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Gastrointestinal metastases from prostate cancer: a review of the literature Francesca Maines1, Orazio Caffo*,1, Antonello Veccia1 & Enzo Galligioni1

ABSTRACT The availability of active new drugs for the treatment of advanced castrationresistant prostate cancer has significantly prolonged overall survival, thus changing the natural history of the disease and raising the likelihood of observing metastases in atypical sites. This review of the literature describes the frequency, clinical-pathological features and presenting symptoms of non-liver gastrointestinal metastases (GIm) from prostate cancer. Its purpose is to increase clinical awareness of the increasing incidence of such GIm, contributing to the early detection, accurate diagnosis and, when feasible, appropriate management. Prostate cancer (PC) is the most common cancer among American males, and accounted for 28% of all tumors newly diagnosed in men in 2013 [1] . It is estimated that there are 238,590 new cases and 29,790 deaths due to PC in the USA every year, and the corresponding figures in Europe are 417,000 new cases and 92,000 deaths [1,2] . Localized PC can usually be cured by means of surgery, external radiotherapy and, in selected cases, brachytherapy but, unfortunately, 40–60% of the men who undergo external radiotherapy or brachytherapy and 20–40% of those who undergo radical prostatectomy experience a biochemical recurrence within 3–5 years with a significant risk of developing distant metastases during the same period [3] . Moreover, about 5% of the patients present distant metastases at the time of the diagnosis of PC. The standard of care for hormone-sensitive disease is androgen-deprivation therapy but most patients develop castration-resistant PC (CRPC) within a few years. The introduction of docetaxel [4] , and the more recent availability of other active treatments with different mechanisms of action such as cabazitaxel [5] , abiraterone acetate [6] enzalutamide [7] and radium-223 [8] for patients progressing after docetaxel failure, have considerably improved the prognosis of patients with CRPC, which was less than 12 months in the predocetaxel era, increased to about 18 months after the i­ntroduction of docetaxel, and is now approaching 3 years with the addition of one of the new agents [9,10] . Advanced disease usually first appears in the form of bone and lymph node metastases, but the incidence of visceral metastases seems to be increasing [11] not only in lung and liver [12,13] , but also in uncommon sites such as brain [14] . One possible explanation for this is that the improvement in prognosis probably due to both earlier diagnosis and the availability of the new treatments that have significantly prolonged the late-phase of the advanced disease has increased the risk of metastatic spread. It has been pointed out that the involvement of gastrointestinal (GI) system is not only due to relatively infrequent liver metastases, but also to metastases to other sites such as the stomach, bowel, pancreas or esophagus, thus leading to the development of what is considered an unusual scenario. The aim of this review is to describe the evidence and hypotheses concerning non-liver g­astrointestinal metastases (GIm) from PC.

KEYWORDS 

• atypical metastases • castration-resistant • gastrointestinal metastases • prostate cancer

Medical Oncology Department, S Chiara Hospital, Largo Medaglie d’Oro 1, 38100 Trento, Italy *Author for correspondence: Tel.: +39 0461 902121; Fax: +39 0461 903364; [email protected] 1

10.2217/FON.14.253 © 2015 Future Medicine Ltd

Future Oncol. (2015) 11(4), 691–702

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Review  Maines, Caffo, Veccia & Galligioni The development of GIm in PC patients Bone and abdominal lymph nodes are the targets of metastatic spread in about 90 and 30% of PC patients, respectively; visceral metastases are less frequent with liver and lung involvement being observed in 4.1 and 5% of cases, respectively [15] . Gastrointestinal tube involvement may be due to direct infiltration, lymphatic or hematogenous spread, or intraperitoneal seeding. Direct invasion from adjacent or contiguous abdominal organs is usually the most frequent mechanism of secondary GI involvement (e.g., direct rectal invasion from locally advanced PC), but this should be not classified as metastasis. The pathological mechanism underlying PC presenting with peritoneal metastases but without bone or lymph node lesions remains unclear, but may be due to particular histological subtypes of PC with biologically peculiar behavior and/or specific patterns of metastatic spread such as mucinous adenocarcinoma [16] . As in the case of other types of cancer, the classic model of GIm development is that of a metastatic cascade: cancer cells invade the surrounding tissue after escaping from the primary tumor site, penetrate blood or lymphatic vessels, and proliferate into a secondary site after arrest and extravasation [17] . However, the ability of tumor cells to metastasize is not ubiquitous, and each tumor type has organ-specific patterns of spread. The organ-specific pattern of spread of PC has historically been explained by the hypothesis of the ‘dependence of the seed on fertile soil’ – that is, cancer cells metastasise with high affinity to particular sites with a fertile tumor microenvironment [18] . On the basis of this assumption, bone and lymph nodes have usually been seen as the “fertile soils” for PC. However, a more modern view of this hypothesis is that cancer cells carry their own soil from the primary site in the form of stromal components, including activated fibroblasts [19,20] and, even more recently, the importance of epithelial-tomesenchymal transition (EMT) as a driver of invasion and metastases has been increasingly recognized as there is evidence of a link between EMT and the cancer stem cells that initiate and maintain tumors, and may be involved in invasion and metastases [21] . However, none of these mechanisms explains why GIm are so rare or why they only occur in some patients. One possible explanation is the genetic instability of metastasising cancer cells, which sequentially accumulate somatic

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alterations as the disease progress. First proposed in 1976 by Nowell [22] , this theory has been indirectly confirmed by a recent study describing high levels of genetic heterogeneity in the same disease [23] . In this view, the presence of metastasis-suppressor genes may regulate metastatic spread by playing a central role in the selection of the target sites of metastases [24] . In the case of PC, it has been documented that various genes are involved in the suppression of metastases, including NM23, 7q21-22, 8p21-p12,10q23, 11p11.2-13, 12qcen-q13, 16q24.2 and 17p1211.2 [25] . However, regardless of the genetic or molecular mechanisms underlying the development of GIm, it cannot be excluded that the prolonged natural history of PC may play a role: rapid systemic disease progression previously led to death before the metastases became symptomatic, but longer patient survival now allows metastatic foci to become clinically apparent. The incidence of GIm in PC patients The tumors with the greatest capacity of metastasising to the GI tract are melanomas, followed by breast cancer and lung carcinomas [26] . In the case of PC, most of the rare reports of GIm have been based on autoptic series: 1589 autopsies of patients with hormone-refractory PC, performed between 1967 and 1995, reported metastases to the GI tract in the peritoneum (7% of the cases), stomach/bowel (1.8%), pancreas (1.4%) and mesentery (1.1%) [27] . Secondary pancreatic involvement was observed in about 10% of a further 30 autopsied patients who died of hormone-refractory PC, whereas no cases of bowel, gastric or peritoneal metastases were mentioned [28] . The historical data from autopsy series indicate an overall incidence of occult GIm from PC ranging from 4.2 to 13% [29–31] , which supports the view that they are more frequent than is clinically documented. The exact incidence of metastases from PC to the GI tract is difficult to assess in living patients unless they became symptomatic: the conventional imaging that can be routinely used in PC follow-up is incapable of identifying secondary lesions in the GI tube, for which endoscopic examinations are usually used in symptomatic patients. Literature review ●●Esophagus

The published cases of hematogenous or lymphatic metastases from PC to the esophagus

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Gastrointestinal metastases from prostate cancer  are anecdotal (Table 1) . In a retrospective evaluation of 62 cases of esophageal involvement by secondary tumors, Agha et al. observed direct invasion from adjacent organs in 45.2% of the cases, the pathological involvement of mediastinal nodes in 35.5%, and hematogenous spread from distant primary tumors in 19.3%, which suggests that the most frequent routes of esophageal invasion involve the contiguity of tissues surrounding the esophagus or lymphatic spread from mediastinal node metastases [32] . Esophageal invasion from contiguous organs is usually seen in the case of stomach, thyroid, larynx or hypopharynx tumors; lung or breast tumors are usually the sources of mediastinal node metastases that may secondarily invade the esophagus; and the pancreas, testis, eye, tongue, bone, liver, kidney, uterus, skin and prostate are most frequently sites of primary tumors giving rise to hematogenous metastases [32] . A monoinstitutional autopsy study of 1835 patients who died of cancer over a period of about 10 years found a 6.1% incidence of hematogenous or lymphatic metastases to the esophagus, with lung, breast, tongue, uterine cervix and ovary being the most frequent primary tumor sites [33] . There are only a few published case reports of esophageal metastases from PC. Two described metastases to the esophagus in patients with advanced PC that had already metastasised to bone and lymph nodes [34] or to the lesser curve of the stomach [35] . A third described the esophagus as the only site of PC metastatic spread, with pathological findings indicating submucosal layer involvement with an intact squamous epithelium [36] . The authors did not exclude esophageal involvement from mediastinal micrometastases, although no macroscopic radiological signs of metastatic disease were observed around the esophagus [36] . In the case reported by Eaves et al., a large tumor (10 × 6 cm) with morphological features consistent with metastases from a prostate adenocarcinoma and characterized by extensive perineural invasion was found on the lesser curve of the stomach in close proximity to the distal esophagus [35] . The tumor caused achalasia and, together with the extensive perineural spread and the site of the PC metastasis, the fact that this was the presenting symptom suggests that the esophageal involvement was due to perineural invasion rather than hematogenous or lymphatic spread.

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●●Stomach

The stomach is a rare site of secondary lesions from distant tumors, most of which are due to primary esophagus, skin (melanoma), lung, uterine cervix, breast, sigmoid colon or testicular cancer [37] . The exact incidence of gastric metastases is difficult to assess, but varies from 0.8% of all autoptic studies [38] to 2.9–5.4% of those of patients with malignant tumors [37,39] . Historical autopsy studies of 1589 and 67 PC patients found that the incidence of stomach metastases was 1.8–3% [27,40] , but there are only nine published case reports describing gastric metastases in PC patients (Table 1) [41–48] , most of whom had concomitant metastases to bone [41–48] or lymph nodes [44–46,48] although there were also concurrent brain [43] , peritoneal [43,48] , liver [48] or pleural metastases [48] . Some of the gastric metastases were observed at the time of the diagnosis of still hormone-sensitive PC [43,46] , but they usually occurred many months or years after the diagnosis of primary PC [41–45,47–48] and were often a sign of disease relapse during androgen-deprivation therapy [41–45] , thus suggesting a possible relationship with CRPC. ●●Small bowel

About 10% of small bowel cancers are secondary tumors of small intestine, and uterus, cervix, colon, lung, breast and skin (melanoma) are usually the most common sites of primary tumors [61] . Bowel involvement has been documented in 1.8% of one autopsy series of 1589 PC patients, and 6% of another of 30 patients [27,62] . Only three case reports of PC metastases to the small bowel have been published since 1966 (Table 1) [49–51] . In the case observed by Lee et al., abdominal fullness, anorexia and body weight loss were the presenting symptoms in a patient experiencing a biochemical relapse after external radiotherapy [49] , who had a single soft tumor with hyperemic mucosa partially narrowing the visceral lumen, and morphological characteristics and immunohistochemical stains consistent with secondary localisations from PC in the secondary portion of duodenum. However, the endoscopic findings of a solitary lesion, the close proximity of the duodenum to known liver metastases, and enlarged pathological retroperitoneal lymph nodes suggest direct infiltration of small bowel rather than a lymphatic or hematogenous spread from a distant site [49] . In another case report, small bowel metastases were observed 9 years

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89

Bone, lymph nodes

Bone

Bone, pleura, liver, lymph nodes, peritoneum

67

69

70

Lymph nodes, liver

Bone, lymph nodes

71

81

Bone, lymph nodes

66

1

3

8

Concomitant

About 9

18 months

15 months

15

4

8

Simultaneous

5

NA

CRPC

CRPC

Hormone sensitive NA

CRPC

CRPC

Hormone sensitive CRPC

CRPC

NA

Progressive disease during treatment with stilbestrol Hormone sensitive

NA

Time between Disease setting diagnosis of PC and GI metastases (years) NA

Treatment

Abdominal fullness, poor appetite, body weight loss

Abdominal discomfort, nausea, vomiting Nausea, anorexia, hematemesis Anorexia, nausea, vomiting, back pain Abdominal discomfort, obstructive nephropathy NA

Weakness, nausea, vomiting and decreased appetite Hematemesis

Nausea, vomiting, epigastric discomfort, decreased appetite Hematemesis, melena

Anorexia, general malaise right back pain

None

NA

NA

ADT

Mitoxantrone

Gamma-knife for brain metastases; palliative care Docetaxel

ADT

ADT

NA

Diethylstilbestrol phosphate, orchiectomy and tegafur-uracil

Dysphagia, regurgitation, NA retrosternal pain, body weight loss, esophageal achalasia

Dysphagia

Presenting signs and symptoms

ADT: Androgen-deprivation therapy; CRPC: Castration-resistant prostate cancer; GI: Gastrointestinal; NA: Not available; PC: Prostate cancer.

Lee et al. (2009)

Small bowel

Hong et al. (2010) Mehrzad et al. (2013) Christoph et al. (2004) Krones et al. (2012) Ben-Izhak et al. (1991)

Bone, possibly omentum Bone, brain

69

Bilici et al. (2012) Onitilo et al. (2010) Onitilo et al. (2010)

57

Bone

88

Bone

None

Large mass on the lesser curve of the stomach

75

65

Bone, lymph nodes

61

Age at time of Other metastatic sites diagnosis of GI metastases (years)

Holderman et al. (1992)

Stomach

Nakamura et al. (1997)

Gore et al. (1982) Eaves et al. (1983)

Esophagus

Study (year)

Table 1. Published case reports of gastrointestinal metastases from prostate cancer by anatomical site.

NA

Postmortem evaluation

NA

NA

Died 12 months later

Died 5 months later

Died 4 months later

NA

Alive after 7 months

NA

Alive after 3 years

NA

NA

Clinical outcome after diagnosis of GI metastases

[49]

[48]

[47]

[46]

[45]

[44]

[43]

[43]

[42]

[41]

[36]

[35]

[34]

Ref.

Review  Maines, Caffo, Veccia & Galligioni

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Bone, lymph nodes

Bone

57

72

None

None

75

67

None

None

76

59

Lymph nodes

83

Bone

Bone

70

60

Bone, lymph nodes

Simultaneous

2

12

4

5

Simultaneous

6 yrs

NA

2

10

About 4

9

Hormone sensitive

CRPC

Hormone sensitive CRPC

CRPC

Hormone sensitive

CRPC

CRPC

CRPC

CRPC

CRPC

CRPC

Time between Disease setting diagnosis of PC and GI metastases (years)

Treatment

Abdominal distension, breathing difficulty, ascites, obstructive nephropathy None

Abdominal distension, leg swelling, ascites Palpable abdominal masses, ascites Ascites

Body weight loss, lower GI bleeding, abdominal pain, vomiting

Abdominal discomfort, lower GI bleeding, palpable mass in the right iliac fossa

NA

Jaundice

Abdominal pain, jaundice

NA

NA

Clinical outcome after diagnosis of GI metastases

NA

ADT

Docetaxel with estramustine Docetaxel

Orchiectomy

ADT withdrawal

ADT

Died 1 year later (presumably because of acute coronary syndrome)

Stable disease for 7 months NA

NA

Died 3 months later

NA

Right Alive after 1 year hemicolectomy and then docetaxel

NA

Cyclophosphamide NA and cisplatin Palliative care Died 2 months later

Anorexia, weakness, anasarca, Estrogens bilateral pleural effusions, massive ascites Abdominal pain, nausea, NA vomiting, intermittent blood in stool

Presenting signs and symptoms

ADT: Androgen-deprivation therapy; CRPC: Castration-resistant prostate cancer; GI: Gastrointestinal; NA: Not available; PC: Prostate cancer.

Talwar et al. (2012)

Amin et al. (2002) Kehinde et al. (2001) Zagouri et al. (2009) Benedict et al. (2010)

Peritoneum

Abbas et al. (2011)

Rectum

Wang et al. (2013) Jacob et al. (2010) Desai et al. (2011) Cecum Kabeer et al. (2007)

Bone

59

42

Kaswala et al. (2011)

Pancreas

69

Malhi-Chowla et al. (2001)

Lymph nodes

Age at time of Other metastatic sites diagnosis of GI metastases (years)

Small bowel (cont.)

Study (year)

Table 1. Published case reports of gastrointestinal metastases from prostate cancer by anatomical site (cont.).

[60]

[59]

[58]

[16]

[57]

[56]

[55]

[54]

[53]

[52]

[51]

[50]

Ref.

Gastrointestinal metastases from prostate cancer 

Review

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after radical prostatectomy and external beam radiation therapy for primary PC in a man with a 2-year history of anasarca probably due to proteins loss [50] . Endoscopy showed normal gastric and duodenal mucosae, but random duodenal biopsies revealed a PSA-positive, submucosainfiltrating adenocarcinoma suggestive of small bowel metastases from PC [50] . Kaswala et al. described a case of small bowel metastases from PC presenting with lower GI bleeding, nausea, vomiting and abdominal pain in a patient with advanced PC with secondary bone involvement [51] . As in the case observed by Mahli-Chowla, duodenal endoscopic findings were normal, but random biopsies revealed a lymphangitic carcinoma consistent with high-grade prostatic adenocarcinoma. Duodenal involvement from PC has usually been observed in clinical contexts of hormone-refractory, progressive PC involving lymph nodes [49,50] , liver [49] or bone [51] . We have recently observed a case of small bowel metastases in a man affected by CRPC with known lymph node and bone metastases who experiencing nausea, weakness, occasional vomiting, abdominal pain and moderate body weight loss about 13 years after the diagnosis of PC in a clinical context of progressive disease [63] . Unlike in the cases of Mahli-Chowla and Kaswala, the duodenal endoscopy findings were clearly pathological: a number of small white lesions with pale mucus but without any narrowing of the lumen. Biopsies of the small bowel revealed a poorly differentiated adenocarcinoma with the same morphological aspect as the primary PSA-positive PC, thus supporting a diagnosis of small bowel metastases arising from PC. Moreover, the endoscopy findings of multiple secondary lesions suggested a hematogenous spread rather than direct infiltration from pre-existing contiguous metastases.

pancreatic tumors arising from nonhematological neoplasms documented only one case of metastases from PC [65] . In the case described by Jacob et al. [53] , acute cholestasis with marked jaundice but without lithiasic or tumoral obstruction of the bile duct was the first presentation of pancreatic metastases in a patient with CRPC diagnosed about 2 years previously. However, despite the histological confirmation that the pancreatic involvement arose from PC, radiographic and endoscopic findings suggesting a tumor mass infiltrating the pancreas head and the presence of enlarged retroperitoneal lymph nodes indicate that it may have been due to extrinsic infiltration of the pancreas head rather than hematogenous or lymphatic spread [53] . Wang et al. reported the case of a man previously treated with multiple anticancer therapies with histologically confirmed adenocarcinoma in a pancreatic mass whose immunohistochemical staining was consistent with pancreatic metastasis from PC (positive for PSA, prostate-specific acid phosphatase, and androgen receptor) [52] . The clinical events that occurred shortly before the diagnosis of pancreatic metastases were acute pancreatitis without any evidence of cholecystitis or choledocholithiasis, followed by acute cholecystitis requiring laparoscopic cholecystectomy and, subsequently, marked cholestasis due to soft tissue infiltration of the hilar liver region. A hypoechoic lesion in the tail of the pancreas was observed radiologically, apparently without any infiltration of the pancreas from adjacent structures. However, the presence of pathological portal and peripancreatic lymph nodes was also described [52] . Most of the published clinical cases are characterized by a long history of CRPC with ­metastatic disease (2–18 years).

●●Pancreas

●●Cecum

Although still uncommon, the frequency of pancreatic metastases has recently increased. They usually arise from renal, colorectal and lung cancers, a melanoma or a sarcoma [64] , and the unusualness of metastases from primary PC is confirmed by the few published cases (Table 1) [52–54]. Pancreas metastases were observed in only in 1.4% of 1589 autopsies of PC patients, and were much rarer than bone (90%), lung (46%) or liver metastases (21%) [27] . Another study that retrospectively evaluated 1050 fine-needle aspiration procedures involving metastatic

There is only one published case of PC metastasising to the cecum (Table 1) [55] . Kabeer et al. described a 72-year-old man with advanced CRPC and bone and lymph node metastases whose presenting symptoms and signs of cecal involvement were abdominal discomfort and a palpable 6 cm mass in the right iliac fossa. Although macroscopic examination of the surgically removed mass suggested a locally advanced cecal carcinoma with regional lymph nodes metastases, the histopathological analyses and (particularly) the immunohistochemical

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Gastrointestinal metastases from prostate cancer  staining were consistent with metastasis from a prostatic adenocarcinoma. ●●Rectum

Rectal involvement in PC patients is usually due to local invasion [66] and so, in order to be able to define true rectal metastases in the presence of a primary tumor, it is necessary to exclude direct infiltration. Rare cases of secondary rectal submucosa localizations have also been reported as a result of invasive diagnostic procedures such as transrectal needle biopsies [67] . Abbas et al. reported one case of rectal metastases from PC without any apparent direct invasion or infiltration (Table 1) [56] . ●●Peritoneum

The peritoneum is a relatively common site of secondary localizations, particularly from intraperitoneal colorectal, gastric, pancreatic or ovarian tumors. Direct intraperitoneal seeding is the most frequent means of metastatic dissemination, although hematogenous or lymphatic spread can also occur. A postmortem study of 1589 PC patients by Bubendorf et al. found that the disease had spread to the peritoneum in about 7% of cases [27] . There only five published reports of peritoneal metastases from PC in living patients (Table 1) [16,57–60] in whom the secondary peritoneal carcinomatosis was accompanied by ascites [16,57–59] and/or palpable intra-abdominal masses due to metastatic implants in the peritoneum [16] . The presenting symptoms were abdominal distension [57,59] and/or breathing difficulty [59] . A rare case of peritoneal carcinomatosis from PC involved a patient with severe chronic nephropathy requiring peritoneal dialysis; a glandular tumor consistent with prostatic adenocarcinoma was found in tissue samples of an umbilical hernia that was surgically resected for elective repair [60] . Most of all reported cases of PC metastasizing to the peritoneum are characterized by the absence of any other metastatic sites: in particular, there is no mention of bone or lymph node metastases in four out of five reported cases. Moreover, most of the cases were observed many years after the diagnosis of primary PC [16,57–59] , at the time of biochemical recurrence. PSA assays and prostate biopsies confirming the diagnosis of PC after the histological suspicion of peritoneal metastases had been aroused were performed in only one case [60] .

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Anecdotal evidences of exclusive peritoneal spread after laparoscopic or robot-assisted radical prostatectomy [68,69] suggest that laparoscopic or robotic surgery could be a cause of iatrogenic peritoneal dissemination. Reported cases of secondary peritoneal involvement after radical mini-invasive surgery (without metastases in sites other than the peritoneum) and increasing use of these new surgical techniques for the treatment of localized prostate cancer emphasize that all surgeons should be aware of this risk and that during the surgical approach all surgical cares must be taken to avoid the risk of peritoneal dissemination. Diagnosis Therapeutic advances and consequently prolonged life expectancy have significantly increased the percentage of patients undergoing radiological restaging of PC, thus also increasing the likelihood of diagnosing atypical metastases. A recent retrospective study of 359 CRPC patients found that visceral metastases were detected by the last imaging evaluation before death in 32% of cases, including 49% of the patients who underwent a radiographic assessment within three months of dying [70] , thus further confirming that visceral metastases are usually related to advanced disease, particularly advanced CRPC. Vinjamoori et al. retrospectively evaluated computed tomography (CT) scans and documented atypical sites of PC metastases in 82 out of 620 consecutive patients with advanced PC, the most frequently identified being the lungs and pleura (40%, 33/82), liver (37%, 30/82), supradiaphragmatic lymph nodes (34%, 28/82), adrenal glands (15%, 12/82) and peritoneum (9.7%, 8/82) [12] . However, in the case of GIm, traditional imaging may detect pancreatic or peritoneal metastases but not metastases to the GI tube, which can only be diagnosed by means of endoscopy as the sensitivity of choline-PET is still unclear. However, endoscopic assessments are only planned in the presence of GI symptoms, which are common to various pathological conditions affecting the GI tube, and frequently underestimated or considered as having a different pathogenesis: for example, gastric pain or vomiting are usually related to the side effects of anticancer or steroidal treatments. These observations should encourage physicians not to ignore nonspecific symptoms such as

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Review  Maines, Caffo, Veccia & Galligioni nausea, vomiting, malabsorption and abdominal pain in PC patients because they are also the presenting symptoms of GI metastases, together with unexplained weight loss, protein-losing enteropathy, jaundice or intermittent occult GI hemorrhaging. GIm-related symptoms are obviously related to the organ in which the metastatic spread occurs. Patients with gastric metastases may present upper GI bleeding, dysphagia, nausea, vomiting, anorexia or abdominal pain. The most frequently described are dyspepsia, nausea and vomiting [41,43–46] , abdominal pain or discomfort [41,44,47] , body weight loss and decreased appetite [41,43] , and weakness [43] ; only a few of the published cases were initially associated with hematemesis [42–43,45] or GI bleeding with melena [42] . Endoscopic findings may vary considerably from gastric ulcerations [42–45] to diffuse linitis plastica-like infiltration [48] or hypertrophic/ prominent gastric folds [41,43,47] . Particular histological features, especially the absence of gastric epithelial dysplasia in pathological specimens and peculiar immunohistochemical staining, are also helpful for a timely diagnosis. Peritoneal metastases may give rise to peritoneal carcinomatosis or ascites which, if severe or massive, can lead to respiratory distress [59] , intestinal subocclusion due to abnormal intestinal motility, nutritional deficit or obstructive and often life-threatening nephropathy [59] . Symptomatic pancreatic metastases may lead to pain or biliary signs, but traditional CT imaging can also detect pancreatic lesions in asymptomatic patients. Lower GI bleeding, body weight loss, nausea, vomiting and abdominal pain are usually the presenting symptoms of rectal metastases. Treatment & prognosis In most of cases, the treatment of GIm from prostate cancer is mainly supportive and palliative, and is aimed at improving symptom control in symptomatic patients or at delaying the onset of symptoms or complications in those still asymptomatic and the patients’ quality of life. However, a promptly diagnosis of GIm, also with aggressive examinations, is desirable also in patients affected by advanced disease because it may sometimes result substantial changes in the therapeutic approach, potentially able to improve disease prognosis. The availability of new therapeutic options such as abiraterone acetate, cabazitaxel, enzalutamide and radium-223

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that have recently demonstrated to significantly improve overall survival in the advanced stages of disease and recent evidences of their potential sequential use [71–73] , further support the importance of a timely diagnosis of progressive disease, also in atypical sites, in order to offer the best treatment option at the right time and in order to avoid unnecessary toxicities or adverse events when a drug has become ineffective. A prompt medical care seems to increase the chance that a disease complication can be successfully treated, sometimes reducing the need of more invasive and expensive medical interventions that not always are recommended in patients with advanced disease and consequently with poor prognosis. The availability of locoregional treatments such as endoscopic insertion of a self-expanding metal stent in patients with malignant intestinal mechanical obstruction or endoscopic cauterization in patients with GI hemorrhage due to GIm, could significantly improve not only symptoms or quality of life but sometimes also the prognosis, although always in a clinical context of palliative care. The possibility of surgery is greatly limited by a number of factors: the patients are frequently old and may have various concomitant diseases; they have an advanced disease which, together with the GIm-related symptoms, has a negative impact on performance status; finally, they usually present metastatic involvement of other organs. Consequently, the treatment that is feasible in this clinical context is not specifically driven by the occurrence of GIm, but has the aim of controlling the disease systemically, an approach that has been favored by the current availability of new agents that are active in CRPC. However, in selected cases, such as patients with oligometastatic disease and good performance status, the timely diagnosis of GIm could support, as in other tumors, a potential role for the surgery of metastases although the clinical useful of this approach in prostate cancer still remains to be confirmed and to prove. The development of visceral metastases is usually considered an unfavorable prognostic event. On the basis of the findings of this review, the occurrence of GIm (which are usually observed in an advanced phase of disease) has the same clinical significance as the occurrence of conventional visceral metastases, although little has been published concerning their clinical course after diagnosis. [5–8]

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Gastrointestinal metastases from prostate cancer  However, it has been reported that one patient with esophageal metastases treated with diethylstilbestrol and tegafur-uracil was still alive and without specific symptoms after three years [36] . The prognosis of gastric metastases is usually poor; the survival of the patients whose outcomes were reported did not exceed 12 months [42–45] . There are no reports of the long-term clinical outcomes of any of the cases of small bowel metastases [49–51] , whereas the only case of a cecal metastasis indicated the presence of stable disease one year after chemotherapy [55] . It has been reported that two CRPC patients with peritoneal metastases showed a good biochemical response to docetaxel [58,59] , with a complete response in ascitic fluid. In another case, androgen deprivation including orchiectomy led to good biochemical and radiographic responses and long-term remission (18 months) [16] . Another patient with peritoneal metastases from PC died within a few months of being diagnosed as having PC, but death was presumably because of other causes [60] . In one case, the prognosis was particularly unfavorable and death

Review

occurred a few weeks after the appearance of massive ascites [57] . Conclusion & future perspective According to the Prostate Cancer Clinical Trials Working Group (PCWG2) guidelines, metastatic sites (visceral metastases vs bone disease with or without nodal metastases vs nodal spread alone) play a key role in classifying advanced PC and reflecting different patterns of disease spread [74] . For these reasons, they strongly recommend reporting outcomes in future clinical trials on the basis of the involved metastatic sites. The presence and sites of visceral metastases have been identified as independent factors predicting overall survival in advanced CRPC patients receiving chemotherapy [75–77] or new generation hormonal therapies after docetaxel failure [78,79] . Moreover, the Phase III clinical trials that led to the FDA approval of sipuleucel-T or abiraterone acetate for the treatment of chemotherapy-naïve patients excluded those with visceral metastases, thus further confirming the prognostic relevance of disease sites

EXECUTIVE SUMMARY The development of GIm in PC patients ●●

The involvement of the GI tract may be due to direct infiltration, lymphatic or hematogenous spread, or intraperitoneal seeding. Direct invasion from adjacent or contiguous abdominal organs is the most frequent mechanism of secondary GI involvement but this should be not classified as metastasis.

The incidence of GIm in PC patients ●●

Autopsy series indicate that the incidence of occult GIm ranges from 4.2 to 13%.

●●

It is difficult to assess the exact incidence of GIm from PC in living patients, but recent observations suggest that it is increasing.

Diagnosis ●●

Improved survival rates have led to more patients with advanced disease undergoing radiological evaluation for the

purpose of disease restaging, thus increasing the likelihood of diagnosing metastases in atypical sites, including the GI tract. ●●

GIm are usually related to advanced disease.

●●

Traditional imaging may detect pancreatic or peritoneal metastases, but not metastatic spread to the gastrointestinal tube where it can only be diagnosed by means of endoscopic examinations.

●●

The most frequent presenting symptoms of GIm are nausea, vomiting, malabsorption and abdominal pain, but

unexplained weight loss, protein-losing enteropathy, jaundice or intermittent occult gastrointestinal bleeding have also been described. Treatment & prognosis ●●

The treatment of GIm is mainly supportive and palliative, aimed at improving symptom control and the quality of life.

●●

The development of GIm is considered an unfavorable prognostic event, and the overall prognosis is usually extremely poor.

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Review  Maines, Caffo, Veccia & Galligioni when designing clinical trials [80,81] . The findings of this review suggest that the behavior and clinical outcomes of visceral metastases in different sites can be heterogeneous, and that there is a need for a more precise definition or classification of visceral involvement. Visceral metastases in atypical sites such as the GI tract are not usually evaluated in prognostic analyses probably because of their low incidence, and this increases uncertainty concerning their real prognostic impact. The heterogeneity of the sites of GIm (stomach, small bowel, pancreas, cecum, rectum or peritoneum), their often different clinical outcomes even in patients with metastases at the same site, and the concomitant presence of other non-GI metastases do not allow any real prognostic quantification. However, the close association between GI metastases from PC and the late phase of CRPC suggests that overall clinical outcomes are poor. References

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O Caffo received honoraria from Sanofi Aventis and Janssen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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Financial & competing interests disclosure

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Papers of special note have been highlighted as: • of interest 1

Although GIm-related symptoms are often related to chemotherapy or progressive disease in patients with a history of PC and new-onset GI symptoms, GIm should be considered in differential diagnosis because they can be detected early after the appearance of symptoms. This is likely to become even more important in the future, when the life expectancy of PC patients may be prolonged by the availability of new drugs that are also active in the early phases of the disease.

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Gastrointestinal metastases from prostate cancer: a review of the literature.

The availability of active new drugs for the treatment of advanced castration-resistant prostate cancer has significantly prolonged overall survival, ...
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