Retroperitoneal Sarcomas Represent
Retroperitoneal sarcomas represent less than 1% of all adult cancers which make them extremely rare, with just 73 cases identified in our center from January 2007 to December 2013. Patients are most commonly diagnosed within the sixth decade of life, with an equal sex distribution. Median tumor size is 15-20cm (16 – 2 a 4).
RPS comprise a spectrum of histological types/subtypes with distinct biologic behaviour. Liposarcomas account for 40-50% of all RPS in large series (16 – 2 a 6 ), which is similar to our results with a prevalence within the period from 2007 to 2013 of 50%. Retroperitoneal liposarcomas are typically either of the well-differentiated/dedifferentiated subtype. Well-differentiated liposarcomas recur locally but not distantly. Dedifferentiated liposarcomas have a higher early risk of local recurrence (within two years), but have an equivalent long-term cumulative risk of local recurrence compared with the well-differentiated liposarcoma (16 -8/9). Dedifferentiated liposarcomas can also spread to distant sites. Leiomyosarcomas are the second most common histologic type of RPS and can arise from major vessels like the inferior vena cava, with almost all leiomyosarcomas being high grade. The disease-specific survival (DSS) for patients with high grade leiomyosarcomas is almost identical to those with dedifferentiated liposarcomas, but with a lower rate of local recurrence (LR) and higher rate of distant metastasis (DM). There are also two less frequent subtypes, such as the malignant peripheral nerve sheath tumors (MPNST), constituting up to 5% of RPS  (16-3,6) that can arise from Schwann cells and solitary fibrous tumors (SFT), formerly known as hemangiopericytomas, comprising approximately 5% of RPS (16-3,6).
In what concerns to the clinical presentation, RPS often presents as an asymptomatic retroperitoneal mass or as an incidental discovery in imaging studies (16-3). When the tumor is symptomatic, usually it is due to the compression of adjacent abdominal structures like the bowel, high calibre veins and/or nerve leading to abdominal discomfort, early satiety, weight loss or bowel obstruction, leg swelling and lower extremity pain or weakness, respectively. In a series of 500 patients  (16-3), 80% of patients presented an abdominal mass, 42% with lower neurologic symptoms and 37% with pain.
LR, rather than distant recurrence (DR), is the major postoperative oncological concern because of the anatomical restraints of the retroperitoneum and the large size of tumors, with around 75-80% of patients dying from the local recurrence. (9) LR is extremely frequent with a 5-year LRR that varies from 44 (9-8) to 85% (9-1). On the other hand, the rate of occurrence of distant metastasis at 5 years is only 13-20%. (11). However, in this case, a G3 pleomorphic liposarcoma, distant metastasis should be a concern in the follow up of this patient, particularly through hematogenous spread. Overall survival (OS) is still low but has increased along the last decades. 5-year OS ranges from 47% to 70% and median overall survival ranging from 45 to 60 months. [14–22] (13-8-16).
Failure to recognize RPS on imaging may lead to inappropriate management. Thus, contrast-enhanced computed-tomography (CT) is the most useful primary imaging investigation, allowing confirmation of site and origin of the mass and often tissue composition (22). Since grade is one of the most important prognostic factors, a histological diagnosis must be established, therefore image-guided percutaneous coaxial core needle biopsy is the most accurate diagnostic modality and since it is safe and reliable should be encouraged unless imaging is pathognomonic and if no preoperative treatment is planned.  (22).
Regarding this, staging stands as an important step for the management of RPS. The 7th edition of the American Joint Committee on Cancer (AJCC) TNM classification was derived from the analysis of soft tissue sarcoma, with some authors questioning its applicability because it does not include histologic type or subtype. [19, 24, 25](16-23, 26-27) However, the 8th edition of the AJCC Cancer Staging Manual endorses finally normograms to predict postoperative survival and DSS for patients with RPS  (25-23 e AJCC).
Quality of surgery is so far the only treatment-related factor that has been proved to exert a strong influence on the oncological outcome and every effort should be made to optimize it. (4) In the case we present, the quality of the first surgery may has certainly compromised outcomes and prognosis, but it is hard to determine to which extent. Complete gross resection is a clear predictor of DSS and should be the therapeutic goal of surgical therapy.  (16-5) Recent literature has posited that a frontline extended surgical approach including removal of all adjacent organs in conjunction with the primary tumor is a critical strategy to obtain increased rates of R0 resection and improve local control and subsequent prognosis. [8, 29](16-6-8), what did not happen in the case we present.
Bonvalot et al. (fonte?????) stated that R0 status was associated with decreased abdominal recurrence and improved OS, but there is still no consistent link between the margin status and the OS. However, this trend should not be applied to every single subtype of RPS, including the case we just present (Grade III dedifferentiated liposarcoma) in which the additional morbidity of extended resections may not be of benefit in patients with high rates of death from metastatic disease. This demonstrates again the importance of a multidisciplinary decision and also the importance of a preoperative histological diagnosis since it is already known that different histological subtypes have different biological behaviours which can modify the therapeutic strategy to adopt.
Regarding the low volume of this specific type of tumors, individual hospitals and surgeons usually manage very few cases (19-13). Considering the highly variable biological behaviour of each histological type among the retroperitoneal sarcomas, it has been suggested that RPS should only be managed at high-volume centers (19-12). Hospital volume was an independent factor of surgical management, R0 resection and R0/R1 resection. Patients treated at high-volume centers (defined as hospitals in the top 10th percentile for volume in a 3141 RPS cases from the National Cancer Database, with a median annual volume of 19.4 cases) had 1.9-fold higher odds of undergoing surgical management and 1.8-fold higher odds of an R0 resection. Also, high-volume hospitals were more likely to employ neoadjuvant radiation. Despite the improvement in surgical outcomes related to high-volume hospitals, they failed to confer a statistically significant OS benefit on RPS patients, maybe due to insufficient follow-up (19). This database lacks surgeon-specific identifiers which could help to characterize the importance of surgeon volume versus hospital volume on outcomes, but some evidence suggests that in what concerns to radical cystectomy, volume-outcome seems to be more dependent of hospital rather than surgeon volume  (19-22), but this can be highly dependent on the outcome of interest. The level of specialization of the surgeon seems to be an important prognostic factor that has shown to influence complete surgery, locoregional relapse and abdominal sarcomatosis in multivariate and univariate analysis in a multicenter analysis of the French Sarcoma Group.  Moreover, since the management of RPS is a multidisciplinary team work, surgeon volume analysis can also overestimate surgeon’s influence on outcome. Radiation oncologist volume and pathologist volume and its impact on outcomes needs to be studied.
Nathan et al , in an analysis of 1365 RPS form the SEER database found that tumor size was not predictive of a worse prognostic.
An extended compartmental resection how it is nowadays proposed requires very often resection of multiple organs (such as kidneys, pancreas, colon, spleen, etc), vascular structures (such as the inferior vena cava, iliac vessels and some major or minor vascular structures) and other structures and tissues (psoas muscle, for example) but there is an absence of literature on whether to resect one and/or another structure in case of involvement in order to obtain a wider negative margin. Again, not only the importance of the oncological surgeon specialization should be considered but also surgeons from other fields/systems (in this case, vascular surgeons and urologists).
In what concerns particularly to vascular structures there are also no standard algorithms about reconstruction of a specific vessel when its resection was performed or even about the best techniques to perform it.
The OS of patients with RPS with secondary vascular involvement is not affected by the need for vascular resection or by the surgical morbidity. In all the retrospective series, major vascular resection for RPS has increased morbidity. In a series of 249 patients with primary RPS retrospectively analysed, morbidity was not substantially affected in resections of three or fewer organs but increased in resections of more than three organs. Three of the patterns of resection were associated with an increased risk for severe adverse events as follows: vascular resection, pancreaticoduodenectomy and the combination of colon, kidney, spleen and pancreas. Surprisingly, no association between surgical morbidity and long-term oncological outcomes was observed.  (24-6).
The secondary involvement or encasement of the aorta wall or iliac arteries (like in the case we present) is much more common than a primary sarcoma of the aorta, for example. When an arterial resection is necessary, primary anastomosis is rarely feasible due to the length of the resection. Arterial reconstructions are usually performed using synthetic prostheses in an anatomic position. In the present case, there was a need to perform a femorofemoral cross-over bypass.
The surgical reconstruction of the IVC is still controversial. The criteria for the decision of reconstruction are not defined yet. However, the major factor influencing the need for vascular replacement when a complete resection is necessary is the presence of a well-established collateral venous system and it is important to preserve these vessels. Other factors that are considered before taking a decision of performing a vascular resection are distant metastasis, performance status, renal function, evaluation of cumulative visceral resection and risk for mortality. In many cases, however, the tumor is only pushing against major vessels and its resection in order to obtain clear margins maybe increases its risks more than its potential benefits, stressing again the need for a multidisciplinary management. It should be considered that a vascular adventitia may prevent better a LR than a margin of fat. There is no indication that a systematic vascular resection strategy would increase the local control and, ultimately, the overall survival. On the other hand, the advantages of not reconstructing the IVC are that pulmonary embolism following thrombosis of the prosthesis is prevented and that it results in no potential lifelong anticoagulation complications or graft infection. (24+24,16).
When it comes to LR involving major vessels, a vascular resection strategy is usually restricted to candidates that present low grade tumors, good performance status, long duration between the primary tumor and LR and possibility of a complete resection. (24)
In addition to surgery and despite the fact that it is so far the only treatment with chances of cure, there are other therapeutic options that when combined with surgery seem to improve local control, namely radiotherapy.
Radiotherapy latu sensu is a term that gathers essentially different techniques of administration and also different points in time when it is administered in the management of a patient with cancer. Several trials on this particular topic have already been published but there is still need of a prospective randomized multicenter trial that compares different types of radiotherapy combined with surgery versus surgery alone and its impact in different outcomes such as LR and OS.
Furthermore, in this case we may admit that the lack of specialization of the first center may not have considered preoperative (neoadjuvant) radiotherapy, which apparently seems to be effective when combined to surgery according to several retrospective trials and has also shown some advantages when compared to postoperative radiotherapy.
Some of its advantages of the preoperative radiotherapy are the following (3):
1. Preoperatively, the gross tumor volume can be more precisely defined on the CT images with smaller safety margins. Potentially the tumor can be downsized with RT (by devitalisation of tumor cells) to facilitate surgical resection.
2. The tumor displaces adjacent normal tissues out of the high-dose region thereby minimising RT-related toxicities of adjacent of radiosensitive organs  (3-13)
3. Prior to surgery, the tumor is better oxygenated and RT is probably more effective in killing neoplastic cells.
4. The tumor is treated in situ thereby reducing risk of peritoneal seeding at the time of surgery.
5. Due to the lower incidence of surgical adhesions, higher doses can be delivered to the tumor bed preoperatively. On the contrary, postoperative radiotherapy may be problematic or hazardous in patients with small bowel adhesions.
6. May avoid treatment delay due to postoperative complications. (3)
On the other hand, it is argued that preoperative radiotherapy may delay surgery which is the only treatment with a curative intent. Radiotherapy can improve local control and LRFS but it has shown to improve OS when combined in surgery just in some trials but not all of them. Radiotherapy (apparently preoperative) when combined with extended surgery with negative margins is the therapeutic combination that has shown the best results so far.
Chemotherapy emerges as another therapeutic line available. However, its apparent efficacy is largely based on randomized trials and meta-analysis where the primary sites were the extremities. Very few patients with RPS were included in the RCTs and RPS may have a unique biology and response to treatment compared to sarcomas at other sites. To sum up, the use of chemotherapy has not been conclusively shown to provide significant downsizing or benefit in RPS. (16)
Regarding the low frequency of this specific kind of tumors and the specific behaviour of each histological type among the retroperitoneal sarcomas, it is important that all the patients diagnosed in a country level should be only managed and followed up in the smallest number of centers possible otherwise surgeons of these centers will not acquire the expertise required to manage such specific tumors.
The rarity of RPS, especially in a small country, makes it especially difficult to standardize the management procedures of these patients. Moreover, due to the mentioned reasons there is a lack of prospective, randomized trials on how to choose between therapies available other than surgery. Until now no other treatment besides surgery has proven to be effective to cure these patients. Since most patients die from local recurrences of the primary tumor, there is now a bigger consensus on how surgery should be. Extended compartment resection instead of piecemeal resection, which includes resection of non-invaded adjacent organs or other structures has proven to be the best strategy to achieve microscopically negative margins and thus reducing LR and increasing OS. However, despite the good results achieved by this strategy, some critics questioned the criteria to choose why some surrounding structures were resected while others were not [40–42](17-21,22). Our center (Centro Hospitalar Lisboa Norte) is one of the five portuguese reference centers for Soft Tissue Sarcomas.
For RPS, as previously mentioned, prospective studies that unequivocally define the optimal extent of surgical resection establish the need for RT and clarify the ideal sequencing of radiotherapy, are lacking. The American College of Surgeons Oncology Group (ACOSOG) started a phase III randomized trial that compared preoperative RT and surgery with surgery alone. Unfortunately, the trial had to be prematurely closed due to poor accrual. This subject is currently being studied in a randomized, controlled trial through the European Organization for the Research and Treatment of Cancer (EORTC), the STRASS Trial (NCT 01344018), which is accruing well, with excellent international collaboration and which, if completed, will significantly advance our approach to RPS. Preliminary results are expected by late 2018 to early 2019.  (17) Clearly, one of the key factors in addressing the unanswered questions in RPS management and advancing our approach to this disease will be the support and initiation of additional clinical trials. (2)(8). The trials now available are retrospective which is associated with several limitations and selection bias is one of them. Since there is an absence of high evidence level literature and since there is no consensus on some therapies available and no standardized procedures, there is still enough flexibility and room for experts’ opinions. Taking this into consideration, a multidisciplinary approach is of utmost importance. The case we present is an example of how the composition of the multidisciplinary meeting can change from patient to patient, from tumor to tumor.
Even though vascular surgeons and urologists were not present at the first meeting, the invasion of vascular and urinary tract structures by the tumor, their opinion should be taken into consideration. Additionally, there is recurrent need for major reconstruction of structures and other specialties are required. In the present case, due to the involvement of the right iliac vessels by the tumor, a femorofemoral bypass was performed by the vascular surgeon and a also a ureterostomy was performed by the urologists.
In what is related to follow up, again there is some data lacking on how often physicians should follow patients. Nevertheless, the National Comprehensive Cancer Network (NCCN) guidelines recommend physical exam and CT scan of the abdomen and pelvis every 3-6 months for two years, then annually. Chest CT should be added for those patients with high grade tumors, since there is also a bigger risk of distant metastasis in those cases. (16-75) Different national and international cancer institutions suggested similar but still slightly different approaches. A recent review by Zaidi et al  (25), in which different international guidelines were taken into consideration, authors argued that since different histological subtypes have totally different natural histories as well as distinct patterns of recurrence, tumor-specific, tailored surveillance strategies are essential and a closer monitoring for locoregional recurrences in WD/DD-LPS and for distant metastasis in DD-LPS and LMS is suggested. It was raised awareness about the risk of radiation from frequent CT scans in younger patients with some arguing that MRI should be the modality of choice to assess local recurrence in abdomen and pelvis.(25). Furthermore, since management of these patients should be done in a reference center, this should be the standard in what concerns to follow up.