, Stuttgart
females (16 and 22-yr-old respectively) who each had been previously irradiated after birth for an "angiomatous" lesion.
Case No 1 A 22 yr-old young woman was admitted to the General Hospital in Reggio Emilia (Italy) with a blue nodule, 4 cm 0344-0338/91/0187-0301$3.50/0
302 . A. Cancellieri et al.
in its greatest axis, located in the right upper chest wall. The patient had undergone radiotherapy in the same site of the present nodule shortly after birth for a lesion defined as "angiomatous" by her parents. After the irradiation the lesion disappeared. The present nodule was excised. It appeared red in colour, showed ill-defined borders and was located in the hypodermis. After the histological diagnosis of welldifferentiated angiosarcoma, the excisional borders were enlarged. Two years after surgery, the patient is diseasefree without any sign of recurrence.
grown nodular and was irradiated when the patient was 2 months old (total dose: 1500 rad roentgentherapy; 1200 rad plesiotherapy). After irradiation, the lesion decreased in size and disappeared after a few months. Eight months after surgery for the present lesion a nodule appeared within the scar. It was 3 em in diameter and red-blue in colour. Histology confirmed a recurrence of the previous tumour. Six years and 1 month after the first excision, the patient is alive and well, with no sign of the disease. Material and Methods
Case No 2 A 16 yr-old girl presented at the University Hospital of Ancona (Italy) with a painless nodule, measuring 3 em in its greatest axis. The nodule, red-blue in colour with polycyclic borders, had appeared one year earlier in the right subscapular region. It showed a spongy-like cut surface (Fig. 1). At histology, a diagnosis of well-differentiated angiosarcoma was made. The lesion was localized in the same site of a red macula, present at birth, which had
Biopsies from the two cases and from the recurrence were fixed in formalin and routinely embedded; 3 !lm sections were cut and stained with Haematoxylin & Eosin (H & E). Immunocytochemistry was performed to show presence of Factor VIII related antigen (F VIII) (Dakopatts, diluted 1 : 2500) using the avidin-biotin-peroxidase complex (ABC) method by Hsu et al. 18 , modified by the use of streptavidin-biorin-peroxidase complex (Orrho Diagnostic Systems, Milan). ABC method was also used to stain the fucose-binding lectin Ulex Europaeus I (UEA I) in the cytoplasm of endothelial cells (Vector Labs, diluted 1: 2000).
Fig. 1. Case 2: The nodule has a spongy-like appearance and shows polycyclic borders (H & E, X 3).
Fig. 2. Case 1: The dermis is dissected by irregular vascular channels where papillary fronds are present (H & E, x 125).
Post-Irradiation Angiosarcoma· 303 For electron-microscopy (EM), formalin fixed tissues from case 1 were fixed in 2.5% glutaraldehyde, postfixed in 1% osmium tetroxide, dehydrated in graded ethanols and embedded in Araldite. Tissues from case 2 were obtained from formalin-fi xed, paraffin embedded blocks. The samples were dewaxed in xylene and successively processed as for case 1. Thin sections were stained with uranyl acetate and lead citrate and examined with a lEOL 100 B transmission electron microscope.
Histological Findings Both lesions consisted of nodules localized in the dermis and subcutis, with ill-defined borders. The nodules were characterized by irregular anastomosing vascular channels where several papillary fronds abutted into the lumina which were filled with red blood cells (Fig. 2) . The papillae were lined by endothelial elements showing hyperchromatic nuclei (Figs. 3-4). In addition, the neoplastic cells disposed in narrow strands or single files appeared to dissect the connective and adipose tissue and infiltrate perineural spaces (Fig. 5). In case 2, diffuse dissection of
Fig. 4. Case 1: Irregular hyperchromatic nuclei line the fibrous core of these papillae (H & E, x 400).
the superficial dermis by the neoplastic channels was evident. The recurrent lesion of case 2 displayed identical features seen in the first excision. In addition, diffuse invasion of the underlying skeletal muscle fibers was present. Mitoses were scanty (2 x 5 HPF) in each case. The neoplastic cells lining the vascular channels displayed intense positivity when the anti F VIII antiserum was used. Some cells also stained consistently when Ulex Europaeus (UE) was employed (Fig. 6). Electron Microscopy
Fig. 3. Case 2: Papillary fronds float inside the irregular vascular spaces. They are lined by endothelial elements showing hyperchromatic nuclei (H & E, x 320).
Ultrastructural features differed between the two cases. In case 1, the neoplastic endothelial elements appeared spindle in sh ape and showed rare desmosomes. The nuclei, round to ovoid in shape, protruded in the vascular spaces, displaying irregularly dispersed chromatin. In case 2, the neoplastic cells were polygonal in shape, exhibited convoluted nuclei with dispersed chromatin. In the cytoplasm, numerous elongated structures reminiscent of WeibelPalade bodies were present.
304 . A. Cancellieri et al.
Discussion Both cases showed irregular vascular channels which dissected the connective tissue of the dermis. Numerous papillae abutted within the vascular spaces. These were lined by atypical endothelial cells showing bizarre hyperchromatic nuclei. Mitoses, although infrequent, were present. The neoplastic cells were immunoreactive with anti-F VIII related antigen antiserum, as well as with UE I. These are well-established markers of endothelial cells. Therefore it appears that the features present in both cases are very consistent with well-differentiated angiosarcomas of the skin lO • Ionizing radiations, even at low doses, are a well-known cause of malignant neoplasms4 • Cases of sarcomas 1, 7,36,41 and angiosarcomas arising after radiotherapy have been reported in the literature. Angiosarcomas are accepted as being caused by previous radiotherapy if there is histological proof that the tumour occurs within the radiation field, after an interval of several years in the absence of chronic lymphoedema 10. Both cases described here met all these criteria; the latency of 15 and 21 years, respectively, excludes a recurrence of the "angiomatous" lesions which had been irradiated shortly after birth. In the literature, 46 cases of post-radiotherapy angiosarcoma 2,3,5,6, 9, 11-16, 19-35,37-39,42,43 have been reported to the best of our knowledge. Nevertheless, in 11 cases the
Fig. 5. Case 1: The neoplastic elements dissect the perineural spaces (H & E, x 200).
Fig. 6. A: Case 2: The endothelial cells of the papillary fronds are stained using the anti F-VIII antiserum (streptavidinbiotin-peroxidase, x 320). - B: Case 1: The endothelial cells lining the irregular vascular spaces contain UEA I (ABC method, x 320) .
Post-Irradiation Angiosarcoma . 305 Table 1. Cases of post-radiotherapy angiosarcoma of the literature Authors
Age+ Sex
Irradiated Lesion
Site (Rx)
Ross35 McCarthy, Pack 26 McCarthy, Pack 26 McCarthy, Pack 26 Legerlotz 22 Mach 24 Rachmanov et al. 33 Girard et al. 12 Podlyaschuku Paik, Komorowski 31 Ward, Buchanan42 Bennett et al. 3 Kim et al. 2O Hodgkinson et al. 16 Chen et al. 6 Hamels et al.14 Maddox, Evans 25 Maddox, Evans 25 Maddox, Evans 25 Maddox, Evans 25
47 33 35 35 50 62 66 55 14 81 20 31 37 71 65 68 60" 60* 60* 60"
F F n.s. n.s. F M F M F F M M M F F F F F F F
carCInoma haemangioma lymphangioma lymphangioma carCInoma eczema eczema lymphangioma haemangioma carCInoma haemangioma haemangioma haemangioma sinusitis carCInoma carcinoma carCInoma carCInoma carcinoma carCInoma
Maddox, Evans 25 Emmett, O'Rourke9 Richards et al. 34 Goette, Detlefs 13 Basso, Bartoli2 Basso, Bartoli2 O'Connor 29 Otis et aJ.3° Otis et aJ.3° Nanus et al. 28 Handfield et al. 15 Sironi et aJ.38 Laskin et aJ.21 Westenberg et al. 43 Present case, 1989 Present case, 1989
60*
M F F F n.s. M F F F F F F M F F F
carCInoma n.s. H.D. carCInoma carCInoma semInoma transplant carCInoma carCInoma dysgerminoma haemangioma haemangioma N.H.L. carCInoma haemangioma haem angioma
77
64 61 n.s. n.s. 49 67 71 42 24 18 72 59 22
16
Dose (rads)
Site (As)
Int.
Follow up
breast needles n.s. thigh leg n.s. leg n.s. cervIx 5900 face n.s. n.s. hand abd. skin n.s. cheek 4800 endometrium 6084 face 1000 n.s. skin skin 3300 face n.s. ovary 6000 breast 8000 breast n.s. cervIx 5500 cervIx 6600 cervIx n.s.
liver thigh leg leg ant. info abd. cheek hand abdomen cheek abdomen ear scalp thigh cheek term. ileum thorax thorax ant.inf.abd. ant.inf.abd. perianal
3 15 4 12 10 42 23 50 12 10 18 30 30 40 8 4 13 4.5 8 20
larynx nose
neck nose spinal L 3/4 info abd. lumbar inguinal skin scar thorax thorax term.ileum face arm chest wall omentum 'f ,. thorax back
8 18 13 23 16 16 6 3 3 14 23 16 7 8 21 15
died (3 yrs) n.s. n.s. n.s. n.s. n.s. died (5 yrs) n.s. died (5 mos) died (1.5 mos) died (2 yrs) died (2 yrs) n.s. A & W (8 mos) died (1 yr) died (11 mos) died (12 yrs*) died (12 yrs*) died (12 yrs") A & W (12 yrs") died (12 yrs'f) A, M (4 yrs) died (2.5 mos) n.s. n.s. n.s. died (1 yr) A, R (2.5 mos) n.s. died (3 yrs) A & W (1 yr) died (1 yr) died (1 yr) A & W (2 yrs) A & W (2 yrs) A, R (6 yrs)
n.s. n.s. 5065 spin~l cervIx 3000 kidney 4000-5000 testis 4000-5000 kidney 600 breast 5000 breast 3000 ovary 4800 face 2600 arm needles mediastinum n.s. cervIx 5000 skin n.s. skin 2700
AS = angiosarcoma, INT = interval in years between radiotherapy and occurrence of AS; * = mean value + age of the patient when the diagnosis of AS was made; n.s. = not stated; H. D. = Hodgkin's disease, N. H. L. = non-Hodgkin's lymphoma. yrs = years, mos = months, A & W = alive and well, A, R = alive with recurrence, A, M = alive with metastasis, "" = presence of ascites.
angiosarcoma was associated with lymphoedema, while one case 8 has to be excluded as the interval between the radiotherapy and the development of angiosarcoma is very short (2 and half years). Prognosis of angiosarcoma in general is very poor in most reports as about 50% of the patients die within 15 months of the diagnosis 17 , with a mean survival of 20 months 25 . Among the 34 cases in the literature, which met Enzinger and Weiss' criteria (Table 1), only 23 have been followed-up. Of these, seventeen patients died (73.9%) after a mean survival of 19.1 months 3,6, 14,21,24,25,28,29,31,32,34,35,38,42; 1 patient is alive and well three years after the excision of a metastasis9; 1 patient had a recurrence of the tumour after 2 and a half months 30 ; 4 patients are alive and well after a period of 8 months l6 , 1 year1,5 2 years 43 and 12 years 25 respectively. Our two patients had a clinical course similar to these latter cases.
Whether the lack of aggressiveness of the present tumours is related to their small size or to the well differentiated histology is controversial. Sordillo et aJ.39 found no histological differences in their series as to depth of invasion or cell morphology between long-term survivors and other groups. In addition, Maddox and Evans 25 found no correlation between survival and signs of malignancy as high mitotic activity or undifferentiated pattern. Therefore, the purpose of the present paper is to draw attention to the occurrence of low-grade malignancy angiosarcomas after radiotherapy. References I Arlen M, Higinbotham NL, Huvos AG, Marcove RC, Miller T, Shah IC (1971) Radiation-induced sarcoma of bone. Cancer 28: 1087-1099
306 . A. Cancellieri et al. 2 Basso-Ricci S, Bartoli C (1985) Cutaneous carcinomas and soft tissue sarcomas induced by ionizing radiation therapy. Presentation of a series of 42 cases. Tumori 71: 29-33 3 Bennet RG, Keller JW, Ditty JF Jr (1978) Hemangiosarcoma subsequent to radiotherapy for a hemangioma in infancy. J Dermatol Surg Oncol4: 881-883 4 Boice JD (1981) Cancer following medical irradiation. Cancer 7: 1081-1090 5 Calnan J, Cowdell RH (1959) Lymphangioendothelioma of the anterior abdominal wall. Br J Cancer 46: 375-379 6 Chen KTK, Hoffman KD, Hendricks EJ (1979) Angiosarcoma following therapeutic irradiation. Cancer 44: 2044-2048 7 Chen KTK, Bauer FW (1982) Sarcomatous transformation of nasopharyngeal angiofibroma. Cancer 49: 369-371 8 Davies JD, Rees GJG, Mera SL (1983) Angiosarcoma in irradiated post-mastectomy chest wall. Histopathology 7: 947-956 9 Emmett AJJ, O'Rourke MGE (1982) Angiosarcoma of skin. Aust NZ J Surg 52: 164-167 10 Enzinger FM, Weiss SW (1988) Soft Tissue Tumours. Mosby, St. Louis 11 Froio GF, Kirkland WG (1952) Lymphangiosarcoma in post-mastectomy lymphedema. Ann Surg 135: 421-425 12 Girard C, Johnson WC, Graham JH (1970) Cutaneous angiosarcoma. Cancer 26: 868-883 13 Goette DK, Detlefs RL (1985) Post-irradiation angiosarcoma. J Am Acad Dermatol12: 922-926 14 Hamels J, Blondian P, Mirgaux M (1981) Cutaneous angiosarcoma arising in a mastectomy scar after therapeutic irradiation. Bull Cancer 68: 353-356 15 Handfield-Jones SE, Kennedy CTC, Bradfield JB (1988) Angiosarcoma arising in an angiomatous naevus following irradiation in childhood. Br J Dermatol118: 109-112 16 Hodgkinson DJ, Soule EH, Woods JE (1979) Cutaneous angiosarcoma of the head and neck. Cancer 44: 1106-1113 17 Holden CA, Spittle MF, Wilson Jones E (1987) Angiosarcoma of the face and scalp, prognosis and treatment. Cancer 59: 1046-1057 18 Hsu SM, Raine L, Fanger H (1981) The use of avidinbiotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP procedures). J Histochem Cytochem 29: 577-580 19 Kettle JH (1957) Lymphangiosarcoma following postmastectomy lymphoedema. Br Med J 1: 193-194 20 KimJH, Chu FC, Woodward HQ, Melamed MR, Huvos A, Cantin J (1978) Radiation-induced soft tissue and bone sarcoma. Radiology 129: 501-508 21 Laskin WE, Silverman TA, Enzinger FM (1988) Postirradiation soft tissue sarcomas. An analysis of 53 cases. Cancer 62: 2330-2340 22 Legerlotz C (1962) Strahleninduziertes malignes Haemangioblastoma. Zentralbl Allg Pathol1 04: 58-66 23 Lo TCM, Silverman ML, Edelstein A (1985) Postirradiation hemangiosarcoma of the chest wall. Report of a case. Acta Radiol Oncol24: 237-240
24 Mach K (1966) Zur Frage des Lymphangioendotheliomas. Arch Klin Exper Dermatol 226: 318-326 25 Maddox JC, Evans HL (1981) Angiosarcoma of skin and soft tissue: a study of forty-four cases. Cancer 48: 1907-1921 26 McCarthy WD, Pack GT (1950) Malignant blood vessel tumors: a report of 56 cases of angiosarcoma and Kaposi's sarcoma. Surg Gynecol Obstet 91: 465-482 27 McSwain B, Whitehead W, Bennet L (1973) Angiosarcoma: report of three cases of postmastectomy lymphangiosarcoma and one of hemangiosarcoma. South Med J 66: 102-106 28 Nanus DM, Kelsen D, Clark DGC (1987) Radiationinduced angiosarcoma. Cancer 60: 777-779 29 O'Connor JP (1986) Cutaneous angiosarcoma following graft irradiation in a renal transplant patient. Clin Nephrol 1: 54-55 30 Otis CN, Peschel R, McKhann C, Merino MJ, Harrison Duray P (1986) The rapid onset of cutaneous angiosarcoma after radiotherapy for breast carcinoma. Cancer 57: 2130-2134 31 Paik HH, Komorowski R (1976) Hemangiosarcoma of the abdominal wall following irradiation therapy of endometrial carcinoma. Am J Clin Pathol 66: 810-814 32 Podlyaschuk EL (1972) Angiosarcoma of the temporal region following roentgen therapy of hemangioma of the cheek. Med Radiol17: 26-30 33 Rachmanov VA, Potiekaeva MA, Romanenko GF (1968) Late ulcerative radiodermatitis complicated by sarcoma. Arkh Pathol 30: 59-62 34 Richards PG, Bessell EM, Goolden AWG (1983) Spinal extradural angiosarcoma occurring after treatment for Hodgkin's disease. Clin Oncol 9: 165-168 35 Ross JM (1932) A case illustrating the effects of prolonged action of radium. J Path Bact 35: 899-912 36 Senyszyn J], Johnston AD, Jacox HW, Chu FCH (1970) Radiation-induced sarcoma after treatment of breast cancer. Cancer 26: 394-403 37 Shaikh NA, Beaconsfield T, Walker M, Ghilchik MW (1988) Postirradiation angiosarcoma of the breast - a case report. Eur J Surg Oncol14: 449-451 38 Sironi M, Marchini R, Taccagni GL, Cantaboni A (1988) Juvenile cutaneous angiosarcoma following radiotherapy of a hemangioma. Pathologica 80: 235-241 39 Sordillo PP, Chapman R, Hajdu SI, Magill GB, Golbey RB (1981) Lymphangiosarcoma. Cancer 48: 1674-1679 40 Spagnolo DV, Papadimitriou JM, Archer M (1984) Postirradiation malignant fibrous histiocytoma arising in juvenile nasopharyngeal angiofibroma and producing alpha-I-antitrypsin. Histopathology 8: 339-352 41 Travis EL, Kreuther A, Young T, Gerald WL (1976) Unusual postirradiation sarcoma of the chest wall. Cancer 38: 2269-2273 42 Ward CM, Buchanan R (1977) Haemangiosarcoma following irradiation of a haemangioma of the face. J Maxillofac Surg 5: 164-166 43 Westenberg AH, Wiggers T, Henzen-Logmans SC, Verweij J, Meerwaldt JA, Van Gell An (1989) Post-irradiation angiosarcoma of the greater omentum. 15: 175-178
Received January 15, 1990 . Accepted April 12, 1990
Key words: Angiosarcoma - Post-irradiation sarcoma - Radiotherapy - Skin sarcoma - F VIII related antigen V. Eusebi, M.D., Istituto di Anatomia Patologica, Universita di Bologna, Sede distaccata Ospedale Bellaria, Via Altura, 3, 40139 Bologna, Italy
Well-Differentiated Angiosarcoma of the Skin Following Radiotherapy Report of two Cases A. Cancellieri and V. Eusebi Istituto di Anatomia e Istologia Patologica, University, Bologna, Italy
V. Mambelli Istituto di Anatomia e Istologia Patologica, Ancona, Italy
G. Ricotti Clinica Dermosifilopatica, Ospedale Regionale, Torrette, Ancona, Italy
G. Gardini Istituto di Anatomia, Istologia Patologica e di Citodiagnostica, Ospedale S. Maria Nuova, Reggio Emillia, Italy
G. Pasquinelli Istituto di Microscopia Elettronica Clinica, PoliC/inico S. Orsola, Bologna, Italy
SUMMARY Two cases of well-differentiated angiosarcoma following radiotherapy together with an immunocytochemical and electron-microscopical study are reported. Both cases occurred in young females (16- and 22-yr-old respectively) who had been irradiated after birth for an "angiomatous" lesion. These cases have to be added to 34 similar cases reported in the literature.
Introduction Angiosarcomas are rare malignant tumours of soft tissues, which arise most frequently in elderly patients 10 . In addition to chronic lymphoedema and other rare conditions 10 , therapeutic irradiation is known to be a rare additional etiological factor lO • In the present paper, two cases of well-differentiated angiosarcoma are described. Both cases appeared in young © 1991 by Gustav Fischer Verlag, Stuttgart
females (16 and 22-yr-old respectively) who each had been previously irradiated after birth for an "angiomatous" lesion.
Case No 1 A 22 yr-old young woman was admitted to the General Hospital in Reggio Emilia (Italy) with a blue nodule, 4 cm 0344-0338/91/0187-0301$3.50/0
302 . A. Cancellieri et al.
in its greatest axis, located in the right upper chest wall. The patient had undergone radiotherapy in the same site of the present nodule shortly after birth for a lesion defined as "angiomatous" by her parents. After the irradiation the lesion disappeared. The present nodule was excised. It appeared red in colour, showed ill-defined borders and was located in the hypodermis. After the histological diagnosis of welldifferentiated angiosarcoma, the excisional borders were enlarged. Two years after surgery, the patient is diseasefree without any sign of recurrence.
grown nodular and was irradiated when the patient was 2 months old (total dose: 1500 rad roentgentherapy; 1200 rad plesiotherapy). After irradiation, the lesion decreased in size and disappeared after a few months. Eight months after surgery for the present lesion a nodule appeared within the scar. It was 3 em in diameter and red-blue in colour. Histology confirmed a recurrence of the previous tumour. Six years and 1 month after the first excision, the patient is alive and well, with no sign of the disease. Material and Methods
Case No 2 A 16 yr-old girl presented at the University Hospital of Ancona (Italy) with a painless nodule, measuring 3 em in its greatest axis. The nodule, red-blue in colour with polycyclic borders, had appeared one year earlier in the right subscapular region. It showed a spongy-like cut surface (Fig. 1). At histology, a diagnosis of well-differentiated angiosarcoma was made. The lesion was localized in the same site of a red macula, present at birth, which had
Biopsies from the two cases and from the recurrence were fixed in formalin and routinely embedded; 3 !lm sections were cut and stained with Haematoxylin & Eosin (H & E). Immunocytochemistry was performed to show presence of Factor VIII related antigen (F VIII) (Dakopatts, diluted 1 : 2500) using the avidin-biotin-peroxidase complex (ABC) method by Hsu et al. 18 , modified by the use of streptavidin-biorin-peroxidase complex (Orrho Diagnostic Systems, Milan). ABC method was also used to stain the fucose-binding lectin Ulex Europaeus I (UEA I) in the cytoplasm of endothelial cells (Vector Labs, diluted 1: 2000).
Fig. 1. Case 2: The nodule has a spongy-like appearance and shows polycyclic borders (H & E, X 3).
Fig. 2. Case 1: The dermis is dissected by irregular vascular channels where papillary fronds are present (H & E, x 125).
Post-Irradiation Angiosarcoma· 303 For electron-microscopy (EM), formalin fixed tissues from case 1 were fixed in 2.5% glutaraldehyde, postfixed in 1% osmium tetroxide, dehydrated in graded ethanols and embedded in Araldite. Tissues from case 2 were obtained from formalin-fi xed, paraffin embedded blocks. The samples were dewaxed in xylene and successively processed as for case 1. Thin sections were stained with uranyl acetate and lead citrate and examined with a lEOL 100 B transmission electron microscope.
Histological Findings Both lesions consisted of nodules localized in the dermis and subcutis, with ill-defined borders. The nodules were characterized by irregular anastomosing vascular channels where several papillary fronds abutted into the lumina which were filled with red blood cells (Fig. 2) . The papillae were lined by endothelial elements showing hyperchromatic nuclei (Figs. 3-4). In addition, the neoplastic cells disposed in narrow strands or single files appeared to dissect the connective and adipose tissue and infiltrate perineural spaces (Fig. 5). In case 2, diffuse dissection of
Fig. 4. Case 1: Irregular hyperchromatic nuclei line the fibrous core of these papillae (H & E, x 400).
the superficial dermis by the neoplastic channels was evident. The recurrent lesion of case 2 displayed identical features seen in the first excision. In addition, diffuse invasion of the underlying skeletal muscle fibers was present. Mitoses were scanty (2 x 5 HPF) in each case. The neoplastic cells lining the vascular channels displayed intense positivity when the anti F VIII antiserum was used. Some cells also stained consistently when Ulex Europaeus (UE) was employed (Fig. 6). Electron Microscopy
Fig. 3. Case 2: Papillary fronds float inside the irregular vascular spaces. They are lined by endothelial elements showing hyperchromatic nuclei (H & E, x 320).
Ultrastructural features differed between the two cases. In case 1, the neoplastic endothelial elements appeared spindle in sh ape and showed rare desmosomes. The nuclei, round to ovoid in shape, protruded in the vascular spaces, displaying irregularly dispersed chromatin. In case 2, the neoplastic cells were polygonal in shape, exhibited convoluted nuclei with dispersed chromatin. In the cytoplasm, numerous elongated structures reminiscent of WeibelPalade bodies were present.
304 . A. Cancellieri et al.
Discussion Both cases showed irregular vascular channels which dissected the connective tissue of the dermis. Numerous papillae abutted within the vascular spaces. These were lined by atypical endothelial cells showing bizarre hyperchromatic nuclei. Mitoses, although infrequent, were present. The neoplastic cells were immunoreactive with anti-F VIII related antigen antiserum, as well as with UE I. These are well-established markers of endothelial cells. Therefore it appears that the features present in both cases are very consistent with well-differentiated angiosarcomas of the skin lO • Ionizing radiations, even at low doses, are a well-known cause of malignant neoplasms4 • Cases of sarcomas 1, 7,36,41 and angiosarcomas arising after radiotherapy have been reported in the literature. Angiosarcomas are accepted as being caused by previous radiotherapy if there is histological proof that the tumour occurs within the radiation field, after an interval of several years in the absence of chronic lymphoedema 10. Both cases described here met all these criteria; the latency of 15 and 21 years, respectively, excludes a recurrence of the "angiomatous" lesions which had been irradiated shortly after birth. In the literature, 46 cases of post-radiotherapy angiosarcoma 2,3,5,6, 9, 11-16, 19-35,37-39,42,43 have been reported to the best of our knowledge. Nevertheless, in 11 cases the
Fig. 5. Case 1: The neoplastic elements dissect the perineural spaces (H & E, x 200).
Fig. 6. A: Case 2: The endothelial cells of the papillary fronds are stained using the anti F-VIII antiserum (streptavidinbiotin-peroxidase, x 320). - B: Case 1: The endothelial cells lining the irregular vascular spaces contain UEA I (ABC method, x 320) .
Post-Irradiation Angiosarcoma . 305 Table 1. Cases of post-radiotherapy angiosarcoma of the literature Authors
Age+ Sex
Irradiated Lesion
Site (Rx)
Ross35 McCarthy, Pack 26 McCarthy, Pack 26 McCarthy, Pack 26 Legerlotz 22 Mach 24 Rachmanov et al. 33 Girard et al. 12 Podlyaschuku Paik, Komorowski 31 Ward, Buchanan42 Bennett et al. 3 Kim et al. 2O Hodgkinson et al. 16 Chen et al. 6 Hamels et al.14 Maddox, Evans 25 Maddox, Evans 25 Maddox, Evans 25 Maddox, Evans 25
47 33 35 35 50 62 66 55 14 81 20 31 37 71 65 68 60" 60* 60* 60"
F F n.s. n.s. F M F M F F M M M F F F F F F F
carCInoma haemangioma lymphangioma lymphangioma carCInoma eczema eczema lymphangioma haemangioma carCInoma haemangioma haemangioma haemangioma sinusitis carCInoma carcinoma carCInoma carCInoma carcinoma carCInoma
Maddox, Evans 25 Emmett, O'Rourke9 Richards et al. 34 Goette, Detlefs 13 Basso, Bartoli2 Basso, Bartoli2 O'Connor 29 Otis et aJ.3° Otis et aJ.3° Nanus et al. 28 Handfield et al. 15 Sironi et aJ.38 Laskin et aJ.21 Westenberg et al. 43 Present case, 1989 Present case, 1989
60*
M F F F n.s. M F F F F F F M F F F
carCInoma n.s. H.D. carCInoma carCInoma semInoma transplant carCInoma carCInoma dysgerminoma haemangioma haemangioma N.H.L. carCInoma haemangioma haem angioma
77
64 61 n.s. n.s. 49 67 71 42 24 18 72 59 22
16
Dose (rads)
Site (As)
Int.
Follow up
breast needles n.s. thigh leg n.s. leg n.s. cervIx 5900 face n.s. n.s. hand abd. skin n.s. cheek 4800 endometrium 6084 face 1000 n.s. skin skin 3300 face n.s. ovary 6000 breast 8000 breast n.s. cervIx 5500 cervIx 6600 cervIx n.s.
liver thigh leg leg ant. info abd. cheek hand abdomen cheek abdomen ear scalp thigh cheek term. ileum thorax thorax ant.inf.abd. ant.inf.abd. perianal
3 15 4 12 10 42 23 50 12 10 18 30 30 40 8 4 13 4.5 8 20
larynx nose
neck nose spinal L 3/4 info abd. lumbar inguinal skin scar thorax thorax term.ileum face arm chest wall omentum 'f ,. thorax back
8 18 13 23 16 16 6 3 3 14 23 16 7 8 21 15
died (3 yrs) n.s. n.s. n.s. n.s. n.s. died (5 yrs) n.s. died (5 mos) died (1.5 mos) died (2 yrs) died (2 yrs) n.s. A & W (8 mos) died (1 yr) died (11 mos) died (12 yrs*) died (12 yrs*) died (12 yrs") A & W (12 yrs") died (12 yrs'f) A, M (4 yrs) died (2.5 mos) n.s. n.s. n.s. died (1 yr) A, R (2.5 mos) n.s. died (3 yrs) A & W (1 yr) died (1 yr) died (1 yr) A & W (2 yrs) A & W (2 yrs) A, R (6 yrs)
n.s. n.s. 5065 spin~l cervIx 3000 kidney 4000-5000 testis 4000-5000 kidney 600 breast 5000 breast 3000 ovary 4800 face 2600 arm needles mediastinum n.s. cervIx 5000 skin n.s. skin 2700
AS = angiosarcoma, INT = interval in years between radiotherapy and occurrence of AS; * = mean value + age of the patient when the diagnosis of AS was made; n.s. = not stated; H. D. = Hodgkin's disease, N. H. L. = non-Hodgkin's lymphoma. yrs = years, mos = months, A & W = alive and well, A, R = alive with recurrence, A, M = alive with metastasis, "" = presence of ascites.
angiosarcoma was associated with lymphoedema, while one case 8 has to be excluded as the interval between the radiotherapy and the development of angiosarcoma is very short (2 and half years). Prognosis of angiosarcoma in general is very poor in most reports as about 50% of the patients die within 15 months of the diagnosis 17 , with a mean survival of 20 months 25 . Among the 34 cases in the literature, which met Enzinger and Weiss' criteria (Table 1), only 23 have been followed-up. Of these, seventeen patients died (73.9%) after a mean survival of 19.1 months 3,6, 14,21,24,25,28,29,31,32,34,35,38,42; 1 patient is alive and well three years after the excision of a metastasis9; 1 patient had a recurrence of the tumour after 2 and a half months 30 ; 4 patients are alive and well after a period of 8 months l6 , 1 year1,5 2 years 43 and 12 years 25 respectively. Our two patients had a clinical course similar to these latter cases.
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Received January 15, 1990 . Accepted April 12, 1990
Key words: Angiosarcoma - Post-irradiation sarcoma - Radiotherapy - Skin sarcoma - F VIII related antigen V. Eusebi, M.D., Istituto di Anatomia Patologica, Universita di Bologna, Sede distaccata Ospedale Bellaria, Via Altura, 3, 40139 Bologna, Italy
