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Endometriosis and the risk of malignancy, especially ovarian cancer
International Congress Series 1271 (2004) 232 – 235
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Endometriosis and the risk of malignancy, especially ovarian cancer Agneta Bergqvist a,*, AnnaSofia Melin b, Pa¨r Spare´n c a
Department of Obstetrics and Gynecology, Karolinska Institutet, Danderyds Hospital, SE-182 88, Stockholm, Sweden b Department of Obstetrics and Gynecology, Karolinska University Hospital, Huddinge, Sweden c Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Abstract. The purpose of this study was to determine the risk of malignancies in a large cohort of patients with endometriosis through long-term follow-up. Results: This extensive Swedish national registry study comprising 64,492 women (766,556 person-years) diagnosed with endometriosis between 1969 and 2000, and followed for a mean of 12.7 years, showed a significantly increased risk of ovarian cancer, other endocrine types of cancer (i.e. in the adrenals, parathyroid glands, thymus, the pituitary gland, and pancreas), non-Hodgkin’s lymphoma, and brain tumours. The risk of ovarian cancer was highest in women with ovarian endometriosis, but was also increased in women with other types of endometriosis; the risk was reduced in women with adenomyosis. Women with a hysterectomy before or at the same time as the endometriosis diagnosis had no increased risk of ovarian cancer. The risk of cervical cancer was reduced. Conclusion: Women with endometriosis have an increased risk of certain types of malignancy, in particular ovarian cancer. Hysterectomy appears to have a preventive effect. D 2004 Published by Elsevier B.V. Keywords: Endometriosis; Malignancy; Ovarian cancer; Hysterectomy
1. Introduction In a previous Swedish national registry study of 20,686 women with a mean follow-up time of 11.4 years, we found an increased risk of cancer in the ovaries, breasts, as well as haematopoietic malignancies, in particular non-Hodgkin’s lymphoma [1]. The risk of ovarian cancer was particularly increased in women with a longstanding history of ovarian endometriosis. The aims of this project were to extend this study to comprise a larger number of women with a longer follow-up time and also relate the risk to the time relationship between the two diagnoses as well as to hysterectomy. Abbreviations: SIR, standardised incidence ratio. * Corresponding author. Tel.: +46-8-6555000; fax: +46-8-7532276. E-mail address: [email protected] (A. Bergqvist). 0531-5131/ D 2004 Published by Elsevier B.V. doi:10.1016/j.ics.2004.06.005
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2. Materials and methods All women, who had been discharged from a Swedish hospital with the diagnosis of endometriosis during the years of 1969 –2000, were identified from the National Swedish Inpatient Registry (NSIR). A total of 67,339 cases were identified with a first admission of endometriosis. The register was combined with the National Swedish Cancer Registry (NSCR). Data on surgical procedures were also collected from the NSIR. The standardised incidence ratios (SIR) and their 95% confidence intervals were calculated as estimates of relative risk. SIR is the ratio of the observed number of cancer cases in the cohort and the expected number of cases in the cohort according to the cancer incidence in the Swedish female population by calendar year and 5-year age class. 3. Results In all, 2847 women were excluded because of incomplete registrations or because they had a cancer diagnosis before or at the same time as the endometriosis diagnosis. The final number for follow-up was 64,492 women (766,556 person-years) diagnosed with endometriosis and followed for a mean of 12.7 years. A diagnosis of malignancy was known before the hospitalisation in 0.003% of the cases. More than one type of cancer was found in 264 women; 7.5% of the malignancies registered were diagnosed within 1 year after the hospitalisation for endometriosis and were excluded from the follow-up group. The study did not show any significant overall increased risk of malignancy (SIR = 1.04) but did show an increased risk of ovarian cancer (SIR = 1.43), other endocrine types of cancer, i.e. cancer in the adrenal glands, parathyroid glands, thymus, the pituitary gland, pancreas and other endocrine organs (SIR = 1.36), non-Hodgkin’s lymphoma (SIR = 1.24), and brain tumours (SIR = 1.22). There was a reduced risk of cervical cancer and cancer in situ of the cervix (SIR = 0.64 and 0.89, respectively). The risk of ovarian cancer was highest in women with ovarian endometriosis (SIR = 1.77) but also increased in women with endometriosis in other locations (SIR = 1.47), whilst it was reduced in women with adenomyosis (SIR = 0.62). Women with a history of long standing endometriosis, i.e. more than 15 years, in the ovaries had the highest risk of ovarian cancer (SIR = 2.23). Diagnosis early in life, i.e. before the age of 40, was related to an increased risk of ovarian cancer, and diagnosis late in life, i.e. after the age of 50 was related to an increased risk of breast cancer (SIR = 1.28). Women with endometriosis had their ovarian cancer diagnosed earlier in life than the general population. Women, who had had a hysterectomy before or at the same time as hospitalisation for endometriosis, had no increased risk of ovarian cancer (SIR = 1.05). 4. Discussion This extensive registry study shows that women with endometriosis have an increased risk of certain types of malignancies, in particular ovarian cancer but also other types of malignancies in the endocrine organs and in the immune system. The results are consistent with a recently published independent Swedish study using the same national registries, including approximately 28,000 women with endometriosis, which shows a significantly
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higher risk of ovarian cancer in women with endometriosis (odds ratio, OR 1.34). There was no increased risk of ovarian cancer in women with other benign ovarian cysts or functional cysts [2]. An obvious time factor was involved in our results, and hysterectomy seemed to have a protective effect. An increased risk of ovarian cancer in women with endometriosis has been shown in other smaller studies [3 –6] and a malignant transformation of ovarian endometriosis was shown by Sampson [7] already in 1925. The frequency of malignant transformation of ovarian endometriosis has been estimated to be 0.7 – 5.0% [4,8]. Erzen et al. [9] suggested that there is a distinct entity of endometriosis associated ovarian carcinoma (EAOC) differing from other ovarian carcinomas in several aspects. They found that patients with EAOC had a lower stage of cancer, a distribution of histological subtypes that differs from the general population (i.e. endometrioid and clear cell cancer being the most common), predominantly lower grade endometriosis lesions, and significantly better overall survival as compared with the group of other ovarian carcinomas. Several studies have shown that endometriosis related malignancies have a favourable prognosis [10 – 12]. Women with extra-ovarian cancer arising in endometriosis are more likely to be postmenopausal [9]. Other endometriotic sites shown to have transformed into malignancy are the bowel, bladder, peritoneal wall, laparotomy scars in the abdominal wall, vagina, fallopian tubes, parametrium, and inguinal region [9,13 – 15]. 5. Conclusion This extensive epidemiologic study shows the increased risk of certain types of malignancies in women with endometriosis, not only in the ovaries but in other organs as well, related to endocrine functions and the immune system. Further studies to explore this relationship are urgently needed. Acknowledgements Financial supports were provided by the Endometriosis Association and the Swedish Medical Research Council (Project Number 9511). References [1] L.A. Brinton, et al., Cancer risk after a hospital discharge diagnosis of endometriosis, Am. J. Obstet. Gynecol. 176 (1997) 572 – 579. [2] C. Borgfeldt, E. Andolf, Cancer risk after hospital discharge diagnosis of benign ovarian cysts and endometriosis, Acta Obstet. Gynecol. Scand. 83 (2004) 395 – 400. [3] H. Jimbo, et al., Prevalence of ovarian endometriosis in epithelial ovarian cancer, Int. J. Gynaecol. Obstet. 59 (1997) 245 – 250. [4] M. Erzen, J. Kovacic, Relationship between endometriosis and ovarian cancer, Eur. J. Gynaecol. Oncol. 19 (1998) 553 – 555. [5] S. Ogawa, et al., Ovarian endometriosis associated with ovarian carcinoma: a clinicopathological and immunohistochemical study, Gynecol. Oncol. 77 (2000) 298 – 304. [6] H. Yoshikawa, et al., Prevalence of endometriosis in ovarian cancer, Gynecol. Obstet. Invest. 50 (Suppl. 1) (2000) 11 – 17. [7] J. Sampson, Endometrial carcinoma of the ovary. Arising in endometrial tissue in that organ, Arch. Surg. 10 (1925) 1 – 72.
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[8] M. Nishida, et al., Malignant transformation of ovarian endometriosis, Gynecol. Obstet. Invest. 50 (Suppl. 1) (2000) 18 – 25. [9] M. Erzen, et al., Endometriosis-associated ovarian carcinoma (EAOC): an entity distinct from other ovarian carcinomas as suggested by a nested case-control study, Gynecol. Oncol. 83 (2001) 100 – 108. [10] S.C. Modesitt, et al., Ovarian and extraovarian endometriosis-associated cancer, Obstet. Gynecol. 100 (2002) 788 – 795. [11] S. Komiyama, et al., Prognosis of Japanese patients with ovarian clear cell carcinoma associated with pelvic endometriosis: clinicopathologic evaluation, Gynecol. Oncol. 72 (1999) 342 – 346. [12] G.S. Leiserowitz, et al., Endometriosis-related malignancies, Int. J. Gynecol. Cancer 13 (2003) 466 – 471. [13] B.M. Slomovitz, et al., Serous adenocarcinoma of the inguinal region arising from endometriosis followed by a successful pregnancy, Gynecol. Oncol. 87 (2002) 152 – 154. [14] K.T. Chen, Endometrioid adenocarcinoma arising from colonic endometriosis mimicking primary colonic carcinoma, Int. J. Gynecol. Pathol. 21 (2002) 285 – 288. [15] V.C. Petersen, et al., Primary endometrioid adenocarcinoma of the large intestine arising in colorectal endometriosis, Histopathology 40 (2002) 171 – 176.
www.ics-elsevier.com
Endometriosis and the risk of malignancy, especially ovarian cancer Agneta Bergqvist a,*, AnnaSofia Melin b, Pa¨r Spare´n c a
Department of Obstetrics and Gynecology, Karolinska Institutet, Danderyds Hospital, SE-182 88, Stockholm, Sweden b Department of Obstetrics and Gynecology, Karolinska University Hospital, Huddinge, Sweden c Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Abstract. The purpose of this study was to determine the risk of malignancies in a large cohort of patients with endometriosis through long-term follow-up. Results: This extensive Swedish national registry study comprising 64,492 women (766,556 person-years) diagnosed with endometriosis between 1969 and 2000, and followed for a mean of 12.7 years, showed a significantly increased risk of ovarian cancer, other endocrine types of cancer (i.e. in the adrenals, parathyroid glands, thymus, the pituitary gland, and pancreas), non-Hodgkin’s lymphoma, and brain tumours. The risk of ovarian cancer was highest in women with ovarian endometriosis, but was also increased in women with other types of endometriosis; the risk was reduced in women with adenomyosis. Women with a hysterectomy before or at the same time as the endometriosis diagnosis had no increased risk of ovarian cancer. The risk of cervical cancer was reduced. Conclusion: Women with endometriosis have an increased risk of certain types of malignancy, in particular ovarian cancer. Hysterectomy appears to have a preventive effect. D 2004 Published by Elsevier B.V. Keywords: Endometriosis; Malignancy; Ovarian cancer; Hysterectomy
1. Introduction In a previous Swedish national registry study of 20,686 women with a mean follow-up time of 11.4 years, we found an increased risk of cancer in the ovaries, breasts, as well as haematopoietic malignancies, in particular non-Hodgkin’s lymphoma [1]. The risk of ovarian cancer was particularly increased in women with a longstanding history of ovarian endometriosis. The aims of this project were to extend this study to comprise a larger number of women with a longer follow-up time and also relate the risk to the time relationship between the two diagnoses as well as to hysterectomy. Abbreviations: SIR, standardised incidence ratio. * Corresponding author. Tel.: +46-8-6555000; fax: +46-8-7532276. E-mail address: [email protected] (A. Bergqvist). 0531-5131/ D 2004 Published by Elsevier B.V. doi:10.1016/j.ics.2004.06.005
A. Bergqvist et al. / International Congress Series 1271 (2004) 232–235
233
2. Materials and methods All women, who had been discharged from a Swedish hospital with the diagnosis of endometriosis during the years of 1969 –2000, were identified from the National Swedish Inpatient Registry (NSIR). A total of 67,339 cases were identified with a first admission of endometriosis. The register was combined with the National Swedish Cancer Registry (NSCR). Data on surgical procedures were also collected from the NSIR. The standardised incidence ratios (SIR) and their 95% confidence intervals were calculated as estimates of relative risk. SIR is the ratio of the observed number of cancer cases in the cohort and the expected number of cases in the cohort according to the cancer incidence in the Swedish female population by calendar year and 5-year age class. 3. Results In all, 2847 women were excluded because of incomplete registrations or because they had a cancer diagnosis before or at the same time as the endometriosis diagnosis. The final number for follow-up was 64,492 women (766,556 person-years) diagnosed with endometriosis and followed for a mean of 12.7 years. A diagnosis of malignancy was known before the hospitalisation in 0.003% of the cases. More than one type of cancer was found in 264 women; 7.5% of the malignancies registered were diagnosed within 1 year after the hospitalisation for endometriosis and were excluded from the follow-up group. The study did not show any significant overall increased risk of malignancy (SIR = 1.04) but did show an increased risk of ovarian cancer (SIR = 1.43), other endocrine types of cancer, i.e. cancer in the adrenal glands, parathyroid glands, thymus, the pituitary gland, pancreas and other endocrine organs (SIR = 1.36), non-Hodgkin’s lymphoma (SIR = 1.24), and brain tumours (SIR = 1.22). There was a reduced risk of cervical cancer and cancer in situ of the cervix (SIR = 0.64 and 0.89, respectively). The risk of ovarian cancer was highest in women with ovarian endometriosis (SIR = 1.77) but also increased in women with endometriosis in other locations (SIR = 1.47), whilst it was reduced in women with adenomyosis (SIR = 0.62). Women with a history of long standing endometriosis, i.e. more than 15 years, in the ovaries had the highest risk of ovarian cancer (SIR = 2.23). Diagnosis early in life, i.e. before the age of 40, was related to an increased risk of ovarian cancer, and diagnosis late in life, i.e. after the age of 50 was related to an increased risk of breast cancer (SIR = 1.28). Women with endometriosis had their ovarian cancer diagnosed earlier in life than the general population. Women, who had had a hysterectomy before or at the same time as hospitalisation for endometriosis, had no increased risk of ovarian cancer (SIR = 1.05). 4. Discussion This extensive registry study shows that women with endometriosis have an increased risk of certain types of malignancies, in particular ovarian cancer but also other types of malignancies in the endocrine organs and in the immune system. The results are consistent with a recently published independent Swedish study using the same national registries, including approximately 28,000 women with endometriosis, which shows a significantly
234
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higher risk of ovarian cancer in women with endometriosis (odds ratio, OR 1.34). There was no increased risk of ovarian cancer in women with other benign ovarian cysts or functional cysts [2]. An obvious time factor was involved in our results, and hysterectomy seemed to have a protective effect. An increased risk of ovarian cancer in women with endometriosis has been shown in other smaller studies [3 –6] and a malignant transformation of ovarian endometriosis was shown by Sampson [7] already in 1925. The frequency of malignant transformation of ovarian endometriosis has been estimated to be 0.7 – 5.0% [4,8]. Erzen et al. [9] suggested that there is a distinct entity of endometriosis associated ovarian carcinoma (EAOC) differing from other ovarian carcinomas in several aspects. They found that patients with EAOC had a lower stage of cancer, a distribution of histological subtypes that differs from the general population (i.e. endometrioid and clear cell cancer being the most common), predominantly lower grade endometriosis lesions, and significantly better overall survival as compared with the group of other ovarian carcinomas. Several studies have shown that endometriosis related malignancies have a favourable prognosis [10 – 12]. Women with extra-ovarian cancer arising in endometriosis are more likely to be postmenopausal [9]. Other endometriotic sites shown to have transformed into malignancy are the bowel, bladder, peritoneal wall, laparotomy scars in the abdominal wall, vagina, fallopian tubes, parametrium, and inguinal region [9,13 – 15]. 5. Conclusion This extensive epidemiologic study shows the increased risk of certain types of malignancies in women with endometriosis, not only in the ovaries but in other organs as well, related to endocrine functions and the immune system. Further studies to explore this relationship are urgently needed. Acknowledgements Financial supports were provided by the Endometriosis Association and the Swedish Medical Research Council (Project Number 9511). References [1] L.A. Brinton, et al., Cancer risk after a hospital discharge diagnosis of endometriosis, Am. J. Obstet. Gynecol. 176 (1997) 572 – 579. [2] C. Borgfeldt, E. Andolf, Cancer risk after hospital discharge diagnosis of benign ovarian cysts and endometriosis, Acta Obstet. Gynecol. Scand. 83 (2004) 395 – 400. [3] H. Jimbo, et al., Prevalence of ovarian endometriosis in epithelial ovarian cancer, Int. J. Gynaecol. Obstet. 59 (1997) 245 – 250. [4] M. Erzen, J. Kovacic, Relationship between endometriosis and ovarian cancer, Eur. J. Gynaecol. Oncol. 19 (1998) 553 – 555. [5] S. Ogawa, et al., Ovarian endometriosis associated with ovarian carcinoma: a clinicopathological and immunohistochemical study, Gynecol. Oncol. 77 (2000) 298 – 304. [6] H. Yoshikawa, et al., Prevalence of endometriosis in ovarian cancer, Gynecol. Obstet. Invest. 50 (Suppl. 1) (2000) 11 – 17. [7] J. Sampson, Endometrial carcinoma of the ovary. Arising in endometrial tissue in that organ, Arch. Surg. 10 (1925) 1 – 72.
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[8] M. Nishida, et al., Malignant transformation of ovarian endometriosis, Gynecol. Obstet. Invest. 50 (Suppl. 1) (2000) 18 – 25. [9] M. Erzen, et al., Endometriosis-associated ovarian carcinoma (EAOC): an entity distinct from other ovarian carcinomas as suggested by a nested case-control study, Gynecol. Oncol. 83 (2001) 100 – 108. [10] S.C. Modesitt, et al., Ovarian and extraovarian endometriosis-associated cancer, Obstet. Gynecol. 100 (2002) 788 – 795. [11] S. Komiyama, et al., Prognosis of Japanese patients with ovarian clear cell carcinoma associated with pelvic endometriosis: clinicopathologic evaluation, Gynecol. Oncol. 72 (1999) 342 – 346. [12] G.S. Leiserowitz, et al., Endometriosis-related malignancies, Int. J. Gynecol. Cancer 13 (2003) 466 – 471. [13] B.M. Slomovitz, et al., Serous adenocarcinoma of the inguinal region arising from endometriosis followed by a successful pregnancy, Gynecol. Oncol. 87 (2002) 152 – 154. [14] K.T. Chen, Endometrioid adenocarcinoma arising from colonic endometriosis mimicking primary colonic carcinoma, Int. J. Gynecol. Pathol. 21 (2002) 285 – 288. [15] V.C. Petersen, et al., Primary endometrioid adenocarcinoma of the large intestine arising in colorectal endometriosis, Histopathology 40 (2002) 171 – 176.