A retrospective, single center cohort study on 65 patients with primary retroperitoneal liposarcoma

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1 ONCOLOGY LETTERS 15: , 2018 A retrospective, single center cohort study on 65 ptients with primry retroperitonel liposrcom YI XI WU 1, JUN YAN LIU 1*, JIA JIA LIU 1*, PENG YAN 1, BO TANG 1, YOU HONG CUI 2, YONG LIANG ZHAO 1, YAN SHI 1, YING XUE HAO 1, PEI WU YU 1 nd FENG QIAN 1 1 Deprtment of Generl Surgery nd Center of Miniml Invsive Gstrointestinl Surgery; 2 Institute of Pthology nd Southwest Cncer Center, Southwest Hospitl, Third Militry Medicl University, nd Key Lbortory of Tumor Immunopthology of Ministry of Eduction of Chin, Chongqing , P.R. Chin Received August 4, 2017; Accepted September 13, 2017 DOI: /ol Abstrct. Primry retroperitonel liposrcom (PRPLS) is the most common soft tissue mlignncy of the retroperitoneum. To determine the pthologicl fetures nd the curtive effects of surgery in ptients with PRPLS, nd to elucidte key prognostic fctors, the present study retrospectively nlyzed the clinicl cses of 65 ptients with PRPLS. Immunohistochemicl nlysis demonstrted tht vimentin nd Ki 67 re better indictors for PRPLS immunohistochemicl dignosis compred with S 100 protein. S 100 protein ws predominntly expressed in well differentited PRPLS. Positive expression of vimentin nd Ki 67 were observed in lmost ll PRPLS smples, nd Ki 67 exhibited higher expression level in high grde PRPLS. The level of Ki 67 expression ws negtively correlted with disese specific survivl (DSS). Survivl nlysis reveled tht the pthologicl subtype nd histologicl grde were ssocited with DSS nd locl recurrence in the ptients, wheres the tumor burden ws ssocited with DSS but not locl recurrence. In ddition, complete tumor resection nd contiguous orgn resection were ble to improve DSS. Microscopiclly positive mrgins did not ffect DSS, wheres gross mrgins did. Multivrite nlysis reveled tht pthologicl subtype, histologicl grde nd contiguous orgn resection were independent prognostic fctors, nd tht histologicl grde ws n independent fctor for locl recurrence. Ptient sex nd ge t presenttion were not Correspondence to: Professor Feng Qin, Deprtment of Generl Surgery nd Center of Miniml Invsive Gstrointestinl Surgery, Southwest Hospitl, Third Militry Medicl University, nd Key Lbortory of Tumor Immunopthology of Ministry of Eduction of Chin, 29 Go Tn Yn Street, Chongqing , P.R. Chin E mil: qinfengpuwi@163.com * Contributed eqully Key words: disese specific survivl, locl recurrence primry retroperitonel liposrcom, immunohistochemistry, primry tumor complete resection independent fctors ssocited with prognosis or locl recurrence. Correltion nlysis demonstrted tht postopertive locl recurrence significntly ffected DSS, nd locl recurrence ws the most common cuse of mortlity mong ptients. Histologicl grde ws strongly ssocited with the invsion of djcent orgns but not with tumor burden. Furthermore, the tumor burden ws not ssocited with recurrence or tumor invsion of djcent orgns. Ki 67 expression ws ssocited with prognosis. Pthologicl subtype, histologicl grde nd contiguous orgn resection were independent prognostic fctors, while histologicl grde ws n independent fctor which ffected tumor recurrence. Introduction Retroperitonel soft tissue srcoms locted in the retroperitoneum/intr bdominl regions ccount for 10 15% of ll soft tissue srcom cses. Liposrcoms, which re the most common histotype, ccount for 20 45% of the cses of retroperitoneum/intr bdominl srcom, nd 20% of the cses of liposrcoms re primry retroperitonel liposrcoms (PRPLS) (1 3). PRPLS often origintes from dipose tissue round the kidney. Due to the huge spces in nd the loose structure of the retroperitoneum, it is difficult to dignose nd tret owing to lck of typicl clinicl symptoms. The srcom grows to lrge size nd often exhibits tumor invsion of djcent orgns by the time of dignosis (4). The tumor usully presents s round or ovl lobulted mss, nd surrounding those msses, there exist stellite lesions. Due to this, the tumor often invdes proximl tissues nd blood vessels. In previous yers, the rte of morbidity of PRPLS hs grdully incresed. PRPLS tumors hve high rte of locl recurrence but rrely result in distnt metstses (5). Compred with other mlignncies, numerous ptients with PRPLS hve succumbed to mortlity due to the effects of locl recurrence (5). This is unsurprising due to the lrge tumor size nd its proximity to vitl structures, which limit the potentil to chieve negtive surgicl mrgins in surgery. Chemotherpy nd rdiotherpy re ineffective for the mjority of PRPLS cses, with chemotherpy response rte of <10% (6,7). Despite the lrge tumor size nd the difficult nture of surgery due to the proximity to vitl structures, complete tumor resection remins the most

2 1800 WU et l: PATHOLOGICAL FEATURES AND PROGNOSTIC FACTORS IN PRPLS effective tretment for the mjority of ptients with PRPLS (8). Immunohistochemistry is considered to be the most importnt dignostic method for PRPLS. Evidence of the presence of PRPSL is the existence of signet ring lipoblstoms or dendritic blood cpillries in tumor cells (9). At present, numerous immune mrkers re utilized in order to dignose nd identify diseses (10 12). However, it remins uncler whether the common PRPLS mrkers (S 100, vimentin nd Ki 67) re specific for different types of PRPLS nd whether incresed Ki 67 expression is ssocited with disese specific survivl (DSS). The present study ws designed to investigte the immunohistochemicl fetures nd effects of surgicl tretment of PRPLS, to retrospectively nlyze DSS using clinicl cses of PRPLS from single institution, nd to use the informtion gined to elucidte key prognostic fctors tht my predict which ptients with PRPLS will benefit from surgicl tretment. Mterils nd methods Ptients. Between 1st Jnury, 2005 nd 31st Mrch, 2015, group of 174 ptients (including 82 mles nd 92 femles, with ges rnging from 16 to 81 yers old nd medin ge of 51.3 yers) with liposrcom who were treted t Southwest Hospitl (Chongqing, Chin) were identified. Of these, 99 ptients were dignosed with retroperitonel liposrcom, nd 65 were dignosed with PRPLS. Follow up, vi outptient re exmintion, or postl or telephone correspondence, ws recorded for ll 65 PRPLS ptients until October 2015, with the follow up time rnging from 3 to 114 months. Of these 65 ptients, 51 ptients received complete primry tumor resection, for which the gross mrgins were ensured to be negtive during the surgery. The remining 14 ptients received pllitive surgery or biopsy. Contiguous orgn resection ws performed in 32 ptients in order to chieve complete resection, with 22 ptients exhibiting primry locl recurrence following complete resection. The 65 ptients dignosed with PRPLS, including the 51 tht received complete primry tumor resection, formed the bsis of the present study (Tble I). Pthology. According to the criteri of the World Helth Orgniztion (WHO) Clssifiction of Tumors of Soft Tissue nd Bone, PRPLS tumors re widely ccepted to be clssified into one of the five following histologicl subtypes, bsed on morphologicl fetures nd cytogenetic berrtions: Well differentited, de differentited, myxoid, round cell nd pleomorphic (13,14). Well differentited PRPLS ws defined s retroperitonel ftty tumors contining mture dipocytes with occsionl typicl cells nd irregulr hyperchromtic nuclei. Lesions with regions of non lipogenic spindle cell srcom rising within ftty tumor were lbeled s de differentited PRPLS. Myxoid PRPLS ws composed of dipocytes with different differentition nd vrible number of smll lipoblsts in prominent myxoid strom, with or without delicte rborizing vsculture. Tumors with similr morphologicl smll round or ovl shped cells nd scttered dipocytes were determined to be round cell PRPLS. Pleomorphic spindle nd gint cells, s well s sheets Tble I. Ptients included in the present study. Ptient group Ptients, n All liposrcoms treted 174 All retroperitonel liposrcoms treted 99 All primry retroperitonel liposrcoms treted 65 Completely resected 51 Pllitive surgery or biopsy 14 Contiguous orgn resection 32 Primry locl recurrence following complete 22 resection Reopertion following primry locl recurrence 16 of pleomorphic lipoblsts, were clssified s pleomorphic PRPLS. The well differentited subtype ccounts for 56% of PRPLS cses, with de differentited, myxoid nd round cell subtypes ccounting for 37, 5 nd 2% of cses, respectively. As certin myxoid liposrcoms exhibit morphologicl similrities to round cell liposrcoms nd re similr in terms of histologicl progression, these two types re difficult to distinguish from ech other. Additionlly, in previous studies, mixed type PRPLS ws defined by the WHO s including two or more subtypes of liposrcom (15,16). Thus, the present study llocted ptients with myxoid nd round cell PRPLS into one group, nd ptients with pleomorphic/mixed type PRPLS into nother group. Although there re five PRPLS subtypes, histologicl grde my be divided into two grdes (high nd low), defined by histologicl subtype (17). The mjority of mixed type PRPLS cses include de differentited or pleomorphic PRPLS. Thus, the high grde tumors include de differentited, pleomorphic nd mixed type cells, wheres the low grde tumors consist of well differentited nd myxoid/round cell types. Immunohistochemistry. The tumor smples of 65 ptients were fixed in 4% formldehyde for 24 h t room temperture, hydrted nd dehydrted with differing concentrtions of ethnol (75, 85, 95 nd 100%) nd 100% xylene embedded in prffin, cut into 4 µm sections nd stined using the hemtoxylin nd eosin (H&E) method for 24 h t room temperture. Immunohistochemistry ws performed by the streptvidin peroxidse method (18) using ntibodies ginst S 100 α2 (ct. no. bs 7873R; Bioss Antibodies, Inc., Woburn, MA, USA), vimentin (ctlog no. 5741; Cell Signling Technology, Inc., Dnvers, MA, USA) nd Ki 67 (ctlog no. bs 2130R; Bioss Antibodies, Inc.). Positive expression ws defined s brown stining in the cytosol, cytomembrne or nuclei of the tumor cells. A totl of 65 H&E stined smples for S 100, vimentin nd Ki 67 respectively were seprted into group 1, group 2 nd group 3 rndomly to test for their specificity for the tumor. The Ki 67 prolifertion index ws lso ssessed using scle reflecting the positive proportion of totl of 1,000 cells in 10 rndom high power fields, s follows: +, 0 nd <10%; ++, 10 nd <20%; +++, 20 nd <30%; ++++, 30 nd <40%; nd +++++, 40% positively stined cells.

3 ONCOLOGY LETTERS 15: , Tble II. Chrcteristics of 65 ptients with primry retroperitonel liposrcom. Vribles Ptients, n Medin survivl time, months Survivl rte, % Follow up ± Primry tumor complete resection ± Pllitive surgery or biopsy ± Histologicl subtype Well differentited ± De differentited ± Myxoid/round cell subtype ± Pleomorphic/mixed type ± Histologicl grde High ± Low ± Contiguous orgn resection ± Primry locl recurrence ± Medin ± stndrd devition. Sttisticl nlysis. The endpoints of the present study were upon ptient mortlity or the dte of lst follow up. DSS ws defined s the time from the primry tretment (time of dignosis or time of primry resection for the 65 ptient nlysis) to the time of mortlity or lst follow up. The endpoint for DSS ws confirmed disese ssocited mortlity (27 of the 65 ptients). The survivl rte ws clculted s the percentge of surviving ptients mong the 65 ptients t the end of the follow up period. A Wilcoxon signed rnk test ws used to determine whether two dependent smples were selected from popultions with the sme distribution, nd Spermn's rnk correltion ws used to compre the correltion between two vribles. The tumor burden ws defined s the dimeter of the mximum dimension upon cross sectionl imging of single mss or the lrgest mss removed from the bdominl cvity, rther thn other dispersive or smll msses removed during primry resection. Adjcent viscerl structures tht were removed during resection, including those in the kidney, liver nd intestines, were included in the mesure of tumor burden. The 51 ptients who underwent complete primry tumor resection were divided into three groups on the bsis of tumor size, from smll to lrge, s follows: Group A, 10 cm; group B, >10 cm nd 20 cm; nd group C, >20 cm. The orgns removed during the resection of djcent orgns, including the kidney, drenl glnds, ureter, spleen, pncres, gll bldder, epityphlon, colon, omentum nd mesentery, were recorded nd orgn identity ws confirmed by postopertive pthologicl exmintion. Clinicl, pthologicl nd therpeutic vribles, including pthologicl subtype, histologicl grde, tumor burden, complete primry tumor resection, djcent orgn resection nd the tumor mrgins, were exmined, nd the ssocition of these fctors with survivl outcome were nlyzed using the Kpln Meier method nd log rnk test. Other univrite nlysis nd sttisticl ssocitions were exmined using the χ 2 test, Wilcoxon signed rnk test nd Spermn's rnk correltion. Multivrite fctors, including ge t presenttion nd gender, were nlyzed using the Cox proportionl hzrds regression model. Results Ptient, primry tumor nd tretment ssocited vribles. Between Jnury 2005 nd Mrch 2015, 65 ptients were dignosed with PRPLS nd 51 ptients underwent complete primry tumor resection t Southwest Hospitl. The distribution of clinicl nd pthologicl chrcteristics mong ptients is illustrted in Tble II. Of the 65 ptients, 14 received pllitive surgery or biopsy lone, due to the invsion of djcent mjor orgns or vessels by the tumor. At the endpoint of the study, 5 of these 14 ptients survived. Of the 51 ptients tht received complete primry tumor resection, the medin survivl time ws 43.3 months. Tumor smples from 25 ptients were determined to be of the well differentited histologicl subtype, 10 were de differentited, 8 were myxoid/round cell nd 8 were pleomorphic/mixed type (Tble II). Thus, 18 tumors were high grde nd the remining 33 tumors were low grde. Following surgery, the gross resection mrgins were negtive for tumor tissue in ll 51 ptients. To chieve complete resection, 32 ptients received djcent orgn resection, with 15 ptients exhibiting tumor positive microscopic mrgins. Following complete primry resection, 22 ptients developed locl recurrence nd the medin time to recurrence ws 29.2 months (rnge, 3 60 months). Of these, 16 ptients underwent further surgery, 4 ptients received djuvnt chemotherpy or rdition, nd 2 ptients declined further tretment. The chrcteristics of the 65 ptients with PRPLS re presented in Tble II. Immunohistochemicl nlysis. Immunohistochemicl nlysis of PRPLS tumors stined for S 100, vimentin nd Ki 67 is presented in Figs Tumors from 23 ptients were positive for S 100, wheres vimentin nd Ki 67 were

4 1802 WU et l: PATHOLOGICAL FEATURES AND PROGNOSTIC FACTORS IN PRPLS Figure 1. Positive expression of S 100 in (A) well differentited nd (B) myxoid PRPLS. Negtive expression of S 100 in (C) undifferentited nd (D) pleomorphic/mixed type PRPLS. PRPLS, primry retroperitonel liposrcoms. Figure 3. Positive expression of Ki 67 in primry retroperitonel liposrcom. Imges indicte the Ki 67 prolifertion indexes of (A) +, (B) ++, (C) +++, (D) ++++ nd (E) Assocition between pthologicl subtype nd DSS time. The durtion of follow up period of ptients rnged between 3 nd 114 months. The medin survivl time of the 51 surgicl ptients ws 43.3 months. The medin survivl time of the 25 ptients with well differentited PRPLS ws 51.2 months, nd the rte of survivl ws 84.0%, compred with 20.7 months nd 50.0% for the 10 ptients with de differentited PRPLS. Additionlly, the 8 ptients with the myxoid/round cell subtype hd medin survivl time of 59.9 months nd survivl rte of 62.5%, compred with 30.1 months nd 25.0% for the 8 ptients with pleomorphic/mixed type tumors (Tble II). Sttisticl nlysis indicted tht DSS time ws significntly incresed in ptients with well differentited PRPLS, compred with those with de differentited PRPLS (χ2=19.467, P<0.0001; Fig. 4). Figure 2. Positive expression of vimentin in (A) well differentited, (B) myxoid/round cell, (C) de differentited nd (D) pleomorphic/mixed type primry retroperitonel liposrcom tissues. expressed in 62 nd 64 ptients, respectively. S 100 expression ws predominntly observed in well differentited PRPLS. The rtes of vimentin nd Ki 67 positive stining were significntly higher compred with tht of S 100 (P<0.0001, P< nd P=0.157 respectively; Tble III). Ki 67 ws highly expressed in high grde PRPLS, with the most pronounced expression observed in de differentited, pleomorphic nd mixed type tumors. Furthermore, negtive correltion ws observed between Ki 67 expression index nd DSS time (Tble IV). Assocition between histologicl grde nd DSS time. Anlysis of tumor grde nd DSS ws performed using the follow up dt of the 51 ptients with PRPLS who received complete primry resection. Histologicl subtype ws used to define the histologicl grde, which included de differentited nd pleomorphic/mixed type subtypes nd low grde included well differentited nd myxoid/round cell subtypes. The medin survivl time of the 18 ptients with high grde PRPLS ws 24.9 months nd the overll survivl rte ws 38.9%, compred with 53.3 months nd 78.8% for the 33 ptients with low grde PRPLS (Fig. 4). DSS ws significntly incresed in the ptients with low grde PRPLS compred with ptients with high grde PRPLS (χ2=19.053, P<0.001). Assocition between tumor burden nd DSS time. The present study investigted the ssocition of tumor burden with

5 ONCOLOGY LETTERS 15: , Tble III. Anlysis on the specificity of S 100, vimentin nd Ki 67 stining. Groups Positive, n Negtive, n Positive rte, % Z vlue P vlue Group < S Vimentin Group < S Ki Group Vimentin Ki Wilcoxon Signed Rnks Test. Tble IV. Correltion between the intension of Ki 67 expression nd survivl time. Ki 67 stining intensity Threshold (%) Symbol Ptients, n R vlue P vlue 0 nd nd nd < nd < > Spermn's rnk correltion. postopertive survivl time. In the 51 ptients tht received complete primry resection, the totl medin tumor burden ws 18.0 cm (rnge, 3 45 cm). There were 7 ptients in group A (tumor size, 10 cm), with medin survivl time of 52.1 months. There were 28 ptients in group B (tumor size, >10 cm nd 20 cm), nd the medin survivl time ws 45.6 months, compred with 35.3 months for the 16 ptients in group C (tumor size, >20 cm). Sttisticl nlysis demonstrted tht tumor burden ws significntly ssocited with DSS (χ 2 =6.826, P=0.033; Fig. 4). Assocition between the DSS time of ptients nd complete resection or pllitive surgery/biopsy. The medin survivl time of the 51 ptients tht received complete resection ws 43.3 months nd the survivl rte ws 64.7%, compred with 19.4 months nd 35.7% for the 14 ptients tht underwent pllitive surgery or biopsy. Thus, complete tumor resection ws demonstrted to be significntly ssocited with incresed DSS time (χ 2 =15.471, P<0.0001), nd lso observbly improved the survivl rte nd survivl time (Fig. 4). Assocition between DSS time nd contiguous orgn resection or pllitive surgery/biopsy. To chieve complete tumor resection, contiguous resection ws performed where necessry. The medin survivl time following contiguous orgn resection (32 ptients) ws 42.7 months nd the rte of survivl ws 53.1%, compred with 19.4 months nd 35.8% following pllitive surgery or biopsy (14 ptients). Anlysis demonstrted tht DSS time ws significntly incresed in ptients who received contiguous orgn resection, compred with those who underwent only pllitive surgery or biopsy (χ 2 =7.130, P=0.008; Fig. 5). Mrgin of resection. Of the 51 ptients who underwent complete resection, ll hd negtive gross mrgins. The medin survivl time for these ptients ws 43.3 months nd the rte of survivl ws 64.7%, compred with 19.4 months nd 35.7% in the 14 ptients who received pllitive surgery or biopsy with tumor positive gross mrgins. Of the 32 ptients who underwent contiguous orgn resection, 15 ptients hd tumor positive microscopic mrgins. The medin survivl time for these ptients ws 36.9 months nd the survivl rte ws 46.7% in these 15 ptients. There ws no sttisticlly significnt difference between the DSS of ptients with tumor negtive gross mrgins nd positive microscopic mrgins (χ 2 =2.240, P=0.134; Fig. 6). However, the sttus of the gross mrgins ws ssocited with prognosis bsed on comprison of the DSS of the 51 ptients with negtive gross mrgins nd the 14 ptients with positive gross mrgins who received pllitive surgery or biopsy (χ 2 =15.471, P<0.0001; Fig. 5). Assocition between DSS time, gender nd ge t dignosis. Among the 65 ptients included in the present study, the 35 mles hd medin survivl time of 36.1 months nd 60.0% survivl rte, compred with 40.5 month medin survivl time nd 56.7% survivl rte in the 30 femle ptients. Anlysis demonstrted tht gender did not ffect DSS time (χ 2 =0.005, P=0.821; Fig. 5). For ptients with ge <60 yers (n=40), the medin survivl time ws 37.1 months, nd the survivl rte ws 57.5%, compred with 38.9 months nd 60.0% survivl rte for ptients with ge 60 yers (n=25). The ge t dignosis did not ffect DSS (χ 2 =0.005, P=0.671; Fig. 5).

6 1804 WU et l: PATHOLOGICAL FEATURES AND PROGNOSTIC FACTORS IN PRPLS Figure 4. Anlysis of ptient prognosis. Assocition between disese specific survivl nd (A) pthologicl subtype (P<0.0001), (B) histologicl grde (P<0.0001), (C) tumor burden (P=0.033) nd (D) complete resection (P<0.0001) re shown. Figure 5. Anlysis of prognosis. Assocition between disese specific survivl nd (A) contiguous orgn resection (P=0.008), (B) microscopic mrgin (P=0.134), the gross mrgin (P<0.0001), (C) gender (P=0.821) nd (D) ge t presenttion (P=0.671) re shown.

7 ONCOLOGY LETTERS 15: , Figure 6. Anlysis of primry locl recurrence. Assocition between disese specific survivl nd (A) pthologicl subtype (P=0.002), (B) histologicl grde (P<0.0001), (C) gender (P=0.466) nd (D) ge t presenttion (P=0.186) re shown. Multivrite nlysis of fctors ffecting prognosis. The pthologicl subtype, histologicl grde, tumor burden, contiguous orgn resection, locl recurrence, tumor mrgins, gender nd ge t presenttion were nlyzed using the Cox proportionl hzrds regression model. The results reveled tht pthologicl subtype, histologicl grde nd contiguous orgn resection were independent fctors tht ffected prognosis, wheres the remining vribles were not (Tble V). Assocition between pthologicl subtype nd DSS time in ptients with primry locl recurrence. Of the 51 ptients who underwent complete resection, 22 experienced primry locl recurrence. The medin time to recurrence of the 8 ptients with well differentited PRPLS ws 34.5 months nd the survivl rte ws 62.5%, compred with 17.2 months nd 16.7% for the 6 ptients with de differentited PRPLS. Additionlly, the 3 ptients with myxoid/round cell tumors exhibited medin time to recurrence of 46.7 months nd survivl rte of 66.7%, compred with 24.8 months nd 0% survivl rte in the 5 ptients with pleomorphic/mixed type PRPLS. Sttisticl nlysis demonstrted tht, in ptients with primry locl recurrence, the pthologicl subtype ws ssocited with DSS (χ 2 =14.995, P=0.002; Fig. 6). Assocition between histologicl grde nd DSS in ptients with primry locl recurrence. Of the 22 ptients with primry locl recurrence, the medin time to recurrence of the 11 ptients with high grde PRPLS ws 20.6 months nd the rte of survivl ws 9.1%, compred with 37.8 months nd 63.6% in the 11 ptients with low grde PRPLS. Anlysis demonstrted tht the DSS time ws significntly higher mong ptients with low grde PRPLS, compred with those with high grde PRPLS (χ 2 =14.810, P<0.0001; Fig. 6). Multivrite nlysis of fctors ffecting locl recurrence. The pthologicl subtype, histologicl grde, tumor burden, gender nd ge t presenttion were exmined in the ptients who exhibited locl recurrence following resection (n=22) using the Cox proportionl hzrds regression model. The nlysis demonstrted tht histologicl grde ws n independent fctor ffecting locl recurrence, while the remining vribles were not independently ssocited with recurrence (Tble VI). Correltion between locl recurrence nd DSS time. Of the 51 ptients who received complete resection, 22 developed primry locl recurrence, with survivl rte of 36.4%. By comprison, the survivl rte ws 86.2% for the 29 ptients without locl recurrence. This finding demonstrted tht locl recurrence strongly ffected DSS, nd sttisticl nlysis indicted tht there ws negtive ssocition between locl recurrence nd DSS (R=0.517, P=0.000; Tble VII). Thus, locl tumor recurrence following complete resection ws the predominnt cuse of mortlity in ptients with PRPLS. Correltion between tumor burden nd histologicl grde. Of the 51 ptients who underwent complete tumor resection, the medin tumor burden ws 18.0 cm. The medin tumor burden of the 33 ptients with low grde PRPLS ws 17.2 cm, nd vlue ws 19.4 cm in the ptients with high grde PRPLS. Sttisticl nlysis reveled tht histologicl grde ws not correlted with tumor burden (R=0.222, P=0.117; Tble VIII).

8 1806 WU et l: PATHOLOGICAL FEATURES AND PROGNOSTIC FACTORS IN PRPLS Tble V. Multivrite nlysis of ptient prognosis. Vribles B SE Wld df P vlue Exp (B) 95% CI Histologicl subtype Histologicl grde < Tumor burden Contiguous orgn resection Primry locl recurrence Mrgin Gender Age Cox proportionl hzrds regression model. B, regression coefficient; SE, stndrd error; Wld, sttisticl mgnitude; df, degree of freedom; Exp (B), reltive risk; CI, confidence intervl. Tble VI. Multivrite nlysis of locl recurrence. Vribles B SE Wld df P vlue Exp (B) 95% CI Histologicl subtype Histologicl grde Tumor burden Gender Age Cox proportionl hzrds regression model. B, regression coefficient; SE, stndrd error; Wld, sttisticl mgnitude; df, degree of freedom; Exp (B), reltive risk; CI, confidence intervl. Tble VII. Correltion between disese dependent survivl nd locl recurrence. Tble VIII. Correltion between tumor burden nd histologicl grde, tumor invsion of djcent orgns or locl recurrence. Prmeter Medin Ptients, n survivl rte, % R vlue P vlue Ptients, Medin tumor Prmeters n burden, cm R vlue P vlue Primry locl <0.001 recurrence Yes No Spermn's rnk correltion. Correltion between tumor burden nd tumor invsion of djcent orgns. Of the 51 PRPLS ptients who underwent complete resection, 32 underwent resection of djcent orgns s result of tumor invsion. The medin tumor burden in ptients who received djcent orgn resection ws 19.3 cm, compred with 15.9 cm in the 19 ptients without tumor invsion of djcent orgns. Sttisticl nlysis demonstrted tht there ws no significnt correltion between tumor burden nd tumor invsion of djcent orgns (R=0.225; P=0.112; Tble VIII). Correltion between tumor burden nd locl recurrence. Following complete primry surgicl resection, 22 ptients Histologicl grde High ±5.1 Low ±8.4 Adjcent orgn invsion Yes ±7.2 No ±7.6 Primry locl recurrence Yes ±5.7 No ±8.6 Spermn's rnk correltion. developed primry locl recurrence nd the medin tumor burden ws 18.6 cm, compred with 17.5 cm in the 29 ptients tht did not exhibit locl recurrence. Sttisticl

9 ONCOLOGY LETTERS 00: 0 00, Tble IX. Correltion between djcent orgns invsion nd histologicl grde. Medin integrl Ptients, number of Prmeter n orgns invded R vlue P vlue b Histologicl <0.001 grde High 27 2±1 Low 38 1±1 Rounding off method; b Spermn's rnk correltion. nlysis indicted tht tumor burden ws not correlted with the development of locl recurrence (R=0.159, P=0.265; Tble VIII). Correltion between tumor invsion of djcent orgns nd histologicl grde. Of ll 65 ptients with PRPLS, medin of 1 orgn ws invded in ech of the 38 ptients with low grde PRPLS, compred with 2 in the 27 ptients with high grde PRPLS. Sttisticl nlysis demonstrted tht there ws positive correltion between tumor invsion of djcent orgns nd tumor histologicl grde (R=0.666, P<0.001; Tble IX). Thus, the histologicl grde ws strongly ssocited with tumor invsion of djcent orgns. Discussion RPLS is the most common soft tissue mlignncy of the retroperitoneum nd ccounts for ~40% of cses of primry soft tissue srcom in the retroperitoneum (1 3). PRPLS typiclly occurs in ptients of yers, with 1:1 rtio between mle nd femle ptients (1,19). Primry liposrcom most commonly develops in the rms, legs, retroperitoneum (20) or the bottom of pelvic cvity (21). PRPLS lcks typicl clinicl symptoms, mening it is difficult to dignose. The mjority of ptients with PRPLS re dignosed t n dvnced disese stge, therefore PRPLS tumors often grow to lrge size nd hve invded djcent orgns upon dignosis (22). The benefits of using djuvnt chemotherpy nd rdition therpy to tret PRPLS remins controversil (23,24). A number of studies hve suggested tht chemotherpy my worsen ptient prognosis (25,26). Other studies hve reported tht chemotherpy hs limited effectiveness for PRPLS, but is beneficil for liposrcoms originting from the lower or upper extremities (23,27). Rdition cn result in clinicl complictions, including nerve lesions, hydronephrosis, ureterl fistul nd ileus (28). For PRPLS, due to the deep loction in the enterocoeli nd close proximity to importnt viscerl orgns, dmge to the viscer by rdition must be considered when deciding upon tretment modlities. According to the criteri of the WHO Clssifiction of Tumors of Soft Tissue nd Bone (29), the histologicl tumor subtype defines the histologicl grde: High grde includes de differentited, pleomorphic nd mixed cell subtypes, wheres low grde comprises well differentited, myxoid nd round cell subtypes, with histologicl subtype predicting DSS (17,26). In previous reports, well differentited nd myxoid PRPLS cses exhibited low rtes of locl recurrence, nd long intervls between tretment nd recurrence compred with other subtypes of PRPLS (17,30). The present study, which ws bsed on Chinese popultion from single medicl center, comprised 49.0% cses of well differentited, 19.6% cses of de differentited nd 15.7% cses of myxoid/round cell PRPLS. The percentge of PRPLS histologicl subtypes ws pproximtely consistent with previous reports (14,17). The biologicl behvior of these tumors indicted tht well differentited tumors grew slowly. By contrst, de differentited tumors grew fster nd centrifuglly. It is more likely for de differentited tumors to led to incresed invsion of djcent orgns. In the present study, the histologicl tumor grde ws significntly ssocited with tumor burden, s the mjority of PRPLS cses exhibited expnsive growth nd formed pseudocpsule. However, histologicl grde ws ssocited with tumor invsion of djcent orgns. This my be due to the highly invsive nture of high grde tumors nd the bility of some of the tumor cells to pss through the tumor pseudocpsule to invde djcent orgns. Pthologicl dignosis currently remins the gold stndrd for the dignosis of PRPL. Common mrkers for investigting the clinicopthologicl fetures nd biologicl behvior in immunohistochemicl nlysis of PRPL tumors include S 100, vimentin nd Ki 67 (31 34). S 100 is n cidic clcium binding protein tht is predominntly present in the cytosol of stroglil cells of the centrl nervous system. Vimentin is n intermedite filment protein tht is expressed in mesenchyml cells nd is closely ssocited with the occurrence nd metstsis of tumors (35). Ki 67 is prolifertion ssocited nucler ntigen nd my be used to mesure the prolifertive ctivity of tumor cells (36). Ki 67 is specificlly expressed in the cytoplsm (membrne) of dipocytes nd in the nuclei of other tumor cells. The results of the present study demonstrted tht vimentin nd Ki 67 were more sensitive mrkers for PRPLS dignosis compred with S 100. S 100 protein ws predominntly expressed in well differentited PRPLS. Furthermore, vimentin nd Ki 67 were expressed in the mjority of the PRPLS cses, nd there ws higher expression of Ki 67 in high grde PRPLS, including de differentited, pleomorphic nd mixed type PRPLS. By contrst, in low grde tumors, ~20.0% of the cell popultion ws Ki 67 positive. However, the Ki 67 positive cell popultion rnged from 20.0 to 60.0% in high grde PRPLS. These results demonstrted tht Ki 67 expression reflected the prolifertive ctivity of the tumor cells, nd its positive expression ws ssocited with DSS. In recent yers, certin reports hve indicted tht de differentited liposrcom is ssocited with poor prognosis, wheres the sclerotic subtype hs the best prognosis in well differentited PRPLS cses (30). Tseng et l (37) reported tht the 5 yer survivl rte of ptients with differentited retroperitonel liposrcom ws 20.0%, compred with 83.0% for those with well differentited PRPLS. In the present study, the survivl times for ptients with well differentited nd myxoid/round cell PRPLS were improved compred with those with de differentited nd pleomorphic/mixed type tumors. Additionlly, the prognosis for ptients with low grde PRPLS ws improved compred with those with

10 1808 WU et l: PATHOLOGICAL FEATURES AND PROGNOSTIC FACTORS IN PRPLS high grde. Furthermore, survivl nlysis demonstrted tht the pthologicl subtype nd histologicl grde were importnt prognostic fctors for DSS, nd tht there ws positive ssocition between tumor invsion of djcent orgns nd histologicl grde. Serio et l (38) proposed tht the complete resection of PRPLS (ccording to the gross mrgins) ws n effective surgicl tretment for PRPLS. Previous studies reported tht ~80.0% of ptients with PRPLS tht required ggressive tretment were suitble for complete surgicl resection, nd this tretment strtegy resulted in medin survivl time of 83 months nd 5 yer DSS of 60.0% (39 41). Singer et l (17) reported 3 nd 5 yer survivl rtes of 73.0 nd 60.0%, respectively, when complete resection ws performed. Additionlly, Milone et l (42) reported 5 yer survivl rte of 85.7%. The rte of complete primry tumor resection ws 78.5% in the present study, compred with 81.0% in previous report (17). This discrepncy my be due to the fct tht 46 ptients in the present study presented with tumor invsion of djcent orgns. However, there ws no significnt difference in the prognosis of ptients with negtive gross mrgins during opertion compred with tht of ptients with positive microscopic mrgins postopertively. It is hypothesized tht this my be becuse these PRPLS tumors hd complete pseudocpsules nd exhibited locl expnsive growth. However, tumor positive gross mrgins strongly ffected DSS. In the present study, the tumor burden ws ssocited with DSS. However, tumor burden did not directly ffect tumor invsion of djcent orgns nd locl recurrence. This is potentilly due to ~80.0% of ptients exhibiting tumor burden of >10 cm, indicting tht the tumor grew expnsively nd the mjority of the tumor pseudocpsules were complete. A previous study hs reported tht the 5 yer survivl rte of ptients who underwent complete tumor resection ws 75.0%, compred with 34.0% for ptients who underwent pllitive surgery or biopsy (43). This effect on survivl rte ws lso observed in the present study. However, the follow up period of certin ptients ws short, nd long term survivl must lso be evluted. Biopsy is not generlly recommended for ptients without the bility to undergo complete resection due to the likelihood of tumor seeding (44). Shibt et l (45) observed tht, for ptients with PRPLS tht were not ble to undergo complete resection, pllitive surgery is ble to increse the survivl time compred with simple biopsy nd reduce 75.0% of the clinicl symptoms. Neuhus et l (25) reported similr results. To chieve complete removl of the tumor, % of ptients with PRPLS required contiguous orgn resection (25,46), nd the resected orgns included kidney, drenls, ureter, colon, smll intestine, omentum, spleen nd other celic orgns (47). Ptients pper to benefit from this ggressive pproch. Furthermore, complete resection tht includes resection of tumor invded djcent orgns hs been shown to be beneficil for the prevention of locl recurrence (17). In the present study, 32 ptients received contiguous orgn resection. The prognosis of these ptients ws improved compred with the 14 ptients who received pllitive surgery or biopsy. Multivrite nlysis demonstrted tht the pthologicl subtype nd histologicl grde of the tumors were independent mrkers of prognosis, therefore, the greter the differentition of the tumor, the better the prognosis of the ptient. Additionlly, contiguous orgn resection ws n independent prognostic fctor; if ptients exhibited tumor invsion of the djcent orgns, the prognosis of ptients who received contiguous orgn resection ws improved compred with ptients who received pllitive surgery. However, lthough tumor burden ffected DSS, it ws not n independent prognostic mrker. The likely reson for this is tht lrger tumors re ble to infiltrte djcent orgns more esily. Additionlly, the rte of complete resection ws lower in ptients with lrger tumor burden. In the present study, gender nd ge were not independent prognostic mrkers for DSS. Clinicl prctice demonstrtes tht PRPLS hs very high locl recurrence rte following surgery (5). The mjority of ptients succumb to disese s result of locl recurrence. Thus, the mjority of ptients with locl recurrence require reopertion (25). It is generlly considered tht the cuse of recurrence is the presence of pseudocpsules contining mlignnt cells, which cn be observed in the mjority of cses of PRPLS, nd the rpid growth of the tumor to oppress the surrounding norml structures. PRPLS frequently recurs in situ (48). The probbility of recurrence doubles over time (48). Certin studies hve reported tht first, second nd third complete resections were 57, 22 nd 10.0%, respectively, in primry locl recurrence of PRPLS following the first resection (39,49). For ptients with recurrence who cnnot undergo complete resection, the im of tretment is to ttenute symptoms, remove oppression of the surrounding orgns nd obstruction of the tumor, mintin viscerl function, extend survivl time nd improve the qulity of life. A previous study indicted tht if the speed of growth of recurrent tumor is >0.9 cm per month, multiple surgeries do not improve the survivl rte (50). Reserch hs demonstrted tht locl recurrence of liposrcoms is closely ssocited with tumor grde. In the present study, of the 22 ptients with locl recurrence, hlf of originl primry tumors were high grde nd lmost ll cses exhibited tumor invsion of djcent orgns, which is in ccordnce with the literture (17,44). Tumor burden ws not ssocited with locl recurrence, nd it ws observed tht lmost ll the tumors hd whole pseudocpsules nd grew expnsively. Of the ptients with locl recurrence, 30 underwent further surgery nd only 8 survived to the end of the study, with survivl rte of 36.4%, compred with 86.2% in ptients without recurrence. According to the present study, locl recurrence ws negtively correlted with DSS time. Thus, postopertive locl recurrence is considered to be the most common cuse of mortlity in ptients with PRPLS. Multivrite nlysis demonstrted tht histologicl grde ws n independent fctor tht ffected locl recurrence, wheres tumor burden ws not n independent prognostic fctor, potentilly s the mjority of ptients exhibited recurrence hd primry tumors >10 cm nd over hlf of these ptients exhibited tumor invsion of djcent orgns. Furthermore, hlf of the ptients tht developed recurrence hd high grde primry tumors. Gender nd ge t presenttion were not independent fctors. In conclusion, despite the high rte of recurrence nd mortlity of PRPLS, surgicl resection is the most effective tretment. Locl recurrence is the predominnt cuse of mortlity in PRPLS. Stining for vimentin nd Ki 67 demonstrted higher

11 ONCOLOGY LETTERS 15: , sensitivity for PRPLS dignosis compred with S 100 protein. S 100 protein ws predominntly expressed in well differentited PRPLS, wheres vimentin nd Ki 67 exhibited positive expression in lmost ll PRPLS smples. Additionlly, Ki 67 ws highly expressed in high grde PRPLS. Notbly, there ws negtive ssocition between the Ki 67 expression index nd DSS. DSS ws strongly ssocited with pthologicl subtype, histologicl grde, tumor burden, complete primry tumor resection nd contiguous orgn resection. Positive microscopic mrgins did not ffect DSS, wheres the sttus of gross mrgins ws strongly ssocited with DSS. Pthologicl subtype, histologicl grde nd contiguous orgn resection were independent mrkers of prognosis. Pthologicl subtype nd histologicl grde were ssocited with locl recurrence, with histologicl grde demonstrted to be n independent mrker for locl recurrence. Ptient ge t presenttion nd gender were not useful mrkers of prognosis or locl recurrence. References 1. 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