Expert Review of Anticancer Therapy
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Personalizing surgical margins in retroperitoneal sarcomas Dario Callegaro, Marco Fiore & Alessandro Gronchi To cite this article: Dario Callegaro, Marco Fiore & Alessandro Gronchi (2015) Personalizing surgical margins in retroperitoneal sarcomas, Expert Review of Anticancer Therapy, 15:5, 553-567 To link to this article: http://dx.doi.org/10.1586/14737140.2015.1028375
Published online: 23 Mar 2015.
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Date: 20 January 2016, At: 15:04
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Personalizing surgical margins in retroperitoneal sarcomas
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Expert Rev. Anticancer Ther. 15(5), 553–567 (2015)
Dario Callegaro, Marco Fiore and Alessandro Gronchi* Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian, 1 – 20133 Milan, Italy *Author for correspondence: Tel.: +39 022 390 3234 Fax: +39 022 390 2404 [email protected]
Retroperitoneal sarcomas are a group of diseases that behave differently from one another. Well-differentiated liposarcomas have an indolent biology but show a tendency to recur locally even years after primary resection. Dedifferentiated liposarcomas are characterized by a very high local recurrence risk, while the metastatic risk mainly depends on the histological characteristics of the dedifferentiated component. In leiomyosarcomas, hematogenous spread informs prognosis while local recurrences are far less common. Surgery is the cornerstone of treatment of all retroperitoneal sarcoma subtypes and its quality is the only treatment-related factor able to improve the oncological outcome. A frontline extended surgical approach is all the more critical in subtypes in which local control directly impacts prognosis. KEYWORDS: leiomyosarcoma . liposarcoma . outcome . prognosis . retroperitoneal sarcoma . sarcoma . solitary fibrous tumor
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surgery
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surgical margins
Adult soft tissue sarcomas (STS) are a group of rare diseases that account for 50 subtypes of soft tissue tumors, each with a specific presentation, biological characteristics and clinical behavior. Moreover, among STS, the same histotype may carry a completely different risk depending on the anatomical location. Retroperitoneal sarcomas (RPS) are a unique entity in the world of STS precisely because of the specific anatomy of the retroperitoneum. They arise close to vital structures in an anatomical compartment that is not readily accessible to both medical examination and surgical exploration. The typical presentation is that of a large mass encasing, invading or displacing adjacent organs. The diagnosis is usually made on the basis of long-standing
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10.1586/14737140.2015.1028375
vague symptoms or accidentally during radiological examinations of the abdomen. Although several different histotypes may arise in the retroperitoneum, four well-defined histological subtypes (well-differentiated liposarcomas [WDLPS], dedifferentiated liposarcomas [DDLPS], leiomyosarcomas [LMS] and solitary fibrous tumors [SFT]) account for about 80% of all RPS patients. Complete surgical resection is the only potentially curative treatment for localized disease. However, the high rate of postoperative recurrence (40–50% at 5 years) remains a major challenge. While in STS of the extremities there has been a growing tendency to decrease surgical aggressiveness, reducing the number of amputations, there has been a somewhat opposite trend in the retroperitoneum: achieving a safer margin at the price of resecting adherent structures is proving to be a crucial issue in maximizing the chances of cure. Moreover, while in the extremities indolent histological subtypes can be readily managed with limited resections, there are no ‘less risky’ histologies in the retroperitoneum since lowgrade tumors also carry a substantial risk of local recurrence (LR) and death, albeit, over a longer time period. The standard example of
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Callegaro, Fiore & Gronchi
atypical lipomatous tumor and WDLPS, a single biological entity with two different names according to the site of origin, as this dominates its outcome is: the former occurring in the extremities and trunk wall is never fatal; the latter occurring in the deep trunk (e.g., retroperitoneum) is often fatal especially on the longer run [3]. In the last 5 years, we and others have advocated the need for more extended surgical policies in RPS. Although a consensus on how far the surgeon should extend the resection has not yet been reached in the surgical community, tumor resection en bloc with adherent structures/organs to minimize marginality was included as the standard treatment in the latest edition of the European Society for Medical Oncology guidelines [4]. The role of adjuvant/neoadjuvant treatments in reducing the systemic and local risk of recurrence remains controversial. Radiotherapy is an option, especially in the preoperative setting, to potentially improve the chance for local control, but its role is far from being established [5]. It is presently under investigation in a large international European Organization for Research and Treatment of Cancer (EORTC)-led randomized trial [6]. Chemotherapy may be offered in high-grade tumors and histologies at higher risk of systemic spread, although no prospective evidence of efficacy is available to date. The surgical, oncological and pathological skills required in the management of RPS should lead patients to be referred to high-volume centers, where a dedicated multidisciplinary team can offer the best diagnostic and therapeutic chances. In this review, we will go through the concept of appropriateness of the surgical margins in RPS and discuss whether surgical policy should be tailored to the specific tumor of the specific patient. Lessons from STS of the extremities: the concept & role of surgical margins
The critical role of the surgical procedure in determining the prognosis of STS patients was primarily investigated in extraabdominal tumors. The question ‘how wide do I need to resect to be adequate?’ has been discussed in the surgical community for over 40 years without finding a simple answer, even today. Resection of the tumor with clear (R0) margins without tumor rupture is the mainstay of treatment. Many aspects need to be taken into account in order to perform a resection that can be considered ‘adequate’. The biology of the tumor and the anatomical compartment should inform the surgeon on how to determine the surgical margin. Characteristics of the surgical margin: margin width
The point of reference for defining surgical margins in sarcomas comes from studies conducted by Enneking et al. in the 1980s [7]. Based on the relationship between the surgical margin and the tumor’s pseudocapsule, procedures were categorized into intralesional (R2 resections), marginal (tumor shelled out), wide (lesion resected with a cuff of normal tissue of the same compartment) and radical (the entire compartment is removed in one block). It became very clear that, even though classical 554
tumor-related prognostic factors had already been identified, surgical technique and margin status were major determinants of the risk of LR [8–17]. In the light of these considerations, it became obvious over the years that the same oncological outcome offered by major amputations could be achieved with limb-sparing surgical techniques, alone or combined with radiotherapy, whenever the tumor could be removed fully covered by a layer of healthy tissue [18–20]. The balance between cure and functional preservation shifted strongly towards the latter with no sacrifice of the former. Nowadays, microscopic examination of the surgical margin has proved to be a benchmark for determining the quality of surgery. In major published series, the rate of macroscopically complete resections (R0/R1) in extra-abdominal STS ranged from 96 to 99% [12,14,17] with 78–88% microscopic negative resection margins [14,17]. While R1 resections lead to a higher risk of LR, the direct correlation between quality of surgery and final outcome remains controversial [11,14,16,17,21]. Characteristics of the surgical margin: margin quality
The most intriguing classification of surgical margins in STS comes from an interesting report by Kawaguchi et al., who meticulously defined surgical procedures based on both the width and quality of the healthy tissue covering the tumor. He derived the concept from Enneking that some tissues resist tumor infiltration. Muscle fasciae, joint capsules, tendons, epineurium, vascular adventitia, cartilage, periosteum and mesothelial tissues can be considered barriers, which are very seldom invaded by soft tissue tumors. Since their capacity to resist is not uniform, he developed a score for each of them. For instance, the presence of joint cartilage in a margin was considered to be equivalent to 5 cm of normal tissue in terms of ability to resist against tumor invasion [22,23]. Although the validity of such equivalence is questionable, this concept was clearly important in guiding surgical decisions. From this perspective, he classified surgical procedures into five groups, according to the least established margin, as curative (normal cuff of 5 cm or more), adequately wide (normal cuff from 1 to 4 cm), inadequately wide (normal cuff of 1 cm), marginal or intralesional. This classification is not, however, practical and only seldom used outside Japan. Tailoring the surgical margins
Achieving gross resection with microscopically negative resection margins provides the best chance for local control but the impact of wide resection on the natural history of the disease differs among different patients. In other words, some cases benefit greatly from a wide margin, others do not. It is crucial to identify this subset of patients in order to strike a balance between wider excision and functional outcome. There are three issues at stake. First of all, the inherent aggressiveness of the tumor and its natural history should be factored in the surgical treatment Expert Rev. Anticancer Ther. 15(5), (2015)
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Personalizing surgical margins in RPS
plan. High-grade tumors, aggressive histologies (e.g., malignant peripheral nerve sheath tumors and myxofibrosarcoma) and tumors that lack sensitivity to available treatments are at higher risk of LR and require a wider resection margin to maximize the chance of local control [17,21,23]. Conversely, atypical lipomatous tumor of the extremity can be managed with more limited resections because they show a lower risk of LR despite marginal excisions [24]. However, tumors with more aggressive biology are also characterized by a higher risk of distant metastasis (DM) and worse overall survival (OS). In these tumors, the weight of LR on the prognosis is intriguing. While patients who develop LR fare worse, it is also true that in this subset of patients LR may simply represent another manifestation of the inherent aggressiveness of the disease irrespective of the surgical margins. The prognostic meaning of quality of surgery in extremity STS has long been debated in the sarcoma literature. Positive surgical margins have consistently been reported to adversely correlate with outcome. This has mainly to do with local control. The correlation is instead weaker in the case of distant spread and cause-specific mortality, but seems to strengthen on extended follow-up of patients who ‘escape’ early DM. In other words, local inadequacy apparently correlates with local relapse and late metastases. It is difficult to prove the causative role of local failure in distant relapse, because the same prognostic factors may well be influencing both local and distant control: ultimately, both may signify higher tumor aggressiveness. Nevertheless there is a correlation, be it causative or not, between local adequacy and both local and distant outcome. The second issue is tumor location. When the tumor is located at a critical site (as the ones that cannot be salvaged by amputation) the association between local adequacy and outcome becomes more evident, as patients who fail locally may die of inoperable locoregional recurrences. Hence, greater surgical aggressiveness is needed when LR can directly affect the prognosis. The third factor is the tumor’s relationship with barriers. Recent evidence suggests that the significance of positive surgical margins after resection also depends on the clinical scenario in which the margin is set. A recent study by O’Donnell et al. [25] evaluated the risk of LR and survival in a monocentric series of 1371 patients operated on for extra-abdominal STS. The outcomes were analyzed with respect to the resection margins. R1 resections were classified into three groups as proposed by Gerrand et al. in 2001 [24]: resections with a critical structure (blood vessels, nerves and bone) positive margin, those with a tumor bed resection positive margin and those with an unexpected positive margin during the primary resection. These categories were found to be associated with a progressive increased risk of LR (5-year LR rates of 14.6, 21.1 and 36.6%, respectively). Specifically, patients with a critical structure positive margin had significantly lower 5-year LR-free survival than patients with planned close but ultimately negative margins (85.4 vs 97%, p = 0.15), but not significantly lower than in cases where informahealthcare.com
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the critical structure was encased or invaded by the tumor and thus en-bloc resected (85.4 vs 91.2%, p = 0.8). This means that after the dissection of a critical structure, a positive margin is an expression of the aggressive behavior of the disease: an aspect which is out of the surgeon’s control. In conclusion, although important for all extremity STS cases, the quality of the margin gains huge prognostic implications in two subsets of patients: those with proximal-located tumors where local control is critical for survival, and those escaping early events due to the inherent aggressiveness of the disease. In addition, if the tumor lies close to major structures, dissection below anatomical barriers is safe. In major series of STS of the extremities, the overall 5-year LR rate was 12–21% with a 5-year disease-specific survival of around 80% [11,12,14,17]. The concept & role of surgical margins in the retroperitoneum
The same concepts that guide surgery in extra-abdominal STS should apply to the retroperitoneum, where anatomical constraints exert a strong influence over the natural history of the disease. The outcome of RPS is characterized by a higher LR rate (50% at 5 years) and a lower survival rate (5-year OS 50%) compared to extremity STS (TABLE 1). When we analyze RPS as a whole group, the natural history reflects the strong tendency of lipomatous tumors (which account for roughly 50% of RPS) to recur locally. Since the post-LR prognosis is poor, this high LR rate directly impacts OS. Surgical anatomy of the retroperitoneum
The retroperitoneum is a complex space lying between the posterior parietal peritoneum and the posterior abdominal wall. The kidneys, adrenal glands, ureters, major abdominal arteries and veins, nerves and lymph nodes are contained in the retroperitoneal connective tissue. The pancreas, second and third parts of the duodenum, and the ascending and descending colon are not retroperitoneal organs but, during embryological development, become apposed to the posterior abdominal wall in direct contact with the retroperitoneal fat. Accordingly, they can be regarded as retroperitoneal anterior margins. The subdivision of the retroperitoneal compartment into the posterior pararenal space, anterior pararenal space and perirenal space by means of the perirenal fascia is not very useful in the context of sarcoma surgery because, unlike in benign tumors or inflammatory processes, these minor planes do not influence the direction of tumor growth [26]. RPS can subvert the retroperitoneal anatomy and, beyond the classical retroperitoneal anatomical margins (TABLE 2), viscera displaced by the tumor may become new unusual margins. The kidney, for instance, may become part of the posterior margin if the tumor arises in the anterior perirenal space (FIGURE 1) and vice versa if it grows in the posterior perirenal space. 555
556
2002–2011
2000–2013
Gronchi et al. (2014)
Bremjit et al. (2014)
Single
Multi-center
Multi-center
Single
Multi-center
Multi-center
Multi-center
132
377
586
200
382
152
136
288
143
165
500
Cases (n)
100
100
92
100
97
72
62
67
96
88
56
Primary† (%)
§
‡
In this table, primary patients are defined as non-metastatic, non-recurrent RPS. Calculated out of primary tumors. Calculated out of all patients. ¶ Calculated out of operated patients. # Calculated out of primary operated patients. †† Calculated out of completely resected patients. ‡‡ Median follow-up for survivors only. Na: Not available.
†
1988–2008
Toulmonde et al. (2014)
2002–2007
1990–2009
1985–2001
Strauss et al. (2010)
Single
1985–2007
Gronchi et al. (2009)
1985–2005
Single
1989–1994
van Dalen et al. (2007)
Bonvalot et al. (2009)
Single
1980–1994
Stoeckle et al. (2001)
Single
1982–1997
Lewis et al. (1998)
Center
Study period
Study (year)
122‡‡ 58§
63¶ 89§
65§ 63‡ 65¶ 93‡ 76‡
29§ 78§ 44§ 32§
85† 76¶ 96# 94#
82
53§
32
75¶
91
§
60
§
120
§
71§
§
88
§
Na
47‡‡
68#
§
77‡
28‡
80#
Na
Contiguous organ resection (%)
Median follow-up (months)
R0/R1 resection (%)
Table 1. Comparison of oncological outcomes in major series.
Na
Na
Na
3
3
Na
Na
Na
4
Na
4
Postoperative mortality (%)#
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§
Na
24%‡
54%‡‡
45%‡‡
49%§
29%
§
48%
Na
Na
57%‡‡
41%#
5-year local recurrence rate (%)
18‡
22‡
Na
Na
34§
22
§
13
§
Na
Na
33‡
21#
5-year distant metastasis rate (%)
71‡
65‡
66‡‡
Na
57§
60§
51
§
Na
40‡
49‡
54‡
5-year overall survival (%)
[37]
[35]
[34]
[36]
[33]
[32]
[31]
[30]
[29]
Ref.
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Personalizing surgical margins in RPS
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The preoperative CT scan is essential Table 2. Retroperitoneal surgical margins. for identifying the surgical margin in the Right side Left side specific scenario. . Posterior parietal peritoneum . Posterior parietal peritoneum Anatomically, the concept of compart- Anterior . Right mesocolon . Transverse mesocolon margin ment does not apply to the retroperitoneal . Right colon . Left mesocolon space because of the absence of true bound. Terminal ileum . Left colon aries and the presence of vital organs lying . Transverse mesocolon . Ligament of treitz within. Conversely, from the surgical . Second and third part of . Pancreatic tail oncologist’s standpoint, tissues that work as . Splenorenal ligament the duodenum natural barriers to tumor spread are also . Pancreatic head and . Stomach recognizable in the retroperitoneum. The uncinate process muscle fasciae posteriorly, the adventitia of major abdominal vessels medially and the Posterior . Lumbar vertebral bodies (and transverse processes covered by psoas muscle margin insertion) peritoneum anteriorly can be used as safe . Diaphragmatic crura margins to conduct a dissection that closely . Psoas major muscle (covered by psoas fascia) resembles the principles of compartmental . Psoas minor muscle resection in the extremities. Moreover, . Iliac muscle (covered by iliac fascia) even though the distinction between the . Quadratus lumborum muscle (covered by quadratus lumborum fascia) two retroperitoneal spaces (left and right) is . Transverse abdominal muscle (covered by transversalis fascia) only artificial, since they are in direct con- Lateral margin tinuation above the major abdominal ves. Inferior vena cava . Abdominal aorta sels, most RPS are confined to one side Medial . . Lumbar vertebral bodies margin Lumbar vertebral bodies only. Completely clearing the ipsilateral . . Mesentery Mesentery retroperitoneal fat by performing dissection beyond safe margins allows the surgical oncologist to treat the retroperitoneum as a Superior . Diaphragm . Diaphragm compartment despite the anatomical limits. margin . Lateral and medial arcuate ligaments . Lateral and medial arcuate ligaments Indeed, the retroperitoneum is in direct . Liver at the Morrison pouch communication laterally with the preperitoneal space, inferiorly with the pelvic . Inguinal ligament extraperitoneal space and anteriorly with Inferior margin the mesentery and mesocolon. RPS can expand through all these paths. Toldt’s fascia in particular, which separates the entire apposed right and left within the French Sarcoma Group [35]. Other studies demonmesocolon from the retroperitoneum, is only a thin barrier [27]. strated that the expertise of the center plays a direct role also in In addition, the boundaries with the posterior mediastinum early mortality rate and OS [34,42,43]. This is consistent with the at the esophageal hiatus, the thigh at the femoral canal, obtura- progress observed in monocentric comparisons over time and tor foramen and sciatic notch, and the scrotum at the inguinal conversely not seen in large multi-centric series, where dedicanal, can occasionally be crossed by RPS with the same mech- cated teams were not involved. Presently, the recommendation to refer patients to highanism as in hernia formation [28]. The weakness of these boundaries and the risk of spread through all these paths volume centers to be evaluated and managed by a dedicated worsen at recurrence. Primary surgery is critical for maximizing multidisciplinary team is endorsed in major guideline statements [4,44,45]. the chance of cure. The current sarcoma staging system of the American Joint Committee on Cancer (AJCC) takes only a few tumor-related Determinants of oncological outcome in RPS In primary RPS, the tumor-related prognostic factors that have factors into account so that almost all RPS patients are proven to be valid prediction tools are: tumor size, multifocal- included in the same stage, except for tumor grade. The ability of this system to work as a valid risk-prediction model for ity, tumor grade and histologic subtype [29–38]. Besides tumor-related characteristics, patient characteristics RPS has proven to be weak [46]. Recently, site-specific nomo(age at presentation) [35,39] and treatment-related features (com- grams have been developed for RPS to overcome the lack of pleteness of resection, tumor rupture and center expertise) also accurate risk-prediction models and to provide a tool for betact as major prognosticators of long-term oncological ter group stratification of RPS patients, which is essential for a trustworthy comparison of different studies [39,47,48]. These outcome [5,30,32,34–38,40,41]. Specifically, the center expertise has recently emerged as a models closely consider the different weights of each prognosmajor prognostic determinant in a series of 586 RPS treated tic factor. informahealthcare.com
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A
C
B
D
Figure 1. Well-differentiated liposarcoma of the right retroperitoneum. (A) Preoperative contrast-enhanced abdominal CT scan. The tumor lies close to the inferior pole of the kidney (without encasing the organ) and disrupts the psoas fibers. (B) Intraoperative view after extended surgery comprising resection of the parietal peritoneum, kidney, adrenal gland, part of the diaphragm, right colon and psoas muscle. (C) Front view of the surgical specimen: the tumor is covered by the last small bowel loop, right colon and right mesocolon. (D) Posterior view of the surgical specimen: in the medial part the tumor is covered by the psoas muscle (white line), in the infero-lateral part (blue line) by the fascia of the iliac muscle; in the upper-medial part by the kidney (green line), in the upper-lateral part by the diaphragm (black line).
Surgical approach to RPS
As in extremity STS, the mainstay of RPS treatment is surgery, which is the primary and only curative therapy of localized disease. Although marginal by definition, for the reasons discussed above, the aim of surgical resection should be to completely remove the tumor en bloc with the adherent surrounding organs to minimize marginality. This may be technically challenging, in particular, the large size of the tumor and its proximity to vital structures may prevent a cuff of healthy tissue/ organs from being left all around the tumor. Overall completeness of surgical resection is the most important treatment-related determinant of oncological outcome [39]. The chance of achieving complete resection of the tumor mass was reported to be as high as 50% until the 1980s [49], while the percentage rose to 70–95% in recent studies (TABLE 1). The upward trend in the complete resection rate may reflect both a more aggressive surgical approach and better patient selection. A retrospective study by Hassan et al. confirms these data in the experience of the Mayo Clinic: the percentage of complete tumor resections increased from 49% in 1960–1982 to 78% in 1983–1995 (p = 0.001). At the same time, the more recent 558
study cohort had more adjacent organs resected (39 vs 58%, p = 0.009), a trend toward a lower 5-year LR rate (42 vs 29%, p = 0.133) and significantly better 5- and 10-year OS (45 and 29% vs 34 and 19%, p = 0.01). The authors identified the increased use of extensive resection and a more aggressive surgical approach as major determinants of better OS [50]. The need for an aggressive surgical policy has been advocated by surgeons for 20 years [30,31,51]. Indeed, the simple resection of the tumor was inevitably followed by a high rate of LRs, as observed in extremity STS. Presently, in the surgical community, while there is consensus on the need to obtain complete tumor removal, there are slightly different attitudes regarding the need for resection of adherent viscera. Specifically, over the last 5 years, a more extended resection policy has been proposed. Basically, it was postulated that encompassing adherent tissues/organs in the resection specimen, even when not directly infiltrated, would improve locoregional control. As most patients with RPS die without DM, this would possibly also have been associated with an improvement in OS. This new surgical strategy has subsequently been named ‘compartmental surgery’ [34], ‘complete compartmental resection’ [52], ‘liberal multivisceral resection’ [53] or ‘radical surgery’ [5] as different from ‘conservative surgery’ or ‘simple resection,’ where only directly involved organs are resected. The terminology could be misleading. On the one hand, a true compartmental resection cannot be performed in the retroperitoneum due to the presence of vital organs, while, on the other hand, the so-called ‘simple resection’ policy is not merely the bare excision of the tumor. The key point that distinguishes the two strategies is whether it is worth resecting close adherent but uninvolved viscera to improve the width and quality of part of the surgical margins. The rationale behind the shift towards this more extended surgical policy was that removal of all retroperitoneal ipsilateral fat would ensure the removal of any potential satellite metastasis and the optimization of the surgical margin would decrease the chance for tumor seeding. The primary assumption was that it had already been demonstrated that enlarging the surgical margins to include a rim of normal tissue in extremity STS was associated with better local control [10]. Moreover, in 2002, a preclinical study by Tsivian et al. [54] conducted on 50 animal models of RPS suggested that aggressive en bloc resection of RPS and surrounding (uninvolved) viscera could have an advantage in terms of both LR rate and OS compared with simple excision of the tumor. The sarcoma centers in Milan (Istituto Nazionale Tumori, Italy) and Paris (Institute Gustave Roussy, France) have been seeking to standardize the approach to RPS, based on the above considerations since early 2000. In 2009, they retrospectively reviewed primary RPS patients operated over an approximately 20-year period with the aim to investigate how the new surgical strategy impacted oncological outcome. In the French study by Bonvalot et al., compartmental resection predicted a 3.29-fold lower rate of abdominal recurrence compared to simple resection. The margin status (R0 vs R1) was also a Expert Rev. Anticancer Ther. 15(5), (2015)
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significant prognostic factor for both LR rate and OS [34]. In the Italian study, patients were analyzed according to the year of surgery. Before 2002, patients were predominantly treated by simple excision of the tumor mass along with the surrounding viscera only when overtly infiltrated. Later on, patients underwent systematic excision of the tumor with surrounding tissues/organs even when not overtly infiltrated. The different surgical policy was found to be a significant positive prognostic factor at multivariable analysis for LR but not for OS [33]. At a later follow-up, low-to-intermediate grade RPS proved to benefit the most from the extended approach and this also translated into a survival benefit [55]. Much has been said about the appropriateness of these observations. In 2009, the editorial accompanying the French and Italian papers raised criticism and limitations of these studies in relation to: the extension of the resections to some but not all adjacent viscera (typically the colon, kidney and psoas muscle but not bone, duodenum, pancreas or major vessels), without standardization of the surgical technique; the retrospective design and related methodological weakness; the absence of a survival benefit in patients treated with the new extended approach and the lack of a description of the morbidity and mortality associated with resecting uninvolved adjacent viscera [56]. The same authors addressed all these concerns in the following years. The extended approach proved to be safe, with a postsurgical major morbidity rate of 18% and a postoperative mortality rate of 3%, comparable to major abdominal resectional surgery for other cancers. The number of resected organs correlated with the risk of morbidity, which increased after more than three resected organs [57]. These results compared favorably even with more recent findings by Tseng et al. on 156 cases of primary RPS extracted from the database of the American College of Surgeons National Surgical Quality Improvement Program (ACSNSQIP). In this series, the postoperative severe morbidity and mortality rates were 11.5 and 1.3%, respectively. However, the percentage of patients undergoing contiguous organ resection was 90% in the series by Bonvalot et al. and 37% in the series by Tseng et al. Moreover, in the study by Tseng et al., there was no difference in terms of overall morbidity, severe morbidity and mortality between patients who underwent resection of contiguous organs and those who did not [58]. Conversely, in a series from the MD Anderson Cancer Center, Houston, a statistically significant difference in postoperative morbidity and mortality was observed between patients treated with conservative excision and those treated with contiguous organ resection in a surgical policy based on histological criteria [59]. The validity of the extended approach became more evident after reporting its association with better survival in 2012. Patients may be willing to accept a higher morbidity rate in exchange for an increased chance of survival, especially considering postoperative mortality is similar. informahealthcare.com
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Notably, an early report by Russo et al. [60] on patients undergoing nephrectomy en bloc with RPS due to macroscopic encasement or abutment of the kidney showed that 73% had no renal capsular invasion and only 9% of patients had renal parenchymal involvement. Conversely, a recent series by Mussi et al. [53] showed much higher infiltration of apparently uninvolved surrounding organs, by meticulous sampling of the specimen. In this study, 60.9% of resected organs were found to be microscopically involved by the tumor. This was also the case for WDLPS, the best approach to which is still under debate. Standardization of the technical principles of the surgical approach to RPS was then published by a group of European and American experts [28]. The general concept closely followed the principles of oncological resection in extremity STS: where barriers exist, proceed beyond the safe tissues leaving the tumor covered by the barriers; where anatomic barriers do not exist, try to use adjacent organs as a new barrier if their sacrifice is acceptable in terms of short- and long-term morbidity. This means that in the medial margin, the dissection is conducted under the adventitia of the major abdominal vessels; in the anterior margin, the ipsilateral colon and kidney (if displaced anteriorly) are resected along with the tumor mass; in the posterior margin, the psoas muscle (and kidney, if on the posterior side) is resected in order to keep the posterior surface of the tumor covered at least on the medial part (FIGURE 1). Some margins remain critical. Upper right RPS lie close to the duodenum and head of the pancreas and their dissection from the tumor surface may leave a very thin layer on the tumor or may be found in a positive margin. In any event, although pancreaticoduodenectomy would provide a safer margin, it is not routinely performed because of the high related morbidity. The same applies to the rectum, bladder, aorta, vena cava (except for LMS arising from these vessels) and vertebral bodies. At the upper surface of the tumor, the diaphragm can be easily resected and then sutured to the posterior abdominal/chest wall (FIGURE 1). In left-sided tumors, the duodenojejunal junction is resected only if invaded, otherwise its dissection can be safely performed leaving the tumor covered by the root of the medial edge of the mesocolon. In upper left tumors, the spleen and left pancreas can also be resected en bloc with the mass (FIGURE 2). By the end of the resection all the ipsilateral retroperitoneal fat has been removed. The surgical field can be seen in FIGURES 1B & 2C. Tailoring the approach to histological subtype & grade
Among the RPS, different histotypes show distinctive behaviors. Several studies have recognized histological subtype as a major prognosticator, with better outcome in terms of survival for patients with WDLPS compared to other histologies. Liposarcomas have also shown a stronger tendency to recur locally while non-liposarcoma histologies, such as LMS have been correlated with a higher DM rate [30,31,33,35,36]. A histology subtype-based prognostic system was proposed by Anaya et al. in order to overcome the limits of the current AJCC staging system. Patients were stratified into three groups characterized 559
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Figure 2. Intermediate-grade dedifferentiated liposarcoma of the left retroperitoneum. (A) Contrast-enhanced abdominal computed tomography scan at the diagnosis. The tumor (T) displaces the left kidney (K). The pancreatic body-tail (PT) and splenic vein border the upper medial part of the mass. The splenic flexure of the colon (C) is adherent to the upper lateral part of the mass. (B) Intraoperative view before tumor resection. After dissection of the colon-epiploic ligament and mobilization of the stomach, the pancreatic body-tail appears to be pushed towards the front. (C) Intraoperative view after extended resection of the mass en bloc with the kidney, adrenal gland, splenic flexure of the colon, pancreatic body and tail, spleen, part of the diaphragm and psoas muscle. (D) Front view of the surgical specimen. The pancreatic body-tail covers the upper medial part of the tumor.
by progressively worse prognosis: WDLPS, non-liposarcoma and non-WDLPS. This model proved to have comparable accuracy to the AJCC staging system with the advantages of allowing more even stratification of patients, in addition to having a prognostic role in recurrent RPS [61,62]. More recently, thanks to the collaboration of four major European and North American institutions, a nomogram for OS and DFS was developed. Both malignancy grade and histology subtype proved to be the strongest determinants of outcome. This tool was externally validated and is presently the best prognostic assay for patient counseling and treatment decisions [39]. In essence, three different major sarcoma subtypes account for >80% of all RPS: WD/DDLPS, LMS and SFT. They have distinct patterns of failures and natural histories, the understanding of which is critical to strategy optimization. Liposarcoma
In several series, liposarcomas are analyzed as a homogeneous group [30–33,38,63]. At present, three main distinctive tumor biological categories are recognizable: WDLPS, G2 DDLPS and G3 DDLPS [36]. Myxoid/round cell liposarcoma and pleomorphic liposarcoma are more rare in the retroperitoneum and should be considered separately [64]. 560
WDLPS grow slowly over time and lack metastatic potential. The 5-year LR rate varies from 18 to 47% in major series. The DM rate is 0–4% and the 5-year OS lies between 87 and 95%, with a reported 5-year DSS of 83% [35,36,61,65]. Although WDLPS are characterized by a favorable LR rate and OS compared to other histological subtypes, outcome after LR is poor. Virtually, all patients who experience a first LR after complete resection of a primary WDLPS end up suffering from other multiple recurrences until they finally die from uncontrollable tumor growth and entrapment of vital structures. Notably, the disease-free interval between primary surgery and LR or between subsequent LR is usually long (median time to LR 55.5 months in recent series) [59]. The LR curve does not flatten out after 5-years of FU, but the risk remains constant over time. This should be taken into account for interpretation of the data: while 5-year curves provide a reliable description of the natural history of highly aggressive tumors, in WDLPS, which behave in a more indolent fashion, we need to have long-term follow-up to capture the whole picture. Hence, differences in the 5-year LR rate do not necessarily translate into differences in cure rate in this histological subtype but their prognostic role may only be revealed at a longer FU. Multifocality is reported to be as high as 18% in primary WDLPS, increasing to 50% when patients present with LR. A classification of the LR pattern has recently been proposed by the group at the MD Anderson Cancer Center, Houston, based on division of the abdominal cavity into eight compartments at preoperative imaging. In this series, out of 32 patients with primary unifocal WDLPS recurring after surgery, 22 (69%) developed a multifocal disease at recurrence while 10 (31%) remained unifocal. In the study, progression to multifocal disease or the development of an ‘extra-field’ recurrence was not correlated with any clinicopathological or treatmentrelated factors [66]. In-depth knowledge of this histotype has paradoxically led to different surgical policies [52,67–69]. On the one hand, given the very indolent biology of the disease, some centers have advocated a less aggressive surgical approach, seeking not to sacrifice contiguous organs whenever possible. Notably, the ‘stripping off’ of the outer kidney capsule has been described to spare kidney parenchymal function. The assumption is that in this group of patients affected by WDLPS, marginal resection of the tumor does not lead to earlier recurrences or shorter OS/DSS as long as complete resection is achieved. In these series, LR at 3 and 5 years occurred in as many as 31 and 58% of patients with a 5-year OS and DSS of 92 and 83%, respectively [59,65]. Conversely, other centers treated patients affected by this specific RPS subtype with the aforementioned systematic extended surgical approach, achieving better local control (5-year LR rate of 19%) and comparable survival data (5-year OS of 87%) [36]. Some considerations favor the latter approach in our view: first, as previously discussed, recent evidence has shown that WDLPS may also present an infiltrative growth pattern. Second, WDLPS might dedifferentiate at the time of recurrence and the dedifferentiation rate seems to increase with Expert Rev. Anticancer Ther. 15(5), (2015)
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Personalizing surgical margins in RPS
subsequent recurrences. Moreover, it is difficult to predict the absence of a dedifferentiated component on a preoperative CT scan/MRI only, even after preoperative biopsy, and the extended approach may benefit both WDLPS and G2 DDLPS. Third, it is important to clear all ipsilateral retroperitoneal fat since it is macroscopically indistinguishable from the tumor [53,65,70,71]. FIGURE 1 presents a case of WDLPS of the right retroperitoneum. The resection encompassed the kidney even though it was not encased by the tumor. The nephrectomy enabled a wide surgical margin to be obtained in the upper medial part of the specimen, which would otherwise have been marginal (FIGURE 1C & 1D). Although the promising results of the extended approach are not conclusive, because longer follow-up is needed to verify whether the advantage in terms of local control is maintained over years, we need to bear in mind that nowadays improvement of the surgical margin at primary surgery is still the only factor capable of changing the natural history of the disease. A more conservative approach can compromise the only available chance for cure. The role of radiotherapy in WDLPS is not yet established. Precisely because these tumors lack metastatic potential, they could be the ones benefiting the most from better local control. Results from the ongoing randomized study on preoperative RT in primary RPS are awaited to clarify this [6]. Standard chemotherapy has a marginal role in these tumors due to the very low mitotic rate. New therapeutic drugs targeting MDM2-p53 interaction and CDK4 are under investigation [72–74]. DDLPS behave in a more aggressive fashion. They exhibit a stronger tendency to recur locally, a shorter time-to-LR and a higher risk of invasion of surrounding organs, muscles or peritoneum compared to WDLPS [35,36,59]. Their capacity to recur at distant sites is proportional to the tumor grade according to French Federation of Cancer Centers Sarcoma Group Grading System and depends on the histological characteristics of the dedifferentiated component [36,41,65,75]. Metastatic spread occurs relatively early in the natural history of the disease and median post-DM disease-specific survival was 11.5 months in a series from the MD Anderson Cancer Center, Houston [76]. In a recent multi-centric European study, the LR rate, DM rate and OS at 5 years in G2 and G3 DDLPS were 44 and 33%, 9 and 44%, 54 and 41%, respectively. The lower LR rate in G3 tumors was likely due to the high DM-related death rate that shortens patients’ life expectancy and their chance of developing LR [36]. In a detailed analysis by the Memorial Sloan Kettering Cancer Center, New York, patients with DDLPS had a sixfold higher risk of death and a fourfold higher risk of LR compared to WDLPS [65]. Multiple other series confirmed the prognostic role of the dedifferentiated component in terms of DSS, LR and OS: the extension and grade of the dedifferentiated informahealthcare.com
Review
component have been associated with a higher LR and DM risk [61,70,71,75]. In addition, a series from our group identified the presence of myogenic differentiation as a major determinant of OS and DM rate in retroperitoneal LPS with a particularly dismal prognosis for tumors showing a rhabdomyosarcomatous component. Out of 144 patients with retroperitoneal LPS, myogenic differentiation was identified in 15.3% of G1/WDLPS, 45% of G2 DDLPS and 56% of G3 DDLPS. Considering patients without myogenic differentiation, with myogenic differentiation and with a rhabdomyoblastic component, the corresponding 5-year OS was 75.4, 42.4 and 28.6% (p
ISSN: 1473-7140 (Print) 1744-8328 (Online) Journal homepage: http://www.tandfonline.com/loi/iery20
Personalizing surgical margins in retroperitoneal sarcomas Dario Callegaro, Marco Fiore & Alessandro Gronchi To cite this article: Dario Callegaro, Marco Fiore & Alessandro Gronchi (2015) Personalizing surgical margins in retroperitoneal sarcomas, Expert Review of Anticancer Therapy, 15:5, 553-567 To link to this article: http://dx.doi.org/10.1586/14737140.2015.1028375
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Date: 20 January 2016, At: 15:04
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Personalizing surgical margins in retroperitoneal sarcomas
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Expert Rev. Anticancer Ther. 15(5), 553–567 (2015)
Dario Callegaro, Marco Fiore and Alessandro Gronchi* Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian, 1 – 20133 Milan, Italy *Author for correspondence: Tel.: +39 022 390 3234 Fax: +39 022 390 2404 [email protected]
Retroperitoneal sarcomas are a group of diseases that behave differently from one another. Well-differentiated liposarcomas have an indolent biology but show a tendency to recur locally even years after primary resection. Dedifferentiated liposarcomas are characterized by a very high local recurrence risk, while the metastatic risk mainly depends on the histological characteristics of the dedifferentiated component. In leiomyosarcomas, hematogenous spread informs prognosis while local recurrences are far less common. Surgery is the cornerstone of treatment of all retroperitoneal sarcoma subtypes and its quality is the only treatment-related factor able to improve the oncological outcome. A frontline extended surgical approach is all the more critical in subtypes in which local control directly impacts prognosis. KEYWORDS: leiomyosarcoma . liposarcoma . outcome . prognosis . retroperitoneal sarcoma . sarcoma . solitary fibrous tumor
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surgery
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surgical margins
Adult soft tissue sarcomas (STS) are a group of rare diseases that account for 50 subtypes of soft tissue tumors, each with a specific presentation, biological characteristics and clinical behavior. Moreover, among STS, the same histotype may carry a completely different risk depending on the anatomical location. Retroperitoneal sarcomas (RPS) are a unique entity in the world of STS precisely because of the specific anatomy of the retroperitoneum. They arise close to vital structures in an anatomical compartment that is not readily accessible to both medical examination and surgical exploration. The typical presentation is that of a large mass encasing, invading or displacing adjacent organs. The diagnosis is usually made on the basis of long-standing
informahealthcare.com
10.1586/14737140.2015.1028375
vague symptoms or accidentally during radiological examinations of the abdomen. Although several different histotypes may arise in the retroperitoneum, four well-defined histological subtypes (well-differentiated liposarcomas [WDLPS], dedifferentiated liposarcomas [DDLPS], leiomyosarcomas [LMS] and solitary fibrous tumors [SFT]) account for about 80% of all RPS patients. Complete surgical resection is the only potentially curative treatment for localized disease. However, the high rate of postoperative recurrence (40–50% at 5 years) remains a major challenge. While in STS of the extremities there has been a growing tendency to decrease surgical aggressiveness, reducing the number of amputations, there has been a somewhat opposite trend in the retroperitoneum: achieving a safer margin at the price of resecting adherent structures is proving to be a crucial issue in maximizing the chances of cure. Moreover, while in the extremities indolent histological subtypes can be readily managed with limited resections, there are no ‘less risky’ histologies in the retroperitoneum since lowgrade tumors also carry a substantial risk of local recurrence (LR) and death, albeit, over a longer time period. The standard example of
2015 Informa UK Ltd
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Callegaro, Fiore & Gronchi
atypical lipomatous tumor and WDLPS, a single biological entity with two different names according to the site of origin, as this dominates its outcome is: the former occurring in the extremities and trunk wall is never fatal; the latter occurring in the deep trunk (e.g., retroperitoneum) is often fatal especially on the longer run [3]. In the last 5 years, we and others have advocated the need for more extended surgical policies in RPS. Although a consensus on how far the surgeon should extend the resection has not yet been reached in the surgical community, tumor resection en bloc with adherent structures/organs to minimize marginality was included as the standard treatment in the latest edition of the European Society for Medical Oncology guidelines [4]. The role of adjuvant/neoadjuvant treatments in reducing the systemic and local risk of recurrence remains controversial. Radiotherapy is an option, especially in the preoperative setting, to potentially improve the chance for local control, but its role is far from being established [5]. It is presently under investigation in a large international European Organization for Research and Treatment of Cancer (EORTC)-led randomized trial [6]. Chemotherapy may be offered in high-grade tumors and histologies at higher risk of systemic spread, although no prospective evidence of efficacy is available to date. The surgical, oncological and pathological skills required in the management of RPS should lead patients to be referred to high-volume centers, where a dedicated multidisciplinary team can offer the best diagnostic and therapeutic chances. In this review, we will go through the concept of appropriateness of the surgical margins in RPS and discuss whether surgical policy should be tailored to the specific tumor of the specific patient. Lessons from STS of the extremities: the concept & role of surgical margins
The critical role of the surgical procedure in determining the prognosis of STS patients was primarily investigated in extraabdominal tumors. The question ‘how wide do I need to resect to be adequate?’ has been discussed in the surgical community for over 40 years without finding a simple answer, even today. Resection of the tumor with clear (R0) margins without tumor rupture is the mainstay of treatment. Many aspects need to be taken into account in order to perform a resection that can be considered ‘adequate’. The biology of the tumor and the anatomical compartment should inform the surgeon on how to determine the surgical margin. Characteristics of the surgical margin: margin width
The point of reference for defining surgical margins in sarcomas comes from studies conducted by Enneking et al. in the 1980s [7]. Based on the relationship between the surgical margin and the tumor’s pseudocapsule, procedures were categorized into intralesional (R2 resections), marginal (tumor shelled out), wide (lesion resected with a cuff of normal tissue of the same compartment) and radical (the entire compartment is removed in one block). It became very clear that, even though classical 554
tumor-related prognostic factors had already been identified, surgical technique and margin status were major determinants of the risk of LR [8–17]. In the light of these considerations, it became obvious over the years that the same oncological outcome offered by major amputations could be achieved with limb-sparing surgical techniques, alone or combined with radiotherapy, whenever the tumor could be removed fully covered by a layer of healthy tissue [18–20]. The balance between cure and functional preservation shifted strongly towards the latter with no sacrifice of the former. Nowadays, microscopic examination of the surgical margin has proved to be a benchmark for determining the quality of surgery. In major published series, the rate of macroscopically complete resections (R0/R1) in extra-abdominal STS ranged from 96 to 99% [12,14,17] with 78–88% microscopic negative resection margins [14,17]. While R1 resections lead to a higher risk of LR, the direct correlation between quality of surgery and final outcome remains controversial [11,14,16,17,21]. Characteristics of the surgical margin: margin quality
The most intriguing classification of surgical margins in STS comes from an interesting report by Kawaguchi et al., who meticulously defined surgical procedures based on both the width and quality of the healthy tissue covering the tumor. He derived the concept from Enneking that some tissues resist tumor infiltration. Muscle fasciae, joint capsules, tendons, epineurium, vascular adventitia, cartilage, periosteum and mesothelial tissues can be considered barriers, which are very seldom invaded by soft tissue tumors. Since their capacity to resist is not uniform, he developed a score for each of them. For instance, the presence of joint cartilage in a margin was considered to be equivalent to 5 cm of normal tissue in terms of ability to resist against tumor invasion [22,23]. Although the validity of such equivalence is questionable, this concept was clearly important in guiding surgical decisions. From this perspective, he classified surgical procedures into five groups, according to the least established margin, as curative (normal cuff of 5 cm or more), adequately wide (normal cuff from 1 to 4 cm), inadequately wide (normal cuff of 1 cm), marginal or intralesional. This classification is not, however, practical and only seldom used outside Japan. Tailoring the surgical margins
Achieving gross resection with microscopically negative resection margins provides the best chance for local control but the impact of wide resection on the natural history of the disease differs among different patients. In other words, some cases benefit greatly from a wide margin, others do not. It is crucial to identify this subset of patients in order to strike a balance between wider excision and functional outcome. There are three issues at stake. First of all, the inherent aggressiveness of the tumor and its natural history should be factored in the surgical treatment Expert Rev. Anticancer Ther. 15(5), (2015)
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Personalizing surgical margins in RPS
plan. High-grade tumors, aggressive histologies (e.g., malignant peripheral nerve sheath tumors and myxofibrosarcoma) and tumors that lack sensitivity to available treatments are at higher risk of LR and require a wider resection margin to maximize the chance of local control [17,21,23]. Conversely, atypical lipomatous tumor of the extremity can be managed with more limited resections because they show a lower risk of LR despite marginal excisions [24]. However, tumors with more aggressive biology are also characterized by a higher risk of distant metastasis (DM) and worse overall survival (OS). In these tumors, the weight of LR on the prognosis is intriguing. While patients who develop LR fare worse, it is also true that in this subset of patients LR may simply represent another manifestation of the inherent aggressiveness of the disease irrespective of the surgical margins. The prognostic meaning of quality of surgery in extremity STS has long been debated in the sarcoma literature. Positive surgical margins have consistently been reported to adversely correlate with outcome. This has mainly to do with local control. The correlation is instead weaker in the case of distant spread and cause-specific mortality, but seems to strengthen on extended follow-up of patients who ‘escape’ early DM. In other words, local inadequacy apparently correlates with local relapse and late metastases. It is difficult to prove the causative role of local failure in distant relapse, because the same prognostic factors may well be influencing both local and distant control: ultimately, both may signify higher tumor aggressiveness. Nevertheless there is a correlation, be it causative or not, between local adequacy and both local and distant outcome. The second issue is tumor location. When the tumor is located at a critical site (as the ones that cannot be salvaged by amputation) the association between local adequacy and outcome becomes more evident, as patients who fail locally may die of inoperable locoregional recurrences. Hence, greater surgical aggressiveness is needed when LR can directly affect the prognosis. The third factor is the tumor’s relationship with barriers. Recent evidence suggests that the significance of positive surgical margins after resection also depends on the clinical scenario in which the margin is set. A recent study by O’Donnell et al. [25] evaluated the risk of LR and survival in a monocentric series of 1371 patients operated on for extra-abdominal STS. The outcomes were analyzed with respect to the resection margins. R1 resections were classified into three groups as proposed by Gerrand et al. in 2001 [24]: resections with a critical structure (blood vessels, nerves and bone) positive margin, those with a tumor bed resection positive margin and those with an unexpected positive margin during the primary resection. These categories were found to be associated with a progressive increased risk of LR (5-year LR rates of 14.6, 21.1 and 36.6%, respectively). Specifically, patients with a critical structure positive margin had significantly lower 5-year LR-free survival than patients with planned close but ultimately negative margins (85.4 vs 97%, p = 0.15), but not significantly lower than in cases where informahealthcare.com
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the critical structure was encased or invaded by the tumor and thus en-bloc resected (85.4 vs 91.2%, p = 0.8). This means that after the dissection of a critical structure, a positive margin is an expression of the aggressive behavior of the disease: an aspect which is out of the surgeon’s control. In conclusion, although important for all extremity STS cases, the quality of the margin gains huge prognostic implications in two subsets of patients: those with proximal-located tumors where local control is critical for survival, and those escaping early events due to the inherent aggressiveness of the disease. In addition, if the tumor lies close to major structures, dissection below anatomical barriers is safe. In major series of STS of the extremities, the overall 5-year LR rate was 12–21% with a 5-year disease-specific survival of around 80% [11,12,14,17]. The concept & role of surgical margins in the retroperitoneum
The same concepts that guide surgery in extra-abdominal STS should apply to the retroperitoneum, where anatomical constraints exert a strong influence over the natural history of the disease. The outcome of RPS is characterized by a higher LR rate (50% at 5 years) and a lower survival rate (5-year OS 50%) compared to extremity STS (TABLE 1). When we analyze RPS as a whole group, the natural history reflects the strong tendency of lipomatous tumors (which account for roughly 50% of RPS) to recur locally. Since the post-LR prognosis is poor, this high LR rate directly impacts OS. Surgical anatomy of the retroperitoneum
The retroperitoneum is a complex space lying between the posterior parietal peritoneum and the posterior abdominal wall. The kidneys, adrenal glands, ureters, major abdominal arteries and veins, nerves and lymph nodes are contained in the retroperitoneal connective tissue. The pancreas, second and third parts of the duodenum, and the ascending and descending colon are not retroperitoneal organs but, during embryological development, become apposed to the posterior abdominal wall in direct contact with the retroperitoneal fat. Accordingly, they can be regarded as retroperitoneal anterior margins. The subdivision of the retroperitoneal compartment into the posterior pararenal space, anterior pararenal space and perirenal space by means of the perirenal fascia is not very useful in the context of sarcoma surgery because, unlike in benign tumors or inflammatory processes, these minor planes do not influence the direction of tumor growth [26]. RPS can subvert the retroperitoneal anatomy and, beyond the classical retroperitoneal anatomical margins (TABLE 2), viscera displaced by the tumor may become new unusual margins. The kidney, for instance, may become part of the posterior margin if the tumor arises in the anterior perirenal space (FIGURE 1) and vice versa if it grows in the posterior perirenal space. 555
556
2002–2011
2000–2013
Gronchi et al. (2014)
Bremjit et al. (2014)
Single
Multi-center
Multi-center
Single
Multi-center
Multi-center
Multi-center
132
377
586
200
382
152
136
288
143
165
500
Cases (n)
100
100
92
100
97
72
62
67
96
88
56
Primary† (%)
§
‡
In this table, primary patients are defined as non-metastatic, non-recurrent RPS. Calculated out of primary tumors. Calculated out of all patients. ¶ Calculated out of operated patients. # Calculated out of primary operated patients. †† Calculated out of completely resected patients. ‡‡ Median follow-up for survivors only. Na: Not available.
†
1988–2008
Toulmonde et al. (2014)
2002–2007
1990–2009
1985–2001
Strauss et al. (2010)
Single
1985–2007
Gronchi et al. (2009)
1985–2005
Single
1989–1994
van Dalen et al. (2007)
Bonvalot et al. (2009)
Single
1980–1994
Stoeckle et al. (2001)
Single
1982–1997
Lewis et al. (1998)
Center
Study period
Study (year)
122‡‡ 58§
63¶ 89§
65§ 63‡ 65¶ 93‡ 76‡
29§ 78§ 44§ 32§
85† 76¶ 96# 94#
82
53§
32
75¶
91
§
60
§
120
§
71§
§
88
§
Na
47‡‡
68#
§
77‡
28‡
80#
Na
Contiguous organ resection (%)
Median follow-up (months)
R0/R1 resection (%)
Table 1. Comparison of oncological outcomes in major series.
Na
Na
Na
3
3
Na
Na
Na
4
Na
4
Postoperative mortality (%)#
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§
Na
24%‡
54%‡‡
45%‡‡
49%§
29%
§
48%
Na
Na
57%‡‡
41%#
5-year local recurrence rate (%)
18‡
22‡
Na
Na
34§
22
§
13
§
Na
Na
33‡
21#
5-year distant metastasis rate (%)
71‡
65‡
66‡‡
Na
57§
60§
51
§
Na
40‡
49‡
54‡
5-year overall survival (%)
[37]
[35]
[34]
[36]
[33]
[32]
[31]
[30]
[29]
Ref.
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Expert Rev. Anticancer Ther. 15(5), (2015)
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Personalizing surgical margins in RPS
Review
The preoperative CT scan is essential Table 2. Retroperitoneal surgical margins. for identifying the surgical margin in the Right side Left side specific scenario. . Posterior parietal peritoneum . Posterior parietal peritoneum Anatomically, the concept of compart- Anterior . Right mesocolon . Transverse mesocolon margin ment does not apply to the retroperitoneal . Right colon . Left mesocolon space because of the absence of true bound. Terminal ileum . Left colon aries and the presence of vital organs lying . Transverse mesocolon . Ligament of treitz within. Conversely, from the surgical . Second and third part of . Pancreatic tail oncologist’s standpoint, tissues that work as . Splenorenal ligament the duodenum natural barriers to tumor spread are also . Pancreatic head and . Stomach recognizable in the retroperitoneum. The uncinate process muscle fasciae posteriorly, the adventitia of major abdominal vessels medially and the Posterior . Lumbar vertebral bodies (and transverse processes covered by psoas muscle margin insertion) peritoneum anteriorly can be used as safe . Diaphragmatic crura margins to conduct a dissection that closely . Psoas major muscle (covered by psoas fascia) resembles the principles of compartmental . Psoas minor muscle resection in the extremities. Moreover, . Iliac muscle (covered by iliac fascia) even though the distinction between the . Quadratus lumborum muscle (covered by quadratus lumborum fascia) two retroperitoneal spaces (left and right) is . Transverse abdominal muscle (covered by transversalis fascia) only artificial, since they are in direct con- Lateral margin tinuation above the major abdominal ves. Inferior vena cava . Abdominal aorta sels, most RPS are confined to one side Medial . . Lumbar vertebral bodies margin Lumbar vertebral bodies only. Completely clearing the ipsilateral . . Mesentery Mesentery retroperitoneal fat by performing dissection beyond safe margins allows the surgical oncologist to treat the retroperitoneum as a Superior . Diaphragm . Diaphragm compartment despite the anatomical limits. margin . Lateral and medial arcuate ligaments . Lateral and medial arcuate ligaments Indeed, the retroperitoneum is in direct . Liver at the Morrison pouch communication laterally with the preperitoneal space, inferiorly with the pelvic . Inguinal ligament extraperitoneal space and anteriorly with Inferior margin the mesentery and mesocolon. RPS can expand through all these paths. Toldt’s fascia in particular, which separates the entire apposed right and left within the French Sarcoma Group [35]. Other studies demonmesocolon from the retroperitoneum, is only a thin barrier [27]. strated that the expertise of the center plays a direct role also in In addition, the boundaries with the posterior mediastinum early mortality rate and OS [34,42,43]. This is consistent with the at the esophageal hiatus, the thigh at the femoral canal, obtura- progress observed in monocentric comparisons over time and tor foramen and sciatic notch, and the scrotum at the inguinal conversely not seen in large multi-centric series, where dedicanal, can occasionally be crossed by RPS with the same mech- cated teams were not involved. Presently, the recommendation to refer patients to highanism as in hernia formation [28]. The weakness of these boundaries and the risk of spread through all these paths volume centers to be evaluated and managed by a dedicated worsen at recurrence. Primary surgery is critical for maximizing multidisciplinary team is endorsed in major guideline statements [4,44,45]. the chance of cure. The current sarcoma staging system of the American Joint Committee on Cancer (AJCC) takes only a few tumor-related Determinants of oncological outcome in RPS In primary RPS, the tumor-related prognostic factors that have factors into account so that almost all RPS patients are proven to be valid prediction tools are: tumor size, multifocal- included in the same stage, except for tumor grade. The ability of this system to work as a valid risk-prediction model for ity, tumor grade and histologic subtype [29–38]. Besides tumor-related characteristics, patient characteristics RPS has proven to be weak [46]. Recently, site-specific nomo(age at presentation) [35,39] and treatment-related features (com- grams have been developed for RPS to overcome the lack of pleteness of resection, tumor rupture and center expertise) also accurate risk-prediction models and to provide a tool for betact as major prognosticators of long-term oncological ter group stratification of RPS patients, which is essential for a trustworthy comparison of different studies [39,47,48]. These outcome [5,30,32,34–38,40,41]. Specifically, the center expertise has recently emerged as a models closely consider the different weights of each prognosmajor prognostic determinant in a series of 586 RPS treated tic factor. informahealthcare.com
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A
C
B
D
Figure 1. Well-differentiated liposarcoma of the right retroperitoneum. (A) Preoperative contrast-enhanced abdominal CT scan. The tumor lies close to the inferior pole of the kidney (without encasing the organ) and disrupts the psoas fibers. (B) Intraoperative view after extended surgery comprising resection of the parietal peritoneum, kidney, adrenal gland, part of the diaphragm, right colon and psoas muscle. (C) Front view of the surgical specimen: the tumor is covered by the last small bowel loop, right colon and right mesocolon. (D) Posterior view of the surgical specimen: in the medial part the tumor is covered by the psoas muscle (white line), in the infero-lateral part (blue line) by the fascia of the iliac muscle; in the upper-medial part by the kidney (green line), in the upper-lateral part by the diaphragm (black line).
Surgical approach to RPS
As in extremity STS, the mainstay of RPS treatment is surgery, which is the primary and only curative therapy of localized disease. Although marginal by definition, for the reasons discussed above, the aim of surgical resection should be to completely remove the tumor en bloc with the adherent surrounding organs to minimize marginality. This may be technically challenging, in particular, the large size of the tumor and its proximity to vital structures may prevent a cuff of healthy tissue/ organs from being left all around the tumor. Overall completeness of surgical resection is the most important treatment-related determinant of oncological outcome [39]. The chance of achieving complete resection of the tumor mass was reported to be as high as 50% until the 1980s [49], while the percentage rose to 70–95% in recent studies (TABLE 1). The upward trend in the complete resection rate may reflect both a more aggressive surgical approach and better patient selection. A retrospective study by Hassan et al. confirms these data in the experience of the Mayo Clinic: the percentage of complete tumor resections increased from 49% in 1960–1982 to 78% in 1983–1995 (p = 0.001). At the same time, the more recent 558
study cohort had more adjacent organs resected (39 vs 58%, p = 0.009), a trend toward a lower 5-year LR rate (42 vs 29%, p = 0.133) and significantly better 5- and 10-year OS (45 and 29% vs 34 and 19%, p = 0.01). The authors identified the increased use of extensive resection and a more aggressive surgical approach as major determinants of better OS [50]. The need for an aggressive surgical policy has been advocated by surgeons for 20 years [30,31,51]. Indeed, the simple resection of the tumor was inevitably followed by a high rate of LRs, as observed in extremity STS. Presently, in the surgical community, while there is consensus on the need to obtain complete tumor removal, there are slightly different attitudes regarding the need for resection of adherent viscera. Specifically, over the last 5 years, a more extended resection policy has been proposed. Basically, it was postulated that encompassing adherent tissues/organs in the resection specimen, even when not directly infiltrated, would improve locoregional control. As most patients with RPS die without DM, this would possibly also have been associated with an improvement in OS. This new surgical strategy has subsequently been named ‘compartmental surgery’ [34], ‘complete compartmental resection’ [52], ‘liberal multivisceral resection’ [53] or ‘radical surgery’ [5] as different from ‘conservative surgery’ or ‘simple resection,’ where only directly involved organs are resected. The terminology could be misleading. On the one hand, a true compartmental resection cannot be performed in the retroperitoneum due to the presence of vital organs, while, on the other hand, the so-called ‘simple resection’ policy is not merely the bare excision of the tumor. The key point that distinguishes the two strategies is whether it is worth resecting close adherent but uninvolved viscera to improve the width and quality of part of the surgical margins. The rationale behind the shift towards this more extended surgical policy was that removal of all retroperitoneal ipsilateral fat would ensure the removal of any potential satellite metastasis and the optimization of the surgical margin would decrease the chance for tumor seeding. The primary assumption was that it had already been demonstrated that enlarging the surgical margins to include a rim of normal tissue in extremity STS was associated with better local control [10]. Moreover, in 2002, a preclinical study by Tsivian et al. [54] conducted on 50 animal models of RPS suggested that aggressive en bloc resection of RPS and surrounding (uninvolved) viscera could have an advantage in terms of both LR rate and OS compared with simple excision of the tumor. The sarcoma centers in Milan (Istituto Nazionale Tumori, Italy) and Paris (Institute Gustave Roussy, France) have been seeking to standardize the approach to RPS, based on the above considerations since early 2000. In 2009, they retrospectively reviewed primary RPS patients operated over an approximately 20-year period with the aim to investigate how the new surgical strategy impacted oncological outcome. In the French study by Bonvalot et al., compartmental resection predicted a 3.29-fold lower rate of abdominal recurrence compared to simple resection. The margin status (R0 vs R1) was also a Expert Rev. Anticancer Ther. 15(5), (2015)
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significant prognostic factor for both LR rate and OS [34]. In the Italian study, patients were analyzed according to the year of surgery. Before 2002, patients were predominantly treated by simple excision of the tumor mass along with the surrounding viscera only when overtly infiltrated. Later on, patients underwent systematic excision of the tumor with surrounding tissues/organs even when not overtly infiltrated. The different surgical policy was found to be a significant positive prognostic factor at multivariable analysis for LR but not for OS [33]. At a later follow-up, low-to-intermediate grade RPS proved to benefit the most from the extended approach and this also translated into a survival benefit [55]. Much has been said about the appropriateness of these observations. In 2009, the editorial accompanying the French and Italian papers raised criticism and limitations of these studies in relation to: the extension of the resections to some but not all adjacent viscera (typically the colon, kidney and psoas muscle but not bone, duodenum, pancreas or major vessels), without standardization of the surgical technique; the retrospective design and related methodological weakness; the absence of a survival benefit in patients treated with the new extended approach and the lack of a description of the morbidity and mortality associated with resecting uninvolved adjacent viscera [56]. The same authors addressed all these concerns in the following years. The extended approach proved to be safe, with a postsurgical major morbidity rate of 18% and a postoperative mortality rate of 3%, comparable to major abdominal resectional surgery for other cancers. The number of resected organs correlated with the risk of morbidity, which increased after more than three resected organs [57]. These results compared favorably even with more recent findings by Tseng et al. on 156 cases of primary RPS extracted from the database of the American College of Surgeons National Surgical Quality Improvement Program (ACSNSQIP). In this series, the postoperative severe morbidity and mortality rates were 11.5 and 1.3%, respectively. However, the percentage of patients undergoing contiguous organ resection was 90% in the series by Bonvalot et al. and 37% in the series by Tseng et al. Moreover, in the study by Tseng et al., there was no difference in terms of overall morbidity, severe morbidity and mortality between patients who underwent resection of contiguous organs and those who did not [58]. Conversely, in a series from the MD Anderson Cancer Center, Houston, a statistically significant difference in postoperative morbidity and mortality was observed between patients treated with conservative excision and those treated with contiguous organ resection in a surgical policy based on histological criteria [59]. The validity of the extended approach became more evident after reporting its association with better survival in 2012. Patients may be willing to accept a higher morbidity rate in exchange for an increased chance of survival, especially considering postoperative mortality is similar. informahealthcare.com
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Notably, an early report by Russo et al. [60] on patients undergoing nephrectomy en bloc with RPS due to macroscopic encasement or abutment of the kidney showed that 73% had no renal capsular invasion and only 9% of patients had renal parenchymal involvement. Conversely, a recent series by Mussi et al. [53] showed much higher infiltration of apparently uninvolved surrounding organs, by meticulous sampling of the specimen. In this study, 60.9% of resected organs were found to be microscopically involved by the tumor. This was also the case for WDLPS, the best approach to which is still under debate. Standardization of the technical principles of the surgical approach to RPS was then published by a group of European and American experts [28]. The general concept closely followed the principles of oncological resection in extremity STS: where barriers exist, proceed beyond the safe tissues leaving the tumor covered by the barriers; where anatomic barriers do not exist, try to use adjacent organs as a new barrier if their sacrifice is acceptable in terms of short- and long-term morbidity. This means that in the medial margin, the dissection is conducted under the adventitia of the major abdominal vessels; in the anterior margin, the ipsilateral colon and kidney (if displaced anteriorly) are resected along with the tumor mass; in the posterior margin, the psoas muscle (and kidney, if on the posterior side) is resected in order to keep the posterior surface of the tumor covered at least on the medial part (FIGURE 1). Some margins remain critical. Upper right RPS lie close to the duodenum and head of the pancreas and their dissection from the tumor surface may leave a very thin layer on the tumor or may be found in a positive margin. In any event, although pancreaticoduodenectomy would provide a safer margin, it is not routinely performed because of the high related morbidity. The same applies to the rectum, bladder, aorta, vena cava (except for LMS arising from these vessels) and vertebral bodies. At the upper surface of the tumor, the diaphragm can be easily resected and then sutured to the posterior abdominal/chest wall (FIGURE 1). In left-sided tumors, the duodenojejunal junction is resected only if invaded, otherwise its dissection can be safely performed leaving the tumor covered by the root of the medial edge of the mesocolon. In upper left tumors, the spleen and left pancreas can also be resected en bloc with the mass (FIGURE 2). By the end of the resection all the ipsilateral retroperitoneal fat has been removed. The surgical field can be seen in FIGURES 1B & 2C. Tailoring the approach to histological subtype & grade
Among the RPS, different histotypes show distinctive behaviors. Several studies have recognized histological subtype as a major prognosticator, with better outcome in terms of survival for patients with WDLPS compared to other histologies. Liposarcomas have also shown a stronger tendency to recur locally while non-liposarcoma histologies, such as LMS have been correlated with a higher DM rate [30,31,33,35,36]. A histology subtype-based prognostic system was proposed by Anaya et al. in order to overcome the limits of the current AJCC staging system. Patients were stratified into three groups characterized 559
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Callegaro, Fiore & Gronchi
A
B PT
C PT T
K
C
D
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PT
Figure 2. Intermediate-grade dedifferentiated liposarcoma of the left retroperitoneum. (A) Contrast-enhanced abdominal computed tomography scan at the diagnosis. The tumor (T) displaces the left kidney (K). The pancreatic body-tail (PT) and splenic vein border the upper medial part of the mass. The splenic flexure of the colon (C) is adherent to the upper lateral part of the mass. (B) Intraoperative view before tumor resection. After dissection of the colon-epiploic ligament and mobilization of the stomach, the pancreatic body-tail appears to be pushed towards the front. (C) Intraoperative view after extended resection of the mass en bloc with the kidney, adrenal gland, splenic flexure of the colon, pancreatic body and tail, spleen, part of the diaphragm and psoas muscle. (D) Front view of the surgical specimen. The pancreatic body-tail covers the upper medial part of the tumor.
by progressively worse prognosis: WDLPS, non-liposarcoma and non-WDLPS. This model proved to have comparable accuracy to the AJCC staging system with the advantages of allowing more even stratification of patients, in addition to having a prognostic role in recurrent RPS [61,62]. More recently, thanks to the collaboration of four major European and North American institutions, a nomogram for OS and DFS was developed. Both malignancy grade and histology subtype proved to be the strongest determinants of outcome. This tool was externally validated and is presently the best prognostic assay for patient counseling and treatment decisions [39]. In essence, three different major sarcoma subtypes account for >80% of all RPS: WD/DDLPS, LMS and SFT. They have distinct patterns of failures and natural histories, the understanding of which is critical to strategy optimization. Liposarcoma
In several series, liposarcomas are analyzed as a homogeneous group [30–33,38,63]. At present, three main distinctive tumor biological categories are recognizable: WDLPS, G2 DDLPS and G3 DDLPS [36]. Myxoid/round cell liposarcoma and pleomorphic liposarcoma are more rare in the retroperitoneum and should be considered separately [64]. 560
WDLPS grow slowly over time and lack metastatic potential. The 5-year LR rate varies from 18 to 47% in major series. The DM rate is 0–4% and the 5-year OS lies between 87 and 95%, with a reported 5-year DSS of 83% [35,36,61,65]. Although WDLPS are characterized by a favorable LR rate and OS compared to other histological subtypes, outcome after LR is poor. Virtually, all patients who experience a first LR after complete resection of a primary WDLPS end up suffering from other multiple recurrences until they finally die from uncontrollable tumor growth and entrapment of vital structures. Notably, the disease-free interval between primary surgery and LR or between subsequent LR is usually long (median time to LR 55.5 months in recent series) [59]. The LR curve does not flatten out after 5-years of FU, but the risk remains constant over time. This should be taken into account for interpretation of the data: while 5-year curves provide a reliable description of the natural history of highly aggressive tumors, in WDLPS, which behave in a more indolent fashion, we need to have long-term follow-up to capture the whole picture. Hence, differences in the 5-year LR rate do not necessarily translate into differences in cure rate in this histological subtype but their prognostic role may only be revealed at a longer FU. Multifocality is reported to be as high as 18% in primary WDLPS, increasing to 50% when patients present with LR. A classification of the LR pattern has recently been proposed by the group at the MD Anderson Cancer Center, Houston, based on division of the abdominal cavity into eight compartments at preoperative imaging. In this series, out of 32 patients with primary unifocal WDLPS recurring after surgery, 22 (69%) developed a multifocal disease at recurrence while 10 (31%) remained unifocal. In the study, progression to multifocal disease or the development of an ‘extra-field’ recurrence was not correlated with any clinicopathological or treatmentrelated factors [66]. In-depth knowledge of this histotype has paradoxically led to different surgical policies [52,67–69]. On the one hand, given the very indolent biology of the disease, some centers have advocated a less aggressive surgical approach, seeking not to sacrifice contiguous organs whenever possible. Notably, the ‘stripping off’ of the outer kidney capsule has been described to spare kidney parenchymal function. The assumption is that in this group of patients affected by WDLPS, marginal resection of the tumor does not lead to earlier recurrences or shorter OS/DSS as long as complete resection is achieved. In these series, LR at 3 and 5 years occurred in as many as 31 and 58% of patients with a 5-year OS and DSS of 92 and 83%, respectively [59,65]. Conversely, other centers treated patients affected by this specific RPS subtype with the aforementioned systematic extended surgical approach, achieving better local control (5-year LR rate of 19%) and comparable survival data (5-year OS of 87%) [36]. Some considerations favor the latter approach in our view: first, as previously discussed, recent evidence has shown that WDLPS may also present an infiltrative growth pattern. Second, WDLPS might dedifferentiate at the time of recurrence and the dedifferentiation rate seems to increase with Expert Rev. Anticancer Ther. 15(5), (2015)
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subsequent recurrences. Moreover, it is difficult to predict the absence of a dedifferentiated component on a preoperative CT scan/MRI only, even after preoperative biopsy, and the extended approach may benefit both WDLPS and G2 DDLPS. Third, it is important to clear all ipsilateral retroperitoneal fat since it is macroscopically indistinguishable from the tumor [53,65,70,71]. FIGURE 1 presents a case of WDLPS of the right retroperitoneum. The resection encompassed the kidney even though it was not encased by the tumor. The nephrectomy enabled a wide surgical margin to be obtained in the upper medial part of the specimen, which would otherwise have been marginal (FIGURE 1C & 1D). Although the promising results of the extended approach are not conclusive, because longer follow-up is needed to verify whether the advantage in terms of local control is maintained over years, we need to bear in mind that nowadays improvement of the surgical margin at primary surgery is still the only factor capable of changing the natural history of the disease. A more conservative approach can compromise the only available chance for cure. The role of radiotherapy in WDLPS is not yet established. Precisely because these tumors lack metastatic potential, they could be the ones benefiting the most from better local control. Results from the ongoing randomized study on preoperative RT in primary RPS are awaited to clarify this [6]. Standard chemotherapy has a marginal role in these tumors due to the very low mitotic rate. New therapeutic drugs targeting MDM2-p53 interaction and CDK4 are under investigation [72–74]. DDLPS behave in a more aggressive fashion. They exhibit a stronger tendency to recur locally, a shorter time-to-LR and a higher risk of invasion of surrounding organs, muscles or peritoneum compared to WDLPS [35,36,59]. Their capacity to recur at distant sites is proportional to the tumor grade according to French Federation of Cancer Centers Sarcoma Group Grading System and depends on the histological characteristics of the dedifferentiated component [36,41,65,75]. Metastatic spread occurs relatively early in the natural history of the disease and median post-DM disease-specific survival was 11.5 months in a series from the MD Anderson Cancer Center, Houston [76]. In a recent multi-centric European study, the LR rate, DM rate and OS at 5 years in G2 and G3 DDLPS were 44 and 33%, 9 and 44%, 54 and 41%, respectively. The lower LR rate in G3 tumors was likely due to the high DM-related death rate that shortens patients’ life expectancy and their chance of developing LR [36]. In a detailed analysis by the Memorial Sloan Kettering Cancer Center, New York, patients with DDLPS had a sixfold higher risk of death and a fourfold higher risk of LR compared to WDLPS [65]. Multiple other series confirmed the prognostic role of the dedifferentiated component in terms of DSS, LR and OS: the extension and grade of the dedifferentiated informahealthcare.com
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component have been associated with a higher LR and DM risk [61,70,71,75]. In addition, a series from our group identified the presence of myogenic differentiation as a major determinant of OS and DM rate in retroperitoneal LPS with a particularly dismal prognosis for tumors showing a rhabdomyosarcomatous component. Out of 144 patients with retroperitoneal LPS, myogenic differentiation was identified in 15.3% of G1/WDLPS, 45% of G2 DDLPS and 56% of G3 DDLPS. Considering patients without myogenic differentiation, with myogenic differentiation and with a rhabdomyoblastic component, the corresponding 5-year OS was 75.4, 42.4 and 28.6% (p
