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Hepatocellular carcinoma after long-term tamoxifen therapy
Annals of Oncology 11: 1195-1196, 2000. © 2000 Kluwer Academic Publishers. Primed in the Netherlands.
Clinical case Hepatocellular carcinoma after long-term tamoxifen therapy D. F. Moffat,1 K. A. Oien,1'2 J. Dickson,3 T. Habeshaw3 & D. R. McLellan4 1
University Department of Pathology, Western Infirmary; 2CRC Department of Medical Oncology, CRC Beatson Laboratories, University of Glasgow, Garscube Estate; 3Bealson Oncology Centre, Western Infirmary; ADepartment of Pathology, Victoria Infirmary, Glasgow, UK
We describe a case of hepatocellular carcinoma (HCC) after long term tamoxifen therapy in a 71-year-old woman. The patient was prescribed tamoxifen for 12 years following right mastectomy and axillary node clearance for breast carcinoma in 1985. In 1997, she complained of abdominal pain and fullness. An abdominal ultrasound scan showed lesions in the right lobe of liver which were thought to be metastases. However, a biopsy showed primary HCC. Studies in rats suggest
Introduction
Tamoxifen has been used as adjuvant hormonal therapy to treat breast carcinoma for almost two decades. It was initially recommended for use in post-menopausal women with node positive, oestrogen receptor positive breast cancer but is now used in women with receptor positive tumours regardless of their menopausal or nodal status [1]. Studies on tamoxifen as a chemopreventative agent are currently underway in the USA, the UK and Europe [2]. Because of the high incidence of breast cancer and the extensive and long-term use of tamoxifen, there has been concern over the potential side-effects of the drug [3]. In the last decade, there have been reports suggesting that one long-term side effect of tamoxifen may be the occurrence of primary hepatocellular carcinoma (HCC) [4, 5] although there are no epidemiological data to support this. We describe a case of HCC after tamoxifen use and discuss the possible association. Case study A 71-year-old woman presented with a history of several months of right upper quadrant discomfort. Twelve years earlier, the patient had undergone right mastectomy and axillary node clearance for a grade 1 (Bloom & Richardson grading system), node negative ductal carcinoma of breast. Then, the liver was normal on ultrasound. She was prescribed tamoxifen 20 mg daily which was continued for 12 years. Her past medical history also included pulmonary tuberculosis, hypertension and
that tamoxifen is involved in hepatic carcinogenesis but studies in humans have failed to show any increased risk. However, these studies followed up patients for less than five years. An increased risk of HCC may not become apparent until after a decade or more of tamoxifen therapy. In addition, HCC in tamoxifen treated patients may be under-reported since there may be reluctance to biopsy liver tumours which are assumed to be secondary carcinoma of the breast. Key words: hepatocellular carcinoma, tamoxifen
angina pectoris (for which she was receiving diltiazem and amlodipine). She had no known risk factors for HCC. On clinical examination there was no evidence of local recurrence of her breast cancer. A mass was palpable in the right side of her abdomen and abdominal ultrasound showed what were assumed to be metastatic lesions in the right lobe of the liver. Liver function tests were mildly deranged (AST 145 U/l, normal range 5-35 U/l; alkaline phophatase 378 U/l, normal range 30-300 U/l; other liver enzymes normal). In view of the length of time since her initial diagnosis, the patient was then admitted for an ultrasound-guided liver biopsy. Pathology Microscopy of the needle core biopsy showed hepatic tissue of abnormal architecture: no portal tract elements were present and reticulin staining revealed loss of the normal sinusoidal pattern. The liver cells had pleomorphic nuclei with prominent nucleoli. There was a high mitotic rate with occasional abnormal mitotic figures. Intranuclear inclusions and intracytoplasmic hyaline globules were identified. A diagnosis of HCC was made. No non-tumorous liver was included in the biopsy. Subsequently, the patient's serum AFP was measured at 320 U/l (normal range 5-20 U/l), reinforcing the diagnosis. She was referred for surgical assessment, but laparoscopic ultrasound revealed irresectable bilobar disease. As she was symptomatic, chemo-embolisation was performed and AFP levels then fell.
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Summary
1196 Discussion
References 1. Consensus conference. Adjuvant chemotherapy for breast cancer. JAMA 1985; 24: 3461-3. 2. Powles TJ. The case for clinical trials of tamoxifen for the prevention of early breast cancer. Lancet 1992; 340: 1145-7. 3. Fugh-Berman A, Epstein S. Tamoxifen: Disease prevention or disease substitution? Lancet 1992; 340: 1143-5. 4. Muhlemann K., Cook LS, Weiss NS. The incidence of hepatocellular carcinoma in US white women with breast cancer after the introduction of tamoxifen in 1977. Breast Cancer Res Treat 1994; 30: 201-4. 5. FornanderT, Cedermark B, Mattsson A et al. Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. Lancet 1989; 8630: 117-20. 6. Forman D, Vincent TJ, Doll R. Cancer of the liver and oral contraceptives. BMJ 1986; 292: 1357-61. 7. Nayfleld SG, Karp JE, Ford LG et al. Potential role of tamoxifen in prevention of breast cancer. J Natl Cancer Inst 1991; 83:1450-9. 8. Furr B, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 1984; 25: 127-204. 9. Jager J, Yuernian E. Synthetic oestrogens and tamoxifen as promoters of hepatocarcinogenesis. Prevent Med 1991; 20. 27-37 10. Williams GM, Iatropoulos J, Djordjevic MV, Kaltenberg OP. The triphenlyethylene drug tamoxifen is a strong liver carcinogen in the rat. Carcinogenesis 1993; 14: 315-7. 11. Martin EA, Carthew P, White IN et al. Investigation of the formation and accumulation of liver DNA adducts in mice chronically exposed to tamoxifen. Carcinogenesis 1997; 18: 2209-15. 12. Martin EA, Rich KJ, White IN et al. 32P-postlabelled DNA adducts in liver obtained from women treated with tamoxifen. Carcinogenesis 1995; 16: 1651-4. 13. Guzelian PS. Relevance of rat liver tumours to human hepatic and endometrial cancer. Semin Oncol 1997; 24 (Suppl): 105-21. 14. Floren LC, Hebert MF, Venook AP et al. Tamoxifen in liver disease: Potential exacerbation of hepatic dysfunction. Ann Oncol 1998; 8: 1123-6. 15. Oien KA, Moffat D, Curry GWet al. Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet 1999; 353 (9146): 36-7. 16. Simonetti RG, Liberati A, Angiolini C, Pagliaro L. Treatment of hepatocellular carcinoma: A systematic review of randomized controlled trials. Ann Oncol 1997; 8: 117-36. 17. Tamoxifen in treatment of hepatocellular carcinoma: A randomised controlled trial. CLIP Group. Lancet 1998; 352 (9121): 17-20. 18. Johnstone AJ, Sarkar TK., Hussey JK. Primary hepatocellular carcinoma in a patient with breast cancer. Clin Oncol 1991; 3: 180-1. Received 22 June 1999; accepted 21 September 1999. Correspondence to: Dr K. A. Oien, MD University Department of Pathology Western Infirmary Dumbarton Road Glasgow Gil 6NT.UK E-mail: k.oien;a clinmed.gla.ac.uk
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Administration of steroids, including the oral contraceptive pill, is a recognised risk factor in the development of HCC [6]. The synthetic steroid tamoxifen is associated with an increased risk of endometrial carcinoma [7]. This has been attributed to the fact that, as well as having anti-oestrogenic effects, tamoxifen has partial agonist activity [8]. Since the growth of HCC has been shown to be modulated by oestrogens [9], the potential role of tamoxifen has a rational basis. This is true in animal models: tamoxifen promotes the development of liver tumours in rats [10] and hamsters but not in mice [11]. The genotoxic lesion is probably a DNA adduct, formed with a metabolite of tamoxifen. In mice these adducts are cleared by the liver but in rats there is a steady increase in their levels. Similar DNA adducts have been demonstrated in the liver of breast cancer patients being treated with tamoxifen [12]. However, it may be that these adducts do not persist in humans as long as they do in the rat [13]. The hepatotoxic effects of tamoxifen in humans are well recognised: the drug has been associated with exacerbation of hepatic dysfunction [14] and cirrhosis with steatohepatitis [15]. Interestingly, it has been hypothesised that, through its anti-oestrogenic effects, tamoxifen could have a therapeutic effect in HCC but trials have shown conflicting results [16, 17]. To date, two major studies of tamoxifen use have assessed the incidence of HCC. In a Swedish trial [5], two cases of HCC were identified in 1846 women. In the United States, an extensive retrospective study of women with breast carcinoma [4] suggested that tamoxifen did not cause any increase in the incidence of HCC. However, the authors themselves admit a number of flaws in this study. Firstly, tamoxifen use was not studied directly, but was predicted from a combination of menopausal status and date of diagnosis (tamoxifen was introduced in 1977). Secondly, mean follow-up time for post-menopausal women diagnosed after 1977 was less than five years (this was also the case in the Swedish trial). The authors suggest that an increased risk may not manifest itself until after a decade of drug use. Adjuvant tamoxifen therapy is currently discontinued atfiveyears. This may hamper recognition of an increased risk of HCC. However, if tamoxifen becomes accepted as a prophylactic agent the duration of therapy is likely to be much longer. Thirdly, prescribing of tamoxifen may not have been commonplace until 1985 when it was recommended as standard therapy in the USA for post-menopausal women with node positive, receptor positive breast carcinoma [3]. There has been a single case report of a patient developing widely disseminated HCC four months after commencing tamoxifen therapy [18], but the interval is too short for an association to be likely. Although the benefits of tamoxifen therapy outweigh the risks in the treatment of breast cancer, its use in prophylaxis remains to be clarified. We believe that any role of long-term tamoxifen therapy in the development
of HCC remains to be clarified. Previous studies have followed patients up for less thanfiveyears but perhaps, as in this case, at least a decade of use is required before an increase in incidence would be observed. We also advocate routine biopsy of hepatic lesions in patients on long-term tamoxifen with a previous history of breast carcinoma. It is possible that HCC is underdiagnosed in patients with breast cancer, since a liver tumour may be assumed to be a metastasis rather than a second primary.
Clinical case Hepatocellular carcinoma after long-term tamoxifen therapy D. F. Moffat,1 K. A. Oien,1'2 J. Dickson,3 T. Habeshaw3 & D. R. McLellan4 1
University Department of Pathology, Western Infirmary; 2CRC Department of Medical Oncology, CRC Beatson Laboratories, University of Glasgow, Garscube Estate; 3Bealson Oncology Centre, Western Infirmary; ADepartment of Pathology, Victoria Infirmary, Glasgow, UK
We describe a case of hepatocellular carcinoma (HCC) after long term tamoxifen therapy in a 71-year-old woman. The patient was prescribed tamoxifen for 12 years following right mastectomy and axillary node clearance for breast carcinoma in 1985. In 1997, she complained of abdominal pain and fullness. An abdominal ultrasound scan showed lesions in the right lobe of liver which were thought to be metastases. However, a biopsy showed primary HCC. Studies in rats suggest
Introduction
Tamoxifen has been used as adjuvant hormonal therapy to treat breast carcinoma for almost two decades. It was initially recommended for use in post-menopausal women with node positive, oestrogen receptor positive breast cancer but is now used in women with receptor positive tumours regardless of their menopausal or nodal status [1]. Studies on tamoxifen as a chemopreventative agent are currently underway in the USA, the UK and Europe [2]. Because of the high incidence of breast cancer and the extensive and long-term use of tamoxifen, there has been concern over the potential side-effects of the drug [3]. In the last decade, there have been reports suggesting that one long-term side effect of tamoxifen may be the occurrence of primary hepatocellular carcinoma (HCC) [4, 5] although there are no epidemiological data to support this. We describe a case of HCC after tamoxifen use and discuss the possible association. Case study A 71-year-old woman presented with a history of several months of right upper quadrant discomfort. Twelve years earlier, the patient had undergone right mastectomy and axillary node clearance for a grade 1 (Bloom & Richardson grading system), node negative ductal carcinoma of breast. Then, the liver was normal on ultrasound. She was prescribed tamoxifen 20 mg daily which was continued for 12 years. Her past medical history also included pulmonary tuberculosis, hypertension and
that tamoxifen is involved in hepatic carcinogenesis but studies in humans have failed to show any increased risk. However, these studies followed up patients for less than five years. An increased risk of HCC may not become apparent until after a decade or more of tamoxifen therapy. In addition, HCC in tamoxifen treated patients may be under-reported since there may be reluctance to biopsy liver tumours which are assumed to be secondary carcinoma of the breast. Key words: hepatocellular carcinoma, tamoxifen
angina pectoris (for which she was receiving diltiazem and amlodipine). She had no known risk factors for HCC. On clinical examination there was no evidence of local recurrence of her breast cancer. A mass was palpable in the right side of her abdomen and abdominal ultrasound showed what were assumed to be metastatic lesions in the right lobe of the liver. Liver function tests were mildly deranged (AST 145 U/l, normal range 5-35 U/l; alkaline phophatase 378 U/l, normal range 30-300 U/l; other liver enzymes normal). In view of the length of time since her initial diagnosis, the patient was then admitted for an ultrasound-guided liver biopsy. Pathology Microscopy of the needle core biopsy showed hepatic tissue of abnormal architecture: no portal tract elements were present and reticulin staining revealed loss of the normal sinusoidal pattern. The liver cells had pleomorphic nuclei with prominent nucleoli. There was a high mitotic rate with occasional abnormal mitotic figures. Intranuclear inclusions and intracytoplasmic hyaline globules were identified. A diagnosis of HCC was made. No non-tumorous liver was included in the biopsy. Subsequently, the patient's serum AFP was measured at 320 U/l (normal range 5-20 U/l), reinforcing the diagnosis. She was referred for surgical assessment, but laparoscopic ultrasound revealed irresectable bilobar disease. As she was symptomatic, chemo-embolisation was performed and AFP levels then fell.
Downloaded from https://academic.oup.com/annonc/article-abstract/11/9/1195/146949 by guest on 03 February 2019
Summary
1196 Discussion
References 1. Consensus conference. Adjuvant chemotherapy for breast cancer. JAMA 1985; 24: 3461-3. 2. Powles TJ. The case for clinical trials of tamoxifen for the prevention of early breast cancer. Lancet 1992; 340: 1145-7. 3. Fugh-Berman A, Epstein S. Tamoxifen: Disease prevention or disease substitution? Lancet 1992; 340: 1143-5. 4. Muhlemann K., Cook LS, Weiss NS. The incidence of hepatocellular carcinoma in US white women with breast cancer after the introduction of tamoxifen in 1977. Breast Cancer Res Treat 1994; 30: 201-4. 5. FornanderT, Cedermark B, Mattsson A et al. Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. Lancet 1989; 8630: 117-20. 6. Forman D, Vincent TJ, Doll R. Cancer of the liver and oral contraceptives. BMJ 1986; 292: 1357-61. 7. Nayfleld SG, Karp JE, Ford LG et al. Potential role of tamoxifen in prevention of breast cancer. J Natl Cancer Inst 1991; 83:1450-9. 8. Furr B, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 1984; 25: 127-204. 9. Jager J, Yuernian E. Synthetic oestrogens and tamoxifen as promoters of hepatocarcinogenesis. Prevent Med 1991; 20. 27-37 10. Williams GM, Iatropoulos J, Djordjevic MV, Kaltenberg OP. The triphenlyethylene drug tamoxifen is a strong liver carcinogen in the rat. Carcinogenesis 1993; 14: 315-7. 11. Martin EA, Carthew P, White IN et al. Investigation of the formation and accumulation of liver DNA adducts in mice chronically exposed to tamoxifen. Carcinogenesis 1997; 18: 2209-15. 12. Martin EA, Rich KJ, White IN et al. 32P-postlabelled DNA adducts in liver obtained from women treated with tamoxifen. Carcinogenesis 1995; 16: 1651-4. 13. Guzelian PS. Relevance of rat liver tumours to human hepatic and endometrial cancer. Semin Oncol 1997; 24 (Suppl): 105-21. 14. Floren LC, Hebert MF, Venook AP et al. Tamoxifen in liver disease: Potential exacerbation of hepatic dysfunction. Ann Oncol 1998; 8: 1123-6. 15. Oien KA, Moffat D, Curry GWet al. Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet 1999; 353 (9146): 36-7. 16. Simonetti RG, Liberati A, Angiolini C, Pagliaro L. Treatment of hepatocellular carcinoma: A systematic review of randomized controlled trials. Ann Oncol 1997; 8: 117-36. 17. Tamoxifen in treatment of hepatocellular carcinoma: A randomised controlled trial. CLIP Group. Lancet 1998; 352 (9121): 17-20. 18. Johnstone AJ, Sarkar TK., Hussey JK. Primary hepatocellular carcinoma in a patient with breast cancer. Clin Oncol 1991; 3: 180-1. Received 22 June 1999; accepted 21 September 1999. Correspondence to: Dr K. A. Oien, MD University Department of Pathology Western Infirmary Dumbarton Road Glasgow Gil 6NT.UK E-mail: k.oien;a clinmed.gla.ac.uk
Downloaded from https://academic.oup.com/annonc/article-abstract/11/9/1195/146949 by guest on 03 February 2019
Administration of steroids, including the oral contraceptive pill, is a recognised risk factor in the development of HCC [6]. The synthetic steroid tamoxifen is associated with an increased risk of endometrial carcinoma [7]. This has been attributed to the fact that, as well as having anti-oestrogenic effects, tamoxifen has partial agonist activity [8]. Since the growth of HCC has been shown to be modulated by oestrogens [9], the potential role of tamoxifen has a rational basis. This is true in animal models: tamoxifen promotes the development of liver tumours in rats [10] and hamsters but not in mice [11]. The genotoxic lesion is probably a DNA adduct, formed with a metabolite of tamoxifen. In mice these adducts are cleared by the liver but in rats there is a steady increase in their levels. Similar DNA adducts have been demonstrated in the liver of breast cancer patients being treated with tamoxifen [12]. However, it may be that these adducts do not persist in humans as long as they do in the rat [13]. The hepatotoxic effects of tamoxifen in humans are well recognised: the drug has been associated with exacerbation of hepatic dysfunction [14] and cirrhosis with steatohepatitis [15]. Interestingly, it has been hypothesised that, through its anti-oestrogenic effects, tamoxifen could have a therapeutic effect in HCC but trials have shown conflicting results [16, 17]. To date, two major studies of tamoxifen use have assessed the incidence of HCC. In a Swedish trial [5], two cases of HCC were identified in 1846 women. In the United States, an extensive retrospective study of women with breast carcinoma [4] suggested that tamoxifen did not cause any increase in the incidence of HCC. However, the authors themselves admit a number of flaws in this study. Firstly, tamoxifen use was not studied directly, but was predicted from a combination of menopausal status and date of diagnosis (tamoxifen was introduced in 1977). Secondly, mean follow-up time for post-menopausal women diagnosed after 1977 was less than five years (this was also the case in the Swedish trial). The authors suggest that an increased risk may not manifest itself until after a decade of drug use. Adjuvant tamoxifen therapy is currently discontinued atfiveyears. This may hamper recognition of an increased risk of HCC. However, if tamoxifen becomes accepted as a prophylactic agent the duration of therapy is likely to be much longer. Thirdly, prescribing of tamoxifen may not have been commonplace until 1985 when it was recommended as standard therapy in the USA for post-menopausal women with node positive, receptor positive breast carcinoma [3]. There has been a single case report of a patient developing widely disseminated HCC four months after commencing tamoxifen therapy [18], but the interval is too short for an association to be likely. Although the benefits of tamoxifen therapy outweigh the risks in the treatment of breast cancer, its use in prophylaxis remains to be clarified. We believe that any role of long-term tamoxifen therapy in the development
of HCC remains to be clarified. Previous studies have followed patients up for less thanfiveyears but perhaps, as in this case, at least a decade of use is required before an increase in incidence would be observed. We also advocate routine biopsy of hepatic lesions in patients on long-term tamoxifen with a previous history of breast carcinoma. It is possible that HCC is underdiagnosed in patients with breast cancer, since a liver tumour may be assumed to be a metastasis rather than a second primary.