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International Journal of Surgery 12 (2014) 1123e1126

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International Journal of Surgery

journal homepage: www.journal-surgery.net

Original research

Impact of acellular mucin pools on survival in patients with completepathological response to neoadjuvant treatment in rectal cancer

Abu Bakar Hafeez Bhatti a, *, Ali Akbar a, Shahid Khattak a, Ather Saeed Kazmi b,Aarif Jamshed c, Aamir Ali Syed a

a Department of Surgical Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistanb Department of Medical Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistanc Department of Radiation Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan

h i g h l i g h t s

� The prognostic role of acellular mucin pools in rectal cancer remains to be defined.� Current recommendation is to consider this as treatment response.� Current study shows minimal impact of acellular mucin pools on survival in rectal cancer.� Acellular mucin probably is just a marker of treatment response.

a r t i c l e i n f o

Article history:Received 18 May 2014Accepted 22 July 2014Available online 27 July 2014

Keywords:Rectal cancerMucinSurvival

* Corresponding author. Shaukat Khanum MemResearch Centre, 7A, R-3, MA Johar Town, Lahore, Pak

E-mail address: abubakar.hafeez@yahoo.co (A.B.H.

http://dx.doi.org/10.1016/j.ijsu.2014.07.2671743-9191/© 2014 Published by Elsevier Ltd on behal

a b s t r a c t

Background: Rarely, patients with pathological complete response (PCR) after neoadjuvant chemo-radiotherapy demonstrate acellular mucin pools. The prognostic significance of this finding is contro-versial. The objective of this study was to determine impact of acellular mucin pools on disease free andoverall survival in patients with complete pathological response to neoadjuvant chemoradiotherapy inrectal cancer. Methods: One hundred and seventy two patients received neoadjuvant chemo-radiotherapy for rectal cancer and underwent surgery. Patients were divided into two groups based onpresence of acellular mucin pools. Locoregional failures, distant failures and deaths were compared.Expected 5 year disease free and overall survival was calculated. Results: Median follow-up was 36(4e94) months. Complete pathological response was identified in 35(20.3%) patients. Of these, 12(34.2%)had acellular mucin pools in resected specimen. Majority of mucin negative tumors were moderatelydifferentiated (78% vs 25%) (P ¼ 0.005). Median overall survival for mucin positive and mucin negativetumors was 4(1.3e5.7) and 3.3(0.1e6.3) years respectively. Expected 5 year disease free and overallsurvival for mucin positive and mucin negative tumors was 73% and 89% (P ¼ 0.1) and 75% and 87%(P ¼ 0.4). Conclusion: Acellular mucin pools in rectal cancer following a PCR to neoadjuvant treatmentdo not impact survival.

© 2014 Published by Elsevier Ltd on behalf of Surgical Associates Ltd.

1. Introduction

Preoperative chemoradiotherapy has emerged as the standardof care in locally advanced rectal cancer [1]. It improves resect-ability, sphincter preservation and negative margin rates in rectalcancer [1e3]. Complete pathological response (PCR) to preopera-tive chemoradiotherapy varies between 10 and 20% [4]. A PCR hasbeen linked to improved outcomes. What is not well defined is the

orial Cancer Hospital andistan.Bhatti).

f of Surgical Associates Ltd.

prognostic impact of acellular mucin pools in resected rectalspecimen after complete pathological response to preoperativechemoradiotherapy. Joint consensus statement by American Col-lege of Pathologists recommends not considering acellular mucinpools as residual tumor but the evidence for this recommendationis lacking [5]. Very few studies have specifically dealt with this topicand their results are conflicting compounded by small sample size.Without standardization of criteria of pathological response, resultsof future prognostic studies and trials would be difficult to inter-pret. At present, it is not clear whether presence of acellular mucinpools in resected rectal cancer after preop chemoradiotherapy have

Table 1Patient characteristics.

Number (N ¼ 12) Percent % Number (N ¼ 23) Percent % P value

Gender Male 8 67 12 52 0.4Female 4 33 11 48

Family history Yes 0 0 1 4 0.4No 12 100 22 96

Clinical tumor size I 1 8 2 8 0.8II 8 67 17 74III 3 25 4 18

Clinical nodal stage N0 3 25 2 9 0.2N1 1 8 6 26N2 8 67 15 65

Distance from anal verge (centimeter) 5 cm 7 59 16 69 0.86e10 cm 4 33 6 27>10 cm 1 8 1 4

Surgical procedure Low anterior resection 6 50 9 39 0.8Ultra low anterior resection 1 8 3 13Abdominoperineal resection 5 42 10 44Others 0 0 1 4

Grade Well 4 33 1 4 0.005Moderate 3 25 18 79Poor 2 17 2 9Mucinous 3 25 1 4Others 0 0 1 4

A.B.H. Bhatti et al. / International Journal of Surgery 12 (2014) 1123e11261124

an impact on disease free and overall survival in patients aftersurgery.

The objective of this study was to determine impact of presenceof acellular mucin pools in resected specimen of rectal cancer ondisease free and overall survival after complete pathologicalresponse to neoadjuvant chemoradiotherapy.

Table 2Failures (locoregional and distant) and deaths in patients with and without acellularmucin pools after pathological complete response to neoadjuvant chemo radiation.

Mucin positive(N ¼ 12)

Percent%

Mucin negative(N ¼ 23)

Percent%

Pvalue

Locoregional 1 8 0 e 0.3Distant 2 16 1 4 0.2Deaths 3 25 3 13 0.5

2. Methods

During a seven year period from 2005 to 2011, a total of 182patients underwent resection for underlying rectal cancer. All pa-tients had non metastatic rectal cancer. Patients were discussed inmulti-disciplinary meeting and a treatment plan was devised.Thirty four patients did not receive preoperative chemo-radiotherapy and were excluded from the study. Eighty nine pa-tients received induction chemotherapy followed by concurrentchemoradiotherapy before surgery while rest had various combi-nations of preoperative chemo and radiotherapy. Capecitabinebased preoperative chemotherapy was used in 114 while 5-Flourouracil based regimen was used in 34 patients. Completepathological response was defined according to AJCC guidelines asabsence of tumor cells in resected rectal specimen or draininglymph nodes. Out of 148 patients, 35 had complete pathologicalresponse (pCR) to neoadjuvant treatment. These patients wereincluded in the study and were divided into two groups based onpresence of acellular mucin pools in resected rectal specimen. Pa-tient demographics, clinical stage at presentation, histopathologicalcharacteristics of tumor and distance from anal verge werecompared. Number of locoregional and distant failures and deathsobserved during the follow-up period was compared.

Chi square test was used for categorical variables while t testwas used for interval variables. Disease free survival was calculatedby subtracting date of local, regional or distant recurrence fromdate of surgery. Overall survival was calculated by subtracting dateof death/last follow-up from date of surgery. Expected 5 year sur-vival was calculated using Kaplan Meier curves and significancewas determined using Log rank test. A P value <0.05 was consid-ered significant. SPSS version 20 was used for statistical analysis.The hospital ethics committee granted exemption from formal re-view of this study.

3. Results

3.1. Patient characteristics

Median follow-up was 36(4e94) months. Complete patholog-ical response was observed in 35(21%) patients. Out of these, 12patients had acellular mucin pools on histopathological examina-tion of resected specimen. No difference was observed between 2groups with respect to preoperative tumor and nodal stage. Choiceof surgical procedure and distance from anal verge was notsignificantly different between the two groups. A significant dif-ference was observed with respect to grade of tumors andmoderately differentiated tumors were seen more frequently inpatients with absence of mucin pools (78% vs 25%) (P ¼ 0.005). Outof 4 patients with mucinous tumors on pre-treatment biopsy,3(75%) had acellular mucin pools in resected specimen as shown inTable 1.

3.2. Relapse and mortality

Table 2 represents relapse and mortality. No locoregionalrelapse was observed in patients with absent acellular mucin pools.One patient with mucin pools had a locoregional relapse. This pa-tient was diagnosed with mucinous adenocarcinoma on endo-scopic biopsy before initiation of treatment. Similarly no significantdifference was observed between 2 groups with respect to distantrelapse and deaths.

3.3. Survival

Median overall survival for mucin positive and mucin negativetumors was 4(1.3e5.7) and 3.3(0.1e6.3) years respectively.

Fig. 1. Expected 5 year disease free survival in patients with and without acellularmucin pools after complete pathological response to neoadjuvant chemoradiotherapy.

A.B.H. Bhatti et al. / International Journal of Surgery 12 (2014) 1123e1126 1125

Expected 5 year disease free survival was 73% and 89% and overallsurvival was 75% and 87% in mucin positive and mucin negativetumors respectively as shown in Figs. 1 and 2. No significant dif-ference was observed between the two groups with respect todisease free and overall survival.

4. Discussion

Significance of acellular mucin pools has been a subject ofdebate and very few studies have attempted to answer this ques-tion. In the current study, no significant difference in adverseevents in patients with PCR with and without acellular mucin poolswas observed. Overall, patients with a pCR had excellent 5 yearactuarial disease free and overall survival. A significant number ofpatients underwent induction chemotherapy before concurrentchemoradiotherapy. Limitations of the study include its retro-spective design and small sample size. It cannot be ruled out thatdisease free and overall survival between the two groups were notsignificantly different because of the small sample size.

The pCR rate in rectal cancer after neoadjuvant treatmentvaries between 10 and 20% [3,4,6,7]. Furthermore, out of patients

Fig. 2. Expected 5 year overall survival in patients with and without acellular mucinpools after complete pathological response to neoadjuvant chemoradiotherapy.

who achieve a pCR, 15e30% demonstrate acellular mucin pools[8,9]. This results in a small group with pCR þve/acellularmucin þve tumors. There are only 4 reports in literature that dealspecifically with impact of acellular mucin pools after pCR toneoadjuvant treatment in rectal cancer and the number of patientsrange from 11 to 35 [8,9,10.11]. Lobato and colleagues in theirstudy analyzed 58 patients with PCR after chemoradiotherapy.Eleven patients had acellular mucin pools. Disease free survival(79% vs 95%) and overall survival (83% vs 95%) was lower in pa-tients with acellular mucin pools but did not reach statisticalsignificance. No significant difference in interval to surgery wasobserved between the two groups. They concluded that acellularmucin pools are associated with aggressive biology [10]. Lim andcolleagues examined 217 specimens with PCR of which 35(16%)had acellular mucin pools. They found a significant associationbetween acellular mucin pools and male gander, mucinous his-tology and interval to surgery (<42 days). The 3 year overall sur-vival (96.8% vs 95.9%) and disease free survival (97% vs 93%) wassimilar in mucin þve and �ve specimens respectively [11]. In thepresent study, 5 year survival was determined and no significantdifference in distribution between mucin pools and gender wasobserved. A significant majority of specimen with eve mucin hadwell/moderately differentiated tumors when compared with þvemucin specimen (82.6% vs 58.3%).

Studies on significance of acellular mucin pools are limited bysmall sample size. The number of patients who achieve a PCR andhave acellular mucin pools is generally very small. The problemhowever has a significant impact on decisions. For example amedical student underwent preoperative chemoradiotherapy forrectal carcinoma starting close to dentate line and had excellentclinical response. Although patient was planned for abdomi-noperineal resection, she refuted the idea of a permanent co-lostomy. It was decided to give her a chance and have aHartman's procedure performed. If there was a PCR in excisedspecimen, she could undergo reversal of colostomy later. Fortu-nately, she had a PCR but with mucin pools on the edge ofresected specimen. The best evidence for management in thesepatients is limited to a few retrospective studies with smallsample size. It is possible that acellular mucin pools represent anaggressive biology but till date no significant difference has beennoted. It has been suggested that a PCR is linked to improvedoutcomes [12,13]. It has also been suggested that colloid typeresponse or mucin pools in rectal cancer is linked to radiationtherapy [8,14e16]. How radiation leads to development of acel-lular mucin pools in specimens with PCR is unknown. Further-more, the notion that mucin pools are seen only in patients withpoorly differentiated/mucinous neoplasms is incorrect. All pre-viously conducted studies have shown that well/moderatelydifferentiated tumors can also have acellular mucin pools in thespecimen after preoperative chemoradiotherapy. In the currentstudy, 75% specimens with a pre-chemoradiotherapy mucinoushistology had acellular mucin pools in resected specimen vs 29%for all other histologies.

All these studies provide preliminary evidence to non-signifi-cant impact of mucin pools without tumor cells in prognosis ofrectal cancer. Large scale multi center studies with data collected ina prospective fashion are needed. Until then, these studies shouldhelp in making treatment decisions in patients with rectal cancerand acellular mucin pools.

Ethical approval

The hospital ethics committee granted exemption from formalreview of this study.

A.B.H. Bhatti et al. / International Journal of Surgery 12 (2014) 1123e11261126

Funding

No sources of funding.

Author contribution

Abu Bakar Hafeez Bhatti: Design, data collection, analysis,writing, darfting manuscript.

Ali Akbar: Data collection, analysis, drafting.Shahid Khattak: Analysis, drafting manuscript, critical review.Ather Saeed Kazmi: Analysis, drafting, critical review.Aarif Jamshed: Analysis, drafting, critical review.Aamir Ali Syed: Design, writing, critical review.

Conflicts of interest

None.

Acknowledgment

None.

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