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ReprintSurgicalcer CenTX 7703

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doi:10.1

Liver resection for liver metastasesfrom nondigestive endocrine cancer:Extrahepatic disease burden definesoutcomeAndreas Andreou, MD,a Antoine Brouquet, MD,a Kishore G. S. Bharathy, MCh,a

Nancy D. Perrier, MD,a Eddie K. Abdalla, MD,a Steven A. Curley, MD,a Matthias Glanemann, MD,b

Daniel Seehofer, MD,b Peter Neuhaus, MD,b Jean-Nicolas Vauthey, MD,a andThomas A. Aloia, MD, FACS,a Houston, TX, and Berlin, Germany

Background. For patients with hepatic nondigestive endocrine metastases (HNEM), the role of liverresection is not well-defined.Methods. We reviewed outcomes for patients who underwent liver resection for HNEM at 2 centers toidentify predictors of survival.Results. From 1991 to 2010, 51 patients underwent liver resection for HNEM. Primary tumor typeswere adrenal gland (n = 26), thyroid (n = 11), testicular germ cell (n = 9), and ovarian granulosa cell(n = 5). 28 patients (55%) had synchronous or early (diagnosed within 12 months after primary tumorresection) liver metastases. At liver resection, 26 patients (51%) had extrahepatic metastases, and 7(14%) had $2 sites of extrahepatic metastases. 32 patients (63%) had major liver resection and19 (37%) had a simultaneous extrahepatic procedure. 90-day postoperative morbidity and mortalityrates were 27% and 2%, respectively. After median follow-up of 20 months (range, 1–144), the 5-yearoverall and recurrence-free survival rates were 58% and 37%, respectively. Survival was not affectedby primary tumor type. In multivariate analysis, $2 sites of extrahepatic metastases (hazard ratio[HR] = 4.80; 95% confidence interval [CI] = 1.18–19.50; P = .028) and interval of #12 monthsbetween primary tumor resection and diagnosis of liver metastases (HR = 5.33; 95% CI = 1.11–25.71;P = .037) were associated with worse overall survival after liver resection.Conclusion. For selected patients, liver resection for HNEM is associated with long-term survival. Thenumber of extrahepatic sites of metastasis and the timing of appearance of liver metastases should beconsidered in patient selection. (Surgery 2012;151:851-9.)

From the Department of Surgical Oncology,a The University of Texas M D Anderson Cancer Center, Houston,TX; and the Department of General, Visceral and Transplant Surgery,b Charit�e - Universit€atsmedizin Berlin,Campus Virchow Klinikum, Berlin, Germany

LIVER RESECTION is currently the treatment of choicefor patients with liver metastases from colorectalcancer; 5-year survival rates as high as 58% havebeen reported with this approach and establish sur-gery as a curative option in patients with this form ofadvanced malignant colorectal disease.1,2 Patientswith liver metastases from neuroendocrine cancer

ed in part by the National Institutes of Health throughderson Cancer Center’s Support Grant CA016672.

d for publication December 22, 2011.

requests: Thomas A. Aloia, MD, FACS, Department ofOncology, The University of Texas M D Anderson Can-ter, 1400 Hermann Pressler Drive, Unit 1484, Houston,0. E-mail: taaloia@mdanderson.org.

60/$ - see front matter

Mosby, Inc. All rights reserved.

016/j.surg.2011.12.025

also benefit from liver resection with 5-year survivalrates of up to 74% and reduction of disease-specificsymptoms justifying liver resection in this patientcohort.3-6

In contrast, the benefit of liver resection forpatients with liver metastases from nondigestiveendocrine cancer (hepatic nondigestive endocrinemetastases [HNEM]) is controversial as most ofthese patients present with coexistent extrahepaticmetastases.7-9 Previously published data on out-comes after resection of HNEM suggest that surgerymay improve survival in selected patients. However,these reports included various types ofmalignanciesand relatively small sample sizes, which limits theability to draw strong conclusions regarding patientselection.9-12 Given improvements in the efficacy ofsystemic therapy for endocrine tumors13,14 and im-provements in the safety of liver resection,15 the

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number of patients with HNEM who are potentialcandidates for surgery is increasing.

In this study, we evaluated the postoperative andlong-term outcomes of patients who underwentliver resection for HNEM. In addition, we analyzedpretreatment factors associated with outcome toidentify a cohort of patients with HNEM who mostbenefit from operative intervention.

PATIENTS AND METHODS

Study inclusion criteria. After receiving Institu-tional Review Board approval, clinicopathologicdata for 51 patients who underwent liver resectionfor HNEM (at The University of Texas M DAnderson Cancer Center, Houston, Texas [n = 32]or the Charit�e – Universit€atsmedizin, Berlin, Ger-many [n = 19]) from April 1991 to April 2010 werereviewed. We included all patients with liver metas-tases from endocrine primary tumors not locatedin the gastrointestinal tract or pancreas who wereoffered surgical treatment at 1 of the 2 centers. Pa-tients with nonmetastatic direct liver invasion froman adrenal tumor were excluded.

Pretreatment assessment. Patients were stagedwith cross-sectional imaging with liver protocol(computed tomography or magnetic resonanceimaging). The therapeutic approach was individu-ally formulated for every patient and planned by amultidisciplinary tumor board, which consisted ofhepatobiliary surgeons, medical oncologists, andhepatobiliary radiologists. Liver resection was con-sidered in patients in whom computed tomogra-phy volumetry indicated that all liver depositscould be safely resected with a sufficient liverremnant. In patients with an anticipated insuffi-cient liver remnant, preoperative portal vein em-bolization was used to increase the volume of thefuture liver remnant.16 Patients with extrahepaticmetastases were considered for liver resection ifthe extrahepatic disease could be resected withcurative intent and/or systemic therapy haddemonstrated the ability to at least stabilize unre-sectable extrahepatic disease. In patients with syn-chronous presentation, the decision whether ornot to perform combined resection of the primarytumor and liver metastases was based on the extentof the liver metastases and/or the proximity of theprimary tumor to the hepatic operative field. Stan-dard perioperative protocols were used to preparepatients with pheochromocytoma for surgery.17

Operative procedure. At operation, the perito-neal cavity was carefully examined to rule out previ-ously unrecognized extrahepatic spread of tumorwithin the abdomen. Intraoperative liver ultrasonog-raphy was systematically performed to confirm and

better define the location of the liver metastases andtheir relationship with portal pedicles and hepaticveins. Liver resection was performed under portaltriad clamping using standard hepatic transectiontechniques. Each resected specimenwas subjected tostandard pathologic analysis.

Postoperative period. Postoperative complica-tions were evaluated according to the Clavien-Dindo classification.18,19 Major complicationswere defined as those requiring operative, endo-scopic, or radiologic intervention (grade III); life-threatening complications requiring intensivecare management (grade IV); and death (gradeV). Postoperative mortality was defined as deathwithin 90 days after resection, and postoperativemorbidity was defined as any complication withinthe same time period. The decision to treat pa-tients with adjuvant therapy after liver resectionwas made on a case-by-case basis by each multidis-ciplinary tumor board.

Statistical analysis. Quantitative and qualitativevariables were expressed as mean values ± standarddeviation, median (range), and frequency. TheChi-square or Fisher exact tests and the Mann–Whitney U test were used to compare categoricaland continuous variables, as appropriate. Overallsurvival and recurrence-free survival were calcu-lated from the date of liver resection to the dateof last follow-up and date of recurrence, respec-tively, using the Kaplan–Meier method. Log-ranktests were used to assess significance for univariateanalysis.

To identify factors associated with outcome afterliver resection in patients with HNEM, we exam-ined correlations between overall and recurrence-free survival and the following clinicopathologicvariables: primary tumor type (adrenal versus thy-roidal versus gonadal), regional lymph node me-tastases from the primary tumor (positive versusnegative), timing of detection of metastases (syn-chronous [present at the time of resection of theprimary tumor] versus metachronous), intervalbetween resection of the primary tumor and diag-nosis of liver metastases (#12 vs >12 months),number of HNEM (>3 vs #3), size of the largestHNEM ($5 vs <5 cm), extrahepatic metastases(present versus absent), $2 sites of extrahepaticmetastases (present versus absent), major postop-erative complications (present versus absent); pre-operative and postoperative systemic therapy forthe liver metastases (administered or not); extentof major hepatectomy (major [$3 liver segments]versus minor), histologic grade of the primarytumor (low or intermediate versus high); statusof the resection margins on microscopic analysis

Table I. HNEM patient preoperativecharacteristics (n = 51)

Characteristic Value

Mean age (SD), yrs 44 (14)Gender (M/F) 25/26Mean body mass index (SD), kg/m2 25.5 (5)Primary tumor, no. of patients (%)Adrenal cortical carcinoma 23 (45)Pheochromocytoma 3 (6)Medullary thyroid cancer 8 (16)H€urthle cell carcinoma of thyroid 3 (6)Ovarian granulosa tumor 5 (10)Germ cell testicular tumor 9 (17)

Primary tumor grade, no. of patients (%)Well-differentiated 19 (37)Intermediate or poorly differentiated 19 (37)Unknown 13 (26)

Node-positive tumor, no. of patients (%) 22 (43)Liver metastasesSynchronous, no. of patients (%) 19 (37)Detected #12 mos after primary

tumor resection, no. of patients (%)28 (55)

Mean number (SD) 2.5 (2.5)Mean size, cm (SD) 5.3 (4.2)

Extrahepatic disease, no. of patients (%) 26 (51)1 site 192 sites 5$3 sites 2

Extrahepatic disease sites, no. of patients*Lymph nodes 13Bone 3Lung 11Peritoneal disease 7

Preoperative systemic therapy targeting livermetastases, no. of patients (%)

24 (47)

*Some patients had >1 extrahepatic site of metastases.HNEM, Hepatic nondigestive endocrine metastases; SD, standarddeviation.

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(positive for tumor cells versus negative) for boththe primary tumor and the HNEM, associatedextrahepatic resection (performed or not); andblood transfusions (required or not). All variablesassociated with survival with P # .1 in univariateproportional hazards models were subsequentlyentered into a Cox multivariate regression modelwith backward elimination. Statistical analysis wasperformed using the statistical software packageSPSS version 17.2 (SPSS, Chicago, IL).

RESULTS

Patient characteristics. Preoperative patientcharacteristics are summarized in Table I. Themean patient age for the whole group was 44 ±14 years. 25 patients were male and 26 werefemale.

The primary tumor was adrenal cortical carci-noma in 23 patients (45%), pheochromocytoma in3 (6%), medullary thyroid cancer in 8 (16%),H€urthle cell carcinoma of the thyroid in 3 (6%),ovarian granulosa cell tumor in 5 (10%), and germcell tumor of the testis in 9 (17%). Tumor cellinvasion of the surgical margins was identified in 9of the primary tumor resection specimens (18%),and 22 (43%) of the primary malignancies wereassociated with regional lymph node metastases.Compared to patients with adrenal cortical carci-noma, those with primary disease at other siteswere more likely to have regional lymph nodemetastases (P = .006).

Nineteen patients (37%) presented with syn-chronous metastases. An additional 9 patients(18%) developed liver metastases within 12 monthsafter resection of the primary tumor. The majorityof patients with synchronous or early liver metasta-ses (17/28) had adrenal cortical carcinoma (P =.013). The mean number of liver metastases was2.5 ± 2.5, and 14 patients (27%) had>3 liver metas-tases. Themean size of the largest metastasis was 5.3± 4.2 cm, and 25 patients (49%) had metastases$5cm removed. At the time of liver resection, extrahe-patic metastases were present in 26 patients (51%),and the sites of extrahepatic metastases were lymphnodes (n = 13), lung (n = 11), bone (n = 3), and per-itoneal disease (n = 7). Nineteen patients presentedwith 1 site of extrahepatic metastasis; 5 patients hadextrahepatic metastases at 2 sites. Two patients hadextrahepatic metastases at >2 sites; 1 had a primarytumor originating from the adrenal cortex and theother had a testicular germ cell tumor.

Twenty-four patients (47%) received systemictherapy prior to liver resection. Preoperative sys-temic therapy differed by tumor type and includedtegafur-uracil in 1 patient with ovarian metastases,

radioiodine for 5 patients with thyroid metastases,and cisplatin/etoposide for 8 patients with testic-ular metastases. The 10 patients with adrenalmetastases treated with preoperative chemother-apy received a wide range of agents, includingmitotane, cisplatin, etoposide, sorafenib, and adri-amycin. The duration of preoperative therapy wasdependent on the radiologic response (range, 3–12 months). In all patients, systemic therapy wasdiscontinued at least 4 weeks before surgery.

Intraoperative and postoperative characteristicsof the 51 study patients are summarized inTable II. A major hepatectomy ($3 contiguousliver segments) was performed in 32 patients(63%), and extended hepatectomy (more than ahemihepatectomy) was required in 8 patients(16%). An associated extrahepatic procedure,

Table II. HNEM patient intraoperative andpostoperative characteristics

Characteristic

No. (%) ofpatients(n = 51)

Major liver resection ($3 contiguousliver segments)

32 (63)

Associated extrahepatic procedure 19 (37)Nephrectomy and/

or adrenalectomy9

Extended lymph node dissection 4Resection of peritoneal mass 4Other 2

Radiofrequency ablation 1 (2)Mean estimated blood loss (SD) 700 mL (1,100)Transfusion required 19 (37)Postoperative mortality 1 (2)Postoperative morbidity 14 (27)Major postoperative complication 7 (14)Surgical margin positive for livermetastases

7 (14)

Postoperative systemic therapy 17 (33)

HNEM, Hepatic nondigestive endocrine metastases; SD, standarddeviation.

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such as nephrectomy, adrenalectomy, extendedlymph node dissection, or resection of a peritonealmass, was necessary in 19 patients (37%) to achievecomplete resection of the visible tumor burden.Radiofrequency ablation was used in 1 patient(2%) for the treatment of a central liver mass. Re-section margins microscopically positive for tumorcells were found in only 7 (14%) of the liver resec-tion specimens. Mean estimated blood loss duringhepatectomy was 700 ± 1100 mL; in 19 patients(37%), perioperative transfusions were required.Seventeen patients (33%) received postoperativesystemic therapy.

Postoperative mortality and morbidity. Thepostoperative mortality rate was 2% (1 patientdied). The postoperative course of the patientwho died was complicated by a biliary leak, ascites,pleural effusions, and acute renal failure, whichled to the death of the patient 86 days after anextended right hepatectomy for 5 metastases froman adrenal cortical carcinoma.

The postoperative morbidity rate was 27% (14patients). Seven patients (14%) had major postop-erative complications, such as intra-abdominalfluid collection necessitating drainage, bleedingnecessitating repeat laparotomy, and acute renalfailure necessitating hemodialysis.

Survival. At a median follow-up time of 20months (range, 1–144), the 3- and 5-year overallsurvival rates were 64% and 58%, respectively. The3- and 5-year recurrence-free survival rates were37% and 37%, respectively (Fig 1). Twenty-eightpatients (55%) developed a recurrence, and themedian time to recurrence after liver resectionwas 5 months (range, 0.8–81). Recurrent lesionswere identified in the lung, liver, brain, bones,lymph nodes, peritoneum, and primary tumorsite. Lung (9 cases) and liver (8 cases) were themost common sites of tumor recurrence. Three pa-tients had 2 sites of recurrence at the same time.Nine patients underwent a re-resection for the re-current metastases; 4 of these patients underwentrepeat hepatectomy.

Predictors of outcome. Only 1 factor was pre-dictive of recurrence-free survival: The presence of$2 sites of extrahepatic disease was associated withshorter recurrence-free survival in the univariate(P = .01; Fig 2) and multivariate analyses (hazardratio, 3.52; 95% confidence interval, 1.26–9.84;P = .016; Table III).

In univariate analysis of overall survival, thepresence of $2 sites of extrahepatic disease (P =.009) and interval of #12 months between resec-tion of the primary tumor and diagnosis of theliver metastases (P = .017) were associated with

worse overall survival after resection of liver metas-tases (Figs 3 and 4, respectively; Table IV). An ad-ditional variable that trended toward significancein univariate analysis was the need for a majorhepatectomy (P = .06). Independent associationswith overall survival identified in multivariate anal-ysis included the presence of $2 sites of extrahe-patic disease (hazard ratio, 4.80; 95% confidenceinterval, 1.18–19.50; P = .028) and interval of#12 months between resection of the primary tu-mor and diagnosis of the liver metastases (hazardratio, 5.33; 95% confidence interval, 1.11–25.71;P = .037; Table IV).

DISCUSSION

This study examined prognostic factors andoutcomes for 51 patients with HNEM treatedwith liver resection. The low morbidity and mor-tality rates in this cohort (27% and 2%, respec-tively) confirm that this approach is feasible andsafe. Results of our survival analysis indicate thatliver resection in this cohort was associated withfavorable oncologic outcomes, including a 5-yearoverall survival rate of 58% and a 5-yearrecurrence-free survival rate of 37%. These long-term outcomes are superior to those in medicallytreated patients with HNEM, particularly patientswith metastases from adrenal cortical carcinoma(5-year overall survival rate, 15%).20,21

Fig 1. Overall and recurrence-free survival in 51 patientswho underwent resection of hepatic nondigestive endo-crine metastases (HNEM).

Fig 2. Recurrence-free survival according to the numberof sites of extrahepatic disease. Patients with $2 sites ofextrahepatic disease had diminished recurrence-free sur-vival in univariate and multivariate analyses (P = .01 andP = .016, respectively).

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There are several important differences be-tween patients presenting with liver metastasesfrom colorectal, gastrointestinal neuroendocrine,and nongastrointestinal endocrine primary tu-mors. Patients with liver metastases from colorectaltumors and gastrointestinal neuroendocrine tu-mors less commonly present to hepatic surgeonswith extrahepatic metastases because: (1) livermetastases in such patients occur as the result oftumor spread via gastrointestinal lymphatic chan-nels and/or the portal vein before tumor cellsreach the systemic circulation12,22,23; and (2) thepresence of extrahepatic metastases has been re-ported to be a poor prognostic factor and a relativecontraindication to resection in these patients.24

In contrast, HNEM are hematogenous, occurringafter malignant cells have already entered the sys-temic circulation. HNEM, therefore, are associatedwith extrahepatic metastases in the majority ofpatients. Despite this mode of tumor spread, theoutcomes of our study patients were similar tothe favorable outcomes of patients with colorectalliver metastases and neuroendocrine metastasestreated with hepatic resection,1,6 validating thistherapeutic strategy as a long-term disease-control-ling, and potentially curative, option for HNEM.

Previous studies on liver resection in patientswith HNEM have failed to define prognostic fac-tors that could guide patient or therapy selection.Our analysis identified the presence of $2 sites ofextrahepatic disease and detection of the livermetastases within 12 months after resection ofthe primary endocrine tumor as patient factorsindependently associated with worse survival. Eachof these factors warrants discussion.

The correlation between extrahepatic diseaseand diminished survival has previously been

reported after resection of liver metastases fromnoncolorectal primary tumors, including gastroin-testinal carcinomas, nonendocrine tumors, andtumors of nonepithelial origin.7,9,25 The presenceof a limited burden of extrahepatic disease didnot have a significant impact on survival in our pa-tient cohort. However, tumor dissemination to $2extrahepatic locations had a drastic influence onoutcome: The associated 5-year disease-free andoverall survival rates were both 0%. Even thoughliver metastases could be removed safely in the 7study patients with $2 sites of extrahepatic disease,surgery did not result in prolonged survival. Onthe basis of these data and the current literature,we consider extensive extrahepatic tumor burdento be a relative contraindication to attempts atcurative resection.

The interval between resection of the primarytumor and detection of hepatic metastases alsoreached significance as a prognostic factor forpoor postoperative outcomes. Studies reportingon operative approaches for noncolorectal livermetastases confirm that early occurrence of livermetastases after resection of the primary tumorsignals a more aggressive tumor biology.9,12,26-28

Because of conflicting results in previous analyses,we chose to analyze the time from primary tumorresection to diagnosis of liver metastases using 2different break points---synchronous versus me-tachronous and liver metastases diagnosed within12 months after the primary tumor or later. Thedifference in outcomes between patients withtrue synchronous metastases and those with anymetachronous presentation was not significant.However, diagnosis of liver metastases within

Table III. Prognostic factors for recurrence-free survival after hepatic resection for HNEM (n = 51)

Predictor of recurrence-free survival n (%)5-year survival

(%)

Univariateanalysis(P value)

Multivariate analysis*

P value HR (95% CI)

Primary tumor type .83Adrenal 26 (51) 36Thyroidal 11 (22) 36Gonadal 14 (27) 42

Regional lymph nodes for primary tumor .45Positive 22 (43) 51Negative 29 (57) 10

Timing of detection of HNEM .20Synchronous 19 (37) 37Metachronous 32 (63) 34

Interval between primary tumor resectionand diagnosis of HNEM (mos)

.10 NS

#12 28 (55) 37>12 23 (45) 41

Number of liver metastases .83>3 14 (27) 31#3 37 (73) 42

Maximum size of liver metastases (cm) .31$5 25 (49) 22<5 26 (51) 50

Extrahepatic disease .55Present 26 (51) 44Absent 25 (49) 31

Two or more sites of extrahepatic disease .01 .016 3.52 (1.26–9.84)Present 7 (14) 0Absent 44 (86) 41

Major postoperative complication .58Present 7 (14) 36Absent 44 (86) 38

Preoperative systemic therapy for liver metastases .32Yes 24 (47) 32No 27 (53) 43

Postoperative systemic therapy for liver metastases .18Yes 17 (33) 19No 34 (67) 48

Extent of hepatectomy .18Major 32 (63) 63Minor 19 (37) 22

Histologic grade of primary tumor .58Low or intermediate 19 (37) 37High 19 (37) 35

Surgical margins for primary tumor .98Positive 9 (18) 19Negative 42 (82) 39

Surgical margins for liver metastases .43Positive 7 (14) 48Negative 44 (86) 34

Associated resection .14Yes 19 (37) 49No 32 (63) 28

Need for transfusions .28Yes 19 (37) 35No 32 (63) 38

*Cox regression multivariate analysis included all variables with P # .1 in univariate analysis.CI, Confidence interval; HNEM, hepatic nondigestive endocrine metastases; HR, hazard ratio; NS, not significant.

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Fig 3. Overall survival according to the number of sitesof extrahepatic disease. Patients with $2 sites of extrahe-patic disease had diminished overall survival in univari-ate and multivariate analyses (P = .009 and P = .028,respectively).

Fig 4. Overall survival according to the interval betweenresection of the primary tumor and diagnosis (Dx) ofHNEM. Patients with an interval of #12 mos betweenprimary tumor resection and diagnosis of HNEM had di-minished overall survival in univariate and multivariateanalyses (P = .017 and P = .037, respectively).

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1 year after resection of the primary tumor was in-dependently predictive of worse overall survival.Because the 5-year survival rate for patients withmetastases diagnosed within 1 year after resectionof the primary tumor was 42%, we continue to con-sider liver resection for selected patients with shortinterval between primary tumor resection andHNEM diagnosis, but only if they are free of extra-hepatic disease or have extrahepatic disease in only1 site.

Various studies investigating the outcome ofpatients after resection for noncolorectal livermetastases have identified the primary tumortype (location and/or histology) as a significantprognostic factor.7,9-12,26,27 These studies indicatedthat patients with gastrointestinal primary tumorshad in many cases an impaired survival.10,27 Ourstudy is the only report that has focused on the spe-cific group of patients with HNEM. Although eachof the histologic tumor types included in this studydemonstrates variable response to systemic thera-pies, interestingly, the primary tumor type wasnot associated with patient outcome.

For patients with colorectal liver metastases, neo-adjuvant chemotherapy is an established treatment,likely contributing to improved overall survivals andreduced risk of relapse.29,30 The inhomogeneity inthe origin of the liver metastases in the patients inour study prohibits an adequate evaluation of therole of perioperative chemotherapy. Nevertheless,becauseHNEMare characterized by systemic dissem-ination, it is reasonable to infer that systemic therapymay contribute to eradication of the circulating tu-mor cells, preventing tumor recurrence and support-ing the curative potential of surgery.

Our study has several potential limitations. Itwas a retrospective analysis of selected patients whounderwent resection, and the lack of a medicalcomparison group does not allow a definite ther-apeutic recommendation for all patients withHNEM. However, the prolonged survival afterhepatectomy observed in our study provides evi-dence that surgery could be effective as part of amultidisciplinary treatment approach. We re-viewed the data of patients who underwent resec-tion over a long period of time (20 years) at 2different centers, and there might be disparities inpatient management between the 2 centers andbetween different time periods. However, charac-teristics of resected patients, operative approaches,and outcomes from the 2 centers were similar.Given the rarity of HNEM, compilation of a cohortlarge enough to facilitate prognostic factor analysisrequired the inclusion of patients from a longertime period as well as the cooperation of 2 high-volume hepatobiliary centers. The use of state-of-the-art radiologic methods to accurately identifymetastatic disease and optimize planning of sur-gery, advanced methods for parenchymal dissec-tion and control of bleeding during liver resection,and evidence-based postoperative intensive care inboth centers are all factors that may have contrib-uted to the excellent short- and long-term results.

Despite these limitations, we conclude that liverresection is safe and should be regarded as apotentially curative approach in patients withHNEM. Extrahepatic metastases are common inthese patients, and although limited extrahepaticdisease should not be considered an absolute

Table IV. Prognostic factors for overall survival after hepatic resection for HNEM (n = 51)

Predictor of overall survival n (%)

5-yearsurvival(%)

Univariateanalysis(P value)

Multivariate analysis*

P value HR (95% CI)

Primary tumor type .75Adrenal 26 (51) 52Thyroidal 11 (22) 67Gonadal 14 (27) 66

Regional lymph nodes for primary tumor .85Positive 22 (43) 69Negative 29 (57) 49

Timing of detection of HNEM .17Synchronous 19 (37) 57Metachronous 32 (63) 62

Interval between primary tumor resectionand diagnosis of HNEM (mos)

.017 .037 5.33 (1.11–25.71)

#12 28 (55) 42>12 23 (45) 82

Number of liver metastases .97>3 14 (27) 60#3 37 (73) 56

Maximum size of liver metastases (cm) .19$5 25 (49) 46<5 26 (51) 76

Extrahepatic disease .68Present 26 (51) 60Absent 25 (49) 58

Two or more sites of extrahepatic disease .009 .028 4.80 (1.18–19.50)Present 7 (14) 0Absent 44 (86) 65

Major postoperative complication .13Present 7 (14) 33Absent 44 (86) 62

Preoperative systemic therapy for liver metastases .74Yes 24 (47) 52No 27 (53) 61

Postoperative systemic therapy for liver metastases .17Yes 17 (33) 52No 34 (67) 63

Extent of hepatectomy .06 NSMajor 32 (63) 44Minor 19 (37) 93

Histologic grade of primary tumor .3Low or intermediate 19 (37) 52High 19 (37) 50

Surgical margins for primary tumor .75Positive 9 (18) 58Negative 42 (82) 59

Surgical margins for liver metastases .21Positive 7 (14) 80Negative 44 (86) 53

Associated resection .13Yes 19 (37) 78No 32 (63) 43

Need for transfusions .58Yes 19 (37) 65No 32 (63) 54

*Cox regression multivariate analysis included all variables with P # .1 on univariate analysis.CI, Confidence interval; HNEM, hepatic nondigestive endocrine metastases; HR, hazard ratio; NS, not significant.

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contraindication to resection, poor survivals indi-cate that patients with extensive extrahepatic dis-semination should be approached cautiously. Earlyonset of liver metastases after resection of theprimary tumor affects outcome and should be alsotaken into consideration in evaluation of theresectability of HNEM.

The authors thank Stephanie P. Deming and Ruth J.Haynes for their assistance with manuscript preparation.

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