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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, MD, William G. Kraybill, MD, and Louis P. Dehner, MD Second malignant neoplasms (SMN) in late childhood or young adulthood in indi- viduals who have been successfully treated for an initial malignancy have emerged as a late effect of therapy in survivors of child- hood cancer. Although radiation therapy is frequently implicated, chemotherapy with alkylating agents and antimetabolites has also been associated with SMN. Soft tissue sarcomas are among the most frequent pri- mary malignancies complicated by a SMN and account for a majority of nonhema- tolymphoid SMN. We present the clinical 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 mul- tidrug chemotherapy, and developed an an- giosarcoma 14 years later. This case repre- sents an uncommon combination of mesenchyrnal malignancies in a young pa- tient with an unusually favorable clinical course following the diagnosis of PNET. 0 1992 Wiley-Liss, Inc. Key words: primitive neuroectodermal 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 adult- hood and arises predominantly in three clinical settings: the face and scalp of elderly individuals, the lymphe- dematous extremity, and in previously irradiated skin [I-31. Angiosarcoma of the skin and soft tissues has occasionally been reported as a second malignant neo- plasm in adults who were successfully treated for another pathologically separate malignancy, principally carci- noma 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. 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 neurofibromato- sis. 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. 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, cyclophospha- mide, doxorubicin, and 5-fluorouracil. The tumor de- creased rapidly in size and had virtually disappeared within 2 months after initiation of therapy. Remission 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, St. Louis, M O 631 10.

Cutaneous angiosarcoma as a second malignant neoplasm after peripheral primitive neuroectodermal tumor

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Page 1: Cutaneous angiosarcoma as a second malignant neoplasm after peripheral primitive neuroectodermal tumor

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, MD, William G. Kraybill, MD, and Louis P. Dehner, MD

Second malignant neoplasms (SMN) in late childhood or young adulthood in indi- viduals who have been successfully treated for an initial malignancy have emerged as a late effect of therapy in survivors of child- hood 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 pri- mary malignancies complicated by a SMN and account for a majority of nonhema- tolymphoid SMN. We present the clinical

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 mul- tidrug chemotherapy, and developed an an- giosarcoma 14 years later. This case repre- sents an uncommon combination of mesenchyrnal malignancies in a young pa- tient with an unusually favorable clinical course following the diagnosis of PNET. 0 1992 Wiley-Liss, Inc.

Key words: pr imi t ive neuroectodermal tumor, angiosarcoma, second primary malignant neoplasm, radiat ion-induced neoplasms, late effects of therapy

INTRODUCTION

Cutaneous angiosarcoma is an infrequent malignant neoplasm which usually occurs in middle or late adult- hood and arises predominantly in three clinical settings: the face and scalp of elderly individuals, the lymphe- dematous extremity, and in previously irradiated skin [I-31. Angiosarcoma of the skin and soft tissues has occasionally been reported as a second malignant neo- plasm in adults who were successfully treated for another pathologically separate malignancy, principally carci- noma 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.

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 neurofibromato- sis. 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.

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, cyclophospha- mide, doxorubicin, and 5-fluorouracil. The tumor de- creased rapidly in size and had virtually disappeared within 2 months after initiation of therapy. Remission

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.

Page 2: Cutaneous angiosarcoma as a second malignant neoplasm after peripheral primitive neuroectodermal tumor

Angiosarcoma as SMN After Peripheral PNET 353

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 angiosar- coma.

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 examina- tion 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

PATH0 LOGIC FIN DI NGS

The tumor excised in December 1975 was 5 cm in greatest dimension and had a tan, fleshy, focally hemor- rhagic cut surface. Microscopically, the tumor was composed of lobules of primitive neoplastic cells demar- cated 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. Im- munohistochemical staining on formalin-fixed paraffin- embedded tissue performed in 1990 revealed diffuse immunoreactivity with monoclonal antibodies to vimen- tin, synaptophysin, chromogranin, actin, and neuron- specific enolase. Immunostains for cytokeratin, epithelial membrane antigen, neurofilaments, S 100 protein, carci- noembryonic antigen, Leu 7, desmin, and leucocyte common antigen were negative. The immunohistochem- ical reagents are listed in Table I.

The skin biopsy from the right arm and the right

TABLE I. Immunohistochemical Reagents*

Antibody or lectin Clonality Source Dilution

C ytokeratins Vimentin M Biogenex Laboratories I :2,000

AE 1 IAE3 M Boehringer- Mannheim 1:150 MAK-6 M Triton Biosciences 1:40 CAM 5.2 M Becton Dickinson 1:150

Neurofilament M Biogenex Laboratories 1 :200 Desmin M Biogenex 1:1,200 Actin (HHF35) M Enzo 1:64,000 Neuron-specific enolase P Biogenex Laboratories 1:450 Chromogranin M Boehringer 1 :4,000 Sy naptophysin M Boehringer Mannheim 1 :40 S 100 protein P Dakopatts 1:3,000 Leu I M Becton Dickinson 1:lOO Epithelial membrane

Carcinoembryonic

Leucocyte common

Factor VIII-related

Ulex europaeus

*M, monoclonal antibodies; P, polyclonal antibodies.

antigen M Dakopatts 1:800

antigen M Boehringer- Mannheim 1 :4,000

antigen M Dakopatts 1:80

antigen M Dakopatts 1:20

agglutinin I - Vector Laboratories 1: 1,000

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354 Coffin et al.

Fig. 2. right arm.

Multiple patches and papules are present on the skin of the

forequarter amputation showed multiple reddish brown patches and papules ranging in size from 0.1 to 1.8 cm (Fig. 2). Approximately 50 lesions were visible on the forearm and medial upper arm and were confined to the skin, without macroscopic involvement of subcutaneous or deep soft tissues or bone. Microscopic examination revealed a well-differentiated angiosarconia (Fig. 3A). Multiple anastomosing vascular channels of varying sizes dissected subtly between collagen fibers of the dermis. The endothelial cells were prominent and focally had a cuboidal configuration (Fig. 3B). No solid areas of tumor, hemorrhage, or necrosis were seen. The bone and cutaneous resection margins showed no evidence of angiosarcoma. The neoplastic endothelial cells were immunoreactive with antibodies to factor VIII-related antigen, U1e.r eirropueus agglutinin I , and vimentin and nonreactive for cytokeratin and epithelial membrane antigen.

DISCUSSION

Although vascular tumors are the most frequent cate- gory of soft tissue neoplasm in the first two decades of life, most are various types of benign hemangioma, and angiosarcoma is distinctly uncommon [ 81. Angiosarcoma is generally regarded as a tumor of the elderly, with a peak age incidence in the fifth decade and beyond 191. For over 40 years, lymphedema has been recognized as a clinical condition which predisposes to the development of angiosarcoma [ I ] . There has been an increasing awareness that irradiation, either for a benign condition or a primary malignant neoplasm, is also a risk factor for subsequent angiosarcoma [2-6,10-12]. In some individ- uals, both conditions are present, and it may be impos- sible to assign a single etiology. Four of the original six patients with postmastectomy angiosarcoma described by Stewart and Treves had radiation to the chest wall and

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 an- giosarcoma 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 con- firmed by the ultrastructural identification of neurosecre- tory-like granules and the immunohistochemical demon- stration of chromogranin, synaptophysin, neuron-specific cnolase, Leu 7, and other neural-associated markers [1&18]. In the past decade, PNET has emerged as an important soft tissue neoplasm in children, adolescents, and young adults mainly through improvements in diag- nostic techniques like immunohistochemistry and elec- tron microscopy [ 191. The clinical course is aggressive, which accounts for the ominous prognosis [ 16,20-231. Recent studies have indicated that the most effective treatment is surgery with combination chemotherapy and high-dose radiation therapy 124,251. None of these studies has reported SMN in survivors of a PNET.

It is currently estimated that I of every 1,000 Amer- icans at 20 years of age can claim to have survived cancer 1261. As this population has increased and as the survival rate for childhood malignancies has improved to exceed SO% at 5 years, the SMN has evolved as a worrisome consequence 1271. Since 1962, there have been 17 examples of SMNs in 1,053 individuals successfully 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). According to other published studies, the cumulative incidence of a SMN is 3-l2% at 2&30 years, with a latent period averaging 9-13 years [7,28-361. The de- velopment of a central nervous system tumor after acute leukemia and of osteosarcoma after retinoblastoma are two of the most frequently reported SMNs [37]. How- ever, the cooperative studies of the Late Effects Study Group (LESG) have shown that any type of childhood malignancy may be followed by a SMN [7,38]. Soft tissue sarcomas were the third most frequent primary malignancy followed by a SMN in the LESG, and bone and soft tissue sarcomas were the most frequent SMN.

It is clear that not all survivors of childhood cancers are equally susceptible to SMN and that radiation ther- apy, chemotherapy, and genetic susceptibility all intlu- ence the risk of SMN [32,39]. A majority of SMNs, especially the sarcomas. are associated with radiation

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Angiosarcoma as SMN After Peripheral PNET 355

Fig. 3. A: Well-differentiated angiosarcoma consists of anastornosing, aubtly infiltrative vascular channels dissecting between dermal collagen fiber5 matic, and focally cuboidal (heinatoxylin-eosin: A .

therapy [35,37,40-441. Radiation for benign conditions in childhood, such as ringworm of the scalp or heman- giomas, 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, dactinomy- cin 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

B: The endothelial cells are prominent, hyperchro- x 100; B. X400).

her long-term survival after metastatic spread 0 1 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.

A C K N O W L E D G M E N T S

We wish to thank Dr. Peter Soto, St. Elizabeth Hospital, Belleville, Illinois, for contributing paraffin- embedded tissue for immunohistochemical studies on the primitive neuroectodermal tumor. We are grateful to Miss Marla Wagner for preparing the manuscript.

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