Abstract
Objective
To report a rare case of paraneoplastic jaundice as a manifestation of prostate cancer.
Clinical Presentation and Intervention
We report on a case of paraneoplastic syndrome in a 72-year-old man with prostate cancer that manifested with idiopathic jaundice. Although steroids can be used as treatment in patients with prostate cancer, they could exacerbate paraneoplastic jaundice. The jaundice that flared up after treatment with 40 mg prednisone was improved with antiandrogen treatment.
Conclusion
Physicians should be aware of the possibility of paraneoplastic jaundice in patients with prostate cancer. Appropriate antiandrogen therapy should be considered for paraneoplastic jaundice in these patients.
Keywords: Androgen receptor, Bicalutamide, Jaundice, Prostate cancer, Prednisone
Significance of the Study
• As a paraneoplastic manifestation of advanced prostate cancer, cholestatic jaundice can be exacerbated by the use of steroids and it can be improved by appropriate antiandrogen therapy.
Introduction
Paraneoplastic cholestasis in patients with prostate cancer, which has been previously shown to improve with the use of antiandrogen agents, has been rarely reported [1, 2, 3, 4, 5, 6, 7, 8, 9]. As maintenance therapy for metastatic prostate cancer, corticosteroids have been widely used for decades [10]. Here, we report a patient with metastatic prostate cancer in whom we observed deterioration of paraneoplastic jaundice after a short course of treatment with 40 mg prednisone. The patient showed improvement after antiandrogen treatment.
Case Report
A 72-year-old man visited our emergency department due to jaundice and anorexia which had persisted for 2 months. The results of his physical examination were unremarkable. Liver function tests revealed the following values: serum bilirubin level (SBL), 13.1 mg/dL; serum albumin level, 4.45 g/dL; serum aspartate aminotransferase level, 112 IU/L; serum alanine aminotransferase level, 146 IU/L; and prothrombin time-international normalized ratio, 1.1. Serum hepatitis B surface antigen and hepatitis C antigen tests were all negative. Abdominal computed tomography revealed enlargement of the prostate gland and no evidence of obstructive jaundice including intrahepatic ductal dilatation (Fig. 1). The serum prostate-specific antigen level was as high as 7,895 ng/mL (normal range: 0–4 ng/mL). A prostate biopsy revealed adenocarcinoma (Fig. 2), and a liver biopsy revealed a canalicular type of cholestasis without evidence of liver metastasis (Fig. 3).
Fig. 1.
Abdominal computed tomography scan showing no evidence of biliary obstruction including common bile duct (arrow) and intrahepatic ductal dilatation.
Fig. 2.
Transrectal prostate biopsy findings that led to the diagnosis of adenocarcinoma Hematoxylin and eosin stain. ×100.
Fig. 3.
Microscopic examination result showing mild infiltration of lymphocytes and bile plugs in the portal tract and bile canaliculi. Hematoxylin and eosin stain. ×200.
Despite 20 days of supportive care, the patient's SBL did not improve. After 3 days of 40 mg prednisone therapy, sudden deterioration of the jaundice was observed. Although the corticosteroid therapy was discontinued, his SBL increased to 25.25 mg/dL. Considering the jaundice to be a paraneoplastic manifestation of prostate cancer, antiandrogen treatments with 50 mg bicalutamide and 3.6 mg goserelin were started. Six days later, his jaundice improved dramatically, with his SBL decreasing to 7.22 mg/dL. Three months after the hormone therapy, his serum prostate-specific antigen level decreased from 7,895 to 311 ng/mL, and his bilirubin level was normalized without any adverse reaction (Fig. 4).
Fig. 4.
Clinical course of the patient. ALT, alanine aminotransferase; PSA, prostate-specific antigen (in mg/mL).
Discussion
Cholestatic manifestation of paraneoplastic syndrome in association with prostate cancer is rare. A few previous cases have been reported [1, 2, 3, 4, 5, 6, 7, 8, 9] and 7 cases showed improvement after hormone therapy (Table 1). From a therapeutic point of view, corticosteroids have been used to treat metastatic prostate cancer for decades [10]. In contrast, we observed a deterioration of paraneoplastic jaundice in a patient with metastatic prostate cancer after a short course of prednisone, which improved after antiandrogen treatment.
Table 1.
Summary of cases of paraneoplastic cholestatic jaundice of prostate cancer
| Age, years | Peak bilirubin | Peak PSA, ng/mL | Liver biopsy | Treatment (cancer) | Prognostic outcome | |
|---|---|---|---|---|---|---|
| Okano et al. [1] | 68 | 23.4 mg/dL | 15,018 | Lymphocyte infiltration, cholestasis | Bicalutamide | Improved |
| Kuramoto et al. [2] | 75 | 17 mg/dL | 9,862 | ND | Bicalutamide, leuprolide | Improved |
| Koruk et al. [3] | 77 | 10 mg/dL | 100 | Normal | Bicalutamide, goserelin | Improved |
| Reddy et al. [4] | 57 | 8 mg/dL | ND | Lymphocyte infiltration, cholestasis | ND | Intermittent worsening |
| Shah [5] | 64 | 302 mmol/L | 970 | ND | Goserelin, cyproterone | Unknown |
| Nguyen et al. [6] | 51 | 19 mmol/L | 556 | ND | Bicalutamide, goserelin | Improved |
| Karakolios et al. [7] | 72 | 18.1 mg/dL | 150 | ND | Flutamide, leuprolide | Improved |
| Hinostroza-Yanahuaya et al. [8] | 70 | 29 mg/dL | 1,548 | ND | Conservative treatment | Expired |
| 84 | 3.96 mg/dL | ND | Expired | |||
| Vieira et al. [9] | 78 | 12.3 mg/dL | >1,000 | ND | Bicalutamide, goserelin | Improved |
| Our case | 72 | 25.25 mg/dL | 7,895 | Lymphocyte infiltration, cholestasis | Bicalutamide, goserelin | Improved |
PSA, prostate-specific antigen; ND, not done.
Although no convincing pathogenesis was found, we suggest a hypothesis on the cause of the sudden deterioration. The use of corticosteroids in prostate cancer inhibits the secretion of adrenocorticotropic hormone in the pituitary gland, thereby reducing the synthesis of the adrenal androgen hormone, preventing cancer and improving the patient's symptoms [10] However, in the literature, corticosteroid use has been associated with the development of resistance to prostate cancer treatment [10, 11]. The interaction of steroid hormones such as corticosteroids and androgens in prostate cancer has not been fully elucidated, especially in terms of growth receptors and androgen receptors (AR) [10]. In advanced stages of prostate cancer, the frequency of AR mutations is significantly increased [12]. Corticosteroids can activate the mutated AR to manifest an androgenic effect in metastatic prostate cancer, which in turn activates the growth receptor to induce cancer growth and stimulate genes that overlap with AR targets [11]. We suggest that administration of steroids may cause a sudden flare of paraneoplastic cholestasis, with elevation of bilirubin levels.
Conclusion
Paraneoplastic cholestasis should be considered when unexplained cholestasis occurs in cancer patients. In addition, paraneoplastic cholestasis due to prostate cancer can be improved with appropriate antiandrogen therapy and may be exacerbated by steroid use.
Disclosure Statement
No conflict of interest is reported.
References
- 1.Okano A, Ohana M, Kusumi F. Idiopathic cholestatic jaundice may be a paraneoplastic manifestation of underlying malignancy: a case of prostate cancer. Clin J Gastroenterol. 2014;7:278–282. doi: 10.1007/s12328-014-0484-4. [DOI] [PubMed] [Google Scholar]
- 2.Kuramoto T, Senzaki H, Koike H, et al. Cholestatic jaundice as a paraneoplastic manifestation of prostate cancer. Case Rep Urol. 2013;2013:303727. doi: 10.1155/2013/303727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Koruk M, Butukberber M, Savas C, et al. Paraneoplastic cholestasis associated with prostate carcinoma. Turk J Gastroenterol. 2004;15:53–55. [PubMed] [Google Scholar]
- 4.Reddy AN, Grosberg SJ, Wapnick S. Intermittent cholestatic jaundice and nonmetastatic prostatic carcinoma. Arch Intern Med. 1977;137:1616–1618. [PubMed] [Google Scholar]
- 5.Shah SH. Paraneoplasic liver dysfunction in prostate cancer. J Pain Symptom Manage. 2006;32:511–513. doi: 10.1016/j.jpainsymman.2006.03.015. [DOI] [PubMed] [Google Scholar]
- 6.Nguyen V, Gurney H, van der Poorten D. Paraneoplastic hepatic dysfunction in metastatic prostate cancer: the role of cytokine dysregulation. J Clin Oncol. 2011;29:e21–e23. doi: 10.1200/JCO.2010.30.6522. [DOI] [PubMed] [Google Scholar]
- 7.Karakolios A, Kasapis C, Kallinikidis T, et al. Cholestatic jaundice as a paraneoplastic manifestation of prostate adenocarcinoma. Clin Gastroenterol Hepatol. 2003;1:480–483. doi: 10.1016/s1542-3565(03)00227-1. [DOI] [PubMed] [Google Scholar]
- 8.Hinostroza-Yanahuaya J, Mon-Mon C, Ortega-Marcos O, et al. Stauffer syndrome and prostate carcinoma, two cases in chronic haemodialysis patients. Nefrologia. 2013;33:749–750. doi: 10.3265/Nefrologia.pre2013.May.10953. [DOI] [PubMed] [Google Scholar]
- 9.Vieira AC, Alvarenga MJ, Santos JC, et al. Paraneoplastic jaundice and prostate cancer. BMJ Case Rep. 2017;2017 doi: 10.1136/bcr-2016-218001. bcr-2016-218001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Porta C, Bracarda S, Danesi R. Corticosteroids and prostate cancer: friend or foe? Eur Urol. 2015;67:680–682. doi: 10.1016/j.eururo.2014.11.002. [DOI] [PubMed] [Google Scholar]
- 11.Chang CY, Walther PJ, McDonnell DP. Glucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer. Cancer Res. 2001;61:8712–8717. [PubMed] [Google Scholar]
- 12.Li Y, Sarkar FH. Role of BioResponse 3,3′-diindolylmethane in the treatment of human prostate cancer: clinical experience. Med Princ Pract. 2016;25((suppl 2)):11–17. doi: 10.1159/000439307. [DOI] [PMC free article] [PubMed] [Google Scholar]