Liver metastases in prostate carcinoma: clinical characteristics and outcome

Authors

  • Damien Pouessel,

    1. Centre Régional de Lutte contre le Cancer Val d’Aurelle, Montpellier, *Clinique Kennedy, Nîmes, and†Clinique du Parc, Montpellier, France
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  • Blandine Gallet,

    1. Centre Régional de Lutte contre le Cancer Val d’Aurelle, Montpellier, *Clinique Kennedy, Nîmes, and†Clinique du Parc, Montpellier, France
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  • Frédéric Bibeau,

    1. Centre Régional de Lutte contre le Cancer Val d’Aurelle, Montpellier, *Clinique Kennedy, Nîmes, and†Clinique du Parc, Montpellier, France
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  • Christophe Avancès,

    1. Centre Régional de Lutte contre le Cancer Val d’Aurelle, Montpellier, *Clinique Kennedy, Nîmes, and†Clinique du Parc, Montpellier, France
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  • François Iborra,

    1. Centre Régional de Lutte contre le Cancer Val d’Aurelle, Montpellier, *Clinique Kennedy, Nîmes, and†Clinique du Parc, Montpellier, France
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  • Pierre Sénesse,

    1. Centre Régional de Lutte contre le Cancer Val d’Aurelle, Montpellier, *Clinique Kennedy, Nîmes, and†Clinique du Parc, Montpellier, France
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  • Stéphane Culine

    1. Centre Régional de Lutte contre le Cancer Val d’Aurelle, Montpellier, *Clinique Kennedy, Nîmes, and†Clinique du Parc, Montpellier, France
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Stéphane Culine, Department of Medical Oncology, C.R.L.C. Val d’Aurelle, Parc Euromédecine, 34298 – Montpellier Cedex 5, France. e-mail: stculine@valdorel.fnclcc.fr

Abstract

OBJECTIVE

To assess the clinical characteristics and outcome of patients with liver metastases in prostate carcinoma.

PATIENTS AND METHODS

From January 1995 to December 2005, 345 patients with metastatic prostate cancer were prospectively recorded in the database of the Montpellier Cancer Centre, France. The clinical characteristics and outcome of 28 patients who developed liver metastases during the course of the disease were analysed.

RESULTS

Six patients had liver metastases as the first site of metastatic disease, and for one of them, liver was the only metastatic site. All but one patient had hormone-refractory disease. Serum measurement of neuroendocrine markers showed increased levels of chromogranin A and neurone-specific enolase in 84% and 44% of patients, respectively. Six patients had a pathological analysis; there were two different histological patterns in liver biopsies, i.e. four were adenocarcinomas with a moderate (one patient) or poor (three) differentiation and two were neuroendocrine carcinomas. Three patients had no treatment because of a poor performance status. One patient had hormone therapy for synchronous liver metastases at diagnosis as the first-line treatment; other patients were treated with chemotherapy. The median (range) overall survival was 6 (1–27) months; the median survival of patients for whom liver was part of the initial metastatic pattern was 14 months.

CONCLUSION

Liver metastases are not very rare but appear to be a rather late event in the course of the disease. They are frequently associated with neuroendocrine characteristics.

Abbreviations
ECOG

PS, Eastern Cooperative Oncology Group, performance status

NSE

neurone specific enolase

CgA

chromogranin A

ALP

alkaline phosphatase

LDH

lactate dehydrogenase

NE

neuroendocrine

IHC

immunohistochemistry

N-CAM

neural cell adhesion molecule

TTF1

thyroid transcription factor 1

ADIC

acute disseminated intravascular coagulation.

INTRODUCTION

Prostate carcinoma remains the second leading cause of cancer deaths in men in Europe and USA. Bone is the most frequent metastatic site, in 83–98% of cases. Visceral locations occur in ≈ 45% of patients and are most often associated with bone metastases [1–4]. Studies of brain and pulmonary metastases from prostate cancer were reported previously [5,6], but no series of patients have been reported to date for liver metastases, to the best of our knowledge. However, in a large autopsy programme including 1589 patients with hormone-refractory prostate cancer, Bubendorf et al.[7] reported 25% had liver metastases, and suggested that liver locations were more frequent when the primary tumour was > 8 cm in diameter. We report the clinical, biological and, when available, histological features of patients with liver metastases from prostate cancer who were managed at the Montpellier Cancer Centre over an 11-year period.

PATIENTS AND METHODS

From January 1995 to December 2005, 345 patients with metastatic prostate cancer were prospectively recorded in the database of the Montpellier Cancer Centre; 28 patients who developed liver metastases during the course of the disease were identified. Six patients had histologically confirmed liver metastases, while 22 had radiological examinations (CT or ultrasonography) only. The following characteristics were collected: age, date of histological prostate cancer diagnosis with Gleason grade, primary treatments, date and site(s) of first metastases, date of liver metastases, other metastatic sites associated with hepatic progression, performance status (PS), serum profile including PSA, neurone-specific enolase (NSE), chromogranin A (CgA), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), haemoglobin and albumin, and type and response to treatments. Patients were assigned a response category based on the WHO standard definitions [8]. Survival was defined as the period from the date of diagnosis of liver metastases to the date of death or last follow-up.

When available, liver biopsies were reviewed by a pathologist (F.B.) for histological and immunohistochemical studies. Liver biopsies were fixed in alcohol-formalin-acetic acid and embedded in paraffin wax. Sections (3 µm) from each case were produced and stained with haematoxylin-eosin for conventional microscopic analysis. For immunohistochemistry, the slides were subjected to heat-induced epitope retrieval by immersing them in a water bath in sodium citrate buffer (pH 6), for 40 min. Immunohistochemistry (IHC) was performed using an autostainer (Dako, Glostrup, Denmark). The following primary polyclonal antibodies were used, with an incubation time of 40 min: CgA, neural cell-adhesion molecule (N-CAM), synaptophysin, cytokeratins 7 and 20, PSA, and thyroid transcription factor 1 (TTF1). Primary antibody was localized using the LSAB® Two Detection System (labelled streptavidin-biotin immunoperoxidase, Dako). Diaminobenzidine (Dako) was used as the chromogen and the sections were lightly counter-stained with haematoxylin.

RESULTS

The median (range) age of the 28 patients at diagnosis of liver metastases was 71 (48–89) years (Table 1). The PS was generally good, with a median (Eastern Cooperative Oncology Group, ECOG, score) of 1 (1–4). Bone was the most frequently associated metastatic site, followed by, respectively, lung, pelvic and retroperitoneal lymph nodes. Six patients had liver metastases as the first site of metastatic disease, and for one of them, liver was the only metastatic site. All but one patient had hormone-refractory disease. Serum measurement of neuroendocrine (NE) markers showed high level of CgA and NSE in 84% and 44% of patients, respectively. Concomitantly eight patients had low (<4 ng/mL) PSA levels. Two patients had an acute disseminated intravascular coagulation (ADIC) at diagnosis of liver metastases.

Table 1. 
The clinical and biological patient characteristics at diagnosis of liver metastases
CharacteristicN (%)
Median (range) age, years 71 (48–89)
ECOG performance status
 1 14 (50)
 2  9 (32)
 3  4 (14)
 4  1 (4)
Associated metastatic sites
 Bone 22 (82)
 Lung 14 (52)
 Pelvic lymph nodes 10 (37)
 Retroperitoneal lymph nodes 10 (37)
 Mediastinal lymph nodes  6 (22)
 Cervical lymph nodes  3 (11)
 Others  8 (29)
PSA, ng/mL
 Normal (<4)  8 (29)
 Elevated 20 (71)
 Median (range) 74 (0–415)
NSE, ng/mL (16 patients)
 Normal (<15)  9 (56)
 Elevated  7 (44)
 Median (range) 12 (0–339)
CgA, ng/mL (19 patients)
 Normal (20–100)  3 (16)
 Elevated 16 (84)
 Median (range)294 (69–12200)
ALP, IU/L (27 patients)
 Normal (91–258)  9 (33)
 Elevated 18 (67)
 Median (range)498 (74–1955)
LDH, IU/L (27 patients)
 Normal (200–480)  7 (26)
 Elevated 20 (74)
 Median (range)645 (296–4137)
Haemoglobin, g/dL
 Normal (13–16) 10 (36)
 Decreased 18 (64)
 Median (range) 11.2 (7.1–15.3)
Albumin, g/L
 Normal (30–45) 25 (89)
 Decreased  3 (11)
 Median (range) 36 (24–42)

At the diagnosis of prostate cancer, all but one patient had moderately or poorly differentiated adenocarcinomas (Table 2). One patient had a small-cell carcinoma of the prostate. Most patients (61%) had metastatic disease and received hormone therapy as primary treatment. The median time to metastatic progression was 14 (0–87) months in patients with localized or locally advanced disease at diagnosis. Bone, pelvic lymph nodes and lung metastases were the most widespread locations, in, respectively, 17 (61%), eight (29%) and eight (29%) patients. Of the 28 patients, 27 had received hormonal therapy, with a median of 2 (1–7) courses. Eleven (39%) patients had been treated with chemotherapy for metastatic hormone-refractory disease. Eight had received one course of chemotherapy, and three a second-line protocol. The median time from initial diagnosis to liver metastases was 38 (0–160) months, and the median time from occurrence of first metastases to liver metastases detection was 17 (0–85) months.

Table 2. 
Patient characteristics and treatments before liver metastases
CharacteristicN (%)
Histology
 Adenocarcinoma27 (96)
 Small cell carcinoma 1 (4)
Gleason score (25 patients)
 4 2 (8)
 5 1 (4)
 6 5 (20)
 7 6 (24)
 8 5 (20)
 9 6 (24)
Status of disease at diagnosis
 Localized11 (39)
 Metastatic17 (61)
Initial treatment
 Prostatectomy 2 (7)
 Radiotherapy 3 (11)
 Hormonal therapy and radiotherapy 6 (21)
 Hormonal therapy17 (61)
First metastases sites
 Bone17 (61)
 Pelvic lymph nodes 8 (29)
 Lung 8 (29)
 Liver 6 (21)
 Retroperitoneal lymph nodes 6 (21)
 Mediastinal lymph nodes 3 (11)
 Pleura 1 (4)
Mean time since diagnosis, months14
Hormone therapy27 (100)
Type
 Orchidectomy 1 (4)
 LHRH agonist27 (100)
 Antiandrogen26 (96)
 Oestrogen 5 (19)
 Estramustine phosphate 7 (26)
Number of courses
 1 7 (25)
 2 8 (29)
 >313 (46)
Chemotherapy 11 (39)
 Docetaxel/cisplatin 5
 Docetaxel 2
 Mitoxantrone 2
 Others 5

For the six patients who had liver biopsies, the initial diagnosis of prostate cancer had revealed moderate or poorly differentiated adenocarcinoma. There were two different histological patterns in liver biopsies after microscopic analysis: four were adenocarcinomas with a moderate (one patient) or poor (three) differentiation and two were NE carcinomas, one of which was poorly differentiated, with a small- cell carcinoma pattern. For IHC, all adenocarcinomas were positive for PSA, whereas none of the NE carcinomas expressed PSA. Conversely, NE tumours expressed specific markers such as synaptophysin, CgA or N-CAM. Notably, CgA was detected in only one case of NE tumour and TTF1 was positive in the poorly differentiated NE component. The other biopsy characteristics are shown in Table 3.

Table 3. 
Pathological analyses of liver metastases
FeaturePatient
123456
  1. AC, adenocarcinoma; −, negative; +, positive; F, focal staining.

HistologyACACACNEACNE
IHC:
 CgA+
 PSA++ (F)+ (F)+
 N-CAM++ (F)
 Synaptophysin++
 Cytokeratin 7+ (F)+ (F)
 Cytokeratin 20+ (F)
 TTF1+

Three patients had no treatment because of a poor PS (Table 4); one had hormone therapy for synchronous liver metastases at diagnosis as the first-line treatment, and the other patients were treated with chemotherapy. A platinum salt was included in first-line chemotherapy in 13 patients. A median (range) of 4 (1–11) cycles per patient was delivered, with seven (29%) partial responses. One patient who had prompt resolution of ADIC after docetaxel and cisplatin was reported previously [9]. There were few responses subsequently, and the median overall survival from the time of liver metastases was 6 (1–27) months. Two patients remained alive with progressive disease at the time of analysis; 24 patients died from disease progression, and two died from causes other than carcinoma, the first after a stroke attack and the second after an acute pulmonary oedema. There were no treatment-related deaths.

Table 4. 
Chemotherapy for liver metastases
CharacteristicNumber of patients
First-lineSecond-lineThird-line
Total25133
Docetaxel/cisplatin 9 00
Docetaxel 3 10
Etoposide/carboplatin 4 30
Doxorubicin 2 01
Mitoxantrone 2 20
Others 5 72
Median no. of cycles 4 33
Disease response:
 Partial 7 20
 Stable disease 4 00
 Progressive disease13113
 Not assessable 1 00

DISCUSSION

Despite the absence of published clinical data liver metastases of prostate cancer are not very rare. In our experience, 28 (8%) patients developed liver metastases during the course of the disease among 345 patients who were managed at the Montpellier Cancer Centre over an 11-year period. This total appears rather lower than in autopsy studies which reported liver metastases rates of 7–48% of patients, while bone then lung were the most frequent sites of metastases [4,7,10–12]. An initial reason explaining this difference could be that autopsy series included cases with microscopic metastases that are not detectable by ultrasonography or CT. A second explanation is the currently greater use of imaging in patients with hormone-refractory prostate cancer. In agreement with this hypothesis is that liver metastases were diagnosed in most of the present patients (22, 78%) after 1999. The influence of the stage migration with time was also reported by Fabozzi et al.[6] in a retrospective review dealing with pulmonary metastases from prostate cancer. A third hypothesis is related to the improved efficacy of systemic treatments, especially chemotherapy, which improves the median overall survival of patients with hormone-refractory prostate cancer [13,14]. Liver metastases occurred late in the course of the disease in most patients, as all but one were hormone-refractory. Also, 11 (39%) patients had received at least one course of chemotherapy. The short median overall survival of 6 months in the present series could be related to the late diagnosis of liver metastases rather than to the specific aggressiveness of this anatomical site. Indeed, the median survival (14 months) of the six patients for whom liver was part of the initial pattern of metastases was grossly similar to that expected with bone metastases, using standard chemotherapy in hormone-refractory disease.

Notably, the pathological analysis of liver metastases revealed a NE pattern in two patients. If the history of prostate cancer was unknown or not specified, pure NE features on liver metastases might represent a challenge for the pathologist, especially when serum PSA levels are not high. Obviously a multidisciplinary approach is required to avoid unnecessary ancillary investigations. The NE pattern is in agreement with the concept of progression from normal prostate to adenocarcinoma and finally to small-cell carcinoma during prostatic tumorigenesis [15]. As the other four patients with liver biopsies had an adenocarcinoma pattern, it is not possible to conclude that the development of liver metastases is related to the NE differentiation of the disease. However, the phenotypic heterogeneity of end-stage metastatic prostate cancer has been highlighted in autopsy studies [4,12]. Therefore it cannot be excluded that NE components could have been detected in other metastatic sites in these patients. In agreement with this latter hypothesis is the high percentage (84%) of patients with supranormal serum CgA levels, as CgA has been shown to be the optimum marker reflecting NE differentiation in patients with prostate cancer, although several diseases, e.g. renal impairment, or drugs, e.g. proton-pump inhibitors, could falsely affect the CgA levels [15–17].

In conclusion, liver metastases from prostate cancer are not very rare but appear to be a rather late event in the course of the disease. They are frequently associated with NE characteristics. In chemotherapy-naive patients, the occurrence of liver metastases does not seem to alter the overall prognosis.

CONFLICT OF INTEREST

None declared.

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