Primitive neuroectodermal tumor (PNET) as second malignancy after treatment of Hodgkin's disease
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《美国医学杂志》
Division of Pediatric Oncology, Tata Memorial Hospital, Mumbai, India
Abstract
Hodgkin's disease survivors are at an increased risk of developing second malignant neoplasms including secondary bone tumors. Common secondary bone tumors are osteogenic sarcoma and fibrosarcoma. Secondary primitive neuroectodermal tumor is extremely rare in this group. We present below, a rare case of secondary PNET in an 8-year-old child with Hodgkin's disease which developed unusually early outside the radiation portal and discuss potential factors responsible for its causation.
Keywords: Hodgkin′s disease; Second malignant neoplasm; Primitive neuroectodermal tumor; Children
Current treatment regimens for early-stage Hodgkin's disease (HD) achieve 20-year disease-free survival rates in excess of 80%. [1] However, the remarkable gains in survival attributable to successful treatments for HD over the past three decades have been accompanied by a significantly increased risk of second malignant neoplasms (SMNs). Several large studies have reported cumulative risks of SMNs ranging from 7.6% (at 20 years) to 21.9% (at 25 years). An increased overall relative risk ranges from 2.0 to 6.1. [2],[3] The malignancies most commonly observed include acute myeloid leukemia, myelodysplastic syndrome, non-hodgkin's lymphoma and solid tumors. We present here a treated case of Hodgkin's disease who suffered from an unusual second malignancy, a primitive neuroectodermal tumour (PNET).
Case Report
An -8-yr-old boy presented with history of recurrent fever, cough, multiple neck swellings and prominent veins over chest wall. Physical examination revealed cervical lymphadenopathy, hepatosplenomegaly and ascites. Investigations revealed a normal hemogram, liver and renal function tests. Serum Lactate dehydrogenase levels were elevated (1038 U/L). A chest x-ray showed a superior mediastinal mass, right middle zone consolidation and right pleural effusion. Abdominopelvic ultrasound revealed multiple abdominal lymphonodes also. Bone marrow was uninvolved. A right supraclavicular lymphnode biopsy showed HD-mixed cellularity. Thus the patient was diagnosed as Ann arbor's stage III B. The child received six cycles of the ABVD (Adriamycin, Bleomycin,Vinblastine and Dacarbazine) regime in the recommended doses and was followed by involved field radiotherapy to mediastinum (25Gy/14 fractions/24 days ). After completion of therapy, the patient was followed up regularly.
Two and half years after initial treatment the child was due for transfer to After Completion of Therapy (ACT) Clinic for long term survivors of childhood cancer after confirmation of disease free status ,he presented with pain in right knee joint and fever. There were no skin changes or distal neurovascular problems. Magnetic resonance imaging (MRI) of right thigh including right knee joint showed diffuse alteration in marrow signal intensity involving the entire femoral shaft extending into the intertrochanteric region superiorly and to the distal metaphysis inferiorly. The involved bone showed a hyperintense marrow signal. A circumferential spiculated periosteal reaction was noted along the femoral shaft. A soft tissue mass surrounding the entire femoral shaft was also seen. A gun biopsy of the mass revealed small blue round cell tumor with rosettes but with no osteoid tissue.
On immunohistochemistry (IHC), the tumor expressed vimentin focally, Mic2 staining was equivocal and did not express lymphoid markers. Thus the patient was diagnosed to have PNET arising as a second malignancy in a treated case of Hodgkin's disease. The family decided against taking any type of definitive treatment.
Discussion
Second cancers now comprise the leading cause of death among 15-year survivors of Hodgkin's lymphoma. [1],[2],[3],[4] Bone malignancies account for the highest risk of any specific type of SMNs to develop after childhood cancer.[5] Hodgkin's disease survivors have 15-38 fold increased risk of developing bone tumors. [2],[4],[5] The most common type of secondary bone tumor in childhood cancer patients is osteogenic sarcoma followed by fibrosarcoma, chondrosarcoma, angiosarcoma, round cell sarcoma, and malignant fibrous histiocytoma. Secondary PNET in childhood cancer survivors is very rare.[5],[6] A comprehensive review of English language literature revealed only 3 cases of secondary PNET in survivors of Hodgkin's disease.[6],[7],[8] A study of 25, 051 ALL (Acute lymphoblatic leukaemia) survivors showed only one case of secondary PNET. [9]
Besides rarity, our case occurred unusually early (median interval is generally 10-11.8 years [2],[6]) and that too outside the radiation portal. Both these factors point to non-radiogenic basis for this tumor, which is the most common culprit behind origin of secondary bone tumors. In a recent study, excess risks of bone tumors in HD survivors were apparent in most with longer latency periods after HD diagnosis, favoring a role for other influences, including chemotherapy, immunosuppression, genetic influences or heightened surveillance.[3]
Many studies have found an association between exposure to alkylating agents and a subsequent risk of bone cancer.[5],[6] This association was found independent of radiation exposure. Similar associations have been found for other solid tumors also.[4] This could potentially be one reason behind SMN in our patient.
Radiotherapy, chemotherapy, and immunosuppression are all likely to contribute to the development of SMNs. The occurrence of multiple neoplasms within individual HD patients, and an increase in the prevalence of a positive family cancer history suggest that an underlying genetic predisposition may also influence second cancer risk in a subset of HD survivors.[10] Additionly, HD is occasionally seen in Li-fraumeni kindreds also.[11] However studies on mutations of ATM gene, TP53, BRCA1, and BRCA2 genes suggest that these tumor suppressor genes do not seem to play a prominent role during secondary tumorigenesis in this population.[12] It is possible that the increased risk of SMNs in HD survivors is a result of inactivating germline mutations in other genes involved in DNA damage repair. Alternatively, it remains possible that gene polymorphisms, which exert more subtle effects on protein function, may contribute to second cancer risk in susceptible individuals.
In conclusion, Hodgkin's disease survivors are at increased risk of a variety of SMNs including rarely PNET. Minimisation of usage of radiation and alkylating agents may improve the long-term outcome of this population. This case illustrates the need for lifetime followup in cancer survivors.
References
1. Ng AK, Bernardo MP, Weller E et al. Long-term survival and competing causes of death in patients with early-stage Hodgkin's disease treated at age 50 or younger. J Clin Oncol 2002; 20: 2101-2108.
2. Bhatia S, Yasui Y, Robison LL et al. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: Report from the Late Effects Study. J Clin Oncol 2003, 21: 4386-4394.
3. Dores GM, Metayer CM, Curtis RE et al. Second malignant neoplasms among long-term survivors of Hodgkin's disease: A population-based evaluation over 25 years. J Clin Oncol 2002; 20: 3484-3494.
4. Swerdlow AJ, Douglas AJ, Hudson GV et al. Risk of second primary cancers after Hodgkin's disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 1992; 304: 1137-1143.
5. Hawkins MM, Wilson LM, Burton HS et al. Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst 1996; 88: 270-278.
6. Tucker MA, D'Angio GJ, Boice JD Jr et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 1987; 317: 588-593.
7. Delgado-Chavez R, Sobrevilla-Calvo P, Green-Schneewiss L et al. Peripheral neuroectodermal tumor of the chest wall in a patient treated for Hodgkin's disease. Leuk Lymphoma 1995; 17: 509-513.
8. Anselmo AP, Cartoni C, Pacchiarotti A et al. Peripheral neuroectodermal tumor of the chest (Askin tumor) as secondary neoplasm after Hodgkin's disease: a case report. Ann Hematol 1994; 68: 311-313.
9. Suarez CR, Bertolone SJ, Raj AB et al. Second malignant neoplasms in childhood acute lymphoblastic leukemia: primitive neuroectodermal tumor of the chest wall with germline p53 mutation as a second malignant neoplasm. Am J Hematol 2004; 76: 52-56.
10. Nichols KE, Levitz S, Shannon KE et al. Heterozygous germline ATM mutations do not contribute to radiation-associated malignancies after Hodgkin's disease. J Clin Oncol 1999; 17: 1259.
11. Nichols KE, Malkin D, Garber JE et al. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev 2001; 10: 83-87.
12. Nichols KE, Heath JA, Friedman D et al. TP53, BRCA1, and BRCA2 tumor suppressor genes are not commonly mutated in survivors of Hodgkin's disease with second primary neoplasms. J Clin Oncol 2003; 21: 4505-4509.(Khadwal A, Biswas G, Aror)
Abstract
Hodgkin's disease survivors are at an increased risk of developing second malignant neoplasms including secondary bone tumors. Common secondary bone tumors are osteogenic sarcoma and fibrosarcoma. Secondary primitive neuroectodermal tumor is extremely rare in this group. We present below, a rare case of secondary PNET in an 8-year-old child with Hodgkin's disease which developed unusually early outside the radiation portal and discuss potential factors responsible for its causation.
Keywords: Hodgkin′s disease; Second malignant neoplasm; Primitive neuroectodermal tumor; Children
Current treatment regimens for early-stage Hodgkin's disease (HD) achieve 20-year disease-free survival rates in excess of 80%. [1] However, the remarkable gains in survival attributable to successful treatments for HD over the past three decades have been accompanied by a significantly increased risk of second malignant neoplasms (SMNs). Several large studies have reported cumulative risks of SMNs ranging from 7.6% (at 20 years) to 21.9% (at 25 years). An increased overall relative risk ranges from 2.0 to 6.1. [2],[3] The malignancies most commonly observed include acute myeloid leukemia, myelodysplastic syndrome, non-hodgkin's lymphoma and solid tumors. We present here a treated case of Hodgkin's disease who suffered from an unusual second malignancy, a primitive neuroectodermal tumour (PNET).
Case Report
An -8-yr-old boy presented with history of recurrent fever, cough, multiple neck swellings and prominent veins over chest wall. Physical examination revealed cervical lymphadenopathy, hepatosplenomegaly and ascites. Investigations revealed a normal hemogram, liver and renal function tests. Serum Lactate dehydrogenase levels were elevated (1038 U/L). A chest x-ray showed a superior mediastinal mass, right middle zone consolidation and right pleural effusion. Abdominopelvic ultrasound revealed multiple abdominal lymphonodes also. Bone marrow was uninvolved. A right supraclavicular lymphnode biopsy showed HD-mixed cellularity. Thus the patient was diagnosed as Ann arbor's stage III B. The child received six cycles of the ABVD (Adriamycin, Bleomycin,Vinblastine and Dacarbazine) regime in the recommended doses and was followed by involved field radiotherapy to mediastinum (25Gy/14 fractions/24 days ). After completion of therapy, the patient was followed up regularly.
Two and half years after initial treatment the child was due for transfer to After Completion of Therapy (ACT) Clinic for long term survivors of childhood cancer after confirmation of disease free status ,he presented with pain in right knee joint and fever. There were no skin changes or distal neurovascular problems. Magnetic resonance imaging (MRI) of right thigh including right knee joint showed diffuse alteration in marrow signal intensity involving the entire femoral shaft extending into the intertrochanteric region superiorly and to the distal metaphysis inferiorly. The involved bone showed a hyperintense marrow signal. A circumferential spiculated periosteal reaction was noted along the femoral shaft. A soft tissue mass surrounding the entire femoral shaft was also seen. A gun biopsy of the mass revealed small blue round cell tumor with rosettes but with no osteoid tissue.
On immunohistochemistry (IHC), the tumor expressed vimentin focally, Mic2 staining was equivocal and did not express lymphoid markers. Thus the patient was diagnosed to have PNET arising as a second malignancy in a treated case of Hodgkin's disease. The family decided against taking any type of definitive treatment.
Discussion
Second cancers now comprise the leading cause of death among 15-year survivors of Hodgkin's lymphoma. [1],[2],[3],[4] Bone malignancies account for the highest risk of any specific type of SMNs to develop after childhood cancer.[5] Hodgkin's disease survivors have 15-38 fold increased risk of developing bone tumors. [2],[4],[5] The most common type of secondary bone tumor in childhood cancer patients is osteogenic sarcoma followed by fibrosarcoma, chondrosarcoma, angiosarcoma, round cell sarcoma, and malignant fibrous histiocytoma. Secondary PNET in childhood cancer survivors is very rare.[5],[6] A comprehensive review of English language literature revealed only 3 cases of secondary PNET in survivors of Hodgkin's disease.[6],[7],[8] A study of 25, 051 ALL (Acute lymphoblatic leukaemia) survivors showed only one case of secondary PNET. [9]
Besides rarity, our case occurred unusually early (median interval is generally 10-11.8 years [2],[6]) and that too outside the radiation portal. Both these factors point to non-radiogenic basis for this tumor, which is the most common culprit behind origin of secondary bone tumors. In a recent study, excess risks of bone tumors in HD survivors were apparent in most with longer latency periods after HD diagnosis, favoring a role for other influences, including chemotherapy, immunosuppression, genetic influences or heightened surveillance.[3]
Many studies have found an association between exposure to alkylating agents and a subsequent risk of bone cancer.[5],[6] This association was found independent of radiation exposure. Similar associations have been found for other solid tumors also.[4] This could potentially be one reason behind SMN in our patient.
Radiotherapy, chemotherapy, and immunosuppression are all likely to contribute to the development of SMNs. The occurrence of multiple neoplasms within individual HD patients, and an increase in the prevalence of a positive family cancer history suggest that an underlying genetic predisposition may also influence second cancer risk in a subset of HD survivors.[10] Additionly, HD is occasionally seen in Li-fraumeni kindreds also.[11] However studies on mutations of ATM gene, TP53, BRCA1, and BRCA2 genes suggest that these tumor suppressor genes do not seem to play a prominent role during secondary tumorigenesis in this population.[12] It is possible that the increased risk of SMNs in HD survivors is a result of inactivating germline mutations in other genes involved in DNA damage repair. Alternatively, it remains possible that gene polymorphisms, which exert more subtle effects on protein function, may contribute to second cancer risk in susceptible individuals.
In conclusion, Hodgkin's disease survivors are at increased risk of a variety of SMNs including rarely PNET. Minimisation of usage of radiation and alkylating agents may improve the long-term outcome of this population. This case illustrates the need for lifetime followup in cancer survivors.
References
1. Ng AK, Bernardo MP, Weller E et al. Long-term survival and competing causes of death in patients with early-stage Hodgkin's disease treated at age 50 or younger. J Clin Oncol 2002; 20: 2101-2108.
2. Bhatia S, Yasui Y, Robison LL et al. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: Report from the Late Effects Study. J Clin Oncol 2003, 21: 4386-4394.
3. Dores GM, Metayer CM, Curtis RE et al. Second malignant neoplasms among long-term survivors of Hodgkin's disease: A population-based evaluation over 25 years. J Clin Oncol 2002; 20: 3484-3494.
4. Swerdlow AJ, Douglas AJ, Hudson GV et al. Risk of second primary cancers after Hodgkin's disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 1992; 304: 1137-1143.
5. Hawkins MM, Wilson LM, Burton HS et al. Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst 1996; 88: 270-278.
6. Tucker MA, D'Angio GJ, Boice JD Jr et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 1987; 317: 588-593.
7. Delgado-Chavez R, Sobrevilla-Calvo P, Green-Schneewiss L et al. Peripheral neuroectodermal tumor of the chest wall in a patient treated for Hodgkin's disease. Leuk Lymphoma 1995; 17: 509-513.
8. Anselmo AP, Cartoni C, Pacchiarotti A et al. Peripheral neuroectodermal tumor of the chest (Askin tumor) as secondary neoplasm after Hodgkin's disease: a case report. Ann Hematol 1994; 68: 311-313.
9. Suarez CR, Bertolone SJ, Raj AB et al. Second malignant neoplasms in childhood acute lymphoblastic leukemia: primitive neuroectodermal tumor of the chest wall with germline p53 mutation as a second malignant neoplasm. Am J Hematol 2004; 76: 52-56.
10. Nichols KE, Levitz S, Shannon KE et al. Heterozygous germline ATM mutations do not contribute to radiation-associated malignancies after Hodgkin's disease. J Clin Oncol 1999; 17: 1259.
11. Nichols KE, Malkin D, Garber JE et al. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev 2001; 10: 83-87.
12. Nichols KE, Heath JA, Friedman D et al. TP53, BRCA1, and BRCA2 tumor suppressor genes are not commonly mutated in survivors of Hodgkin's disease with second primary neoplasms. J Clin Oncol 2003; 21: 4505-4509.(Khadwal A, Biswas G, Aror)