Prostate Cancer in a Man With Multiple Previous Cancers

ABSTRACT: Multidisciplinary Consultations on Challenging Cases The University of Colorado Health Sciences Center holds weekly second opinion conferences focusing on cancer cases that represent most major cancer sites. Patients seen for second opinions are evaluated by an oncologist. Their history, pathology, and radiographs are reviewed during the multidisciplinary conference, and then specific recommendations are made. These cases are usually challenging, and these conferences provide an outstanding educational opportunity for staff, fellows, and residents in training. The second opinion conferences include actual cases from genitourinary, lung, melanoma, breast, neurosurgery, and medical oncology. On an occasional basis, ONCOLOGY will publish the more interesting cases discussions and the resultant recommendations. We would appreciate your feedback; please contact us at second.opinion@uchsc.edu. E. David Crawford, MD, and Al Barqawi, MD, Guest Editors University of Colorado Health Sciences Center and University of Colorado Cancer Center Denver, Colorado

The patient is a 67-year-old male with mild obstructive symptoms and an American Urology Association symptom score of 8.[1] He was noted to have a prostate-specific antigen (PSA) level of 3.2 ng/mL. Because this represented a significant increase in his PSA velocity (rate of change over time), he proceeded to have a biopsy, which was positive for prostate cancer. He has no other complaints and visits us for an opinion on the treatment of his prostate cancer.

History, Physical Exam, and Laboratory Findings

Dr. L. Michael Glodé: The patient's past medical history is remarkable for a previous neoplasm. Ten years ago, he was diagnosed with a pituitary adenoma that was treated with radiation therapy. Eight years ago, he underwent a right nephrectomy for renal cell carcinoma. Three years ago, he developed a Hürthle cell adenoma and papillary carcinoma of the thyroid, treated with a near-total thyroidectomy. He is also being treated for hypertension and hyperlipidemia. Of note, he has a positive family history of cancer, with reported renal cell carcinoma in his father, brain cancer in his sister, and testis cancer in two of his nephews.

A physical exam reveals the patient's blood pressure is 131/79 mm Hg, heart rate is 66/min, respiratory rate is 16/min, temperature is 97.5°F. He is in no acute distress. Lungs are clear to auscultation. Abdomen is soft, nontender, without organomegaly. There is no lymphadenopathy. His skin exam is normal. Rectal exam reveals a soft, approximately 20-g prostate, without nodularity.

Laboratory findings include the following: PSA = 3.2 ng/mL, testosterone = 195 ng/dL (institutional normal range: 122-534 ng/dL), sodium = 141 mmol/L, potassium = 3.7 mmol/L, creatinine = 1.9 mg/dL, bilirubin (total) = 0.7 mg/dL, thyroid-stimulating hormone = 0.08 µIU/dL, free T4 = 0.99 ng/dL, white blood cell count = 6.1 × 10⁹/L, hemoglobin = 14.3 g/dL, and platelet count = 187 × 10⁹/L.

Pathology

Dr. Glodé: Drs. Lucia and La Rosa, would you please review the patient's prostate biopsy findings?

Dr. Scott Lucia: Pathologic slides from an outside hospital, with corresponding identification for this patient, were reviewed. The histologic grade of prostate cancer, or Gleason score, is determined by assigning a pathologic grade to the two most prevalent patterns noted in the cancer tissue, with the larger numbers representing more undifferentiated tumors. These two scores are added together for a maximum possible score of 10. In this case, two biopsy regions demonstrated the presence of cancer. The right midsection reveals adenocarcinoma of the prostate, Gleason 3+3=6, involving 5% to 10% of two cores. The right base demonstrates prostatic adenocarcinoma, Gleason 3+4=7, involving 20% of each of two cores (Figure 1).

Dr. Francisco La Rosa: The Gleason grade 3 region of the tumor shows most of the malignant glands as independent units surrounded by stromal tissue. The Gleason grade 4 portion of the tumor is represented by some glands showing fusion of their borders, making it difficult to identify them as individual units. They still resemble glandular morphology but are fused in groups of two or more. The sum of these two grades of tumor gives the final score of 7.

Radiology

Dr. Glodé: No imaging studies have been obtained by the patient's referring physicians to date. We know from the natural history of prostate cancer that not all patients require imaging as part of their evaluation. With a PSA less than 10 ng/mL, only about 2% of bone scans will be positive. However, if a Gleason score of greater than 7 is present, a positive bone scan becomes much more likely.[2] A computed tomography (CT) scan is generally believed to be a relatively insensitive test, unlikely to be helpful in patients with a PSA less than 20 ng/mL. In light of this patient's other contributing history, let us revisit the need for further imaging after considering unique factors in this case.

Differential Diagnosis

Dr. Glodé: Dr. Flaig, will you discuss potential etiologies for this patient's cancer history?

Dr. Thomas Flaig: This patient represents a dramatic case of both a personal and family history of cancer. Careful consideration must be given to identify a cancer syndrome that would guide our clinical management, family screening, and genetic testing.[3] Li-Fraumeni syndrome, with a mutation in p53, is a well described hereditable cancer syndrome.[4] However, the classic presentation is with multiple cancers including sarcomas, brain cancers, and breast cancers, none of which are present here, making it an unlikely cause.[5] Von Hippel-Lindau disease should also be considered, in light of the patient's renal cell carcinoma.[6] With this syndrome, hemangioblastomas, clear-cell renal cell carcinomas, and pheochromocytomas are observed with a variety of other benign tumors. Hemangioblastomas are present in the great majority of cases but absent in our patient, again making it an improbable diagnosis.

With this patient's history of thyroid and pituitary cancer, the possibility of a multiple endocrine neoplasia (MEN) syndrome should be considered. MEN 1 is seen with pituitary, parathyroid, and pancreatic tumors.[7] Nearly all patients with MEN 2 have medullary carcinoma of the thyroid, with parathyroid involvement seen in type 2A and pheochromocytoma noted in types 2A and 2B. In this case, the thyroid pathology showed a papillary carcinoma and there is no evidence for a pheochromocytoma, making MEN 2 unlikely. The patient's pituitary tumor was treated with radiation therapy but we do not know the histologic type. A pituitary tumor is consistent with MEN 1, but renal cell carcinoma and thyroid papillary carcinoma are not classically seen in this syndrome.[8]

Dr. Glodé: Are you able to associate prostate cancer with his previous cancer diagnoses or family history?

Dr. Flaig: Prostate cancer is the most common solid-organ malignancy in American men, with an estimated 234,000 new cases in the United States for 2006.[9] Good evidence suggests that one's risk for prostate cancer is increased by having a first-degree relative with prostate cancer, with a relative risk of approximately 2.[10,11] Although it was earlier believed that those with familial prostate cancer may have a worse prognosis, the prognostic implications of familial prostate cancer are less clear in the PSA era.[12]

Among the well known hereditary cancer syndromes, BRCA1 and BRCA2 mutations include prostate cancer as a manifestation. The breast cancer linkage consortium has reported that carriers of a germline mutation of the BRCA2 gene have an increased risk for prostate cancer development with a relative risk of 4.6.[13] However, the association between BRCA1 and prostate cancer appears much more modest, if present at all.[14] A small amount of data indicates that first-degree relatives of prostate cancer patients are at increased risks for a variety of other cancers including brain cancer, colon cancer, and non-Hodgkin's lymphoma,[15,16] but none of these are present in this case. Therefore, this patient's multiple cancers and his family history of cancers do not readily fit into any currently recognized clinical syndrome.

Treatment Considerations for Prostate Cancer

Dr. Glodé: Dr. Crawford, in light of this discussion, what treatment recommendations would you make for this patient's prostate cancer?

Dr. E. David Crawford: I think it would be important to try and determine if there is an identifiable familial syndrome, although our discussion highlights the complexity of determining this association. As has been stated, prostate cancer is a common disease, and it is not clear that it is related to the other cancers seen in this case. In fact, the end-of-study biopsies in the Prostate Cancer Prevention Trial (PCPT) demonstrated that about 27% of men in this age group with a PSA between 3.1 and 4 ng/mL will have a positive biopsy for prostate cancer.[17]

As long as we don't believe that his life expectancy is less than 10 years from his other problems, I would recommend definitive therapy with either a radical prostatectomy or radiation therapy. The basis for this recommendation is the presence of multiple positive biopsies and a "4" component on the pathology giving him a Gleason score of 7. We have good evidence that the Gleason score remains a good predictor of mortality from prostate cancer, and scores of 7 or higher carry an increased risk.[18]

Dr. Glodé: Dr. Kavanagh, does the history of prior cancers cause any concern about the risk of radiation-induced cancer in this patient if he chooses radiation therapy?

Dr. Brian Kavanagh: That's a good question, and it's a topic that has received a good deal of interest lately. Two particularly interesting reports have addressed the issue of second cancers in men treated for prostate cancer. First, there was an analysis of Surveillance, Epidemiology, and End Results (SEER) data published in 2005 suggesting that 15 years after treatment for prostate cancer, men who had radiation therapy had an absolute risk of developing rectal cancer that was approximately 0.5% higher than men who had surgery for prostate cancer.[19] However, in a subsequent reanalysis of the same data, Kendal and colleagues noted that when the effects of age and other key differences between the men who had surgery and those who had radiotherapy were taken into consideration, there was in fact no significant difference in the incidence of rectal cancer between these two groups.[20]

In this particular patient's case, the unusually prominent past medical history of multiple cancers is noteworthy, but there is nothing in his history to suggest a higher-than-average likelihood of treatment-induced cancer. In fact, the patient has already had radiation therapy in the past, with no apparent problem resulting. So, overall, I agree with Dr. Crawford that surgery and radiation therapy are valid options for him, offering comparable chances of long-term disease control.

If the patient chooses the nonsurgical option, I would also suggest a 6-month course of adjuvant androgen-suppression therapy, since there is evidence of a significant benefit in outcome for patients with Gleason 7 cancer.[21]

Dr. Glodé: Dr. Barqawi, this patient's testosterone level was 195 ng/dL (reference range: 241-500 ng/dL) What are the prognostic and treatment implications of this finding?

Dr. Al Barqawi: This patient's testosterone level appears to be low. However, the normal range of serum testosterone has not been established, and it is difficult to interpret its value clinically. Mounting evidence in published observational studies has indicated a likely correlation between low pretreatment total testosterone levels and an increased risk of more aggressive tumors,[22] advanced clinical stage,[23] and worse outcome after treatment.[24] In contrast, other studies report no correlation with posttreatment biochemical relapse-free survival or clinical progression of the disease.[25,26] In fact, one study reported a higher tumor-relapse rate associated with high testosterone levels.[27]

This conflicting evidence aside, most experts believe the correlation between pretreatment total testosterone levels and prostate cancer risk of progression is complex. Other factors such as estradiol, growth hormone, and insulin level as well as androgen-receptor activity in the prostate, serum levels of sex hormone-binding globulin (SHBG), and percentage free testosterone or bioavailable testosterone may be involved as well. Since the patient has a history of pituitary adenoma, it would be worthwhile to measure serum follicular-stimulating hormone, luteinizing hormone, and prolactin levels to help determine the etiology of his apparent hypogonadism.

Dr. Glodé: What interventions could be considered for prostate cancer patients with hypogonadism?

Dr. Barqawi: Hypogonadism is a clinical diagnosis, and replacement therapy should not be solely based on low testosterone levels. The topic of testosterone replacement therapy (TRT) in hypogonadal men who are diagnosed with prostate cancer is very controversial. Although small, short-term prospective studies have indicated its potential safe use after primary treatment with curative intent,[28] TRT is currently contraindicated in men diagnosed with prostate cancer and is not recommended outside of carefully conducted research protocols.

Dr. Glodé: Dr. Crighton, what else would you discuss with this patient as he considers his treatment options?

Dr. Frances Crighton: Certainly, the National Comprehensive Cancer Network guidelines for the treatment of prostate cancer support the second opinion treatment decisions given by members of this conference. However, many patients seeking a second opinion desire a concrete single best treatment recommendation. There is evidence to support that outlining the patient's treatment risk factors and chances for cancer control will increase his confidence in treatment decisions.[29] He can be assisted by answering all treatment questions and reviewing his concern for risk factors and desired quality of life.

Summary

Dr. Glodé: I agree with the discussion points raised by all participants. Although we may not be able to define a specific cancer syndrome at this juncture, the patient certainly appears to have a biologic predisposition for tumor development based on his personal and family history. I will be referring him to our cancer center's genetic and familial cancer clinic for further evaluation. In agreement with the earlier discussion, I advise that he consider a radical prostatectomy or radiation therapy with androgen-deprivation therapy to treat the prostate cancer. Since this is his fourth cancer diagnosis, I will also recommend a chest, abdomen, and pelvis CT scan and a colonoscopy. The identification of another tumor site may aid us in identifying a clinical syndrome or may change our treatment recommendation.

Disclosures:

The participants in this conference have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Barry MJ, Fowler FJ Jr, O'Leary MP, et al: The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 148:1549-1564 (incl discussion), 1992.

2. Abuzallouf S, Dayes I, Lukka H: Baseline staging of newly diagnosed prostate cancer: A summary of the literature. J Urol 171:2122-2127, 2004.

3. Garber JE, Offit K: Hereditary cancer predisposition syndromes. J Clin Oncol 23:276-292, 2005.

4. Li FP, Fraumeni JF Jr: Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71:747-752, 1969.

5. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al: A cancer family syndrome in twenty-four kindreds. Cancer Res 48:5358-5362,
1988.

6. Latif F, Tory K, Gnarra J, et al: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317-1320, 1993.

7. Pang JT, Thakker RV: Multiple endocrine neoplasia type 1 (MEN1). Eur J Cancer 30A:1961-1968, 1994.

8. Brandi ML, Gagel RF, Angeli A, et al: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86:5658-5671, 2001.

9. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2006. CA Cancer J Clin 56:106-130, 2006.

10. Bruner DW, Moore D, Parlanti A, et al: Relative risk of prostate cancer for men with affected relatives: Systematic review and meta-analysis. Int J Cancer 107:797-803, 2003.

11. Steinberg GD, Carter BS, Beaty TH, et al: Family history and the risk of prostate cancer. Prostate 17:337-347, 1990.

12. Kupelian PA, Reddy CA, Reuther AM, et al: Aggressiveness of familial prostate cancer. J Clin Oncol 24:3445-3450, 2006.

13. Cancer risks in BRCA2 mutation carriers.The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91:1310-1316, 1999.

14. Thompson D, Easton DF: Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94:1358-1365, 2002.

15. Isaacs SD, Kiemeney LA, Baffoe-Bonnie A, et al: Risk of cancer in relatives of prostate cancer probands. J Natl Cancer Inst 87:991-996, 1995.

16. Neuhausen SL, Skolnick MH, Cannon-Albright L: Familial prostate cancer studies in Utah. Br J Urol 79(suppl 1):15-20, 1997.

17. Thompson IM, Pauler DK, Goodman PJ, et al: Prevalence of prostate cancer among men with a prostate-specific antigen level < or = 4.0 ng per milliliter. N Engl J Med 350:2239-2246, 2004.

18. Albertsen PC, Hanley JA, Fine J: 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 293:2095-2101, 2005.

19. Baxter NN, Tepper JE, Durham SB, et al: Increased risk of rectal cancer after prostate radiation: A population-based study. Gastroenterology 128:819-824, 2005.

20. Kendal WS, Eapen L, Macrae R, et al: Prostatic irradiation is not associated with any measurable increase in the risk of subsequent rectal cancer. Int J Radiat Oncol Biol Phys 65:661-668, 2006.

21. D'Amico AV, Manola J, Loffredo M, et al: 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial. JAMA 292:821-827, 2004.

22. Massengill JC, Sun L, Moul JW, et al: Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy. J Urol 169:1670-1675, 2003.

23. Chen SS, Chen KK, Lin AT, et al: The correlation between pretreatment serum hormone levels and treatment outcome for patients with prostatic cancer and bony metastasis. BJU Int 89:710-713, 2002.

24. Ribeiro M, Ruff P, Falkson G: Low serum testosterone and a younger age predict for a poor outcome in metastatic prostate cancer. Am J Clin Oncol 20:605-608, 1997.

25. Mikkola AK, Aro JL, Rannikko SA, et al: Pretreatment plasma testosterone and estradiol levels in patients with locally advanced or metastasized prostatic cancer. FINNPROSTATE Group. Prostate 39:175-181, 1999.

26. Isom-Batz G, Bianco FJ Jr, Kattan MW, et al: Testosterone as a predictor of pathological stage in clinically localized prostate cancer. J Urol 173:1935-1937, 2005.

27. Zagars GK, Pollack A, von Eschenbach AC: Serum testosterone-a significant determinant of metastatic relapse for irradiated localized prostate cancer. Urology 49:327-334, 1997.

28. Agarwal PK, Oefelein MG: Testosterone replacement therapy after primary treatment for prostate cancer. J Urol 173:533-536, 2005.

29. Clark JA, Talcott JA: Confidence and uncertainty long after initial treatment for early prostate cancer: Survivors' views of cancer control and the treatment decisions they made. J Clin Oncol 24:4457-4463, 2006.