Medical and Pediatric Oncology 20:352-356 (1992)

Cutaneous Angiosarcoma as a Second Malignant Neoplasm After Peripheral Primitive Neuroectodermal Tumor Cheryl M. Coffin, MD, Teresa J. Vietti, MD, Vita J. Land, Kraybill, MD, and Louis P. Dehner, MD Second malignant neoplasms (SMN) in late childhood or young adulthood in individuals who have been successfully treated for an initial malignancy have emerged as a late effect of therapy in survivors of childhood cancer. Although radiation therapy i s frequently implicated, chemotherapy with alkylating agents and antimetabolites has also been associated with SMN. Soft tissue sarcomas are among the most frequent primary malignancies complicated by a SMN and account for a majority of nonhematolymphoid SMN. We present the clinical

MD,

William G.

and pathologic findings in a patient who had a peripheral neuroepithelioma (primitive neuroectodermal tumor, PNET) of the soft tissues diagnosed at 17 years of age, was treated with high-dose irradiation and multidrug chemotherapy, and developed an angiosarcoma 14 years later. This case represents an uncommon combination of mesenchyrnal malignancies in a young patient with an unusually favorable clinical course following the diagnosis of PNET. 0 1992 Wiley-Liss, Inc.

Key words: p r i m i t i v e n e u r o e c t o d e r m a l tumor, angiosarcoma, second primary malignant neoplasm, radiation-induced neoplasms, late effects of therapy

INTRODUCTION

Cutaneous angiosarcoma is an infrequent malignant neoplasm which usually occurs in middle or late adulthood and arises predominantly in three clinical settings: the face and scalp of elderly individuals, the lymphedematous extremity, and in previously irradiated skin [I-31. Angiosarcoma of the skin and soft tissues has occasionally been reported as a second malignant neoplasm in adults who were successfully treated for another pathologically separate malignancy, principally carcinoma of the breast [4-6]. Although soft tissue sarcomas are a frequent SMN among survivors of childhood cancer and are usually attributed to radiation therapy, the occurrence of angiosarcoma following peripheral PNET is a combination which has not been previously observed to the best of our knowledge 171.

and by January, 1976, a firm, focally cystic mass had attained a maximum diameter of 25 crn in addition to the presence of a 2 cm right axillary lymph node, which was biopsied and interpreted as metastatic neuroectodermal neoplasm. A chest X-ray, bone scan, and bone marrow aspirate yielded no evidence of metastatic disease. The patient was referred to the St. Louis Children’s Hospital for further evaluation and treatment. Combined irradiation and chemotherapy without additional surgery were selected. A total radiation dosage of 6,600 cGy was administered to the right forearm and 5,600 cGy to the right axilla and supraclavicular region in a period of 7 weeks. Chemotherapy from January, 1976, through December, 1977, included vincristine, cyclophosphamide, doxorubicin, and 5-fluorouracil. The tumor decreased rapidly in size and had virtually disappeared within 2 months after initiation of therapy. Remission

CASE REPORT

In November, 1975, a 17-year-old white female noticed a painless 5 cm lump on the volar aspect of her right forearm. She had been previously healthy, with no history of trauma, family history of malignancy, or a documented genetic syndrome, such as neurofibromatosis. An excisional biopsy with resection margins free of tumor was performed in early December; the diagnosis was a peripheral neuroepithelioma. The tumor recurred 0 1992 Wiley-Liss, Inc.

From the Departments of Pathology (C.M.C., L.P.D.) (Lauren V. Ackerman Laboratory of Surgical Pathology), Pediatrics (T.J.V., V.J.L.) (Division of Hematology-Oncology), and Surgery (W.G.K.), Barnes and St. Louis Children’s Hospitals, Washington University School of Medicine, St. Louis, MO. Received May 21, 1991; accepted August 6, 1991. Address reprint requests to Cheryl M. Coffin, MD, Division of Anatomic Pathology, Barnes Hospital, 1 Barnes Hospital Plaza, S t . Louis, M O 631 10.

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present in the arm. A skin biopsy showed angiosarcoma. A bone scan and magnetic resonance image of the right arm revealed no demonstrable abnormalities. A right forequarter amputation resulted in complete removal of the tumor. In July 1991, one year after surgery, the patient had no clinical evidence of recurrent angiosarcoma. P A T H 0LOGIC FINDINGS

Fig. 1. The primitive neuroectodermal tumor consists of oval and polygonal hyperchromatic cells with prominent rosette lormation (hematoxylin-eosin, X 200).

was maintained. Chemotherapy was discontinued in December, 1977. The patient remained well for the next 12 years. In December, 1989, several violaceous foci were noted on the skin of the right medial upper arm;these lesions had been present for 2-3 years and had increased slowly in size and number over that period. The largest lesion was 1.5 X 1.2 cm. There were no palpable nodules or masses associated with the violaceous areas. Physical examination in July, 1990, revealed multiple violaceous lesions on the right arm extending proximally to within 5 cm. of the axilla. Some mild lymphedematous changes were

The tumor excised in December 1975 was 5 cm in greatest dimension and had a tan, fleshy, focally hemorrhagic cut surface. Microscopically, the tumor was composed of lobules of primitive neoplastic cells demarcated by fibrovascular septa (Fig. I ) . The cells were oval, with scanty eosinophilic cytoplasm, round or oval nuclei, and frequent mitoses. Many lobules contained central foci of necrosis, and individual cell necrosis was frequent. In some areas, rosettes with a central solid core of eosinophilic fibrillary processes were prominent. Immunohistochemical staining on formalin-fixed paraffinembedded tissue performed in 1990 revealed diffuse immunoreactivity with monoclonal antibodies to vimentin, synaptophysin, chromogranin, actin, and neuronspecific enolase. Immunostains for cytokeratin, epithelial membrane antigen, neurofilaments, S 100 protein, carcinoembryonic antigen, Leu 7, desmin, and leucocyte common antigen were negative. The immunohistochemical reagents are listed in Table I. The skin biopsy from the right arm and the right

TABLE I. Immunohistochemical Reagents* Antibody or lectin Vimentin C ytokeratins AE 1IAE3 MAK-6 CAM 5.2 Neurofilament Desmin Actin (HHF35) Neuron-specific enolase Chromogranin Synaptophysin S 100 protein Leu I Epithelial membrane antigen Carcinoembryonic antigen Leucocyte common antigen Factor VIII-related antigen Ulex europaeus agglutinin I

Clonality

Source

Dilution

M

Biogenex Laboratories

I :2,000

M M M M M M P M M P M

Boehringer- Mannheim Triton Biosciences Becton Dickinson Biogenex Laboratories Biogenex Enzo Biogenex Laboratories Boehringer Boehringer Mannheim Dakopatts Becton Dickinson

1:150

M

Dakopatts

1:800

M

Boehringer- Mannheim

1 :4,000

M

Dakopatts

1:80

M

Dakopatts

1:20

-

Vector Laboratories

1: 1,000

*M, monoclonal antibodies; P, polyclonal antibodies.

1:40 1:150 1 :200 1:1,200 1:64,000 1:450 1:4,000 1 :40 1:3,000

1:lOO

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axilla in addition to chronic lymphedema [ I ] . In the present patient, the relatively young age at diagnosis of angiosarcoma and its origin in previously irradiated, lymphedematous skin lead us to conclude that the angiosarcoma represents a SMN related to the previous treatment for PNET and not a random event. Primitive neuroectodermal tumor of the soft tissues shares certain histologic features with neuroblastoma and Ewing’s sarcoma of soft tissues. One of the earliest descriptions was by Stout, and Penfield subsequently introduced the term “peripheral neuroepithelioma” for a peripheral neuroectodermal tumor of the soft tissues composed of small rounded cells which formed rosettes and separated into lobules by fibrovascular trabeculae [ I 3-1 51. The neuroectodermal phenotype has been conFig. 2. Multiple patches and papules are present on the skin of the firmed by the ultrastructural identification of neurosecreright arm. tory-like granules and the immunohistochemical demonstration of chromogranin, synaptophysin, neuron-specific cnolase, Leu 7, and other neural-associated markers forequarter amputation showed multiple reddish brown [1&18]. In the past decade, PNET has emerged as an patches and papules ranging in size from 0.1 to 1.8 cm important soft tissue neoplasm in children, adolescents, (Fig. 2). Approximately 50 lesions were visible on the and young adults mainly through improvements in diagforearm and medial upper arm and were confined to the nostic techniques like immunohistochemistry and elecskin, without macroscopic involvement of subcutaneous tron microscopy [ 191. The clinical course is aggressive, or deep soft tissues or bone. Microscopic examination which accounts for the ominous prognosis [ 16,20-231. revealed a well-differentiated angiosarconia (Fig. 3A). Recent studies have indicated that the most effective Multiple anastomosing vascular channels of varying sizes treatment is surgery with combination chemotherapy and dissected subtly between collagen fibers of the dermis. high-dose radiation therapy 124,251. None of these The endothelial cells were prominent and focally had a studies has reported SMN in survivors of a PNET. cuboidal configuration (Fig. 3B). No solid areas of It is currently estimated that I of every 1,000 Amertumor, hemorrhage, or necrosis were seen. The bone and icans at 20 years of age can claim to have survived cancer cutaneous resection margins showed no evidence of 1261. As this population has increased and as the survival angiosarcoma. The neoplastic endothelial cells were rate for childhood malignancies has improved to exceed immunoreactive with antibodies to factor VIII-related SO% at 5 years, the SMN has evolved as a worrisome antigen, U1e.r eirropueus agglutinin I , and vimentin and consequence 1271. Since 1962, there have been 17 nonreactive for cytokeratin and epithelial membrane examples of SMNs in 1,053 individuals successfully antigen. treated at St. Louis Children’s Hospital for a childhood primary malignancy with an incidence of 1.6% for SMN in this group (Dr. Vita Land, unpublished findings). DISCUSSION According to other published studies, the cumulative Although vascular tumors are the most frequent cate- incidence of a S M N is 3-l2% at 2&30 years, with a gory of soft tissue neoplasm in the first two decades of latent period averaging 9-13 years [7,28-361. The delife, most are various types of benign hemangioma, and velopment of a central nervous system tumor after acute angiosarcoma is distinctly uncommon [ 81. Angiosarcoma leukemia and of osteosarcoma after retinoblastoma are is generally regarded as a tumor of the elderly, with a two of the most frequently reported SMNs [37]. Howpeak age incidence in the fifth decade and beyond 191. ever, the cooperative studies of the Late Effects Study For over 40 years, lymphedema has been recognized as Group (LESG) have shown that any type of childhood a clinical condition which predisposes to the development malignancy may be followed by a SMN [7,38]. Soft of angiosarcoma [ I ] . There has been an increasing tissue sarcomas were the third most frequent primary awareness that irradiation, either for a benign condition malignancy followed by a SMN in the LESG, and bone or a primary malignant neoplasm, is also a risk factor for and soft tissue sarcomas were the most frequent SMN. subsequent angiosarcoma [2-6,10-12]. In some individIt is clear that not all survivors of childhood cancers uals, both conditions are present, and it may be impos- are equally susceptible to SMN and that radiation thersible to assign a single etiology. Four of the original six apy, chemotherapy, and genetic susceptibility all intlupatients with postmastectomy angiosarcoma described by ence the risk of SMN [32,39]. A majority of SMNs, Stewart and Treves had radiation to the chest wall and especially the sarcomas. are associated with radiation

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Fig. 3. A: Well-differentiated angiosarcoma consists of anastornosing, aubtly infiltrative vascular channels dissecting between dermal collagen fiber5 B: The endothelial cells are prominent, hyperchromatic, and focally cuboidal (heinatoxylin-eosin: A . x 100; B. X400).

therapy [35,37,40-441. Radiation for benign conditions in childhood, such as ringworm of the scalp or hemangiomas, has also been found to increase the risk of both benign and malignant tumors [35,45]. There are few studies that specifically address the combined role of radiation therapy and chemotherapy in SMN [ 34,38,46], In a series of 32 patients with SMN after treatment of a childhood malignancy, a radiation dose greater than 50 cGy was identified as a risk factor for SMN; after adjustment for the dose of radiation therapy, dactinomycin increased further the relative risk of bone and soft tissue sarcomas, but cyclophosphamide was found to be less carcinogenic than other alkylating agents [36]. Genetic factors have been identified in 33% of SMN, although none were documented in the patient we report [ 32,37,38]. The present case of an angiosarcoma arising in the arm of a young adult female 14 years after a previously diagnosed and treated PNET is an example of the potential morphologic diversity of the SMNs. In some respects, this patient was already remarkable by virtue of

her long-term survival after metastatic spread 01 PNET to a regional lymph node at the time of local recurrence. After recurrence and metastasis of a PNET, the period of survival is generally brief and is insufficient to permit the development of a SMN. ACKNOWLEDGMENTS

We wish to thank Dr. Peter Soto, St. Elizabeth Hospital, Belleville, Illinois, for contributing paraffinembedded tissue for immunohistochemical studies on the primitive neuroectodermal tumor. We are grateful to Miss Marla Wagner for preparing the manuscript. REFERENCES I . Stewart FW. Treves N: Lymphangiosarcorna in postmastcctomy lymphedema: a report of six cases in elephantiasis chirurgica. Cancer I :h4-8 I . 1948. 2. Maddox JC. Evans HL: Angiosarcoma of skin and soft tissue: a study of forty-four cases. Cancer 48: 1907-192 I , 1081. 3. Cooper PH: Angiosarcomas of the skin. Semin Diagn Pathol 4:2-17. 1087.

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4 . Otis CN, Peschel R, McKhann C , Merino MJ, Duray PH: The rapid onset of cutaneous angiosarcoma after radiotherapy for breast carcinoma. Cancer 57:2130-2134, 1986. 5. Shaikh NA, Beaconsfield T. Walker M, Chilchik MW: Postirradiation angiosarcoma of the breast: a case report. Eur J Surg Oncol 14:449451, 1988. 6. Rubin E, Maddox WA. Mazur MT: Cutaneous angiosarcoma of the breast 7 years after lumpectomy and radiation therapy. Radiol I74:258-260, 1990. 7. Meadows AT: Risk factors for second malignant neoplasms: a report from the Late Effects Study Group. Bull Cancer 75: 125130, 1988. 8. Coffin CM, Dehner LP: Vascular tumors in children and adolescents. A clinicopathologic study of 228 tumors in 222 patients. Mod Pathol 3:20A. 1990. 9. Enzinger FM. Weiss SW: Malignant vascular tumors. In Enzinger FM, Weiss SW (eds): “Soft Tissue Tumors.” St. Louis: The C.V. Mosby Company, 1988, pp, 545-561. 10. Chen KTK, Hoffman KD, Hendricks EJ: Angiosarcoma following therapeutic irradiation. Cancer 44:2044-2048, 1979. 1 1 . Handfield-Jones SE, Kennedy CTC, Bradfield JB: Angiosarcoma arising in an angiomatous naevus following irradiation in childhood. Br J Dermatol I18:109-112, 1988. 12. Lo TCM, Silverman ML, Edelstein A: Postirradiation hemangiosarcoma of the chest wall. Acta Radiol [Oncol] 24:237-240, 1985. 13. Stout AP: A tumor of the ulnar nerve. Proc NY Pathol Soc 1812-12. 1918. 14. Penfield W: Tumors of the sheaths of the nervous system. In Penfield W (ed): “Cytology and Cellular Pathology of the Nervous System,” Vol. 3. New York: Paul B. Hoeber, 1932, pp. 980-984. IS. Seemayer TA, Thelmo WL, Bolande RP, Wiglesworth FW. Peripheral neuroectodermal tumors. In Rosenberg HS, Bolande RP (eds): “Perspectives in Pediatric Pathology,” Vol. 2. Chicago: Year Book Medical Publishers, 1975, pp. 151-172. 16. Hashimoto H. Enjoji M, Nakajima T , Kiryu H, Daimau Y: Malignant neuroepithelioma (peripheral neuroblastoma): a clinicopathologic study of 15 cases. Am J Surg Pathol 7309-318, 1983. 17. Schmidt D. Harms 0, Burdach S: Malignant peripheral neuroectodermal tuniours of childhood and adolescence. Virchows Arch IA] 4 0 6 3 - 3 6 5 , 1985. 18. Llombart-Bosch A, Terrier-Lacombe J , Peydro-Olaya A, Contesso CT: Peripheral neuroectodermal sarcoma of soft tissue (peripheral neuroepithelioma): a pathologic study of ten cases with differential diagnosis regarding other small, round-cell sarcomas. Hum Pathol 20:273-280. 1989. 19. Dehner LP: A contemporary view of neoplasms in children. The pathologist’s role. Pediatr Clin North Am 36:l 13-137, 1989. 20. Nesbitt KA, Vidone RA: Primitive neuroectodermal tumor (neuroblastoma) arising in sciatic nerve of a child. Cancer 37: 15621570, 1976. 21. Bolen JW, Thorning D: Peripheral neuroepithelioma: a light and electron microscopic study. Cancer 46:245&2462, 1980. 22. Coffin CM, Dehner LP: Peripheral neurogenic tumors in children and adolescents. A clinicopathologic study of 139 cases. Pediatr Pathol 9:387407, 1989. 23. Marina NM, Etcubanas E, Parham DM, Bowman LC, Green A: Peripheral primitive neuroectodermal tumor (peripheral neuroepithelioma) in children: a review of the St. Jude Experience and controversies in diagnosis and management. Cancer 64: 19521960, 1989. 24. Miser JS, Kinsella TJ, Triche TJ, Steis R, Tsokos M, Wesley R, Horvath K, Belasco J , Longo DL, Glatstein E, Israel MA: Treatment of peripheral neuroepithelioma in children and young adults. J Clin Oncol 5:1752-1758, 1987. 25. Jurgens H, Bier V , Harms D, Beck J , Brandeis W, Et Spuler G ,

26. 27. 28. 29.

30.

31.

32. 33.

34.

35.

36.

37.

38.

39.

40.

41.

42. 43.

44. 45. 46.

Gadner H, Schmidt D, Treuner J , Winkler K, Gobel U: Malignant peripheral neuroectodermal tumors: a retrospective analysis of 42 patients. Cancer 61:349-357, 1988. Raymond CA: Fate of childhood cancer survivors comes under increasing scrutiny. JAMA 260:3246-3247, 1988. Kingston JE: Second primary tumours. Arch Dis Child 60:695697, 1985. Tefft M, Vawter GF, Mitus A: Second primary neoplasms in children. Am J Roentgenol 103:800-822, 1968. Regelson W, Bross IDJ, Hananian J , Nigogosyan G: Incidence of second primary tumors in children with cancer and leukemia. Cancer 18:58-72, 1965. Li FP: Second malignant tumors after cancer in childhood. Cancer 40: 1899- I 902, 1977. Mike V, Meadows AT, D’Angio DJ: Incidence of second malignant neoplasms in children: results of an international study. Lancet 2:1326-1331, 1982. Meadows AT: Second malignant neoplasms. Clin Oncol 4:247261, 1985. Potish RA, Dehner LP, Haselow RE, Kim TH, Levitt SH, Nesbit M: The incidence of second neoplasms following megavoltage radiation for pediatric tumors. Cancer 56: 1534-1537, 1985. Hawkins MM, Draper GJ, Kingston JE: Incidence of second primary tumours among childhood cancer survivors. Br J Cancer 56:339-347, 1987. Amendola BE. Amendola MA, McClatchey KD, Miller CH: Radiation-associated sarcoma: a review of 23 patients with postradiation sarcoma over a 50-year period. Am J Clin Oncol 12:4l1415, 1989. de Vathaire F, Francois P, Hill C, Schweisguth 0, Rodary C, Sarrazin D, Oberlin 0. Buertheret C , Dutreix A, Flamant R: Role of radiotherapy and chemotherapy in the risk of second malignant neoplasms after cancer in childhood. Br J Cancer 59:792-796, 1989. Kingston JE, Hawkins MM, Draper GJ, Marsden HB, KinnerWilson LM: Patterns of multiple primary tumours in patients treated for cancer during childhood. Br J Cancer 56:331-338, 1987. Meadows AT, Baum E, Fossati-Bellani F, Green D, Jenkin RDT, Marsden B, Nesbit M, Newton W, Oberlin 0 , Sallan SG. Siege1 S , Strong LC, Voute PA: Second malignant neoplasms in children: an update from the Late Effects Study Group. J Clin Oncol 3532-538, 1985. Terracini B, Pastore G. Zurlo MG, Masera G. Fossati-Bellani F, Castello M, Tamaro P, Massolo F, Rosati D, Biddau PF, Russo A: Late deaths and second primary malignancies among long-term survivors of childhood cancer: an Italian multicenter study. Eur J Cancer Clin Oncol 23:499-504, 1987. Meadows AT, D’Angio GJ, Mike V, Banfi A , Harris C , Jenkin RDT, Schwartz A: Patterns of second malignant neoplasms in children. Cancer 40:1903-191 I , 1977. Boriani S , Picci P, Sudanese A, Toni A, Mancini A, Frezza CT, Barbieri E, Baldini N, Monesi M, Ciaroni D, Bacci G: Radioinduced sarcomas in survivors of Ewing’s sarcoma. Tumori 74543-551, 1988. Laskin WB, Silverman TA, Enzinger FM: Postradiation soft tissue sarcomas. Cancer 62:2330-2340, 1988. Haselow RE, Nesbit M, Dehner LP, Khan FM, McHugh R, Levitt SH: Second neoplasms following megavoltage radiation in a pediatric population. Cancer 42:1185-1191, 1978. Hutchinson GB: Late neoplastic changes following medical irradiation. Cancer 37:l 102-1 107, 1976. Modan B, Baidatz D, Mart H, Steinitz R, Levin SG: kadiationinduced head and neck tumours. Lancet 1:277-279, 1974. Schmahl D, Habs M: Drug-induced cancer. Curr Top Path01 69 :333-36Y, 1980.