Isolated peritoneal carcinomatosis in prostate cancer: from a successful hormonal management to a review of the literature

Metastases from prostate cancer involve mainly the bone compartment. However, visceral metastases are found in up to 49% of metastatic patients, occurring mainly in late stages of the disease, and are correlated with poor outcome. Peritoneal carcinomatosis is rarely described in literature, particularly when not associated with other distant metastatic lesions. We present the management of a patient with prostate cancer progressing on androgen deprivation therapy with description of omental involvement on 68Ga PSMA-PET. There was no ascite or other distant lesion, reflecting thus a specific tropism of the cancer in this patient who had no history of prostate surgery. Abiraterone acetate resulted in a long-lasting complete response. We also present a review focusing on this entity.

frequency is probably underestimated in clinical practice due to the poor sensitivity of conventional imaging such as abdominal CT to detect early stages of omental implants [7,8].
The mechanism of this metastatic evolution is not clearly understood, even if some authors proposed iatrogenic spread following prostate surgery. Many questions remain unanswered concerning the prognosis of this entity as well as its optimal management. We report the case of a patient with PC and isolated peritoneal carcinomatosis, without bone or lymph node metastases and no history of previous surgery. Abiraterone acetate resulted in successful long-lasting control of the cancer.

Case presentation
In 2009, a 64-year-old man was diagnosed with a PC based on prostate specific antigen (PSA) increase (117 ng/l). He had no relevant medical history except a tobacco-related obstructive broncho-pneumopathy; he did not describe any surgical history. Abdominal CT confirmed locally advanced PC with seminal vesicles and bladder invasion but without any evidence of lymph node or intra-abdominal anomaly ( Figure 1A). Biopsy showed a moderately differentiated Gleason 7 (4 + 3) score with perineural infiltration (Figure 2A). Bone scan, thoracic CT and axial skeletal MRI did not show any secondary lesion ( Figure 3). No pelvic MRI was performed at this time due to the fact that bladder invasion was clearly demonstrated on CT scan and that local treatment was not proposed first. The tumor was thus classified as T4 N0 M0 based on these imaging modalities. Due to the high value of PSA and the high risk of occult metastatic lesions, we first started androgen deprivation therapy (ADT) (leuproreline) that rapidly decreased PSA value after 1 month (25 ng/l); PSA continued to decrease and reached a value of 7 ng/l after 12 months. At this time, the thoraco-abdominal CT showed a regression of the primary tumor and of the bladder infiltration ( Figure 1B). The pelvic MRI further did not show any any suspect lymph node ( Figure 4); bone scan did not demonstrate any suspect distant lesion, as well as axial skeletal MRI. Radiotherapy (78 Gy on prostate area including the bladder infiltration location) was then performed; lymph nodes were also involved in the irradiated area (46 Gy) due to the high PSA level and the important local infiltration. This treatment, combined with ADT, resulted in PSA normalization (<0.2 ng/l) 6 months later. Leuproreline was stopped in March 2012.
In 2014, PSA level raised progressively to 2.2 ng/ml with a PSA doubling time of 3 months. Bone scan and thoraco-abdominal CT did not reveal any suspect lesions; no modern imaging such as 68 Ga PSMA-PET or wholebody MRI was done as it was not easily available. The very short PSA doubling time led us to start ADT (degarelix) that resulted in a rapid normalization of PSA after 3 months (<0.2 ng/l). PSA remained unchanged for 2 years but in 2016, it showed a rapid increase to 12 ng/l, reflecting development of castration resistance. Bone scan and thoraco-abdominal CT were considered as normal but 68 Ga PSMA-PET showed five peritoneal infra-centimetric lesions without any other suspect lesions in bone or in lymph node. Based on 68 Ga PSMA-PET imaging, peritoneal implants were retrospectively visualized on the synchronous abdominal CT ( Figure 5) but not on the previous ones including the abdominal CT of the diagnosis. In order to exclude false positive lesion on 68 Ga PSMA-PET, we decided to perform laparoscopic exploration that showed multiple suspect lesions in the peritoneal cavity; histology confirmed prostate adenocarcinoma without neuroendocrine, mucinous or small cell differentiation ( Figure 2B). Abiraterone acetate (1000 mg daily + prednisone 10 mg daily) was initiated and PSA level rapidly decreased to 0.4 ng/l in 3 months and to 0.01 ng/l after 6 months. Treatment was well tolerated without any toxicity. Peritoneal lesions disappeared on abdominal CT. Three years later the patient remains in radiological complete remission and with undetectable PSA.

Figure 5. (A) PSMA-PET showing peritoneal implant (arrow). (B)
Abdominal computed tomography that was performed on the same time and that initially misdiagnosed these peritoneal implants due to its very small size (arrow).

Discussion
Peritoneal carcinomatosis is very rarely described in PC, particularly when isolated and not associated with other distant lesions, reflecting a potential specific way of dissemination and/or a specific tropism.
In this patient, peritoneal carcinomatosis was isolated; bone and other extra-abdominal synchronous macrometastases were excluded by combining conventional imaging (bone scan and thoraco-abdominal CT) and modern imaging ( 68 Ga PSMA-PET) suggesting that peritoneal cavity was the preferential and first homing in this patient. The mechanism of dissemination remains of course unknown. Some authors postulated iatrogenic spread following laparoscopic surgery and port-site metastases (Table 1). Our patient did not have previous prostate surgery, suggesting lymphatic or hematological dissemination. Although the primary tumor was locally advanced and invaded bladder wall, there was no direct peritoneal invasion visualized on first abdominal CT, on the 12-month pelvic MRI, on the 68 Ga PSMA-PET and at laparoscopy. Few cases report similarly isolated peritoneal carcinomatosis occurring in patient without history of prostate surgery (Table 1); among the 13 patients with available data, 9 patients had a Gleason score >7 at initial cancer histology, including one patient with neuroendocrine differentiation, suggesting that these aggressive variants could be associated with development of omental involvement.
Peritoneal carcinomatosis was diagnosed at a very early stage with 68 Ga PSMA-PET, before the apparition of ascites or symptoms. Conventional imaging such as CT initially misdiagnosed peritoneal involvement and could thus in clinical practice result in delay in diagnosis, explaining the low frequency of nonascitic peritoneal carcinomatosis reported in literature. When analyzing the patients from Table 1, among the ten nonascitic patients, four patients were diagnosed with modern imaging ( 68 Ga PSMA-PET, PET-Choline or MRI) [9,26,27,33] and four were diagnosed incidentally during surgery [10,13,25,26]. The increasing use of modern imaging such as 68 Ga PSMA-PET will probably allow more frequent atypical metastatic localization at early stage of development.
It remains unknown whether omental carcinomatosis should be considered as a poor prognosis factor. The majority of cases were treated with ADT ± docetaxel with, in some patients, biological and radiological response. Only four patients have been treated with new generation hormonal agents (three with abiraterone acetate and one with enzalutamide) with description of response without any precision in outcome [26,[31][32][33]. In our patient, due to the prior sensitivity to ADT (biological response lasting more than 1 year), we started abiraterone acetate that resulted in rapid decrease of PSA and long lasting complete radiological response for more than 4 years.
Limitation in our interpretation includes the absence of pelvic MRI and 68 Ga PSMA-PET at diagnosis and at biochemical recurrence (unavailable in current practice in 2009 and 2014). We cannot exclude presence of metastases (bone and/or omental) that could have initially regressed with ADT and led to emergent clones with particular tropism for omental compartment. Whether a delayed diagnosis of this carcinomatosis would had led to similar outcome remains also unknown; however, this case highlights the role of modern imaging in detecting early stage of such potentially complicating metastases. It also opens discussion concerning potential and unknown dissemination ways and specific tropism of PC cells.
To our knowledge, we are the first to demonstrate a such successful long-term response with abiraterone acetate in this entity.

Conclusion
Peritoneal carcinomatosis is rarely described in PC, particularly when not associated with other metastatic lesions. In this case, we describe the role of 68 Ga PSMA-PET in allowing detection of peritoneal metastases at early stage and the successful response to abiraterone acetate.

Future perspectives
The management of PC is significantly improving with new drugs and new strategies. The better understanding of the PC pathogenesis helps to develop new targeted therapies, increasing the treatment options and offering tailored strategies. New imaging modalities such as metabolic imaging also allow better stratification of cancer, which can improve early management of patients. Improvement in genomics will also help to predict patients at high risk of resurgence in order to improve their follow-up.

Executive summary
• Visceral metastases are frequently observed in prostate cancer (PC), mainly in late stages of the disease.
• Atypical presentation such as peritoneal involvement can occur in PC and could be isolated. This peritoneal involvement can occur regardless of previous surgery on PC. However, some authors have presented case series highlighting the potential relationship with PC surgery. • Modern imaging approaches such as 68 Ga PSMA-PET allow early and accurate stratification of PC.
• Abiraterone acetate is a new hormonal agent improving the outcome of patients with metastatic PC.
Abiraterone acetate was shown to be efficient in peritoneal carcinomatosis from PC, resulting in long-lasting complete response. • Even in the case of initially locally advanced cancer, radical treatment should be offered to any patient, as prognosis is drastically improved with new therapeutic strategies and in order to prevent local complications.