Atypical Metastases From Prostate Cancer: 10-Year Experience at a Single Institution

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1 Genitourinary Imaging Original Research Vinjamoori et al. Atypical Metastases From Prostate Cancer Genitourinary Imaging Original Research Anant H. Vinjamoori 1 Jyothi P. Jagannathan Atul B. Shinagare Mary-Ellen Taplin William K. Oh Annick D. Van den Abbeele Nikhil H. Ramaiya Vinjamoori AH, Jagannathan JP, Shinagare AB, et al. Keywords: atypical metastatic sites, oncologic imaging, osseous metastases, prostate cancer DOI: /AJR Received July 14, 2011; accepted after revision November 7, All authors: Department of Imaging, Dana-Farber Cancer Institute/Brigham and Women s Hospital, Harvard Medical School, 450 Brookline Ave, Boston, MA Address correspondence to A. B. Shinagare (ashinagare@partners.org). AJR 2012; 199: X/12/ American Roentgen Ray Society Atypical Metastases From Prostate Cancer: 10-Year Experience at a Single Institution OBJECTIVE. The purpose of the study was to retrospectively review the frequency, sites, and patterns of atypical metastases from prostate cancer and to determine whether any correlation exists between the atypical sites and biochemical or histologic variables. MATERIALS AND METHODS. All available imaging studies of 620 consecutive patients with biopsy-proven prostate carcinoma seen at our institute between 1999 and 2009 were reviewed. Eighty-two patients (mean age, 72 years; age range, years) with atypical sites of metastases were identified. Patients were separated into groups on the basis of the presence or absence of concurrent osseous metastasis and high or low Gleason grade, and metastatic patterns were compared using the Fisher exact test. The maximum prostate-specific antigen (PSA) level for each patient was recorded and correlated with metastatic pattern using the Mann-Whitney test. RESULTS. The most frequent sites of atypical metastases were the lungs and pleura (40%, 33/82), liver (37%, 30/82), supradiaphragmatic lymph nodes (34%, 28/82), and adrenal glands (15%, 12/82). Supradiaphragmatic lymphadenopathy was more common in patients with osseous metastases (45%, 25/56) than in patients without concurrent osseous involvement (12%, 3/26; p < 0.05). There was no significant correlation between the other atypical metastatic sites and osseous metastases. Abdominal visceral metastasis occurred more frequently in patients with a high Gleason grade (25/43, 58%) than in patients with a low Gleason grade (9/29, 31%; p < 0.05). There was no significant correlation between metastatic pattern and PSA level. CONCLUSION. The lungs and pleura, liver, supradiaphragmatic lymph nodes, and adrenal glands are the most common extranodal metastatic sites of prostate cancer. Supradiaphragmatic lymphadenopathy was strongly associated with concurrent osseous metastases. P rostate carcinoma ranks as the most common noncutaneous cancer and as the third most common cause of cancer death in men in the United States [1]. Metastatic prostate cancer has a recognizable pattern of spread, most often to regional lymph nodes and the bones [2, 3]. Pelvic and abdominal retroperitoneal lymph nodes are the most common sites of adenopathy in prostate cancer. Any lymphadenopathy occurring outside the abdomen and pelvis is considered atypical [4, 5]. The incidence of prostate carcinoma is increasing in the United States and worldwide [6, 7]. Currently, survival rates are rising as diagnoses are made earlier and treatments for advanced disease improve [8, 9]. These longer survival times coupled with increased therapeutic options have resulted in more patients undergoing radiologic evaluation for restaging or evidence of relapse, raising the likelihood of encountering atypical metastatic sites from prostate cancer. Therefore, radiologists should be familiar with the pathways of spread including common and uncommon sites of metastases. However, to date little attention has been focused on documenting the radiologic and clinical features of the less common sites of metastases from prostate cancer. Moreover, heightened awareness, vigilant screening efforts, and aggressive intervention have led to a marked increase in imaging of prostate cancer patients over the past 10 years, creating a more diverse patient pool for the study of the patterns of this disease and its atypical manifestations [10 12]. A retrospective review of 36 patients previously identified the orbit, liver, lungs, and adrenal glands as the most common sites (in descending order) of atypical metastasis [4]. However, that study was lim- AJR:199, August

2 Vinjamoori et al. ited because of a small sample size and limited staging workup and thus may not have fully captured the true spectrum and distribution of atypical metastases in prostate cancer patients. The purpose of this study was to retrospectively review the sites, frequency of occurrence, and patterns of atypical metastases in a larger population of patients with advanced prostate cancer and to correlate these findings with Gleason score and maximum prostate specific antigen (PSA) level. Materials and Methods Subjects In this institutional review board approved, HIPAA-compliant retrospective study, the electronic medical records and imaging studies of 620 consecutive men with biopsy-proven prostate carcinoma seen at our institution between 1999 and 2009 were reviewed for the presence of atypical sites of metastatic prostate cancer. Atypical metastases were defined as metastases localizing to sites other than bones or lymph nodes outside the pelvis or abdomen. Image Analysis A systematic retrospective review of all available CT scans and bone scintigraphic scans of the 620 patients was performed in consensus by two radiologists who specialize in cancer imaging, with 5 10 years of experience, who were blinded to the clinical information. They evaluated a total of 2012 CT studies and 1834 bone scans and documented the atypical metastatic sites. Then, a third reader independently reviewed the medical records to confirm the documented metastatic sites. Metastatic sites either were confirmed histologically by biopsy or were presumed to be metastatic if they showed unequivocal progression or treatment response on follow-up scans consistent with the overall clinical picture. Bone scintigraphy was used as a standard of reference for assessment of bone involvement. The Gleason score and the maximum PSA value for each patient during the disease course were documented. Statistical Analysis For analysis of metastatic patterns, patients were separated into groups on the basis of the presence or absence of osseous involvement and high or low Gleason grade. Patients with a Gleason grade of 8 or higher were classified as having a high Gleason score, whereas patients with a Gleason grade of 7 or lower were classified as having a low Gleason score in accordance with previously published criteria [13]. Statistical significance for comparisons among these two groups (i.e., high vs low Gleason score and positive vs negative osseous involvement) was determined by the Fisher exact test. We also compared median PSA values between patients with and those without coexistent osseous metastases. In this case, a nonparametric Mann-Whitney test was used to minimize the effect of outlying values. Results Of 620 patients, 85 patients (mean, 72 years; range, years) were found to have atypical sites of prostate cancer metastases. The most frequent sites of atypical metastases were the lungs and pleura (40%, 33/82), liver (37%, 30/82), supradiaphragmatic lymph nodes (34%, 28/82), and adrenal glands (15%, 12/82) (Table 1). Nodal metastases occurred in both typical (pelvic, retroperitoneal) and atypical (supradiaphragmatic) lymph node stations for prostate cancer metastases. Extranodal involvement included metastases to lung parenchyma or pleura, abdominal viscera (liver, spleen, kidneys, and adrenal glands), breast, TABLE 1: Pattern of Atypical Extranodal Metastases From Prostate Cancer Site Total No. of Patients With Atypical Extranodal Metastases (n = 82) No. of Patients With Concurrent Bone Metastases (n = 56) No. of Patients Without Concurrent Bone Metastases (n = 26) Lung parenchyma or pleura Solitary lung nodule Multiple lung nodules Lymphangitic carcinomatosis Pleural nodules and masses Pleural effusions Abdomen and pelvis Liver Spleen Adrenal gland Pancreas Ureter Kidneys Peritoneum Breast Subcutaneous tissue Muscles Orbit Parotid gland Fig year-old man with Gleason grade = 7 prostate cancer with prostate-specific antigen value of 49.9 ng/ ml. Contrast-enhanced CT scan in axial plane shows enlarged retrocrural lymph node (arrow) and sclerotic osseous metastasis involving vertebra (arrowhead). 368 AJR:199, August 2012

3 Atypical Metastases From Prostate Cancer A B Fig year-old man with Gleason grade = 7 prostate cancer with prostate-specific antigen value of 250 ng/ml. A, Contrast-enhanced CT scan in axial plane shows bulky anterior mediastinal lymphadenopathy (arrowhead) and left pleural effusion (arrow). B, Contrast-enhanced CT scan in axial plane shows nodularity of left breast (arrowhead), that was initially thought to be gynecomastia. However, histopathology showed metastatic disease in breast. Left pleural effusion (arrow) is again noted. orbit, and soft tissue. Overall, 56 of 82 patients (68%) who had evidence of atypical metastases by our criteria had coexistent osseous Fig year-old man with Gleason grade = 9 prostate cancer with prostate-specific antigen value of 593 ng/ml. Contrast-enhanced CT scan in coronal plane shows multiple metastatic lesions in liver (arrowheads), right adrenal (straight arrow), and spleen (curved arrow). metastases, whereas the remaining 26 patients (32%) had atypical metastases without osseous involvement. Lymphadenopathy Of the 82 patients, 28 (34%) had supradiaphragmatic nodal involvement. The most commonly involved nodes were the posterior mediastinal (including retrocrural) (n = 21) (Fig. 1), hilar (n = 15), and supraclavicular (n = 11) stations (Table 2). Lymph node involvement was also noted in the anterior mediastinum (n = 8) (Fig. 2) and axilla (n = 1). Supradiaphragmatic lymphadenopathy was observed in 10 patients in the absence of adenopathy in the pelvis or abdomen. None of these patients had undergone prior radiation or pelvic lymphadenectomy. Pleuroparenchymal Metastases Evidence of pulmonary pleural or parenchymal metastases (or both) was noted in 33 of 82 TABLE 2: Pattern of Supradiaphragmatic Lymphadenopathy Nodal Station Total No. of Patients With Supradiaphragmatic Lymphadenopathy No. of Patients With Concurrent Bone Metastases No. of Patients Without Concurrent Bone Metastases Hilar Anterior mediastinal Posterior mediastinal Supraclavicular Axillary Total patients (Table 1). Of these 33 patients, 13 had solitary lung nodules and 18 had multiple lung nodules; the nodules ranged in size from 3 mm to 2.5 cm. Pleural nodules and masses were identified in six of 33 patients and seven patients had pleural effusions (Fig. 2). Pulmonary lymphangitic carcinomatosis was observed in four of 33 patients. Metastatic pleural or parenchymal disease was seen concomitantly with supradiaphragmatic lymphadenopathy in 25 of the 33 patients. Twenty of the 33 patients had concurrent osseous metastases. Abdominal Visceral Metastases Forty-four patients had radiologic evidence of extranodal metastases in the abdomen and pelvis (Table 1). Coexistent osseous metastasis was present in 32 of these patients. Twenty-one of 44 patients in this group had concurrent regional (pelvic or abdominal) lymphadenopathy versus 23 patients who did not. The most common sites of extranodal metastasis in the abdomen were the liver (n = 30) (Fig. 3), adrenal glands (n = 12) (Fig. 3), and peritoneum (n = 8). Other involved sites included the spleen (n = 3) (Fig. 3), pancreas (n = 1), kidneys (n = 1), and ureter (n = 2) (Fig. 4). One patient presented with disseminated intraabdominal metastases involving the adrenal glands, ureter, peritoneal cavity, and retroperitoneum as well as discrete pancreatic and renal metastases. Miscellaneous An intraorbital metastasis presenting as a painful enlarging intraconal mass without adja- AJR:199, August

4 Vinjamoori et al. cent osseous metastasis was seen in one patient. Two patients had parotid masses in association with widespread adenopathy. One patient had an enlarging left breast mass accompanied by an ipsilateral pleural effusion and diffuse supradiaphragmatic lymphadenopathy that was initially suspected to be primary breast carcinoma. Biopsy revealed metastatic prostate cancer (Fig. 2). Intramuscular metastases were identified in three patients, all of whom had concurrent osseous and nodal metastases (Table 2). TABLE 3: Gleason Grade and Distribution of Atypical Metastases Gleason Score (Gleason Tumor Grade) No. of Patients Presence Versus Absence of Concurrent Osseous Metastasis We divided the patients into two groups on the basis of the presence or absence of osseous involvement. Supradiaphragmatic lymphadenopathy was seen in 25 of 56 patients with osseous metastases but in only three of 26 patients without osseous metastasis (Fisher exact test, p < 0.005) (Table 2). All 25 patients with isolated supradiaphragmatic lymphadenopathy (i.e., without pelvic or abdominal lymphadenopathy) had osseous metastases in the thorax. Additionally, in all these patients, osseous involvement was noted to either occur with or precede the detection of supradiaphragmatic nodal metastasis. Moreover, for all 25 patients, detection of these nodal metastases preceded the detection of pleuroparenchymal involvement. All 15 patients with pleural metastases (malignant effusion, pleural mass) also had concurrent osseous metastases, again predating the pleural involvement. However, there was no difference in the frequency of pulmonary parenchymal metastases in the patients with osseous disease and in those without osseous disease. There was no difference in the frequency of abdominal visceral metastasis in patients with and those without osseous involvement. No. (%) of Patients Gleason Score and Tumor Histology Of 82 cases, 81 tumors (98.8%) were adenocarcinoma and one tumor (1.2%) showed neuroendocrine differentiation. Gleason tumor grades among our patients with atypical metastasis ranged from grade 5 to 10, with a median score of 8. Ten patients had no Gleason score available on record. Among our patients, a higher Gleason score was associated with a greater likelihood of abdominal or pelvic extranodal metastasis (Fisher exact test, p < 0.03)) (Table 3). Specifically, 58% of patients with a high Gleason score had metastasis to this area as compared with 31% of patients with a low Gleason score. There was no statistically significant difference in the frequency of supradiaphragmatic lymphadenopathy or pleuroparenchymal metastasis between the high and low Gleason score groups. Prostate-Specific Antigen Maximum PSA levels showed a significant variation in our patients, ranging from as low as 1.47 ng/ml to as high as 23,162 ng/ ml, with a median of 229 ng/ml. Patients presenting with isolated atypical metastasis without osseous involvement were found to have a lower median PSA (54 ng/ml) compared with a median of 326 ng/ml for those with osseous involvement (Mann-Whitney test, p < ). PSA levels did not correlate with any specific distribution of disease or tumor histologic grade. Discussion In this study, we retrospectively reviewed atypical metastatic patterns of prostate cancer in 82 patients from a cohort of 620 patients with metastatic prostate cancer. We aimed to use this large patient population to Bone Metastases Supradiaphragmatic Lymph Nodes Lung Parenchyma or Pleura Abdominopelvic Extranodal High score (8 10) (60) 9 (21) 14 (33) 25 (58) Low score (5 7) (86) 9 (31) 12 (41) 9 (31) No score A Fig year-old man with Gleason grade = 9 prostate cancer with prostate-specific antigen value of 475 ng/ml. A, Contrast-enhanced CT (CECT) scan in axial plane shows circumferential right ureteral wall thickening (arrow) that was proven to be metastatic involvement on histopathology. B, Axial follow-up CECT scan obtained 3 months after A shows contiguous more proximal involvement that now reaches up to right renal pelvis (arrows). B 370 AJR:199, August 2012

5 Atypical Metastases From Prostate Cancer capture a broad spectrum of unusual prostate cancer metastases and to report on the observed patterns of distribution and radiologic features of disease. To our knowledge, this study is the largest to date that examines atypical prostate cancer metastases. Heightened awareness of the manifestations of prostate cancer metastases may enable accurate staging and help in appropriate management of disease [2]. Long and Husband [4] previously conducted a retrospective review of CT scans of patients with atypical prostate cancer metastasis. The criteria for defining atypical metastasis in that study were essentially the same as the criteria used for our study. The authors identified 45 instances of atypical metastasis in 36 patients. However, the sites of extranodal metastasis described were limited to the orbit and skull base (11 cases), lungs (four cases), liver (three cases), ocular cavity (one case), and adrenal glands (one case) with no mention of coexistent osseous or nodal involvement. In our study, we found a much broader range of extranodal metastases, including breast, spleen, and subcutaneous tissue. Moreover, the frequency of distribution of metastases detailed in our study differed significantly from that described by Long and Husband. Lung parenchyma and pleura (33/82 patients) and liver (30/82 patients) were the most common sites of unusual metastases in our study, whereas only one instance of metastasis to the orbit was identified. The distribution of metastasis identified in our study was consistent with that described in an autopsy review of more than 556 patients with metastatic prostate cancer conducted by Bubendorf et al. [14]. They identified bone as the most common site of metastasis (90%) with lung (46%) and liver (23%) as the next most common sites. However, despite the relatively high prevalence of pulmonary metastasis secondary to prostate cancer at autopsy, it is discovered in less than 1% of patients during their lifetime [15]. The currently widely accepted model of prostate cancer metastasis implicates hematogenous spread via venous drainage of the prostate into the vena cava. More than 60 years ago, Batson [16] hypothesized that a backward venous metastatic pathway from the prostate to the lower spine existed on basis of the high prevalence of lower spine metastasis in prostate cancer as well as cadaver experiments that revealed that contrast liquid could flow from prostatic veins to the spinal column. This model was not well supported until Bubendorf et al. found an inverse relationship between the prevalence of spine and lung metastasis in their autopsy study, suggesting a mechanism of spinal metastasis independent of hematogenous spread [14]. However, in our study, supradiaphragmatic lymphadenopathy, pleural masses, and malignant pleural effusions all occurred more frequently in patients with concurrent osseous involvement, which included the spine in all cases. Tumor spread via lymphatic vessels is important only as far as the regional lymph nodes; thereafter, the venous system represents the conduit for metastasis [17]. Given the fact that all the patients with isolated intrathoracic lymphadenopathy had preexisting osseous metastases involving the thoracic spine, it is possible that intrathoracic metastases in these patients occurred via backward spread from the spine. This finding may further indicate that the retrograde metastatic model via the spine may be a clinically significant mechanism of metastasis to the thoracic cavity in addition to the vena cava type pathway. PSA is the most widely used biomarker for prostate cancer screening and treatment monitoring [18, 19]. We found no significant correlation between PSA levels and disease distribution or histologic grade in our study of atypical metastasis. We also observed that patients who presented with atypical metastasis without concurrent osseous involvement actually had significantly lower median PSA values than those with concurrent osseous involvement. However, this finding is expected given the larger disease burden seen in patients with osseous involvement. Moreover, given that the patients in our study presented to our institution with various stages of disease, were followed for variable amounts of time, and received a wide range of treatment regimens, these interpretations of our PSA data are limited. Together, our findings are consistent with the belief in the clinical community that it is challenging to infer metastatic potential from PSA values [20, 21]. The data from our study suggest that a higher Gleason tumor grade may be positively associated with abdominal visceral metastasis. Although Gleason grade is clinically assigned on the basis of cell morphology, high-grade (poorly differentiated) tumors may differ from lower-grade (well-differentiated) tumors at the molecular level as well [22, 23]. A genomic analysis conducted by Bibikova et al. [22] identified a panel of 16 genes whose expression was significantly linked to Gleason grade. Taken together with the patterns of metastases described in our study, this finding suggests that these differentially expressed genes, as well as others not presently identified, may encode factors that determine an organ-specific tropism of primary tumor metastasis. In conjunction with increased imaging of prostate cancer patients, the adoption of tumor molecular profiling in clinical practice promises to offer opportunities to study this hypothesis in the future [24 26]. There are several limitations to our study. This study was retrospective in nature, the study cohort consisted of patients with varying tumor stages, and stratification was not performed by individual stage. To our knowledge, there is no standard protocol for imaging follow-up of patients with prostate cancer; imaging was performed at variable intervals based on clinical parameters. Correlation with PSA levels was not determined at every imaging time point. Also, given that our institution is a tertiary cancer center, many of our patients represent complex cases that were referred from outside centers, thus leading to a greater selection of refractory and advanced metastatic cases that may not accurately represent the spectrum of tumor behavior in the general population. In conclusion, we identified lungs, liver, supradiaphragmatic lymph nodes, and adrenal glands as the most common atypical metastatic sites from prostate cancer. Supradiaphragmatic lymphadenopathy is strongly associated with concurrent osseous metastases. References 1. American Cancer Society. Cancer facts & figures New York, NY: American Cancer Society, Spencer JA, Golding SJ. Patterns of lymphatic metastases at recurrence of prostate cancer: CT findings. Clin Radiol 1994; 49: Hayward SJ, McIvor J, Burdge AH, Jewkes RF, Williams G. Staging of prostatic carcinoma with radionuclide bone scintography and lymphography. Br J Radiol 1987; 60: Long MA, Husband JE. Features of unusual metastases from prostate cancer. Br J Radiol 1999; 72: Coakley FV, Lin RY, Schwartz LH, Panicek DM. Mesenteric adenopathy in patients with prostate cancer: frequency and etiology. AJR 2002; 178: Hsing AW, Tsao L, Devesa SS. International trends and patterns of prostate cancer incidence and mortality. Int J Cancer 2000; 85: McDavid K, Lee J, Fulton JP, Tonita J, Thompson TD. Prostate cancer incidence and mortality rates AJR:199, August

6 Vinjamoori et al. and trends in the United States and Canada. Public Health Rep 2004; 119: Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I. International comparisons. BJU Int 2002; 90: Collin SM, Martin RM, Metcalfe C, et al. Prostate-cancer mortality in the USA and UK in : an ecological study. Lancet Oncol 2008; 9: Mettlin CJ, Murphy GP, McDonald CJ, Menck HR. The National Cancer Database Report on increased use of brachytherapy for the treatment of patients with prostate carcinoma in the U.S. Cancer 1999; 86: Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol 1999; 17: Akin O, Hricak H. Imaging of prostate cancer. Radiol Clin North Am 2007; 45: Abouelfadel Z, Miller GJ, Glode LM, et al. High Gleason scores and lower prostate-specific antigen levels in a single institution over the past decade. Clin Prostate Cancer 2002; 1: Bubendorf L, Schöpfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 2000; 31: Tan W, Buskirk S. Histologically diagnosed lung metastasis from prostate cancer: diagnosis, clinical course and response to treatment (abstr). ASCO 2005: American Society of Clinical Onclogy. Alexandria, VA: ASCO, 2005: abstract no Batson OV. The function of the vertebral veins and their role in the spread of metastases. Ann Surg 1940; 112: Morgan-Parkes JH. Metastases: mechanisms, pathways, and cascades. AJR 1995; 164: Sirovich BE, Schwartz LM, Woloshin S. Screening men for prostate and colorectal cancer in the United States: does practice reflect the evidence? JAMA 2003; 289: Moul JW. Population screening for prostate cancer and emerging concepts for young men. Clin Prostate Cancer 2003; 2: Schröder FH, Hugosson J, Roobol MJ, et al.; ERSPC Investigators. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009; 360: Andriole GL, Crawford ED, Grubb RL 3rd, et al.; PLCO Project Team. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009; 360: [Erratum in N Engl J Med 2009; 360:1797] 22. Bibikova M, Chudin E, Arsanjani A, et al. Expression signatures that correlated with Gleason score and relapse in prostate cancer. Genomics 2007; 89: Furusato B, Shaheduzzaman S, Petrovics G, et al. Transcriptome analyses of benign and malignant prostate epithelial cells in formalin-fixed paraffin-embedded whole-mounted radical prostatectomy specimens. Prostate Cancer Prostatic Dis 2008; 11: Golias Ch, Charalabopoulos A, Stagikas D, et al. Molecular profiling and genomic microarrays in prostate cancer. Exp Oncol 2007; 29: Foye A, Febbo PG. Cancer gene profiling in prostate cancer. Methods Mol Biol 2010; 576: Qian DZ, Huang CY, O Brien CA, et al. Prostate cancer associated gene expression alterations determined from needle biopsies. Clin Cancer Res 2009; 15: FOR YOUR INFORMATION The AJR has made getting the articles you really want really easy with an online tool, Really Simple Syndication, available at It s simple. Click the RSS button located in the menu on the right side of the page. You ll be on your way to syndicating your AJR content in no time. 372 AJR:199, August 2012