Annals of Oncology Advance Access originally published online on April 10, 2007
Annals of Oncology 2007 18(7):1260-1267; doi:10.1093/annonc/mdm092
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© 2007 European Society for Medical Oncology
supportive care |
Familial blood vessel tumors and subsequent cancers
1 Center for Family and Community Medicine, Karolinska Institute, 141 83 Huddinge, Sweden
2 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
* Correspondence to: Dr J. Ji, Center for Family and Community Medicine, Karolinska Institute, 141 83 Huddinge, Sweden. Tel: +46-8-524-88671; Fax: +46-8-524-88706; E-mail: jianguang.ji{at}ki.se
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Abstract |
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Background: Population-based data on the familial risk for vascular tumors are largely lacking. Such data are important for clinical counseling and cancer genetics.
Methods: We used the Swedish Family-Cancer Database to calculate standardized incidence ratios for specific subtypes of vascular tumors in offspring using parents as probands. In addition, risks for second cancers were analyzed.
Results: Offspring hemangioblastoma in the nervous system was associated with parental kidney cancer and nervous system hemangioblastoma and hemangioma. Offspring nervous system hemangiopericytoma was associated with parental pituitary adenomas. Offspring angiosarcoma in the trunk and extremities was associated with maternal breast cancer. Second Kaposi's sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease and myeloma were increased following primary skin Kaposi's sarcoma. Kidney and endocrine gland tumors and nervous system hemangioblastomas and hemangiomas were in excess following primary nervous system hemangioblastoma and hemangioma.
Conclusions: Our data showed that familial clustering of nervous system hemangioblastoma and hemangioma and the risks of subsequent cancers were primarily related to von-Hippel-Lindau disease. As a novel association, offspring nervous system hemangiopericytomas were in excess when parents were diagnosed with pituitary adenoma. Similarly, offspring angiosarcoma is associated with maternal breast cancer. Immunodeficiency may explain the excess of lymphoproliferative diseases after skin Kaposi's sarcoma.
Key words: blood vessel tumors, familial risk, hemangioblastoma, hemangioma, Kaposi's sarcoma
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introduction |
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TopAbstractintroductionmaterials and methodsresultsdiscussionAcknowledgementsReferences |
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Blood vessel (vascular) tumors are a heterogeneous group of neoplasms, which are divided into benign, intermediate and malignant neoplasms depending on endothelial cell proliferation and clinical characteristics [1]. Benign ‘vascular tumors’, hemangiomas, are the most common subtype and are often found at birth. Most hemangiomas are superficial lesions with a predilection to the head and neck region. They may also develop internally, including the nervous system and the liver [1, 2]. Glomangioma is a rare benign lesion. Intermediate vascular malignancies, such as the various types of hemangioendothelioma, can recur locally and have some ability to metastasize [3]. Malignant vascular tumors, including ‘hemangioblastoma’ (synonyms with ‘angiosarcoma’) and Kaposi's sarcoma, can occur at any location in the body and they may be aggressive tumors with a poor prognosis [4, 5]. Malignant tumors arising at different sites have distinct features. To be in agreement with the literatures, we used the term hemangioblastoma to define malignant tumors developed in the central nervous system, and angiosarcoma to define those occurred in other region of the body, such as in the skin and soft tissue. Although the causes of vascular tumors are largely unknown, some risk factors have been indicated for specific histologies, such as the associations of chronic lymphedema and irradiation with hemangioblastoma [4, 6, 7], and human herpesvirus and acquired immunodeficiency syndrome (AIDS) with Kaposi's sarcoma [4, 8]. Hemangioblastoma in the central nervous system has been shown to be a component of von-Hippel-Lindau (VHL) disease, in addition to other tumors, including renal cell cancer and pheochromocytoma [9]. The VHL susceptibility gene has been identified, and the VHL protein was found to have a variety of cellular functions, including regulation of hypoxia-inducible factor 1 [10, 11].
A reliable determination of familial risks for cancer is important for clinical counseling and prevention, and it is helpful to our understanding of cancer etiology. In view of the lack of systematic studies on familial clustering of vascular tumors, we examined here familial risks for histology and site-specific vascular tumors using the 2004 update of the nationwide Swedish Family-Cancer Database, which covered an offspring population up to age 70 years, together with the parental population. The associations with other cancer sites are also studied. As multiple primary carcinomas may be informative of the same environmental or genetic factors that influence the first tumors, we also analyze the occurrence of second cancers after primary vascular tumors. The special properties of the database are the registered sources of family relationships and medically verified cancer cases with a practically complete national coverage, which offer unique possibilities for reliable estimation of familial and second cancer risks.
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materials and methods |
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Statistics Sweden maintains a ‘Multigeneration Register’ where children born in Sweden in 1932 and later are registered with their parents and they are organized as families [12]. This Register was linked by the individually unique national registration number to the Cancer Registry to create the Swedish Family-Cancer Database. The current update (2004) of the database has recently been described [13]. The data on families and cancers have a complete coverage, barring some groups of deceased offspring, which affected those born in the 1930s and those who died before 1991. Although this small group of offspring with missing links to parents has a negligible effect on the estimate of familial risk [14], we limited the present study to offspring whose parents were known to eliminate the possibility of bias. Cancer registration is currently considered to be
100% [15]. A four-digit diagnosis code according to the 7th revision of the International Classification of Diseases (ICD-7) has been used since 1958 together with a code for histological type (WHO/HS/CANC/24.1 histology code). The following ICD-7 codes were grouped: ‘upper aerodigestive tract’ cancer codes 161 (larynx) and 140–148 (lip, mouth and pharynx), except for code 142 (salivary glands); ‘non-Hodgkin's lymphoma’ code 200 and 202; and ‘leukemia’ codes 204–207 (leukemias), 208 (polycytemia vera) and 209 (myelofibrosis). Rectal cancer, ICD-7 code 154, was subdivided into the anus (squamous cell carcinoma, 154.1) and mucosal rectum (154.0). Basal cell carcinoma of the skin is not registered in the Cancer Registry. In our database, vascular tumors are not recorded as an independence cancer, and they usually are registered into various cancer sites. The common sites are the skin, nervous system and ‘connective tissue’. The site connective tissue covers only soft tissue in the ‘trunk and extremities’, and we use the term trunk and extremities in the present study. The patho-anatomic diagnosis code was used to define hemangioma (501), hemangioblastoma or angiosarcoma (506, 511), hemangiopericytoma (536), glomangioma (531) and Kaposi's sarcoma (505, 566). Hemangioendothelioma and hemangioblastoma were recorded by the same histology code. We use here the terms ‘blood vessel tumors’ and vascular tumors interchangeably. Standardized incidence ratios (SIRs) were used to measure the cancer risks for offspring according to the occurrence of cancers in their parents, i.e. using parents as proband. Because of the lack of significant associations among siblings, sibling relationship was not discussed in the present study. The follow-up was started for each offspring at birth, immigration or on January 1, 1958, whichever was the latest time. Follow-up was terminated at the diagnosis of first cancer, death, emigration or the closing date of the study on December 31, 2002. Parents' ages were not limited, but offspring were 0–70 years of age. SIRs were calculated as the ratio of observed to expected number of cases. The expected numbers were calculated from 5-year-age-, gender-, tumour type-, period-, socioeconomic status- (six groups) and residential area- (three groups) specific standard incidence rates for all offspring lacking a family history [16]. Confidence intervals (95% CI) were calculated assuming a Poisson distribution, and they were rounded to the nearest two decimals [16]. SIRs for second cancers were calculated as for first cancers using similar adjustment for the standard rate, starting follow-up from the data of diagnosis of the first vascular tumors. All individuals, parents and offspring, were included in the analysis of second cancers.
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results |
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The Swedish Family-Cancer Database, which covered years 1958–2002 from the Swedish Cancer Registry, included 1730 patients diagnosed with vascular tumors (Table 1). The most common type was Kaposi's sarcoma (32.7%), followed by hemangioblastoma (29.5%), hemangioma (22.7%) and hemangiopericytoma (12.3%). It should be noted that only hemangiomas in the nervous system were recorded by the Swedish Cancer Registry. Almost all of the reported vascular tumors in the skin were Kaposi's sarcomas (95.9%). Vascular tumors in the nervous system were mainly hemangioblastomas and hemangiomas.
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The highest incidence rate of Kaposi's sarcoma was noted in the 1970s, and the rate decreased afterward (Figure 1). Hemangioblastoma continuously increased during the study period of 1958–2002. Conversely, glomangioma decreased successively. For specific sites, the incidence of nervous system hemangioblastoma increased continuously from 1970 to 2002. The rates of angiosarcoma and hemangiopericytoma in the trunk and extremities were highest in the 1970s and the 1980s, respectively.
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For the age-specific incidence rate (Figure 2), most of the vascular tumors showed the peak incidence at the seventh or eighth decades of life. The rate of skin Kaposi's sarcoma increased sharply after age 65 years. Note that the scale for y-axis is changed for tumors in the nervous system and the trunk and extremities. The incidence of nervous system hemangioma and hemangioblastoma increased towards age 50 years, and then leveled off and declined. The incidence for vascular tumors in the trunk and extremities peaked at age 70s.
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Familial risks for site-specific vascular tumors in offspring were calculated when parents were affected with cancer (Table 2). Only those cancer sites with at least three parent–offspring pairs were listed. For all offspring vascular tumors, the occurrence was significantly increased when parents were diagnosed with kidney cancer (SIR 2.25) and nervous system hemangioma of (69.51) and hemangioblastoma (105.80). For specific vascular sites, offspring hemangioblastomas in the nervous system were associated with parental kidney cancer (5.12) and parental nervous system hemangioma (283.65) and hemangioblastoma (289.38). All the offspring hemangioblastomas were diagnosed in the brain. Five of the nine parental kidney cancers were noted before age 45 years. Offspring nervous system hemangiomas (all in the brain) were associated with parental combined hemangioma and hemangioblastoma (56.96). Nervous system hemangiopericytoma was increased when parents were diagnosed with endocrine gland tumors (29.97); the two parental tumors were pituitary adenomas, giving an SIR of 182.14 (95% CI 17.17–669.85). Angiosarcoma in the trunk and extremities was associated with maternal breast cancer (2.89); all these maternal breast cancers were adenocarcinomas diagnosed after age 50 years.
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The risks of second cancers after first vascular tumors are shown in Table 3. The SIRs of second cancers of the kidney (5.73), skin (6.95), nervous system (2.65) and endocrine glands (6.27) and second non-Hodgkin's lymphoma (3.84) and Hodgkin's disease (8.95) were increased after all primary vascular tumors. For specific sites, second skin cancer (11.03), non-Hodgkin's lymphoma (5.52), Hodgkin's disease (25.86) and myeloma (5.10) were increased after skin Kaposi's sarcoma. Second kidney, nervous system and endocrine gland tumors were in excess after nervous system hemangioblastoma and hemangioma, but the risks after hemangioma were somewhat lower than those after hemangioblastoma. Four of the five subsequent endocrine gland tumors after hemangioblastoma were insulomas of the pancreas and one was a pituitary adenoma; all the four endocrine gland tumors after hemangioma were in situ pheochromocytomas. Skin cancer (6.88), mainly skin Kaposi's sarcoma (323.93), was in excess after primary angiosarcoma of the trunk and extremities.
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discussion |
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TopAbstractintroductionmaterials and methodsresultsdiscussionAcknowledgementsReferences |
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Blood vessel tumors are relatively rare compared with other neoplasms [15]. Moreover, among benign vascular tumors, such as hemangiomas, only those occurring in the nervous system are recorded in the Swedish Cancer Registry [17]. Kaposi's sarcoma was the most common recorded subtype of vascular tumors. Four different forms of Kaposi's sarcoma are recognized, chronic (classic), lymphadenopathic, transplantation associated and AIDS related [4]. Most of the Kaposi's sarcomas in our database belonged to the classic form, because they were diagnosed at a very late age (Figure 2) and because the prevalence of human immunodeficiency virus is low in Sweden [18]. Hemangioblastoma is one of the rarest forms of soft tissue tumors, but the incidence of nervous system hemangioblastoma has been increased continuously during the study periods (Figure 1), which may be related to the increasing use of modern imaging techniques [19]. The age–incidence curves for hemangioblastoma and hemangioma in the nervous system differed extensively from vascular tumors at other sites; the maximum for hemangioblastoma in the nervous system occurred
20 years before its peaking in the trunk and extremities. According to World Health Organization classification, hemangioendotheliomas are considered to be a separate entity with intermediate malignancy [3]. Unfortunately, they were coded together with hemangioblastoma in the Swedish Cancer Registry; such nondifferential misclassification would somewhat bias the calculation of the familial and second cancer risks of hemangioblastoma and dilute the estimated risks. Such effects could, however, be small as hemangioendothelioma is relatively rarer compared with hemangioblastoma. Some associations in this study may be spurious because of multiple comparisons; thus, some cautious is required in the interpretations.
Nervous system hemangioblastomas are one of the most common manifestations of VHL disease, with a penetration of 35%–59% [11]. Other tumors, such as retinal hemangioma, renal cell carcinoma, pheochromocytoma, insuloma and cysts of the pancreas are also commonly observed in VHL [11]. Retinal hemangiomas and pancreatic cysts are not recorded in the Swedish Cancer Registry. Offspring nervous system hemangioblastomas were dramatically increased when parents were diagnosed with tumors manifested in VHL disease, including kidney cancer and nervous system hemangioblastoma and hemangioma. The early onset of nervous system hemangioblastomas, as well as the early diagnosis of parental kidney cancers, is also typical of VHL disease [9]. Even familial hemangioblastomas often harbor a germ line mutation or deletion of one copy of the VHL tumor suppressor gene and a somatic mutation in the remaining wild-type copy [9, 20, 21]. Genetic testing for VHL germ line mutations is recommended to all patients with hemangioblastoma [22]. Hemangioma of the nervous system was also probably related to VHL disease, because it was significantly increased when parents were diagnosed with hemangioblastoma and/or hemangioma; it may be difficult to distinguish these two related neoplasms in pathology assessment. In addition to the excessive familial risk, VHL tumors tend to be bilateral and/or multifocal. In this study, we found that in addition to second hemangioblastoma and hemangioma, other VHL tumors, such as kidney cancer, insuloma of the pancreas and pheochromocytoma, were also in excess following primary nervous system hemangioblastoma and hemangioma [9, 23], suggesting that VHL disease was the cause.
Nervous system hemangiopericytomas were associated with parental pituitary adenomas. The two tumors may be mechanistically related through the growth hormone (GH) pathway [24]: some pituitary adenomas secrete GH [25], which stimulates the production of insulin-like growth factor; hemangiopericytomas are rich in insulin-like growth factor receptors [24]. Our database, however, has no information on the hormone-secreting properties of pituitary adenomas, and these are known to be a minority of all pituitary adenomas.
A novel finding was noted for an association of offspring angiosarcoma in the trunk and extremities with maternal breast cancer. Earlier studies have shown that angiosarcoma can produce vascular endothelial growth factor (VEGF) and its receptors, stimulating the growth of endothelial cells [26, 27]. VEGF can facilitate cancer cells to evade apoptosis and progress towards invasive and metastatic disease, in addition to its promoting effect on angiogenesis [28]. It is plausible that the VEGF pathway may explain this association, which needs to be confirmed in other studies, however.
There was a significant increase in second cancers after all vascular tumors. As all tumors reported to the Swedish Cancer Registry are histologically and/or cytologically verified [17], false reporting should be excluded as an explanation to this increase. Treatment and follow-up procedures are, however, not available in the Cancer Registry, and thus their effects could not be considered in this study. Second Kaposi's sarcoma was greatly increased after first skin Kaposi's sarcoma, with an SIR of 312; this is in agreement with the clinical features of Kaposi's sarcoma as a multifocal lesion [4, 29]. Other lymphoproliferative diaseases, such as non-Hodgkin's lymphoma, Hodgkin's lymphoma and multiple myeloma, were also in excess after Kaposi's sarcoma. Common risk factors or susceptibility among them may explain these excesses. Patients with Kaposi's sarcoma usually have lower amount of functional T and B cells and they are immunosuppressed [29], which may be the cause of the subsequent development of a lymphoproliferative disease. The high risk for second Kaposi's sarcoma after hemangioblastoma in the trunk and extremities is noteworthy, but the finding is based on only two cases.
In summary, the present study showed that the familial aggregation of vascular tumors is limited to specific histologies and to specific sites. The familial clustering of nervous system hemangioblastoma and hemangioma and the risks of subsequent cancers were primarily related to VHL disease. Nervous system hemangiopericytoma and pituitary adenomas may have a common pathway through GH action. The association of offspring angiosarcoma in trunk and extremities and maternal breast cancer may be related by VEGF overproduction. The increased risk for lymphoproliferative diseases after skin Kaposi's sarcoma could be explained by the immunodeficiency.
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Acknowledgements |
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The Family-Cancer Database was created by linking registries maintained by Statistics Sweden and the Swedish Cancer Register. The study was supported by the Deutsche Krebshilfe, the Swedish Cancer Society, the Swedish Council for Working Life and Social Research and the EU, LSHC-LT-2004-503465.
Received for publication September 14, 2006. Revision received December 13, 2006. Accepted for publication February 13, 2007.
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