Urologic Oncology: Seminars and Original Investigations 24 (2006) 216 –219
Original article
Prostate adenocarcinoma manifesting as generalized lymphadenopathy Fabiana M. Moura, M.D.a, Luisimara T. Garcia, M.D.a, Lúcia P.F. Castro, M.D.b, Teresa C.A. Ferrari, M.D., Ph.D.a,* a
b
Department of Internal Medicine, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil Department of Pathology and Legal Medicine, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil Received 9 March 2005; received in revised form 28 June 2005; accepted 30 June 2005
Abstract Generalized lymphadenopathy is a rare manifestation of metastatic prostate cancer. Here, we report the case of a 65-year-old patient with supraclavicular, mediastinal, hilar, and retroperitoneal lymphadenopathy and pulmonary infiltration, which suggested the diagnosis of lymphoma. There were no urinary symptoms, and the serum prostate-specific antigen (PSA) was only mildly increased with a normal free PSA. A biopsy of the supraclavicular lymph node was compatible with adenocarcinoma, whose prostatic origin was shown by immunohistochemical staining with PSA. The origin of the primary tumor was confirmed by directed prostate biopsy. We emphasize that a suspicion of prostate cancer in men with adenocarcinoma of undetermined origin is important for an adequate diagnostic and therapeutic approach. © 2006 Elsevier Inc. All rights reserved. Keywords: Prostate adenocarcinoma; Metastatic prostate cancer; Generalized lymphadenopathy; Prostate-specific antigen
1. Introduction Generalized lymphadenopathy can be the initial manifestation of different diseases, with lymphomas and metastatic neoplasias being the most common in elderly individuals [1]. However, generalized lymphatic metastases are a very uncommon manifestation of prostate cancer [2]. The diagnosis of prostate adenocarcinoma with nonregional lymph node involvement might be difficult not only because this condition is uncommon but also because it can occur in the presence of normal serum prostate-specific antigen (PSA) and in the absence of urinary symptoms. Here, we report a case of prostate adenocarcinoma, which clinically manifested as generalized lymphadenopathy in the absence of urinary symptoms and in the presence of only mildly increased serum PSA with a normal free PSA, simulating lymphoma. 2. Case report A 65-year-old man was admitted to the University Hospital, Federal University of Minas Gerais, Belo Horizonte, * Corresponding author. Tel.: ⫹55-031-32489746; fax: ⫹55-03132489664. E-mail address:
[email protected] (T.C.A. Ferrari). 1078-1439/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2005.06.022
Brazil, with complaints of abdominal pain and a 24-kg weight loss in 3 months. There was no history of previous disease or drug intake. Upon admission, a hardened supraclavicular mass on the left and a firm abdominal mass in the right paramedial position at the height of the umbilical scar were detected by physical examination. Computerized tomography (CT) of the chest (Fig. 1) and abdomen (Fig. 2) showed extensive mediastinal, hilar, and retroperitoneal lymphadenopathy, in addition to frosted-glass opacities and pulmonary consolidations predominantly at the periphery. There were no respiratory symptoms. A biopsy of the supraclavicular mass was compatible with adenocarcinoma of undetermined origin. The patient was anti-human immunodeficiency virus negative, chorionic gonadotropin beta-subunit was ⬍1 mU/mL (normal ⬍5), total serum PSA was 10.1 ng/mL (normal 0⫺4), and free-to-total PSA ratio was 0.57 (⬎0.25 associated with benign prostatic hyperplasia). Digital rectal examination showed an enlarged and hardened left prostate lobe. However, there were no symptoms of prostatism. Ultrasonography revealed an enlarged prostate, weighing 46 g, with perineal invasion. A guided prostate biopsy showed Gleason score 7 (4 ⫹ 3) usual acinar type invasive prostate adenocarcinoma. Six core biopsies were obtained, and 5 of them had cancer involving 70%, 90%, 90%, 5%, and 60% of the
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Fig. 1. CT of the thorax showing hilar lymphadenopathy and pulmonary consolidations predominantly at the periphery.
biopsies from the left apical area, mid zone of the left lobe, base of the left lobe, mid portion of the right lobe, and base of the right lobe, respectively. Only the core from the apex of the right lobe was free from cancer. The histologic picture was similar to that observed for the biopsied supraclavicular mass (Fig. 3). On this occasion, the patient reported pain in a left costal arch, and had radionuclide bone scanning that showed areas of increased uptake compatible
Fig. 3. Poorly differentiated metastatic prostatic adenocarcinoma with signet ring cells. Similar appearance between supraclavicular mass biopsy (A) and prostate core biopsy (B) (hematoxylin-eosin, magnification ⫻250 in A, ⫻400 in B).
with metastases in the costal arches, vertebrae, right shoulder, and left ischium. The immunohistochemical staining of the biopsy specimen obtained from the supraclavicular mass was positive for PSA, confirming its prostatic origin. Treatment was initiated with diethylstilbestrol (DES) hormone therapy because the patient refused the proposed orchiectomy, in combination with paclitaxel chemotherapy. Soon after the third chemotherapy cycle, the patient had symptoms of intestinal obstruction, and he underwent laparotomy. During this procedure, ventricular fibrillation developed, and the patient did not respond to the resuscitation maneuvers. The death occurred on approximately the 70th day after diagnosis. An autopsy was not performed, but it is possible that the death was a consequence of a pulmonary embolism related to the cancer itself and mainly to the use of DES. It was impossible to evaluate if there was any reduction in the tumor volume in response to the treatment because the patient died before having CT, which had been scheduled between the third and fourth chemotherapy cycles.
3. Discussion Fig. 2. CT of the abdomen showing extensive retroperitoneal lymphadenopathy.
Prostate adenocarcinoma is a common neoplasia and is the second most frequent cancer among men in the United
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States, with an estimated 232,090 new cases and approximately 30,350 deaths in 2005 [3]. However, this tumor is responsible for only 2% of metastatic carcinomas of undetermined origin. Its most frequent pattern of nonregional metastases involves bone, lungs, liver, and the epidural space, with supradiaphragmatic lymph node involvement being uncommon [4]. The prostate is richly supplied with lymphatic vessels that drain into the obturator-hypogastric and presacral nodes. Further spread occurs via the iliac and para-aortic nodes to the cisterna chyli, thoracic duct, and, once this level has been reached, the tumor gains direct entry into the systemic blood circulation via the subclavian vein. However, lymphatic spread is neither obligatory nor contiguous, and both lymphaticovenous spread to the vertebral column and “skip-like” spread to high proximal nodes can occur. The left supraclavicular lymph nodes are located close to the entry of the thoracic duct into the left subclavian vein into which they themselves drain via the left jugular trunk, and one may postulate that tumor cells lodge in these nodes by retrograde spread. This fact may explain the occurrence of metastases in these lymph nodes [1]. Except for bone involvement, distant metastases are relatively rare at diagnosis, and include supraclavicular, mediastinal, pulmonary, and retroperitoneal metastases, which seldom are the first evident clinical manifestation of prostate adenocarcinoma [1]. This pattern of nonregional lymphatic involvement observed in prostate cancer can clinically and radiologically simulate a malignant lymphoma, a fact impairing diagnosis, as observed in the current case. The distant lymph nodes most commonly affected are the left supraclavicular nodes, probably because of the characteristic lymphatic dissemination of the tumor. A retrospective survey of 250 cervical lymph node biopsies from men yielded 11 cases of metastatic prostate carcinoma, all on the left side, corresponding to just over one tenth of all metastatic carcinomas in the neck and one fifth of those on the left side [1]. Metastatic involvement of the right cervical lymph nodes has already been described but is extremely rare [5]. Metastases to the mediastinal lymph nodes have been reported in approximately 10% of autopsy cases of prostate carcinoma but are rare during the early stages of the disease [6]. Pulmonary metastases are common in advanced prostate carcinoma, with autopsy studies showing an incidence of 25% to 50% [7] and, therefore, like mediastinal metastases, are rare at diagnosis. Pulmonary manifestations are clinically recognized in only 5% of cases. Carcinomatous lymphangitis is another rare manifestation of this neoplasia. A review of 178 cases of carcinomatous lymphangitis has shown that only 7 patients (3.9%) had prostate cancer as the primary focus [7]. Abdominal metastases have only been reported in isolated cases [8-10]. To our knowledge, there is no study reporting the frequency of such involvement in patients with prostate adenocarcinoma. Clinical symptoms of prostatism,
such as dysuria, nocturia, and urinary retention, are poorly sensitive for the diagnosis of prostate adenocarcinoma. Saeter et al. [11] observed urinary symptoms in only 40% of cases of locally advanced prostate cancer associated with generalized lymphadenopathy. Serum PSA, a specific marker of prostatic tissue, permits the definition of the prostatic origin of a metastatic adenocarcinoma. However, increased levels of this glycoprotein are also observed in benign prostatic hyperplasia, and levels may be normal in poorly differentiated metastatic prostate adenocarcinomas. Epstein and Eggleston [12] have shown that prostate tumors with normal or slightly increased PSA are more aggressive than other types. Levels of serum PSA and/or of the free/total PSA fraction not suggestive of malignancy are not sufficient to exclude the diagnosis of prostate cancer. Studying patients with prostate cancer and cervical lymph node involvement, Jones and Anthony [1] observed an increase in serum PSA levels in only 5 (45.5%) of the 11 cases reported. In view of this fact, immunohistochemical staining with PSA of the biopsied peripheral lymph nodes has been suggested for all cases of adenocarcinoma without a defined site of origin [13]. Immunohistochemical staining with PSA has been a reliable method to establish the prostatic origin of a tumor [1,2,6,14]. Presently, the primary approach to advanced prostate cancer is hormone therapy, including orchiectomy, exogenous estrogens, antiandrogens, adrenal enzyme synthesis inhibitors, and gonadotropin-releasing hormone analogues. Results of large-scale randomized trials have shown that when used alone, these methods are comparable regarding their antitumor effects, differing only in terms of side effects and costs [4]. Because of the increase in cardiovascular complications induced by the high doses of estrogens necessary for treatment, this is no longer a treatment option. DES was used in the present case because of its availability in the Brazilian public health sector. The patient was unable to pay for the other alternative medicine and refused to undergo orchiectomy. Although it was not confirmed, we believe that the cause of the death, as stated previously, was a pulmonary embolism related to the cancer itself and mainly to the use of DES. Generally, chemotherapy is used in patients with advanced prostate cancer after hormone therapy has failed. This failure is established based on clinical criteria and/or progression of PSA during hormone administration [15,16]. In the present case, introduction of paclitaxel chemotherapy concomitantly with hormone therapy was chosen because of the extent of the disease. The number of patients with prostate cancer and nonregional lymph node involvement is not very large, and data regarding the prognosis of such patients are relatively limited. Available evidence suggests that the presence of generalized lymphatic metastases does not worsen the prognosis of prostate cancer compared to tumors with the same Gleason score because even widespread lymph node involvement can be hormonally responsive [2,11,14]. In con-
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trast, bone metastases have been associated with a poor prognosis [2,14]. In an observational study on 205 cases of metastatic prostate cancer, including 17 with distant lymph node metastases, Furuya et al. [2] reported a better prognosis for patients with lymph node involvement only, even if nonregional, compared to those with bone metastases. The diagnostic difficulty in the present case was a result of the fact that the patient presented supraclavicular, mediastinal, hilar, pulmonary, and retroperitoneal involvement as the initial manifestation of prostate cancer without, however, showing symptoms of prostatism or serum PSA levels suggestive of malignancy. A suspicion of prostate cancer in men with adenocarcinoma of undetermined origin is important for an adequate diagnostic and therapeutic approach. It should be emphasized that male patients with metastatic adenocarcinoma of an unknown primary site should have their lymph node biopsies immunohistochemically stained for PSA.
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