Malignant Ascites As Only Manifestation of Metastatic Prostate Cancer

Home , Thalidomide

Prostate Cancer and Prostatic Diseases (1999) 2, 290±293 ß 2000 Macmillan Publishers Ltd All rights reserved 1365±7852/99 $15.00 www.nature.com/pcan Case Report Malignant ascites as only manifestation of metastatic prostate cancer

MW Saif1, WD Figg1*, S Hewitt2, K Brosky2, E Reed & W Dahut1 1Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892, USA; and 2Laboratory of Pathology, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD, 20892, USA

Prostate cancer is the most common malignancy in men in the US. Both at diagnosis and throughout the disease progression it can metastasize to multiple organs (bone and lymph being the most common). Effusions (either pleural or abdominal) are relatively uncommon, but usually occur as a result of soft tissue lesions. Herein we report on a patient with androgen independent prostate cancer and an elevated PSA with disease con®ned to ascites of the abdomen.

Keywords: cancer; hormone refractory; androgen independent; urology; PSA; prostatic

Introduction 128 ng/ml. In June 1994, the patient received 6700 cGy of external radiation, with a subsequent decline in PSA to Carcinoma of the prostate is the most common cancer in less than 2 ng/ml. However, 3 y later his PSA was found men in the United States, with an estimated 184,500 new to be 11.1 ng/ml, without evidence of metastatic disease cases in 1999 and 39,000 deaths. Following failure of on either CT scan or bone scan. In November 1997, he was hormonal therapy, treatment options are limited, with started on combined androgen blockade (leuprolide and no regimen being shown to prolong survival. Approxi- ¯utamide), but his PSA response lasted for less than 1 y. mately 20% of patients with androgen independent dis- In July 1998, ¯utamide was discontinued and bicaluta- ease have metastatic lesions detectable on CT scan with mide was initiated. In September 1998, his PSA was over 90% having bone metastases that are followable on noted to have continued to increase (9.1 ng/ml) and, nuclear imaging. Effusions (either pleural or abdominal) thus, bicalutamide was discontinued. In October 1998, a are relatively uncommon in this disease, but usually occur repeat CT scan and bone scan failed to document meta- as a result of soft tissue lesions. In this report, we present static disease. Furthermore, there was no evidence of a patient with androgen independent disease and an lymphadenopathy on physical exam. In October 1998, elevated prostate speci®c androgen (PSA) who had the patient was enrolled on an NCI approved trial which failed multiple therapeutic maneuvers with disease con- was evaluating thalidomide in patients with refractory ®ned to ascites. prostate cancer. Biopsy at the time of enrollment demon- strated residual/recurrent adenocarcinoma within the prostate and a serum PSA of 262 ng/ml. Neuro- endocrine stains were negative in the primary tumor. Case Report Five days into treatment, the patient was noted to have increased abdominal bloating and fullness with increas- JF is a 70- y-old White male who was initially diagnosed ing lower extremity adema without pain. The patient had with adenocarcinoma of the prostate (Gleason grade been taking hydrochlorothiazide for hypertension for 4 5 9/10) in April 1994. His PSA at that time was many years, thus his dose was increased from 25 mg per day to 50 mg per day. Two weeks later he was *Correspondence: WD Figg, Medicine Branch, Bldg 10, Room 5A01, found to have abdominal ascites and a weight gain of 9000 Rockville Pike, Bethesda, MD 20892, USA. E-mail: wd®[email protected] 7.3 kg. Received 4 November 1999; revised 7 January 2000; accepted A venogram failed to show an inferior vena cava 14 January 2000 thrombosis. A CT scan of the abdomen showed no Ascites in prostate cancer MW Saif et al 291

Figure 1 The papinacolou staining of the malignant cells in peritoneal Figure 3 The positive PAP (prostatic acid phosphatase) staining of the ¯uid from this patient with androgen independent prostate cancer with peritoneal ¯uid (600Â). metastatic disease con®ned to ascites (600Â).

evidence of adenopathy, or compression of the lymphatic or the venous system. It was thought that his ascites was most likely due to ¯uid retention secondary to thalidomide. He continued on hydrochlorothiazide along with furosemide 40 mg per day. Later that month, his ascites worsened resulting in shortness of breath. Examination of the abdomen revealed a large distended abdomen, hyper- resonant to percussion with the presence of shifting dullness and ¯uid thrill. The lower extremities were found to have 1 edema up to the ankles. His neurolo- gical examination was normal except for decreased vibra- tion sense in the lower extremities. His LFTs were normal (alkaline phosphatase 94 U/l, alanine aminotransferase 27 U/l, aspartate aminotransferase 23 U/l, total bilirubin 0.8 mg/dl, lactate dehydrogenase 184 U/l) and his albumin was 184 g/dl. Repeat CT scan showed that the patient had fat stranding consistent with carcinomatosis. A paracentesis was done, and the examination of the ascitic ¯uid revealed a glucose of 121 mg/dl, albumin of 2.8 g/dl and an albumin gradient of less than 1.1. The ascitic ¯uid revealed malignant cells (Figure 1), which were consistent with poorly differentiated carcinoma of the prostate. Staining for PSA and prostatic acid phosphatase was also positive for cells in the peritoneal ¯uid con®rming the diagnosis of ascites secondary to carcinoma of the prostate (see Figures 2 and 3). Two months later, his bone scan and CT scan were still negative, but Figure 2 The positive staining of PSA (prostate speci®c antigen) of the his PSA continued to rise. The patient was removed from peritoneal ¯uid (600Â). study due to progressive disease. Ascites in prostate cancer MW Saif et al

292 Table 1 Regions involved by metastases and the number of times an effusion may have exfoliated from the primary lesion each was involved1 as evidenced by the positive cytological examination of Region involved Times involved these ¯uids. It is also suggested that the effusion may develop secondary to the obstruction of lymphatics, or Lymph node 178 that it may be the result of prostatic lymphatic carcino- Bone 46 matosis. Other benign and malignant etiologies should be Lung 22 considered in these cases. A case of chylous ascites as a Liver 22 Pleura 15 presenting sign of prostate adenocarcinoma has also been Adrenal 13 reported.6 In that report, the patient presented with Kidney 6 enlarged retroperitoneal lymph nodes and wide dissemi- Peritoneum 5 nation of the cancer of the prostate, development of Spleen 5 chylous ascites, which was thought to be secondary Skin 4 Pancreas 3 to diffuse metastases to periaortic lymph nodes, and 6 Brain 3 regional lymphatics draining the prostate carcinoma. Vena cava 2 Thalidomide was initially thought to be the cause of Stomach 2 the patient's ascites and leg edema. The preliminary data Small intestine 2 from our phase II trial involving thalidomide revealed Colon 1 peripheral edema in approximately 50% of cases, but Mesocolon 1 Portal vein 1 clinically prominent ascites or other effusions have not Gallbladder 1 been seen. However, immunohistochemical assessment of PSA and prostatic acid phosphatase in malignant cells from the ascites ¯uid strongly suggests that prostate cancer Discussion may be the primary cause of third space ¯uid in this circumstance.12,13 This ®nding emphasizes the impor- Carcinoma of the prostate can metastasize to nearly every tance of determining the etiology of adverse events in organ, but metastasis without osseous involvement is early trials of novel agents, and not simply assuming that extremely rare. Arnheim and others have described post- a clinical symptom is drug related. mortem cases of patients with prostate cancer1±4 (Table Malignant effusions in cases of prostate carcinoma 1). The most common sites of metastatic disease include have been noted not to resolve with endocrine therapy bones, lymph nodes and lungs. Adrenal gland, kidney, even in patients without prior hormonal ablation.7 How- brain, pancreas, genitalia and breasts are relatively ever, Hefner et al reported a case in which a patient had a uncommon sites of metastases. Malignant effusions, poor response to diethylstilbestrol diproprionate therapy whether pleural or peritoneal, are extremely rare clinical in resolving pleural effusions on two occasions.7 Calton manifestations of prostate cancer. Broghamer et al et al reported a response to orchiectomy with control of described a series of 33 patients with prostate cancer, ascites for 9 months in which no other immediate therapy the peritoneal ¯uid involvement in most cases was caused was instituted.8 Malignant effusions, whether peritoneal by a second primary malignancy or concomitant reactive or pleural, are rare with carcinomas of prostatic origin condition.5 Furthermore, review of the medical literature and much less so in patients without osseous or lymph failed to ®nd any case of androgen independent prostate node involvement. cancer in which ascites is the only manifestation. We did In conclusion, malignant effusions like ascites are identify six cases in which the initial presentation at the potential complications of carcinoma of the prostate. time of diagnosis was one or more effusions (Table 2).6±10 Although these effusions may constitute the initial man- Invasion of the mesothelial lining by malignant cells is ifestation of prostatic adenocarcinoma, such effusions considered to be a triggering factor in the pathogenesis of may be the only signs of recurrence of prostatic disease a body cavity effusion such as ascites. Neoplastic cells in following hormonal ablation. Prostatic cancer is a

Table 2 Case reports of patients with prostate cancer who developed ascites

Serial no. Age Time of diagnosis Other sites of mets Therapy Reference

1 63 Initial presentation Visceral Type: orchectomy 6 Direct extension Response: 9 months Lymph node 2 29 Initial presentation Bone Patient refused therapy 6 Wide spread dissemination found upon autopsy 3 78 Initial presentation Lymph node Type: endocrine 9 Response: ameliorated ascites 4 58 Initial presentation 7 none Type: diethylstilbestrol 10 Response: 6 months 5 76 Late manifestation Lymph nodes Type: 5 FU and thiotepa 11 Direct extension intraperitoneal Response: progressed Ascites in prostate cancer MW Saif et al common disease of the elderly male and presents typi- 6 Beigel Y, Zelikovski A, Shimoni S, Ekstein J, Melloul M, Mor C, 293 cally, either with obstructive uropathy or disease in the Fuchs J. Chylous ascites as a presenting sign of prostate adeno- axial skeleton. However, an unusual presentation like carcinoma. Lymphology 1990; 23: 183 ± 186. 7 Hefner JE, Duffey DJ, Schwaz MI. Massive pleural effusions from malignant effusions may be encountered. Therefore, prostatic lymphangitic carcinomatosis: resolution with endocrine urologists, oncologists and primary physicians should therapy. Arch Inter Med 1982; 142: 375 ± 376. be aware of this complication of prostatic disease. Immu- 8 Catton PA, Warren R, Hartwick J, Stigley JR. Prostate cancer nohistochemical methods should be employed in sorting presenting with malignant ascites: Signet-ring cell variant of out the tumor origin, since these malignant effusions have prostate adenocarcinoma. Urol. 1992; 39: 495 ± 497. a signi®cant impact on morbidity and mortality. 9 Disdier P, Harle JR, Swiader L, Coulange C, Mongin M, Weiller PJ. Ascites with cachexia revealing prostatic carcinoma. Presse Med 1990; 19: 220. 10 Megalli MR, Gursel EO, Veenema RJ. Ascites as an unusual presentation of carcinoma of the prostate. JUrol1973; 110: 232 ± 234. References 11 Rapoport AH, Omenn GS. Dermatomyositis and malignant effusions: rare manifestation of cancer of the prostate. J Urol 1968; 1 Arnheim FK. Carcinoma of the prostate: a study of the post- 100: 183 ± 187. mortem ®ndings in one hundred and seventy-six cases. JUrol 12 Satz N, Joller-Jemelka HI, Grob PJ, Hofer C, Schmid E, Knoblauch 1948; 60: 599 ± 603. M. Tumor markers and immunomodulator substances in ascites: 2 Harada M, Iida M, Yamaguchi M, Shida K. Analysis of bone their value as screening and diagnosis parameters. Schwelz Med metastasis of prostatic adenocarcinoma in 137 autopsy cases. Adv Wocherschr 1989; 119: 762 ± 765. Exp Med Biol 1992; 324: 173 ± 182. 13 Yam LT, Winkler CF, Janckila AJ, Li CY, Lam KW. Prostate cancer 3 Saitoh H, Hida M, Shimbo T, Nakamura K, Yamagata J, Satoh T. presenting as metastatic adenocarcinoma of undetermined origin. Metastatic patterns of prostatic cancer. Correlation between sites Immunodiagnosis by prostatic acid phosphatase. Cancer 1983; 51: and number of organs involved. Cancer 1984; 54: 3078 ± 3084. 283 ± 287. 4 Suzuki T, Shimizu T, Kurokawa K, Jimbo H, Sato J, Yamanaka H. Pattern of prostate cancer metastasis to the vertebral column. Prostate 1994; 25: 141 ± 146. 5 Broghamer WL, Richardson ME, Faurest S, Parker JE. Prostatic acid phosphatase immunoperoxidase staining of cytologically positive effusions associated with adenocarcinomas of the prostate and neoplasms of undetermined origin. Acta Cytol 1985; 29: 272 ± 278.