Thyroid Autoantibodies, Telomerase Activity, Vascular Endothelial Growth Factor, and Bone Scanning

Nonprostate Urologic Oncology

REVIEWING THE LITERATURE Nonprostate Urologic Oncology Thyroid Autoantibodies, Telomerase Activity, Vascular Endothelial Growth Factor, and Bone Scanning Arndt van Ophoven, MD, Belur Patel, MD, Mitchell K. Rauch, MD, Arie Belldegrun, MD, FACS UCLA School of Medicine, Los Angeles [Rev Urol. 1999;1(4):209-211, 214] T he ongoing search for markers—to predict therapeutic potential or presence of metastases—continues, with promising findings in 3 studies. In addition, Staudenherz and colleagues step into the controversy over whether bone scanning has a diagnostic value in patients with renal cell carcinoma (RCC). sies were categorized as metaplastic and/or dysplastic, and 20 of 29 (69%) of these exhibited telomerase activity. Seventeen of 21 (81%) urine cell samples had telomerase activity, while telomerase activity was detectable in only 3 of 14 (21%) control urine samples (Figure). 100% (10 of 10) Telomerase Activity in Patients With Transitional Carcinoma: A Preliminary Study 30 Rahat MA, Lahat N, Gazawi H, et al. Cancer. 1999;85(4):919-924. Telomeres, the essential structures at the ends of chromosomes, stabilize and protect the chromosomes from degradation and recombination. Telomeres are involved in the molecular mechanisms of aging and chromosomal instability that result in cell death. Telomerase activity is not detectable in normal cells; in these cells, telomeres shorten until chromosomes cannot replicate. Immortal cells have short but stable chromosomes, yet have increased telomerase activity. Since transitional cell carcinoma (TCC) comes only with a few and limited diagnostic and prognostic markers, the study sought to determine whether a correlation existed between telomerase activity and the grade or stage of TCC. Furthermore, the authors looked into whether the telomerase activity could serve as a biochemical marker of TCC. The study included 29 patients presenting with TCC. Both urine samples and cup biopsies from apparently normal and tumorous bladder areas were obtained from each patient. Biopsies were examined histologically and subjected to telomerase activity determination; exfoliated cells were analyzed for telomerase activity. Control samples were taken from non-TCC patients. Twenty-six of 29 (90%) specimens identified as TCC showed telomerase activity. The majority of the cup biop- 25 Telomerase activity Number of Patients No Telomerase activity 20 17 15 11 10 5 4 3 0 Patients With TCC Controls Urine Cell Samples Figure. In urine cell samples of patients withTCC, 81% exhibited telomerase activity, while there was only 21% telomerase activity in the control group. of the non-TCC control biopsies did not show any telomerase activity. This study demonstrates that telomerase activity could be detected in most tumor biopsy samples and with a high incidence in the exfoliative urine cell samples. No correlation was found between the grade and the stage of TCC, whereas previous studies showed a clear association with the pathologic grade and clinical stage of TCC.1 However, the ability to detect the enzyme activity in urine samples FALL 1999 REVIEWS IN UROLOGY 209 Nonprostate Urologic Oncology continued with proper sensitivity and specificity suggests that it is a promising marker for detection and follow-up of TCC. A recent study by Ito and colleagues confirmed the high incidence of enzyme activity in these tumor specimens and emphasized that the combination of molecular assays and cytologic testing increases sensitivity and specificity and may contribute to early detection of TCC.2 References 1. Lin Y, Miyamoto H, Fujinami K, et al. Telomerase activity in human bladder cancer. Clin Cancer Res. 1996;2(6):929-932. 2. Ito H, Kyo S, Kanaya T, et al. Detection of human telomerase reverse transcriptase messenger RNA in voided urine samples as a useful diagnostic tool for bladder cancer. Clin Cancer Res. 1998;4(11):2807-2810. expression and microvessel density and prognosis in other urologic tumors.1 The authors found TP was not expressed in most GCT cells; it was, however, expressed predominantly in infiltrating cells that surrounded the tumor. Still, the role of TP producing cells is unclear. The authors point out that the significance of the analysis of their data might be limited by the prophylactic use of chemotherapy or radiotherapy that may reduce tumor recurrence rates. However, the role of VEGF in the pathogenesis of tumor recurrence has been shown in a recent study on bladder tumors generally demonstrating the promising potentials of anti-VEGF strategies in the treatment of patients with urologic malignancies.2 References Expression of Vascular Endothelial Growth Factor in Patients With Testicular Germ Cell Tumors as an Indicator of Metastatic Disease Fukuda S, Shirahama T, Imazono Y, et al. Cancer. 1999;85(6):1323-1330. Vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP), which has been shown to be identical with platelet-derived endothelial growth factor, are principal growth factors mediating tumor angiogenesis and are involved in disease progression of solid tumors. The objective of this study was to explore whether there is correlation between these angiogenic factors and the clinicopathologic findings in testicular germ cell tumors (GCTs). Expression of VEGF and TP were examined immunohistochemically in 80 GCTs, including 33 seminomas (25 tumors with organ-confined disease, 8 with metastasis) and 47 nonseminomatous testicular GCTs (NSGCTs) (20 tumors with organ-confined disease, 27 with metastasis). In addition, the authors measured the microvessel density of the tumor specimens. VEGF protein was expressed more highly in GCTs compared with nonneoplastic testes, and its expression in GCTs was correlated significantly with microvessel count. Moreover, VEGF expression was correlated significantly with metastasis in both seminomas and NSGCTs. Microvessel density was significantly higher in NSGCT with metastasis than in NSGCT without. High levels of TP were observed in infiltrating cells but not in most cancer cells. The results of this study exhibit the involvement of VEGF in angiogenic activity in GCT. The data suggest the biologic significance of VEGF for tumor development, angiogenesis, and metastasis in GCT. VEGF appears to be an independent predictor for clinically detectable metastasis during diagnosis of GCT. Furthermore, the presented data suggest that VEGF may be prognostic for patients with stage I GCT, who have a high risk for occult metastasis. Other studies have show a correlation between TP 210 REVIEWS IN UROLOGY FALL 1999 1. Imazano Y, Takebayashi Y, Nishiyama K, et al. Correlation between thymidine phosphorylase expression and prognosis in human renal cell carcinoma. J Clin Oncol. 1997;15(7):2570-2578. 2. Crew JP, O’Brien T, Bicknell R, et al. Urinary vascular endothelial growth factor and its correlation with bladder cancer recurrence rates. J Urol. 1999;161:799-804. Autoimmunity Resulting From Cytokine Treatment Predicts Long-Term Survival in Patients With Metastatic Renal Cell Cancer Franzke A, Peest D, Kepper M, et al. J Clin Oncol. 1999;17(2):529-533. Immunotherapy for the treatment of metastatic RCC can result in dramatic tumor regression in a select group of responding patients. In this paper, the authors analyzed the correlation of thyroid autoimmunity with HLA phenotype, other autoimmune parameters, and survival in patients with metastatic RCC receiving immunotherapy. Reversible thyroid dysfunction and transient induction of thyroid autoantibodies are known to occur in up to 60% of patients with metastatic cancer who receive cytokine therapy with either interleukin-2 (IL-2) alone, or in combination with interferon-alpha (IFN-α) or lymphokine-activated killer cells. This study analyzed 329 patients with metastatic RCC who received 8 weeks of IL-2 and IFN-α2 administered subcutaneously, with 82 patients also receiving fluorouracil. None of the patients received any agents with antithyroid activity. Patients had various thyroid parameters measured before and after immunotherapy: triiodothyronine, thyroxine, thyrotropin, thyroglobulin autoantibodies (ATA), antimicrosomal autoantibodies, and thyroid receptor antibodies. Other autoimmune factors were also tested in 125 patients. HLA analysis was also performed on 70 patients. Statistical analysis was calculated by the Cox proportional hazards model for univariate and multivariate analysis of overall survival. The results showed that 60 (18%) patients had thyroid Nonprostate Urologic Oncology autoantibodies. There was also a strong correlation between development of thyroid dysfunction and the presence of thyroid autoantibodies. Of the autoantibody-positive patients, 65% developed thyroid dysfunction, while 68% of the patients with negative autoantibody remained free of dysfunction. Additionally, 25 patients had preexisting autoantibodies and developed even higher titers after treatment (mean, 3.9-fold increase). The median survival for all the patients was 22 months; there was a statistically significant difference between thyroid autoantibodypositive and -negative 5-year survival estimate of 54% versus 15%, respectively. This result also proved to be an independent prognostic factor. Moreover, prolonged survival in patients with positive autoantibody was independent of the autoantibody subtype and the time of autoantibody formation (preexisting versus induced). A statistically significantly higher association was also noted between the frequency of presented HLA antigens in thyroid autoantibody-positive patients compared with autoantibody-negative patients. This interesting study confirms the previously hypothesized notion of development of thyroid dysfunction with cytokine therapy for advanced malignancies. Previous studies have also shown improved response to cytokine therapy when thyroid dysfunction develops.1-3 The authors in this study confirmed these findings but also demonstrated that the presence of thyroid autoantibodies confers a significant and independent predictor of survival in patients with RCC treated with cytokines. The correlation of survival and autoantibodies is also independent of the type of antibody and the time of autoantibody formation. Though this correlation cannot be explained at this time, it provides an insight into the possible mechanisms for the immune response to RCC. The detection of thyroid autoantibodies may provide a prognostic value in patients who are to receive adjuvant immunotherapy and determine patients who may benefit from adjuvant cytokine therapy. The results also suggest an association between HLA class I antigens and increased antigen presentation to a MHCrestricted immune system, and specifically for the HLACw7 antigen. These findings need further evaluation, but at this time they infer that cytokine therapy with IL-2 and IFN-α may be more effective in patients who have either preexisting or induced thyroid autoantibodies, which may lead to better survival rates. References 1. Atkins MB, Mier JW, Parkinson DP, et al. Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N Engl J Med. 1988;318:1557-1562. 2. Scalzo S, Gengaro A, Boccoli G, et al. Primary hypothyroidism associated with interleukin-2 and interferon alpha-2 therapy of melanoma and renal carcinoma. Eur J Cancer. 1990;26:1152-1156. 3. Weijl NI, Van Der Harst D, Brand A, et al. Hypothyroidism during immunotherapy with interleukin-2 is associated with antithyroid antibodies and response to treatment. J Clin Oncol. 1993;11:1376-1383. Is There a Diagnostic Role for Bone Scanning of Patients With a High Pretest Probability for Metastatic Renal Cell Carcinoma? Staudenherz A, Steiner B, Puig S, et al. Cancer. 1999;85(1):153-155. This study investigated the diagnostic value of whole body bone scintigraphy (BS) in patients with high pretest probability for bone metastases due to abnormal laboratory tests, bone pain, or confirmed nonosseous metastases. Thirty-six patients with RCC and clinical suspicion of having metastatic disease who underwent whole body BS were retrospectively reviewed. Mean patient age was 62 ± 11 years. Six patients had bone pain; 18 had nonosseous metastasis. Fourteen patients had bone metastases diagnosed by computed tomography or magnetic resonance imaging. All bone scans were reviewed by 2 observers blinded to any prior radiologic findings. All patients had routine laboratory tests done within 2 weeks of BS so that a logistic regression analysis could be performed. Only 1 bone scan was unequivocally positive (“hot spot”) for metastases. Based on finding hot lesions only, a sensitivity of 7% (1 of 14) and a specificity of 100% (22 of 22) was obtained. If additional faint lesions were considered as bone metastases, there was a sensitivity of 79% (11 of 14) and a specificity of 73% (16 of 22). Laboratory tests selected as indicative for metastatic disease were analyzed. Twenty-three patients had abnormal tests. Alkaline phosphatase (AP) was elevated in 4 of 14 patients who had bone metastasis and in 7 of 22 patients who did not. No significant differences were found between patients with and without bone metastasis. Logistic regression analysis, including all scintigraphic, clinical, and laboratory parameters, failed to identify a diagnostic pattern suggestive of bone metastases. The authors concluded that even in patients with high pretest probabilities of bone metastasis, presence of pain, extraosseous metastasis, or abnormal laboratory tests, the diagnostic utility of bone scan was very low. They state that the accuracy of bone scan in RCC cannot be satisfactorily increased by preselection of patients based on clinical or laboratory parameters, and BS should be omitted from the diagnostic workup of patients with RCC. About 25% of patients with RCC present with metastatic disease.1 A significant number of these patients will have osseous metastasis. deKernion et al2 found that 41% of patients with metastatic RCC had bone involvement. There have been studies in the literature examining the role of bone scan in the evaluation of the patient with RCC. Campbell et al3 looked at 42 patients with RCC; 5 patients had bone metastasis. Of these patients, 3 had bone involvement detectable on chest imaging, and one had an elevated AP. Benson et al4 reviewed 64 patients with renal, bladder, or prostate cancer undergoing evaluation for metastacontinued on page 214 FALL 1999 REVIEWS IN UROLOGY 211 Nonprostate Urologic Oncology Urologic Surgery continued from page 211 continued from page 212 sis. Of patients with metastatic disease, 65% had disease in the bone. All of these patients had either an elevated AP and/or symptoms of bone pain. The authors concluded that routine preoperative bone scans are not needed in the absence of chemical or clinical signs of metastatic disease. Additionally, deKernion found that no patient without symptoms of skeletal involvement and with normal AP and serum calcium levels had detectable skeletal metastases on BS (personal communication, 1999). Atlas and associates5 concluded that elevated AP is a strong indicator of disease progression or death and is a better predictor of eventual outcome than BS in patients with RCC. Seaman and colleagues6 studied a high risk group of patients with metastatic RCC; 31% had bone metastases. Elevated AP levels, the presence of bone pain, or the presence of other metastases correctly predicted bone metastasis in all but 1 patient. We agree that the newly diagnosed patient with RCC, without bone pain, elevation of AP, or nonosseous metastasis should not undergo routine BS. However, considering the literature that supports a diagnostic role for BS in patients with a high pretest probability for metastatic disease, we feel that the current authors recommendations are incorrect. A positive finding on bone scan in a patient with a high pretest probability may alter the clinical decision making and aid in patient care. ■ of the inconsistencies and redundancies often associated with multiauthored texts. The most obvious omission is that of female pelvic reconstruction—understandable considering entire textbooks have been devoted to this subject and vaginal reconstruction is not a common procedure for most urologists. Additionally, only the more common pediatric reconstructive procedures are included; however, few urologists will ever be faced with reconstruction of these rare anomalies. Although many areas of urologic surgery are not considered because of the book’s purpose of including only reconstructive procedures, this omission allows these procedures to be described more fully. Overall, this textbook fulfills the goal of the editor: To present the salient technical aspects of the major pediatric and adult reconstructive procedures performed today using a combination of ample text complimented by abundant illustrations. I enthusiastically recommend this textbook to all urology residents and urologists who perform reconstructive procedures. Book reviewed by R. Duane Cespedes, MD Department of Urology Wilford Hall Medical Center Lackland Air Force Base, Tex. References 1. Swanson DA, Oravan WL, Johnson DE, Giacco G. Osseous metastases secondary to renal cell carcinoma. Urology. 1981;8:556-561. 2. deKernion JB, Ramming KP, Smith RB. The natural history of metastatic renal cell carcinoma: a computer analysis. J Urol. 1978;120:148-152. 3. Campbell RJ, Broaddus SB, Leadbetter GW Jr. Staging of renal cell carcinoma: cost effectiveness of routine preoperative bone scans. Urology. 1985;25:326329. 4. Benson MA, Haaga JR, Resnick MI. Staging renal carcinoma: what is sufficient? Arch Surg. 1989;124:71-73. 5. Atlas I, Kwan D, Stnoe N. Value of serum alkaline phosphatase and radionuclide bone scans in patients with renal cell carcinoma. Urology. 1991;38:220222. 6. Seaman E, Goluboff ET, Ross S, Sawczuk IS. Association of radionuclide bone scan and serum alkaline phosphatase in patients with metastatic renal cell carcinoma. Urology. 1996;48:692-695. RESIDENTS IN UROLOGY YOU’RE INVITED Write a Case Review, including history, evaluation, treatment, and discussion. Submit your Case Review by e-mail or mail (instructions below). Those approved by the Medical Editors and peer reviewers will be edited for publication in Reviews in Urology. The primary author of a published Case Review will receive $250. Name by the Medical Editors of Reviews in Urology to Submit a Case Review for Publication in Reviews in Urology Title Mailing address Telephone ______________Fax __________________E- mail __________________ Department head Case Review topic Mail to (include disk): Case Review, Reviews in Urology, 330 Boston Post Road, Darien, CT 06820-4027; E-mail to: herbert.lepor@med.nyu.edu 214 REVIEWS IN UROLOGY FALL 1999