Abstract
Prostate cancer is the second most common urological malignancy to be associated with paraneoplastic syndromes after renal cell carcinoma. These syndromes tend to occur in the setting of late stage and aggressive tumors with poor overall outcomes. Recognition of these syndromes is clinically important as it might lead to the detection of underlying malignancy and impact on the treatment options available. The literature features around 100 cases of paraneoplastic syndromes associated with prostate cancer and these include endocrine manifestations, neurological entities, dermatological conditions, and other syndromes. Over 70% of cases document the syndrome as the initial clinical manifestation of prostate cancer, while in just under 20% the syndrome was an initial sign of disease progression to the castrate-resistant state. The vast majority of cases involved advanced metastatic malignancy. The syndromes generally resolve upon institution of treatment for the underlying prostate cancer, but some syndromes require specific therapies. Some syndromes are associated with serum markers that are readily detectable and demonstration of these putative markers within prostate cancer tissue at an individual level would firmly link the paraneoplastic syndrome with its underlying prostatic malignancy. The causes of paraneoplastic syndromes in prostate cancer are incompletely understood, and further research into their biology might shed more light on the complex molecular mechanisms that underpin prostate cancer and its lethal potential.
Key Points
-
Prostate cancer is the second most common urological malignancy (after renal cell carcinoma) to be associated with paraneoplastic syndromes
-
Prostate cancer associated with a paraneoplastic syndrome tends to be metastatic and follow an aggressive course
-
Paraneoplastic syndromes might be the initial presenting manifestation of occult prostate cancer or might represent the first signs of progression to castrate-resistant disease
-
Histology of prostate cancer associated with a paraneoplastic syndrome frequently reveals neuroendocrine features or small cell carcinoma
-
Demonstration within prostate tissue of the putative marker responsible for the paraneoplastic syndrome strongly supports a diagnosis
-
Symptoms of paraneoplastic syndromes usually resolve with treatment of the underlying malignancy although initial symptomatic therapy might be required
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Pelosof, L. C. & Gerber, D. E. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin. Proc. 85, 838–854 (2010).
Sacco, E. et al. Paraneoplastic syndromes in patients with urological malignancies. Urol. Int. 83, 1–11 (2009).
Nimalasena, S., Freeman, A. & Harland, S. Paraneoplastic Cushing's syndrome in prostate cancer: a difficult management problem. BJU Int. 101, 424–427 (2008).
Mauri, D., Pentheroudakis, G., Tolis, C., Chojnacka, M. & Pavlidis, N. Inflammatory prostate cancer: an underestimated paraneoplastic clinical manifestation. Urol. Oncol. 23, 318–322 (2005).
Matzkin, H. & Braf, Z. Paraneoplastic syndromes associated with prostatic carcinoma. J. Urol. 138, 1129–1133 (1987).
Sellwood, R. A. et al. Inappropriate secretion of antidiuretic hormone by carcinoma of the prostate. Br. J. Surg. 56, 933–935 (1969).
Sacks, S. A., Rhodes, D. B., Malkasian, D. R. & Rosenbloom, A. A. Prostatic carcinoma producing syndrome of inappropriate secretion of antidiuretic hormone. Urology 6, 489–492 (1975).
Ghandur-Mnaymneh, L., Satterfield, S. & Block, N. L. Small cell carcinoma of the prostate gland with inappropriate antidiuretic hormone secretion: morphological, immunohistochemical and clinical expressions. J. Urol. 135, 1263–1266 (1986).
Oesterling, J. E., Hauzeur, C. G. & Farrow, G. M. Small cell anaplastic carcinoma of the prostate: a clinical, pathological and immunohistological study of 27 patients. J. Urol. 147, 804–807 (1992).
Gasparini, M. E., Broderick, G. A. & Narayan, P. The syndrome of inappropriate antidiuretic hormone secretion in a patient with adenocarcinoma of the prostate. J. Urol. 150, 978–980 (1993).
Ito, H. et al. Adenocarcinoma of the prostate with ectopic antidiuretic hormone production: a case report. Hinyokika Kiyo 46, 499–503 (2000).
Yalçin, S., Erman, M., Tekuzman, G. & Ruacan, S. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with prostatic carcinoma. Am. J. Clin. Oncol. 23, 384–385 (2000).
Yamazaki, T. et al. Prostate adenocarcinoma producing syndrome of inappropriate secretion of antidiuretic hormone. Int. J. Urol. 8, 513–516 (2001).
Garzotto, M. & Beer, T. M. Syndrome of inappropriate antidiuretic hormone secretion: a rare complication of prostate cancer. J. Urol. 166, 1386 (2001).
Kawai, S. et al. Small cell carcinoma of the prostate expressing prostate-specific antigen and showing syndrome of inappropriate secretion of antidiuretic hormone: an autopsy case report. Pathol. Int. 53, 892–896 (2003).
Bogdanos, J., Karamanolakis, D., Milathianakis, C. & Koutsilieris, M. Syndrome of inappropriate antidiuretic hormone secretion in a patient with hormone refractory prostate cancer. Anticancer Res. 23, 1755–1756 (2003).
Kumar, S. & Berl, T. Sodium. Lancet 352, 220–228 (1998).
Newell-Price, J., Trainer, P., Besser, M. & Grossman, A. The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states. Endocr. Rev. 19, 647–672 (1998).
Hall, T. C. Symptomatic hypokalemic alkalosis in hyperadrenocorticism secondary to carcinoma of the prostate. Cancer 21, 190–192 (1968).
Newmark, S. R., Dluhy, R. G. & Bennett, A. H. Ectopic adrenocorticotropin syndrome with prostatic carcinoma. Urology 2, 666–668 (1973).
Wenk, R. E., Bhagavan, B. S., Levy, R., Miller, D. & Weisburger, W. Ectopic ACTH, prostatic oat cell carcinoma, and marked hypernatremia. Cancer 40, 773–778 (1977).
Vuitch, M. F. & Mendelsohn, G. Relationship of ectopic ACTH production to tumor differentiation: a morphologic and immunohistochemical study of prostatic carcinoma with Cushing's syndrome. Cancer 47, 296–299 (1981).
Ghali, V. S. & Garcia, R. L. Prostatic adenocarcinoma with carcinoidal features producing adrenocorticotropic syndrome. Immunohistochemical study and review of the literature. Cancer 54, 1043–1048 (1984).
Slater, D. Carcinoid tumour of the prostate associated with inappropriate ACTH secretion. Br. J. Urol. 57, 591–592 (1985).
Rickman, T., Garmany, R., Doherty, T., Benson, D. & Okusa, M. D. Hypokalemia, metabolic alkalosis, and hypertension: Cushing's syndrome in a patient with metastatic prostate adenocarcinoma. Am. J. Kidney Dis. 37, 838–846 (2001).
Kataoka, K. et al. Cushing syndrome associated with prostatic tumor adrenocorticotropic hormone (ACTH) expression after maximal androgen blockade therapy. Int. J. Urol. 14, 436–439 (2007).
Rajec, J. et al. Paraneoplastic Cushing's syndrome as the first sign of progression of prostate cancer. Bratisl. Lek. Listy. 109, 362–363 (2008).
Alwani, R. A. et al. Cushing's syndrome due to ectopic ACTH production by (neuroendocrine) prostate carcinoma. Pituitary 12, 280–283 (2009).
Carey, R. M. et al. Ectopic secretion of corticotropin-releasing factor as a cause of Cushing's syndrome. A clinical, morphologic, and biochemical study. N. Engl. J. Med. 311, 13–20 (1984).
McMahon, G. T., Blake, M. A. & Wu, C. L. Case records of the Massachusetts General Hospital. Case 1–2010. A 75-year-old man with hypertension, hyperglycemia, and edema. N. Engl. J. Med. 362, 156–166 (2010).
Agarwal, N., Hutson, T. E., Vogelzang, N. J. & Sonpavde, G. Abiraterone acetate: a promising drug for the treatment of castration-resistant prostate cancer. Future Oncol. 6, 665–679 (2010).
Barkin, J., Crassweller, P. O., Roncari, D. A. & Onrot, J. Hypercalcemia associated with cancer of prostate without bony metastases. Urology 24, 368–371 (1984).
Rojas-Corona, R. R., Chen, L. Z. & Mahadevia, P. S. Prostatic carcinoma with endocrine features. A report of a neoplasm containing multiple immunoreactive hormonal substances. Am. J. Clin. Pathol. 88, 759–762 (1987).
Smith, D. C., Tucker, J. A. & Trump, D. L. Hypercalcemia and neuroendocrine carcinoma of the prostate: a report of three cases and a review of the literature. J. Clin. Oncol. 10, 499–505 (1992).
Iwamura, M. et al. Immunohistochemical localization of parathyroid hormone-related protein in human prostate cancer. Cancer Res. 53, 1724–1726 (1993).
Haznedar, R. Pancytopenia with a hypercellular bone marrow as a possible paraneoplastic syndrome. Am. J. Hematol. 19, 205–206 (1985).
Cooper, D. L., Sandler, A. B., Wilson, L. D. & Duffy, T. P. Disseminated intravascular coagulation and excessive fibrinolysis in a patient with metastatic prostate cancer. Response to epsilon-aminocaproic acid. Cancer 70, 656–658 (1992).
Jensen, J. B. & Langkilde, N. C. Subcutaneous bleeding: first sign of prostate cancer. Scand. J. Urol. Nephrol. 34, 215–216 (2000).
Duran, I. & Tannock, I. F. Disseminated intravascular coagulation as the presenting sign of metastatic prostate cancer. J. Gen. Intern. Med. 21, C6–C8 (2006).
Hicks, J. Case report: disseminated intravascular coagulation as the presenting sign of metastatic prostate cancer. J. Gen. Intern. Med. 22, 1062 (2007).
Pinto, F. et al. Disseminated intravascular coagulation secondary to metastatic prostate cancer: case report and review of the literature. Arch. Ital. Urol. Androl. 81, 212–214 (2009).
Chargari, C. et al. Prostate cancer and disseminated intravascular coagulation: review of the literature [French]. Prog. Urol. 18, 9–13 (2008).
Adamson, A. S., Francis, J. L., Witherow, R. O. & Snell, M. E. Coagulopathy in the prostate cancer patient: prevalence and clinical relevance. Ann. R. Coll. Surg. Engl. 75, 100–104 (1993).
Ansai, S., Koseki, S., Takeda, H., Kondo, S. & Yamakawa, M. Dermatomyositis accompanied by prostatic cancer and elevated serum CA 19.9. Int. J. Dermatol. 35, 570–571 (1996).
Joseph, J. V., Turner, K. J. & Bramwell, S. P. Dermatomyositis: a rare initial presentation of adenocarcinoma of the prostate. J. Urol. 168, 637 (2002).
Masuda, H., Urushibara, M. & Kihara, K. Successful treatment of dermatomyositis associated with adenocarcinoma of the prostate after radical prostatectomy. J. Urol. 169, 1084 (2003).
Subramonian, K., Sundaram, S. K. & MacDonald Hull, S. P. Carcinoma of the prostate associated with dermatomyositis. BJU Int. 86, 401–402 (2000).
Dyall-Smith, D. & Billson, V. Sweet's syndrome associated with adenocarcinoma of the prostate. Australas. J. Dermatol. 29, 25–27 (1988).
da Rosa, A. C., Pinto, G. M., Bortoluzzi, J. S., Duquia, R. P. & de Almeida, H. L. Jr. Three simultaneous paraneoplastic manifestations (ichthyosis acquisita, Bazex syndrome, and Leser-Trélat sign) with prostate adenocarcinoma. J. Am. Acad. Dermatol. 61, 538–540 (2009).
Obasi, O. E. & Garg, S. K. Bazex paraneoplastic acrokeratosis in prostate carcinoma. Br. J. Dermatol. 117, 647–651 (1987).
Momm, F., Pflieger, D. & Lutterbach, J. Paraneoplastic erythroderma in a prostate cancer patient. Strahlenther. Onkol. 178, 393–395 (2002).
Vogt, T., Coras, B., Hafner, C., Landthaler, M. & Reichle, A. Antiangiogenic therapy in metastatic prostate carcinoma complicated by cutaneous lupus erythematodes. Lancet Oncol. 7, 695–697 (2006).
Agarawal, S. K., Birch, B. R. & Abercrombie, G. F. Adenocarcinoma of the prostate and Eaton-Lambert syndrome. A previously unreported association. Scand. J. Urol. Nephrol. 29, 351–353 (1995).
Delahunt, B., Abernethy, D. A., Johnson, C. A. & Nacey, J. N. Prostate carcinoma and the Lambert-Eaton myasthenic syndrome. J. Urol. 169, 278–279 (2003).
Têtu, B. et al. Small cell carcinoma of prostate associated with myasthenic (Eaton-Lambert) syndrome. Urology 33, 148–152 (1989).
Clouston, P. D. et al. Paraneoplastic cerebellar degeneration. III. Cerebellar degeneration, cancer, and the Lambert-Eaton myasthenic syndrome. Neurology 42, 1944–1950 (1992).
Baloh, R. W. et al. Novel brainstem syndrome associated with prostate carcinoma. Neurology 43, 2591–2596 (1993).
Berger, J. R., Bensalem, M. & Dalmau, J. A brainstem paraneoplastic syndrome associated with prostate cancer. J. Neurol. Neurosurg. Psychiatry 80, 934–935 (2009).
Stern, R. C. & Hulette, C. M. Paraneoplastic limbic encephalitis associated with small cell carcinoma of the prostate. Mod. Pathol. 12, 814–818 (1999).
Campbell, J. R., Godsall, J. W. & Bloch, S. Neurologic complications in prostatic carcinoma. Prostate 2, 417–423 (1981).
Baird, A. D., Cornford, P. A., Helliwell, T. & Woolfenden, K. A. Small cell prostate cancer with anti-Hu positive peripheral neuropathy. J. Urol. 168, 192 (2002).
Venkatesh, P. K. et al. Metastatic pure small-cell carcinoma of prostate. Am. J. Med. Sci. 328, 286–289 (2004).
McLoughlin, J., Gingell, J. C., Harper, G. & Hinchliffe, A. Cerebellar manifestations of prostatic carcinoma. Postgrad. Med. J. 68, 584–586 (1992).
Matschke, J. et al. Paraneoplastic cerebellar degeneration and anti-Yo antibodies in a man with prostatic adenocarcinoma. J. Neurol. Neurosurg. Psychiatry 78, 775–777 (2007).
Rosenfeld, M. R. & Dalmau, J. Current therapies for paraneoplastic neurologic syndromes. Curr. Treat. Options Neurol. 5, 69–77 (2003).
Hommel, B. L. & Grovit, M. Neuropathy associated with prostate cancer. J. Am. Podiatr. Med. Assoc. 88, 249–250 (1998).
Hernández Hernández, A., Lorente Cruz, A., Pigrau Serrallach, C., Palou Redorta, J. & Martinez-Vazquez, J. M. Presentation of a neoplasm of the prostate as a fever syndrome [Spanish]. Arch. Esp. Urol. 40, 43–44 (1987).
Koizumi, K. et al. The hemophagocytic syndrome in prostate cancer revealed by disseminated carcinomatosis of the bone marrow. J. Urol. 168, 1101–1102 (2002).
Le, B. H. & Rosenthal, M. A. Prostate cancer presenting with fever and rigors. Intern. Med. J. 35, 638 (2005).
Nakamura, J., Papac, R. & Ward, R. Fever as initial manifestation of prostatic carcinoma. Urology 19, 72–73 (1982).
Zgliczynski, W., Szymanowski, J. & Lazicka-Frelek, M. Fever as the first symptom of prostatic cancer [Polish]. Pol. Tyg. Lek. 40, 109–111 (1985).
Chun, J. Y. et al. Interleukin-6 regulates androgen synthesis in prostate cancer cells. Clin. Cancer Res. 15, 4815–4822 (2009).
Corcoran, N. M. & Costello, A. J. Interleukin-6: minor player or starring role in the development of hormone-refractory prostate cancer? BJU Int. 91, 545–553 (2003).
Drachenberg, D. E., Elgamal, A. A., Rowbotham, R., Peterson, M. & Murphy, G. P. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 41, 127–133 (1999).
Feng, S. et al. Interleukin-6 increases prostate cancer cells resistance to bicalutamide via TIF2. Mol. Cancer Ther. 8, 665–671 (2009).
Irani, J. et al. High-grade inflammation in prostate cancer as a prognostic factor for biochemical recurrence after radical prostatectomy. Pathologist Multi Center Study Group. Urology 54, 467–472 (1999).
Lucia, M. S. & Torkko, K. C. Inflammation as a target for prostate cancer chemoprevention: pathological and laboratory rationale. J. Urol. 171, S30–S34 (2004).
Smith, P. C., Hobisch, A., Lin, D. L., Culig, Z. & Keller, E. T. Interleukin-6 and prostate cancer progression. Cytokine Growth Factor Rev. 12, 33–40 (2001).
Tumminello, F. M. et al. Serum interleukin-6 in patients with metastatic bone disease: correlation with cystatin C. Med. Oncol. 26, 10–15 (2009).
Dorff, T. B. et al. Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer. Clin. Cancer Res. 16, 3028–3034 (2010).
Shah, S. H. Paraneoplastic liver dysfunction in prostate cancer. J. Pain Symptom Manage. 32, 511–513 (2006).
Karakolios, A., Kasapis, C., Kallinikidis, T., Kalpidis, P. & Grigoriadis, N. Cholestatic jaundice as a paraneoplastic manifestation of prostate adenocarcinoma. Clin. Gastroenterol. Hepatol. 1, 480–483 (2003).
Koruk, M., Buyukberber, M., Savas, C. & Kadayifci, A. Paraneoplastic cholestasis associated with prostate carcinoma. Turk. J. Gastroenterol. 15, 53–55 (2004).
Harper, D. G., Arsura, E. L., Bobba, R. K., Reddy, C. M. & Sawh, A. K. Acquired color blindness in an elderly male patient from recurrent metastatic prostate cancer. J. Am. Geriatr. Soc. 53, 1265–1267 (2005).
Reese, D. M. & Rosen, P. J. Oncogenic osteomalacia associated with prostate cancer. J. Urol. 158, 887 (1997).
Acknowledgements
M. Hong is supported by scholarships from the Royal Australasian College of Surgeons and the National Health and Medical Research Council (Australia). Charles P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.
Author information
Authors and Affiliations
Contributions
M. K. Hong and J. Kong contributed equally to the research, discussion, writing and editing of this manuscript. B. Namdarian contributed to the research and discussion of the paper. A. Longano was involved in researching data for the article and reviewing the manuscript before submission. J. Grummet made a substantial contribution to the discussion of content. C. M. Hovens, A. J. Costello and N. M. Corcoran were involved in the discussion of content and reviewing the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Hong, M., Kong, J., Namdarian, B. et al. Paraneoplastic syndromes in prostate cancer. Nat Rev Urol 7, 681–692 (2010). https://doi.org/10.1038/nrurol.2010.186
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrurol.2010.186
This article is cited by
-
Prostate cancer, Hu antibodies and paraneoplastic neurological syndromes
Journal of Neurology (2016)
-
Skin Manifestations of Internal Disease in Older Adults
Current Geriatrics Reports (2015)
-
Paraneoplastic cerebellar degeneration with anti-CV2/CRMP5 antibodies and prostate adenocarcinoma
Neurological Sciences (2015)
-
Durable remission of leptomeningeal metastases from hormone-responsive prostate cancer
Medical Oncology (2012)